Goldfrank’s Toxicologic Emergencies 9th Edition

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Goldfrank’s Toxicologic Emergencies

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NOTICE Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy are required. The authors and the publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standards accepted at the time of publication. However, in view of the possibility of human error or changes in medical sciences, neither the authors nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they disclaim all responsibility for any errors or omissions or for the results obtained from use of the information contained in this work. Readers are encouraged to confirm the information contained herein with other sources. For example and in particular, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this work is accurate and that changes have not been made in the recommended dose or in the contraindications for administration. This recommendation is of particular importance in connection with new or infrequently used drugs.

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NINTH EDITION

Goldfrank’s Toxicologic Emergencies Lewis S. Nelson, MD, FAACT, FACEP, FACMT

Robert S. Hoffman, MD, FAACT, FACMT

Associate Professor of Emergency Medicine New York University School of Medicine Attending Physician, Emergency Medicine Bellevue Hospital Center and New York University Langone Medical Center Director, Fellowship in Medical Toxicology New York City Poison Center and New York University School of Medicine New York, New York

Associate Professor of Emergency Medicine and Medicine (Clinical Pharmacology) New York University School of Medicine Attending Physician, Emergency Medicine and Internal Medicine Bellevue Hospital Center and New York University Langone Medical Center Director, New York City Poison Center New York, New York

Neal A. Lewin, MD, FACEP, FACMT, FACP

Lewis R. Goldfrank, MD, FAAEM, FAACT, FACEP, FACMT, FACP

The Stanley and Fiona Druckenmiller Clinical Professor of Emergency Medicine and Medicine (Pharmacology) New York University School of Medicine Director, Didactic Education Emergency Medicine Residency Attending Physician, Emergency Medicine and Internal Medicine Bellevue Hospital Center and New York University Langone Medical Center Consultant, New York City Poison Center New York, New York

Herbert W. Adams Professor and Chair Department of Emergency Medicine New York University School of Medicine Director, Emergency Medicine Bellevue Hospital Center and New York University Langone Medical Center Medical Director, New York City Poison Center New York, New York

Mary Ann Howland, PharmD, DABAT, FAACT

Neal E. Flomenbaum, MD, FACEP, FACP

Clinical Professor of Pharmacy St. John’s University College of Pharmacy Adjunct Professor of Emergency Medicine New York University School of Medicine Bellevue Hospital Center and New York University Langone Medical Center Senior Consultant in Residence New York City Poison Center New York, New York

Professor of Clinical Medicine Weill Cornell Medical College of Cornell University Emergency Physician-in-Chief New York-Presbyterian Hospital Weill Cornell Medical Center Consultant, New York City Poison Center New York, New York

New York Chicago San Francisco Lisbon London Madrid Mexico City Milan New Delhi San Juan Seoul Singapore Sydney Toronto

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Copyright © 2011 by The McGraw-Hill Companies, Inc. All rights reserved. Except as permitted under the United States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by any means, or stored in a database or retrieval system, without the prior written permission of the publisher. ISBN: 978-0-07-160594-6 MHID: 0-07-160594-0 The material in this eBook also appears in the print version of this title: ISBN: 978-0-07-160593-9, MHID: 0-07-160593-2. All trademarks are trademarks of their respective owners. Rather than put a trademark symbol after every occurrence of a trademarked name, we use names in an editorial fashion only, and to the benefit of the trademark owner, with no intention of infringement of the trademark. Where such designations appear in this book, they have been printed with initial caps. McGraw-Hill eBooks are available at special quantity discounts to use as premiums and sales promotions, or for use in corporate training programs. To contact a representative please e-mail us at [email protected]. The editors’ and authors’ royalties for this edition, as in the case of the previous editions, are being donated to the department to further the efforts of the New York City Poison Center and to help improve the care of poisoned patients. TERMS OF USE This is a copyrighted work and The McGraw-Hill Companies, Inc. (“McGrawHill”) and its licensors reserve all rights in and to the work. Use of this work is subject to these terms. Except as permitted under the Copyright Act of 1976 and the right to store and retrieve one copy of the work, you may not decompile, disassemble, reverse engineer, reproduce, modify, create derivative works based upon, transmit, distribute, disseminate, sell, publish or sublicense the work or any part of it without McGraw-Hill’s prior consent. You may use the work for your own noncommercial and personal use; any other use of the work is strictly prohibited. Your right to use the work may be terminated if you fail to comply with these terms. THE WORK IS PROVIDED “AS IS.” McGRAW-HILL AND ITS LICENSORS MAKE NO GUARANTEES OR WARRANTIES AS TO THE ACCURACY, ADEQUACY OR COMPLETENESS OF OR RESULTS TO BE OBTAINED FROM USING THE WORK, INCLUDING ANY INFORMATION THAT CAN BE ACCESSED THROUGH THE WORK VIA HYPERLINK OR OTHERWISE, AND EXPRESSLY DISCLAIM ANY WARRANTY, EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED TO IMPLIED WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. McGraw-Hill and its licensors do not warrant or guarantee that the functions contained in the work will meet your requirements or that its operation will be uninterrupted or error free. Neither McGraw-Hill nor its licensors shall be liable to you or anyone else for any inaccuracy, error or omission, regardless of cause, in the work or for any damages resulting therefrom. McGraw-Hill has no responsibility for the content of any information accessed through the work. Under no circumstances shall McGraw-Hill and/ or its licensors be liable for any indirect, incidental, special, punitive, consequential or similar damages that result from the use of or inability to use the work, even if any of them has been advised of the possibility of such damages. This limitation of liability shall apply to any claim or cause whatsoever whether such claim or cause arises in contract, tort or otherwise.

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Digitalis purpurea, the purple foxglove, is a legendary plant that contains the cardiac glycoside digitoxin, closely related to the therapeutically useful but potentially toxic cardiac glycoside digoxin. The electrocardiogram demonstrates high degree atrioventrical nodal blockade in a patient with atrial fibrillation/flutter, an abnormality closely linked to cardioactive steroid poisoning. The vial contains the widely available digoxin-specific Fab antibody fragment that is used to treat poisoning by digoxin and other cardioactive steroids. The 3-dimensional ribbon structure of digoxin specific Fab illustrates its ability engulf and render harmless the active non-glycoside form of the digoxin molecule.

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DEDICATION To the staffs of our hospital emergency departments who have worked with remarkable courage, concern, compassion, and understanding in treating the patients discussed in this text and many thousands more like them To the staff of the New York City Poison Center who have quietly and conscientiously integrated their skills with ours to serve these patients and to the many others who never needed a hospital visit because of their efforts To all the faculty, fellows, residents, and students who have studied toxicology with us whose inquisitiveness has helped us continually strive to understand complex and evolving problems and develop methods to teach them to others To my wife Laura for her unwavering support; to my children Daniel, Adina, and Benjamin for their inquisitiveness and insight; to my parents Dr. Irwin and Myrna Nelson for the foundation they provided; and to my family, friends, and colleagues who keep me focused on what is important in life. (L.N.) To my wife Gail; to my children Justin and Jesse for their support and patience; and to my parents, who made it possible (N.L.) To my husband Bob; to my children Robert and Marcy; to my mother and to the loving memory of my father; and to family, friends, colleagues, and students for all their help and continuing inspiration (M.A.H.) To my wife Ali; my children Casey and Jesse; my parents; and my friends, family, and colleagues for their never-ending patience and forgiveness for the time I have spent away from them (R.H.) To my children Rebecca, Jennifer, Andrew and Joan, Michelle and James; to my grandchildren Benjamin, Adam, Sarah, Kay, Samantha, and Herbert who have kept me acutely aware of the ready availability of possible poisons; and to my wife, partner, and best friend Susan whose support was and is essential and whose contributions will be found throughout the text (L.G.) To the memories of my parents Mollie and Lieutenant H. Stanley Flomenbaum whose constant encouragement to help others nonjudgmentally led me to consider toxicologic emergencies many years ago. To my wife Meredith Altman Flomenbaum, RNP, and to my children Adam, David, and Sari who have competed with this text for my attention but who have underscored the importance of these efforts (N.F.) To the memory of Donald A. Feinfeld, MD. Don was a wonderful collaborator, thoughtful intellectual, nephrologist, and poet who was an active participant at our monthly meetings as well as a critical author for the previous five editions of our text. His warmth, compassion and intellect will be missed.

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TABLE OF ANTIDOTES IN DEPTH Readers of previous editions of Goldfrank’s Toxicologic Emergencies are undoubtedly aware that the editors have always felt that an emphasis on general management of poisoning or overdoses coupled with sound medical management is more important or as important as the selection and use of a specific antidote in the vast majority of cases. Nevertheless, there are some instances where nothing other than the timely use of a specific antidote or therapy will be essential for a patient. For this reason, and also because the use of such strategies may be problematic, controversial, or unfamiliar to the practitioner (as new antidotes continue to emerge), we have included a section (or sections) at the end of each chapter where an in-depth discussion of such antidotes and therapies are relevant. The following Antidotes in Depth are included in this edition.

Activated Charcoal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108

Ethanol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1419

Mary Ann Howland

Mary Ann Howland

Antivenom (Crotaline) . . . . . . . . . . . . . . . . . . . . . . . . . . . 1611

Flumazenil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1072

Anthony F. Pizon, Bradley D. Riley, and Anne-Michelle Ruha

Mary Ann Howland

Antivenom (Scorpion and Spider) . . . . . . . . . . . . . . . . 1582

Fomepizole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1414

Richard F. Clark

Mary Ann Howland

Atropine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1473

Glucagon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 910

Mary Ann Howland

Mary Ann Howland

Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1109

Glucarpidase (Carboxypeptidase G2) . . . . . . . . . . . . . . 787

Robert S. Hoffman, Lewis S. Nelson, and Mary Ann Howland

Silas W. Smith

Botulinum Antitoxin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 695

Hydroxocobalamin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1695

Lewis R. Goldfrank and Howard L. Geyer

Mary Ann Howland

Calcium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1381

Hyperbaric Oxygen. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1671

Mary Ann Howland

Stephen R. Thom

Dantrolene Sodium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1001

Insulin-Euglycemia Therapy . . . . . . . . . . . . . . . . . . . . . . 893

Kenneth M. Sutin

William Kerns II

Deferoxamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 604

Intravenous Fat Emulsions. . . . . . . . . . . . . . . . . . . . . . . . 976

Mary Ann Howland

Theodore C. Bania

Dextrose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 728

L-Carnitine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 711

Larissa I. Velez and Kathleen A. Delaney

Mary Ann Howland

Digoxin-Specific Antibody Fragments . . . . . . . . . . . . . 946

Leucovorin (Folinic Acid) and Folic Acid. . . . . . . . . . . 783

Mary Ann Howland

Mary Ann Howland

Dimercaprol (British Anti-Lewisite or BAL). . . . . . . 1229

Methylene Blue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1708

Mary Ann Howland

Mary Ann Howland

N-Acetylcysteine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500

DTPA [Pentetic Acid or Pentetate (Zinc or Calcium) Trisodium] . . . . . . . . . . . . . . . . . . . . 1779

Mary Ann Howland and Robert G. Hendrickson

Joseph G. Rella

Octreotide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 734

Edetate Calcium Disodium (CaNa2EDTA) . . . . . . . . . 1290

Mary Ann Howland

Mary Ann Howland

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Table of Antidotes in Depth

Opioid Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 579 Mary Ann Howland and Lewis S. Nelson

Physostigmine Salicylate . . . . . . . . . . . . . . . . . . . . . . . . . 759 Mary Ann Howland

Potassium Iodide. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1775 Joseph G. Rella

Pralidoxime . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1467 Mary Ann Howland

Protamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 880 Mary Ann Howland

Prussian Blue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1334 Robert S. Hoffman

Pyridoxine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 845 Mary Ann Howland

Sodium and Amyl Nitrite . . . . . . . . . . . . . . . . . . . . . . . . 1689

Sodium Bicarbonate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 520 Paul M. Wax

Sodium Thiosulfate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1692 Mary Ann Howland

Succimer (2,3-Dimercaptosuccinic Acid) . . . . . . . . . . . 1284 Mary Ann Howland

Syrup of Ipecac . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 Mary Ann Howland

Thiamine Hydrochloride . . . . . . . . . . . . . . . . . . . . . . . . . 1129 Robert S. Hoffman

Vitamin K1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 876 Mary Ann Howland

Whole-Bowel Irrigation and Other Intestinal Evacuants . . . . . . . . . . . . . . . . . . . . . . . . 114 Mary Ann Howland

Mary Ann Howland

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TABLE OF CONTENTS Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xv

PART B

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xxvii

THE FUNDAMENTAL PRINCIPLES OF MEDICAL TOXICOLOGY . . . . . . . . . . . . . . . . . . . . . . . . 155

Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .xxviii

1 Historical Principles and Perspectives . . . . . . . . . . . . 1

SECTION 1

Paul M. Wax

Biochemical and Molecular Basis . . . . . . . . . . . . . . . . . . . . 157

2 Toxicologic Plagues and Disasters in History . . . . . 18 Paul M. Wax

11 Chemical Principles . . . . . . . . . . . . . . . . . . . . . . . . . . 157 Stephen J. Traub and Lewis S. Nelson

12 Biochemical and Metabolic Principles . . . . . . . . . . 170

PART A

Kurt C. Kleinschmidt and Kathleen A. Delaney

13 Neurotransmitters and Neuromodulators . . . . . . . 189

THE GENERAL APPROACH TO MEDICAL TOXICOLOGY . . . . . 31

Steven C. Curry, Kirk Charles Mills, Anne-Michelle Ruha, and Ayrn D. O’Connor

3 Initial Evaluation of the Patient: Vital Signs and Toxic Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

14 Withdrawal Principles . . . . . . . . . . . . . . . . . . . . . . . . 221

Lewis S. Nelson, Neal A. Lewin, Mary Ann Howland, Robert S. Hoffman, Lewis R. Goldfrank, and Neal E. Flomenbaum

Richard J. Hamilton

SECTION 2

4 Principles of Managing the Acutely Poisoned or Overdosed Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

Pathophysiologic Basis: Organ Systems . . . . . . . . . . . . . . . 228

Lewis S. Nelson, Neal A. Lewin, Mary Ann Howland, Robert S. Hoffman, Lewis R. Goldfrank, and Neal E. Flomenbaum

15 Thermoregulatory Principles . . . . . . . . . . . . . . . . . . 228

5 Diagnostic Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

Susi U. Vassallo and Kathleen A. Delaney

David T. Schwartz

16 Fluid, Electrolyte, and Acid–Base Principles . . . . . 249

6 Laboratory Principles . . . . . . . . . . . . . . . . . . . . . . . . . . 70

Alan N. Charney and Robert S. Hoffman

Petrie M. Rainey

17 Psychiatric Principles . . . . . . . . . . . . . . . . . . . . . . . . . 265

7 Techniques Used to Prevent Gastrointestinal

Kishor Malavade and Mark R. Serper

Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90

18 Neurologic Principles . . . . . . . . . . . . . . . . . . . . . . . . . 275

Anne-Bolette Gude and Lotte C. G. Hoegberg

Rama B. Rao

A1 Syrup of Ipecac . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104

19 Ophthalmic Principles . . . . . . . . . . . . . . . . . . . . . . . . 285

Mary Ann Howland

Adhi Sharma

A2 Activated Charcoal . . . . . . . . . . . . . . . . . . . . . . . . . . . 108

20 Otolaryngologic Principles . . . . . . . . . . . . . . . . . . . . 292

Mary Ann Howland

William K. Chiang

A3 Whole-Bowel Irrigation and Other Intestinal

21 Respiratory Principles . . . . . . . . . . . . . . . . . . . . . . . . 303

Evacuants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114

Andrew Stolbach and Robert S. Hoffman

Mary Ann Howland

22 Electrophysiologic and Electrocardiographic

8 Pharmacokinetic and Toxicokinetic Principles . . . . . . .119

Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314

Mary Ann Howland

Cathleen Clancy

9 Principles and Techniques Applied to Enhance

23 Hemodynamic Principles . . . . . . . . . . . . . . . . . . . . . 330

Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135

Robert A. Hessler

David S. Goldfarb

24 Hematologic Principles . . . . . . . . . . . . . . . . . . . . . . . 340

10 Use of The Intensive Care Unit . . . . . . . . . . . . . . . . 148

Marco L. A. Sivilotti

Mark A. Kirk

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Contents

25 Gastrointestinal Principles . . . . . . . . . . . . . . . . . . . . 359 Richard G. Church and Kavita M. Babu

26 Hepatic Principles. . . . . . . . . . . . . . . . . . . . . . . . . . . . 367 Kathleen A. Delaney

27 Renal Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381 Donald A. Feinfeld and Nikolas B. Harbord

28 Genitourinary Principles . . . . . . . . . . . . . . . . . . . . . . 396 Jason Chu

37 Colchicine, Podophyllin, and the Vinca Alkaloids . . . 537 Joshua G. Schier

SC2 Intrathecal Administration of Xenobiotics . . . . . . . 548 Rama B. Rao

38 Opioids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 559 Lewis S. Nelson and Dean Olsen

A6 Opioid Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . 579 Mary Ann Howland and Lewis S. Nelson

29 Dermatologic Principles . . . . . . . . . . . . . . . . . . . . . . 410 Neal A. Lewin and Lewis S. Nelson

SECTION 3

Special Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423 30 Reproductive and Perinatal Principles . . . . . . . . . . 423 Jeffrey S. Fine

31 Pediatric Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . 447 Jeffrey S. Fine

32 Geriatric Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . 461 Judith C. Ahronheim and Mary Ann Howland

33 Postmortem Toxicology . . . . . . . . . . . . . . . . . . . . . . 471 Rama B. Rao and Mark A. Flomenbaum

SC1 Organ Procurement from Poisoned Patients . . . . 479 Rama B. Rao

B. Foods, Dietary and Nutritional Xenobiotics . . . . . . . 586 39 Dieting Agents and Regimens . . . . . . . . . . . . . . . . . 586 Jeanna M. Marraffa

40 Iron . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 596 Jeanmarie Perrone

A7 Deferoxamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 604 Mary Ann Howland

41 Vitamins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 609 Beth Y. Ginsburg

42 Essential Oils . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 624 Sarah Eliza Halcomb

43 Herbal Preparations . . . . . . . . . . . . . . . . . . . . . . . . . . 631 Oliver L. Hung

44 Athletic Performance Enhancers . . . . . . . . . . . . . . . 654 Susi U. Vassallo

45 Food Poisoning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 668

PART C

Michael G. Tunik

46 Botulism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 682 THE CLINICAL BASIS OF MEDICAL TOXICOLOGY. . . . . . . 481 SECTION 1

Howard L. Geyer

A8 Botulinum Antitoxin . . . . . . . . . . . . . . . . . . . . . . . . . 695 Lewis R. Goldfrank and Howard L. Geyer

A. Analgesics and Antiinflammatory Medications . . . . 483

C. Pharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . . . . 698

34 Acetaminophen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483

47 Anticonvulsants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 698

Robert G. Hendrickson

A4 N-Acetylcysteine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500 Mary Ann Howland and Robert G. Hendrickson

35 Salicylates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 508 Neal E. Flomenbaum

A5 Sodium Bicarbonate . . . . . . . . . . . . . . . . . . . . . . . . . . 520 Paul M. Wax

36 Nonsteroidal Antiinflammatory Drugs . . . . . . . . . . 528 William J. Holubek

Suzanne Doyon

A9 l-Carnitine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 711 Mary Ann Howland

48 Antidiabetics and Hypoglycemics . . . . . . . . . . . . . . 714 George M. Bosse

A10 Dextrose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 728 Larissa I. Velez and Kathleen A. Delaney

A11 Octreotide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 734 Mary Ann Howland

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Contents

49 Thyroid and Antithyroid Medications . . . . . . . . . . 738 Nicole C. Bouchard

50 Antihistamines and Decongestants . . . . . . . . . . . . . 748 Anthony J. Tomassoni and Richard S. Weisman

A12 Physostigmine Salicylate . . . . . . . . . . . . . . . . . . . . . . 759 Mary Ann Howland

51 Antimigraine Medications . . . . . . . . . . . . . . . . . . . . 763 Jason Chu

52 Antineoplastics Overview . . . . . . . . . . . . . . . . . . . . . 770 Richard Y. Wang

53 Antineoplastics: Methotrexate . . . . . . . . . . . . . . . . . 778 Richard Y. Wang

A13 Leucovorin (Folinic Acid) and Folic Acid . . . . . . . 783 Mary Ann Howland

A14 Glucarpidase (Carboxypeptidase G2). . . . . . . . . . . . 787 Silas W. Smith

SC3 Extravasation of Xenobiotics . . . . . . . . . . . . . . . . . . 793

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A18 Insulin-Euglycemia Therapy . . . . . . . . . . . . . . . . . . . 893 William Kerns

61 β-Adrenergic Antagonists . . . . . . . . . . . . . . . . . . . . . 896 Jeffrey R. Brubacher

A19 Glucagon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 910 Mary Ann Howland

62 Other Antihypertensives . . . . . . . . . . . . . . . . . . . . . . 914 Francis Jerome DeRoos

63 Antidysrhythmics . . . . . . . . . . . . . . . . . . . . . . . . . . . . 925 Lewis S. Nelson and Neal A. Lewin

64 Cardioactive Steroids . . . . . . . . . . . . . . . . . . . . . . . . . 936 Jason B. Hack

A20 Digoxin-Specific Antibody Fragments . . . . . . . . . . 946 Mary Ann Howland

65 Methylxanthines and Selective β2 Adrenergic

Agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 952

Robert J. Hoffman

Richard Y. Wang

54 Miscellaneous Antineoplastics . . . . . . . . . . . . . . . . . 796 Richard Y. Wang

55 Pharmaceutical Additives . . . . . . . . . . . . . . . . . . . . . 803 Sean P. Nordt and Lisa E. Vivero

F. Anesthetics and Related Medications . . . . . . . . . . . . 965 66 Local Anesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . 965 David R. Schwartz and Brian Kaufman

A21 Intravenous Fat Emulsions . . . . . . . . . . . . . . . . . . . . 976 Theodore C. Bania

D. Antimicrobials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 817 56 Antibacterials, Antifungals, and Antivirals . . . . . . 817 Christine M. Stork

57 Antituberculous Medications . . . . . . . . . . . . . . . . . . 834 Christina H. Hernon and Edward W. Boyer

A15 Pyridoxine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 845

67 Inhalational Anesthetics . . . . . . . . . . . . . . . . . . . . . . 982 Brian Kaufman and Martin Griffel

68 Neuromuscular Blockers . . . . . . . . . . . . . . . . . . . . . . 989 Kenneth M. Sutin

A22 Dantrolene Sodium . . . . . . . . . . . . . . . . . . . . . . . . . 1001 Kenneth M. Sutin

Mary Ann Howland

58 Antimalarials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 849 J. Dave Barry

G. Psychotropic Medications. . . . . . . . . . . . . . . . . . . . . 1003 69 Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1003 David N. Juurlink

E. Cardiopulmonary Medications . . . . . . . . . . . . . . . . . 861 59 Anticoagulants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 861 Mark Su

A16 Vitamin K1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 876 Mary Ann Howland

A17 Protamine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 880 Mary Ann Howland

60 Calcium Channel Blockers . . . . . . . . . . . . . . . . . . . . 884

70 Lithium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1016 Howard A. Greller

71 Monoamine Oxidase Inhibitors . . . . . . . . . . . . . . . 1027 Alex F. Manini

72 Serotonin Reuptake Inhibitors and Atypical Antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1037 Christine M. Stork

73 Cyclic Antidepressants . . . . . . . . . . . . . . . . . . . . . . . 1049 Erica L. Liebelt

Francis Jerome DeRoos

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Contents

74 Sedative-Hypnotics . . . . . . . . . . . . . . . . . . . . . . . . . . 1060 David C. Lee and Kathy Lynn Ferguson

A23 Flumazenil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1072 Mary Ann Howland

A26 Dimercaprol (British Anti-Lewisite or BAL) . . . . 1229 Mary Ann Howland

89 Bismuth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1233 Rama B. Rao

90 Cadmium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1237 H. Substances of Abuse . . . . . . . . . . . . . . . . . . . . . . . . 1078 75 Amphetamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1078 William K. Chiang

76 Cocaine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1091 Jane M. Prosser and Robert S. Hoffman

SC4 Internal Concealment of Xenobiotics . . . . . . . . . . 1103 Jane M. Prosser

A24 Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1109 Robert S. Hoffman, Lewis S. Nelson, and Mary Ann Howland

77 Ethanol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1115 Luke Yip

A25 Thiamine Hydrochloride . . . . . . . . . . . . . . . . . . . . . 1129 Robert S. Hoffman

78 Ethanol Withdrawal . . . . . . . . . . . . . . . . . . . . . . . . . 1134 Jeffrey A. Gold and Lewis S. Nelson

79 Disulfiram and Disulfiram-Like Reactions . . . . . . 1143 Edwin K. Kuffner

80 f-Hydroxybutyric Acid . . . . . . . . . . . . . . . . . . . . . . 1151 Brenna M. Farmer

81 Inhalants. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1157 Heather Long

82 Hallucinogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1166 Kavita M. Babu

83 Cannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1177 Michael A. McGuigan

84 Nicotine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1185 Sari Soghoian

85 Phencyclidine and Ketamine . . . . . . . . . . . . . . . . . 1191 Ruben E. Olmedo

86 Aluminum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1202 Brenna M. Farmer

Stephen J. Traub and Robert S. Hoffman

91 Chromium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1243 Steven B. Bird

92 Cobalt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1248 Gar Ming Chan, MD

93 Copper . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1256 Lewis S. Nelson

94 Lead . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1266 Fred M. Henretig

A27 Succimer (2,3-Dimercaptosuccinic Acid). . . . . . . . 1284 Mary Ann Howland

A28 Edetate Calcium Disodium (CaNa2EDTA) . . . . . 1290 Mary Ann Howland

95 Manganese . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1294 Sari Soghoian

96 Mercury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1299 Young-Jin Sue

97 Nickel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1308 John A. Curtis and David A. Haggerty

98 Selenium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1316 Diane P. Calello

99 Silver . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1321 Melisa W. Lai Becker and Michele Burns Ewald

100 Thallium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1326 Maria Mercurio-Zappala and Robert S. Hoffman

A29 Prussian Blue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1334 Robert S. Hoffman

101 Zinc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1339 Nima Majlesi

J. Household Products . . . . . . . . . . . . . . . . . . . . . . . . 1345 102 Antiseptics, Disinfectants, and Sterilants . . . . . . . 1345

I. Metals. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1207 87 Antimony . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1207 Asim F. Tarabar

88 Arsenic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1214 Stephen W. Munday and Marsha D. Ford

Paul M. Wax

103 Camphor and Moth Repellents . . . . . . . . . . . . . . . 1358 Edwin K. Kuffner

104 Caustics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1364 Jessica A. Fulton

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105 Hydrofluoric Acid and Fluorides . . . . . . . . . . . . . . 1374 Mark Su

A30 Calcium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1381 Mary Ann Howland

106 Hydrocarbons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1386 David D. Gummin

107 Toxic Alcohols. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1400 Sage W. Wiener

SC5 Diethylene Glycol . . . . . . . . . . . . . . . . . . . . . . . . . . . 1411 Joshua G. Schier

A31 Fomepizole. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1414 Mary Ann Howland

A32 Ethanol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1419 Mary Ann Howland

K. Pesticides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1423 108 Pesticides: An Overview of Rodenticides and a Focus on Principles . . . . . . . . . . . . . . . . . . . . 1423 Neal E. Flomenbaum

109 Barium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1434 Andrew Dawson

110 Sodium Monofluoroacetate and Fluoroacetamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1437 Fermin Barrueto, Jr.

111 Phosphorus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1440 Michael C. Beuhler

112 Strychnine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1445 Yiu-cheung Chan

113 Insecticides: Organic Phosphorus Compounds and Carbamates . . . . . . . . . . . . . . . . . 1450 Michael Eddleston and Richard Franklin Clark

A33 Pralidoxime . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1467 Mary Ann Howland

A34 Atropine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1473 Mary Ann Howland

114 Insecticides: Organic Chlorines, Pyrethrins/Pyrethroids, and Insect Repellents . . . 1477 Michael G. Holland

115 Herbicides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1494 Darren M. Roberts

116 Methyl Bromide and Other Fumigants . . . . . . . . . 1516

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L. Natural Toxins and Envenomations . . . . . . . . . . . . 1522 117 Mushrooms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1522 Lewis R. Goldfrank

118 Plants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1537 Mary Emery Palmer and Joseph M. Betz

119 Arthropods. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1561 In-Hei Hahn

A35 Antivenom (Scorpion and Spider) . . . . . . . . . . . . . 1582 Richard Franklin Clark

120 Marine Envenomations . . . . . . . . . . . . . . . . . . . . . . 1587 D. Eric Brush

121 Snakes and Other Reptiles . . . . . . . . . . . . . . . . . . . . 1601 Bradley D. Riley, Anthony F. Pizon, and Anne-Michelle Ruha

A36 Antivenom (Crotaline) . . . . . . . . . . . . . . . . . . . . . . 1611 Anthony F. Pizon, Bradley D. Riley, and Anne-Michelle Ruha

M. Occupational and Environmental Toxins . . . . . . . . 1615 122 Industrial Poisoning: Information and Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1615 Peter H. Wald

123 Nanotoxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1625 Silas W. Smith

124 Simple Asphyxiants and Pulmonary Irritants . . . 1643 Lewis S. Nelson and Oladapo A. Odujebe

125 Carbon Monoxide. . . . . . . . . . . . . . . . . . . . . . . . . . . 1658 Christian Tomaszewski

A37 Hyperbaric Oxygen . . . . . . . . . . . . . . . . . . . . . . . . . 1671 Stephen R. Thom

126 Cyanide and Hydrogen Sulfide. . . . . . . . . . . . . . . . 1678 Christopher P. Holstege, Gary E. Isom, and Mark A. Kirk

A38 Sodium and Amyl Nitrite . . . . . . . . . . . . . . . . . . . . 1689 Mary Ann Howland

A39 Sodium Thiosulfate . . . . . . . . . . . . . . . . . . . . . . . . . 1692 Mary Ann Howland

A40 Hydroxocobalamin . . . . . . . . . . . . . . . . . . . . . . . . . . 1695 Mary Ann Howland

127 Methemoglobin Inducers . . . . . . . . . . . . . . . . . . . . 1698 Dennis P. Price

Keith K. Burkhart

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Contents

A41 Methylene Blue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1708 Mary Ann Howland

128 Smoke Inhalation . . . . . . . . . . . . . . . . . . . . . . . . . . . 1711 Nathan Phillip Charlton and Mark A. Kirk

SECTION 2

Poison Centers and Epidemiology . . . . . . . . . . . . . . . . . . 1782 134 Poison Prevention and Education . . . . . . . . . . . . . 1782 Lauren Schwartz

N. Disaster Preparedness . . . . . . . . . . . . . . . . . . . . . . 1721 129 Risk Assessment and Risk Communication . . . . . 1721 Charles A. McKay

130 Hazmat Incident Response . . . . . . . . . . . . . . . . . . . 1727 Bradley J. Kaufman

131 Chemical Weapons . . . . . . . . . . . . . . . . . . . . . . . . . . 1735 Jeffrey R. Suchard

132 Biological Weapons . . . . . . . . . . . . . . . . . . . . . . . . . 1750 Jeffrey R. Suchard

133 Radiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1759 Joseph G. Rella

A42 Potassium Iodide . . . . . . . . . . . . . . . . . . . . . . . . . . . 1775 Joseph G. Rella

A43 DTPA [Pentetic Acid or Pentetate

135 Poison Centers and Poison Epidemiology . . . . . . 1789 Robert S. Hoffman

136 International Perspectives on Medical Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1796 Michael Eddleston

137 Principles of Epidemiology and Research Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1803 Kevin C. Osterhoudt

138 Adverse Drug Events and Postmarketing Surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1811 Louis R. Cantilena

139 Medication Safety and Adverse Drug Events . . . . 1820 Brenna M. Farmer

140 Risk Management and Legal Principles . . . . . . . . 1831 Barbara M. Kirrane and Dainius A. Drukteinis

(Zinc or Calcium) Trisodium] . . . . . . . . . . . . . . . . 1779 Joseph G. Rella

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1839

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CONTRIBUTORS Judith C. Ahronheim, MD

Michael C. Beuhler, MD, FACMT

Professor of Medicine SUNY Downstate Brooklyn, New York Adjunct Professor of Medicine and Member Bioethics Institute, New York Medical College Valhalla, New York Chapter 32, “Geriatric Principles”

Adjunct Assistant Professor of Emergency Medicine University of North Carolina at Chapel Hill Medical Director, Carolinas Poison Center Charlotte, North Carolina Chapter 111, “Phosphorus”

Steven B. Bird, MD Assistant Professor of Emergency Medicine University of Massachusetts Medical School Worcester, Massachusetts Chapter 91, “Chromium”

Kavita M. Babu, MD Assistant Professor of Emergency Medicine Brown University Alpert Medical School Program in Medical Toxicology Department of Emergency Medicine Rhode Island Hospital Providence, Rhode Island Chapter 25, “Gastrointestinal Principles” Chapter 82, “Hallucinogens”

George M. Bosse, MD Associate Professor of Emergency Medicine University of Louisville Medical Director Kentucky Regional Poison Center Louisville, Kentucky Chapter 48, “Antidiabetics and Hypoglycemics”

Theodore C. Bania, MD, MS Assistant Professor of Medicine Columbia University College of Physicians and Surgeons Director of Research and Toxicology St. Luke’s Roosevelt Hospital Center New York, New York Antidote in Depth A21, “Intravenous Fat Emulsions”

Nicole C. Bouchard, MD, FRCPC Assistant Clinical Professor Columbia University Medical Center Director of Medical Toxicology Assistant Site Director New York-Presbyterian Hospital New York, New York Chapter 49, “Thyroid and Antithyroid Medications”

Fermin Barrueto, Jr., MD Clinical Assistant Professor of Emergency Medicine University of Maryland Chair, Department of Emergency Medicine Upper Chesapeake Health Systems Baltimore, Maryland Chapter 110, “Sodium Monofluoroacetate and Fluoroacetamide”

Edward W. Boyer, MD, PhD Associate Professor of Emergency Medicine University of Massachusetts Medical School Chief, Division of Medical Toxicology UMass-Memorial Medical Center Worcester, Massachusetts Chapter 57, “Antituberculous Medications”

James Dave Barry, MD

Jeffrey R. Brubacher, MD

Program Director, Naval Medical Center Portsmouth Emergency Medicine Residency Assistant Adjunct Professor Uniformed Services University of the Health Sciences Portsmouth, Virginia Chapter 58, “Antimalarials”

Assistant Professor University of British Columbia Emergency Physician Vancouver General Hospital Vancouver, British Columbia, Canada Chapter 61, “b-Adrenergic Antagonists”

Joseph M. Betz, PhD

D. Eric Brush, MD

Director, Dietary Supplement Methods and Reference Materials Program Office of Dietary Supplements U.S. National Institutes of Health Bethesda, Maryland Chapter 118, “Plants”

Assistant Professor of Emergency Medicine Division of Toxicology University of Massachusetts Medical Center Worcester, Massachusetts Chapter 120, “Marine Envenomations”

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Contributors

Keith K. Burkhart, MD

William K. Chiang, MD

Professor of Clinical Emergency Medicine Pennsylvania State University College of Medicine Medical Officer Center for Drug Evaluation and Research Food and Drug Administration Silver Spring, Maryland Chapter 116, “Methyl Bromide and Other Fumigants”

Associate Professor of Emergency Medicine New York University School of Medicine Chief of Emergency Services, Bellevue Hospital Center Attending Physician Bellevue Hospital Center and New York University Langone Medical Center New York, New York Chapter 20, “Otolaryngologic Principles” Chapter 75, “Amphetamines”

Michelle Burns Ewald, MD Assistant Professor of Pediatrics Harvard Medical School Fellowship Director, Harvard Medical Toxicology Fellowship Medical Director, Regional Center for Poison Control and Prevention Attending Physician, Emergency Medicine Children’s Hospital Boston Boston, Massachusetts Chapter 99, “Silver”

Diane P. Calello, MD Assistant Professor of Pediatrics and Emergency Medicine Chief, Section of Toxicology Robert Wood Johnson Medical School UMDNJ Staff Toxicologist, New Jersey Poison Information and Education Systems (NJPIES) New Brunswick, New Jersey Chapter 98, “Selenium”

Louis R. Cantilena, MD, PhD Professor of Medicine and Pharmacology Department of Medicine Uniformed Services University Bethesda, Maryland Chapter 138, “Adverse Drug Events and Postmarketing Surveillance”

Gar Ming Chan, MD Assistant Clinical Professor of Emergency Medicine New York University School of Medicine Attending Physician, North Shore University Hospital Manhasset, New York Chapter 92, “Cobalt”

Jason Chu, MD Assistant Professor of Clinical Medicine Columbia University College of Physicians and Surgeons Medical Toxicologist St. Luke’s-Roosevelt Hospital Center New York, New York Chapter 28, “Genitourinary Principles” Chapter 51, “Antimigraine Medications”

Richard Church, MD Fellow in Medical Toxicology University of Massachusetts Medical Center Worcester, Massachusetts Chapter 25, “Gastrointestinal Principles”

Cathleen Clancy, MD Associate Medical Director National Capital Poison Center Associate Professor Department of Emergency Medicine George Washington University Medical Center Attending Physician Bethesda Naval Emergency Department Washington, District of Columbia Chapter 22, “Electrophysiologic and Electrocardiographic Principles”

Richard Franklin Clark, MD

Associate Consultant, Director of Toxicology Training Hong Kong Poison Information Centre Hong Kong SAR, China Chapter 112, “Strychnine”

Professor of Medicine University of California at San Diego Director, Division of Medical Toxicology University of California San Diego Medical Center San Diego, California Chapter 113, “Insecticides: Organic Phosphorus Compounds and Carbamates” Antidote in Depth A35, “Antivenom (Scorpion and Spider)”

Nathan Phillip Charlton, MD

Steven C. Curry, MD

Assistant Professor of Emergency Medicine University of Virginia Charlottesville, Virginia Chapter 128, “Smoke Inhalation”

Director, Department of Medical Toxicology Banner Good Samaritan Medical Center Professor of Clinical Medicine University of Arizona College of Medicine Phoenix, Arizona Chapter 13, “Neurotransmitters and Neuromodulators”

Yiu-cheung Chan, MD, MBBS, FHKAM, FHKCEM, FRCS(Ed)

Alan N. Charney, MD Clinical Professor of Medicine New York University School of Medicine New York, New York Chapter 16, “Fluid, Electrolyte, and Acid–Base Principles”

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Contributors

John A. Curtis, MD

Brenna M. Farmer, MD

Assistant Professor of Emergency Medicine Associate Director, Fellowship in Medical Toxicology Drexel University College of Medicine Attending Physician Hahnemann University Hospital Philadelphia, Pennsylvania Chapter 97, “Nickel”

Assistant Professor of Medicine Weill-Cornell Medical College Attending Physician New York Presbyterian-Weill-Cornell Medical Center New York, New York Chapter 80, “g-Hydroxybutyric Acid” Chapter 86, “Aluminum” Chapter 139, “Medication Safety and Adverse Drug Events”

Andrew Dawson, MBBS Professor, Peradeniya University Program Director South Asian Clinical Toxicology Research Collaboration Peradeniya, Sri Lanka Chapter 109, “Barium”

Kathleen A. Delaney, MD Clinical Professor, Division of Emergency Medicine University of Texas Southwestern Medical School Dallas, Texas Chapter 12, “Biochemical and Metabolic Principles” Chapter 15, “Thermoregulatory Principles” Chapter 26, “Hepatic Principles” Antidote in Depth A10, “Dextrose”

Francis Jerome DeRoos, MD Associate Professor of Emergency Medicine University of Pennsylvania School of Medicine Residency Director Hospital of the University of Pennsylvania Philadelphia, Pennsylvania Chapter 60, “Calcium Channel Blockers” Chapter 62, “Other Antihypertensives”

Suzanne Doyon, MD, FACMT Medical Director, Maryland Poison Center University of Maryland School of Pharmacy Baltimore, Maryland Chapter 47, “Anticonvulsants”

Dainius A. Drukteinis, MD, JD Attending Physician MetroWest Medical Center Framingham, Massachusetts Chapter 140, “Risk Management and Legal Principles”

Michael Eddleston, MD, PhD, MRCP Clinical Pharmacology Unit University of Edinburgh Scottish Poisons Information Bureau Royal Infirmary of Edinburgh Edinburgh, United Kingdom Chapter 113, “Insecticides: Organic Phosphorus Compounds and Carbamates” Chapter 136, “International Perspectives on Medical Toxicology”

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Donald A. Feinfeld, MD (Deceased) Nephrology Fellowship Director Beth Israel Medical Center Professor of Medicine Albert Einstein College of Medicine Consultant in Nephrology New York City Poison Center New York, New York Chapter 27, “Renal Principles”

Kathy Lynn Ferguson, DO Attending Physician Emergency Medicine and Medical Toxicology New York Hospital Queens Flushing, New York Chapter 74, “Sedative–Hypnotics”

Jeffrey S. Fine, MD Assistant Professor of Emergency Medicine and Pediatrics New York University School of Medicine Attending Physician Bellevue Hospital Center and New York University Langone Medical Center New York, New York Chapter 30, “Reproductive and Perinatal Principles” Chapter 31, “Pediatric Principles”

Mark A. Flomenbaum, MD, PhD Associate Professor of Pathology and Laboratory Medicine Boston University School of Medicine Director, Autopsy Services Boston Medical Center Boston, Massachusetts Chapter 33, “Postmortem Toxicology”

Neal E. Flomenbaum, MD, FACEP, FACP Professor of Clinical Medicine Weill Cornell Medical College of Cornell University Emergency Physician-in-Chief New York-Presbyterian Hospital Weill Cornell Medical Center Consultant, New York City Poison Center New York, New York Chapter 3, “Initial Evaluation of the Patient: Vital Signs and Toxic Syndromes” Chapter 4, “Principles of Managing the Acutely Poisoned or Overdosed Patient” Chapter 35, “Salicylates” Chapter 108, “Pesticides: An Overview of Rodenticides and a Focus on Principles”

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Contributors

Marsha D. Ford, MD

Howard A. Greller, MD, FACEP, FACMT

Adjunct Professor of Emergency Medicine University of North Carolina, Chapel Hill Director, Carolinas Poison Center Carolinas Medical Center Charlotte, North Carolina Chapter 88, “Arsenic”

Assistant Professor of Emergency Medicine New York University School of Medicine Attending Physician North Shore University Hospital Manhasset, New York Chapter 70, “Lithium” Workbook Cases and Questions

Jessica A. Fulton, DO Attending Physician Grandview Hospital Grandview, New Jersey Chapter 104, “Caustics”

Howard L. Geyer, MD, PhD Assistant Professor of Neurology Albert Einstein College of Medicine Director, Division of Movement Disorders Montefiore Medical Center Bronx, New York Chapter 46, “Botulism” Antidote in Depth A8, “Botulinum Antitoxin”

Martin Griffel, MD Associate Professor of Anesthesiology New York University School of Medicine Director, Cardiovascular ICU New York University Langone Medical Center New York, New York Chapter 67, “Inhalational Anesthetics”

Anne-Bolette Gude, MD Clinical Pharmacologist Novo Nordisk Virum, Denmark Chapter 7, “Techniques Used to Prevent Gastrointestinal Absorption”

Beth Y. Ginsburg, MD

David D. Gummin, MD, FAACT, FACEP, FACMT

Assistant Professor of Emergency Medicine Mount Sinai School of Medicine Attending Physician Elmhurst Hospital Center Elmhurst, New York Chapter 41, “Vitamins”

Clinical Assistant Professor Medical College of Wisconsin Medical Director Wisconsin Poison Center Milwaukee, Wisconsin Chapter 106, “Hydrocarbons”

Jeffrey A. Gold, MD

Jason B. Hack, MD

Associate Professor of Medicine Oregon Health and Sciences University Portland, Oregon Chapter 78, “Ethanol Withdrawal”

Associate Professor of Emergency Medicine Program Director, Medical Toxicology Brown University, Warren Alpert Medical School Rhode Island Hospital Providence, Rhode Island Chapter 64, “Cardioactive Steroids”

David S. Goldfarb, MD Professor of Medicine and Physiology New York University School of Medicine Chief, Nephrology Section New York Harbor VA Medical Center New York, New York Chapter 9, “Principles and Techniques Applied to Enhance Elimination”

Lewis R. Goldfrank, MD, FAACT, FAAEM, FACEP, FACMT, FACP Herbert W. Adams Professor and Chair Department of Emergency Medicine New York University School of Medicine Director, Emergency Medicine Bellevue Hospital Center and New York University Langone Medical Center Medical Director, New York City Poison Center New York, New York Chapter 3, “Initial Evaluation of the Patient: Vital Signs and Toxic Syndromes” Chapter 4, “Principles of Managing the Acutely Poisoned or Overdosed Patient” Chapter 117, “Mushrooms” Antidote in Depth A8, “Botulinum Antitoxin”

David A. Haggerty, MD Fellow in Medical Toxicology Division of Medical Toxicology Department of Emergency Medicine Drexel University College of medicine Philadelphia, Pennsylvania Chapter 97, “Nickel”

In-Hei Hahn, MD Assistant Professor of Clinical Medicine Columbia University College of Physicians and Surgeons Associate Attending, Emergency Medicine Assistant Director of Research St. Luke’s-Roosevelt Hospital Center, Danbury Hospital New York, New York Chapter 119, “Arthropods”

Sarah Eliza Halcomb, MD Assistant Professor of Emergency Medicine Washington University School of Medicine Section Chief - Medical Toxicology Washington University-Barnes-Jewish Hospital St. Louis, Missouri Chapter 42, “Essential Oils”

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Contributors

Richard J. Hamilton, MD

Robert J. Hoffman, MD, MS

Professor and Chairman of Emergency Medicine Drexel University College of Medicine Philadelphia, Pennsylvania Chapter 14, “Withdrawal Principles”

Assistant Professor Albert Einstein College of Medicine Research Director Beth Israel Medical Center New York, New York Chapter 65, “Methylxanthines and Selective β2 Adrenergic Agonists”

Nikolas B. Harbord, MD Assistant Professor of Medicine Albert Einstein College of Medicine Attending Nephrologist Beth Israel Medical Center Brooklyn, New York Chapter 27, “Renal Principles”

Robert G. Hendrickson, MD Associate Professor of Emergency Medicine Oregon Health and Science University Associate Medical Director Oregon Poison Center Emergency Physician and Medical Toxicologist Oregon Health and Science University Portland, Oregon Chapter 34, “Acetaminophen” Antidote in Depth A4, “N-Acetylcysteine”

Fred M. Henretig, MD Professor of Pediatrics and Emergency Medicine University of Pennsylvania School of Medicine Director, Section of Clinical Toxicology Children’s Hospital of Philadelphia Philadelphia, Pennsylvania Chapter 94, “Lead”

Christina H. Hernon, MD Assistant Professor of Emergency Medicine University of Massachusetts Medical School Division of Medical Toxicology University of Massachusetts Memorial Medical Center Worcester, Massachusetts Chapter 57, “Antituberculous Medications”

Robert A. Hessler, MD, PhD Associate Professor of Emergency Medicine New York University School of Medicine Attending Physician Bellevue Hospital Center, New York University Langone Medical Center and Veterans Administration Medical Center, Manhattan New York, New York Chapter 23, “ Hemodynamic Principles”

Lotte C. G. Hoegberg, MS (Pharm), PhD Pharmacist, Danish Poison Information Centre Copenhagen, Denmark Chapter 7, “Techniques Used to Prevent Gastrointestinal Absorption”

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Robert S. Hoffman, MD, FAACT, FACMT Associate Professor of Emergency Medicine and Medicine (Pharmacology) New York University School of Medicine Attending Physician, Emergency Medicine and Internal Medicine Bellevue Hospital Center and New York University Langone Medical Center Director, New York City Poison Center New York, New York Chapter 3, “Initial Evaluation of the Patient: Vital Signs and Toxic Syndromes” Chapter 4, “Principles of Managing the Acutely Poisoned or Overdosed Patient” Chapter 16, “Fluid, Electrolyte, and Acid-Base Principles” Chapter 21, “Respiratory Principles” Chapter 76, “Cocaine” Chapter 90, “Cadmium” Chapter 100, “Thallium” Chapter 135, “Poison Centers and Poison Epidemiology” Antidote in Depth A24, “Benzodiazepines” Antidote in Depth A25, “Thiamine Hydrochloride” Antidote in Depth A29, “Prussian Blue”

Michael G. Holland, MD, FAACT, FACEP, FACMT, FACOEM Clinical Assistant Professor SUNY Upstate Medical University Consultant Medical Toxicologist Upstate New York Poison Center Syracuse, New York Attending Physician Center for Occupational Health at Glens Falls Hospital Glens Falls, New York Chapter 114, “Insecticides: Organic Chlorines, Pyrethrins/Pyrethroids, and Insect Repellents”

Christopher P. Holstege, MD Associate Professor of Emergency Medicine and Pediatrics University of Virginia School of Medicine Director, Division of Medical Toxicology University of Virginia Health System Charlottesville, Virginia Chapter 126, “Cyanide and Hydrogen Sulfide”

William J. Holubek, MD Attending Physician Department of Emergency Medicine New York Methodist Hospital Brooklyn, New York Chapter 36, “Nonsteroidal Antiinflammatory Drugs”

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Contributors

Mary Ann Howland, PharmD, DABAT, FAACT Clinical Professor of Pharmacy St. John’s University College of Pharmacy Adjunct Professor of Emergency Medicine New York University School of Medicine Bellevue Hospital Center and New York University Langone Medical Center Senior Consultant in Residence New York City Poison Center New York, New York Chapter 3, “Initial Evaluation of the Patient: Vital Signs and Toxic Syndromes” Chapter 4, “Principles of Managing the Acutely Poisoned or Overdosed Patient” Chapter 8, “Pharmacokinetic and Toxicokinetic Principles” Chapter 32, “Geriatric Principles” Antidote in Depth A1, “Syrup of Ipecac” Antidote in Depth A2, “Activated Charcoal” Antidote in Depth A3, “Whole-Bowel Irrigation and Other Intestinal Evacuants” Antidote in Depth A4, “N-Acetylcysteine” Antidote in Depth A6, “Opioid Antagonists” Antidote in Depth A7, “Deferoxamine” Antidote in Depth A9, “L-Carnitine” Antidote in Depth A11, “Octreotide” Antidote in Depth A12, “Physostigmine Salicylate” Antidote in Depth A13, “Leucovorin (Folinic Acid) and Folic Acid” Antidote in Depth A15, “Pyridoxine” Antidote in Depth A16, “Vitamin K1” Antidote in Depth A17, “Protamine” Antidote in Depth A19, “Glucagon” Antidote in Depth A20, “Digoxin-Specific Antibody Fragments (Fab)” Antidote in Depth A23, “Flumazenil” Antidote in Depth A24, “Benzodiazepines” Antidote in Depth A26, “Dimercaprol (British Anti-Lewisite or BAL)” Antidote in Depth A27, “Succimer (2,3-Dimercaptosuccinic Acid)” Antidote in Depth A28, “Edetate Calcium Disodium (CaNa2EDTA)” Antidote in Depth A30, “Calcium” Antidote in Depth A31, “Fomepizole” Antidote in Depth A32, “Ethanol” Antidote in Depth A33, “Pralidoxime” Antidote in Depth A34, “Atropine” Antidote in Depth A38, “Sodium and Amyl Nitrite” Antidote in Depth A39, “Sodium Thiosulfate” Antidote in Depth A40, “Hydroxocobalamin” Antidote in Depth A41, “Methylene Blue”

Oliver L. Hung, MD Attending Physician Department of Emergency Medicine Morristown Memorial Hospital Morristown, New Jersey Chapter 43, “Herbal Preparations”

Gary E. Isom, PhD Professor of Toxicology Purdue University Clinical Assistant Professor of Pharmacology Indiana University School of Medicine West Lafayette, Indiana Chapter 126, “Cyanide and Hydrogen Sulfide”

David N. Juurlink, BPhm, MD, PhD, FAACT, FACMT, FRCPC Associate Professor, Faculty of Medicine University of Toronto Division Head, Clinical Pharmacology and Toxicology Sunnybrook Health Sciences Centre Toronto, Ontario, Canada Chapter 69, “Antipsychotics”

Bradley J. Kaufman, MD, MPH Assistant Professor, Department of Emergency Medicine Albert Einstein College of Medicine Bronx, New York Attending Physician Department of Emergency Medicine Long Island Jewish Medical Center New Hyde Park, New York Division Medical Director Fire Department of the City of New York New York, New York Chapter 130, “Hazmat Incident Response”

Brian Kaufman, MD Associate Professor of Medicine, Anesthesiology and Neurosurgery New York University School of Medicine Co-Director Critical Care New York University Langone Medical Center New York, New York Chapter 66, “Local Anesthetics” Chapter 67, “Inhalational Anesthetics”

William Kerns, II, MD, FACEP, FACMT Medical Toxicology Fellowship Director Division of Medical Toxicology Department of Emergency Medicine and Carolinas Poison Center Attending Toxicologist Carolinas Medical Center and Carolinas Poison Center Charlotte, North Carolina Antidote in Depth A18, “Insulin-Euglycemia Therapy”

Mark A. Kirk, MD Associate Professor of Emergency Medicine and Pediatrics University of Virginia Charlottesville, Virginia Special Advisor for Chemical Defense and Medical Toxicology Office of Health Affairs Department of Homeland Security Washington, DC Chapter 10, “Use of the Intensive Care Unit” Chapter 126, “Cyanide and Hydrogen Sulfide” Chapter 128, “Smoke Inhalation”

Barbara M. Kirrane, MD Assistant Professor of Emergency Medicine Yale University Attending Physician New Haven, Connecticut Chapter 140, “Risk Management and Legal Principles”

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Contributors

Kurt C. Kleinschmidt, MD

Nima Majlesi, DO

Professor of Surgery, Division of Emergency Medicine University of Texas Southwestern Medical Center Medical Director, Toxicology Parkland Memorial Hospital Dallas, Texas Chapter 12, “Biochemical and Metabolic Principles”

Research Director Attending Physician Staten Island University Hospital Staten Island, New York Chapter 101, “Zinc”

Edwin K. Kuffner, MD Senior Director for Medical Affairs McNeil Pharmaceuticals Fort Washington, Pennsylvania Chapter 79, “Disulfiram and Disulfiramlike Reactions” Chapter 103, “Camphor and Moth Repellents”

Clinical Assistant Professor of Psychiatry New York University School of Medicine Director, Comprehensive Psychiatric Emergency Program Bellevue Hospital Center New York, New York Chapter 17, “Psychiatric Principles”

Melisa W. Lai Becker, MD

Alex F. Manini, MD, MS

Instructor, Harvard Medical School Director, Division of Medical Toxicology Emergency Physician Department of Emergency Medicine Cambridge Health Alliance Cambridge, Massachusetts Chapter 99, “Silver”

Assistant Professor of Emergency Medicine Mount Sinai School of Medicine Co-Director, Toxicology Service and Attending Physician Elmhurst Hospital Center New York, New York Chapter 71, “Monoamine Oxidase Inhibitors”

David C. Lee, MD

Assistant Professor of Emergency Medicine and Medicine Section of Clinical Pharmacology SUNY Upstate Medical University Clinical Toxicologist Upstate New York Poison Center Clinical Toxicologist Syracuse, New York Chapter 39, “Dieting Agents and Regimens”

Clinical Associate Professor of Emergency Medicine New York University School of Medicine Director of Research North Shore University Hospital–Manhasset Manhasset, New York Chapter 74, “Sedative–Hypnotics”

Neal A. Lewin, MD, FACEP, FACMT, FACP The Stanley and Fiona Druckenmiller Clinical Professor of Emergency Medicine and Medicine (Pharmacology) New York University School of Medicine Director, Didactic Education Emergency Medicine Residency Attending Physician, Emergency Medicine and Internal Medicine Bellevue Hospital Center and New York University Langone Medical Center Consultant, New York City Poison Center New York, New York Chapter 3, “Initial Evaluation of the Patient: Vital Signs and Toxic Syndromes” Chapter 4, “Principles of Managing the Acutely Poisoned or Overdosed Patient” Chapter 29, “Dermatologic Principles” Chapter 63, “Antidysrhythmics”

Erica L. Liebelt, MD Professor of Pediatrics and Emergency Medicine University of Alabama at Birmingham School of Medicine Director Medical Toxicology Services Birmingham, Alaska Chapter 73, “Cyclic Antidepressants”

Heather Long, MD Assistant Professor of Emergency Medicine Albany Medical Center Albany, New York Chapter 81, “Inhalants”

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Kishor Malavade, MD

Jeanna M. Marraffa, PharmD, DABAT

Michael A. McGuigan, MDCM, MBA Clinical Professor of Emergency Medicine State University of New York Stony Brook, New York Medical Director Long Island Regional Poison and Drug Information Center Mineola, New York Chapter 83, “Cannabinoids”

Charles A. McKay, Jr., MD Associate Professor of Emergency Medicine University of Connecticut School of Medicine Section Chief, Division of Medical Toxicology Hartford Hospital Hartford, Connecticut Chapter 129, “Risk Assessment and Risk Communication”

Maria Mercurio-Zappala, RPh, MS Associate Director New York City Poison Control Center New York, New York Chapter 100, “Thallium”

Kirk Charles Mills, MD, FACMT Medical Toxicologist Wayne State University Detroit Medical Center Detroit, Michigan Chapter 13, “Neurotransmitters and Neuromodulators”

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Contributors

Stephen W. Munday, MD, MPH, MS

Ruben E. Olmedo, MD

Clinical Assistant Professor University of California, San Diego Medical Toxicologist Sharp Rees Stealy Medical Group San Diego, California Chapter 88, “Arsenic”

Clinical Assistant Professor of Emergency Medicine Mount Sinai Hospital Director, Division of Toxicology Mount Sinai School of Medicine New York, New York Chapter 85 “Phencyclidine and Ketamine”

Lewis S. Nelson, MD, FAACT, FACEP, FACMT

Dean G. Olsen, DO

Associate Professor of Emergency Medicine New York University School of Medicine Attending Physician, Emergency Medicine Bellevue Hospital Center and New York University Langone Medical Center Director, Fellowship in Medical Toxicology New York City Poison Center and New York University School of Medicine New York, New York Chapter 3, “Initial Evaluation of the Patient: Vital Signs and Toxic Syndromes” Chapter 4, “Principles of Managing the Acutely Poisoned or Overdosed Patient” Chapter 11, “Chemical Principles” Chapter 29, “Dermatologic Principles” Chapter 38, “Opioids” Chapter 63, “Antidysrhythmics” Chapter 78, “Ethanol Withdrawal” Chapter 93, “Copper” Chapter 124, “Simple Asphyxiants and Pulmonary Irritants” Antidotes in Depth A6, “Opioid Antagonists” Antidotes in Depth A24, “Benzodiazepines”

Attending Staff New York City Poison Center Assistant Professor New York College of Osteopathic Medicine Old Westbury, New York Director of Research Attending Physician Emergency Medicine, Toxicology St. Barnabas Hospital Bronx, New York Chapter 38, “Opioids” Work Book: Cases and Questions

Sean Patrick Nordt, MD, PharmD Adjunct Assistant Clinical Professor of Medicine University of California, San Diego Fellow in Medical Toxicology Division of Medical Toxicology and Department of Emergency Medicine San Diego, California Chapter 55, “Pharmaceutical Additives”

Ayrn D. O’Connor, MD Clinical Assistant Professor of Emergency Medicine Department of Emergency Medicine University of Arizona College of Medicine Assistant Fellowship Director Department of Medical Toxicology Banner Good Samaritan Medical Center Phoenix, Arizona Chapter 13, “Neurotransmitter Principles”

Oladapo A. Odujebe, MD, MT-ACSP Assistant Professor of Emergency Medicine Emory University Medical Toxicologist Georgia Poison Control Center Atlanta, Georgia Chapter 124, “Simple Asphyxiants and Pulmonary Irritants”

Kevin C. Osterhoudt, MD, MS Associate Professor of Pediatrics and Emergency Medicine The University of Pennsylvania School of Medicine Medical Director, The Poison Control Center at The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania Chapter 137, “Principles of Epidemiology and Research Design”

Mary Emery Palmer, MD Director, ToxEM LLC Clinical Assistant Professor of Emergency Medicine The George Washington University Washington, District of Columbia Chapter 118, “Plants”

Jeanmarie Perrone, MD, FACMT Associate Professor of Emergency Medicine University of Pennsylvania School of Medicine, Director, Division of Medical Toxicology Hospital of the University of Pennsylvania Philadelphia, Pennsylvania Chapter 40, “Iron”

Anthony F. Pizon, MD Assistant Professor University of Pittsburgh School of Medicine Medical Director, West Virginia Poison Center UPMC Presbyterian Pittsburgh, Pennsylvania Chapter 121, “Snakes and Other Reptiles” Antidotes in Depth A36, “Antivenom (Crotaline)”

Dennis P. Price, MD Assistant Professor of Emergency Medicine New York University School of Medicine New York, New York Attending Physician Bellevue Hospital Center and New York University Langone Medical Center Chapter 127, “Methemoglobin Inducers”

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Contributors

Jane M. Prosser, MD

Anne-Michelle Ruha, MD

Assistant Professor New York Presbyterian Hospital Weill Cornell Medical College New York, New York Chapter 76, “Cocaine” Special Considerations SC-4, “Internal Concealment of Xenobiotics”

Director, Medical Toxicology Fellowship Program Banner Good Samaritan Medical Center Clinical Assistant Professor of Emergency Medicine University of Arizona College of Medicine Phoenix, Arizona Chapter 13, “Neurotransmitters and Neuromodulators” Chapter 121, “Snakes and Other Reptiles” Antidotes in Depth A36, “Antivenom (Crotaline)”

Petrie M. Rainey, MD, PhD Professor of Laboratory Medicine University of Washington School of Medicine Director of Clinical Chemistry University of Washington Medical Center Seattle, Washington Chapter 6, “Laboratory Principles”

Rama B. Rao, MD, FACMT Assistant Professor Weill-Cornell Medical College Emergency Physician and Medical Toxicologist New York Presbyterian Hospital at the Weill Cornell Medical Center New York, New York Chapter 18, “Neurologic Principles” Chapter 33, “Postmortem Toxicology” Chapter 89, “Bismuth” Special Considerations SC-1, “Organ Procurement from Poisoned Patients” Special Considerations SC-2, “Intrathecal Administration of Xenobiotics”

Joseph G. Rella, MD Assistant Professor of Emergency Medicine School of Medicine and Dentistry of New Jersey Attending Physician University Hospital Newark, New Jersey Chapter 133, “Radiation” Antidotes in Depth A42, “Potassium Iodide” Antidotes in Depth A43, “DTPA [Pentetic Acid or Pentetate (Zinc or Calcium) Trisodium]”

Bradley D. Riley, MD

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Joshua G. Schier, MD, FACMT Assistant Professor of Emergency Medicine Section of Toxicology Emory University School of Medicine Medical Toxicologist Centers for Disease Control and Prevention Chamblee, Georgia Chapter 37, “Colchicine, Podophyllin, and Vinca Alkaloids” Special Considerations SC-5, “Diethylene Glycol”

David R. Schwartz, MD Assistant Professor of Medicine New York University School of Medicine Section Chief, Critical Care Medicine New York University Langone Medical Center New York, New York Chapter 66, “Local Anesthetics”

David T. Schwartz, MD Associate Professor of Emergency Medicine New York University School of Medicine Attending Physician Bellevue Hospital Center and New York University Langone Medical Center New York, New York Chapter 5, “Diagnostic Imaging”

Lauren Schwartz, MPH Public Education Coordinator New York City Poison Center New York, New York Chapter 134, “Poison Prevention and Education”

Assistant Medical Director Helen DeVos Children’s Hospital Regional Poison Center Attending Physician Spectrum Health Department of Emergency Medicine Grand Rapids, Michigan Chapter 121, “Snakes and Other Reptiles” Antidotes in Depth A36, “Antivenom (Crotaline)”

Mark R. Serper, PhD

Darren M. Roberts, BPharm, MBBS, PhD

Adhi Sharma, MD

Adjunct Associate Professor University of Canberra Medical Officer The Canberra Hospital Garran, ACT, Australia Chapter 115, “Herbicides”

Assistant Professor of Emergency Medicine Mount Sinai School of Medicine Chairman, Emergency Medicine Good Samaritan Hospital Medical Center West Islip, New York Chapter 19, “Ophthalmic Principles”

Associate Professor of Psychology Hofstra University Research Associate Professor of Psychiatry New York University School of Medicine New York, New York Chapter 17, “Psychiatric Principles”

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Contributors

Marco L. A. Sivilotti, MD, MSc

Jeffrey R. Suchard, MD, FACEP, FACMT

Associate Professor of Emergency Medicine, Pharmacology and Toxicology Queen’s University Kingston, Ontario Canada Consultant, Ontario Poison Centre Hospital for Sick Children Toronto, Ontario, Canada Chapter 24, “Hematologic Principles”

Professor of Clinical Emergency Medicine Director of Medical Toxicology University of California, Irvine Medical Center Orange, California Chapter 131, “Chemical Weapons” Chapter 132, “Biological Weapons”

Silas W. Smith, MD Assistant Professor of Emergency Medicine Assistant Director of Medical Toxicology Fellowship Program New York University School of Medicine Attending Physician Bellevue Hospital Center and New York University Langone Medical Center New York, New York Chapter 123, “Nanotoxicology” Antidote in Depth 14, “Glucarpidase (Carboxypeptidase G2)”

Sari Soghoian, MD Assistant Professor of Emergency Medicine New York University School of Medicine Attending Physician Bellevue Hospital Center and New York University Langone Medical Center New York, New York Chapter 84, “Nicotine” Chapter 95, “Manganese”

Andrew Stolbach, MD Assistant Professor of Emergency Medicine Johns Hopkins University School of Medicine Attending Physician Johns Hopkins Hospital Baltimore, Maryland Chapter 21, Respiratory Principles

Christine M. Stork, PharmD, DABAT Clinical Associate Professor of Emergency Medicine, Medicine and Pharmacology Upstate Medical University Clinical Director Upstate New York Poison Center Syracuse, New York Chapter 56, “ Antibacterials, Antifungals, and Antivirals” Chapter 72, “Serotonin Reuptake Inhibitors and Atypical Antidepressants”

Mark Su, MD Assistant Professor of Emergency Medicine SUNY Downstate Medical Center Attending Physician North Shore University Hospital Manhasset, New York Chapter 59, “Anticoagulants” Chapter 105, “Hydrofluoric Acid and Fluorides”

Young-Jin Sue, MD Clinical Associate Professor of Pediatrics Division of Pediatric Emergency Medicine Albert Einstein College of Medicine Attending Physician Pediatric Emergency Services Children’s Hospital at Montefiore Bronx, New York Chapter 96, “Mercury”

Kenneth M. Sutin, MD Associate Professor of Anesthesiology and Surgery New York University School of Medicine Director of Critical Care and PACU Department of Anesthesiology Bellevue Hospital Center New York, New York Chapter 68, “Neuromuscular Blockers” Antidotes in Depth A22, “Dantrolene Sodium”

Asim F. Tarabar, MD, MS Assistant Professor of Surgery Section of Emergency Medicine Department of Surgery Yale University School of Medicine Yale New Haven Hospital New Haven, Connecticut Chapter 87, “Antimony”

Stephen R. Thom, MD, PhD Professor of Emergency Medicine Chief, Hyperbaric Medicine University of Pennsylvania Philadelphia, Pennsylvania Antidotes in Depth A37, “Hyperbaric Oxygen”

Anthony J. Tomassoni, MD, MS Assistant Professor of Emergency Medicine Division of Emergency Medical Services Yale University School of Medicine Medical Director, Yale New Haven Center for Healthcare Solutions Yale New Haven Health System New Haven, Connecticut Chapter 50,”Antihistamines and Decongestants”

Christian Tomaszewski, MD Clinical Associate Professor of Emergency Medicine Department of Emergency Medicine University of California San Diego Division of Medical Toxicology University of California San Diego Medical Center San Diego, California Chapter 125, “Carbon Monoxide”

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Contributors

Stephen J. Traub, MD

Richard Y. Wang, DO

Assistant Professor of Medicine Harvard Medical School Division of Toxicology and Department of Emergency Medicine Beth Israel Deaconess Medical Center Boston, Massachusetts Chapter 11, “Chemical Principles” Chapter 90, “Cadmium”

Medical Officer National Center for Environmental Health Centers for Disease Control and Prevention Chamblee, Georgia Chapter 52, “Antineoplastics Overview” Chapter 53, “Antineoplastics: Methotrexate” Chapter 54, “Miscellaneous Antineoplastics” Special Considerations SC-3, “Extravasation of Xenobiotics”

Michael G. Tunik, MD

Paul M. Wax, MD, FACMT

Associate Professor of Emergency Medicine New York University School of Medicine Attending Physician Bellevue Hospital Center New York, New York Chapter 45, “Food Poisoning”

Professor, Division of Emergency Medicine University of Texas Southwestern Medical School Medical Director, Toxicology Clinic Dallas, Texas Executive Director American College of Medical Toxicology Phoenix, Arizona Chapter 1, “Historical Principles and Perspectives” Chapter 2, “Toxicologic Plagues and Disasters in History” Chapter 102, “Antiseptics, Disinfectants and Sterilants” Antidotes in Depth A5, “Sodium Bicarbonate”

Susi U. Vassallo, MD Associate Professor of Emergency Medicine New York University School of Medicine Attending Physician Bellevue Hospital Center and New York University Langone Medical Center New York, New York Chapter 15, “Thermoregulatory Principles” Chapter 44, “Athletic Performance Enhancers”

Larissa I. Velez, MD Associate Professor, Associate Program Director University of Texas Southwestern Medical Center Staff Toxicologist, North Texas Poison Center Parkland Health and Hospital System Dallas, Texas Antidotes in Depth A10, “Dextrose”

Lisa E. Vivero, PharmD Manager Drug Information MedImpact San Diego, California Chapter 55, “Pharmaceutical Additives”

Peter H. Wald, MD, MPH Vice President, Enterprise Medical Director USAA San Antonio, Texas Chapter 122, “Industrial Poisoning: Information and Control”

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Richard S. Weisman, PharmD, DABAT Associate Dean University of Miami Miller School of Medicine Director, Florida Poison Center–Miami Miami, Florida Chapter 50,”Antihistamines and Decongestants”

Sage W. Wiener, MD Assistant Professor of Emergency Medicine SUNY Downstate Medical Center Director of Medical Toxicology SUNY Downstate Medical Center/Kings County Hospital Brooklyn, New York Chapter 107, “Toxic Alcohols”

Luke Yip, MD Assistant Professor School of Pharmacy, University of Colorado Health Sciences Center Attending, Rocky Mountain Poison and Drug Center Attending, Department of Medicine Denver Health Medical Center Denver, Colorado Chapter 77, “Ethanol”

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PREFACE Goldfrank’s Toxicologic Emergencies is a multi-authored text of close to 2000 pages prepared by using the education and management principles we apply at the New York City Poison Center and at our clinical sites. In this ninth edition of Goldfrank’s Toxicologic Emergencies, we proudly offer readers an approach to medical toxicology using evidence-based principles viewed through a lens of bedside clinical practice. The case history is no longer incorporated in the chapter, but these cases and the critical questions appropriate for discussion are available on the website initially established in the eighth edition. We believe that this supplementary use of the cases recreates a learning environment much like the original text published in 1976 and permits us to use additional text space without creating a heavier, less portable text. In this edition, all the chapters have been revised, and several new chapters have been added. The greatest additions are found in the form of both Antidotes in Depth and Special Considerations, which allow us to address major advances in thought in a highly focused fashion. Our goal is to assist in understanding new intellectual approaches with an emphasis on the ever-expanding role of medical and clinical toxicologists at the beginning of the twenty-first century. We have continued to increase the number of nationally and internationally known authors who have expertise in their respective areas by reassigning many of the chapters to these experts. The ninth edition expands on our progress in the eighth edition to use the electronic format. The book has been dramatically improved with the use of full-color graphics and a single art style that will expand and enhance the educational value of the imagery of each chapter and of the image section on the website. The complete “text” now consists of a hard copy component that offers readers the option of holding while consulting, as they have done previously, as well as an electronic workbook component available on our website (goldfrankstoxicology.com). The workbook, which includes both case studies and annotated multiple-choice questions, is now available on this website and is dramatically enhanced. Many of the cases are relevant classic examples of toxicologic emergencies, and the remainder are new, extensively discussed cases from our

regional monthly meetings at the New York City Poison Center. The collective wisdom of many of the current and former text authors continues to guide these sessions as it has for 30 years. Drs. Lewis S. Nelson and Robert S. Hoffman have analyzed these problems, distilled the discussions, and recreated the spirit of these meetings in the printed versions of the cases. Revised annotated multiple-choice questions based on each chapter were developed by the respective chapter authors and edited by Drs. Howard A. Greller and Dean G. Olsen to enhance self-learning and meet the intellectual needs of our readers. Each question has been meticulously meta-tagged by these editors. This allows the learner to sort by a variety of test strategies that are focused on a particular xenobiotic, clinical finding, or therapeutic strategy, to name a few, with the goal of improved individualized learning. The rewriting and reorganization of this edition of the text has again required an enormous personal effort by each author and the editors as it has in the past, which we hope will facilitate reading, learning, and better patient care. Work on the next edition of this text literally begins the day that the current edition is published because this is such a rapidly evolving field. Although “tearing down” and reconstructing the text between each edition is an extreme exercise, it prevents the editors from accepting and promulgating unfounded treatments and outdated concepts. We hope that you agree that this exercise is worthwhile and that each “new text” continues to serve you well. As always, we encourage your thoughtful comments, and we will do our best, as always, to incorporate your suggestions into future editions. If this text helps to provide better patient care and stimulates interest in medical toxicology for students of medicine, nursing, and pharmacy and by residents, fellows, and faculty in diverse specialties, our efforts will have indeed been worthwhile. Lewis S. Nelson Neal A. Lewin Mary Ann Howland Robert S. Hoffman Lewis R. Goldfrank Neal E. Flomenbaum

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ACKNOWLEDGMENTS We are grateful to Joan Demas, who worked with authors across the country and the world to ensure that their ideas were effectively expressed. She has assisted all of us in checking the facts, finding essential references, improving the structure and function of our text while dedicating her efforts to ensuring the precision and rigor of the text. The authors’ and editors’ work is better because of her devotion to excellence, calm demeanor in the face of editorial chaos and consistent presence throughout each stage of the production of this text. The many letters and verbal communications we have received with the reviews of the previous editions of this book continue to improve our efforts. We are deeply indebted to our friends, associates, and students, who stimulated us to begin this book with their questions and then faithfully criticized our answers. We thank the many volunteers, students, librarians, and particularly the St. John’s University College of Pharmacy students and drug information staff who provide us with vital technical assistance in our daily attempts to deal with toxicologic emergencies. No words can adequately express our indebtedness to the many authors who worked on earlier editions of many of the chapters in this book. As different authors write and

rewrite topics with each new edition, we recognize that without the foundation work of their predecessors this book would not be what it is today. We appreciate the creative and rigorous advances in design and scientific art that the Mc-Graw Hill team, led by Armen Ovsepyan, Anne Sydor, and John Williams have added to the text. The devotion to the creation of high quality art graphics and tables is greatly appreciated. Anne Sydor’s commitment to excellence is most easily recognized in the immense progress in the aesthetics and intellectual rigor of our text. We appreciate the calm, thoughtful, and cooperative spirit of Karen Edmonson at McGraw-Hill. Her intelligence and ever vigilant commitment to our efforts has been wonderful. We are pleased with the creative developmental editorial efforts of Christie Naglieri. The organized project management by Gita Raman has found errors hiding throughout our pages. Her carefully posed questions have facilitated the process of correcting the text. It has been a pleasure to have her assistance. We greatly appreciate the compulsion and rigor that Kathrin Unger has applied to make this edition’s index one of unique value. We appreciate the work of Catherine Saggese in ensuring the quality of production in the finished work.

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1

CHAPTER 1

HISTORICAL PRINCIPLES AND PERSPECTIVES Paul M. Wax The term poison first appeared in the English literature around the year 1230 a.d. to describe a potion or draught that was prepared with deadly ingredients.41,140 The history of poisons and poisoning, however, dates back thousands of years. Throughout the millennia, poisons have played an important role in human history—from political assassination in Roman times, to weapons of war, to contemporary environmental concerns, and to weapons of terrorism. This chapter offers a perspective on the impact of poisons and poisoning on history. It also provides a historic overview of human understanding of poisons and the development of toxicology from antiquity to the present. The development of the modern poison control center, the genesis of the field of medical toxicology, and the recent increasing focus on medication errors and biologic and chemical weapons are examined. Chapter 2 describes poison plagues and unintentional disasters throughout history and examines the societal consequences of these unfortunate events. An appreciation of past failures and mistakes in dealing with poisons and poisoning promotes a keener insight and a more critical evaluation of present-day toxicologic issues and helps in the assessment and management of future toxicologic problems.

POISONS, POISONERS, AND ANTIDOTES OF ANTIQUITY The earliest poisons consisted of plant extracts, animal venoms, and minerals. They were used for hunting, waging war, and sanctioned and unsanctioned executions. The Ebers Papyrus, an ancient Egyptian text written about 1500 b.c. that is considered to be among the earliest medical texts, describes many ancient poisons, including aconite, antimony, arsenic, cyanogenic glycosides, hemlock, lead, mandrake, opium, and wormwood.91,140 These poisons were thought to have mystical properties, and their use was surrounded by superstition and intrigue. Some agents, such as the Calabar bean (Physostigma venenosum) containing physostigmine, were referred to as “ordeal poisons.” Ingestion of these substances was believed to be lethal to the guilty and harmless to the innocent.91 The “penalty of the peach” involved the administration of peach pits, which we now know contain the cyanide precursor amygdalin, as an ordeal poison. Magicians, sorcerers, and religious figures were the toxicologists of antiquity. The Sumerians, in about 4500 b.c., were said to worship the deity Gula, who was known as the “mistress of charms and spells” and the “controller of noxious poisons” (Table 1–1).140

■ ARROW AND DART POISONS The prehistoric Masai hunters of Kenya, who lived 18,000 years ago, used arrow and dart poisons to increase the lethality of their weapons.19 One of these poisons appears to have consisted of extracts of Strophanthus species, an indigenous plant that contains strophanthin, a digitalis-like substance.91 Cave paintings of arrowheads and spearheads reveal that these weapons were crafted with small depressions at the end to hold the poison.141 In fact, the term toxicology is derived

from the Greek terms toxikos (“bow”) and toxikon (“poison into which arrowheads are dipped”).2,141 References to arrow poisons are cited in a number of other important literary works. The ancient Indian text Rig Veda, written in the 12th century b.c., refers to the use of Aconitum species for arrow poisons.19 In the Odyssey, Homer (ca. 850 b.c.) wrote that Ulysses anointed his arrows with a variety of poisons, including extracts of Helleborus orientalis (thought to act as a heart poison) and snake venoms.108 Aristotle (384–322 b.c.) described how the Scythians prepared and used arrow poisons.143 Finally, reference to weapons poisoned with the blood of serpents can be found in the writings of Ovid (43 b.c.–18 a.d.).148

■ CLASSIFICATION OF POISONS The first attempts at poison identification and classification and the introduction of the first antidotes took place during Greek and Roman times. An early categorization of poisons divided them into fast poisons, such as strychnine, and slow poisons, such as arsenic. In his treatise, Materia Medica, the Greek physician Dioscorides (40–80 a.d.) categorized poisons by their origin—animal, vegetable, or mineral.141 This categorization remained the standard classification for the next 1500 years.141 Animal Poisons Animal poisons usually referred to the venom from poisonous animals. Although the venom from poisonous snakes has always been among the most commonly feared poisons, poisons from toads, salamanders, jellyfish, stingrays, and sea hares are often as lethal. Nicander of Colophon (204–135 b.c.), a Greek poet and physician who is considered to be one of the earliest toxicologists, experimented with animal poisons on condemned criminals.127 Nicander’s poems Theriaca and Alexipharmaca are considered to be the earliest extant Greek toxicologic texts, describing the presentations and treatment of poisonings from animal toxins.140 A notable fatality from the effects of an animal toxin was Cleopatra (69–30 b.c.), who reportedly committed suicide by deliberately falling on an asp.71 Vegetable Poisons Theophrastus (ca. 370–286 b.c.) described vegetable poisons in his treatise De Historia Plantarum.72 Notorious poisonous plants included Aconitum species (aconite, monks-hood), Conium maculatum (poison hemlock), Hyoscyamus niger (henbane), Mandragora officinarum (mandrake), Papaver somniferum (opium poppy), and Veratrum album (hellebore). Aconite was among the most frequently encountered poisonous plants and was described as the “queen mother of poisons.”140 Hemlock was the official poison used by the Greeks and was used in the execution of Socrates (ca. 470–399 b.c.) and many others.129 Poisonous plants used in India at this time included Cannabis indica (marijuana), Croton tiglium (croton oil), and Strychnos nux vomica (poison nut, strychnine).72 Mineral Poisons The mineral poisons of antiquity consisted of the metals antimony, arsenic, lead, and mercury. Undoubtedly, the most famous of these was lead. Lead was discovered as early as 3500 b.c. Although controversy continues about whether an epidemic of lead poisoning among the Roman aristocracy contributed to the fall of the Roman Empire, lead was certainly used extensively during this period.53,106 In addition to its considerable use in plumbing, lead was also used in the production of food and drink containers.60 It was common practice to add lead directly to wine or to intentionally prepare the wine in a lead kettle to improve its taste. Not surprisingly, chronic lead poisoning became widespread. Nicander described the first case of lead poisoning in the 2nd century b.c.145 Dioscorides, writing in the 1st century a.d., noted that fortified wine was “most hurtful to the nerves.”145 Lead-induced gout (“saturnine gout”) may have also been widespread among the Roman elite.106

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■ POISONERS OF ANTIQUITY TABLE 1–1. Important Early Figures in the History of Toxicology Person

Date

Importance

Gula Shen Nung

ca. 4500 B.C. ca. 2000 B.C.

Homer

ca. 850 B.C.

Aristotle

384–322 B.C.

Theophrastus

ca. 370–286 B.C.

Socrates Nicander

ca. 470–399 B.C. 204–135 B.C.

First deity associated with poisons Chinese emperor who experimented with poisons and antidotes and wrote treatise on herbal medicine Wrote how Ulysses anointed arrows with the venom of serpents Described the preparation and use of arrow poisons Referred to poisonous plants in De Historia Plantarum Executed by poison hemlock Wrote two poems that are among the earliest works on poisons: Theriaca and Alexipharmaca Fanatical fear of poisons; developed mithradatum, one of the first universal antidotes Issued Lex Cornelia, the first antipoisoning law Committed suicide with deliberate cobra envenomation Refined mithradatum; known as the Theriac of Andromachus Wrote Materia Medica, which classified poisons by animal, vegetable, and mineral Prepared “nut theriac” for Roman emperors, a remedy against bites, stings, and poisons; wrote De Antidotis I and II, which provided recipes for different antidotes, including mithradatum and panacea Famed Arab toxicologist; wrote toxicology treatise Book on Poisons, combining contemporary science, magic, and astrology Wrote Treatise on Poisons and Their Antidotes Wrote De Venenis, major work on poisoning

King Mithridates VI ca. 132–63 B.C.

Sulla

81 B.C.

Cleopatra

69–30 B.C.

Andromachus

37–68 A.D.

Dioscorides

40–80 A.D.

Galen

ca. 129–200 A.D.

Ibn Wahshiya

9th century

Moses Maimonides 1135–1204 Petrus Abbonus

1250–1315

Gases Although not animal, vegetable, or mineral in origin, the toxic effects of gases were also appreciated during antiquity. In the 3rd century b.c., Aristotle commented that “coal fumes (carbon monoxide) lead to a heavy head and death”69 and Cicero (106–43 b.c.) referred to the use of coal fumes in suicides and executions.

Given the increasing awareness of the toxic properties of some naturally occurring substances and the lack of analytical detection techniques, homicidal poisoning was common during Roman times. In an attempt to curtail this practice, in 81 b.c. the Roman dictator Sulla issued the first law against poisoning, the Lex Cornelia. According to its provisions, a perpetrator convicted of poisoning, would be sentenced to either loss of property and exile (if the guilty party was of high social rank) or exposure to wild beasts (if of low social rank). During this period, members of the aristocracy commonly used “tasters” to shield themselves from potential poisoners, a practice also in vogue during the reign of Louis XIV in 16th century France.148 One of the most infamous poisoners of ancient Rome was Locusta, who was known to experiment on slaves with poisons that included aconite, arsenic, belladonna, henbane, and poisonous fungi. In 54 a.d., Nero’s mother, Agrippina, hired Locusta to poison Emperor Claudius (Agrippina’s husband and Nero’s stepfather) as part of a scheme to make Nero emperor. As a result of these activities, Claudius, who was a great lover of mushrooms, died from Amanita phalloides poisoning,17 and in the next year, Britannicus (Nero’s stepbrother) also became one of Locusta’s victims. In his case, Locusta managed to fool the taster by preparing unusually hot soup that required additional cooling after the soup had been officially tasted. At the time of cooling, the poison was surreptitiously slipped into the soup. Almost immediately after drinking the soup, Britannicus collapsed and died. The exact poison remains in doubt, although some authorities suggest that it was a cyanogenic glycoside.133

■ EARLY QUESTS FOR THE UNIVERSAL ANTIDOTE The recognition, classification, and use of poisons in ancient Greece and Rome were accompanied by an intensive search for a universal antidote. In fact, many of the physicians of this period devoted significant parts of their careers to this endeavor.140 Mystery and superstition surrounded the origins and sources of these proposed antidotes. One of the earliest specific references to a protective agent can be found in Homer’s Odyssey, when Ulysses is advised to protect himself by taking the antidote “moli.” Recent speculation suggests that moli referred to Galanthus nivalis, which contains a cholinesterase inhibitor. This agent could have been used as an antidote against poisonous plants such as Datura stramonium (jimsonweed) that contain the anticholinergic alkaloids scopolamine, atropine, and hyoscyamine.114 Theriacs and the Mithradatum The Greeks referred to the universal antidote as the alexipharmaca or theriac.140 The term alexipharmaca was derived from the words alexipharmakos (“which keeps off poison”) and antipharmakon (“antidote”). Over the years, alexipharmaca was increasingly used to refer to a method of treatment, such as the induction of emesis by using a feather. Theriac, which originally had referred to poisonous reptiles or wild beasts, was later used to refer to the antidotes. Consumption of the early theriacs (ca. 200 b.c.) was reputed to make people “poison-proof “ against bites of all venomous animals except the asp. Their ingredients included aniseed, anmi, apoponax, fennel, meru, parsley, and wild thyme.140 The quest for the universal antidote was epitomized by the work of King Mithradates VI of Pontus (132–63 b.c.).70 After repeatedly being subjected to poisoning attempts by his enemies during his youth, Mithradates sought protection by the development of universal antidotes. To find the best antidote, he performed acute toxicity experiments on criminals and slaves. The theriac he concocted, known as the “mithradatum,” contained a minimum of 36 ingredients and was thought to be protective against aconite, scorpions, sea slugs, spiders, vipers, and all other poisonous substances.69 Mithradates took his concoction every day.

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Ironically, when an old man, Mithradates attempted suicide by poison but supposedly was unsuccessful because he had become poison-proof. Having failed at self-poisoning, Mithradates was compelled to have a soldier kill him with a sword. Galen described Mithradates’ experiences in a series of three books: De Antidotis I, De Antidotis II, and De Theriaca ad Pisonem.70,146 The Theriac of Andromachus, also known as the “Venice treacle” or “galene,” is probably the most famous theriac. According to Galen, this preparation, formulated during the 1st century a.d., was considered an improvement over the mithradatum.146 It was prepared by Andromachus (37–68 a.d.), physician to Emperor Nero. Andromachus added to the mithradatum ingredients such as the flesh of vipers, squills, and generous amounts of opium.152 Other ingredients were removed. Altogether, 73 ingredients were required. It was advocated to “counteract all poisons and bites of venomous animals,” as well as a host of other medical problems, such as colic, dropsy, and jaundice, and it was used both therapeutically and prophylactically.140,146 As evidence of its efficacy, Galen demonstrated that fowl receiving poison followed by theriac had a higher survival rate than fowl receiving poison alone.140 It is likely, however, that the scientific rigor and methodology used differed from current scientific practice. By the Middle Ages, the Theriac of Andromachus contained more than 100 ingredients. Its synthesis was quite elaborate; the initial phase of production lasted months, followed by an aging process that lasted years, somewhat similar to that of vintage wine.87 The final product was often more solid than liquid in consistency. Other theriac preparations were named after famous physicians (Damocrates, Nicolaus, Amando, Arnauld, and Abano) who contributed additional ingredients to the original formulation. Over the centuries, certain localities were celebrated for their own peculiar brand of theriac. Notable centers of theriac production included Bologna, Cairo, Florence, Genoa, Istanbul, and Venice. At times, theriac production was accompanied by great fanfare. For example, in Bologna, the mixing of the theriac could take place only under the direction of the medical professors at the university.140 Whether these preparations were of actual benefit is uncertain. Some suggest that the theriac may have had an antiseptic effect on the gastrointestinal tract, but others state that the sole benefit of the theriac derived from its formulation with opium.87 Theriacs remained in vogue throughout the Middle Ages and Renaissance, and it was not until 1745 that their efficacy was finally questioned by William Heberden in Antitheriaka: An Essay on Mithradatum and Theriaca.70 Nonetheless, pharmacopeias in France, Spain, and Germany continued to list these agents until the last quarter of the 19th century, and theriac was still available in Italy and Turkey in the early 20th century.18,87 Sacred Earth Beginning in the 5th century b.c., an adsorbent agent called terra sigillata was promoted as a universal antidote. This agent, also known as the “sacred sealed earth,” consisted of red clay that could be found on only one particular hill on the Greek island of Lemnos. Perhaps somewhat akin to the 20th-century “universal antidote,” it was advocated as effective in counteracting all poisons.140 With great ceremony, once per year, the terra sigillata was retrieved from this hill and prepared for subsequent use. According to Dioscorides, this clay was formulated with goat’s blood to make it into a paste. At one time, it was included as part of the Theriac of Andromachus. Demand for terra sigillata continued into the 15th century. Similar antidotal clays were found in Italy, Malta, Silesia, and England.140 Charms Charms, such as toadstones, snakestones, unicorn horns, and bezoar stones, were also promoted as universal antidotes. Toadstones, found in the heads of old toads, were reputed to have the capability to extract poison from the site of a venomous bite or sting. In addition, the toadstone was supposedly able to detect the mere presence of poison

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by producing a sensation of heat upon contact with a poisonous substance.140 Similarly, snakestones extracted from the heads of cobras (known as piedras della cobra de Capelos) were also reported to have magical qualities.14 The 17th-century Italian philosopher Athanasius Kircher (1602–1680) became an enthusiastic supporter of snakestone therapy for the treatment of snakebite after conducting experiments, demonstrating the antidotal attributes of these charms “in front of amazed spectators.” Kircher attributed the efficacy of the snakestone to the theory of “attraction of like substances.” Francesco Redi (1626–1698), a court physician and contemporary of Kircher, debunked this quixotic approach. A harbinger of future experimental toxicologists, Redi was unwilling to accept isolated case reports and field demonstrations as proof of the utility of the snakestone. Using a considerably more rigorous approach, provando et riprovando (by testing and retesting), Redi assessed the antidotal efficacy of snakestone on different animal species and different toxins and failed to confirm any benefit.14 Much lore has surrounded the antidotal effects of the mythical unicorn horn. Ctesias, writing in 390 b.c., was the first to chronicle the wonders of the unicorn horn, claiming that drinking water or wine from the “horn of the unicorn” would protect against poison.140 The horns were usually narwhal tusks or rhinoceros horns, and during the Middle Ages, the unicorn horn may have been worth as much as 10 times the price of gold. Similar to the toadstone, the unicorn horn was used both to detect poisons and to neutralize them. Supposedly, a cup made of unicorn horn would sweat if a poisonous substance was placed in it.85 To give further credence to its use, a 1593 study on arsenic-poisoned dogs reportedly showed that the horn was protective.85 Bezoar stones, also touted as universal antidotes, consisted of stomach or intestinal calculi formed by the deposition of calcium phosphate around a hair, fruit pit, or gallstone. They were removed from wild goats, cows, and apes and administered orally to humans. The Persian name for the bezoar stone was pad zahr (“expeller of poisons”); the ancient Hebrews referred to the bezoar stone as bel Zaard (“every cure for poisons”). Over the years, regional variations of bezoar stones were popularized, including an Asian variety from wild goat of Persia, an Occidental variety from llamas of Peru, and a European variety from chamois of the Swiss mountains.48,140

OPIUM, COCA, CANNABIS, AND HALLUCINOGENS IN ANTIQUITY Although it was not until the mid-19th century that the true perils of opiate addiction were first recognized, juice from the Papaver somniferum was known for its medicinal value in Egypt at least as early as the writing of the Ebers Papyrus in 1500 b.c. Egyptian pharmacologists of that time reportedly recommended opium poppy extract as a pacifier for children who exhibited incessant crying.126 In Ancient Greece, Dioscorides and Galen were early advocates of opium as a therapeutic agent. During this time, it was also used as a means of suicide. Mithradates’ lack of success in his own attempted suicide by poisoning may have been the result of an opium tolerance that had developed from previous repetitive use.126 One of the earliest descriptions of the abuse potential of opium is attributed to Epistratos (304–257 b.c.), who criticized the use of opium for earache because it “dulled the sight and is a narcotic.”126 Cocaine use dates back to at least 300 b.c., when South American Indians reportedly chewed coca leaves during religious ceremonies.100 Chewing coca to increase work efficacy and to elevate mood has remained commonplace in some South American societies for thousands of years. An Egyptian mummy from about 950 b.c. revealed

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significant amounts of cocaine in the stomach and liver, suggesting oral use of cocaine during this time period.104 Large amounts of tetrahydrocannabinol (THC) were also found in the lung and muscle of the same mummy. Another investigation of 11 Egyptian (1079 b.c.–395 a.d.) and 72 Peruvian (200–1500 a.d.) mummies found cocaine, thought to be indigenous only to South America, and hashish, thought to be indigenous only to Asia, in both groups.113 Cannabis use in China dates back even further, to around 2700 b.c., when it was known as the “liberator of sin.”100 In India and Iran, cannabis was used as early as 1000 b.c. as an intoxicant known as bhang.103 Other currently abused agents that were known to the ancients include cannabis, hallucinogenic mushrooms, nutmeg, and peyote. As early as 1300 b.c., Peruvian Indian tribal ceremonies included the use of mescaline-containing San Pedro cacti.100 The hallucinogenic mushroom, Amanita muscaria, known as “fly agaric,” was used as a ritual drug and may have been known in India as “soma” around 2000 b.c.

■ EARLY ATTEMPTS AT GASTROINTESTINAL DECONTAMINATION Nicander’s Alexipharmaca (Antidotes for Poisons) recommended induction of emesis by one of several methods: (a) ingesting warm linseed oil; (b) tickling the hypopharynx with a feather; or (c) “emptying the gullet with a small twisted and curved paper.”87 Nicander also advocated the use of suction to limit envenomation.141 The Romans referred to the feather as the “vomiting feather” or “pinna.” Most commonly, the feather was used after a hearty feast to avoid the gastrointestinal discomfort associated with overeating. At times, the pinna was dipped into a nauseating mixture to increase its efficacy.90

TOXICOLOGY DURING THE MEDIEVAL AND RENAISSANCE PERIODS After Galen (ca. a.d. 129–200), there is relatively little documented attention to the subject of poisons until the works of Ibn Wahshiya in the 9th century. Citing Greek, Persian, and Indian texts, Wahshiya’s work, titled Book of Poisons, combines contemporary science, magic, and astrology during his discussion of poison mechanisms (as they were understood at that time), symptomatology, antidotes (including his own recommendation for a universal antidote), and prophylaxis. He categorized poisons as lethal by sight, smell, touch, and sound, as well as by drinking and eating. For victims of an aconite-containing dart arrow, Ibn Wahshiya recommended excision, followed by cauterization and topical treatment with onion and salt.82 Another significant medieval contribution to toxicology can be found in Moses Maimonides’ (1135–1204) Treatise on Poisons and Their Antidotes (1198). In part one of this treatise, Maimonides discussed the bites of snakes and mad dogs and the stings of bees, wasps, spiders, and scorpions.124 He also discussed the use of cupping glasses for bites (a progenitor of the modern suctioning device) and was one of the first to differentiate the hematotoxic (hot) from the neurotoxic (cold) effects of poison. In part two, he discussed mineral and vegetable poisons and their antidotes. He described belladonna poisoning as causing a “redness and a sort of excitation.”124 He suggested that emesis should be induced by hot water, Anethum graveolens (dill), and oil, followed by fresh milk, butter, and honey. Although he rejected some of the popular treatments of the day, he advocated the use of the great theriac and the mithradatum as first- and second-line agents in the management of snakebite.124 On the subject of oleander poisoning, Petrus Abbonus (1250–1315) wrote that those who drink the juice, spines, or bark of oleander will

develop anxiety, palpitations, and syncope.21 He described the clinical presentation of opium overdose as someone who “will be dull, lazy, and sleepy, without feeling, and he will neither understand nor feel anything, and if he does not receive succor, he will die.” Although this “succor” is not defined, he recommended that treatment of opium intoxication include drinking the strongest wine, rubbing the extremities with alkali and soap, and olfactory stimulation with pepper. To treat snakebite, Abbonus suggested the immediate application of a tourniquet, as well as oral suctioning of the bite wound, preferably performed by a servant. Interestingly, from a 21st-century perspective, Abbonus also suggested that St. John’s wort had the magical power to free anything from poisons and attributed this virtue to the influence of the stars.21

■ THE SCIENTISTS Paracelsus’ (1493–1541) study on the dose–response relationship is usually considered the beginning of the scientific approach to toxicology (Table 1–2). He was the first to emphasize the chemical nature of toxic agents.111 Paracelsus stressed the need for proper observation and experimentation regarding the true response to chemicals. He underscored the need to differentiate between the therapeutic and toxic properties of chemicals when he stated in his Third Defense, “What is there that is not poison? All things are poison and nothing [is] without poison. Solely, the dose determines that a thing is not a poison.”40 Although Paracelsus is the best known Renaissance toxicologist, Ambroise Pare (1510–1590) and William Piso (1611–1678) also contributed to the field. Pare argued against the use of the unicorn horn and bezoar stone.89 He also wrote an early treatise on carbon monoxide poisoning. Piso is credited as one of the first to recognize the emetic properties of ipecacuanha.121

■ MEDIEVAL AND RENAISSANCE POISONERS Along with these advances in toxicologic knowledge, the Renaissance is mainly remembered as the age of the poisoner, a time when the art of poisoning reached new heights (Table 1–3). In fact, poisoning was so rampant during this time that in 1531, King Henry VIII decreed that convicted poisoners should be boiled alive.50 From the 15th to 17th centuries, schools of poisoning existed in Venice and Rome. In Venice, poisoning services were provided by a group called the Council of Ten, whose members were hired to perform murder by poison.148 Members of the infamous Borgia family were considered to be responsible for many poisonings during this period. They preferred to use a poison called “La Cantarella,” a mixture of arsenic and phosphorus.143 Rodrigo Borgia (1431–1503), who became Pope Alexander VI, and his son, Cesare Borgia, were reportedly responsible for the poisoning of cardinals and kings. In the late 16th century, Catherine de Medici, wife of Henry II of France, introduced Italian poisoning techniques to France. She experimented on the poor, the sick, and the criminal. By analyzing the subsequent complaints of her victims, she is said to have learned the site of action and time of onset, the clinical signs and symptoms, and the efficacy of poisons.54 Murder by poison remained quite popular during the latter half of the 17th and the early part of the 18th centuries in Italy and France. The Marchioness de Brinvilliers (1630–1676) tested her poison concoctions on hospitalized patients and on her servants and allegedly murdered her husband, father, and two siblings.52,133 Among the favorite poisons of the Marchioness were arsenic, copper sulfate, corrosive sublimate (mercury bichloride), lead, and tartar emetic (antimony potassium tartrate).143 Catherine Deshayes (1640–1680), a fortuneteller and sorceress, was one of the last “poisoners for hire” and

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TABLE 1–2. Important Figures in Toxicology from Paracelsus to the 1900s Person

Date

Importance

Paracelsus Ambroise Pare William Piso Bernardino Ramazzini Richard Mead Percivall Pott Felice Fontana Philip Physick Baron Guillaume Dupuytren Francois Magendie Bonaventure Orfila James Marsh Robert Christison Grand Marshall Bertrand Claude Bernard Edward Jukes Theodore Wormley Pierre Touery Hugo Reinsch Alfred Garrod Max Gutzeit Benjamin Howard Rand O.H. Costill Louis Lewin

1493–1541 1510–1590 1611–1678 1633–1714 1673–1754 1714–1788 1730–1805 1767–1837 1777–1835 1783–1855 1787–1853 1794–1846 1797–1882 1813 1813–1878 1820 1826–1897 1831 1842–1884 1846 1847–1915 1848 1848 1850–1929

Rudolf Kobert Albert Niemann Alice Hamilton

1854–1918 1860 1869–1970

Introduced the dose–response concept to toxicology Spoke out against unicorn horns and bezoars as antidotes First to study emetic qualities of ipecacuanha Father of occupational medicine; wrote De Morbis Artificum Diatriba Wrote English-language book about poisoning Wrote the first description of occupational cancer, relating the chimney sweep occupation to scrotal cancer First scientific study of venomous snakes Early advocate of orogastric lavage to remove poisons Early advocate of orogastric lavage to remove poisons Discovered emetine and studied the mechanisms of cyanide and strychnine Father of modern toxicology; wrote Traite des Poisons; first to isolate arsenic from humans organs Developed reduction test for arsenic Wrote Treatise on Poisons, one of the most influential texts of the early 19th century Demonstrated the efficacy of charcoal in arsenic ingestion Studied the mechanisms of toxicity of carbon monoxide and curare Self-experimented with orogastric lavage apparatus known as Jukes’ syringe Wrote Micro-Chemistry of Poisons, the first American book devoted exclusively to toxicology Demonstrated the efficacy of charcoal in strychnine ingestion Developed qualitative tests for arsenic and mercury Conducted the first systematic study of charcoal in an animal model Developed method to quantitate small amounts of arsenic Conducted the first study of the efficacy of charcoal in humans Wrote the first book on symptoms and treatment of poisoning Studied many toxins, including methanol, chloroform, snake venom, carbon monoxide, lead, opioids, and hallucinogenic plants Studied digitalis and ergot alkaloids Isolated cocaine alkaloid Conducted landmark investigations associating worksite chemical hazards with disease; led reform movement to improve worker safety

was implicated in countless poisonings, including the killing of more than 2000 infants.54 Better known as “La Voisine,” she reportedly sold poisons to women wishing to rid themselves of their husbands. Her particular brand of poison was a concoction of aconite, arsenic, belladonna, and opium known as “la poudre de succession.”143 Ultimately, de Brinvilliers was beheaded, and Deshayes was burned alive for their crimes. In an attempt to curtail these rampant poisonings, Louis XIV issued a decree in 1662 banning the sale of arsenic, mercury, and other poisons to customers not known to apothecaries and requiring poison buyers to sign a register declaring the purpose for their purchase.133 A major center for poison practitioners was Naples, the home of the notorious Madame Giulia Toffana. She reportedly poisoned more than 600 people, preferring a particular solution of white arsenic (arsenic trioxide), better known as “aqua toffana,” and dispensed under the guise of a cosmetic. Eventually convicted of poisoning, Madame Toffana was executed in 1719.20

EIGHTEENTH- AND NINETEENTH-CENTURY DEVELOPMENTS IN TOXICOLOGY The development of toxicology as a distinct specialty began during the 18th and 19th centuries (see Table 1–2).112 The mythological and magical mystique of poisoners began to be gradually replaced by an increasingly rational, scientific, and experimental approach to these agents. Much of the poison lore that had survived for almost 2000 years was finally debunked and discarded. The 18th-century Italian Felice Fontana was one of the first to usher in the modern age. He was an early experimental toxicologist who studied the venom of the European viper and wrote the classic text Traite sur le Venin de la Vipere in 1781.75 Through his exacting experimental study on the effects of venom, Fontana brought a scientific insight to toxicology previously lacking and demonstrated that clinical symptoms resulted

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TABLE 1–3. Notable Poisoners from Antiquity to the Present Poisoner

Date

Victim(s)

Poison(s)

Locusta Cesare Borgia Catherine de Medici Hieronyma Spara Marchioness de Brinvilliers Catherine Deshayes

54–55 A.D. 1400s 1519–1589 Died 1659 Died 1676 Died 1680

Claudius and Britannicus Cardinals and kings Poor, sick, criminals Taught women how to poison their husbands Hospitalized patients, husband, father >2000 infants, many husbands

Madame Giulia Toffana Mary Blandy Anna Maria Zwanizer Marie Lefarge John Tawell William Palmer, MD Madeline Smith (acquitted) Edmond de la Pommerais, MD Edward William Pritchard, MD George Henry Lamson, MD Adelaide Bartlett (acquitted) Florence Maybrick Thomas Neville Cream, MD Johann Hoch Cordelia Botkin Roland Molineux Hawley Harvey Crippen, MD Frederick Henry Seddon Henri Girard Landru Robert Armstrong Landru Suzanne Fazekas Sadamichi Hirasawa Christa Ambros Lehmann Nannie Doss Carl Coppolino, MD Graham Frederick Young Judias V. Buenoano Ronald Clark O’Bryan Unknown Jim Jones Harold Shipman, MD Unidentified Donald Harvey George Trepal Michael Swango, MD Charles Cullen, RN Unknown

Died 1719 1752 1807 1839 1845 1855 1857 1863 1865 1881 1886 1889 1891 1892–1905 1898 1898 1910 1911 1912 1921 1922 1929 1948 1954 1954 1965 1971 1971 1974 1978 1978 1974–1998 1982 1983–1987 1988 1980s–1990s 1990s–2003 2004

Unknown

2006

>600 people Father Random people Husband Mistress Fellow gambler Lover Patient and mistress Wife and mother-in-law Brother-in-law Husband Husband Prostitutes Serial wives Feminine rival Acquaintance Wife Boarder Acquaintances Wife Many women Supplied poison to 100 wives to kill husbands Bank employees Friend, husband, father-in-law 11 relatives, including five husbands Wife Stepmother, coworkers Husband, son Son and neighborhood children Georgi Markov, Bulgarian dissident >900 people in mass suicide Patients (100s) Seven people Patients Neighbors Hospitalized patients Hospitalized patients Viktor Yushchenko, Ukrainian presidential candidate Alexander Litvinenko

Amanita phalloides, cyanide La Cantarella (arsenic and phosphorus) Unknown agents Mana of St. Nicholas of Bari (arsenic trioxide) Antimony, arsenic, copper, lead, mercury La poudre de succession (arsenic mixed with aconite, belladonna, and opium) Aqua toffana (arsenic trioxide) Arsenic Antimony, arsenic Arsenic (first use of Marsh test) Cyanide Strychnine Arsenic Digitalis Antimony Aconite Chloroform Arsenic Strychnine Arsenic Arsenic (in chocolate candy) Cyanide of mercury Hyoscine Arsenic (fly paper) Amanita phalloides Arsenic (weed killer) Cyanide Arsenic Potassium cyanide E-605 (parathion) Arsenic Succinylcholine Antimony, thallium Arsenic Cyanide (in Halloween candy) Ricin Cyanide Heroin Extra Strength Tylenol mixed with cyanide Arsenic Thallium Arsenic, potassium chloride, succinylcholine Digoxin Dioxin Polonium-210

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from the poison (venom) acting on specific target organs. During the 18th and 19th centuries, attention focused on the detection of poisons and the study of toxic effects of drugs and chemicals in animals.105 Issues relating to adverse effects of industrialization and unintentional poisoning in the workplace and home environment were raised. Also during this time, early experience and experimentation with methods of gastrointestinal decontamination took place.

■ DEVELOPMENT OF ANALYTICAL TOXICOLOGY AND THE STUDY OF POISONS The French physician Bonaventure Orfila (1787–1853) is often called the father of modern toxicology.105 He emphasized toxicology as a distinct, scientific discipline, separate from clinical medicine and pharmacology.11 He was also an early medical-legal expert who championed the use of chemical analysis and autopsy material as evidence to prove that a poisoning had occurred. His treatise Traite des Poisons (1814)110 evolved over five editions and was regarded as the foundation of experimental and forensic toxicology.149 This text classified poisons into six groups: acrids, astringents, corrosives, narcoticoacrids, septics and putrefiants, and stupefacients and narcotics. A number of other landmark works on poisoning also appeared during this period. In 1829, Robert Christison (1797–1882), a professor of medical jurisprudence and Orfila’s student, wrote A Treatise on Poisons.29 This work simplified Orfila’s poison classification schema by categorizing poisons into three groups: irritants, narcotics, and narcoticoacrids. Less concerned with jurisprudence than with clinical toxicology, O.H. Costill’s A Practical Treatise on Poisons, published in 1848, was the first modern clinically oriented text to emphasize the symptoms and treatment of poisoning.33 In 1867, Theodore Wormley (1826–1897) published the first American book written exclusively on poisons titled the Micro-Chemistry of Poisons.46,151 During this time, important breakthroughs in the chemical analysis of poisons resulted from the search for a more reliable assay for arsenic. Arsenic was widely available and was the suspected cause of a large number of deaths. In one study, arsenic was used in 31% of 679 homicidal poisonings.143 A reliable means of detecting arsenic was much needed by the courts. Until the 19th century, poisoning was mainly diagnosed by its resultant symptoms rather than by analytic tests. The first use of a chemical test as evidence in a poisoning trial occurred in the 1752 trial of Mary Blandy, who was accused of poisoning her father with arsenic.93 Although Blandy was convicted and hanged publicly, the test used in this case was not very sensitive and depended in part on eliciting a garlic odor upon heating the gruel that the accused had fed to her father. During the 19th century, James Marsh (1794–1846), Hugo Reinsch, and Max Gutzeit (1847–1915) each worked on this problem. Assays bearing their names are important contributions to the early history of analytic toxicology.94,105 The “Marsh test” to detect arsenic was first used in a criminal case in 1839 during the trial of Marie Lefarge, who was accused of using arsenic to murder her husband.133 Orfila’s trial testimony that the victim’s viscera contained minute amounts of arsenic helped to convict the defendant, although subsequent debate suggested that contamination of the forensic specimen may have also played a role. In a further attempt to curtail criminal poisoning by arsenic, the British Parliament passed the Arsenic Act in 1851. This bill, which was one of the first modern laws to regulate the sale of poisons, required that the retail sale of arsenic be restricted to chemists, druggists, and apothecaries and that a poison book be maintained to record all arsenic sales.15

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Homicidal poisonings remained common during the 19th century and early 20th century. Infamous poisoners of that time included William Palmer, Edward Pritchard, Harvey Crippen, and Frederick Seddon.143 Many of these poisoners were physicians who used their knowledge of medicine and toxicology in an attempt to solve their domestic and financial difficulties by committing the “perfect” murder. Some of the poisons used were aconitine (by Lamson, who was a classmate of Christison), Amanita phalloides (Girard), arsenic (by Maybrick, Seddon, and others), antimony (by Pritchard), cyanide (by Molineux and Tawell), digitalis (by Pommerais), hyoscine (by Crippen), and strychnine (by Palmer and Cream) (see Table 1–3).23,140,143 In the early 20th century, forensic investigation into suspicious deaths, including poisonings, was significantly advanced with the development of the medical examiner system replacing the much-flawed coroner system that was subject to widespread corruption. In 1918, the first centrally controlled medical examiner system was established in New York City. Alexander Gettler, considered the father of forensic toxicology in the United States, established a toxicology laboratory within the newly created New York City Medical Examiner’s Office. Gettler pioneered new techniques for the detection of a variety of substances in biologic fluids, including carbon monoxide, chloroform, cyanide, and heavy metals.47,105 Systematic investigation into the underlying mechanisms of toxic substances also commenced during the 19th century. To cite just a few important accomplishments, Francois Magendie (1783–1855) studied the mechanisms of toxicity and sites of action of cyanide, emetine, and strychnine.45 Claude Bernard (1813–1878), a pioneering physiologist and a student of Magendie, made important contributions to the understanding the toxicity of carbon monoxide and curare.81 Rudolf Kobert (1854–1918) studied digitalis and ergot alkaloids and authored a textbook on toxicology for physicians and students.79,108 Louis Lewin (1850–1929) was the first person to intensively study the differences between the pharmacologic and toxicologic actions of drugs. Lewin studied chronic opium intoxication, as well as the toxicity of carbon monoxide, chloroform, lead, methanol, and snake venom. He also developed a classification system for psychoactive drugs, dividing them into euphorics, phantastics, inebriants, hypnotics, and excitants.88

■ THE ORIGIN OF OCCUPATIONAL TOXICOLOGY The origins of occupational toxicology can be traced to the early 18th century and to the contributions of Bernardino Ramazzini (1633–1714). Considered the father of occupational medicine, Ramazzini wrote De Morbis Artificum Diatriba (Diseases of Workers) in 1700, which was the first comprehensive text discussing the relationship between disease and workplace hazards.51 Ramazzini’s essential contribution to the care of the patient is epitomized by the addition of a standard question to a patient’s medical history: “What occupation does the patient follow?”49 Altogether Ramazzini described diseases associated with 54 occupations, including hydrocarbon poisoning in painters, mercury poisoning in mirror makers, and pulmonary diseases in miners. In 1775, Sir Percivall Pott proposed the first association between workplace exposure and cancer when he noticed a high incidence of scrotal cancer in English chimney sweeps. Pott’s belief that the scrotal cancer was caused by prolonged exposure to tar and soot was confirmed by further investigation in the 1920s, indicating the carcinogenic nature of the polycyclic aromatic hydrocarbons contained in coal tar (including benzo[a]pyrene).67 Dr. Alice Hamilton (1869–1970) was another pioneer in occupational toxicology, whose rigorous scientific inquiry had a profound impact on linking chemical toxins with human disease. A physician, scientist, humanitarian, and social reformer, Hamilton became the first

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female professor at Harvard University and conducted groundbreaking studies of many different occupational exposures and problems, including carbon monoxide poisoning in steelworkers, mercury poisoning in hatters, and wrist drop in lead workers. Hamilton’s overriding concerns about these “dangerous trades” and her commitment to improving the health of workers led to extensive voluntary and regulatory reforms in the workplace.8,58

But, it was not until the early 20th century that an activation process was added to the manufacture of charcoal to increase its effectiveness. In 1900, the Russian Ostrejko demonstrated that treating charcoal with superheated steam significantly enhanced its adsorbing power.32 Despite this improvement and the favorable reports mentioned, charcoal was only occasionally used in gastrointestinal decontamination until the early 1960s, when Holt and Holz repopularized its use.61

■ ADVANCES IN GASTROINTESTINAL DECONTAMINATION

■ THE INCREASING RECOGNITION OF THE PERILS OF DRUG ABUSE

Using gastric lavage and charcoal to treat poisoned patients was introduced in the late 18th and early 19th century. A stomach pump was first designed by Munro Secundus in 1769 to administer neutralizing substances to sheep and cattle for the treatment of bloat.24 The American surgeon Philip Physick (1768–1837) and the French surgeon Baron Guillaume Dupuytren (1777–1835) were two of the first physicians to advocate gastric lavage for the removal of poisons.24 As early as 1805, Physick demonstrated the use of a “stomach tube” for this purpose. Using brandy and water as the irrigation fluid, he performed stomach washings in twins to wash out excessive doses of tincture of opium.24 Dupuytren performed gastric emptying by first introducing warm water into the stomach via a large syringe attached to a long flexible sound and then withdrawing the “same water charged with poison.”24 Edward Jukes, a British surgeon, was another early advocate of poison removal by gastric lavage. Jukes first experimented on animals, performing gastric lavage after the oral administration of tincture of opium. Attempting to gain human experience, he experimented on himself, by first ingesting 10 drams (600 g) of tincture of opium and then performing gastric lavage using a 25-inch-long, 0.5-inch-diameter tube, which became known as Jukes’ syringe.99 Other than some nausea and a 3-hour sleep, he suffered no ill effects, and the experiment was deemed a success. The principle of using charcoal to adsorb poisons was first described by Scheele (1773) and Lowitz (1785), but the medicinal use of charcoal dates to ancient times.32 The earliest reference to the medicinal uses of charcoal is found in Egyptian papyrus from about 1500 b.c.32 The charcoal used during Greek and Roman times, referred to as “wood charcoal,” was used to treat those with anthrax, chlorosis, epilepsy, and vertigo. By the late 18th century, topical application of charcoal was recommended for gangrenous skin ulcers, and internal use of a charcoal-water suspension was recommended for use as a mouthwash and in the treatment of bilious conditions.32 The first hint that charcoal might have a role in the treatment of poisoning came from a series of courageous self-experiments in France during the early 19th century. In 1813, the French chemist Bertrand publicly demonstrated the antidotal properties of charcoal by surviving a 5-g ingestion of arsenic trioxide that had been mixed with charcoal.64 Eighteen years later, before the French Academy of Medicine, the pharmacist Touery survived an ingestion consisting of 10 times the lethal dose of strychnine mixed with 15 g of charcoal.64 One of the first reports of charcoal used in a poisoned patient was in 1834 by the American Hort, who successfully treated a mercury bichloride– poisoned patient with large amounts of powdered charcoal.4 In the 1840s, Garrod performed the first controlled study of charcoal when he examined its utility on a variety of poisons in animal models.64 Garrod used dogs, cats, guinea pigs, and rabbits to demonstrate the potential benefits of charcoal in the management of strychnine poisoning. He also emphasized the importance of early use of charcoal and the proper ratio of charcoal to poison. Other toxic substances, such as aconite, hemlock, mercury bichloride, and morphine were also studied during this period. The first charcoal efficacy studies in humans were performed by the American physician B. Rand in 1848.64

Opioids Although the medical use of opium was promoted by Paracelsus in the 16th century, the popularity of this agent was given a significant boost when the distinguished British physician Thomas Sydenham (1624–1689) formulated laudanum, which was a tincture of opium containing cinnamon, cloves, saffron, and sherry. Sydenham also formulated a different opium concoction known as “syrup of poppies.”78 A third opium preparation called Dover’s powder was designed by Sydenham’s protégé, Thomas Dover; this preparation contained ipecac, licorice, opium, salt-peter, and tartaric acid. John Jones, the author of the 18th century text The Mysteries of Opium Reveal’d, was another enthusiastic advocate of its “medicinal” uses.78 A well-known opium user himself, Jones provided one of the earliest descriptions of opiate addiction. He insisted that opium offered many benefits if the dose was moderate but that discontinuation or a decrease in dose, particularly after “leaving off after long and lavish use,” would result in such symptoms as sweating, itching, diarrhea, and melancholy. His recommendation for the treatment of these withdrawal symptoms included decreasing the dose of opium by 1% each day until the drug was totally withdrawn. During this period, the number of English writers who became well-known opium addicts, included Elizabeth Barrett Browning, Samuel Taylor Coleridge, and Thomas De Quincey. De Quincey, author of Confessions of an English Opium Eater, was an early advocate of the recreational use of opiates. The famed Coleridge poem Kubla Khan referred to opium as the “milk of paradise,” and De Quincey’s Confessions suggested that opium held the “key to paradise.” In many of these cases, the initiation of opium use for medical reasons led to recreational use, tolerance, and dependence.78 Although opium was first introduced to Asian societies by Arab physicians some time after the fall of the Roman Empire, the use of opium in Asian countries grew considerably during the 18th and 19th centuries. In one of the more deplorable chapters in world history, China’s growing dependence on opium was spurred on by the English desire to establish and profit from a flourishing drug trade.126 Opium was grown in India and exported east. Despite Chinese protests and edicts against this practice, the importation of opium persisted throughout the 19th century, with the British going to war twice in order to maintain their right to sell opium. Not surprisingly, by the beginning of the 20th century, opium abuse in China was endemic. In England, opium use continued to increase during the first half of the 19th century. During this period, opium was legal and freely available from the neighborhood grocer. To many, its use was considered no more problematic than alcohol use.56 The Chinese usually self-administered opium by smoking, a custom that was brought to the United States by Chinese immigrants in the mid-19th century; the English use of opium was more often by ingestion, that is, “opium eating.” The liberal use of opiates as infant-soothing agents was one of the most unfortunate aspects of this period of unregulated opiate use.79 Godfrey’s Cordial, Mother’s Friend, Mrs. Winslow’s Soothing Syrup, and Quietness were among the most popular opiates for children.83 They were advertised as producing a natural sleep and recommended for teething and bowel regulation, as well as for crying. Because of the

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wide availability of opiates during this period, the number of acute opiate overdoses in children was consequential and would remain problematic until these unsavory remedies were condemned and removed from the market. With the discovery of morphine in 1805 and Alexander Wood’s invention of the hypodermic syringe in 1853, parenteral administration of morphine became the preferred route of opiate administration for therapeutic use and abuse.66 A legacy of the generous use of opium and morphine during the United States Civil War was “soldiers’ disease,” referring to a rather large veteran population that returned from the war with a lingering opiate habit.118 One hundred years later, opiate abuse and addiction would again become common among US military serving during the Vietnam War. Surveys indicated that as many as 20% of American soldiers in Vietnam were addicted to opiates during the war—in part because of its widespread availability and high purity there.123 Growing concerns about opiate abuse in England led to the passing of the Pharmacy Act of 1868, which restricted the sale of opium to registered chemists. But in 1898, the Bayer Pharmaceutical Company of Germany synthesized heroin from opium (Bayer also introduced aspirin that same year).134 Although initially touted as a nonaddictive morphine substitute, problems with heroin use quickly became evident in the United States. Cocaine Ironically, during the later part of the 19th century, Sigmund Freud and Robert Christison, among others, promoted cocaine as a treatment for opiate addiction. After Albert Niemann’s isolation of cocaine alkaloid from coca leaf in 1860, growing enthusiasm for cocaine as a panacea ensued.74 Some of the most important medical figures of the time, including William Halsted, the famed Johns Hopkins surgeon, also extolled the virtues of cocaine use. Halsted championed the anesthetic properties of this drug, although his own use of cocaine and subsequent morphine use in an attempt to overcome his cocaine dependency would later take a considerable toll.109 In 1884, Freud wrote Uber Cocaine,142 advocating cocaine as a cure for opium and morphine addiction and as a treatment for fatigue and hysteria. During the last third of the 19th century, cocaine was added to many popular over-the-counter tonics. In 1863, Angelo Mariani, a Frenchman, introduced a new wine, “Vin Mariani,” that consisted of a mixture of cocaine and wine (6 mg of cocaine alkaloid per ounce) and was sold as a digestive aid and restorative.100 In direct competition with the French tonic was the American-made Coca-Cola, developed by J.S. Pemberton. It was originally formulated with coca and caffeine and marketed as a headache remedy and invigorator. With the public demand for cocaine increasing, patent medication manufacturers were adding cocaine to thousands of products. One such asthma remedy was “Dr. Tucker’s Asthma Specific,” which contained 420 mg of cocaine per ounce and was applied directly to the nasal mucosa.74 By the end of the 19th century, the first American cocaine epidemic was underway.102 Similar to the medical and societal adversities associated with opiate use, the increasing use of cocaine led to a growing concern about comparable adverse effects. In 1886, the first reports of cocaine-related cardiac arrest and stroke were published.119 Reports of cocaine habituation occurring in patients using cocaine to treat their underlying opiate addiction also began to appear. In 1902, a popular book, Eight Years in Cocaine Hell, described some of these problems. Century Magazine called cocaine “the most harmful of all habit-forming drugs,” and a report in The New York Times stated that cocaine was destroying “its victims more swiftly and surely than opium.”39 In 1910, President William Taft proclaimed cocaine to be “public enemy number 1.” In an attempt to curb the increasing problems associated with drug abuse and addiction, the 1914 Harrison Narcotics Act mandated stringent control over the sale and distribution of narcotics (defined as

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opium, opium derivatives, and cocaine).39 It was the first federal law in the United States to criminalize the nonmedical use of drugs. The bill required doctors, pharmacists, and others who prescribed narcotics to register and to pay a tax. A similar law, the Dangerous Drugs Act, was passed in the United Kingdom in 1920.56 To help enforce these drug laws in the United States, the Narcotics Division of the Prohibition Unit of the Internal Revenue Service (a progenitor of the Drug Enforcement Agency) was established in 1920. In 1924, the Harrison Act was further strengthened with the passage of new legislation that banned the importation of opium for the purpose of manufacturing heroin, essentially outlawing the medicinal uses of heroin. With the legal venues to purchase these drugs now eliminated, users were forced to buy from illegal street dealers, creating a burgeoning black market that still exists today. Sedative-Hypnotics The introduction to medical practice of the anesthetic agents nitrous oxide, ether, and chloroform during the 19th century was accompanied by the recreational use of these agents and the first reports of volatile substance abuse. Chloroform “jags,” ether “frolics,” and nitrous parties became a new type of entertainment. Humphrey Davies was an early self-experimenter with the exhilarating effects associated with nitrous oxide inhalation. In certain Irish towns, especially where the temperance movement was strong, ether drinking became quite popular.97 Horace Wells, the American dentist who introduced chloroform as an anesthetic, became dependent on this volatile solvent and later committed suicide. Until the last half of the 19th century aconite, alcohol, hemlock, opium, and prussic acid (cyanide) were the primary agents used for sedation.30 During the 1860s, new, more specific sedative-hypnotics, such as chloral hydrate and potassium bromide, were introduced into medical practice. In particular, chloral hydrate was hailed as a wonder drug that was relatively safe compared with opium, and was recommended for insomnia, anxiety, and delirium tremens, as well as for scarlet fever, asthma, and cancer. But within a few years, problems with acute toxicity of chloral hydrate, as well as its potential to produce tolerance and physical dependence, became apparent.30 Mixing chloral hydrate with ethanol was noted to produce a rather powerful “knockout” combination that would become known as a “Mickey Finn.” Abuse of chloral hydrate, as well as other new sedatives such as potassium bromide, would prove to be a harbinger of 20th-century sedative-hypnotic abuse. Hallucinogens American Indians used peyote in religious ceremonies since at least the 17th century. Hallucinogenic mushrooms, particularly Psilocybe mushrooms, were also used in the religious life of Native Americans. These were called “teonanacatl,” which means “God’s sacred mushrooms” or “God’s flesh.”115 Interest in the recreational use of cannabis also accelerated during the 19th century after Napoleon’s troops brought the drug back from Egypt, where its use among the lower classes was widespread. In 1843, several French Romantics, including Balzac, Baudelaire, Gautier, and Hugo, formed a hashish club called “Le Club des Hachichins” in the Parisian apartment of a young French painter. Fitz Hugh Ludlow’s The Hasheesh Eater, published in 1857, was an early American text espousing the virtues of marijuana.86 Absinthe, an ethanol-containing beverage that was manufactured with an extract from wormwood (Artemisia absinthium), was very popular during the last half of the 19th century.80 This emeraldcolored, very bitter drink was memorialized in the paintings of Degas, Toulouse-Lautrec, and Van Gogh and was a staple of French society during this period.12 α-Thujone, a psychoactive component of wormwood and a noncompetitive γ-aminobutyric acid type A GABAA blocker, is thought to be responsible for the pleasant feelings, as well as for the hallucinogenic effects, hyperexcitability, and significant neurotoxicity associated with this drink.63 Van Gogh’s debilitating episodes

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of psychosis were likely exacerbated by absinthe drinking.137 Because of the medical problems associated with its use, absinthe was banned throughout most of Europe by the early 20th century. A more recent event that had significant impact on modern-day hallucinogen use was the synthesis of lysergic acid diethylamide (LSD) by Albert Hofmann in 1938.62 Working for Sandoz Pharmaceutical Company, Hofmann synthesized LSD while investigating the pharmacologic properties of ergot alkaloids. Subsequent self-experimentation by Hofmann led to the first description of its hallucinogenic effects and stimulated research into the use of LSD as a therapeutic agent. Hofmann is also credited with isolating psilocybin as the active ingredient in Psilocybe mexicana mushrooms in 1958.100

TWENTIETH-CENTURY EVENTS ■ EARLY REGULATORY INITIATIVES The development of medical toxicology as a medical subspecialty and the important role of poison control centers began shortly after World War II. Before then, serious attention to the problem of household poisonings in the United States had been limited to a few federal legislative antipoisoning initiatives (Table 1–4). The 1906 Pure Food and Drug Act was the first federal legislation that sought to protect the public from problematic and potentially unsafe drugs and food. The driving force behind this reform was Harvey Wiley, the chief chemist at the Department of Agriculture. Beginning in the 1880s, Wiley investigated the problems of contaminated food. In 1902, he organized the “poison squad,” which consisted of a group of volunteers who did selfexperiments with food preservatives.5 Revelations from the “poison squad,” as well as the publication of Upton Sinclair’s muckraking novel The Jungle132 in 1906, exposed unhygienic practices of the meatpacking industry and led to growing support for legislative intervention. Samuel Hopkins Adams’ reports about the patent medicine industry revealed that some drug manufacturers added opiates to soothing syrups for infants and led to the call for reform.120 Although the 1906 regulations were mostly concerned with protecting the public from adulterated food, regulations protecting against misbranded patent medications were also included. The Federal Caustic Poison Act of 1927 was the first federal legislation to specifically address household poisoning. As early as 1859, bottles clearly demarcated “poison” were manufactured in response to a rash of unfortunate dispensing errors that occurred when oxalic acid was unintentionally substituted for a similarly appearing Epsom salts solution.26 Before 1927, however, “poison” warning labels were not required on chemical containers, regardless of toxicity or availability. The 1927 Caustic Act was spearheaded by the efforts of Chevalier Jackson, an otolaryngologist, who showed that unintentional exposures to household caustic agents were an increasingly frequent cause of severe oropharyngeal and gastrointestinal burns. Under this statute, for the first time, alkali- and acid-containing products had to clearly display a “poison” warning label.139 The most pivotal regulatory initiative in the United States before World War II—and perhaps the most significant American toxicologic regulation of the 20th century—was the Federal Food, Drug, and Cosmetic Act of 1938. Although the Food and Drug Administration (FDA) had been established in 1930 and legislation to strengthen the 1906 Pure Food and Drug Act was considered by Congress in 1933, the proposed revisions still had not been passed by 1938. Then the elixir of sulfanilamide tragedy in 1938 (see Chap. 2) claimed the lives of 105 people who had ingested a prescribed liquid preparation of the antibiotic sulfanilamide inappropriately dissolved in diethylene glycol. This event finally provided the catalyst for legislative intervention.98,147

Before the elixir disaster, proposed legislation called only for the banning of false and misleading drug labeling and for the outlawing of dangerous drugs without mandatory drug safety testing. After the tragedy, the proposal was strengthened to require assessment of drug safety before marketing, and the legislation was ultimately passed.

■ THE DEVELOPMENT OF POISON CONTROL CENTERS World War II led to the rapid proliferation of new drugs and chemicals in the marketplace and in the household.36 At the same time, suicide was recognized as a leading cause of death from these agents.9 Both of these factors led the medical community to develop a response to the serious problems of unintentional and intentional poisonings. In Europe during the late 1940s, special toxicology wards were organized in Copenhagen and Budapest,57 and a poison information service was begun in the Netherlands (Table 1–5).144 A 1952 American Academy of Pediatrics study revealed that more than 50% of childhood “accidents” in the United States were the result of unintentional poisonings.60 This study led Edward Press to open the first US poison control center in Chicago in 1953.116 Press believed that it had become extremely difficult for individual physicians to keep abreast of product information, toxicity, and treatment for the rapidly increasing number of potentially poisonous household products. His initial center was organized as a cooperative effort among the departments of pediatrics at several Chicago medical schools, with the goal of collecting and disseminating product information to inquiring physicians, mainly pediatricians.117 By 1957, 17 poison control centers were operating in the United States.36 With the Chicago center serving as a model, these early centers responded to physician callers by providing ingredient and toxicity information about drug and household products and making treatment recommendations. Records were kept of the calls, and preventive strategies were introduced into the community. As more poison control centers opened, a second important function, providing information to calls from the general public, became increasingly common. The physician pioneers in poison prevention and poison treatment were predominantly pediatricians who focused on unintentional childhood ingestions.122 During these early years in the development of poison control centers, each center had to collect its own product information, which was a laborious and often redundant task.35 In an effort to coordinate poison control center operations and to avoid unnecessary duplication, Surgeon General James Goddard responded to the recommendation of the American Public Health Service and established the National Clearinghouse for Poison Control Centers in 1957.96 This organization, placed under the Bureau of Product Safety of the Food and Drug Administration, disseminated 5-inch by 8-inch index cards containing poison information to each center to help standardize poison center information resources. The Clearinghouse also collected and tabulated poison data from each of the centers. Between 1953 and 1972, a rapid, uncoordinated proliferation of poison control centers occurred in the United States.92 In 1962, there were 462 poison control centers.1 By 1970, this number had risen to 590,84 and by 1978, there were 661 poison control centers in the United States, including 100 centers in the state of Illinois alone.128 The nature of calls to centers changed as lay public–generated calls began to outnumber physician-generated calls. Recognizing the public relations value and strong popular support associated with poison centers, some hospitals started poison control centers without adequately recognizing or providing for the associated responsibilities. Unfortunately, many of these centers offered no more than a part-time telephone service located in the back of the emergency department or pharmacy, staffed by poorly trained personnel.128

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TABLE 1–4. Protecting Our Health: Important US Regulatory Initiatives Pertaining to Xenobiotics Since 1900 Date

Federal Legislation

Intent

1906 1914

Pure Food and Drug Act Harrison Narcotics Act

1927 1930 1937 1938 1948

1970 1970

Federal Caustic Poison Act Food and Drug Administration (FDA) Marijuana Tax Act Federal Food, Drug, and Cosmetic Act Federal Insecticide, Fungicide, and Rodenticide Act Durham-Humphrey Amendment Federal Hazardous Substances Labeling Act Kefauver-Harris Drug Amendments Clean Air Act Child Protection Act Comprehensive Drug Abuse and Control Act Environmental Protection Agency (EPA) Occupational Safety and Health Act (OSHA)

Early regulatory initiative. Prohibits interstate commerce of misbranded and adulterated foods and drugs. First federal law to criminalize the nonmedical use of drugs. Taxed and regulated distribution and sale of narcotics (opium, opium derivatives, and cocaine). Mandated labeling of concentrated caustics. Established successor to the Bureau of Chemistry; promulgation of food and drug regulations. Applied controls to marijuana similar to those applied to narcotics. Required toxicity testing of pharmaceuticals before marketing. Provided federal control for pesticide sale, distribution, and use.

1970

Poison Prevention Packaging Act

1972 1972 1972

Clean Water Act Consumer Product Safety Act Hazardous Material Transportation Act

1973 1973 1974 1976

Drug Enforcement Administration (DEA) Lead-based Paint Poison Prevention Act Safe Drinking Water Act Resource Conservation and Recovery Act (RCRA) Toxic Substance Control Act

1951 1960 1962 1963 1966 1970

1976 1980 1983 1986 1986 1986 1988 1994 1997 2002 2005 2009

Comprehensive Environmental Response Compensation and Liability act (CERCLA) Federal Anti-Tampering Act Controlled Substance Analogue Enforcement Act Drug-Free Federal Workplace Program Superfund Amendments and Reauthorization Act (SARA) Labeling of Hazardous Art Materials Act Dietary Supplement Health and Education Act FDA Modernization Act The Public Health Security and Bioterrorism Preparedness and Response Act Combat Methamphetamine Epidemic Act Family Smoking Prevention and Tobacco Control Act

Restricted many therapeutic drugs to sale by prescription only Mandated prominent labeling warnings on hazardous household chemical products. Required drug manufacturer to demonstrate efficacy before marketing Regulated air emissions by setting maximum pollutant standards. Banned hazardous toys when adequate label warnings could not be written. Replaced and updated all previous laws concerning narcotics and other dangerous drugs. Established and enforced environmental protection standards. Enacted to improve worker and workplace safety. Created National Institute for Occupational Safety and Health (NIOSH) as research institution for OSHA. Mandated child-resistant safety caps on certain pharmaceutical preparations to decrease unintentional childhood poisoning. Regulated discharge of pollutants into US waters. Established Consumer Product Safety Commission to reduce injuries and deaths from consumer products. Authorized the Department of Transportation to develop, promulgate, and enforce regulations for the safe transportation of hazardous materials. Successor to the Bureau of Narcotics and Dangerous Drugs; charged with enforcing federal drug laws. Regulated the use of lead in residential paint. Lead in some paints was banned by Congress in 1978. Set safe standards for water purity. Authorized EPA to control hazardous waste from the “cradle-to-grave,” including the generation, transportation, treatment, storage, and disposal of hazardous waste. Emphasis on law enforcement. Authorized EPA to track 75,000 industrial chemicals produced or imported into the United States. Required testing of chemicals that pose environmental or human health risk. Set controls for hazardous waste sites. Established trust fund (Superfund) to provide cleanup for these sites. Agency for Toxic Substances and Disease Registry (ATSDR) created. Response to cyanide laced Tylenol deaths. Outlawed tampering with packaged consumer products. Instituted legal controls on analog (designer) drugs with chemical structures similar to controlled substances. Executive order mandating drug testing of federal employees in sensitive positions. Amendment to CERCLA. Increased funding for the research and cleanup of hazardous waste (SARA) sites. Required review of all art materials to determine hazard potential and mandated warning labels for hazardous materials. Permitted dietary supplements including many herbal preparations to bypass FDA scrutiny. Accelerated FDA reviews, regulated advertising of unapproved uses of approved drugs Tightened control on biologic agents and toxins; increased safety of the US food and drug supply, and drinking water; and strengthened the Strategic National Stockpile. Part of the Patriot Act, this legislation restricted nonprescription sale of the methamphetamine precursor drugs ephedrine and pseudoephedrine used in the home production of methamphetamine Empowered FDA to set standards for tobacco products

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TABLE 1-5. Twentieth Century Milestones in the Development of Medical Toxicology Year

Milestone

1949 1949 1952

First toxicology wards open in Budapest and Copenhagen First poison information service begins in the Netherlands American Academy of Pediatrics study shows that 51% of children’s “accidents” are the result of the ingestion of potential poisons First US poison control center opens in Chicago National Clearinghouse for Poison Control Centers established American Association of Poison Control Centers (AAPCC) founded First Poison Prevention Week Initial call for development of regional Poison Control Centers (PCCs) Creation of European Association for PCCs American Academy of Clinical Toxicology (AACT) established Introduction of microfiche technology to poison information American Board of Medical Toxicology (ABMT) established AAPCC introduces standards of regional designation First examination given for Specialist in Poison Information (SPI) American Board of Applied Toxicology (ABAT) established Medical Toxicology recognized by American Board of Medical Specialties (ABMS) First ABMS examination in Medical Toxicology Accreditation Council for Graduate Medical Education (ACGME) approval of residency training programs in Medical Toxicology Poison Control Center Enhancement and Awareness Act Institute of Medicine (IOM) Report on the future of poison centers is released, calling for a greater integration between public health sector and poison control services

1953 1957 1958 1961 1963 1964 1968 1972 1974 1978 1983 1985 1992 1994 2000 2000 2004

Despite the “growing pains” of these poison control services during this period, there were many significant achievements were made. A dedicated group of physicians and other healthcare professionals began devoting an increasing proportion of their time to poison related matters. In 1958, the American Association of Poison Control Centers (AAPCC) was founded to promote closer cooperation between poison centers, to establish uniform standards, and to develop educational programs for the general public and healthcare professionals.59 Annual research meetings were held, and important legislative initiatives were stimulated by the organization’s efforts.96 Examples of such legislation include the Federal Hazardous Substances Labeling Act of 1960, which improved product labeling; the Child Protection Act of 1966, which extended labeling statutes to pesticides and other hazardous substances; and the Poison Prevention Packaging Act of 1970, which mandated safety packaging. In 1961, in an attempt to heighten public awareness of the dangers of unintentional poisoning, the third week of March was designated as the Annual National Poison Prevention Week. Another organization that would become important, the American Academy of Clinical Toxicology (AACT), was founded in 1968 by a diverse group of toxicologists.31 This group was “interested in applying principles of rational toxicology to patient treatment” and in improving the standards of care on a national basis.125 The first modern

textbooks of clinical toxicology began to appear in the mid-1950s with the publication of Dreisbach’s Handbook of Poisoning (1955)43; Gleason, Gosselin, and Hodge’s Clinical Toxicology of Commercial Products (1957)55; and Arena’s Poisoning (1963).10 Major advancements in the storage and retrieval of poison information were also instituted during these years. Information as noted above on consumer products initially appeared on index cards distributed regularly to poison centers by the National Clearinghouse, and by 1978, more than 16,000 individual product cards had been issued.129 The introduction of microfiche technology in 1972 enabled the storage of much larger amounts of data in much smaller spaces at the individual poison centers. Toxifile and POISINDEX, two large drug and poison databases using microfiche technology, were introduced and gradually replaced the much more limited index card system.128 During the 1980s, POISINDEX, which had become the standard database, was made more accessible by using CD-ROM technology. Sophisticated information about the most obscure toxins was now instantaneously available by computer at every poison center. In 1978, the poison control center movement entered an important new stage in its development when the AAPCC introduced standards for regional poison center designation.92 By defining strict criteria, the AAPCC sought to upgrade poison center operations significantly and to offer a national standard of service. These criteria included using poison specialists dedicated exclusively to operating the poison control center 24 hours per day and serving a catchment area of between 1 and 10 million people. Not surprisingly, this professionalization of the poison center movement led to a rapid consolidation of services. An AAPCC credentialing examination for poison information specialists was inaugurated in 1983 to help ensure the quality and standards of poison center staff.7 In 2000, the Poison Control Center Enhancement and Awareness Act was passed by Congress and signed into law by President Clinton. For the first time, federal funding became available to provide assistance for poison prevention and to stabilize the funding of regional poison control centers. This federal assistance permitted the establishment of a single nationwide toll-free phone number (800222-1222) to access poison centers. At present, 59 centers contribute data to a National Poison Database System (NPDS) which from 1983 to 2006 was known as Toxic Exposure Surveillance System (TESS). Recently, the Centers for Disease Control and Prevention (CDC) has been collaborating with the AAPCC to conduct real-time surveillance of this data to help facilitate the early detection of chemical exposures of public health importance.150 A poison control center movement has also grown and evolved in Europe over the past 35 years, but unlike the movement in the United States, it focused from the beginning on establishing strong centralized toxicology treatment centers. In the late 1950s, Gaultier in Paris developed an inpatient unit dedicated to the care of poisoned patients.57 In the United Kingdom, the National Poison Information Service developed at Guys Hospital in 1963 under Roy Goulding57 and Henry Matthew initiated a regional poisoning treatment center in Edinburgh about the same time.117 In 1964, the European Association for Poison Control Centers was formed at Tours, France.57

■ THE RISE OF ENVIRONMENTAL TOXICOLOGY AND FURTHER REGULATORY PROTECTION FROM TOXIC SUBSTANCES The rise of the environmental movement during the 1960s can be traced, in part, to the publication of Rachel Carson’s Silent Spring in 1962, which revealed the perils of an increasingly toxic environment.27 The movement also benefited from the new awareness by those

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involved with the poison control movement of the growing menace of toxins in the home environment.25 Battery casing fume poisoning, resulting from the burning of discarded lead battery cases, and acrodynia, resulting from exposure to a variety of mercury-containing products,38 both demonstrated that young children are particularly vulnerable to low-dose exposures from certain toxins. Worries about the persistence of pesticides in the ecosystem and the increasing number of chemicals introduced into the environment added to concerns of the environment as a potential source of illness, heralding a drive for additional regulatory protection. Starting with the Clean Air Act in 1963, laws were passed to help reduce the toxic burden on our environment (see Table 1–4). The establishment of the Environmental Protection Agency in 1970 spearheaded this attempt at protecting our environment, and during the next 10 years, numerous protective regulations were introduced. Among the most important initiatives was the Occupational Safety and Health Act of 1970, which established the Occupational Safety and Health Administration (OSHA). This act mandates that employers provide safe work conditions for their employees. Specific exposure limits to toxic chemicals in the workplace were promulgated. The Consumer Product Safety Commission was created in 1972 to protect the public from consumer products that posed an unreasonable risk of illness or injury. Cancer-producing substances, such as asbestos, benzene, and vinyl chloride, were banned from consumer products as a result of these new regulations. Toxic waste disasters such as those at Love Canal, New York, and Times Beach, Missouri, led to the passing of the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA, also known as the Superfund) in 1980. This fund is designed to help pay for cleanup of hazardous substance releases posing a potential threat to public health. The Superfund legislation also led to the creation of the Agency for Toxic Substances and Disease Registry (ATSDR), a federal public health agency charged with determining the nature and extent of health problems at Superfund sites and advising the US Environmental Protection Agency and state health and environmental agencies on the need for cleanup and other actions to protect the public’s health. In 2003, the ATSDR became part of the National Center for Environmental Health of the CDC.

■ MEDICAL TOXICOLOGY COMES OF AGE Over the past 25 years, the primary specialties of medical toxicologists have changed. The development of emergency medicine and preventive medicine as medical specialties led to the training of more physicians with a dedicated interest in toxicology. By the early 1990s, emergency physicians accounted for more than half the number of practicing medical toxicologists.43 The increased diversity of medical toxicologists with primary training in emergency medicine, pediatrics, preventive medicine, or internal medicine has helped broaden the goals of poison control centers and medical toxicologists beyond the treatment of acute unintentional childhood ingestions. The scope of medical toxicology now includes a much wider array of toxic exposures, including acute and chronic, adult and pediatric, unintentional and intentional, and occupational and environmental exposures. The development of medical toxicology as a medical subspecialty began in 1974, when the AACT created the American Board of Medical Toxicology (ABMT) to recognize physician practitioners of medical toxicology.6 From 1974 to 1992, 209 physicians obtained board certification, and formal subspecialty recognition of medical toxicology by the American Board of Medical Specialties (ABMS) was granted in 1992. In that year, a conjoint subboard with representatives from the American Board of Emergency Medicine, American Board of Pediatrics, and American Board of Preventive Medicine was established, and the first ABMS-sanctioned examination in medical toxicology

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was offered in 1994. By 2009, a total of more than 400 physicians were board certified in medical toxicology. The American College of Medical Toxicology (ACMT) was founded in 1994 as a physician-based organization designed to advance clinical, educational, and research goals in medical toxicology. In 1999, the Accreditation Council of Graduate Medical Education (ACGME) in the United States formally recognized postgraduate education in medical toxicology, and by 2009, 25 fellowship training programs had been approved. During the 1990s in the United States, some medical toxicologists began to work on establishing regional toxicology treatment centers. Adapting the European model, such toxicology treatment centers could serve as referral centers for patients requiring advanced toxicologic evaluation and treatment. Goals of such inpatient regional centers included enhancing care of poisoned patients, strengthening toxicology training, and facilitating research. The evaluation of the clinical efficacy and fiscal viability of such programs is ongoing. The professional maturation of advanced practice pharmacists and nurses with primary interests in clinical toxicology has also taken place over the past two decades. In 1985, the AACT established the American Board of Applied Toxicology (ABAT) to administer certifying examinations for nonphysician practitioners of medical toxicology who meet their rigorous standards.5 By 2009, more than 85 toxicologists, who mostly held either a PharmD or a PhD in pharmacology or toxicology, were certified by this board.

■ RECENT POISONINGS AND POISONERS Although accounting for just a tiny fraction of all homicidal deaths (0.16% in the United States), notorious lethal poisonings continued throughout the 20th century (Table 1–3).1 In England, Graham Frederick Young developed a macabre fascination with poisons.73 In 1971, at age 14 years, he killed his stepmother and other family members with arsenic and antimony. Sent away to a psychiatric hospital, he was released at age 24 years, when he was no longer considered to be a threat to society. Within months of his release, he again engaged in lethal poisonings, killing several of his coworkers with thallium. Ultimately, he died in prison in 1990. In 1978, Georgi Markov, a Bulgarian defector living in London, developed multisystem failure and died 4 days after having been stabbed by an umbrella carried by an unknown assailant. The postmortem examination revealed a pinhead-sized metal sphere embedded in his thigh where he had been stabbed. Investigators hypothesized that this sphere had most likely carried a lethal dose of ricin into the victim.34 This theory was greatly supported when ricin was isolated from the pellet of a second victim who was stabbed under similar circumstances. In 1982, deliberate tampering with nonprescription tylenol preparations with potassium cyanide caused 7 deaths in Chicago.44 Because of this tragedy, packaging of nonprescription medications was changed to decrease the possibility of future product tampering.101 The perpetrator(s) were never apprehended, and other deaths from nonprescription product tampering were reported in 1991.28 In 1998, Judias Buenoano, known as the “black widow,” was executed for murdering her husband with arsenic in 1971 to collect insurance money. She was the first female executed in Florida in 150 years. The fatal poisoning had remained undetected until 1983, when Buenoano was accused of trying to murder her fiancé with arsenic and by car bombing. Exhumation of the husband’s body, 12 years after he died, revealed substantial amounts of arsenic in the remains.3 Healthcare providers have been implicated in several poisoning homicides as well. An epidemic of mysterious cardiopulmonary arrests at the Ann Arbor Veterans Administration Hospital in Michigan in July and August 1975 was attributed to the homicidal use of pancuronium by two nurses.138 Intentional digoxin poisoning by hospital

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personnel may have explained some of the increased number of deaths on a cardiology ward of a Toronto pediatric hospital in 1981, but the cause of the high mortality rate remained unclear.22 In 2000, an English general practitioner Harold Shipman was convicted of murdering 15 female patients with heroin and may have murdered as many as 297 patients during his 24-year career. These recent revelations prompted calls for strengthening the death certification process, improving preservation of case records, and developing better procedures to monitor controlled drugs.65 Also in 2000, Michael Swango, an American physician, pleaded guilty to the charge of poisoning a number of patients under his care during his residency training. Succinylcholine, potassium chloride, and arsenic were some of the agents he used to kill his patients.136 Attention to more careful physician credentialing and to maintenance of a national physician database arose from this case because the poisonings occurred at several different hospitals across the country. Continuing concerns about healthcare providers acting as serial killers is highlighted by a recent case in New Jersey in which a nurse, Charles Cullen, was found responsible for killing patients with digoxin.16 By the end of the 20th century, 24 centuries after Socrates was executed by poison hemlock, the means of implementing capital punishment had come full circle. Government-sanctioned execution in the United States again favored the use of a “state” poison—this time, the combination of sodium thiopental, pancuronium, and potassium chloride. The use of a poison to achieve political ends has again resurfaced in several incidents from the former Soviet Union. In December 2004, it was announced that the Ukrainian presidential candidate Viktor Yushchenko was poisoned with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent dioxin.130 The dramatic development of chloracne over the face of this public person during the previous several months suggested dioxin as a possibly culprit. Given the paucity of reports of acute dioxin poisoning, however, it wasn’t until laboratory tests confirmed that Yushenko’s dioxin levels were more than 6000 times normal that this diagnosis was confirmed. In another case, a former KGB agent and Russian dissident Alexander Litvinenko was murdered with polonium-210. Initially thought to be a possible case of heavy metal poisoning, Litvinenko developed acute radiation syndrome manifested by acute gastrointestinal symptoms followed by alopecia and pancytopenia before he died.95

■ RECENT DEVELOPMENTS Medical Errors Beginning in the 1980s, several highly publicized medication errors received considerable public attention and provided a stimulus for the initiation of change in policies and systems. Ironically, all of the cases occurred at nationally preeminent university teaching hospitals. In 1984, 18-year-old Libby Zion died from severe hyperthermia soon after hospital admission. Although the cause of her death was likely multifactorial, drug–drug interactions and the failure to recognize and appropriately treat her agitated delirium also contributed to her death.13 State and national guidelines for closer house staff supervision, improved working conditions, and a heightened awareness of consequential drug–drug interactions resulted from the medical, legislative, and legal issues of this case. In 1994, a prominent health journalist for the Boston Globe, Betsy Lehman, was the unfortunate victim of another preventable dosing error when she inadvertently received four times the dose of the chemotherapeutic agent cyclophosphamide as part of an experimental protocol.76 Despite treatment at a world-renowned cancer center, multiple physicians, nurses, and pharmacists failed to notice this erroneous medication order. An overhaul of the medication-ordering system was implemented at that institution after this tragic event.

Another highly publicized death occurred in 1999, when 18-year-old Jesse Gelsinger died after enrolling in an experimental gene-therapy study. Gelsinger, who had ornithine transcarbamylase deficiency, died from multiorgan failure 4 days after receiving, by hepatic infusion, the first dose of an engineered adenovirus containing the normal gene. Although this unexpected death was not the direct result of a dosing or drug–drug interaction error, the FDA review concluded that major research violations had occurred, including failure to report adverse effects with this therapy in animals and earlier clinical trials and to properly obtain informed consent.131 In 2001, Ellen Roche, a 24-year-old healthy volunteer in an asthma study at John Hopkins University, developed a progressive pulmonary illness and died 1 month after receiving 1 g of hexamethonium by inhalation as part of the study protocol.135 Hexamethonium, a ganglionic blocker, was once used to treat hypertension but was removed from the market in 1972. The investigators were cited for failing to indicate on the consent form that hexamethonium was experimental and not FDA approved. Calls for additional safeguards to protect patients in research studies resulted from these cases. In late 1999, the problems of medical errors finally received the high visibility and attention that it deserved in the United States with the publication and subsequent reaction to an Institute of Medicine (IOM) report suggesting that 44,000 to 98,000 fatalities each year were the result of medical errors.77 Many of these errors were attributed to preventable medication errors. The IOM report focused on its findings that errors usually resulted from system faults and not solely from the carelessness of individuals. Chemical Terrorism and Preparedness The terrorist attacks on the World Trade Center and the Pentagon on September 11, 2001, with the subsequent release of a multitude of toxic substances followed within days by the mailing of letters containing lethal amounts of anthrax in October 2001, resulted in profound changes in preparedness strategies against future terrorist strikes. Defending against biologic and chemical terrorism suddenly took on a much heightened sense of urgency. The asymmetric nature of the terrorism menace has led to increasing concerns that traditional industrial chemicals—so-called “chemical agents of opportunity”—may pose a more likely threat than a military chemical warfare agent attack. Responding to these events, poison centers and medical toxicologists from both emergency response and public health backgrounds are playing an increasingly visible role in terrorism preparedness training and leadership. These events have led to a new realization that poison control centers serve an essential public health function that extends significantly beyond the traditional prevention of childhood poisonings. Responding to these new challenges, an IOM report released in 2004 calls for a more formal integration of poison center services into local, state, and federal public health preparedness and response.68

TOXICOLOGY IN THE TWENTY-FIRST CENTURY As new challenges and opportunities arise in the 21st century, two new toxicologic disciplines have emerged: toxicogenomics and nanotoxicology.37,42,107 These nascent fields constitute the toxicologic responses to rapid advances in genetics and material sciences. Toxicogenomics combines toxicology with genomics dealing with how genes and proteins respond to toxic substances. The study of toxicogenomics attempts to better decipher the molecular events underlying toxicologic mechanisms, develop predictors of toxicity through the establishment of better molecular biomarkers, and better understand genetic susceptibilities that pertain to toxic substances such as unanticipated idiosyncratic drug reactions.

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Nanotoxicology refers to the toxicology of engineered tiny particles, usually smaller than 100 nm. Given the extremely small size of nanoparticles, typical barriers at portals of entry may not prevent absorption or may themselves be adversely affected by the nanoparticles. Ongoing studies focus on the translocation of these particles to sensitive target sites such as the central nervous system or bone marrow.107

SUMMARY Since the dawn of recorded history, toxicology has impacted greatly on human events, and although over the millennia the important poisons of the day have changed to some degree, toxic substances continue to challenge our safety. The era of poisoners for hire may have long ago reached its pinnacle, but problems with drug abuse, intentional self-poisoning, exposure to environmental chemicals, and the potential for biologic and chemical terrorism continues to challenge us. Unfortunately, knowledge acquired by one generation is often forgotten or discarded inappropriately by the next generation, leading to a cyclical historic course. This historic review is meant to describe the past and to better prepare toxicologists and society for the future.

REFERENCES 1. Adelson L: Homicidal poisoning: A dying modality of lethal violence? Am J Forensic Med Pathol. 1987;8:245-251. 2. American Heritage Dictionary. Toxicology Boston: Houghton Mifflin; 1991. 3. Anderson C, McGehee S: Bodies of Evidence: The True Story of Judias Buenoano: Florida’s Serial Murderess. New York: St. Martins; 1993. 4. Anderson H: Experimental studies on the pharmacology of activated charcoal. Acta Pharmacol. 1946;2:69-78. 5. Anonymous: American Board of Applied Toxicology. AACTion. 1992;1:3. 6. Anonymous: American Board of Medical Toxicology. Vet Hum Toxicol. 1987;29:510. 7. Anonymous: Certification examination for poison information specialists. Vet Human Toxicol. 1983;25:54-55. 8. Anonymous: Landmark article in occupational medicine. Forty years in the poisonous trades. American Industrial Hygiene Association Quarterly, April 1948. By Alice Hamilton. Am J Ind Med. 1985;7:3-18. 9. Anonymous: Suicide: A leading cause of death. JAMA. 1952;150:696-697. 10. Arena J: Poisoning: Chemistry, Symptoms, Treatments. Springfield, IL: Charles C. Thomas; 1963. 11. Arena JM: The pediatrician’s role in the poison control movement and poison prevention. Am J Dis Child. 1983;137:870-873. 12. Arnold WN: Vincent van Gogh and the thujone connection. JAMA. 1988;260:3042-3044. 13. Asch DA, Parker RM: The Libby Zion case. One step forward or two steps backward? N Engl J Med. 1988;318:771-775. 14. Baldwin M: The snakestone experiments. An early modern medical debate. Isis. 1995;86:394-418. 15. Bartrip P: A “pennurth of arsenic for rat poison”: the Arsenic Act, 1851 and the prevention of secret poisoning. Med Hist. 1992;36:53-69. 16. Becker C: Killer credential. In wake of nurse accused of killing patient, the health system wrestles with balancing shortage, ineffectual reference process. Mod Healthc. 2003;33:6-7. 17. Benjamin DR: Mushrooms: Poisons and Panaceas. New York: WH Freeman; 1995. 18. Berman A: The persistence of theriac in France. Pharmacy in History. 1970;12:5-12. 19. Bisset NG: Arrow and dart poisons. J Ethnopharmacol. 1989;25:1-41. 20. Bond RT: Handbook for Poisoners: A Collection of Great Poison Stories. New York: Collier Books; 1951. 21. Brown HM: De Venenis of Petrus Abbonus: A translation of the Latin. Ann Med Hist. 1924;6:25-53. 22. Buehler JW, Smith LF, Wallace EM, et al: Unexplained deaths in a children’s hospital. An epidemiologic assessment. N Engl J Med. 1985;313: 211-216.

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23. Burchell HB: Digitalis poisoning: historical and forensic aspects. J Am Coll Cardiol. 1983;1:506-516. 24. Burke M: Gastric lavage and emesis in the treatment of ingested poisons: a review and a clinical study of lavage in ten adults. Resuscitation. 1972;1: 91-105. 25. Burnham JC: How the discovery of accidental childhood poisoning contributed to the development of environmentalism in the United States. Environ Hist Rev. 1995;19:57-81. 26. Campbell WA: Oxalic acid, epsom salt and the poison bottle. Hum Toxicol 1982;1:187-193. 27. Carson RL: Silent Spring. Boston: Houghton Mifflin; 1962. 28. CDC: Cyanide poisonings associated with over-the-counter medication— Washington State, 1991. MMWR Morb Mortal Wkly Rep. 1991;40:161,7-8. 29. Christison R: A Treatise on Poisons. London: Adam Black; 1829. 30. Clarke MJ: Chloral hydrate: medicine and poison? Pharm Hist. 1988; 18:2-4. 31. Comstock EG: Roots and circles in medical toxicology: a personal reminiscence. J Toxicol Clin Toxicol. 1998;36:401-407. 32. Cooney DO: Activated Charcoal in Medical Applications. New York: Marcel Dekker; 1995. 33. Costill OH: A Practical Treatise on Poisons. Philadelphia: Grigg, Elliot; 1848. 34. Crompton R, Gall D: Georgi Markov—death in a pellet. Med Leg J. 1980;48: 51-62. 35. Crotty J, Armstrong G: National Clearinghouse for Poison Control Centers. Clin Toxicol. 1978;12:303-307. 36. Crotty JJ, Verhulst HL: Organization and delivery of poison information in the United States. Pediatr Clin North Am. 1970;17:741-746. 37. Curtis J, Greenberg M, Kester J, et al: Nanotechnology and nanotoxicology: a primer for clinicians. Toxicol Rev. 2006;25:245-260. 38. Dally A: The rise and fall of pink disease. Soc Hist Med. 1997;10:291-304. 39. Das G: Cocaine abuse in North America: a milestone in history. J Clin Pharmacol. 1993;33:296-310. 40. Deichmann WB, Henschler D, Holmsted B, Keil G: What is there that is not poison? A study of the Third Defense by Paracelsus. Arch Toxicol Suppl. 1986;58:207-13. 41. Dictionary OE, 2nd ed. Oxford: Clarendon Press; 1989:328. 42. Donaldson K, Stone V, Tran CL, et al: Nanotoxicology. Occup Environ Med. 2004;61:727-728. 43. Dreisbach RH. Handbook of Poisoning: Diagnosis and Treatment. Los Altos, CA: Lange; 1955. 44. Dunea G: Death over the counter. Br Med J (Clin Res Ed). 1983;286:211-212. 45. Earles MP: Early theories of mode of action of drugs and poisons. Ann Sci. 1961;17:97-110. 46. Eckert WG: Historical aspects of poisoning and toxicology. Am J Forensic Med Pathol. 1981;2:261-264. 47. Eckert WG: Medicolegal investigation in New York City. History and activities 1918-1978. Am J Forensic Med Pathol. 1983;4:33-54. 48. Elgood C: A treatise on the bezoar stone. Ann Med Hist. 1935;7:73-80. 49. Felton JS: The heritage of Bernardino Ramazzini. Occup Med (Oxf). 1997;47:167-179. 50. Ferner RE. Forensic Pharmacology: Medicine, Mayhem, and Malpractice. Oxford: Oxford University Press; 1996. 51. Franco G: Ramazzini and workers’ health. Lancet. 1999;354:858-861. 52. Funck-Brentano F: Princes and Poisoners: Studies of the Court of Louis IV. London: Duckworth & Co.; 1901. 53. Gaebel RE: Saturnine gout among Roman aristocrats. N Engl J Med. 1983;309:431. 54. Gallo MA: History and scope of toxicology. In: Klassen CD, ed. Casarett and Doull’s Toxicology: The Basic Science of Poisons, 5th ed. New York: McGraw-Hill; 1996:3-11. 55. Gleason MN, Gosselin RE, Hodge HC: Clinical Toxicology of Commercial Products: Acute Poisoning (Home and Farm). Baltimore: Williams & Wilkins; 1957. 56. Golding AM: Two hundred years of drug abuse. J R Soc Med. 1993;86: 282-286. 57. Govaerts M: Poison control in Europe. Pediatr Clin North Am. 1970;17: 729-739. 58. Grant MP: Alice Hamilton: Pioneer Doctor in Industrial Medicine. London: Abelard-Schuman; 1967. 59. Grayson R: The poison control movement in the United States. Indust Med Surg. 1962;31:296-297.

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60. Green DW: The saturnine curse: a history of lead poisoning. South Med J. 1985;78:48-51. 61. Greensher J, Mofenson HC, Caraccio TR: Ascendency of the black bottle (activated charcoal). Pediatrics. 1987;80:949-951. 62. Hofmann A: How LSD originated. J Psychedelic Drugs. 1979;11:53-60. 63. Hold KM, Sirisoma NS, Ikeda T, et al: Alpha-thujone (the active component of absinthe): gamma-aminobutyric acid type A receptor modulation and metabolic detoxification. Proc Natl Acad Sci U S A. 2000;97:3826-3831. 64. Holt LE, Holz PH: The black bottle: a consideration of the role of charcoal in the treatment of poisoning in children. J Pediatr. 1963;63:306-314. 65. Horton R: The real lessons from Harold Frederick Shipman. Lancet. 2001;357:82-83. 66. Howard-Jones N: The origins of hypodermic medication. Sci Am. 1971;224:96-102. 67. Hunter D: The Diseases of Occupations, 6th ed. London: Hodder & Stoughton; 1978. 68. Institute of Medicine: Forging a Poison Prevention and Control System. Washington, DC: National Academies Press; 2004. 69. Jain KK: Carbon Monoxide Poisoning. St. Louis: Warren H. Green; 1990. 70. Jarcho S: Medical numismatic notes. VII. Mithridates IV. Bull N Y Acad Med. 1972;48:1059-1064. 71. Jarcho S: The correspondence of Morgagni and Lancisi on the death of Cleopatra. Bull Hist Med. 1969;43:299-325. 72. Jensen LB. Poisoning Misadventures. Springfield, IL: Charles C. Thomas; 1970. 73. Johnson H: R v Young—murder by thallium. Med Leg J. 1974;42:76-90. 74. Karch SB: The history of cocaine toxicity. Hum Pathol. 1989;20:10371039. 75. Knoefel PK: Felice Fontana on poisons. Clio Med. 1980;15:35-66. 76. Knox RA: Doctor’s orders killed cancer patient: Dana Farber admits drug overdose caused death of Globe columnist, damage to second woman. Boston Globe. March 23, 1995;Sect. 1. 77. Kohn LT, Corrigan J, Donaldson MS, eds: To Err Is Human: Building a Safer Health System. Washington, DC: National Academy Press; 2000. 78. Kramer JC: Opium rampant: medical use, misuse and abuse in Britain and the West in the 17th and 18th centuries. Br J Addict Alcohol Other Drugs. 1979;74:377-389. 79. Kramer JC: The opiates: two centuries of scientific study. J Psychedelic Drugs. 1980;12:89-103. 80. Lanier D. Absinthe: The Cocaine of the Nineteenth Century. Jefferson, NC: McFarland; 1995. 81. Lee JA: Claude Bernard (1813-1878). Anaesthesia. 1978;33:741-747. 82. Levey M: Medieval Arabic toxicology: The book on poison of Ibn Wahshiya and its relation to early Indian and Greek texts. Trans Am Philosph Soc. 1966;56:5-130. 83. Lomax E: The uses and abuses of opiates in nineteenth-century England. Bull Hist Med. 1973;47:167-176. 84. Lovejoy FH, Jr., Alpert JJ: A future direction for poison centers. A critique. Pediatr Clin North Am. 1970;17:747-753. 85. Lucanie R: Unicorn horn and its use as a poison antidote. Vet Hum Toxicol. 1992;34:563. 86. Ludlow FH: The Hasheesh Eater Microform: Being Passages from the Life of a Pythagorean. New York: Harper; 1857. 87. Lyon AS: Medicine: An Illustrated History. New York: Abradale; 1978. 88. Macht DI: Louis Lewin: pharmacologist, toxicologist, medical historian. Ann Med Hist. 1931;3:179-194. 89. Magner LN: A History of Medicine. New York: Marcel Dekker; 1992. 90. Major RH: History of the stomach tube. Ann Med Hist. 1934;6:500-509. 91. Mann RH: Murder, Magic, and Medicine. New York: Oxford University Press; 1992. 92. Manoguerra AS, Temple AR: Observations on the current status of poison control centers in the United States. Emerg Med Clin North Am. 1984;2:185-197. 93. Mant AK: Forensic medicine in Great Britain. II. The origins of the British medicolegal system and some historic cases. Am J Forensic Med Pathol. 1987;8:354-361. 94. Marsh J: Account of a method of separating small quantities of arsenic from substances with which it may be mixed. Edinb New Phil J. 1836;21:229-236. 95. McFee R, Leikin, JB: Death by Polonium-210: Lessons learned from the murder of former Soviet spy Alexander Litvinenko. JEMS. 2008;33: 18-23.

96. McIntire M: On the occasion of the twenty-fifth anniversary of the American Association of Poison Control Centers. Vet Hum Toxicol. 1983;25:35-37. 97. Mead GO: Ether drinking in Ireland. JAMA. 1891;16:391-392. 98. Modell W: Mass drug catastrophes and the roles of science and technology. Science. 1967;156:346-351. 99. Moore SW: A case of poisoning by laudanum, successfully treated by means of Juke’s syringe. NY Med Phys J. 1825;4:91-92. 100. Moriarty KM, Alagna SW, Lake CR: Psychopharmacology. An historical perspective. Psychiatr Clin North Am. 1984;7:411-433. 101. Murphy DH: Cyanide-tainted Tylenol: what pharmacists can learn. Am Pharm. 1986;NS26:19-23. 102. Musto DF: America’s first cocaine epidemic. Wilson Q. 1989;13:59-64. 103. Nahas GG: Hashish in Islam 9th to 18th century. Bull N Y Acad Med. 1982;58:814-831. 104. Nerlich AG, Parsche F, Wiest I, et al: Extensive pulmonary haemorrhage in an Egyptian mummy. Virchows Arch. 1995;427:423-429. 105. Niyogi SK: Historic development of forensic toxicology in America up to 1978. Am J Forensic Med Pathol. 1980;1:249-264. 106. Nriagu JO: Saturnine gout among Roman aristocrats. Did lead poisoning contribute to the fall of the Empire? N Engl J Med. 1983;308:660-663. 107. Oberdorster G, Oberdorster E, Oberdorster J, et al: Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles. Environ Health Perspect. 2005;113:823-839. 108. Oehme FW: The development of toxicology as a veterinary discipline in the United States. Clin Toxicol. 1970;3:211-220. 109. Olch PD: William S. Halsted and local anesthesia: contributions and complications. Anesthesiology. 1975;42:479-486. 110. Orfila MP. Traites des Poisons. Paris: Ches Crochard; 1814. 111. Pachter HM: Paracelsus: Magic into Science. New York: Collier; 1961. 112. Pappas AA, Massoll NA, Cannon DJ: Toxicology: past, present, and future. Ann Clin Lab Sci. 1999;29:253-262. 113. Parsche F, Balabanova S, Pirsig W: Drugs in ancient populations. Lancet. 1993;341:503. 114. Plaitakis A, Duvoisin RC: Homer’s moly identified as Galanthus nivalis L.: physiologic antidote to stramonium poisoning. Clin Neuropharmacol. 1983;6:1-5. 115. Pollack SH: The psilocybin mushroom pandemic. J Psychedelic Drugs. 1975;7:73-84. 116. Press E, Mellins RB: A poisoning control program. Am J Public Health. 1954;44:1515-1525. 117. Proudfoot AT: Clinical toxicology—past, present and future. Hum Toxicol. 1988;7:481-487. 118. Quinones MA: Drug abuse during the Civil War (1861-1865). Int J Addict. 1975;10:1007-1020. 119. Randall T: Cocaine deaths reported for century or more. JAMA. 1992;267:1045-1046. 120. Regier CC: The struggle for federal food and drugs legislation. Law Contemp Prob. 1933;1:3-15. 121. Reid DH: Treatment of the poisoned child. Arch Dis Child. 1970;45: 428-433. 122. Robertson WO: National organizations and agencies in poison control programs: a commentary. Clin Toxicol. 1978;12:297-302. 123. Robins LN, Helzer JE, Davis DH: Narcotic use in southeast Asia and afterward. An interview study of 898 Vietnam returnees. Arch Gen Psychiatry. 1975;32:955-961. 124. Rosner F: Moses Maimonides’ treatise on poisons. JAMA. 1968;205: 914-916. 125. Rumack BH, Ford P, Sbarbaro J, et al: Regionalization of poison centers–a rational role model. Clin Toxicol. 1978;12:367-375. 126. Sapira JD: Speculations concerning opium abuse and world history. Perspect Biol Med. 1975;18:379-398. 127. Scarborough J: Nicander’s toxicology II: spiders, scorpions, insects and myriapods. Pharmacy in History. 1979;21:73-92. 128. Scherz RG, Robertson WO: The history of poison control centers in the United States. Clin Toxicol. 1978;12:291-296. 129. Scutchfield FD, Genovese EN: Terrible death of Socrates: some medical and classical reflections. Pharos. 1997;60:30-33. 130. Shane S. Poison’s use as political tool: Ukraine is not exceptional. NY Times. December 15, 2004;Sect. NY. 131. Silberner J: A gene therapy death. Hastings Cent Rep. 2000;30:36. 132. Sinclair U: The Jungle. New York: Doubleday; 1906.

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133. Smith S: Poisons and poisoners through the ages. Med Leg J. 1952;20:153-167. 134. Sneader W: The discovery of heroin. Lancet 1998;352:1697-1699. 135. Steinbrook R: Protecting research subjects—the crisis at Johns Hopkins. N Engl J Med. 2002;346:716-720. 136. Stewart JB. Blind Eye: The Terrifying Story of a Doctor Who Got Away with Murder. New York: Touchstone; 1999. 137. Strang J, Arnold WN, Peters T: Absinthe: what’s your poison? Though absinthe is intriguing, it is alcohol in general we should worry about. Br Med J. 1999;319:1590-1592. 138. Stross JK, Shasby M, Harlan WR: An epidemic of mysterious cardiopulmonary arrests. N Engl J Med. 1976;295:1107-1110. 139. Taylor HM: A preliminary survey of the effect which lye legislations had had on the incident of esophageal stricture. Ann Otol Rhinol Laryngol. 1935;44:1157-1158. 140. Thompson CJ: Poison and Poisoners. London: Harold Shaylor; 1931. 141. Timbrell JA: Introduction to Toxicology. London: Taylor & Francis; 1989. 142. Freud S: Über Coca, Secundararzt im k.k. Allgemeinen Krandenhause in Wien. Centralblatt für die Gesellschaft Therapie, 2, 289-314; reprinted in English (1984), J Subst Abuse Treat 1984;1:206-217. 143. Trestrail JH: Criminal Poisoning: Investigational Guide for Law Enforcement, Toxicologists, Forensic Scientists, and Attorneys. Totowa, NJ: Humana Press; 2000.

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144. Vale JA, Meredith TJ. Poison information services. In: Vale JA, Meredith TJ, eds. Poisoning, Diagnosis and Treatment. London: Update Books; 1981:9-12. 145. Waldron HA: Lead poisoning in the ancient world. Med Hist. 1973;17: 391-399. 146. Watson G. Theriac and Mithradatum: A Study in Therapeutics. London: Wellcome Historical Medical Library; 1966. 147. Wax PM: Elixirs, diluents, and the passage of the 1938 Federal Food, Drug and Cosmetic Act. Ann Intern Med. 1995;122:456-461. 148. Witthaus RA: Manual of Toxicology. New York: William Wood; 1911. 149. Witthaus RA, Becker TC: Medical Jurisprudence: Forensic Medicine and Toxicology. New York: William Wood; 1894. 150. Wolkin AF, Patel M, Watson W, et al: Early detection of illness associated with poisonings of public health significance. Ann Emerg Med. 2006;47:170-176. 151. Wormley TG: Micro-Chemistry of Poisons. New York: William Wood; 1869. 152. Wright-St Clair RE: Poison or medicine? N Z Med J. 1970;71:224-229.

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CHAPTER 2

TOXICOLOGIC PLAGUES AND DISASTERS IN HISTORY Paul M. Wax Throughout history, mass poisonings have caused suffering and misfortune. From the ergot epidemics of the Middle Ages to contemporary industrial disasters, these plagues have had great political, economic, social, and environmental ramifications. Particularly within the past 100 years, as the number of toxins and potential toxins has risen dramatically, toxic disasters have become an increasingly common event. The sites of some of these events—Bhopal (India), Chernobyl (Ukraine), Jonestown (Guyana), Love Canal (New York), Minamata Bay (Japan), Seveso (Italy), West Bengal (India)—have come to symbolize our increasingly toxic habitat. Globalization has led to the proliferation of toxic chemicals throughout the world and their rapid distribution. Many chemical factories that store large amounts of potentially lethal chemicals are not secure. Given the increasing attention to terrorism preparedness, an appreciation of chemicals as agents of opportunity for terrorists has suddenly assumed great importance. This chapter provides an overview of some of the most consequential and historically important toxin-associated disasters.

GAS DISASTERS Inhalation of toxic gases and oral ingestions resulting in food poisoning tend to subject the greatest number of people to adverse consequences of a toxic exposure. Toxic gas exposures may be the result of a natural disaster (volcanic eruption), industrial mishap (fire, chemical release), chemical warfare, or an intentional homicidal or genocidal endeavor (concentration camp gas chamber). Depending on the toxin, the clinical presentation may be acute, with a rapid onset of toxicity (cyanide), or subacute or chronic, with a gradual onset of toxicity (air pollution). One of the earliest recorded toxic gas disasters resulted from the eruption of Mount Vesuvius near Pompeii, Italy, in 79 a.d. (Table 2–1). Poisonous gases generated from the volcanic activity reportedly killed thousands.37 A much more recent natural disaster occurred in 1986 in Cameroon, when excessive amounts of carbon dioxide spontaneously erupted from Lake Nyos, a volcanic crater lake.20 Approximately 1700 human and countless animal fatalities resulted from exposure to this asphyxiant. A toxic gas leak at the Union Carbide pesticide plant in Bhopal, India in 1984 resulted in one of the greatest civilian toxic disasters in modern history.136 An unintended exothermic reaction at this carbarylproducing plant caused the release of more than 24,000 kg of methyl isocyanate. This gas was quickly dispersed through the air over the densely populated area surrounding the factory where many of the workers lived, resulting in at least 2500 deaths and 200,000 injuries.87 The initial response to this disaster was greatly limited by a lack of pertinent information about the toxicity of this chemical as well as the poverty of the residents. A follow-up study 10 years later showed persistence of small-airway obstruction among survivors.32 Chronic

eye problems were also reported.2 Calls for improvement in disaster preparedness and strengthened right-to-know laws regarding potential toxic exposures resulted from this tragedy.53,136 The release into the atmosphere of 26 tons of hydrofluoric acid at a petrochemical plant in Texas in October 1987 resulted in 939 people seeking medical attention at nearby hospitals. Ninety-four people were hospitalized, but there were no deaths.144 More than any other single toxin, carbon monoxide has been involved with the largest number of toxic disasters. Catastrophic fires, such as the Cocoanut Grove Nightclub fire in 1943, have caused hundreds of deaths at a time, many of them from carbon monoxide poisoning.39 A 1990 fire deliberately started at the Happy Land Social Club in the Bronx, New York, claimed 87 victims, including a large number of nonburn deaths,80 and the 2003 fire at the Station nightclub in West Warwick, Rhode Island, killed 98 people.122 Carbon monoxide poisoning was a major determinant in many of these deaths, although hydrogen cyanide gas and simple asphyxiation may have also contributed to the overall mortality. Another notable toxic gas disaster involving a fire occurred at the Cleveland Clinic in Cleveland, Ohio in 1929, where a fire in the radiology department resulted in 125 deaths.36 The burning of nitrocellulose radiographs produced nitrogen dioxide, cyanide, and carbon monoxide gases held responsible for many of the fatalities. In 2003, at least 243 people died and 10,000 people became ill after a drilling well exploded in Gaogiao, China, releasing hydrogen sulfide and natural gas into the air.149 A toxic gas cloud covered 25 square kilometers. Ninety percent of the villagers who lived in the village adjoining the gas well died. The release of a dioxin-containing chemical cloud into the atmosphere from an explosion at a hexachlorophene production factory in Seveso, Italy in 1976, resulted in one of the most serious exposures to dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin).52 The lethality of this agent in animals has caused considerable concern for acute and latent injury from human exposure. Despite this apprehension, chloracne was the only significant clinical finding related to the dioxin exposure at 5-year follow-up.10 Air pollution is another source of toxic gases that causes significant disease and death. Complaints about smoky air date back to at least 1272, when King Edward I banned the burning of sea-coal.134 By the 19th century—the era of rapid industrialization in England—winter “fogs” became increasingly problematic. An 1873 London fog was responsible for 268 deaths from bronchitis. Excessive smog in the Meuse Valley of Belgium in 1930, and in Donora, Pennsylvania, in 1948, was also blamed for excess morbidity and mortality. In 1952, another dense sulfur dioxide–laden smog in London was responsible for 4000 deaths.78 Both the initiation of long-overdue air-pollution reform in England and Parliament’s passing of the 1956 Clean Air Act resulted from this latter “fog.”

WARFARE AND TERRORISM Exposure to xenobiotics with the deliberate intent to inflict harm claimed an extraordinary number of victims during the 20th century (Table 2–2). During World War I, chlorine and phosgene gases and the liquid vesicant mustard were used as battlefield weapons, with mustard causing approximately 80% of the chemical casualties.112 Reportedly, 100,000 deaths and 1.2 million casualties were attributable to these chemical attacks.37 The toxic exposures resulted in severe airway irritation, acute lung injury, hemorrhagic pneumonitis, skin blistering, and ocular damage. Chemical weapons were used again in the 1980s during the Iran—Iraq war.

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TABLE 2–1. Gas Disasters Xenobiotic

Location

Date

Significance

Poisonous gas Smog (SO2) N02, CO, CN Smog (SO2) CO, CN CO Smog (SO2) Smog (SO2) Dioxin Methyl isocyanate Carbon dioxide Hydrofluoric acid CO, ?CN Hydrogen sulfide CO, ?CN

Pompeii, Italy London Cleveland Clinic, Cleveland, OH Meuse Valley, Belgium Cocoanut Grove Night Club, Boston Salerno, Italy Donora, PA London Seveso, Italy Bhopal, India Cameroon Texas City, TX Happy Land Social Club, Bronx, NY Xiaoying, China West Warwick, RI

79 A.D. 1873 1929 1930 1942 1944 1948 1952 1976 1984 1986 1987 1990 2003 2003

>2000 deaths from eruption of Mt. Vesuvius 268 deaths from bronchitis Fire in radiology department; 125 deaths 64 deaths 498 deaths from fire >500 deaths on a train stalled in a tunnel 20 deaths; thousands ill 4000 deaths attributed to the fog/smog Unintentional industrial release of dioxin into environment; chloracne >2000 deaths; 200,000 injuries >1700 deaths from release of gas from Lake Nyos Atmospheric release; 94 hospitalized 87 deaths in fire from toxic smoke 243 deaths and 10,000 became ill from gas poisoning after a gas well exploded 98 deaths in fire

The Nazis used poisonous gases during World War II to commit mass murder and genocide. Initially, the Nazis used carbon monoxide to kill. To expedite the killing process, Nazi scientists developed Zyklon-B gas (hydrogen cyanide gas). As many as 10,000 people per day were killed by the rapidly acting cyanide, and millions of deaths were attributable to the use of these gases. Agent Orange was widely used as a defoliant during the Vietnam War. This herbicide consisted of a mixture of 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and 2,4-dichlorophenoxyacetic acid (2,4-D), as well as small amounts of a contaminant, 2,3,7,8-tetrachlorodibenzop-dioxin (TCDD), better known as dioxin. Over the years, a large number of adverse health effects have been attributed to Agent Orange exposure. A 2002 Institute of Medicine study concluded that among Vietnam veterans, there is sufficient evidence to demonstrate an association between this herbicide exposure and chronic lymphocytic

leukemia, soft tissue sarcomas, non-Hodgkin lymphomas, Hodgkin disease, and chloracne.59 Mass exposure to the very potent organic phosphorus compound sarin occurred in March 1995, when terrorists released this chemical warfare agent in three separate Tokyo subway lines.102 Eleven people were killed, and 5510 people sought emergency medical evaluation at more than 200 hospitals and clinics in the area.124 This mass disaster introduced the spectra of terrorism to the modern emergency medical services system, resulting in a greater emphasis on hospital preparedness, including planning for the psychological consequences of such events. Sarin exposure also resulted in several deaths and hundreds of casualties in Matsumoto, Japan in June 1994.92,99 During recent wars and terrorism events, a variety of physical and neuropsychologic ailments have been attributed to possible exposure to toxic agents.27,57 Gulf War syndrome is a constellation of chronic

TABLE 2–2. Warfare and Terrorism Disasters Toxin

Location

Date

Significance

Chlorine Chlorine, mustard gas, phosgene CN, CO Agent Orange Mustard gas Possible toxin Sarin Sarin Dust and other particulates Fentanyl derivative

Iraq Ypres, Belgium

2007 1915–1918

Europe Vietnam Iraq–Iran Persian Gulf Matsumoto, Japan Tokyo New York City Moscow

1939–1945 1960s 1982 1991 1994 1995 2001 2002

Ricin

Washington, DC

2004

Used against US troops and Iraqi civilians 100,000 dead and 1.2 million casualties from chemicals during World War I Millions murdered by Zyklon-B (HCN) gas Contains dioxin; excess skin cancer New cycle of war gas casualties Gulf War syndrome First terrorist attack in Japan using sarin Subway exposure; 5510 people sought medical attention World Trade Center collapse from terrorist air strike Used by the Russian military to subdue terrorists in Moscow theatre Detected in Dirksen Senate Office Building; no illness reported

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symptoms, including fatigue, headache, muscle and joint pains, ataxia, paresthesias, diarrhea, skin rashes, sleep disturbances, impaired concentration, memory loss, and irritability, noted in thousands of Persian Gulf War veterans without a clearly identifiable cause. A number of etiologies have been advanced to explain these varied symptoms, including exposure to the smoke from burning oil wells; chemical and biologic warfare agents, including nerve agents; and medical prophylaxis, such as the use of pyridostigmine bromide or anthrax and botulinum toxin vaccines, although the actual etiology remains unclear. An agreed upon toxicologic mechanism remains elusive.41,57,60,61,62,71,113,133 After the terrorist attacks on New York City in September 11, 2001, that resulted in the collapse of World Trade Center, persistent cough and increased bronchial responsiveness was noted among 8% of New York City Fire Department workers who were exposed to large amounts of dust and other particulates during the clean-up.108,109 This condition, known as World Trade Center cough syndrome, is characterized by upper airway (chronic rhinosinusitis) and lower airway findings (bronchitis, asthma, or both) as well as, at times, gastroesophageal reflux dysfunction (GERD).108 The risk of development of hyperreactivity and reactive airways dysfunction was clearly associated with the intensity of exposure.17 The Russian military used a mysterious “gas” to incapacitate Chechen rebels at a Moscow theatre in 2002, resulting in the deaths of more

than 120 hostages. Although never publically indentified, the gas may have consisted of a highly potent aerosolized fentanyl derivative such as carfentanil and an inhalational anesthetic such as halothane. Better preparation of the rescuers with suitable amounts of naloxone may have help prevent many of these seemingly unanticipated casualties.140 Ricin was found in several government buildings, including a mail processing plant in Greenville, South Carolina in 2003 and the Dirksen Senate Office Building in Washington, DC in 2004. Although no cases of ricin-associated illness ensued, increased concern was generated because the method of delivery was thought to be the mail, and irradiation procedures designed to kill microbials such as anthrax would not inactivate chemical toxins such as ricin.15,118

FOOD DISASTERS Unintentional contamination of food and drink has led to numerous toxic disasters (Table 2–3). Ergot, produced by the fungus Claviceps purpurea, caused epidemic ergotism as the result of eating breads and cereals made from rye contaminated by C. purpurea. In some epidemics, convulsive manifestations predominated, and in others, gangrenous manifestations predominated.89 Ergot-induced severe vasospasm was thought to be responsible for both presentations.88 In 994 a.d.,

TABLE 2–3. Food Disasters Xenobiotic

Location

Date

Significance

Ergot Ergot Lead Arsenious acid Lead

Aquitania, France Salem, Massachusetts Devonshire, England France Canada

994 A.D. 1692 1700s 1828 1846

Arsenic Cadmium Hexachlorobenzene Methyl mercury Triorthocresyl phosphate Cobalt Methylenedianiline Polychlorinated biphenyls Methyl mercury Polybrominated biphenyls Polychlorinated biphenyls Rapeseed oil (denatured) Arsenic Arsenic

Staffordshire, England Japan Turkey Minamata Bay, Japan Meknes, Morocco Quebec City, Canada and others Epping, England Japan Iraq Michigan Taiwan Spain Buenos Aires Bangladesh and West Bengal, India

1900 1939–1954 1956 1950s 1959 1960s 1965 1968 1971 1973 1979 1981 1987 1990s–present

Tetramine

China

2002

Arsenic

Maine

2003

Nicotine Melamine

Michigan China

2003 2008

40,000 died in the epidemic Neuropsychiatric symptoms may be attributable to ergot Colic from cider contaminated during production 40,000 cases of polyneuropathy from contaminated wine and bread 134 men died during the Franklin expedition, possibly because of contamination of food stored in lead cans Arsenic-contaminated sugar used in beer production Itai-Itai (“ouch-ouch”) disease 4000 cases of porphyria cutanea tarda Consumption of organic mercury poisoned fish Cooking oil adulterated with turbojet lubricant Cobalt beer cardiomyopathy Jaundice Yusho (“rice oil disease”) >400 deaths from contaminated grain 97% of state contaminated through food chain Yu-Cheng (“oil disease”) Toxic oil syndrome affected 19,000 people Malicious contamination of meat; 61 people underwent chelation Ground water contaminated with arsenic; millions exposed; 100,000s with symptoms; greatest mass poisoning in history Snacks deliberated contaminated, resulting in 42 deaths and 300 people with symptoms Intentional contamination of coffee; one death and 16 cases of illness Deliberate contamination of ground beef; 92 people became ill 50,000 hospitalized from tainted infant formula

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40,000 people died in Aquitania, France, in one such epidemic.76 Convulsive ergotism was initially described as a “fire which twisted the people,” and the term “St. Anthony’s fire” (ignis sacer) was used to refer to the excruciating burning pain experienced in the extremities that is an early manifestation of gangrenous ergotism. The events surrounding the Salem, Massachusetts witchcraft trials have also been attributed to the ingestion of contaminated rye. The bizarre neuropsychiatric manifestations exhibited by some of the individuals associated with this event may have been caused by the hallucinogenic properties of ergotamine, a lysergic acid diethylamide (LSD) precursor.23,85 During the last half of the 20th century, unintentional mass poisoning from food and drink contaminated with toxic chemicals became all too common. One of the more unusual poisonings occurred in Turkey in 1956, when wheat seed intended for planting was treated with the fungicide hexachlorobenzene and then inadvertently used for human consumption. Approximately 4000 cases of porphyria cutanea tarda were attributed to the ingestion of this toxic wheat seed.119 Another example of chemical food poisoning took place in Epping, England in 1965. In this incident, a sack of flour became contaminated with methylenedianiline when the chemical unintentionally spilled onto the flour during transport to a bakery. Subsequent ingestion of bread baked with the contaminated flour produced hepatitis in 84 people. This outbreak of toxic hepatitis became known as Epping jaundice.67 The manufacture of polybromated biphenyls (PBBs) in a factory that also produced food supplements for livestock resulted in the unintentional contamination of a large amount of livestock feed in Michigan in 1973.24 Significant morbidity and mortality among the livestock population resulted, and increased human tissue concentrations of PBBs were reported,145 although human toxicity seemed limited to vague constitutional symptoms and abnormal liver function tests.22 The chemical contamination of rice oil in Japan in 1968 caused a syndrome called Yusho (“rice oil disease”). This occurred when heatexchange fluid containing polychlorinated biphenyls (PCBs) and polychlorinated dibenzofurans (PCDFs) leaked from a heating pipe into the rice oil. More than 1600 people developed chloracne, hyperpigmentation, an increased incidence of liver cancer, or adverse reproductive effects. In 1979 in Taiwan, 2000 people developed similar clinical manifestations after ingesting another batch of PCB-contaminated rice oil. This latter epidemic was referred to as Yu-Cheng (“oil disease”).63 In another oil contamination epidemic, consumption of illegally marketed cooking oil in Spain in 1981 was responsible for a mysterious poisoning epidemic that affected more than 19,000 people and resulted in at least 340 deaths. Exposed patients developed a multisystem disorder referred to as toxic oil syndrome (or toxic epidemic syndrome), characterized by pneumonitis, eosinophilia, pulmonary hypertension, scleroderma-like features, and neuromuscular changes. Although this syndrome was associated with the consumption of rapeseed oil denatured with 2% aniline, the exact etiologic agent was not definitively identified at the time. Subsequent investigations suggest that the fatty acid oleyl anilide may have been the putative agent.35,64,65 In 1999, an outbreak of health complaints related to consuming Coca Cola occurred in Belgium, when 943 people, mostly children, complained of gastrointestinal symptoms, malaise, headaches, and palpitations after drinking Coca Cola.100 Many of those affected complained of an “off taste” or bad odor to the soft drink. Millions of cans and bottles were removed from the market at a cost of $103 million.100 In some of the bottles, the carbon dioxide was contaminated with small amounts of carbonyl sulfide, which hydrolyzes to hydrogen sulfide, and may have been responsible for odor-triggered reactions. Mass psychogenic illness may have contributed to the large number of medical complaints because the concentrations of the carbonyl sulfide (5–14 g/L) and hydrogen sulfide (8–17 g/L) were very low and unlikely to cause systemic toxicity.42

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Epidemics of heavy metal poisoning from contaminated food and drink have also occurred throughout history. Epidemic lead poisoning is associated with many different vehicles of transmission, including leaden bowls, kettles, and pipes. A famous 18th-century epidemic was known as the Devonshire colic. Although the exact etiology of this disorder was unknown for many years, later evidence suggested that the ingestion of lead-contaminated cider was responsible.137 Intentional chemical contamination of food may also occur. Multiple cases of metal poisoning occurred in Buenos Aires in 1987, when vandals broke into a butcher’s shop and poured an unknown amount of acaricide (45% sodium arsenite solution) over 200 kg of partly minced meat.115 The contaminated meat was purchased by 718 people. Of 307 meat purchasers who submitted to urine sampling, 49 had urine arsenic concentrations of 76 to 500 μg/dL, and 12 had urine arsenic concentrations above 500 μg/dL (normal urine arsenic is 88 pediatric deaths Cough preparation contaminated with DEG, causing 78 deaths Teething formula contaminated with DEG, causing 84 deaths

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sulfathiazole), and the typical sulfathiazole dosing regimen was several tablets within the first few hours of therapy. Twenty-nine percent of the production lot was contaminated. Food and Drug Administration (FDA) intervention was required to assist with the recovery of the tablets, although 22,000 contaminated tablets were never found.129 In the early 1960s, one of the worst drug related modern-day events occurred with the release of thalidomide as an antiemetic and sedative– hypnotic.33 Its use as a sedative–hypnotic by pregnant women caused about 5000 babies to be born with severe congenital limb anomalies.89 This tragedy was largely confined to Europe, Australia, and Canada, where the drug was initially marketed. The United States was spared because of the length of time required for review and the rigorous scrutiny of new drug applications by the FDA.86 A major therapeutic drug event that did occur in the United States involved the recommended and subsequent widespread use of diethylstilbestrol (DES) for the treatment of threatened and habitual abortions. Despite the lack of convincing efficacy data, as many as 10 million Americans received DES during pregnancy or in utero during a 30-year period, until the drug was prohibited for use during pregnancy in 1971. Adverse health effects associated with DES use include increased risk for breast cancer in “DES mothers” and increased risk of a rare form of vaginal cancer, reproductive tract anomalies, and premature births in “DES daughters.”47,51 Thorotrast (thorium dioxide 25%) is an intravenous radiologic contrast medium that was widely used between 1928 and 1955. Its use was associated with the delayed development of hepatic angiosarcomas, as well as skeletal sarcomas, leukemia, and “thorotrastomas” (malignancies at the site of extravasated thorotrast).126,141 The use of thallium to treat ringworm infections in the 1920s and 1930s also led to needless morbidity and mortality.48 Understanding that thallium caused alopecia, dermatologists and other physicians prescribed thallium acetate, both as pills and as a topical ointment (Koremlu), to remove the infected hair. A 1934 study found 692 cases of thallium toxicity after oral and topical application and 31 deaths after oral use.96 “Medicinal” thallium was subsequently removed from the market. The “Stalinon affair” in France in 1954 involved the unintentional contamination of a proprietary oral medication that was marketed for the treatment of staphylococcal skin infections, osteomyelitis, and anthrax. Although it was supposed to contain diethyltin diiodide and linoleic acid, triethyltin, a potent neurotoxin and the most toxic of organotin compounds, and trimethyltin were present as impurities. Of the approximately 1000 people who received this medication, 217 patients developed symptoms, and 102 patients died.11,18 An unusual syndrome, featuring a constellation of abdominal symptoms (pain and diarrhea) followed by neurologic symptoms (peripheral neuropathy and visual disturbances, including blindness) was experienced by approximately 10,000 Japanese people between 1955 and 1970, resulting in several hundred deaths.70 This presentation, subsequently labeled subacute myelooptic neuropathy (SMON), was associated with the use of the gastrointestinal disinfectant clioquinol, known in the West as Entero-Vioform and most often used for the prevention of travelers’ diarrhea.98 In Japan, this drug was referred to as “sei-cho-zai” (“active in normalizing intestinal function”). It was incorporated into more than 100 nonprescription proprietary medications and was used by millions of people, often for weeks or months. The exact mechanism of toxicity has not been determined, but recent investigators theorize that clioquinol may enhance the cellular uptake of certain metals, particularly zinc, and that the clioquinol–zinc chelate may act as a mitochondrial toxin, causing this syndrome.14 New cases declined rapidly when clioquinol was banned in Japan. In 1981, a number of premature neonates died with a “gasping syndrome,” manifested by severe metabolic acidosis, respiratory depression

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with gasping, and encephalopathy.46 Before the development of these findings, the infants had all received multiple injections of heparinized bacteriostatic sodium chloride solution (to flush their indwelling catheters) and bacteriostatic water (to mix medications), both of which contained 0.9% benzyl alcohol. Accumulation of large amounts of benzyl alcohol and its metabolite benzoic acid in the blood was thought to be responsible for this syndrome.46 A nursery mass poisoning occurred in 1967, when nine neonates developed extreme diaphoresis, fever, and tachypnea without rash or cyanosis. Two fatalities resulted, although the other infants responded dramatically to exchange transfusions. The illness was traced to sodium pentachlorophenate used as an antimildew agent in the hospital laundry.8 In 1989 and 1990, eosinophilia-myalgia syndrome, a debilitating syndrome somewhat similar to toxic oil syndrome, developed in more than 1500 people who had used the dietary supplement l-tryptophan.64,135 These patients presented with disabling myalgias and eosinophilia, often accompanied by extremity edema, dyspnea, and arthralgias. Skin changes, neuropathy, and weight loss sometimes developed. Intensive investigation revealed that all affected patients had ingested l-tryptophan produced by a single manufacturer that had recently introduced a new process involving genetically altered bacteria to improve l-tryptophan production. A contaminant produced by this process probably was responsible for this syndrome.21 The banning of l-tryptophan by the FDA set in motion the passage of the Dietary Supplement Health and Education Act of 1994. This legislation, which attempted to regulate an uncontrolled industry, inadvertently facilitated industry marketing of dietary supplements bypassing FDA scrutiny. In recent years, a number of therapeutic drugs previously approved by the FDA have been withdrawn from the market because of concerns about health risks.148 Many more drugs have been given “black box warnings” by the FDA because of their propensity to cause serious or life-threatening adverse effects. In 2009, more than 400 drugs had such black box warnings.45 Some of the withdrawn drugs had been responsible for causing serious drug–drug interactions (astemizole, cisapride, mibefradil, terfenadine).95 Other drugs were withdrawn because of a propensity to cause hepatotoxicity (troglitazone), anaphylaxis (bromfenac sodium), valvular heart disease (fenfluramine, dexfenfluramine), rhabdomyolysis (cerivastatin), hemorrhagic stroke (phenylpropanolamine), and other adverse cardiac and neurologic effects (ephedra, rofecoxib). One of the more disconcerting drug problems to arise was the development of cardiac valvulopathy and pulmonary hypertension in patients taking the weight-loss drug combination fenfluramine and phentermine (fen-phen) or dexfenfluramine.29,123 The histopathologic features observed with this condition were similar to the valvular lesions associated with ergotamine and carcinoid. Interestingly, appetite suppressant medications, as well as ergotamine and carcinoid, all increase available serotonin.

ALCOHOL AND ILLICIT DRUG DISASTERS Unintended toxic disasters have also involved the use of alcohol and other drugs of abuse (Table 2-5). Arsenical neuropathy developed in an estimated 40,000 people in France in 1828, when wine and bread were unintentionally contaminated by arsenious acid.84 The use of arseniccontaminated sugar in the production of beer in England in 1900 resulted in at least 6000 cases of peripheral neuropathy and 70 deaths (Staffordshire beer epidemic).105 During the early 20th century, particularly during Prohibition, the ethanolic extract of Jamaican ginger (sold as “the Jake”) was a popular ethanol substitute in the southern and midwestern United States.90 It was sold legally because it was considered a medical supplement to

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Toxicologic Plagues and Disasters in History

TABLE 2–5. Alcohol and Illicit Drug Disasters Xenobiotic

Location

Date

Significance

Triorthocresyl phosphate Methanol Methanol MPTP Heroin heated on aluminum foil 3-Methyl fentanyl Methanol Fentanyl Methanol Methanol Scopolamine Methanol Methanol

US Atlanta, GA Jackson, Ml San Jose, CA Netherlands Pittsburgh, PA Baroda, India New York City New Delhi, India Cuttack, India US East Coast Cambodia Nicaragua

1930–1931 1951 1979 1982 1982 1988 1989 1990 1991 1992 1995–1996 1998 2006

Ginger Jake paralysis Epidemic from ingesting bootleg whiskey Occurred in a prison Illicit meperidine manufacturing resulting in drug-induced parkinsonism Spongiform leukoencephalopathy “China-white” epidemic Moonshine contamination; 100 deaths “Tango and Cash” epidemic Antidiarrheal medication contaminated with methanol; >200 deaths Methanol-tainted liquor; 162 deaths 325 cases of anticholinergic poisoning in heroin users >60 deaths 800 became ill, 15 blind, 45 deaths

MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

treat headaches and aid digestion and was not subject to Prohibition. For years, the Jake was sold adulterated with castor oil, but in 1930, as the price of castor oil rose, the Jake was reformulated with an alternative adulterant, triorthocresyl phosphate (TOCP). Little was previously known about the toxicity of this compound, and TOCP proved to be a potent neurotoxin. From 1930 to 1931, at least 50,000 people who drank the Jake developed TOCP poisoning, manifested by upper and lower extremity weakness (“ginger Jake paralysis”) and gait impairment (“Jake walk” or “Jake leg”).90 A quarter century later, in Morocco, the dilution of cooking oil with a turbojet lubricant containing TOCP caused an additional 10,000 cases of TOCP-induced paralysis.125 In the 1960s, cobalt was added to several brands of beer as a foam stabilizer. Certain local breweries in Quebec City, Canada; Minneapolis, Minnesota; Omaha, Nebraska; and Louvain, Belgium added 0.5–5.5 ppm cobalt to their beer. This resulted in epidemics of fulminant heart failure among heavy beer drinkers (cobalt-beer cardiomyopathy).1,91 Epidemic methanol poisoning among those seeking ethanol and other inebriants is well described. In one such incident in Atlanta, Georgia in 1951, the ingestion of methanol-contaminated bootleg whiskey caused 323 cases of methanol poisoning, including 41 deaths. In another epidemic in 1979, 46 prisoners became ill after ingesting a methanol-containing diluent used in copy machines.130 In recent years, major mass methanol poisonings have continued to occur in developing countries, where store-bought alcohol is often prohibitively expensive. In Baroda, India in 1989, at least 100 people died and another 200 became ill after drinking a homemade liquor that was contaminated with methanol.5 In New Delhi, India in 1991, an inexpensive antidiarrheal medicine, advertised to contain large amounts of ethanol, was instead contaminated with methanol, causing more than 200 deaths.28 The following year, in Cuttack, India, 162 people died and an additional 448 were hospitalized after drinking methanol-tainted liquor.12 A major epidemic of methanol poisoning occurred in 1998 in Cambodia, when rice wine was contaminated with methanol.4 At least 60 deaths and 400 cases of illness were attributed to the methanol. Most recently, in Nicaragua in 2006, more than 800 people became ill and 45 died after drinking “aguardiente,” an alcoholic beverage made with methanol instead of the more expensive ethanol. Fifteen people became blind.128

So-called “designer drugs” are responsible for several toxicologic disasters. In 1982, several injection drug users living in San Jose, California who were attempting to use a meperidine analog MPPP (1-methyl-4-phenyl-4-propionoxy-piperidine) developed a peculiar, irreversible neurologic disease closely resembling parkinsonism.73 Investigation revealed that these patients had unknowingly injected trace amounts of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), which was present as an inadvertent product of the clandestine MPPP synthesis. The subsequent metabolism of MPTP to MPP+ resulted in a toxic compound that selectively destroyed cells in the substantia nigra, causing severe and irreversible parkinsonism. The vigorous pursuit of the cause of this disaster led to a better understanding of the pathophysiology of parkinsonism and the development of possible future treatments. Another example of a “designer drug” mass poisoning occurred in the New York City metropolitan area in 1991, when a sudden epidemic of opioid overdoses occurred among heroin users who bought envelopes labeled “Tango and Cash.”40 Expecting to receive a new brand of heroin, the drug users instead purchased the much more potent fentanyl. Increased and unpredictable toxicity resulted from the inability of the dealer to adjust (“cut”) the fentanyl dose properly. Some purchasers presumably received little or no fentanyl, while others received potentially lethal doses. A similar epidemic involving 3-methylfentanyl occurred in 1988 in Pittsburgh, Pennsylvania.82 At least 325 cases of anticholinergic poisoning occurred among heroin users in New York City; Newark, New Jersey; Philadelphia, Pennsylvania; and Baltimore, Maryland from 1995 to 1996.9 The “street drug” used in these cases was adulterated with scopolamine. Whereas naloxone treatment was associated with increased agitation and hallucinations, physostigmine administration resulted in resolution of symptoms. Why the heroin was adulterated was unknown, although the use of an opiate– scopolamine mixture was reminiscent of the morphine–scopolamine combination therapy known as “twilight sleep” that was extensively used in obstetric anesthesia during the early 20th century.104 Another unexpected complication of heroin use was observed in the Netherlands in the 1980s, when 47 heroin users developed mutism and spastic quadriparesis that was pathologically documented to be spongiform leukoencephalopathy.147 In these and subsequent cases in Europe

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and the United States, the users inhaled heroin vapors after the heroin powder had been heated on aluminum foil, a drug administration technique known as “chasing the dragon.”68,147 The exact toxic mechanism has not been elucidated.

OCCUPATION-RELATED CHEMICAL DISASTERS Unfortunately, occupation-related toxic epidemics have become increasingly common (Table 2-6). Such poisoning syndromes tend to have an insidious onset and may not be recognized clinically until years after the exposure. A specific toxin may cause myriad problems, among the most worrisome being the carcinogenic and mutagenic potentials. Although the 18th-century observations of Ramazzini and Pott introduced the concept of certain diseases as a direct result of toxic exposures in the workplace, it was not until the height of the 19th-century industrial revolution that the problems associated with the increasingly hazardous workplace became apparent.56 During the 1860s, a peculiar disorder, attributed to the effects of inhaling mercury vapor, was described among manufacturers of felt hats in New Jersey.142 Mercury nitrate was used as an essential part of the felting process at the time. “Hatter’s shakes” refers to the tremor that developed in an estimated 10% to 60% of hatters surveyed.142 Extreme shyness, another manifestation of mercurialism, also developed in many hatters in later studies. Five percent of hatters during this period died from renal failure. Other notable 19th-century and early 20th-century occupational tragedies included an increased incidence of mandibular necrosis (phossy jaw) among workers in the matchmaking industry who were exposed to white phosphorus,54 an increased incidence of bladder tumors among synthetic dye makers who used β−Naphthylamine,49 and an increased incidence of aplastic anemia among artificial leather manufacturers who used benzene.121 The epidemic of phossy jaw among matchmakers had a latency period of 5 years and a mortality rate of 20% and has been called the “greatest tragedy in the whole story of occupational disease.”25 The problem continued in the United States until Congress passed the White Phosphorus Match Act in 1912, which established a prohibitive tax on white phosphorus matches.85 Since antiquity, occupational lead poisoning has been a constant threat. Workplace exposure to lead was particularly problematic during the 19th century and early 20th century because of the large number of industries that relied heavily on lead. One of the most notorious of the

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“lead trades” was the actual production of white lead and lead oxides. Palsies, encephalopathy, and death from severe poisoning were reported.50 Other occupations that resulted in dangerous lead exposures included pottery glazing, rubber manufacturing, pigment manufacturing, painting, printing, and plumbing.81 Given the increasing awareness of harm suffered in the workplace, the British Factory and Workshop Act of 1895 required governmental notification of occupational diseases caused by lead, mercury, and phosphorus poisoning, as well as of occupational diseases caused by anthrax.75 Exposures to asbestos during the 20th century have resulted in continuing extremely consequential occupational and environmental disasters.30,97 Despite the fact that the first case of asbestosis was reported in 1907, asbestos was heavily used in the shipbuilding industries in the 1940s as an insulating and fireproofing material. Since the early 1940s, 8 to 11 million individuals were occupationally exposed to asbestos,77 including 4.5 million individuals who worked in the shipyards. Asbestos-related diseases include mesothelioma, lung cancer, and pulmonary fibrosis (asbestosis). A threefold excess of cancer deaths, primarily of excess lung cancer deaths, has been observed in asbestos-exposed insulation workers.120 The manufacture and use of a variety of newly synthesized chemicals has also resulted in mass occupational poisonings. In Louisville, Kentucky in 1974, an increased incidence of angiosarcoma of the liver was first noticed among polyvinyl chloride polymerization workers who were exposed to vinyl chloride monomer.38 In 1975, chemical factory workers exposed to the organochlorine insecticide chlordecone (Kepone) experienced a high incidence of neurologic abnormalities, including tremor and chaotic eye movements.131 An increased incidence of infertility among male Californian pesticide workers exposed to 1,2-dibromochloropropane (DBCP) was noted in 1977.143

RADIATION DISASTERS A discussion of mass poisonings is incomplete without mention of the large number of radiation disasters that have characterized the 20th century (Table 2-7). The first significant mass exposure to radiation occurred among several thousand teenage girls and young women employed in the dial-painting industry.26 These workers painted luminous numbers on watch and instrument dials with paint that contained radium. Exposure occurred by licking the paint brushes and inhaling radium-laden dust. Studies showed an increase in bone-related cancers, as well as aplastic anemia and leukemia, in exposed workers.83,106

TABLE 2–6. Occupational Disasters Xenobiotic

Location

Date

Significance

Polycyclic aromatic hydrocarbons Mercury White phosphorus β-Naphthylamine Benzene Asbestos Vinyl chloride Chlordecone 1, 2-Dibromochloropropane

England

1700s

New Jersey Europe Worldwide Newark, NJ Worldwide Louisville, KY James River, VA California

Mid to late 1800s Mid to late 1800s Early 1900s 1916–1928 20th century 1960s–1970s 1973–1975 1974

Scrotal cancer among chimney sweeps; first description of occupational cancer Outbreak of mercurialism in hatters Phossy jaw in matchmakers Bladder cancer in dye makers Aplastic anemia among artificial leather manufacturers Millions at risk for asbestos-related disease Hepatic angiosarcoma among polyvinyl chloride polymerization workers Neurologic abnormalities among insecticide workers Infertility among pesticide makers

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TABLE 2–7. Radiation Disasters Xenobiotic

Location

Date

Significance

Radium Radium Radiation Radiation Cesium

Orange, NJ US Hiroshima and Nagasaki, Japan Chernobyl, Ukraine Goiania, Brazil

1910s–1920s 1920s 1945 1986 1987

Increase in bone cancer in dial-painting workers “Radithor” (radioactive water) sold as radium-containing patent medication First atomic bombs dropped at end of World War II; clinical effects still evident today Unintentional radioactive release; acute radiation sickness Acute radiation sickness and radiation burns

At the time of the “watch” disaster, radium was also being sold as a nostrum touted to cure all sorts of ailments, including rheumatism, syphilis, multiple sclerosis, and sexual dysfunction. Referred to as “mild radium therapy” to differentiate it from the higher-dose radium that was used in the treatment of cancer at that time, such particle-emitting isotopes were hailed as powerful natural elixirs that acted as metabolic catalysts to deliver direct energy transfusions.79 During the 1920s, dozens of patent medications containing small doses of radium were sold as radioactive tablets, liniments, or liquids. One of the most infamous preparations was Radithor. Each half-ounce bottle contained slightly more than 1 Ci of radium-228 and radium-226. This radioactive water was sold all over the world “as harmless in every respect” and was heavily promoted as a sexual stimulant and aphrodisiac, taking on the glamour of a recreational drug for the wealthy.79 More than 400,000 bottles were sold. The 1932 death of Eben Byers a Radithor connoisseur from chronic radiation poisoning drew increased public and governmental scrutiny to this unregulated radium industry and helped end the era of radioactive patent medications.79 Concerns about the health effects of radiation have continued to escalate since the dawn of the nuclear age in 1945. Long-term follow-up studies 50 years after the atomic bombings at Hiroshima and Nagasaki demonstrate an increased incidence of leukemia, other cancers, radiation cataracts, hyperparathyroidism, delayed growth and development, and chromosomal anomalies in exposed individuals.66 The unintentional nuclear disaster at Chernobyl, Ukraine in April 1986 again forced the world to confront the medical consequences of 20th-century scientific advances that created the atomic age.43 The release of radioactive material resulted in 31 deaths and the hospitalization of more than 200 people for acute radiation sickness. By 2003, the predominant long-term effects of the event appeared to be childhood thyroid cancer and psychological consequences.111 In some areas of heavy contamination, the increase in childhood thyroid cancer has increased 100-fold.116 Another serious radiation event occurred in Goiania, Brazil in 1987 when an abandoned radiotherapy unit was opened in a junkyard and 244 people were exposed to cesium-137. Of those exposed, 104 showed evidence of internal contamination, 28 had local radiation injuries, and eight developed acute radiation syndrome. There were at least four deaths.103,114 In September 1999, a nuclear event at a uranium-processing plant in Japan set off an uncontrolled chain reaction, exposing 49 people to radiation.69 Radiation measured outside the facility reached 4000 times the normal ambient level. Two workers died from the effects of the radiation.

MASS SUICIDE BY POISON Toxic disasters have also manifested themselves as events of mass suicide. In 1978 in Jonestown, Guyana, 911 members of the Peoples

Temple died after drinking a beverage containing cyanide.13 Although the majority of those deaths may have been by suicide, some appear to have been involuntary.74 In 1997, phenobarbital and ethanol (sometimes assisted by physical asphyxiation) was the suicidal method favored by 39 members of the Heavens Gate cult in Rancho Santa Fe, California, a means of suicide recommended in the book Final Exit.55 Apparently, the cult members committed suicide to shed their bodies in hopes of hopping aboard an alien spaceship they believed was in the wake of the Hale-Bopp comet.72

SUMMARY Unfortunately, toxicologic plagues and disasters have had all-tooprominent roles in history. An understanding of the pathogenesis of these toxic plagues pertaining to drug, food, and occupational safety is critically important to prevent future disasters. Such events make us aware that many of the toxic agents involved are potential agents of opportunity for terrorists and nonterrorists who seek to harm others. Given the practical and ethical limitations in studying the effects of many specific toxins in humans, lessons from these unfortunate tragedies must be fully mastered and retained for future generations.

REFERENCES 1. Alexander CS: Cobalt-beer cardiomyopathy. A clinical and pathologic study of twenty-eight cases. Am J Med. 1972;53:395-417. 2. Anderson HA, Wolff MS, Lilis R, et al: Symptoms and clinical abnormalities following ingestion of polybrominated-biphenyl-contaminated food products. Ann N Y Acad Sci. 1979;320:684-702. 3. Anonymous: Cadmium pollution and Itai-itai disease. Lancet. 1971;1: 382-383. 4. Anonymous: Cambodian mob kills two Vietnamese in poisoning hysteria. Deutsche Presse-Agentur. 1998;September 4. 5. Anonymous: Fatal moonshine in India. Newsday. 1989;March 6. 6. Anonymous: Nicotine poisoning after ingestion of contaminated ground beef—Michigan, 2003. MMWR Morb Mortal Wkly Rep.. 2003;52:413-416. 7. Anonymous: Nigeria: 12 held over tainted syrup. The New York Times. 2009; February 12. 8. Anonymous: Pentachlorophenol poisoning in newborn infants—St. Louis Missouri, April–August 1967. MMWR Morb Mortal Wkly Rep. 1996;45:545-549. 9. Anonymous: Scopolamine poisoning among heroin users—New York City, Newark, Philadelphia, and Baltimore, 1995 and 1996. MMWR Morb Mortal Wkly Rep. 1996;45:457-460. 10. Anonymous: Seveso after five years. Lancet. 1981;2:731-732. 11. Anonymous: Stalinon: A therapeutic disaster. Br Med J. 1958;1:515. 12. Anonymous. Tainted liquor kills 162, sickens 228. Los Angeles Times. 1992; May 10. 13. Anonymous: The Guyana tragedy—an international forensic problem. Forensic Sci Int. 1979;13:167-172.

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14. Arbiser JL, Kraeft SK, van Leeuwen R, et al: Clioquinol-zinc chelate: a candidate causative agent of subacute myelo-optic neuropathy. Mol Med. 1998;4:665-670. 15. Audi J, Belson M, Patel M, et al: Ricin poisoning: a comprehensive review. JAMA. 2005;294:2342-351. 16. Bakir F, Damluji SF, Amin-Zaki L, et al: Methylmercury poisoning in Iraq. Science. 1973;181:230-241. 17. Banauch GI, Alleyne D, Sanchez R, et al: Persistent hyperreactivity and reactive airway dysfunction in firefighters at the World Trade Center. Am J Respir Crit Care Med. 2003;168:54-62. 18. Barnes JM, Stoner HB: The toxicology of tin compounds. Pharmacol Rev. 1959;11:211-232. 19. Barr DB, Barr JR, Weerasekera G, et al: Identification and quantification of diethylene glycol in pharmaceuticals implicated in poisoning epidemics: an historical laboratory perspective. J Anal Toxicol. 2007;31:295-303. 20. Baxter PJ, Kapila M, Mfonfu D: Lake Nyos disaster, Cameroon, 1986: the medical effects of large scale emission of carbon dioxide? Br Med J. 1989;298:1437-1441. 21. Belongia EA, Hedberg CW, Gleich GJ, et al: An investigation of the cause of the eosinophilia-myalgia syndrome associated with tryptophan use. N Engl J Med. 1990;323:357-365. 22. Brown CA, Jeong K-S, Poppenga RH, et al: Outbreaks of renal failure associated with melamine and cyanuric acid in dogs and cats in 2004 and 2007. J Vet Diagn Invest. 2007;19:525-531. 23. Caporael LR: Ergotism: The Satan loosed in Salem? Science. 1976;192:21-26. 24. Carter LJ: Michigan PBB incident: Chemical mix-up leads to disaster. Science. 1976;192:240-243. 25. Cherniack MG: Diseases of unusual occupations: an historical perspective. Occup Med. 1992;7:369-384. 26. Clark C: Radium Girls: Women and Industrial Health Reform, 1910–1935. Chapel Hill, NC: University of North Carolina Press; 1997. 27. Clauw DJ, Engel CC, Jr., Aronowitz R, et al: Unexplained symptoms after terrorism and war: An expert consensus statement. J Occup Environ Med. 2003;45:1040-1048. 28. Coll S: Tainted foods, medicine make mass poisoning rife in India: Critics press for tougher inspections, more accurate labels. Washington Post. 1991;December 8:Sect. A36. 29. Connolly HM, Crary JL, McGoon MD, et al: Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med. 1997;337:581-588. 30. Corn JK, Starr J: Historical perspective on asbestos: policies and protective measures in World War II shipbuilding. Am J Indust Med. 1987;11: 359-373. 31. Croddy E, Croddy E: Rat poison and food security in the People’s Republic of China: Focus on tetramethylene disulfotetramine (tetramine). Arch Toxicol. 2004;78:1-6. 32. Cullinan P, Acquilla S, Dhara VR: Respiratory morbidity 10 years after the Union Carbide gas leak at Bhopal: A cross sectional survey. The International Medical Commission on Bhopal. Br Med J. 1997;314: 338-342. 33. Dally A: Thalidomide: Was the tragedy preventable? Lancet. 1998;351: 1197-1199. 34. Das D, Chatterjee A, Mandal BK, et al: Arsenic in ground water in six districts of West Bengal, India: the biggest arsenic calamity in the world. Part 2. Arsenic concentration in drinking water, hair, nails, urine, skin-scale and liver tissue (biopsy) of the affected people. Analyst. 1995;120:917-924. 35. de la Paz MP, Philen RM, Borda IA: Toxic oil syndrome: The perspective after 20 years. Epidemiol Rev. 2001;23:231-247. 36. Easton WH: Smoke and fire gases. Ind Med. 1942;11:466-468. 37. Eckert WG: Mass deaths by gas or chemical poisoning. A historical perspective. Am J Forensic Med Pathol. 1991;12:119-125. 38. Falk H, Creech JL Jr, Heath CW Jr, et al: Hepatic disease among workers at a vinyl chloride polymerization plant. JAMA. 1974;230:59-63. 39. Faxon NW, Churchill ED: The Coconut Grove disaster in Boston. JAMA. 1942;120:1385-1388. 40. Fernando D: Fentanyl-laced heroin. JAMA. 1991;265:2962. 41. Ficarra BJ: Medical mystery: Gulf war syndrome. J Med. 1995;26:87-94. 42. Gallay A, Van Loock F, Demarest S, et al: Belgian Coca-Cola-related outbreak: Intoxication, mass sociogenic illness, or both? Am J Epidemiol. 2002;155:140-147. 43. Geiger HJ: The accident at Chernobyl and the medical response. JAMA. 1986;256:609-612.

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44. Geiling EHK, Cannon PR: Pathological effects of elixir of sulfanilamide (Diethylene glycol) poisoning: A clinical and experimental correlation— Final report. JAMA. 1938;111:919-926. 45. Generali J: Black Box Warnings, 2008. Available at http://www.formularyproductions.com/master/showpage.php?dir=blackbox&whichpage=9. Accessed August 17, 2009. 46. Gershanik J, Boecler B, Ensley H, et al: The gasping syndrome and benzyl alcohol poisoning. N Engl J Med. 1982;307:1384-1388. 47. Giusti RM, Iwamoto K, Hatch EE: Diethylstilbestrol revisited: a review of the long-term health effects. Ann Intern Med. 1995;122:778-788. 48. Gleich M: Thallium acetate poisoning in the treatment of ringworm of the scalp. JAMA. 1931;97:851. 49. Goldblatt MW: Vesical tumours induced by chemical compounds. Br J Indust Med. 1949;6:65-81. 50. Hamilton A: Landmark article in occupational medicine. “Forty years in the poisonous trades.” Am J Indust Med. 1985;7:3-18. 51. Herbst AL, Ulfelder H, Poskanzer DC: Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women. N Engl J Med. 1971;284:878-881. 52. Holmstedt B: Prolegomena to Seveso. Ecclesiastes I 18. Arch Toxicol. 1980;44:211-230. 53. Hood E: Lessons learned? Chemical plant safety since Bhopal. Environ Health Perspect. 2004;112:A352-359. 54. Hughes JP, Baron R, Buckland DH, et al: Phosphorus necrosis of the jaw: A present day study. Br J Indust Med. 1962;19:83-99. 55. Humphry D: Final Exit. New York: Dell; 1991. 56. Hunter D: The Diseases of Occupations, 6th ed. London: Hodder & Stoughton; 1978. 57. Hyams KC, Wignall FS, Roswell R: War syndromes and their evaluation: From the U.S. Civil War to the Persian Gulf War. Ann Intern Med. 1996;125:398-405. 58. Ingelfinger JR: Melamine and the global implications of food contamination. N Engl J Med. 2008;359:2745-2748. 59. Institute of Medicine: Veterans and Agent Orange: Update 2002. Washington, DC: National Academies Press; 2002. 60. Iowa Persian Gulf Study Group: Self-reported illness and health status among Gulf War veterans. A population-based study. JAMA. 1997;277:238-245. 61. Ismail K, Everitt B, Blatchley N, et al: Is there a Gulf War syndrome? Lancet. 1999;353:179-182. 62. Iversen A, Chalder T, Wessely S, et al: Gulf War Illness: lessons from medically unexplained symptoms. Clin Psychol Rev. 2007;27:842-854. 63. Jones GR: Polychlorinated biphenyls: where do we stand now? Lancet. 1989;2:791-794. 64. Kilbourne EM, Posada de la Paz M, Abaitua Borda I, et al: Toxic oil syndrome: A current clinical and epidemiologic summary, including comparisons with the eosinophilia-myalgia syndrome. J Am Coll Cardiol. 1991;18:711-717. 65. Kilbourne EM, Rigau-Perez JG, Heath CW, Jr., et al: Clinical epidemiology of toxic-oil syndrome. Manifestations of a new illness. N Engl J Med. 1983;309:1408-1414. 66. Kodama K, Mabuchi K, Shigematsu I: A long-term cohort study of the atomic-bomb survivors. J Epidemiol. 1996;6:S95-S105. 67. Kopelman H, Robertson MH, Sanders PG, Ash I: The Epping jaundice. Br Med J. 1966;5486:514-516. 68. Kriegstein AR, Shungu DC, Millar WS, et al: Leukoencephalopathy and raised brain lactate from heroin vapor inhalation (“chasing the dragon”). Neurology. 1999;53:1765-1773. 69. Lamar J: Japan’s worst nuclear accident leaves two fighting for life. Br Med J. 1999;319:937. 70. Lambert ED: Modern Medical Mistakes. Bloomington, IN: Indiana University Press; 1978. 71. Landrigan PJ: Illness in Gulf War veterans. Causes and consequences. JAMA. 1997;277:259-261. 72. Lang J: Heavens’s Gate suicide still a mystery 1 year later. Arizona Republic. 1998; March 26:Sect. A11. 73. Langston JW, Ballard P, Tetrud JW, Irwin I: Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science. 1983;219:979-980. 74. Layton D: Seductive Poison: A Jonestown Survivor’s story of Life and Death in the Peoples Temple. New York: Anchor; 1998. 75. Lee WR: The history of the statutory control of mercury poisoning in Great Britain. Br J Ind Med. 1968;25:52-62.

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Chapter 2

Toxicologic Plagues and Disasters in History

76. Leschke E: Clinical Toxicology: Modern Methods in the Diagnosis and Treatment of Poisoning. Baltimore: William Wood; 1934. 77. Levin SM, Kann PE, Lax MB: Medical examination for asbestos-related disease. Am J Indust Med. 2000;37:6-22. 78. Logan WPD: Mortality in the London fog incident. Lancet. 1953;1:336-338. 79. Macklis RM: Radithor and the era of mild radium therapy. JAMA. 1990;264:614-618. 80. Magnuson E: The devil made him do it. Time. 1990; April 9:38. 81. Markowitz G, Rosner D: “Cater to the children”: The role of the lead industry in a public health tragedy, 1900–1955. Am J Public Health. 2000;90:36-46. 82. Martin M, Hecker J, Clark R, et al: China White epidemic: An eastern United States emergency department experience. Ann Emerg Med. 1991;20:158-164. 83. Martland HS: Occupational poisoning in manufacture of luminous watch dials. JAMA. 1929;92:466-73, 552-559. 84. Massey EW, Wold D, Heyman A: Arsenic: Homicidal intoxication. South Med J. 1984;77:848-851. 85. Matossian MK: Ergot and the Salem witchcraft affair. Am Sci. 1982;70: 355-357. 86. McFadyen RE: Thalidomide in America: A brush with tragedy. Clio Med. 1976;11:79-93. 87. Mehta PS, Mehta AS, Mehta SJ, Makhijani AB: Bhopal tragedy’s health effects. A review of methyl isocyanate toxicity. JAMA. 1990;264:2781-2787. 88. Merhoff GC, Porter JM: Ergot intoxication: historical review and description of unusual clinical manifestations. Ann Surg. 1974;180:773-779. 89. Modell W: Mass drug catastrophes and the roles of science and technology. Science. 1967;156:346-351. 90. Morgan JP: The Jamaica ginger paralysis. JAMA. 1982;248:1864-1867. 91. Morin YL, Foley AR, Martineau G, Roussel J: Quebec beer-drinkers’ cardiomyopathy: Forty-eight cases. Can Med Assoc J. 1967;97:881-883. 92. Morita H, Yanagisawa N, Nakajima T, et al: Sarin poisoning in Matsumoto, Japan. Lancet. 1995;346:290-293. 93. Mudur G: Arsenic poisons 220,000 in India. Br Med J. 1996;313:319. 94. Mudur G: Half of Bangladesh population at risk of arsenic poisoning. Br Med J. 2000;320:822. 95. Mullins ME, Horowitz BZ, Linden DH, et al: Life-threatening interaction of mibefradil and beta-blockers with dihydropyridine calcium channel blockers. JAMA. 1998;280:157-158. 96. Munch JC: Human thallotoxicosis. JAMA. 1934;102:1929-1934. 97. Murray R: Asbestos: A chronology of its origins and health effects. Br J Ind Med. 1990;47:361-365. 98. Nakae K, Yamamoto S, Shigematsu I, Kono R: Relation between subacute myelo-optic neuropathy (S.M.O.N.) and clioquinol: Nationwide survey. Lancet. 1973;1:171-173. 99. Nakajima T, Ohta S, Morita H, et al: Epidemiological study of sarin poisoning in Matsumoto City, Japan. J Epidemiol. 1998;8:33-41. 100. Nemery B, Fischler B, Boogaerts M, et al: The Coca-Cola incident in Belgium, June 1999. Food Chem Toxicol. 2002;40:1657-1667. 101. O’Brien KL, Selanikio JD, Hecdivert C, et al: Epidemic of pediatric deaths from acute renal failure caused by diethylene glycol poisoning. Acute Renal Failure Investigation Team. JAMA. 1998;279:1175-1180. 102. Okumura T, Takasu N, Ishimatsu S, et al: Report on 640 victims of the Tokyo subway sarin attack. Ann Emerg Med. 1996;28:129-135. 103. Oliveira AR, Hunt JG, Valverde NJ, et al: Medical and related aspects of the Goiania accident: An overview. Health Phys. 1991;60:17-24. 104. Pitcock CD, Clark RB: From Fanny to Fernand: The development of consumerism in pain control during the birth process. Am J Obstet Gynecol. 1992;167:581-587. 105. Poisoning FrotRCoA. Lancet. 1903;2:1674-1676. 106. Polednak AP, Stehney AF, Rowland RE: Mortality among women first employed before 1930 in the U.S. radium dial-painting industry. A group ascertained from employment lists. Am J Epidemiol. 1978;107:179-195. 107. Powell PP: Minamata disease: A story of mercury’s malevolence. South Med J. 1991;84:1352-1358. 108. Prezant DJ, Prezant DJ: World Trade Center cough syndrome and its treatment. Lung. 2008;186(suppl 1):S94-S102. 109. Prezant DJ, Weiden M, Banauch GI, et al: Cough and bronchial responsiveness in firefighters at the World Trade Center site. N Engl J Med. 2002;347:806-815. 110. Rahman MM, Chowdhury UK, Mukherjee SC, et al: Chronic arsenic toxicity in Bangladesh and West Bengal, India—a review and commentary. J Toxicol Clin Toxicol. 2001;39:683-700.

111. Rahu M: Health effects of the Chernobyl accident: Fears, rumours and the truth. Eur J Cancer. 2003;39:295-299. 112. Rentz EL, Lewis L, Mujica, OJ, et al: Outbreak of acute renal failure in Panama in 2006: A case-control study. Bull World Health Organ. 2008;86:749-756. 113. Research Advisory Committee on Gulf War Veterans’ Illnesses: Gulf War Illness and the Health of Gulf War Veterans: Scientific Findings and Recommendations 2008. Available at http://www1.va.gov/RAC-GWVI/. Accessed August 18, 2009. 114. Roberts L: Radiation accident grips Goiania. Science. 1987;238:1028-1031. 115. Roses OE, Garcia Fernandez JC, Villaamil EC, et al: Mass poisoning by sodium arsenite. J Toxicol Clin Toxicol. 1991;29:209-213. 116. Rytomaa T: Ten years after Chernobyl. Ann Med. 1996;28:83-87. 117. Scalzo AJ: Diethylene glycol toxicity revisited: the 1996 Haitian epidemic. J Toxicol Clin Toxicol. 1996;34:513-516. 118. Schier JG, Patel MM, Belson MG, et al: Public health investigation after the discovery of ricin in a South Carolina postal facility. Am J Public Health. 2007;97(suppl 1):S152-S157. 119. Schmid R: Cutaneous porphyria in Turkey. N Engl J Med. 1960;263:397398. 120. Selikoff IJ, Hammond EC, Seidman H: Mortality experience of insulation workers in the United States and Canada, 1943–1976. Ann N Y Acad Sci. 1979;330:91-116. 121. Sharpe WD: Benzene, artificial leather and aplastic anemia: Newark, 1916–1928. Bull N Y Acad Med. 1993;69:47-60. 122. Sheridan RL, Schulz JT, Ryan CM, McGinnis PJ: Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 6-2004. A 35-year-old woman with extensive, deep burns from a nightclub fire. N Engl J Med. 2004;350:810-821. 123. Shively BK, Roldan CA, Gill EA, et al: Prevalence and determinants of valvulopathy in patients treated with dexfenfluramine. Circulation. 1999;100:2161-2167. 124. Sidell FR: Chemical agent terrorism. Ann Emerg Med. 1996;28:223-224. 125. Smith HV, Spalding JM: Outbreak of paralysis in Morocco due to orthocresyl phosphate poisoning. Lancet. 1959;2:1019-1021. 126. Stover BJ: Effects of Thorotrast in humans. Health Phys. 1983;44(suppl 1):253-257. 127. Subramanian KS, Kosnett MJ: Human exposures to arsenic from consumption of well water in West Bengal, India. Int J Occup Environ Health. 1998;4:217-230. 128. Surburban Emergency Management Project: Largest Mass Methanol Poisoning in History Sickens 800 and Kills 45, Nicaragua, September, 2006. Available at http://www.semp.us/publications/biot_reader. php?BiotID=412. Accessed August 18, 2009. 129. Swann JP: The 1941 sulfathiazole disaster and the birth of good manufacturing practices. PDA J Pharm Sci Technol. 1999;53:148-153. 130. Swartz RD, Millman RP, Billi JE, et al: Epidemic methanol poisoning: Clinical and biochemical analysis of a recent episode. Medicine. 1981;60:373-382. 131. Taylor JR, Selhorst JB, Houff SA, Martinez AJ: Chlordecone intoxication in man. I. Clinical observations. Neurology. 1978;28:626-630. 132. Tsuchiya K: The discovery of the causal agent of Minamata disease. Am J Indust Med. 1992;21:275-280. 133. Unwin C, Blatchley N, Coker W, et al: Health of UK servicemen who served in Persian Gulf War. Lancet. 1999;353:169-178. 134. Urbinato D: London’s historic “pea-soupers.” EPA J. 1994:59. 135. Varga J, Uitto J, Jimenez SA: The cause and pathogenesis of the eosinophilia-myalgia syndrome. Ann Intern Med. 1992;116:140-147. 136. Varma DR, Guest I: The Bhopal accident and methyl isocyanate toxicity. J Toxicol Environ Health. 1993;40:513-529. 137. Waldron HA: The Devonshire colic. J Hist Med Allied. Sci 1970;25:383413. 138. Wax PM: Elixirs, diluents, and the passage of the 1938 Federal Food, Drug and Cosmetic Act. Ann Intern Med. 1995;122:456-461. 139. Wax PM: It’s happening again—another diethylene glycol mass poisoning. J Toxicol Clin Toxicol. 1996;34:517-520. 140. Wax PM, Becker CE, Curry SC: Unexpected “gas” casualties in Moscow: A medical toxicology perspective. Ann Emerg Med. 2003;41:700-705. 141. Weber E, Laarbaui F, Michel L, Donckier J: Abdominal pain: Do not forget Thorotrast! Postgrad Med J. 1995;71:367-368. 142. Wedeen RP: Were the hatters of New Jersey “mad”? Am J Indust Med. 1989;16:225-233.

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Chapter 2

143. Whorton D, Krauss RM, Marshall S, Milby TH: Infertility in male pesticide workers. Lancet. 1977;2:1259-1261. 144. Wing JS, Brender JD, Sanderson LM, et al: Acute health effects in a community after a release of hydrofluoric acid. Arch Environ Health. 1991;46:155-160. 145. Wolff MS, Anderson HA, Selikoff IJ: Human tissue burdens of halogenated aromatic chemicals in Michigan. JAMA. 1982;247:2112-2116. 146. Wolkin AF, Patel M, Watson W, et al: Early detection of illness associated with poisonings of public health significance. Ann Emerg Med. 2006;47:170-176.

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147. Wolters EC, van Wijngaarden GK, Stam FC, et al: Leucoencephalopathy after inhaling “heroin” pyrolysate. Lancet. 1982;2:1233-1237. 148. Wysowski DK, Swartz L, Wysowski DK, Swartz L: Adverse drug event surveillance and drug withdrawals in the United States, 1969–2002: the importance of reporting suspected reactions. Arch Intern Med. 2005;165:1363-1369. 149. Yardley J: 40,000 Chinese evacuated from explosion “death zone.” The New York Times. 2003;December 27:Sect. A3.

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PART A

THE GENERAL APPROACH TO MEDICAL TOXICOLOGY

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CHAPTER 3

INITIAL EVALUATION OF THE PATIENT: VITAL SIGNS AND TOXIC SYNDROMES Lewis S. Nelson, Neal A. Lewin, Mary Ann Howland, Robert S. Hoffman, Lewis R. Goldfrank, and Neal E. Flomenbaum For more than 200 years, American physicians and nurses have attempted to standardize their approach to the assessment of patients. At the New York Hospital in 1865, pulse rate, respiratory rate, and temperature were incorporated into the bedside chart and called “vital signs.”6 It was not until the early part of the 20th century, however, that blood pressure determination also became routine. Additional components of the standard emergency assessment, such as oxygen saturation by pulse oximetry, capillary blood glucose, and pain severity, are now also beginning to be considered vital signs. Although assessment of oxygen saturation, capillary glucose, and pain severity are essential components of the clinical assessment and are important considerations throughout this text, they are not discussed in this chapter. In the practice of medical toxicology, vital signs play an important role beyond assessing and monitoring the overall status of a patient, as they frequently provide valuable physiologic clues to the toxicologic etiology and severity of an illness. The vital signs also are a valuable parameter, which are used to assess and monitor a patient’s response to supportive treatment and antidotal therapy. Table 3–1 presents the normal vital signs for various age groups. However, this broad range of values considered normal should serve merely as a guide. Only a complete assessment of a patient can determine whether or not a particular vital sign is truly clinically normal. This table of normal vital signs is useful in assessing children because normal values for children vary considerably with age, and knowing the range of normal variation is essential. Normal temperature is defined as 95° to 100.4°F (35° to 38°C). The difficulty in defining what constitutes “normal” vital signs in an emergency setting has been inadequately addressed and may prove to be an impossible undertaking. Published normal values may have little relevance to an acutely ill or anxious patient in the emergency setting, yet that is precisely the environment in which we must define abnormal vital signs and address them accordingly. Even in nonemergent situations, “normalcy” of vital signs depends on the clinical condition of the patient. A sleeping or comatose patient may have physiologic bradycardia; a slow heart rate appropriate for his or her low energy requiring state. For these reasons, descriptions of vital signs as “normal” or “stable” are too nonspecific to be meaningful and therefore should never be accepted as defining normalcy in an individual patient. Conversely, no patient should be considered too agitated, too young, or too gravely ill for the practitioner to obtain a complete set of vital signs; indeed, these patients urgently need a thorough evaluation that includes all of the vital signs. Also, the vital signs must be recorded as accurately as possible first in the prehospital setting, again with precision and accuracy

as soon as a patient arrives in the emergency department, and serially thereafter as clinically indicated. Many xenobiotics affect the autonomic nervous system, which, in turn, affects the vital signs via the sympathetic pathway, the parasympathetic pathway, or both. Meticulous attention to both the initial and repeated determinations of vital signs is of extreme importance in identifying a pattern of changes suggesting a particular xenobiotic or group of xenobiotics. The value of serial monitoring of the vital signs is demonstrated by the patient who presents with an anticholinergic overdose who is then given the antidote, physostigmine. In this situation, it is important to recognize when tachycardia becomes bradycardia (i.e., anticholinergic syndrome followed by physostigmine excess). Meticulous attention to these changes ensures that the therapeutic interventions can be modified or adjusted accordingly. Similarly, consider the course of a patient who has opioid-induced bradypnea (a decreased rate of breathing) and then develops tachypnea (an increased rate of breathing) after the administration of the opioid antagonist naloxone. The analysis becomes exceedingly complicated when that patient may have been exposed to two or more substances, such as an opioid combined with cocaine. In this situation, the effects of cocaine may be “unmasked” by the naloxone used to counteract the opioid, and the clinician must then be forced to differentiate naloxoneinduced opioid withdrawal from cocaine toxicity. The assessment starts by analyzing diverse information, including vital signs, history, and physical examination. Table 3–2 describes the most typical toxic syndromes. This table includes only vital signs that are thought to be characteristically abnormal or pathognomonic and directly related to the toxicologic effect of the xenobiotic. The primary purpose of the table, however, is to include many findings, in addition to the vital signs, that together constitute a toxic syndrome. Mofenson and Greensher5 coined the term toxidromes from the words toxic syndromes to describe the groups of signs and symptoms that consistently result from particular toxins. These syndromes are usually best described by a combination of the vital signs and clinically apparent end-organ manifestations. The signs that prove most clinically useful are those involving the central nervous system (CNS; mental status), ophthalmic system (pupil size), gastrointestinal system (peristalsis), dermatologic system (skin dryness versus diaphoresis), mucous membranes (moistness versus dryness), and genitourinary system (urinary retention versus incontinence). Table 3–2 includes some of the most important signs and symptoms and the xenobiotics most commonly responsible for these manifestations. A detailed analysis of each sign, symptom, and toxic syndrome can be found in the pertinent chapters throughout the text. In this chapter, the most typical toxic syndromes (see Table 3–2) are considered to enable the appropriate assessment and differential diagnosis of a poisoned patient. In considering a toxic syndrome, the reader should always remember that the actual clinical manifestations of a poisoning are far more variable than the syndromes described in Table 3–2. The concept of the toxic syndrome is most useful when thinking about a clinical presentation and formulating a framework for assessment. Although some patients may present as “classic” cases, others manifest partial toxic syndromes or formes frustes. These incomplete syndromes may still provide at least a clue to the correct diagnosis. It is important to understand that partial presentations (particularly in the presence of multiple xenobiotics) do not necessarily imply less severe disease and, therefore, are comparably important to appreciate. In some instances, an unexpected combination of findings may be particularly helpful in identifying a xenobiotic or a combination of xenobiotics. For example, a dissociation between such typically paired changes as an increase in pulse with a decrease in blood pressure (cyclic antidepressants or phenothiazines), or the presentation of a decrease

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Part A

The General Approach to Medical Toxicology

TABLE 3–1. Normal Vital Signs by Agea Age Adult 16 years 12 years 10 years 6 years 4 years 4 months 2 months Newborn

Systolic BP (mm Hg)

Diastolic BP (mm Hg)

≤120 ≤120 119 115 107 104 90 85 65

41.1°C) from any cause may lead to extensive rhabdomyolysis, myoglobinuric renal failure, and direct liver and brain injury and must therefore be identified and corrected immediately. Hyperthermia may result from a distinct neurologic response to a signal demanding thermal “upregulation.” This signal can be from internal generation of heat beyond the capacity of the body to cool, such as occurs in association with agitation or mitochondrial uncoupling, or from an externally imposed physical or environmental factor, such as the environmental conditions causing heat stroke or the excessive swaddling in clothing causing hyperthermia in infants. Fever, or pyrexia, is hyperthermia due to an elevation in the hypothalamic thermoregulatory set-point. Regardless of etiology, core temperatures higher than 106°F (41.1°C) are extremely rare unless normal feedback mechanisms are overwhelmed. Hyperthermia of this extreme nature is usually attributed to environmental heat stroke; extreme psychomotor agitation; or xenobiotic-related

TABLE 3–6. Common Xenobioticsa That Affect Temperatureb Hyperthermia

Hypothermia

Anticholinergics Chlorphenoxy herbicides Dinitrophenol and congeners Malignant hyperthermiaa Monoamine oxidase inhibitors Neuroleptic malignant syndromea Phencyclidine Salicylates Sedative-hypnotic or ethanol withdrawal Serotonin syndromea Sympathomimetics Thyroid hormone

α2-Adrenergic agonists Carbon monoxide Ethanol γ Hydroxybutyric Acid Hypoglycemics Opioids Sedative-hypnotics Thiamine deficiency

a

Three common xenobiotic-induced syndromes are also included.

b

Chap. 15 lists additional xenobiotics that affect temperature.

temperature disturbances such as malignant hyperthermia, the serotonin syndrome, or the neuroleptic malignant syndrome. A common xenobiotic-related hyperthermia pattern that frequently occurs in the emergency department is defervescence after an acute temperature elevation resulting from agitation or a grand mal seizure. Table 3–6 is a representative list of xenobiotics that affect body temperature. (Chap. 15 provides greater detail.) Hypothermia is probably less of an immediate threat to life than hyperthermia, but it requires rapid appreciation, accurate diagnosis, and skilled management. Hypothermia impairs the metabolism of many xenobiotics, leading to unpredictable delayed toxicologic effects when the patient is warmed. Many xenobiotics that lead to an alteration of metal status place patients at great risk for becoming hypothermic from exposure to cold climates. Most importantly, a hypothermic patient should never be declared dead without both an extensive assessment and a full resuscitative effort of adequate duration, taking into consideration the difficulties in resuscitating cold but living patients. This is true whenever the body temperature remains less than 95°F (35°C) (Chap. 15 ).

SUMMARY Early, accurate determinations followed by serial monitoring of the vital signs are as essential in medical toxicology as in any other type of emergency or critical care medicine. For this reason, the vital signs are an essential part of the initial evaluation of every case, and serial vital signs are always necessary throughout the patient’s clinical evaluation. Careful observation of the vital signs helps to determine appropriate therapeutic interventions and guide the clinician in making necessary adjustments to initial and subsequent therapeutic interventions. When pathognomonic clinical and laboratory findings are combined with accurate initial and sometimes changing vital signs, a toxic syndrome may become evident, which will aid in both general supportive and specific antidotal treatment. Toxic syndromes will also guide further diagnostic testing.

REFERENCES 1. Gravelyn TR, Weg JG: Respiratory rate as an indicator of acute respiratory dysfunction. JAMA. 1980;244:1123-1125. 2. Hooker EA, Danzl DF, Brueggmeyer M, Harper E: Respiratory rates in pediatric emergency patients. J Emerg Med. 1992;10:407-412. 3. Hooker EA, O’Brien DJ, Danzl DF, et al: Respiratory rates in emergency department patients. J Emerg Med. 1989;7:129-132. 4. Karajalainen J, Vitassalo M: Fever and cardiac rhythm. Arch Intern Med. 1986;146:1169-1171. 5. Mofenson HC, Greensher J: The unknown poison. Pediatrics. 1974;54: 336-342. 6. Musher DM, Dominguez EA, Bar-Sela A: Edouard Seguin and the social power of thermometry. N Engl J Med. 1987;316:115-117. 7. Opthof T: The normal range and determinants of the intrinsic heart rate in man. Cardiovasc Res. 2000;45:177-184. 8. Spodick DH: Normal sinus heart rate: Appropriate rate thresholds for sinus tachycardia and bradycardia. South Med J. 1996;89:666-667.

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CHAPTER 4

PRINCIPLES OF MANAGING THE ACUTELY POISONED OR OVERDOSED PATIENT Lewis S. Nelson, Neal A. Lewin, Mary Ann Howland, Robert S. Hoffman, Lewis R. Goldfrank, and Neal E. Flomenbaum

OVERVIEW For almost 5 decades, medical toxicologists and information specialists have used a clinical approach to poisoned or overdosed patients that emphasizes treating the patient rather than treating the poison. Too often in the past, patients were initially all but neglected while attention was focused on the ingredients listed on the containers of the product(s) to which they presumably were exposed. Although the astute clinician must always be prepared to administer a specific antidote immediately in instances when nothing else will save a patient, all poisoned or overdosed patients will benefit from an organized, rapid clinical management plan (Fig. 4-1). Over the past 2 decades, some basic tenets and long-held beliefs regarding the initial therapeutic interventions in toxicologic management have been questioned and subjected to an “evidence-based” analysis. For example, in the mid-1970s, most medical toxicologists began to advocate a standardized approach to a comatose and possibly overdosed adult patient, typically calling for the intravenous (IV) administration of 50 mL of D50W, 100 mg of thiamine and 2 mg of naloxone along with 100% oxygen at high flow rates. The rationale for this approach was to compensate for the previously idiosyncratic style of overdose management encountered in different healthcare settings and for the unfortunate likelihood that omitting any one of these measures at the time that care was initiated in the emergency department (ED) would result in omitting it altogether. It was not unusual then to discover from a laboratory chemistry report more than 1 hour after a supposedly overdosed comatose patient had arrived in the ED that the initial blood glucose was 30 or 40 mg/dL—a critical delay in the management of unsuspected and consequently untreated hypoglycemic coma. Today, however, with the widespread availability of accurate rapid bedside testing for capillary glucose and pulse oximetry for oxygen saturation, coupled with a much greater appreciation by all physicians of what needs to be done for each suspected overdose patient, clinicians can safely provide a more rational, individualized approach to determine the need for, and in some instances more precise amounts of, dextrose, thiamine, naloxone, and oxygen. A second major approach to providing more rational individualized early treatment for toxicologic emergencies involves a closer examination of the actual risks and benefits of various gastrointestinal (GI) emptying interventions. Appreciation of the potential for significant adverse effects associated with all types of GI emptying interventions and recognition of the absence of clear evidence-based support of efficacy have led to a significant reduction in the routine use of activated charcoal (AC) and almost complete elimination of syrup of ipecac– induced emesis or orogastric lavage and cathartic-induced intestinal evacuation. In 2004, the American Academy of Pediatricians (AAP)

all but entirely abandoned its recommendations for the use of syrup of ipecac in the home. The efficacy of orogastric lavage, even when indicated by the nature or type of ingestion, is limited by the amount of time elapsed since the ingestion. The value of whole-bowel irrigation (WBI) with polyethylene glycol electrolyte solution (PEG-ELS) appears to be much more specific and limited than originally thought, and some of the limitations and (uncommon) adverse effects of AC are now more widely recognized. Similarly, interventions to eliminate absorbed xenobiotics from the body are now much more narrowly defined or, in some cases, abandoned. Multiple-dose activated charcoal (MDAC) is useful for select but not all xenobiotics. Ion trapping in the urine is only beneficial, achievable, and relatively safe when the urine can be maximally alkalinized after a significant salicylate, phenobarbital, or chlorpropamide poisoning. Finally, the roles of hemodialysis, hemoperfusion, and other extracorporeal techniques are now much more specifically defined. With the foregoing in mind, this chapter represents our current efforts to formulate a logical and effective approach to managing a patient with probable or actual toxic exposure. Table 4-1 provides a recommended stock list of antidotes and therapeutics for the treatment of poisoned or overdosed patients.

MANAGING ACUTELY POISONED OR OVERDOSED PATIENTS Rarely, if ever, are all of the circumstances involving a poisoned patient known. The history may be incomplete, unreliable, or unobtainable; multiple xenobiotics may be involved; and even when a xenobiotic etiology is identified, it may not be easy to determine whether the problem is an overdose, an allergic or idiosyncratic reaction, or a drug– drug interaction. Similarly, it is sometimes difficult or impossible to differentiate between adverse effects of a correct dose of medication and the consequences of a deliberate or unintentional overdose. The patient’s presenting signs and symptoms may force an intervention at a time when there is almost no information available about the etiology of the patient’s condition (Table 4-2), and as a result, therapeutics must be thoughtfully chosen empirically to treat or diagnose a condition without exacerbating the situation.

INITIAL MANAGEMENT OF PATIENTS WITH A SUSPECTED EXPOSURE Similar to the management of any seriously compromised patient, the clinical approach to the patient potentially exposed to a xenobiotic begins with the recognition and treatment of life-threatening conditions, including airway compromise, breathing difficulties, and circulatory problems such as hemodynamic instability and serious dysrhythmias. After the “ABCs” (airway, breathing, and circulation) have been addressed, the patient’s level of consciousness should be assessed because this helps determine the techniques to be used for further management of the exposure.

MANAGEMENT OF PATIENTS WITH ALTERED MENTAL STATUS Altered mental status (AMS) is defined as the deviation of a patient’s sensorium from normal. Although it is commonly construed as a depression in the patient’s level of consciousness, a patient with agitation, delirium, psychosis, and other deviations from normal is also

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Part A

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Is the patient having difficulty breathing? No

Yes Obtain control of the airway, ventilation, and oxygenation

Obtain oxygen saturation by pulse oximetry

Obtain vital signs. Are life-threatening abnormalities present? Yes

No

1. Attach the patient to a cardiac monitor; obtain a 12-lead ECG 2. Obtain oxygen saturation by pulse oximetry and an ABG (or VBG) and give supplemental oxygen if not already done 3. Start an intravenous line 4. Obtain rapid bedside glucose concentration and send blood for glucose and electrolytes; save blood for other studies

Consider empiric administration of 1. Hypertonic dextrose 2. Thiamine 3. Naloxone

Consider the use of emergent therapies for seizures, significant psychomotor agitation, cardiac dysrhythmias, or severe metabolic abnormalities

Obtain a rapid history; perform a rapid physical examination

Can a specific toxic syndrome be identified? Yes

No

Treat the toxic syndrome

Obtain a thorough history Reassess and complete the physical examination Send bloods: electrolytes, glucose, CBC, ABG,(or VBG), acetaminophen, as indicated

Consider gastric emptying with orogastric lavage

Consider prevention of xenobiotic absorption with 1. Activated charcoal 2. Whole-bowel irrigation

Evaluate for enhanced elimination 1. Multiple-dose activated charcoal 2. Urinary alkalinization 3. Extracorporeal drug removal

Evaluate for ICU admission or continued emergency department management; assess psychiatric status, and determine social services needs prior to discharge, as indicated FIGURE 4-1 This algorithm is a basic guide to the management of poisoned patients. A more detailed description of the steps in management may be found in the accompanying text. This algorithm is only a guide to actual management, which must, of course, consider the patient’s clinical status.

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Principles of Managing the Acutely Poisoned or Overdosed Patient

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TABLE 4–1. Antidotes and Therapeutics for the Treatment of Poisonings and Overdosesa Therapeuticsb

Uses

Therapeuticsb

Uses

Activated charcoal (p. 108) Antivenom (Crotalinae) (p. 1608) Antivenom (Elapidae) (p. 1308) Antivenom (Latrodectus mactans) (p. 1582) Atropine (p. 1473)

Adsorbs xenobiotics in the GI tract Crotaline snake envenomations Coral snake envenomations Black widow spider envenomations

Ipecac, syrup of (p. 104) Magnesium sulfate or magnesium citrate (p. 114) Magnesium sulfate injection

Induces emesis Induces catharsis

Benzodiazepines (p1109)

Botulinum antitoxin (ABE-trivalent) (p. 695) Calcium chloride, calcium gluconate (p. 1381) L-Carnitine (p. 711) Cyanide kit (nitrites, p. 1689; sodium thiosulfate, p. 1692) Dantrolene (p. 1001) Deferoxamine mesylate (Desferal) (p. 604) Dextrose in water (50% adults; 20% pediatrics; 10% neonates) (p. 728) Digoxin-specific antibody fragments (Digibind and Digifab) (p. 946) Dimercaprol (BAL, British anti-Lewisite) (p. 1229) Diphenhydramine DTPA (p. 1779) Edetate calcium disodium (calcium disodium versenate, CaNa2 EDTA) (p. 1290) Ethanol (oral and parenteral dosage forms) (p. 1419) Fat emulsion (Intralipid 20% (p. 976) Flumazenil (Romazicon) (p. 1072) Folinic acid (Leucovorin) (p. 783) Fomepizole (Antizole) (p. 1414) Glucagon (p. 910) Glucarpidase (p. 787) Hydroxocobalamin (Cyanokit) (p. 1695) Insulin (p. 893) Iodide, potassium (SSKI) (p. 1775)

Bradydysrhythmias, cholinesterase inhibitors (organic phosphorus compounds, physostigmine) muscarinic mushrooms (Clitocybe, Inocybe) ingestions Seizures, agitation, stimulants, ethanol and sedative–hypnotic withdrawal, cocaine, chloroquine, organic phosphorus compounds Botulism Fluoride, hydrofluoric acid, ethylene glycol, CCBs, hypomagnesemia, β-adrenergic antagonists Valproic acid Cyanide Malignant hyperthermia Iron Hypoglycemia

Cardioactive steroids

Arsenic, mercury, gold, lead Dystonic reactions, allergic reactions Radioactive isotopes Lead, other selected metals

Methanol, ethylene glycol Cardiac arrest, local anesthetics Benzodiazepines Methotrexate, methanol Ethylene glycol, methanol β-Adrenergic antagonists, CCBs Methotrexate Cyanide β-Adrenergic antagonists, CCBs, hyperglycemia Radioactive iodine (I131)

Methylene blue (1% solution) (p. 1708) N-acetylcysteine (Acetadote) (p. 500) Naloxone hydrochloride (Narcan) (p. 579) Norepinephrine (Levophed)

Cardioactive steroids, hydrofluoric acid, hypomagnesemia, ethanol withdrawal, torsades de pointes Methemoglobinemia Acetaminophen and other causes of hepatotoxicity Opioids, clonidine

Hypotension (preferred for cyclic antidepressants) Octreotide (Sandostatin) (p. 734) Oral hypoglycemic induced hypoglycemia Oxygen (Hyperbaric) (p. 1671) Carbon monoxide, cyanide, hydrogen sulfide D-Penicillamine (Cuprimine) (p. 1261) Copper Phenobarbital Seizures, agitation, stimulants, ethanol and sedative–hypnotic withdrawal Phentolamine (p. 1096) Cocaine, MAOI interactions, epinephrine, and ergot alkaloids Physostigmine salicylate Anticholinergics (Antilirium) (p. 759) Polyethylene glycol electrolyte Decontaminates GI tract solution (p. 114) Pralidoxime chloride, (2-PAMAcetylcholinesterase inhibitors chloride; Protopam) (p. 1467) (organic phosphorus agents and carbamates) Protamine sulfate (p. 880) Heparin anticoagulation Prussian blue (Radiogardase) (p. 1334) Thallium, cesium Pyridoxine hydrochloride Isoniazid, ethylene glycol, (Vitamin B6) (p. 845) gyromitrin-containing mushrooms Sodium bicarbonate (p. 520) Ethylene glycol, methanol, salicylates, cyclic antidepressants, methotrexate, phenobarbital, quinidine, chlorpropamide, type 1 antidysrhythmics, chlorphenoxy herbicides Sorbitol (p. 114) Induces catharsis Starch (p. 1349) Iodine Succimer (Chemet) (p. 1284) Lead, mercury, arsenic Thiamine hydrochloride Thiamine deficiency, ethylene (Vitamin B1.) (p. 1129) glycol, chronic ethanol consumption (“alcoholism”) Vitamin K1 (Aquamephyton) (p. 876) Warfarin or rodenticide anticoagulants

a Each emergency department should have the vast majority of these antidotes immediately available, some of these antidotes may be stored in the pharmacy, and others may be available from the Centers for Disease Control and Prevention, but the precise mechanism for locating each one must be known by each staff member. b A detailed analysis of each of these agents is found in the text in the Antidotes in Depth section on the page cited to the right of each antidote or therapeutic listed. CCB, calcium channel blocker; DTPA, diethylenetriaminepentaacetic acid; EDTA, ethylenediamine tetraacetic acid; GI, gastrointestinal; MAOI, monoamine oxidase inhibitor; SSKI, saturated solution of potassium iodide.

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TABLE 4–2. Clinical and Laboratory Findings in Poisoning and Overdose Agitation Alopecia Ataxia Blindness or decreased visual acuity Blue skin Constipation Deafness, tinnitus Diaphoresis Diarrhea Dysesthesias, paresthesias Gum discoloration Hallucinations Headache Metabolic acidosis (elevated anion gap) Miosis Mydriasis Nystagmus Purpura Radiopaque ingestions Red skin Rhabdomyolysis Salivation Seizures Tremor Weakness Yellow skin

Anticholinergics,a hypoglycemia, phencyclidine, sympathomimetics,b withdrawal from ethanol and sedative–hypnotics Alkylating agents, radiation, selenium, thallium Benzodiazepines, carbamazepine, carbon monoxide, ethanol, hypoglycemia, lithium, mercury, nitrous oxide, phenytoin Caustics (direct), cocaine, cisplatin, mercury, methanol, quinine, thallium Amiodarone, FD&C #1 dye, methemoglobinemia, silver Anticholinergics,a botulism, lead, opioids, thallium (severe) Aminoglycosides, cisplatin, metals, loop diuretics, quinine, salicylates Amphetamines, cholinergics,c hypoglycemia, opioid withdrawal, salicylates, serotonin syndrome, sympathomimetics,b withdrawal from ethanol and sedative–hypnotics Arsenic and other metals, boric acid (blue-green), botanical irritants, cathartics, cholinergics,c colchicine, iron, lithium, opioid withdrawal, radiation Acrylamide, arsenic, ciguatera, cocaine, colchicine, thallium Arsenic, bismuth, hypervitaminosis A, lead, mercury Anticholinergics,a dopamine agonists, ergot alkaloids, ethanol, ethanol and sedative–hypnotic withdrawal, LSD, phencyclidine, sympathomimetics,b tryptamines Carbon monoxide, hypoglycemia, monoamine oxidase inhibitor–food interaction (hypertensive crisis), serotonin syndrome Methanol, uremia, ketoacidosis (diabetic, starvation, alcoholic), paraldehyde, phenformin, metformin, iron, isoniazid, lactic acidosis, cyanide, protease inhibitors, ethylene glycol, salicylates, toluene Cholinergics,c clonidine, opioids, phencyclidine, phenothiazines Anticholinergics,a botulism, opioid withdrawal, sympathomimeticsb Barbiturates, carbamazepine, carbon monoxide, ethanol, lithium, monoamine oxidase inhibitors, phencyclidine, phenytoin, quinine Anticoagulant rodenticides, clopidogrel, corticosteroids, heparin, pit viper venom, quinine, salicylates, warfarin Arsenic, enteric-coated tablets, halogenated hydrocarbons, metals (e.g., iron, lead) Anticholinergics,a boric acid, disulfiram, hydroxocobalamin, scombroid, vancomycin Carbon monoxide, doxylamine, HMG-CoA reductase inhibitors, sympathomimetics,b Tricholoma equestre Arsenic, caustics, cholinergics,c ketamine, mercury, phencyclidine, strychnine Bupropion, camphor, carbon monoxide, cyclic antidepressants, Gyromitra mushrooms, hypoglycemia, isoniazid, methylxanthines, ethanol and sedative–hypnotic withdrawal Antipsychotics, arsenic, carbon monoxide, cholinergics,c ethanol, lithium, mercury, methyl bromide, sympathomimetics,b thyroid replacement Botulism, diuretics, magnesium, paralytic shellfish, steroids, toluene Acetaminophen (late), pyrrolizidine alkaloids, β carotene, amatoxin mushrooms, dinitrophenol

a

Anticholinergics, including antihistamines, atropine, cyclic antidepressants, and scopolamine.

b

Sympathomimetics, including adrenergic agonists, amphetamines, cocaine, and ephedrine.

c

Cholinergics, including muscarinic mushrooms; organic phosphorus compounds and carbamates, including select Alzheimer’s disease drugs and physostigmine; and pilocarpine and other direct-acting xenobiotics. HMG-CoA, 3-hydroxy-3-methyl-glutaryl-CoA); LSD, lysergic acid diethylamide; MAOI, monoamine oxidase inhibitor.

considered to have an AMS. After airway patency is established or secured, an initial bedside assessment should be made regarding the adequacy of breathing. If it is not possible to assess the depth and rate of ventilation, then at least the presence or absence of regular breathing should be determined. In this setting, any irregular or slow breathing pattern should be considered a possible sign of the incipient apnea, requiring ventilation with 100% oxygen by bag–valve–mask followed as soon as possible by endotracheal intubation and mechanical ventilation. Endotracheal intubation may be indicated for some cases of coma resulting from a toxic exposure to ensure and maintain control of the

airway and to enable safe performance of procedures to prevent GI absorption or eliminate previously absorbed xenobiotics. Although in many instances, the widespread availability of pulse oximetry to determine O2 saturation has made arterial blood gas (ABG) analysis less of an immediate priority, pulse oximetry has not eliminated the importance of blood gas analysis entirely. An ABG determination will more accurately define the adequacy not only of oxygenation (PO2, O2 saturation) and ventilation (PCO2) but may also alert the physician to possible toxic-metabolic etiologies of coma characterized by acid–base disturbances (pH, PCO2) (Chap. 16).

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In addition, carboxyhemoglobin determinations are now available by point of care testing and both carboxyhemoglobin and methemoglobin may be determined on venous or arterial blood specimens (Chaps. 125 and 127). In every patient with an AMS, a bedside rapid capillary glucose concentration should be obtained as soon as possible. After the patient’s respiratory status has been assessed and managed appropriately, the strength, rate, and regularity of the pulse should be evaluated, the blood pressure determined, and a rectal temperature obtained. Both a 12-lead electrocardiogram (ECG) and continuous rhythm monitoring are essential. Monitoring will alert the clinician to dysrhythmias that are related to toxic exposures either directly or indirectly via hypoxemia or electrolyte imbalance. For example, a 12-lead ECG demonstrating QRS widening and a right axis deviation might indicate a life-threatening exposure to a cyclic antidepressant or another xenobiotic with sodium channel–blocking properties. In these cases, the physician can anticipate such serious sequelae as ventricular tachydysrhythmias, seizures, and cardiac arrest and consider both the early use of specific treatment (antidotes), such as IV sodium bicarbonate, and avoidance of medications, such as procainamide and other class IA and IC antidysrhythmics, which could exacerbate the situation. Extremes of core body temperature must be addressed early in the evaluation and treatment of a comatose patient. Life-threatening hyperthermia (temperature >105°F; >40.5°C) is usually appreciated when the patient is touched (although the widespread use of gloves as part of universal precautions has made this less apparent than previously). Most individuals with severe hyperthermia, regardless of the etiology, should have their temperatures immediately reduced to about 101.5°F (38.7°C) by sedation if they are agitated or displaying muscle rigidity and by ice water immersion (Chap. 15). Hypothermia is probably easier to miss than hyperthermia, especially in northern regions during the winter months, when most arriving patients feel cold to the touch. Early recognition of hypothermia, however, helps to avoid administering a variety of medications that may be ineffective until the patient becomes relatively euthermic, which may cause iatrogenic toxicity as a result of a sudden response to xenobiotics previously administered. For a hypotensive patient with clear lungs and an unknown overdose, a fluid challenge with IV 0.9% sodium chloride or lactated Ringer’s solution may be started. If the patient remains hypotensive or cannot tolerate fluids, a vasopressor or an inotropic agent may be indicated, as may more invasive monitoring. At the time that the IV catheter is inserted, blood samples for glucose, electrolytes, blood urea nitrogen (BUN), a complete blood count (CBC), and any indicated toxicologic analysis can be obtained. A pregnancy test should be obtained in any woman with childbearing potential. If the patient has an AMS, there may be a temptation to send blood and urine specimens to identify any central nervous system (CNS) depressants or so-called drugs of abuse along with other medications. But the indiscriminate ordering of these tests rarely provides clinically useful information. For the potentially suicidal patient, an acetaminophen concentration should be routinely requested, along with tests affecting the management of any specific xenobiotic, such as carbon monoxide, lithium, theophylline, iron, salicylates, and digoxin (or other cardioactive steroids), as suggested by the patient’s history, physical examination, or bedside diagnostic tests. In the vast majority of cases, the blood tests that are most useful in diagnosing toxicologic emergencies are not the toxicologic assays but rather the “nontoxicologic” routine metabolic profile tests such as BUN, glucose, electrolytes, and blood gas analysis. Xenobiotic-related seizures may broadly be divided into three categories: (1) those that respond to standard anticonvulsant treatment (typically using a benzodiazepine); (2) those that either require specific

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antidotes to control seizure activity or that do not respond consistently to standard anticonvulsant treatment, such as isoniazid-induced seizures requiring pyridoxine administration; and (3) those that may appear to respond to initial treatment with cessation of tonic–clonic activity but that leave the patient exposed to the underlying, unidentified toxin or to continued electrical seizure activity in the brain, as is the case with carbon monoxide poisoning and hypoglycemia. Within the first 5 minutes of managing a patient with an AMS, four therapeutic interventions should be considered, and if indicated, administered: 1. High-flow oxygen (8–10 L/min) to treat a variety of xenobioticinduced hypoxic conditions 2. Hypertonic dextrose: 0.5–1.0 g/kg of D50W for an adult or a more dilute dextrose solution (D10W or D25W) for a child; the dextrose is administered as an IV bolus to diagnose and treat or exclude hypoglycemia 3. Thiamine (100 mg IV for an adult; usually unnecessary for a child) to prevent or treat Wernicke encephalopathy 4. Naloxone (0.05 mg IV with upward titration) for an adult or child with opioid-induced respiratory compromise The clinician must consider that hypoglycemia may be the sole or contributing cause of coma even when the patient manifests focal neurologic findings; therefore, dextrose administration should only be omitted when hypoglycemia can be definitely excluded by accurate rapid bedside testing. Also, while examining a patient for clues to the etiology of a presumably toxic-metabolic form of AMS, it is important to search for any indication that trauma may have caused, contributed to, or resulted from the patient’s condition. Conversely, the possibility of a concomitant drug ingestion or toxic metabolic disorder in a patient with obvious head trauma should also be considered. The remainder of the physical examination should be performed rapidly but thoroughly. In addition to evaluating the patient’s level of consciousness, the physician should note abnormal posturing (decorticate or decerebrate), abnormal or unilateral withdrawal responses, and pupil size and reactivity. Pinpoint pupils suggest exposure to opioids or organic phosphorus insecticides, and widely dilated pupils suggest anticholinergic or sympathomimetic poisoning. The presence or absence of nystagmus, abnormal reflexes, and any other focal neurologic findings may provide important clues to a structural cause of AMS. For clinicians accustomed to applying the Glasgow Coma Score (GCS) to all patients with AMS, assigning a score to the overdosed or poisoned patient may provide a useful measure for assessing changes in neurologic status. However, in this situation, the GCS should never be used for prognostic purposes because despite a low GCS, complete recovery from properly managed toxic-metabolic coma is the rule rather than the exception (Chap. 18). Characteristic breath or skin odors may identify the etiology of coma. The fruity odor of ketones on the breath suggests diabetic or alcoholic ketoacidosis but also the possible ingestion of acetone or isopropyl alcohol, which is metabolized to acetone. The pungent, minty odor of oil of wintergreen on the breath or skin suggests methyl salicylate poisoning. The odors of other substances such as cyanide (“bitter almonds”), hydrogen sulfide (“rotten eggs”), and organic phosphorus compounds (“garlic”) are described in detail in Chap. 20 and summarized in Table 20-1.

FURTHER EVALUATION OF ALL PATIENTS WITH SUSPECTED XENOBIOTIC EXPOSURES Auscultation of breath sounds, particularly after a fluid challenge, helps to diagnose pulmonary edema, acute lung injury, or aspiration

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pneumonitis when present. Coupled with an abnormal breath odor of hydrocarbons or organic phosphorus compounds, for example, crackles and rhonchi may point to a toxic pulmonary etiology instead of a cardiac etiology; this is important because the administration of certain cardioactive medications may be inappropriate or dangerous in the former circumstances. Heart murmurs in an injection drug user, especially when accompanied by fever, may indicate bacterial endocarditis. Dysrhythmias may suggest overdoses or inappropriate use of cardioactive xenobiotics, such as digoxin and other cardioactive steroids, β-adrenergic antagonists, calcium channel blockers, and cyclic antidepressants. The abdominal examination may reveal signs of trauma or alcoholrelated hepatic disease. The presence or absence of bowel sounds helps to exclude or to diagnose anticholinergic toxicity and is important in considering whether to manipulate the GI tract in an attempt to remove the toxin. Examination of the extremities might reveal clues to current or former drug use (track marks, skin-popping scars); metal poisoning (Mees lines, arsenical dermatitis); and the presence of cyanosis or edema suggesting preexisting cardiac, pulmonary, or renal disease (Chap. 29). Repeated evaluation of the patient suspected of an overdose is essential for identifying new or developing findings or toxic syndromes and for early identification and treatment of a deteriorating condition. Until the patient is completely recovered or considered no longer at risk for the consequences of a xenobiotic exposure, frequent reassessment must be provided, even as the procedures described below are carried out. Toxicologic etiologies of abnormal vital signs and physical findings are summarized in Tables 3–1 to 3–6. Toxic syndromes, sometimes called “toxidromes,” are summarized in Table 3-1. Typically in the management of patients with toxicologic emergencies, there is both a necessity and an opportunity to obtain various diagnostic studies and ancillary tests interspersed with stabilizing the patient’s condition, obtaining the history, and performing the physical examination. Chapters 5, 6, and 22 discuss the timing and indications for diagnostic imaging procedures, qualitative and quantitative diagnostic laboratory studies, and the use and interpretation of the ECG in evaluating and managing poisoned or overdosed patients.

THE ROLE OF GASTROINTESTINAL EVACUATION A series of highly individualized treatment decisions must now be made. As noted previously and as discussed in detail in Chapter 7, the decision to evacuate the GI tract or administer AC can no longer be considered standard or routine toxicologic care for most patients. Instead, the decision should be based on the type of ingestion, estimated quantity and size of pill or tablet, time since ingestion, concurrent ingestions, ancillary medical conditions, and age and size of the patient. The indications, contraindications, and procedures for performing orogastric lavage and for administering WBI, AC, MDAC, and cathartics are listed in Tables 7–1 through 7–4 and are discussed both in Chapter 7 and in the specific Antidotes in Depth sections immediately following Chapter 7.

■ ELIMINATING ABSORBED XENOBIOTICS FROM THE BODY After deciding whether or not an intervention to try to prevent absorption of a xenobiotic is indicated, the clinician must next consider the applicability of techniques available to eliminate xenobiotics already absorbed. Detailed discussions of the indications for and techniques of manipulating urinary pH (ion trapping), diuresis, hemodialysis, hemoperfusion, hemofiltration, and exchange transfusion are found in

Chapter 9. Briefly, patients who may benefit from these procedures are those who have systemically absorbed xenobiotics amenable to one of these techniques and whose clinical condition is both serious (or potentially serious) and unresponsive to supportive care or whose physiologic route of elimination (liver–feces, kidney–urine) is impaired. Alkalinization of the urinary pH for acidic xenobiotics has only limited applicability. Commonly, sodium bicarbonate can be used to alkalinize the urine (as well as the blood) and enhance salicylate elimination (phenobarbital and chlorpropamide are less common indications), and sodium bicarbonate also prevents toxicity from methotrexate (see Antidotes in Depth: Sodium Bicarbonate). Acidifying the urine to hasten the elimination of alkaline substances is difficult to accomplish, probably useless, and possibly dangerous and therefore has no role in poison management. Forced diuresis also has no indication and may endanger the patient by causing pulmonary or cerebral edema. If extracorporeal elimination is contemplated, hemodialysis should be considered for overdoses of salicylates, methanol, ethylene glycol, lithium, and xenobiotics that are both dialyzable and cause fluid and electrolyte problems. If available, hemoperfusion or high-flux hemodialysis should be considered for overdoses of theophylline, phenobarbital, and carbamazepine (although rarely, if ever, for the last two). When hemoperfusion is the method of choice (as for a theophylline overdose) but not available, hemodialysis is a logical, effective alternative and certainly preferable to delaying treatment until HP becomes available. Peritoneal dialysis is too ineffective to be of practical utility, and hemodiafiltration is not as efficacious as hemodialysis or hemoperfusion, although it may play a role between multiple runs of dialysis or in hemodynamically compromised patients who cannot tolerate hemodialysis. In theory, both hemodialysis and hemoperfusion in series may be useful for a very few life-threatening overdoses such as salicylates. Plasmapheresis and exchange transfusion are used to eliminate xenobiotics with large molecular weights that are not dialyzable (Chap. 9).

AVOIDING PITFALLS The history alone may not be a reliable indicator of which patients require naloxone, hypertonic dextrose, thiamine, and oxygen. Instead, these therapies should be considered (unless specifically contraindicated) only after a clinical assessment for all patients with AMS. The physical examination should be used to guide the use of naloxone. If dextrose or naloxone is indicated, sufficient amounts should be administered to exclude or treat hypoglycemia or opioid toxicity, respectively. In a patient with a suspected but unknown overdose, the use of vasopressors should be avoided in the initial management of hypotension before administering fluids or assessing filling pressures. Attributing an AMS to alcohol because of its odor on a patient’s breath is potentially dangerous and misleading. Small amounts of alcohol and its congeners generally produce the same breath odor as do intoxicating amounts. Conversely, even when an extremely high blood ethanol concentration is confirmed by the laboratory, it is dangerous to ignore other possible causes of an AMS. Because chronic alcoholics may be awake and seemingly alert with ethanol concentrations in excess of 500 mg/dL, a concentration that would result in coma and possibly apnea and death in a nontolerant person, finding a high ethanol concentration does not eliminate the need for further search into the cause of a depressed level of consciousness. The metabolism of ethanol is fairly constant at 15 to 30 mg/dL/h. Therefore, as a general rule, regardless of the initial blood alcohol concentration, a presumably “inebriated” comatose patient who is still unarousable 3 to 4 hours after initial assessment should be considered to have head trauma, a cerebrovascular accident, CNS infection, or other toxic-metabolic etiology for the alteration in consciousness, until

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Chapter 4

Principles of Managing the Acutely Poisoned or Overdosed Patient

proven otherwise. Careful neurologic evaluation of the completely undressed patient supplemented by a head computed tomography scan or a lumbar puncture is frequently indicated in such cases. This is especially important in dealing with a seemingly “intoxicated” patient who appears to have only a minor bruise because the early treatment of a subdural or epidural hematoma or subarachnoid hemorrhage is critical to a successful outcome.

ADDITIONAL CONSIDERATIONS IN MANAGING PATIENTS WITH A NORMAL MENTAL STATUS As in the case of the patient with AMS, vital signs must be obtained and recorded. Initially, an assumption may have been made that the patient was breathing adequately, and if the patient is alert, talking, and in no respiratory distress, all that remains to document is the respiratory rate and rhythm. Because the patient is alert, additional history should be obtained, keeping in mind that information regarding the number and types of xenobiotics ingested, time elapsed, prior vomiting, and other critical information may be unreliable, depending in part on whether the ingestion was intentional or unintentional. When indicated for the potential benefit of the patient, another history should be privately and independently obtained from a friend or relative after the patient has been initially stabilized. Recent emphasis on compliance with the federal Health Insurance Portability and Accountability Act (HIPAA) may inappropriately discourage clinicians from attempting to obtain information necessary to evaluate and treat patients. Obtaining such information from a friend or relative without unnecessarily giving that person information about the patient may be the key to successfully helping such a patient without violating confidentiality. Speaking to a friend or relative of the patient may provide an opportunity to learn useful and reliable information regarding the ingestion, the patient’s frame of mind, a history of previous ingestions, and the type of support that is available if the patient is discharged from the ED. At times, it may be essential to initially separate the patient from any relatives or friends to obtain greater cooperation from the patient and avoid violating confidentiality and because their anxiety may interfere with therapy. Even if the history obtained from a patient with an overdose proves to be unreliable, it may nevertheless provide clues to an overlooked possibility of a second ingestant or reveal the patient’s mental and emotional condition. As is often true of the history, physical examination, or laboratory assessment in other clinical situations, the information obtained may confirm but never exclude possible causes. At this point in the management of a conscious patient, a focused physical examination should be performed, concentrating on the pulmonary, cardiac, and abdominal examinations. A neurologic survey should emphasize reflexes and any focal findings.

APPROACHING PATIENTS WITH INTENTIONAL EXPOSURES Initial efforts at establishing rapport with the patient by indicating to the patient concern about the problems that led to the ingestion and the availability of help after the xenobiotic is removed (if such procedures are planned) may help make management easier. If GI decontamination is deemed necessary, the reason for and nature of the procedure should be clearly explained to the patient together with reassurance that after the procedure is completed, there will be ample time to discuss related problems and provide additional care. These considerations are especially important in managing the patient with an intentional overdose

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who may be seeking psychiatric help or emotional support. In deciding on the necessity of GI decontamination, it is important to consider that a resistant patient may transform a procedure of only potential value into one with predictable adverse consequences.

SPECIAL CONSIDERATIONS FOR MANAGING PREGNANT PATIENTS In general, a successful outcome for both the mother and fetus depends on optimum management of the mother, and proven effective treatment for a potentially serious toxic exposure to the mother should never be withheld based on theoretical concerns regarding the fetus.

■ PHYSIOLOGIC FACTORS A pregnant woman’s total blood volume and cardiac output are elevated through the second trimester and into the later stages of the third trimester. This means that signs of hypoperfusion and hypotension manifest later than they would in a woman who is not pregnant, and when they do, uterine blood flow may already be compromised. For these reasons, the possibility of hypotension in a pregnant woman must be more aggressively sought and, if found, more rapidly treated. Maintaining the patient in the left-lateral decubitus position helps prevent supine hypotension resulting from impairment of systemic venous return by compression of the inferior vena cava. The left lateral decubitus position is also the preferred position for orogastric lavage, if this procedure is deemed necessary. Because the tidal volume is increased in pregnancy, the baseline PCO2 will normally be lower by approximately 10 mm Hg. Appropriate adjustment for this effect should be made when interpreting ABG results.

■ USE OF ANTIDOTES Limited data is available on the use of antidotes in pregnancy. In general, antidotes should not be used if the indications for use are equivocal. On the other hand, antidotes should not be withheld if their use may reduce potential morbidity and mortality. Risks and benefits of either decision must be considered. For example, reversal of opioidinduced respiratory depression calls for the use of naloxone, but in an opioid-dependent woman, the naloxone can precipitate acute opioid withdrawal, including uterine contractions and possible induction of labor. Very slow, careful, IV titration starting with 0.05 mg naloxone may be indicated unless apnea is present, cessation of breathing appears imminent, or the PO2 or O2 saturation is already compromised. In these instances, naloxone may have to be administered in higher doses (i.e., 0.4–2.0 mg) or assisted ventilation provided or a combination of assisted ventilation and small doses of naloxone used. An acetaminophen overdose is a serious maternal problem when it occurs throughout pregnancy, but the fetus is at greatest risk in the third trimester. Although acetaminophen crosses the placenta easily, N-acetylcysteine has somewhat diminished transplacental passage. During the third trimester, when both the mother and the fetus may be at substantial risk from a significant acetaminophen overdose with manifest hepatoxicity, immediate delivery of a mature or viable fetus may need to be considered. In contrast to the situation with acetaminophen, the fetal risk from iron poisoning is less than the maternal risk. Because deferoxamine is a large charged molecule with little transplacental transport, deferoxamine should never be withheld out of unwarranted concern for fetal toxicity when indicated to treat the mother. Carbon monoxide (CO) poisoning is particularly threatening to fetal survival. The normal PO2 of the fetal blood is approximately 15 to

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20 mm Hg. Oxygen delivery to fetal tissues is impaired by the presence of carboxyhemoglobin, which shifts the oxyhemoglobin dissociation curve to the left, potentially compromising an already tenuous balance. For this reason, hyperbaric oxygen is recommended for much lower carboxyhemoglobin concentrations in the pregnant compared with the nonpregnant woman (Chap. 125 and Antidotes in Depth: Hyperbaric Oxygen). Early notification of the obstetrician and close cooperation among involved physicians are essential for best results in all of these instances.

MANAGEMENT OF PATIENTS WITH CUTANEOUS EXPOSURE The xenobiotics that people are commonly exposed to externally include household cleaning materials; organic phosphorus or carbamate insecticides from crop dusting, gardening, or pest extermination; acids from leaking or exploding batteries; alkalis, such as lye; and lacrimating agents that are used in crowd control. In all of these cases, the principles of management are as follows: 1. Avoid secondary exposures by wearing protective (rubber or plastic) gowns, gloves, and shoe covers. Cases of serious secondary poisoning have occurred in emergency personnel after contact with xenobiotics such as organic phosphorus compounds on the victim’s skin or clothing.

for serious exposures. More than 40% of exposures reported to poison centers annually are judged to be nontoxic or minimally toxic. The following general guidelines1,2 for considering an exposure nontoxic or minimally toxic will assist clinical decision making: 1. Identification of the product and its ingredients is possible. 2. None of the US Consumer Product Safety Commission “signal words” (CAUTION, WARNING, or DANGER) appear on the product label. 3. The history permits the route(s) of exposure to be determined. 4. The history permits a reliable approximation of the maximum quantity involved with the exposure. 5. Based on the available medical literature and clinical experience, the potential effects related to the exposure are expected to be at most benign and self-limited and do not require referral to a clinician.1,2 6. The patient is asymptomatic or has developed the expected benign self-limited toxicity.

ENSURING OPTIMAL OUTCOME

5. Avoid using any greases or creams because they will only keep the xenobiotic in close contact with the skin and ultimately make removal more difficult. Chapter 29 discusses the principles of managing cutaneous exposures.

The best way to ensure an optimal outcome for the patient with a suspected toxic exposure is to apply the principles of basic and advanced life support in conjunction with a planned and staged approach, always bearing in mind that a toxicologic etiology or coetiology for any abnormal conditions necessitates modifying whatever standard approach is brought to the bedside of a severely ill patient. For example, it is extremely important to recognize that xenobiotic-induced dysrhythmias or cardiac instability require alterations in standard protocols that assume a primary cardiac or nontoxicologic etiology (Chaps. 22 and 23). Typically, only some of the xenobiotics to which a patient is exposed will ever be confirmed by laboratory analysis. The thoughtful combination of stabilization, general management principles, and specific treatment when indicated will result in successful outcomes in the vast majority of patients with actual or suspected exposures.

MANAGEMENT OF PATIENTS WITH OPHTHALMIC EXPOSURES

SUMMARY

2. Remove the patient’s clothing, place it in plastic bags, and then seal the bags. 3. Wash the patient with soap and copious amounts of water twice regardless of how much time has elapsed since the exposure. 4. Make no attempt to neutralize an acid with a base or a base with an acid. Further tissue damage may result from the heat generated by this reaction.

Although the vast majority of toxicologic emergencies result from ingestion, injection, or inhalation, the eyes are occasionally the routes of systemic absorption or are the organs at risk. The eyes should be irrigated with the eyelids fully retracted for no less than 20 minutes. To facilitate irrigation, a drop of an anesthetic (e.g., proparacaine) in each eye should be used, and the eyelids should be kept open with an eyelid retractor. An adequate irrigation stream may be obtained by running 1 L of normal saline through regular IV tubing held a few inches from the eye or by using an irrigating lens. Checking the eyelid fornices with pH paper strips is important to ensure adequate irrigation; the pH should normally be 6.5 to 7.6 if accurately tested, although when using paper test strips, the measurement will often be near 8.0. Chapter 19 describes the management of toxic ophthalmic exposures in more detail.

Patients with a suspected overdose or poisoning and an AMS present some of the most serious initial challenges. Conscious patients, asymptomatic patients, and pregnant patients with possible xenobiotic exposures raise additional management issues, as do the victims of toxic cutaneous or ophthalmic exposures. One of the most frequent toxicologic emergencies that clinicians must deal with is a patient with a suspected toxic exposure to an unidentified xenobiotic (medication or substance), sometimes referred to as an unknown overdose. Considering not only those patients who have an AMS but also those who are suicidal, those who use illicit drugs, or those who are exposed to xenobiotics of which they are unaware, many toxicologic emergencies at least partly involve an unknown component.

IDENTIFYING PATIENTS WITH NONTOXIC EXPOSURES

REFERENCES

There is a risk of needlessly subjecting a patient to potential harm when a patient with a nontoxic exposure is treated aggressively with GI evacuation techniques and other forms of management indicated

1. McGuigan MA, Guideline Consensus Panel: Guideline for the out-of-hospital management of human exposures to minimally toxic substances. J Toxicol Clin Toxicol. 2003;41:907-917. 2. Mofenson HC, Greensher J: The unknown poison. Pediatrics 1974;54: 336-342.

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CHAPTER 5

DIAGNOSTIC IMAGING David T. Schwartz Diagnostic imaging can play a significant role in the management of many toxicologic emergencies. Radiographic studies can directly visualize the xenobiotic in some cases, but in others, they reveal the effects of the xenobiotic on various organ systems (Table 5–1). Radiography can confirm a diagnosis (e.g., by visualizing the xenobiotic), assist in therapeutic interventions such as monitoring gastrointestinal (GI) decontamination, and detect complications of the xenobiotic exposure.180 Conventional radiography is readily available in the emergency department (ED) and is the imaging modality most frequently used in acute patient management. However, other imaging modalities can be used in toxicologic emergencies, including computed tomography (CT); enteric and intravascular contrast studies; ultrasonography; transesophageal echocardiography (TEE); magnetic resonance imaging (MRI/MRA); and nuclear scintigraphy, including positron emission tomography (PET) and single-photon emission tomography (SPECT).

VISUALIZING THE XENOBIOTIC A number of xenobiotics are radiopaque and can potentially be detected by conventional radiography. Radiography is most useful when a substance that is known to be radiopaque has been ingested or injected. When the identity of the xenobiotic is unknown, the usefulness of radiography is very limited. When ingested, a radiopaque xenobiotic may be seen on an abdominal radiograph. Injected radiopaque xenobiotics are also amenable to radiographic detection. If the toxic material itself is available for examination, it can be radiographed outside of the body to detect any radiopaque contents (Fig. 103-1).76

■ RADIOPACITY The radiopacity of a xenobiotic is determined by several factors. First, the intrinsic radiopacity of a substance depends on its physical density (g/cm3) and the atomic numbers of its constituent atoms. Biologic tissues are composed mostly of carbon, hydrogen, and oxygen and have an average atomic number of approximately 6. Substances that are more radiopaque than soft tissues include bone, which contains calcium (atomic number 20); radiocontrast agents containing iodine (atomic number 53) and barium (atomic number 56); iron (atomic number 26); and lead (atomic number 82). Some xenobiotics have constituent atoms of high atomic number, such as chlorine (atomic number 17), potassium (atomic number 19), and sulfur (atomic number 16), that contribute to their radiopacity. The thickness of an object also affects its radiopacity. Small particles of a moderately radiopaque xenobiotic are often not visible on a radiograph. Finally, the radiographic appearance of the surrounding area also affects the detectability of an object. A moderately radiopaque tablet is easily seen against a uniform background, but in a patient, overlying bone or bowel gas often obscures the tablet.

■ ULTRASONOGRAPHY Compared with conventional radiography, ultrasonography theoretically is a useful tool for detecting ingested xenobiotics because it

depends on echogenicity rather than radiopacity for visualization. Solid pills within the fluid-filled stomach may have an appearance similar to gallstones within the gallbladder. In one in vitro study using a waterbath model, virtually all intact pills could be visualized.7 The authors were also successful at detecting pills within the stomachs of human volunteers who ingested pills. Nonetheless, reliably finding pills scattered throughout the GI tract, which often contains air and feces that block the ultrasound beam, is a formidable task. Ultrasonography, therefore, has limited clinical practicality.

INGESTION OF AN UNKNOWN XENOBIOTIC Although a clinical policy issued by the American College of Emergency Physicians in 1995 suggested that an abdominal radiograph should be obtained in unresponsive overdosed patients in an attempt to identify the involved xenobiotic, the role of abdominal radiography in screening a patient who has ingested an unknown xenobiotic is questionable.6 The number of potentially ingested xenobiotics that are radiopaque is limited. In addition, the radiographic appearance of an ingested xenobiotic is not sufficiently distinctive to determine its identity (Fig. 5–1).202 However, when ingestion of a radiopaque xenobiotic such as ferrous sulfate tablets or another metal with a high atomic number is suspected, abdominal radiographs are helpful.5 In addition, knowledge of potentially radiopaque xenobiotics is useful in suggesting diagnostic possibilities when a radiopaque xenobiotic is discovered on an abdominal radiograph that was obtained for reasons other than suspected xenobiotic ingestion, such as in a patient with abdominal pain (Fig. 5–2).179,186 Several investigators have studied the radiopacity of various medications.52,59,81,87,97,147,176,189,197 These investigators used an in vitro water-bath model to simulate the radiopacity of abdominal soft tissues.176 The studies found that only a small number of medications exhibit some degree of radiopacity. A short list of the more consistently radiopaque xenobiotics is summarized in the mnemonic CHIPES—chloral hydrate, “heavy metals,” iron, phenothiazines, and enteric-coated and sustainedrelease preparations. The CHIPES mnemonic has several limitations.176 It does not include all of the pills that are radiopaque in vitro such as acetazolamide and busulfan. Most radiopaque medications are only moderately radiopaque, and when ingested, they dissolve rapidly, becoming difficult or impossible to detect. “Psychotropic medications” include a wide variety of compounds of varying radiopacity.147,176 For example, whereas trifluoperazine (containing fluorine; atomic number 9) is radiopaque in vitro, chlorpromazine (containing chlorine; atomic number 17) is not.176 Finally, sustained-release preparations and those with enteric coatings have variable composition and radiopacity. Pill formulations of fillers, binders, and coatings vary between manufacturers, and even a specific product can change depending on the date of manufacture. Furthermore, the insoluble matrix of some sustained-release preparations is radiopaque, and when seen on a radiograph, these tablets may no longer contain active medication. Some sustained-release cardiac medications such as verapamil and nifedipine have inconsistent radiopacity.119,188,199

EXPOSURE TO A KNOWN XENOBIOTIC When a xenobiotic that is known to be radiopaque is involved in an exposure, radiography plays an important role in patient care.5 Radiography can confirm the diagnosis of a radiopaque xenobiotic exposure, quantify the approximate amount of xenobiotic involved,

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TABLE 5–1. Xenobiotics with Diagnostic Imaging Findings Xenobiotic

Imaging Studya

Finding

Amiodarone Asbestos Beryllium Body packer

Chest Chest Chest Upper GI series or abdominal CT Head CT, MRI SPECT, PET Enteric contrast Chest

Phospholipidosis (interstitial and alveolar filling), pulmonary fibrosis Interstitial fibrosis (asbestosis), calcified pleural plaques, mesothelioma Acute: Airspace filling; chronic: hilar adenopathy Ingested packets, ileus, bowel obstruction

Corticosteroids Ethanol

Chest Chest, abdominal Noncontrast Head CT, MRI, TEE, SPECT, PET Skeletal Chest Head CT, MRI, SPECT, PET

Fluorosis Hydrocarbons (low viscosity) Inhaled allergens Iron Irritant gases Lead

Skeletal Chest Chest Abdominal Chest Skeletal, abdominal

Diffuse airspace filling (bronchorrhea) Diffuse airspace filling, pneumomediastinum, pneumothorax, aortic dissection, perforation SAH, intracerebral hemorrhage, infarction, cerebral dysfunction, dopamine receptor downregulation Avascular necrosis (femoral head) Dilated cardiomyopathy, aspiration pneumonitis, rib fractures, cortical Cortical atrophy, cerebellar atrophy, SDH (head trauma), cerebellar and cortical dysfunction Osteosclerosis, osteophytosis, ligament calcification Aspiration pneumonitis Hypersensitivity pneumonitis Radiopaque tablets Diffuse airspace filling thorax Metaphyseal bands in children (proximal tibia, distal radius), bullets (dissolution near joints) Ingested leaded paint chips or other leaded compounds Basal ganglia and midbrain hyperintensity Ingested, injected, or embolic deposits Ingested xenobiotic Hypersensitivity pneumonitis Acute lung injury Ileus Hilar lymphadenopathy Pleural and pericardial effusions (xenobiotic-induced lupus syndrome) Acute lung injury Interstitial fibrosis, hilar adenopathy (egg-shell calcification) Hepatic and splenic deposition

Carbon monoxide Caustic ingestion Chemotherapeutics (busulfan, bleomycin) Cholinergics Cocaine

Manganese Mercury (elemental) Metals (Pb, Hg, TI, As) Nitrofurantoin Opioids

Brain MRI Abdominal, skeletal, or chest Abdominal Chest Chest Abdominal Phenytoin Chest Procainamide, INH, hydralazine Chest Salicylates Chest Silica, coal dust Chest Thorium dioxide Abdominal a

Bilateral basal ganglia lucencies, white matter demyelinization, cerebral dysfunction Esophageal perforation or stricture Interstitial pneumonitis

Conventional radiography unless otherwise stated.

CT, computed tomography; INH, isoniazid; MRI, magnetic resonance imaging; PET, positron emission tomography; SAH, subarachnoid hemorrhage; SDH, subdural hematoma; SPECT, single-photon emission tomography.

and monitor its removal from the body. Examples include ferrous sulfate, sustained-release potassium chloride,193 and heavy metals.

■ IRON TABLET INGESTION Adult-strength ferrous sulfate tablets are readily detected radiographically because they are highly radiopaque and disintegrate slowly when ingested. Aside from confirming an iron tablet ingestion and quantifying the amount ingested, radiographs repeated after whole-bowel irrigation help to determine whether further GI decontamination is needed (Fig. 5–3).51,61,101,146,151,153,205 Nonetheless, caution must be exercised in

using radiography to exclude an iron ingestion. Some iron preparations are not radiographically detectable. Liquid, chewable, or encapsulated (“Spansule”) iron preparations rapidly fragment and disperse after ingestion. Even when intact, these preparations are less radiopaque than ferrous sulfate tablets.52

■ HEAVY METALS Heavy metals, such as arsenic, cesium, lead, manganese, mercury, potassium, and thallium, can be detected radiographically. Examples of metal exposure include leaded ceramic glaze (Fig. 5–4),168 paint chips

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FIGURE 5–1. Ingestion of an unknown substance. A 46-year-old man presented to the emergency department with a depressed level of consciousness. Because he also complained of abdominal pain and mild diffuse abdominal tenderness, a computed tomography (CT) scan of the abdomen was obtained. The CT revealed innumerable tablet-shaped densities within the stomach (arrows). The CT finding was suspicious for an overdose of an unknown xenobiotic. Orogastric lavage was attempted, and the patient vomited a large amount of whole navy beans. CT is able to detect small, nearly isodense structures such as these that cannot be seen using conventional radiography. (Image contributed by Dr. Earl J. Reisdorff, MD, Michigan State University, Lansing, Michigan.)

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FIGURE 5–2. Detection of a radiopaque substance on an abdominal radiograph. An abdominal radiograph obtained on a patient with upper abdominal pain revealed radiopaque material throughout the intestinal tract (arrows). Further questioning of the patient revealed that he had been consuming bismuth subsalicylate (Pepto-Bismol) tablets to treat his peptic ulcer (bismuth, atomic number 83). The identification of radiopaque material does not allow determination of the nature of the substance.

B

FIGURE 5–3. Iron tablet overdose. (A) The identification of the large amount of radiopaque tablets confirms the diagnosis in a patient with a suspected iron overdose and permits rough quantification of the amount ingested. (B) After emesis and whole-bowel irrigation, a second radiograph revealed some remaining tablets and indicated the need for further intestinal decontamination. A third radiograph after additional bowel irrigation demonstrated clearing of the intestinal tract. (Images contributed by the Toxicology Fellowship of the New York City Poison Center.)

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FIGURE 5–4. An abdominal radiograph of a patient who intentionally ingested ceramic glaze containing 40% lead. (Image contributed by the Toxicology Fellowship of the New York City Poison Center.)

containing lead (Fig. 94–5),112,133mercuric oxide (Fig. 96–1),122 thallium salts (atomic number 81),44,134 and zinc (atomic number 30).23 Arsenic (atomic number 33; Fig. 5–5)77,116,203 with lower atomic numbers is also radiopaque. Mercury Unintentional ingestion of elemental mercury can occur when a glass thermometer or a long intestinal tube with a mercury-containing balloon breaks. Liquid elemental mercury can be injected subcutaneously or intravenously. Radiographic studies assist débridement by detecting mercury that remains after the initial excision. Elemental mercury that is injected intravenously produces a dramatic radiographic picture of pulmonary embolization (Fig. 5–6).23,26,112,126,130,143 Lead Ingested lead can be detected only by abdominal radiography, such as in a child with lead poisoning who has ingested paint chips (see Fig. 91-5). Metallic lead (e.g., a bullet) that is embedded in soft tissues is not usually systemically absorbed. However, when the bullet is in contact with an acidic environment such as synovial fluid or cerebrospinal fluid (CSF), there may be significant absorption. Over many years, mechanical and chemical action within the joint causes the bullet to fragment and gradually dissolve.43,45,53,192,196 Radiography can confirm the source of lead poisoning by revealing metallic material in the joint or CSF (Fig. 5–7).

■ XENOBIOTICS IN CONTAINERS In some circumstances, ingested xenobiotics can be seen even though they are of similar radiopacity to surrounding soft tissues. If a xenobiotic is ingested in a container, the container itself may be visible. Body Packers “Body packers” are individuals who smuggle large quantities of illicit drugs across international borders in securely sealed

FIGURE 5–5. An abdominal radiograph in an elderly woman incidentally revealed radiopaque material in the pelvic region. This was residual from gluteal injection of antisyphilis therapy she had received 35 to 40 years earlier. The injections may have contained an arsenical. (Image contributed by Dr. Emil J. Balthazar, Department of Radiology, Bellevue Hospital Center.)

packets.3,15,16,25,36,56,95,109,125,132,156,181,183,201 The uniformly shaped, oblong packets can be seen on abdominal radiographs either because there is a thin layer of air or metallic foil within the container wall or because the packets are outlined by bowel gas (Fig. 5–8). In some cases, a “rosette” representing the knot at the end of the packet is seen.183 Intraabdominal calcifications (pancreatic calcifications and bladder stones) have occasionally been misinterpreted as drug-containing packets.201,217 The sensitivity of abdominal radiography for such packets is high, in the range of 85% to 90%. The major role of radiography is as a rapid screening test to confirm the diagnosis in individuals suspected of smuggling drugs, such as persons being held by airport customs agents. However, because packets are occasionally not visualized and the rupture of even a single packet can be fatal, abdominal radiography should not be relied on to exclude the diagnosis of body packing. Ultrasonography has also been used to rapidly detect packets, although it also should not be relied on to exclude such a life-threatening ingestion.33,78,136 After intestinal decontamination, an upper GI series with oral contrast or CT with enteric contrast can reveal any remaining packets.80,91,148 Body stuffers A “body stuffer” is an individual who, in an attempt to avoid imminent arrest, hurriedly ingests contraband in insecure packaging.170 The risk of leakage from such haphazardly constructed

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FIGURE 5–6. Elemental mercury exposures. (A) Unintentional rupture of a Cantor intestinal tube distributed mercury throughout the bowel. (B) The chest radiograph in a patient after intravenous injection of elemental mercury showing metallic pulmonary embolism. The patient developed respiratory failure, pleural effusions, and uremia and expired despite aggressive therapeutic interventions. (C) Subcutaneous injection of liquid elemental mercury is readily detected radiographically. Because mercury is systemically absorbed from subcutaneous tissues, it must be removed by surgical excision. (D) A radiograph after surgical débridement reveals nearly complete removal of the mercury deposit. Surgical staples and a radiopaque drain are visible. (Image A contributed by Dr. Richard Lefleur, Department of Radiology, Bellevue Hospital Center; image B contributed by Dr. N. John Stewart, Department of Emergency Medicine, Palmetto Health, University of South Carolina School of Medicine and images C and D contributed by the Toxicology Fellowship of the New York City Poison Center.)

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■ RADIOLUCENT XENOBIOTICS A radiolucent xenobiotic may be visible because it is less radiopaque than surrounding soft tissues. Hydrocarbons such as gasoline are relatively radiolucent when embedded in soft tissues. The radiographic appearance resembles subcutaneous gas as seen in a necrotizing soft tissue infection (Fig. 5–10).

■ SUMMARY Obtaining an abdominal radiograph in an attempt to identify pills or other xenobiotics in a patient with an unknown ingestion is unlikely to be helpful and is, in general, not warranted. Radiography is most useful when the suspected xenobiotic is known to be radiopaque, as is the case with iron tablets and heavy metals. If the material is available, the xenobiotic can be radiographed within the patient’s abdomen, elsewhere in the patient’s body, or outside of the patient. FIGURE 5–7. A “lead arthrogram” discovered many years after a bullet wound to the shoulder. At the time of the initial injury, the bullet was embedded in the articular surface of the humeral head (arrow). The portion of the bullet that protruded into the joint space was surgically removed, leaving a portion of the bullet exposed to the synovial space. A second bullet was embedded in the muscles of the scapula. Eight years after the injury, the patient presented with weakness and anemia. Extensive lead deposition throughout the synovium is seen. The blood lead concentration was 91 μg/dL. (Image contributed by the Toxicology Fellowship of the New York City Poison Center.)

containers is high. Unfortunately, radiographic studies cannot reliably confirm or exclude such ingestions.187 Occasionally, a radiograph will demonstrate the ingested container (Fig. 5–9). If the drug is in a glass or in a hard-plastic crack vial, the container may be seen.90 If the body stuffer swallows soft plastic bags containing the drug, the containers are not usually visible. However, in three reported cases, “baggies” were visualized by abdominal CT.37,48,83,105,85,157,180

■ HALOGENATED HYDROCARBONS Some halogenated hydrocarbons can be visualized radiographically.31,38 Radiopacity is proportionate to the number of chlorine atoms. Both carbon tetrachloride (CCl4) and chloroform (CHCl3) are radiopaque. Because these liquids are immiscible in water, a triple layer may be seen within the stomach on an upright abdominal radiograph—an uppermost air bubble, a middle radiopaque chlorinated hydrocarbon layer, and a lower gastric fluid layer. However, these ingestions are rare, and the quantity ingested is usually too small to show this effect. Other halogenated hydrocarbons such as methylene iodide are highly radiopaque.216

■ MOTHBALLS Some types of mothballs can be visualized by radiography. Whereas relatively nontoxic paradichlorobenzene mothballs (containing chlorine; atomic number 17) are moderately radiopaque, more toxic naphthalene mothballs are radiolucent.194 If the patient is known to have swallowed mothballs, the difference in radiopacity may help determine the type. However, if a mothball ingestion is not already suspected, the more toxic naphthalene type may not be detected. Radiographs of mothballs outside of the patient can help distinguish these two types (see Fig. 103–1).

EXTRAVASATION OF INTRAVENOUS CONTRAST MATERIAL Extravasation of intravenous (IV) radiographic contrast material is a common occurrence. In most cases, the volume extravasated is small, and there are no clinical sequelae.17,35,54,169 Rarely, a patient has an extravasation large enough to cause cutaneous necrosis and ulceration. Recently, the incidence of sizable extravasations has increased because of the use of rapid-bolus automated power injectors for CT studies.208 Fortunately, nonionic low-osmolality contrast solutions are currently nearly always used for these studies. These solutions are far less toxic to soft tissues than older ionic high-osmolality contrast materials. The treatment of contrast extravasation has not been studied in a large series of human subjects and is therefore controversial. Various strategies have been proposed. The affected extremity should be elevated to promote drainage. Although topical application of heat causes vasodilation and could theoretically promote absorption of extravasated contrast material, the intermittent application of ice packs has been shown to lower the incidence of ulceration.35 Rarely, an extremely large volume of liquid is injected into the soft tissues, which requires surgical decompression when there are signs of a compartment syndrome. A radiograph of the extremity will demonstrate the extent of extravasation.35 Precautions should be taken to prevent extravasation. A recently placed, well-running IV catheter should be used. The distal portions of the extremities (hands, wrist, and feet) should not be used as IV sites for injecting contrast. Patients who are more vulnerable to complications and those whose veins may be more fragile, such as infants, debilitated patients, and those with an impaired ability to communicate, must be closely monitored to prevent or determine if extravasation occurs.

VISUALIZING THE EFFECTS OF A XENOBIOTIC ON THE BODY The lungs, central nervous system (CNS), GI tract, and skeleton are the organ systems that are most amenable to diagnostic imaging. Disorders of the lungs and skeletal system are seen by plain radiography. For abdominal pathology, contrast studies and CT are more useful, although plain radiographs can diagnose intestinal obstruction, perforation, and radiopaque foreign bodies. Imaging of the CNS uses CT, MRI, and nuclear scintigraphy (PET and SPECT).

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B

C FIGURE 5–8. Radiographs of three “body packers” showing the various appearances of drug packets. Drug smuggling is accomplished by packing the gastrointestinal tract with large numbers of manufactured, well-sealed containers. (A) Multiple oblong packages of uniform size and shape are seen throughout the bowel. (B) The packets are visible in this patient because they are surrounded by a thin layer of air within the wall of the packet. (C) Metallic foil is part of the packet’s container wall in this patient. ( Images contributed by Dr. Emil J. Balthazar, Department of Radiology, Bellevue Hospital Center.)

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FIGURE 5–9. Two “body stuffers.” Radiography infrequently helps with the diagnosis. (A) An ingested glass crack vial is seen in the distal bowel (arrow). The patient had ingested his contraband several hours earlier at the time of a police raid. Only the tubular-shaped container, and not the xenobiotic, is visible radiographically. The patient did not develop signs of cocaine intoxication during 24 hours of observation. (B) Another patient in police custody was brought to the emergency department for allegedly ingesting his drugs. The patient repeatedly denied this. The radiographs revealed “nonsurgical” staples in his abdomen (arrows). When questioned again, the patient admitted that he had swallowed several plastic bags that were stapled closed. (Images contributed by the Toxicology Fellowship of the New York City Poison Center.)

■ SKELETAL CHANGES CAUSED BY XENOBIOTICS A number of xenobiotics affect bone mineralization. Toxicologic effects on bone result in either increased or decreased density (Table 5–2). Some xenobiotics produce characteristic radiographic pictures, although exact

FIGURE 5–10. Subcutaneous injection of gasoline into the antecubital fossa. The radiolucent hydrocarbon mimics gas in the soft tissues that is seen with a necrotizing soft tissue infection such as necrotizing fasciitis or gas gangrene (arrows). (Image contributed by the Toxicology Fellowship of the New York City Poison Center.)

diagnoses usually depend on correlation with the clinical scenario.10,145 Furthermore, alterations in skeletal structure develop gradually and are usually not visible unless the exposure continues for at least 2 weeks. Lead Poisoning Skeletal radiography may suggest the diagnosis of chronic lead poisoning even before the blood lead concentration is obtained. With lead poisoning, the metaphyseal regions of rapidly growing long bones develop transverse bands of increased density along the growth plate (Fig. 5–11).21,160,163,174 Characteristic locations are the distal femur and proximal tibia. Flaring of the distal metaphysis also occurs. Such lead lines are also seen in the vertebral bodies and iliac crest. Detected in approximately 80% of children with a mean lead concentration of 49 ± 17 μg/dL, lead lines usually occur in children between the ages of 2 and 9 years.21 In most children, it takes several weeks for lead lines to appear, although in very young infants (2–4 months old), lead lines may develop within days of exposure.221 After exposure ceases, lead lines diminish and may eventually disappear. Lead lines are caused by the toxic effect of lead on bone growth and do not represent deposition of lead in bone. Lead impedes resorption of calcified cartilage in the zone of provisional calcification adjacent to the growth plate. This is termed chondrosclerosis.21,47 Other xenobiotics that cause metaphyseal bands are yellow phosphorus, bismuth, and vitamin D (Chap. 41). Fluorosis Fluoride poisoning causes a diffuse increase in bone mineralization. Endemic fluorosis occurs where drinking water contains very high levels of fluoride (≥2 or more parts per million), or as an occupational exposure among aluminum workers handling cryolite (sodium–aluminum fluoride). The skeletal changes associated with fluorosis are osteosclerosis (hyperostosis

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TABLE 5–2. Xenobiotic Causes of Skeletal Abnormalities Increased Bone Density Metaphyseal bands (children) Lead, bismuth, phosphorus: Chondrosclerosis caused by toxic effect on bone growth Diffuse increased bone density Fluorosis: Osteosclerosis (hyperostosis deformans), osteophytosis, ligament calcification; usually involves the axial skeleton (vertebrae and pelvis) and may cause compression of the spinal cord and nerve roots Hypervitaminosis A (pediatric): Cortical hyperostosis and subperiosteal new bone formation; diaphyses of long bones have an undulating appearance Hypervitaminosis D (pediatric): Generalized osteosclerosis, cortical thickening, and metaphyseal bands

Diminished Bone Density (Either Diffuse Osteoporosis or Focal Lesions) Corticosteroids: Osteoporosis: Diffuse Osteonecrosis: Focal lesions, e.g. avascular necrosis of the femoral head; loss of volume with both increased and decreased bone density; osteonecrosis also occurs in alcoholism, bismuth arthropathy, Caisson disease (dysbarism), trauma Hypervitaminosis D (adult): Focal or generalized osteoporosis. Injection drug use: Osteomyelitis (focal lytic lesions) caused by septic emboli; usually affects vertebral bodies and sternomanubrial joint. Vinyl chloride monomer: Acroosteolysis (distal phalanges)

A

deformans), osteophytosis, and ligament calcification. Fluorosis primarily affects the axial skeleton, especially the vertebral column and pelvis. Thickening of the vertebral column may cause compression of the spinal cord and nerve roots. Without a history of fluoride exposure, the clinical and radiographic findings can be mistaken for osteoblastic skeletal metastases. The diagnosis of fluorosis is confirmed by histologic examination of the bone and measurement of fluoride levels in the bone and urine.22,210 Focal Loss of Bone Density Skeletal disorders associated with focal diminished bone density (or mixed rarefaction and sclerosis) include osteonecrosis, osteomyelitis, and osteolysis. Osteonecrosis, also known as avascular necrosis, most often affects the femoral head, humeral head, and proximal tibia.127 There are many causes of osteonecrosis. Xenobiotic causes include long-term corticosteroid use and alcoholism. Radiographically, focal skeletal lucencies and sclerosis are seen, ultimately with loss of bone volume and collapse (Fig. 5–12A). Acroosteolysis is bone resorption of the distal phalanges and is associated with occupational exposure to vinyl chloride monomer. Protective measures have reduced its incidence since it was first described in the early 1960s.164 Osteomyelitis is a serious complication of injection drug use. It usually affects the axial skeleton, especially the vertebral bodies, as well as the sternomanubrial and sternoclavicular joints (Fig. 5–12B).74,79 Back pain or neck pain in IV drug users warrants careful consideration. A spinal epidural abscess causing spinal cord compression may accompany vertebral osteomyelitis.92,125 Radiographs are negative early in the disease course before skeletal changes are visible and the diagnosis is confirmed by MRI or CT (Fig. 5–12C).

B FIGURE 5–11. (A) A radiograph of the knees of a child with lead poisoning. The metaphyseal regions of the distal femur and proximal tibia have developed transverse bands representing bone growth abnormalities caused by lead toxicity. The multiplicity of lines implies repeated exposures to lead. (B) The abdominal radiograph of the child shows many radiopaque flakes of ingested leaded paint chips. Lead poisoning also caused abnormally increased cortical mineralization of the vertebral bodies, which gives them a boxlike appearance. (Images contributed by Dr. Nancy Genieser, Department of Radiology, Bellevue Hospital Center.)

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C FIGURE 5–12. (A) Avascular necrosis causing collapse of the femoral head in a patient with long-standing steroid-dependent asthma (arrow). (B) A patient with vertebral body osteomyelitis complicating injection drug use. Destruction of the intervertebral disk and endplates of C3 and C4 are seen (arrow). Operative culture of the bone grew Staphylococcus aureus. (C) An injection drug user with thoracic back pain, leg weakness, and low-grade fever. Radiographs of the spine were negative. Magnetic resonance image showing an epidural abscess (arrow) compressing the spinal cord. The cerebral spinal fluid in the compressed thecal sac is bright white on this T2-weighted image. (From Levitan R: Thoracolumbar spine. In: Schwartz DT, Reisdorff EJ, eds: Emergency Radiology. New York, McGraw-Hill; 2000:343, with permission.)

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■ SOFT TISSUE CHANGES Certain abnormalities in soft tissues, predominantly as a consequence of infectious complications of injection drug use, are amenable to radiographic diagnosis.74,75,79,99,198 In an injection drug user who presents with signs of local soft tissue infections, radiography is indicated to detect a retained metallic foreign body, such as a needle fragment, or subcutaneous gas, as may be seen in a necrotizing soft tissue infection such as necrotizing fasciitis. CT is more sensitive at detecting soft tissue gas than is conventional radiography. CT and ultrasonography can also detect subcutaneous or deeper abscesses that require surgical or percutaneous drainage.

■ PULMONARY AND OTHER THORACIC PROBLEMS Many xenobiotics that affect intrathoracic organs produce pathologic changes that can be detected on chest radiographs.9,12,24,49,63,75,140,172,219 The lungs are most often affected, resulting in dyspnea or cough, but the pleura, hilum, heart, and great vessels may also be involved.6 Patients with chest pain may have a pneumothorax, pneumomediastinum, or aortic dissection. Patients with fever, with or without respiratory symptoms, may have a focal infiltrate, pleural effusion, or hilar lymphadenopathy.

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Chest radiographic findings may suggest certain diseases, although the diagnosis ultimately depends on a thorough clinical history. When a specific xenobiotic exposure is known or suspected, the chest radiograph can confirm the diagnosis and help in assessment. If a history of xenobiotic exposure is not obtained, a patient with an abnormal chest radiograph may initially be misdiagnosed as having pneumonia or another disorder that is more common than xenobiotic-mediated lung disease.166 Therefore, all patients with chest radiographic abnormalities must be carefully questioned regarding possible xenobiotic exposures at work or at home, as well as the use of medications or other drugs. Many pulmonary disorders are radiographically detectable because they result in fluid accumulation within the normally air-filled lung. Fluid may accumulate within the alveolar spaces or interstitial tissues of the lung, producing the two major radiographic patterns of pulmonary disease: airspace filling and interstitial lung disease (Table 5–3). Most xenobiotics are widely distributed throughout the lungs and produce a diffuse rather than a focal radiographic abnormality. Diffuse Airspace Filling. Overdose with various xenobiotics, including salicylates, opioids, and paraquat, may cause acute lung injury (formerly known as noncardiogenic pulmonary edema) with or without

TABLE 5–3. Chest Radiographic Findings in Toxicologic Emergencies Radiographic Finding

Responsible Xenobiotic

Disease Processes

Diffuse airspace filling

Salicylates Opioids Paraquat Irritant gases: NO2 (silo filler’s disease), phosgene (COCl2), Cl2, H2S Organic phosphorus compounds, carbamates Alcoholic cardiomyopathy, cocaine, doxorubicin, cobalt Low-viscosity hydrocarbons Gastric contents aspiration: CNS depressants, alcohol, seizures Injection drug user Inhaled organic allergens: Farmer’s lung, pigeon breeder’s lung Nitrofurantoin, penicillamine

Acute lung injury

Antineoplastics: Busulfan, bleomycin, carmustine, cyclophosphamide, methotrexate Amiodarone Talcosis (illicit drug contaminant) Pneumoconiosis: Asbestosis, silicosis, coal dust, berylliosis (chronic) Procainamide, hydralazine, INH, methyldopa “Crack” cocaine and marijuana (forceful inhalation), ipecac and alcoholism (forceful vomiting), subclavian vein injection puncture Asbestos exposure Phenytoin, methotrexate (rare) Silicosis (eggshell calcification), berylliosis Ethanol, doxorubicin, cocaine, cobalt amphetamine, ipecac syrup Drug-induced systemic lupus erythematosus (procainamide, hydralazine, INH) Cocaine

Cytotoxic lung damage

Focal airspace filling Multifocal airspace filling Interstitial patterns Fine or coarse reticular or reticulonodular pattern Patchy airspace filling is seen in some cases

Pleural effusion Pneumomediastinum ⎫ ⎬ Pneumothorax ⎭ Pleural plaques (calcified) Lymphadenopathy Cardiomegaly (chronic exposure)

Aortic enlargement

Cholinergic stimulation (bronchorrhea) Congestive heart failure Aspiration pneumonitis Septic emboli Hypersensitivity pneumonitis

Phospholipidosis Injected particulates Inhaled inorganic particulates Drug-induced systemic lupus erythematosus Barotrauma Fibrosis or asbestosis Pseudolymphoma Pneumoconiosis Dilated cardiomyopathy Pericardial effusion Aortic dissection.

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FIGURE 5–13. Diffuse airspace filling. The chest radiograph of a patient who had recently injected heroin intravenously presented with respiratory distress and acute lung injury. The heart size is normal.

diffuse alveolar damage and characterized by leaky capillaries (Fig. 5–13 ).75,85,89,123,184,191,218 There are, of course, many other causes of acute lung injury, including sepsis, anaphylaxis, and major trauma.213 Other xenobiotic exposures that may result in diffuse airspace filling include inhalation of irritant gases that are of low water solubility such as phosgene (COC12), nitrogen dioxide (silo filler’s disease), chlorine, hydrogen sulfide, and sulfur dioxide (Chaps. 124, 128).79,102 Organic phosphorus insecticide poisoning causes cholinergic hyperstimulation, resulting in bronchorrhea (Chap. 113). Smoking “crack” cocaine is associated with diffuse alveolar hemorrhage.60,75,79,165,219

FIGURE 5–14. Focal airspace filling as a result of hydrocarbon aspiration. A 34-year-old man aspirated gasoline. The chest radiograph shows bilateral lower lobe infiltrates.

Inhaled organic allergens such as those in moldy hay (farmer’s lung) and bird droppings (pigeon breeder’s lung) cause hypersensitivity pneumonitis in sensitized individuals. There are two clinical syndromes: an acute, recurrent illness and a chronic, progressive disease. The acute illness presents with fever and dyspnea. In these cases, the

Focal Airspace Filling. Focal infiltrates are usually caused by bacterial pneumonia, although aspiration of gastric contents also causes localized airspace disease.75,195Aspiration may occur during sedative– hypnotic or alcohol intoxication or during a seizure. During ingestion, low-viscosity hydrocarbons often enter the lungs while they are being swallowed (Figs. 5–14 and 105–2). There may be a delay in the development of radiographic abnormalities, and the chest radiograph may not appear to be abnormal until 6 hours after the ingestion.8 During aspiration, the most dependent portions of the lung are affected. When the patient is upright at the time of aspiration, the lower lung segments are involved. When the patient is supine, the posterior segments of the upper and lower lobes are affected.62 Multifocal Airspace Filling. Multifocal airspace filling occurs with septic pulmonary emboli, which is a complication of injection drug use and right-sided bacterial endocarditis. The foci of pulmonary infection often undergo necrosis and cavitation (Fig. 5–15).75,79 Interstitial Lung Diseases. Toxicologic causes of interstitial lung disease include hypersensitivity pneumonitis, use of medications with direct pulmonary toxicity, and inhalation or injection of inorganic particulates.75 Interstitial lung diseases may have an acute, subacute, or chronic course. On the chest radiograph, acute and subacute disorders cause a fine reticular or reticulonodular pattern (Fig. 5–16). Chronic interstitial disorders cause a coarse reticular “honeycomb” pattern. Hypersensitivity pneumonitis. Hypersensitivity pneumonitis is a delayedtype hypersensitivity reaction to an inhaled or ingested allergen.40,96,166

FIGURE 5–15. Multifocal airspace filling. The chest radiograph in an injection drug user who presented with high fever but without pulmonary symptoms. Multiple ill-defined pulmonary opacities are seen throughout both lungs, which are characteristic of septic pulmonary emboli. His blood cultures grew Staphylococcus aureus.

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chest radiograph is normal or may show fine interstitial or alveolar infiltrates. Chronic hypersensitivity pneumonitis causes progressive dyspnea, and the radiograph shows interstitial fibrosis. The most common medication causing hypersensitivity pneumonitis is nitrofurantoin. Respiratory symptoms occur after taking the medication for 1 to 2 weeks. Other medications that may cause hypersensitivity pneumonitis include sulfonamides and penicillins. Antineoplastics. Various chemotherapeutic agents, such as busulfan, bleomycin, cyclophosphamide, and methotrexate, cause pulmonary injury by their direct cytotoxic effect on alveolar cells.39,65 The radiographic pattern is usually interstitial (reticular or nodular) but may include airspace filling or mixed patterns. The patient presents with dyspnea, fever, and pulmonary infiltrates that begin after several weeks of therapy. Other causes of these clinical and radiographic findings must be considered, including opportunistic infection, pulmonary carcinomatosis, pulmonary edema, and intraparenchymal hemorrhage. Symptoms usually resolve with discontinuation of the offending medication. Amiodarone. Amiodarone toxicity causes phospholipid accumulation within alveolar cells and may result in pulmonary fibrosis. An interstitial radiographic pattern is seen, although airspace filling may also occur (see Fig. 5–16) (Chap. 63).

FIGURE 5–16. Reticular interstitial pattern. The chest radiograph of a patient with cardiac disease who presented to the emergency department with progressive dyspnea. The initial diagnostic impression was interstitial pulmonary edema. The patient was taking amiodarone for malignant ventricular dysrhythmias (note the implanted automatic defibrillator). The lack of response to diuretics and the high-resolution CT pattern suggested that this was toxicity to amiodarone. The medication was stopped, and there was partial clearing over several weeks. (Image contributed by Dr. Georgeann McGuinness, Department of Radiology, New York University.)

A

Particulates. Inhaled inorganic particulates, such as asbestos, silica, and coal dust, cause pneumoconiosis. This is a chronic interstitial lung disease characterized by interstitial fibrosis and loss of lung volume.32,138,167,215 IV injection of illicit xenobiotics that have particulate contaminants, such as talc, causes a chronic interstitial lung disease known as talcosis.1,55,212 Pleural Disorders Asbestos-related calcified pleural plaques develop many years after asbestos exposure (Fig. 5–17). These lesions do not cause clinical symptoms and have only a minor association with malignancy and interstitial lung disease. Asbestos-related pleural plaques should not be called asbestosis because that term refers specifically to the interstitial lung disease caused by asbestos. Pleural plaques must be distinguished from mesotheliomas, which are not calcified, enlarge at a rapid rate, and erode into nearby structures such as the ribs.

B

FIGURE 5–17. (A) Calcified plaques typical of asbestos exposure are seen on the pleural surfaces of the lungs, diaphragm, and heart. The patient was asymptomatic; this was an incidental radiographic finding. (B) The computed tomography (CT) scan demonstrates that the opacities seen on the chest radiograph do not involve the lung itself. A lower thoracic image shows calcified pleural plaques (the diaphragmatic plaque is seen on the right). The CT confirms that there is no interstitial lung disease (“asbestosis”).

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FIGURE 5–18. Two patients with chest pain after cocaine use. (A) Pneumomediastinum after forceful inhalation while smoking “crack” cocaine. A fine white line representing the pleura elevated from the mediastinal structures is seen (arrows). The patient’s chest pain resolved during a 24-hour period of observation. (B) Thoracic aortic dissection and rupture after cocaine use. The patient presented with chest pain radiating to the back. Chest radiography reveals a wide and indistinct aortic contour (arrow). (Images contributed by the Toxicology Fellowship of the New York City Poison Center.)

Pleural effusions occur with drug-induced systemic lupus erythematosus.140 The medications most frequently implicated are procainamide, hydralazine, isoniazid, and methyldopa. The patient presents with fever as well as other symptoms of systemic lupus erythematosus. Pneumothorax and pneumomediastinum are associated with illicit drug use. These complications are related to the route of administration rather than to the particular drug. Barotrauma associated with Valsalva maneuver or intense inhalation with breath holding during the smoking of “crack” cocaine or marijuana results in pneumomediastinum (Fig. 5–18A).20,50,75,150 Pneumomediastinum is one cause of cocaine-related chest pain that can be diagnosed by chest radiography. Forceful vomiting after ingestion of syrup of ipecac or alcohol may produce a Mallory-Weiss syndrome, pneumomediastinum, and mediastinitis (Boerhaave syndrome).220 Intravenous drug users who attempt to inject into the subclavian and internal jugular veins may cause a pneumothorax.46 Lymphadenopathy Phenytoin may cause drug-induced lymphoid hyperplasia with hilar lymphadenopathy.140 Chronic beryllium exposure results in hilar lymphadenopathy that mimics sarcoidosis, with granulomatous changes in the lung parenchyma. Silicosis is associated with “eggshell” calcification of hilar lymph nodes. Cardiovascular Abnormalities Dilated cardiomyopathy occurs in chronic alcoholism and exposure to cardiotoxic medications such as doxorubicin (Adriamycin). Enlargement of the cardiac silhouette may also be caused by a pericardial effusion, which may accompany druginduced systemic lupus erythematosus. Aortic dissection is associated with use of cocaine and amphetamines.66,75,114,152,162 The chest radiograph may show an enlarged or indistinct aortic knob and an ascending or descending aorta (Fig. 5–18B).

■ ABDOMINAL PROBLEMS Abdominal imaging modalities include conventional radiography, CT, GI contrast studies, and angiography.68 Conventional radiography is

limited in its ability to detect most intraabdominal pathology because most pathologic processes involve soft tissue structures that are not well seen. Plain radiography readily visualizes gas in the abdomen and is therefore usable to diagnose pneumoperitoneum (free intraperitoneal air) and bowel distension caused by mechanical obstruction or diminished gut motility (adynamic ileus). Other abnormal gas collections, such as intramural gas associated with intestinal infarction, are seen infrequently (Table 5–4).73,120,128,137,186 Pneumoperitoneum GI perforation is diagnosed by seeing free intraperitoneal air under the diaphragm on an upright chest radiograph. Peptic ulcer perforation is associated with crack cocaine use.2,29,107 Esophageal or gastric perforation (or tear) can be a complication of forceful emesis induced by syrup of ipecac or alcohol intoxication or attempted placement of a large-bore orogastric tube (Fig. 5–19).220 Esophageal and gastric perforation may also occur after the ingestion of caustics such as iron, alkali, or acid.103 Esophageal perforation causes pneumomediastinum and mediastinitis. Obstruction and Ileus Both mechanical bowel obstruction and adynamic ileus (diminished gut motility) cause bowel distension. With mechanical obstruction, there is a greater amount of intestinal distension proximal to the obstruction and a relative paucity of gas and intestinal collapse distal to the obstruction. In adynamic ileus, the bowel distension is relatively uniform throughout the entire intestinal tract. On the upright abdominal radiograph, both mechanical obstruction and adynamic ileus show air-fluid levels. In mechanical obstruction, air-fluid levels are seen at different heights and produce a “stepladder” appearance. Mechanical bowel obstruction may be caused by large intraluminal foreign bodies such as a body packer’s packets or a medication bezoar.64,197 Adynamic ileus may result from the use of opioids, anticholinergics, and tricyclic antidepressants (Fig. 5–20).15,68 Because adynamic ileus is seen in many diseases, the radiographic finding of an ileus is not helpful diagnostically. When the distinction between obstruction and adynamic ileus cannot be made based on the abdominal radiographs, abdominal CT can clarify the diagnosis.135

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TABLE 5–4. Plain Abdominal Radiography in Toxicologic Emergencies Radiographic Finding

Xenobiotic

Pneumoperitoneum (hollow viscus perforation)

Caustics: Iron, alkali, acids Cocaine GI decontamination (ipecac, lavage tube) Foreign-body ingestion: Body packer, enteric-coated pills (bezoar)

Mechanical obstruction (intraluminal foreign body) Intestinal gastric outlet ⎫ Upper GI ⎬ esophageal ⎭ series lleus (diminished gut motility)

Intramural gas (intestinal infarction) Bowel wall thickening Hepatic portal venous gas (CT is more sensitive) Foreign-body ingestion

Opioids Anticholinergics Cyclic antidepressants Mesenteric ischemia caused by cocaine, oral contraceptives, cardioactive steroids, hypokalemia, hypomagnesemia Cocaine Ergot alkaloids Oral contraceptives Calcium channel blockers Hypotension Iron pills Metals (As, Cs, Hg, K, Pb, TI) Body packers and stuffers Bismuth subsalicylate Calcium carbonate Enteric-coated and sustained-release tablets Pica (calcareous clay).

FIGURE 5–20. Methadone maintenance therapy causing marked abdominal distension. The radiograph reveals striking large bowel dilatation, termed colonic ileus, caused by chronic opioid use. A similar radiographic picture is seen with anticholinergic poisoning. A contrast enema can clarify the diagnosis. (Image contributed by Dr. Emil J. Balthazar, Department of Radiology, Bellevue Hospital Center.)

Mesenteric Ischemia In most patients with intestinal ischemia, plain abdominal radiographs show only a nonspecific or adynamic ileus pattern. In a small proportion of patients with ischemic bowel (5%), intramural gas is seen.15 Rarely, gas is also seen in the hepatic portal venous system. CT is better able to detect signs of mesenteric ischemia, particularly bowel wall thickening.14 Intestinal ischemia and infarction may be caused by use of cocaine, other sympathomimetics, and the ergot alkaloids, which induce mesenteric vasoconstriction.79,110,130 Calcium channel blocker overdoses cause splanchnic vasodilation and hypotension that may result in intestinal ischemia. Superior mesenteric vein thrombosis may be caused by hypercoagulability associated with chronic oral contraceptive use.

FIGURE 5–19. Gastrointestinal perforation after gastric lavage with a large-bore orogastric tube. The upright chest radiograph shows air under the right hemidiaphragm and pneumomediastinum (arrows). An esophagram with water-soluble contrast did not demonstrate the perforation. Laparotomy revealed perforation of the anterior wall of the stomach.

Gastrointestinal Hemorrhage and Hepatotoxicity Radiography is not usually helpful in the diagnosis of such common abdominal complications as GI bleeding and hepatotoxicity. The now obsolete radiocontrast agent thorium dioxide (Thorotrast; thorium, atomic number 90) provides a unique example of pharmaceutical-induced hepatotoxicity. It was used as an angiographic contrast agent until 1947, when it was found to cause hepatic malignancies. The radioactive isotope of thorium has a half-life of 400 years. It accumulates within the reticuloendothelial system and remains there for the life of the patient. It had a characteristic radiographic appearance, with multiple punctate opacities in the liver,

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FIGURE 5–21. An abdominal radiograph of a patient who had received thorium dioxide (Thorotrast) for a radiocontrast study many years previously. The spleen (vertical white arrow), liver (horizontal black arrow), and lymph nodes (horizontal white arrow) are demarcated by thorium retained in the reticuloendothelial system. (Image contributed by Dr. Emil J. Balthazar, Department of Radiology, Bellevue Hospital Center.)

spleen, and lymph nodes (Fig. 5–21). Patients who received thorium before its removal from the market may still present with hepatic malignancies.18,204

A

Contrast Esophagram and Upper Gastrointestinal Series Ingestion of a caustic may cause severe damage to the mucosal lining of the esophagus. This can be demonstrated by a contrast esophagram. However, in the acute setting, upper endoscopy should be performed rather than an esophagram because it provides more information about the extent of injury and prognosis.111 In addition, administration of barium will coat the mucosa, making endoscopy difficult. For later evaluation, a contrast esophagram identifies mucosal defects, scarring, and stricture formation (Figs. 5–22 and 104–3).129 The choice of radiographic contrast agent (barium or watersoluble material) depends on the clinical situation. If the esophagus is severely strictured and there is risk of aspiration, barium should be used because water-soluble contrast material is damaging to the pulmonary parenchyma. If, on the other hand, esophageal or gastric perforation is suspected, water-soluble contrast is safer because extravasated barium is highly irritating to mediastinal and peritoneal tissues, but extravasated water-soluble contrast is gradually absorbed into the circulation. Ingested foreign bodies may cause esophageal and gastric outlet obstruction. Esophageal obstruction because of a drug packet can be demonstrated by a contrast esophagram. Concretions of ingested material in the stomach may cause gastric outlet obstruction. This has been reported with potassium chloride tablets and enteric-coated aspirin.11,185 Abdominal Computed Tomography CT provides great anatomic definition of intraabdominal organs and plays an important role in the diagnosis of a wide variety of abdominal disorders. In most cases, both oral and IV contrast are administered. Oral contrast delineates the intestinal lumen. IV contrast is needed to reliably detect lesions in hepatic and splenic parenchyma, the kidneys, and the bowel wall. Certain abdominal complications of poisonings are amenable to CT diagnosis. Intestinal ischemia causes bowel wall thickening; intramural hemorrhage; and at a later stage, intramural gas and hepatic portal venous gas.14 Splenic infarction and splenic and psoas abscesses

B FIGURE 5–22. (A) A barium swallow performed several days after ingestion of liquid lye shows intramural dissection and extravasation of barium with early stricture formation. (B) At 3 weeks postingestion, there is an absence of peristalsis, diffuse narrowing of the esophagus, and reduction in size of the fundus and antrum of the stomach as a result of scarring. (Images contributed by Dr. Emil J. Balthazar, Department of Radiology, Bellevue Hospital Center.)

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B

FIGURE 5–23. (A) Chest radiograph of a young drug abuser who used the supraclavicular approach for heroin injection. The large mass in the left chest was suspicious for a pseudoaneurysm. (B) An arch aortogram performed on the patient revealed a large pseudoaneurysm and hematoma subsequent to an arterial tear during attempted injection. Surgical repair was performed. (Images contributed by Dr. Richard Lefleur, Department of Radiology, Bellevue Hospital.)

are complications of IV drug use that may be diagnosed on CT.15 Radiopaque foreign substances such as intravenously injected elemental mercury may be detected and accurately localized by CT.126 Radiolucent foreign bodies, such as a body packer’s packets, may be detected by using enteric contrast.83,85 Vascular Lesions Angiography may detect such complications of injection drug use as venous thrombosis and arterial laceration causing pseudoaneurysm formation (Figs. 5–23 and 5–24). IV injection of amphetamine, cocaine, or ergotamine causes necrotizing angiitis that is associated with microaneurysms, segmental stenosis, and arterial thrombosis. These lesions are seen in the kidneys, small bowel, liver, pancreas, and cerebral circulation (Fig. 5–25).34,161 Complications include aneurysm rupture and visceral infarction. Renal lesions cause severe hypertension and renal failure.175

■ NEUROLOGIC PROBLEMS Diagnostic imaging studies have revolutionized the management of CNS disorders.57,71 Both acute brain lesions and chronic degenerative changes can be detected (Table 5–5).118 Some xenobiotics have a direct toxic effect on the CNS; others indirectly cause neurologic injury by causing hypoxia, hypotension, hypertension, cerebral vasoconstriction, head trauma, or infection. Imaging Modalities CT can directly visualize brain tissue and many intracranial lesions.70 CT is the imaging study of choice in the emergency setting because it readily detects acute intracranial hemorrhage as well as parenchymal lesions that are causing mass effect. CT is fast, widely available on an emergency basis, and can accommodate critical support and monitoring devices. Infusion of IV contrast further delineates intracerebral mass lesions such as tumors and abscesses. MRI has largely supplanted CT in nonemergency neurodiagnosis. It offers better anatomic discrimination of brain tissues and areas of cerebral edema and demyelination. However, MRI is no better than CT

FIGURE 5–24. Venogram of a 50-year-old patient who routinely injected heroin into his groin. Occlusion of the femoral vein (black arrow) with diffuse aneurysmal dilation (small arrow) and extensive collaterals are shown. Incidental radiopaque materials are noted in the right buttock (double arrow). By history, this represents either bismuth or arsenicals he received as antisyphilitic therapy. (Image contributed by Dr. Richard Lefleur, Department of Radiology, Bellevue Hospital.)

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FIGURE 5–25. A selective renal angiogram in an injection methamphetamine user demonstrating multiple small and large aneurysms (arrows). (Image contributed by Dr. Richard Lefleur, Department of Radiology, Bellevue Hospital Center.)

FIGURE 5–26. Subarachnoid hemorrhage after intravenous cocaine use. The patient had sudden severe headache followed by a generalized seizure. Extensive hemorrhage is seen surrounding the midbrain (white arrows) and in the right Sylvian fissure (black arrow). Angiography revealed an aneurysm at the origin of the right middle cerebral artery.

in detecting acute blood collections or mass lesions. In the emergency setting, the disadvantages of MRI outweigh its strengths. MRI is usually not readily available on an emergency basis, image acquisition time is long, and critical care supportive and monitoring devices are often incompatible with MR scanning machines.121 Nuclear scintigraphy that uses CT technology (SPECT and PET) is being used as a tool to elucidate functional characteristics of the CNS. Examples include both immediate and long-term effects of various xenobiotics on regional brain metabolism, blood flow, and neurotransmitter function.115,154,207

Emergency Head CT Scanning An emergency noncontrast head CT scan is obtained to detect acute intracranial hemorrhage and focal brain lesions causing cerebral edema and mass effect. Patients with these lesions present with focal neurologic deficits, seizures, headache, or altered mental status. Toxicologic causes of intraparenchymal and subarachnoid hemorrhage include cocaine and other sympathomimetics (Fig. 5–26).113,117 Cocaine-induced vasospasm may cause ischemic infarction, although this is not well seen by CT until 6 to 24 or more hours after onset of the neurologic deficit (Fig. 5–27). Drug-induced CNS depression, most commonly ethanol intoxication, predisposes the patient to head

TABLE 5–5. Head CT (Noncontrast) in Toxicologic Emergencies CT Finding

Brain Lesion

Xenobiotic Etiology

Hemorrhage

Intraparenchymal hemorrhage Subarachnoid hemorrhage

Sympathomimetics: cocaine (“crack”), amphetamine, phenylpropanolamine, phencyclidine, ephedrine, pseudoephedrine Mycotic aneurysm rupture (IDU) Trauma secondary to ethanol, sedative-hypnotics, seizures Anticoagulants Carbon monoxide, cyanide, hydrogen sulfide, methanol, manganese

Subdural hematoma Brain lucencies

Loss of brain tissue

Basal ganglia focal necrosis (also subcortical white matter lucencies) Stroke: Vasoconstriction Mass lesion: tumor, abscess Atrophy: Cerebral, cerebellar

Sympathomimetics: cocaine (“crack”), amphetamine, phenylpropanolamine, phencyclidine, ephedrine, pseudoephedrine, ergotamine Septic emboli, AIDS-related CNS toxoplasmosis or lymphoma Alcoholism, toluene

CNS, central nervous system; IDU, injection drug use.

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C

E

FIGURE 5–27. Acute stroke confirmed by diffusion-weighted magnetic resonance image (MRI). A 39-year-old man presented with left facial weakness that began 3 hours earlier after smoking crack cocaine. He also complained of left arm “tingling” but had a normal examination. A stat noncontrast computed tomography (CT) scan was obtained that was interpreted as normal (A), although in retrospect there was subtle loss of the normal gray/white differentiation (arrow). MRI was obtained to confirm that the facial palsy was a stroke and not a peripheral seventh cranial nerve palsy. Standard MRI sequence (T1-weighted, T2 weighted, and FLAIR) were normal in this early ischemic lesion (B and C). Diffusionweighed imaging (DWI) is able to show such early ischemic change—cytotoxic (intracellular) edema (D). The patient’s facial paresis improved but did not entirely resolve. A repeat CT scan 2 days later showed an evolving (subacute) infarction with vasogenic edema (E). Infarction was presumably due to vasospasm because no carotid artery lesion or cardiac source of embolism was found. (From Schwartz DT: Emergency Radiology: Case Studies, New York, McGraw-Hill; 2008:517, with permission.)

trauma, which may result in a subdural hematoma or cerebral contusion (Fig. 5-28). Toxicologic causes of intracerebral mass lesions include septic emboli complicating injection drug use and HIVassociated CNS toxoplasmosis and lymphoma (Fig. 5-29).19,74,79,149 On a contrast CT, such tumors and focal infections exhibit a pattern of “ring enhancement.” Xenobiotic-Mediated Neurodegenerative Disorders A number of xenobiotics directly damage brain tissue, producing morphologic changes that may be detectable using CT and MRI. Such changes include generalized atrophy, focal areas of neuronal loss, demyelinization, and cerebral edema. Imaging abnormalities may help

establish a diagnosis or predict prognosis in a patient with neurologic dysfunction after a xenobiotic exposure. In some cases, the imaging abnormality will suggest a toxicologic diagnosis in a patient with a neurologic disorder in whom a xenobiotic exposure was not suspected clinically.4,13,57,100,104,155,165,214 Atrophy Ethanol is the most widely used neurotoxin. With long-term ethanol use, there is a widespread loss of neurons and resultant atrophy. In some alcoholics, the loss of brain tissue is especially prominent in the cerebellum. However, the amount of cerebral or cerebellar atrophy does not always correlate with the extent of cognitive impairment or gait disturbance.42,67,84,86,106,209,211 Chronic solvent exposure, such as

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FIGURE 5–28. An acute subdural hematoma in an alcoholic patient after an alcohol binge. A crescent-shaped blood collection is seen between the right cerebral convexity and the inner table of the skull (arrow). FIGURE 5–30. A head computed tomography scan of a patient with mental status changes after carbon monoxide poisoning. The scan shows characteristic bilateral symmetrical lucencies of the globus pallidus (arrows). (Image contributed by Dr. Paul Blackburn, Maricopa Medical Center, Arizona.)

to toluene (occupational and illicit use), also causes diffuse cerebral atrophy.93,171

FIGURE 5–29. An injection drug user with ring-enhancing intracerebral lesions. The patient presented with fever and altered mental status. In this patient, the lesions represent multiple septic emboli complicating acute Staphylococcus aureus bacterial endocarditis. A similar ring-enhancing appearance is seen with lesions caused by toxoplasmosis or primary central nervous system lymphoma in patients with AIDS. This patient was HIV negative.

Focal Degenerative Lesions Carbon monoxide poisoning produces focal degenerative lesions in the brain. In about half of patients with severe neurologic dysfunction after carbon monoxide poisoning, CT scans show bilateral symmetric lucencies in the basal ganglia, particularly the globus pallidus (Figs. 5-30 and 125–1).27,94,100,141,155,158,159,177,178,182,200,206 The basal ganglia are especially sensitive to hypoxic damage because of their limited blood supply and high metabolic requirements. Subcortical white matter lesions also occur after carbon monoxide poisoning. Although less frequent than lesions of the basal ganglia, white matter lesions are more clearly associated with a poor neurologic outcome. MRI is more sensitive than CT at detecting these white matter abnormalities.27,57,104,159,200 Basal ganglion lucencies, white matter lesions, and atrophy are caused by other xenobiotics such as methanol,12,41,69,82,142,173 ethylene glycol, cyanide,58,139 hydrogen sulfide, inorganic and organic mercury,131 manganese,13,190 heroin,104,108 barbiturates, chemotherapeutic agents, solvents such as toluene,57,93,17150,83,156 and podophyllin.28,144 Nontoxicologic disorders may cause similar imaging abnormalities, including hypoxia, hypoglycemia, and infectious encephalitis.82,88 Nuclear Scintigraphy Whereas both CT and MRI display cerebral anatomy, nuclear medicine studies provide functional information about the brain. Nuclear scintigraphy uses radioactive isotopes that are bound to carrier molecules (ligands). The choice of ligand depends

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on the biologic function being studied. Brain cells take up the radiolabeled ligand in proportion to their physiologic activity or the regional blood flow. The radioactive emission from the isotope is detected by a scintigraphic camera, which produces an image showing the quantity and distribution of tracer. Better anatomic detail is provided by using CT techniques to generate cross-sectional images. There are two such technologies: SPECT and PET. These imaging modalities have been used in the research and clinical settings to study the neurologic effects of particular xenobiotics and the mechanisms of xenobiotic-induced neurologic dysfunction. SPECT uses conventional isotopes such as technetium-99m and iodine-123.115 These isotopes are bound to ligands that are taken up in the brain in proportion to regional blood flow, reflecting the local metabolic rate. PET uses radioactive isotopes of biologic elements such as carbon-11, oxygen-15, nitrogen-13, and fluoride-18 (a substitute for hydrogen).154 These radioisotopes have very short half-lives so that PET scanning requires an onsite cyclotron to produce the isotope. The isotopes are incorporated into molecules such as glucose, oxygen, water, various neurotransmitters, and drugs. Labeled glucose is taken up in proportion to the local metabolic rate for glucose. Uptake of labeled oxygen demonstrates the local metabolic rate for oxygen. Labeled neurotransmitters generate images reflecting their concentration and distribution within the brain. Both PET and SPECT have been used to study the effects of various xenobiotics on cerebral function. For example, although both CT and MRI can detect cerebellar atrophy in chronic alcoholics, there is a poor correlation between the magnitude of cerebellar atrophy and the clinical signs of cerebellar dysfunction. PET scans may demonstrate diminished cerebellar metabolic rate for glucose, which correlates more accurately with the patient’s clinical status.72,209 In patients with severe neurologic dysfunction after carbon monoxide poisoning, SPECT regional blood flow measurements show diffuse hypometabolism in the frontal cortex.30 In one patient, severe perfusion abnormalities improved slightly over several months in proportion to the patient’s gradual clinical improvement.98 In another patient treated with hyperbaric oxygen, a SPECT scan revealed increased blood flow in the frontal lobes, although the blood flow still remained significantly less than normal.124 In patients who chronically use cocaine, SPECT blood flow scintigraphy demonstrates focal cortical perfusion defects. The extent of these perfusion defects correlates with the frequency of drug use. Focal perfusion defects probably represent local vasculitis or small areas of infarction.92,202 PET scanning has been used to demonstrate the effects of cocaine on cerebral blood flow and regional glucose metabolism. PET neurotransmitter studies show promise in elucidating potential mechanisms of action of cocaine. Using radiolabeled dopamine analogs, downregulation of dopamine (D2) receptors has been noted after a cocaine binge. This finding may be responsible for cocaine craving that occurs during cocaine withdrawal. Using 11C-labeled cocaine, uptake of cocaine can be demonstrated in the basal ganglia, a region rich in dopamine receptors.207 Much has been learned about these imaging modalities, and initial applications can be applied to patient care. These imaging modalities are capable of demonstrating abnormalities in many patients with xenobiotic exposures, although other patients with significant cerebral dysfunction have normal studies.

SUMMARY This chapter has highlighted a variety of situations in which diagnostic imaging studies are useful in toxicologic emergencies. Imaging can be an important tool in establishing a diagnosis, assisting in the treatment

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of patients, and detecting complications of a toxicologic emergency. The imaging modalities include plain radiography, CT, enteric and intravascular contrast studies, nuclear scintigraphy, and ultrasonography. However, effective use of a diagnostic test requires a firm understanding of the clinical situations in which each test can be useful, knowledge of the capabilities and limitations of the tests, and how the results should be applied to the care of an individual patient.

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145. Neustadter LM, Weiss M: Medication-induced changes of bone. Semin Roentgenol. 1995;30:88-95. 146. Ng RC, Perry K, Martin DJ: Iron poisoning: assessment of radiography in diagnosis and management. Clin Pediatr (Phila). 1979;18:614-616. 147. O’Brien RP, McGeehan PA, Helmeczi AW, Dula DJ: Detectability of drug tablets and capsules by plain radiography. Am J Emerg Med. 1986;4:302-312. 148. Olmedo RE, Hoffman RS, Nelson LS: Limitations of whole bowel irrigation and laparotomy in a cocaine “body packer” [abstract]. J Toxicol Clin Toxicol. 1999;37:645. 149. Olsen WL, Cohen W: Neuroradiology of AIDS. In: Federle MP, Megibow AJ, Naidich DP, eds. Radiology of Acquired Immune Deficiency Syndrome. New York: Raven Press; 1988:21-45. 150. Palat D, Denson M, Sherman M, Matz R: Pneumomediastinum induced by inhalation of alkaloidal cocaine. N Y State J Med. 1988;88:438-439. 151. Palatnick W, Tenenbein M: Leukocytosis, hyperglycemia, vomiting, and positive X-rays are not indicators of severity of iron overdose in adults. Am J Emerg Med. 1996;14:454-455. 152. Perron AD, Gibbs M: Thoracic aortic dissection secondary to crack cocaine ingestion. Am J Emerg Med. 1997;15:507-509. 153. Peterson CD, Fifield GC: Emergency gastrotomy for acute iron poisoning. Ann Emerg Med. 1980;9:262-264. 154. Phelps ME: Positron emission tomography. In: Mazzotta JG, Gilman S, ed. Clinical Brain Imaging: Principles and Applications. Philadelphia: FA Davis; 1992:71-106. 155. Piatt JP, Kaplan AM, Bond GR, Berg RA: Occult carbon monoxide poisoning in an infant. Pediatr Emerg Care. 1990;6:21-23. 156. Pidoto RR, Agliata AM, Bertolini R, et al: A new method of packaging cocaine for international traffic and implications for the management of cocaine body packers. J Emerg Med. 2002;23:149-153. 157. Pollack CV, Biggers DW, Carlton FB: Two crack cocaine body stuffers. Ann Emerg Med. 1992;21:1370-1380. 158. Pracyk JB, Stolp BW, Fife CE, Gray L, Piantadosi CA: Brain computerized tomography after hyperbaric oxygen therapy for carbon monoxide poisoning. Undersea Hyperb Med. 1995;22:1-7. 159. Prockop LD, Naidu KA: Brain CT and MRI findings after carbon monoxide toxicity. J Neuroimaging. 1999;9:175-181. 160. Raber SA: The dense metaphyseal band sign. Radiology. 1999;211:773-774. 161. Ramchandani P, Pollack HM: Radiology of drug-related genitourinary disease. Semin Roentgenol. 1995;30:77-87. 162. Rashid J, Eisenberg MJ, Topol EJ: Cocaine-induced aortic dissection. Am Heart J. 1996;132:1301-1304. 163. Resnick D: Heavy metal poisoning and deficiency. In: Resnick D, ed. Diagnosis of Bone and Joint Disorders. Philadelphia: W.B. Saunders; 1995:3353-3364. 164. Resnick D, Niwayama G: Osteolysis and chondrolysis. In: Resnick D, ed. Diagnosis of Bone and Joint Disorders. Philadelphia: W.B. Saunders; 1995:4467-4469. 165. Restrepo CS, Carrillo JA, Mart??nez S, et al: Pulmonary complications from cocaine and cocaine-based substances: imaging manifestations. Radiographics. 2007;27:941-956. 166. Richerson HB: Hypersensitivity pneumonitis (extrinsic allergic alveolitis). In: Fishman AP, eds. Pulmonary Diseases and Disorders, 2nd ed. New York: McGraw-Hill; 1988:667-674. 167. Roach HD, Davies GJ, Attanoos R, Crane M, Adams H, Phillips S: Asbestos: when the dust settles an imaging review of asbestos-related disease. Radiographics. 2002;22(suppl):S167-S184. 168. Roberge RJ, Martin TG: Whole bowel irrigation in an acute oral lead intoxication. Am J Emerg Med. 1992;10:577-583. 169. Roberts JR: Complications of radiographic contrast material. Emerg Med News. 2004;31-34. 170. Roberts JR, Price D, Goldfrank L, Hartnett L: The bodystuffer syndrome: a clandestine form of drug overdose. Am J Emerg Med. 1986;4:24-27. 171. Rosenberg NL, Kleinschmidt-DeMasters BK, Davis KA, Dreisbach JN, Hormes JT, Filley CM: Toluene abuse causes diffuse central nervous system white matter changes. Ann Neurol. 1988;23:611-614. 172. Rossi SE, Erasmus JJ, McAdams HP, Sporn TA, Goodman PC: Pulmonary drug toxicity: radiologic and pathologic manifestations. Radiographics. 2000;20:1245-1259. 173. Rubinstein D, Escott E, Kelly JP: Methanol intoxication with putaminal and white matter necrosis: MR and CT findings. AJNR Am J Neuroradiol. 1995;16:1492-1494. 174. Sachs HK: The evolution of the radiologic lead line. Radiology. 1981;139:81-85.

175. Saleem TM, Singh M, Murtaza M, Singh A, Kasubhai M, Gnanasekaran I: Renal infarction: a rare complication of cocaine abuse. Am J Emerg Med. 2001;19:528-529. 176. Savitt DL, Hawkins HH, Roberts JR: The radiopacity of ingested medications. Ann Emerg Med. 1987;16:331-339. 177. Sawada Y, Sakamoto T, Nishide K, et al: Correlation of pathological findings with computed tomographic findings after acute carbon monoxide poisoning. N Engl J Med. 1983;308:1296. 178. Sawada Y, Takahashi M, Ohashi N, et al: Computerised tomography as an indication of long-term outcome after acute carbon monoxide poisoning. Lancet. 1980;1:783-784. 179. Schabel SI, Rogers CI: Opaque artifacts in a health food faddist simulating ovarian neoplasm. AJR Am J Roentgenol. 1978;130:789-790. 180. Schwartz DT: Toxicologic emergencies. In: Schwartz DT, Reisdorff EJ, eds. Emergency Radiology. New York: McGraw-Hill; 2000:627-648. 181. Sengupta A, Page P: Window manipulation in diagnosis of body packing using computed tomography. Emerg Radiol. 2008;15:203-205. 182. Silver DA, Cross M, Fox B, Paxton RM: Computed tomography of the brain in acute carbon monoxide poisoning. Clin Radiol. 1996;51:480-483. 183. Sinner WN: The gastrointestinal tract as a vehicle for drug smuggling. Gastrointest Radiol. 1981;6:319-323. 184. Smith DA, Leake L, Loflin JR, Yealy DM: Is admission after intravenous heroin overdose necessary? Ann Emerg Med. 1992;21:1326-1330. 185. Sogge MR, Griffith JL, Sinar DR, Mayes GR: Lavage to remove enteric-coated aspirin and gastric outlet obstruction. Ann Intern Med. 1977;87:721-722. 186. Spitzer A, Caruthers SB, Stables DP: Radiopaque suppositories. Radiology. 1976;121:71-73. 187. Sporer KA, Firestone J: Clinical course of crack cocaine body stuffers. Ann Emerg Med. 1997;29:596-601. 188. Sporer KA, Manning JJ: Massive ingestion of sustained-release verapamil with a concretion and bowel infarction. Ann Emerg Med. 1993;22: 603-605. 189. Staple TW, McAlister WH: Roentgenographic visualization of iron preparations in the gastrointestinal tract. Radiology. 1964;83:1051-1056. 190. Stepens A, Logina I, Liguts V, Aldins P, Eksteina I, Platkajis A: A parkinsonian syndrome in methcathinone users and the role of manganese. N Engl J Med. 2008;358:1009-1017. 191. Stern WZ, Spear PW, Jacobson HG: The roentgen findings in acute heroin intoxication. Am J Roentgenol Radium Ther Nucl Med. 1968;103:522-532. 192. Stromberg BV: Symptomatic lead toxicity secondary to retained shotgun pellets: case report. J Trauma. 1990;30:356-357. 193. Su M, Stork C, Ravuri S, et al: Sustained-release potassium chloride overdose. J Toxicol Clin Toxicol. 2001;39:641-648. 194. Sue YJ, Saperstein A, Zawin J, et al: Radiopacity of paradichlorobenzenecontaining household products. Vet Hum Toxicol. 1992;34:350. 195. Swartz MN: Approach to the patient with pulmonary infections. In: Fishman AP, ed. Pulmonary Diseases and Disorders, 2nd ed. New York: McGraw-Hill; 1988:1375-1750. 196. Switz DM, Elmorshidy ME, Deyerle WM: Bullets, joints, And lead intoxication. A remarkable and instructive case. Arch Intern Med. 1976;136:939-941. 197. Tatekawa Y, Nakatani K, Ishii H, et al: Small bowel obstruction caused by a medication bezoar: report of a case. Surg Today. 1996;26:68-70. 198. Theodorou SJ, Theodorou DJ, Resnick D: Imaging findings of complications affecting the upper extremity in intravenous drug users. Emerg Radiol. 2008;15:227-239. 199. Tillman DJ, Ruggles DL, Leikin JB: Radiopacity study of extended-release formulations using digitalized radiography. Am J Emerg Med. 1994;12:310-314. 200. Tom T, Abedon S, Clark RI, Wong W: Neuroimaging characteristics in carbon monoxide toxicity. J Neuroimaging. 1996;6:161-166. 201. Traub SJ, Hoffman RS, Nelson LS: False-positive abdominal radiography in a body packer resulting from intraabdominal calcifications. Am J Emerg Med. 2003;21:607-608. 202. Tumeh SS, Nagel JS, English RJ, Moore M, Holman BL: Cerebral abnormalities in cocaine abusers: demonstration by SPECT perfusion brain scintigraphy. Work in progress. Radiology. 1990;176:821-824. 203. Vantroyen B, Heilier JF, Meulemans A, et al: Survival after a lethal dose of arsenic trioxide. J Toxicol Clin Toxicol. 2004;42:889-895. 204. Velasquez G, Ward CF, Bohrer SP: Thorium dioxide: still around. South Med J. 1985;78:743-745. 205. Vernace MA, Bellucci AG, Wilkes BM: Chronic salicylate toxicity due to consumption of over-the-counter bismuth subsalicylate. Am J Med. 1994;97:308-309.

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206. Vieregge P, Klostermann W, Blumm RG, Borgis KJ: Carbon monoxide poisoning: clinical, neurophysiological, and brain imaging observations in acute disease and follow-up. J Neurol. 1989;236:478-481. 207. Volkow ND, Fowler JS, Wolf AP: Use of positron emission tomography to investigate cocaine. In: Nahas GG, Latour C, eds. Physiopathology of Illicit Drugs: Cannabis, Cocaine, Opiates. Oxford: Pergamon Press; 1991:129-141. 208. Wang CL, Cohan RH, Ellis JH, Adusumilli S, Dunnick NR: Frequency, management, and outcome of extravasation of nonionic iodinated contrast medium in 69,657 intravenous injections. Radiology. 2007;243:80-87. 209. Wang GJ, Volkow ND, Roque CT, et al: Functional importance of ventricular enlargement and cortical atrophy in healthy subjects and alcoholics as assessed with PET, MR imaging, and neuropsychologic testing. Radiology. 1993;186:59-65. 210. Wang Y, Yin Y, Gilula LA, Wilson AJ: Endemic fluorosis of the skeleton: radiographic features in 127 patients. AJR Am J Roentgenol. 1994;162:93-98. 211. Warach SJ, Charness ME: Imaging the brain lesions of alcoholics. In: Greenberg JO, Adams RD, eds. Neuroimaging: A companion to Adams and Victor’s Principles of Neurology. New York: McGraw-Hill; 1995:503-515. 212. Ward S, Heyneman LE, Reittner P, Kazerooni EA, Godwin JD, Muller NL: Talcosis associated with IV abuse of oral medications: CT findings. AJR Am J Roentgenol. 2000;174:789-793.

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213. Ware LB, Matthay MA: The acute respiratory distress syndrome. N Engl J Med. 2000;342:1334-1349. 214. Weidauer S, Nichtweiss M, Lanfermann H, Zanella FE: Wernicke encephalopathy: MR findings and clinical presentation. Eur Radiol. 2003;13: 1001-1009. 215. Weill H, Jones RN: Occupational pulmonary diseases. In: Fishman AP, ed. Pulmonary Diseases and Disorders, 2nd ed. New York: McGraw-Hill; 1988:1465-1474. 216. Weimerskirch PJ, Burkhart KK, Bono MJ, Finch AB, Montes JE: Methylene iodide poisoning. Ann Emerg Med. 1990;19:1171-1176. 217. Wilgoren J: Misdiagnosis led to man’s handcuffing, suit claims. The New York Times. December 8, 1998;62. 218. Williams MH: Pulmonary complications of drug abuse. In: Fishman AP, ed. Pulmonary Diseases and Disorders, 2nd ed. New York: McGraw-Hill; 1988:819-860. 219. Wolff AJ, O’Donnell AE: Pulmonary effects of illicit drug use. Clin Chest Med. 2004;25:203-216. 220. Wolowodiuk OJ, McMicken DB, O’Brien P: Pneumomediastinum and retropneumoperitoneum: an unusual complication of syrup-of-ipecacinduced emesis. Ann Emerg Med. 1984;13:1148-1151. 221. Woolf DA, Riach IC, Derweesh A, Vyas H: Lead lines in young infants with acute lead encephalopathy: A reliable diagnostic test. J Trop Pediatr. 1990;36:90-93.

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CHAPTER 6

LABORATORY PRINCIPLES Petrie M. Rainey Medical toxicology addresses harm caused by acute and chronic exposures to excessive amounts of a xenobiotic. The management of toxicologic emergencies is a major component of medical toxicology. Detecting the presence or measuring the concentration of xenobiotics and other acutely toxic xenobiotics is the primary activity of the analytical toxicology laboratory. Such testing is closely intertwined with therapeutic drug monitoring, in which drug concentrations are measured as an aid to optimizing drug dosing regimens. In addition to drugs, measurements may be made of a variety of xenobiotics such as pesticides, herbicides, and poisons found in plants, animals, or the environment. The toxicology laboratory is frequently viewed in much the same way as other clinical laboratories often are—as a “black box” that converts orders into test results. Because toxicology testing volumes are relatively low and menus are extensive, testing is not as highly automated as in other clinical laboratories. Many results may be “hand-made the old-fashioned way.” The downside of this may be somewhat longer turnaround times. But the upside is that toxicology laboratory personnel have the incentive and flexibility to develop substantial expertise. Medical toxicologists who understand how toxicology testing is done will be able to apply the results more effectively.

RECOMMENDATIONS FOR ROUTINELY AVAILABLE TOXICOLOGY TESTS Despite a common focus, there is remarkable variability in the range of tests offered by analytical toxicology laboratories. Test menus may range from once-daily testing for routinely monitored drugs and common drugs of abuse to around-the-clock availability of a broad array of assays with the theoretical potential to identify several thousand compounds. Recently, consensus documents have been developed that recommend tests that should be available to support management of poisoned patients presenting to emergency departments.22,37 Although they make specific recommendations, these guidelines recognize that no set of recommendations will be universally appropriate and note that it is impossible for a clinical laboratory to offer a full spectrum of toxicology testing in real time. Decisions on the menu of tests to be offered by any specific laboratory should be decided by the laboratory director in consultation with the medical toxicologists and other clinicians who will use the service and should take into account regional patterns of use of licit and illicit drugs and environmental toxins, as well as resources available and competing priorities. The recommendations in Table 6–1 were developed by the National Academy of Clinical Biochemists (NACB) from a consensus process that involved clinical biochemists, medical toxicologists, forensic toxicologists, and emergency physicians.37 Although these tests should be readily available in the clinical laboratory, they should not be considered as a test panel for possibly poisoned patients. As with all laboratory tests, they should be selectively ordered based on the patient’s clinical presentation or other relevant factors. Suggested turnaround time for reporting serum concentrations of the drugs listed in Table 6-1 was 1 hour or less. Quantitative tests for serum methanol and ethylene glycol were also

recommended, with the reservations that these tests are not needed in all settings and that a realistic turnaround time is 2 to 4 hours. Serum cholinesterase testing with a turnaround time of less than 4 hours was proposed by some participants but did not achieve a general consensus. In the United Kingdom, the National Poisons Information Service and the Association of Clinical Biochemists have recommended a nearly identical list of tests, omitting the anticonvulsants.22 Although the consensus for the menu of serum assays was generally excellent, there was less agreement as to the need for qualitative urine assays. This was largely a result of issues of poor sensitivity and specificity, poor correlation with clinical effects, and infrequent alteration of patient management. Although these were potential issues for all of the urine drug tests, they led to explicit omission of tests for tetrahydrocannabinol (THC) and benzodiazepines from the recommended list despite their widespread use. THC results were thought to have little value in managing patients with acute problems, and tests for benzodiazepines were believed to have an inadequate spectrum of detection. Testing for amphetamines, propoxyphene, and phencyclidine were only recommended in areas where use was prevalent. It was also suggested that diagnosis of tricyclic antidepressant (TCA) toxicity not be based solely on the results of a urine screening immunoassay because a number of other drugs may cross-react. The significance of TCA results should always be correlated with electrocardiographic and clinical findings. The only urine test included in the United Kingdom guidelines was a spot test for paraquat.22 Paraquat testing was omitted in the NACB guidelines because of a very low incidence of paraquat exposure in North America.37 The NACB guidelines also recommend the availability of broadspectrum toxicology testing with the tests in Table 6–1 to be used for selected patients with presentations compatible with poisoning but who remain undiagnosed and who are not improving. In general, such testing should not be ordered until the patient is stabilized and input has been obtained from a medical toxicologist or poison center. This second level of testing may be provided directly by the local laboratory or by referral to a reference laboratory or a regional toxicology center. Many physicians order a broad-spectrum toxicology screen on a poisoned patient if one is readily available, but only approximately 2% of clinical laboratories provide relatively comprehensive toxicology services (as estimated from proficiency testing data3). Although broadspectrum toxicology screens can identify most drugs present in overdosed patients,12 the results of broad-spectrum screens infrequently alter management or outcomes.11,12,15,21,24,25 The extent to which the NACB recommendations are being followed may be estimated from the numbers of laboratories participating in various types of proficiency testing. Result summaries from the 2007 series of proficiency surveys administered by the College of American Pathologists suggest that quantitative assays for acetaminophen, carbamazepine, carboxyhemoglobin, digoxin, ethanol, iron, lithium, methemoglobin, phenobarbital, salicylate, theophylline, and valproic acid are available in 50% to 60% of laboratories that offer routine clinical testing, as are screening tests for drugs of abuse in urine. About one in four laboratories offers measurement of transferrin or iron-binding capacity.3 About 2% of laboratories participated in proficiency testing for a full range of toxicology services. These full-service laboratories typically offer quantitative assays for additional therapeutic drugs, particularly TCAs, as well as assays that are designated as broad-spectrum or comprehensive toxicology screens. About two-thirds of these full-service toxicology laboratories offer testing for volatile alcohols other than ethanol.3 Although relatively few laboratories offer a wide range of in-house testing, most laboratories send out specimens to reference laboratories that offer large toxicology menus. The turnaround time for such

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TABLE 6–1. Toxicology Assays Recommended by the National Academy of Clinical Biochemists Quantitative Serum Assays

Qualitative Urine Assays

Acetaminophen Carbamazepine Cooximetry (carboxyhemoglobin, methemoglobin, oxygen saturation)

Amphetamines Barbiturates Cocaine Opiates Propoxyphene Phencyclidine Tricyclic antidepressants

Digoxin Ethanol Iron (plus transferrin or iron-binding capacity) Lithium Phenobarbital Salicylate Theophylline Valproic acid

“send-out” tests ranges from a few hours to several days, depending on the proximity of the reference laboratory and the type of test requested. Even in full-service toxicology laboratories, the test menu may vary substantially from institution to institution. Larger laboratories typically offer one or more broad-spectrum testing choices, often referred to as “tox screens.” There is as much variety in the range of xenobiotics detected by various toxicologic screens as there is in the total menu of toxicologic tests. Routinely available tests are usually listed in a printed or online laboratory manual. Laboratories with comprehensive services may be able to offer ad hoc chromatographic assays for additional xenobiotics that are not listed. Testing that is sent to a reference laboratory is often not listed in the laboratory manual. The best way to determine if a particular xenobiotic can be detected or quantitated is to ask the director or supervisor of the toxicology or clinical chemistry section because laboratory clerical staff may only be aware of tests listed in the manual.

USING THE TOXICOLOGY LABORATORY There are many reasons for toxicologic testing. The most common function is to confirm or exclude toxic exposures suspected from a patient’s history and physical examination results. A laboratory result provides a level of confidence not readily obtained otherwise and may avert other unproductive diagnostic investigations driven by the desire for completeness and medical certainty. Testing increased diagnostic certainty in more than half of cases,2,11,15 and in some instances, a diagnosis may be based primarily on the results of testing. This can be particularly important in poisonings with xenobiotics having delayed onset of clinical toxicity, such as acetaminophen, or in patients with ingestion of multiple xenobiotics. In these instances, characteristic clinical findings may not have developed at the time of presentation or may be obscured or altered by the effects of coingestants. Testing can provide two key parameters that will have a major impact on the clinical course, namely, the xenobiotic involved and the intensity of the exposure. This information can assist in triage decisions, such as whether to admit a patient or to observe the individual

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for expectant discharge. Serum concentrations can facilitate decisions to use specific antidotes or specific interventions to hasten elimination. Well-defined exposure information can also facilitate provision of optimum advice by poison centers, whose personnel do not have the ability to make decisions based on direct observation of the patient. Serum concentrations can be used to determine when to institute and when to terminate interventions such as hemodialysis or antidote administration and can support the decision to transfer the patient from intensive care or discharge him or her from the hospital. Finally, positive findings for ethanol or drugs of abuse in trauma patients may serve as an indication for substance use intervention as well as a risk marker for the likelihood of future trauma.11 The confirmation of a clinical diagnosis of poisoning provides an important feedback function, whereby the physician may evaluate the diagnosis against a “gold standard.” Another important benefit is reassurance (e.g., reassurance that an unintentional ingestion did not result in absorption of a toxic amount of xenobiotic). Such reassurance may allow a physician to avoid spending excessive time with patients who are relatively stable. It may also allow admissions to be made and interventions undertaken more confidently and efficiently than would be likely based solely on a clinical diagnosis. Testing may also be indicated for medicolegal reasons. Diagnoses with legal implications should be established “beyond a reasonable doubt.” Although testing for illicit drugs is often done for medical purposes, it is almost impossible to dissociate such testing from legal considerations. Documentation is also important in malevolent poisonings, intentional or unintentional child abuse or neglect involving therapeutic or illicit drugs, and pharmacologic elder abuse. When test results may be used to document criminal activity, consideration should be given to having testing done in a forensic laboratory maintaining a full chain of custody. This is usually done in conjunction with a law enforcement request or protocol (e.g., drug-facilitated sexual assault) and not usually for medical purposes. The documentation function is also important outside the medicolegal arena. Results of testing in a central laboratory are almost invariably entered into the patient’s medical record and may often provide definitive confirmation of a problem. Documentation also has an additional importance that goes beyond the individual cases. Medical toxicology does not lend itself readily to experimental human investigation. Much of toxicologic knowledge has been derived from experiments of nature recorded in case reports and case series. Hard data, such as xenobiotic concentrations, may serve as key quantitative variables in summarizing and correlating data. That laboratory results can be reliably and generally easily found in the medical record makes them particularly valuable in retrospective reviews. A related service that the toxicology laboratory may provide is testing in support of experimental investigations. The key to optimum use of the toxicology laboratory is communication. This begins with learning the laboratory’s capabilities, including what xenobiotics are on its menus, which ones can be measured and which merely detected, and what are anticipated turnaround times. For screening assays, one should know which xenobiotics are routinely detected; which ones can be detected if specifically requested; and which ones cannot be detected, even when present at concentrations that result in toxicity. A key item is learning which specimens are appropriate for the test requested. A general rule is that quantitative tests require serum (red stopper) or heparinized plasma (green stopper) but not ethylenediamine tetraacetic acid (EDTA) plasma (lavender stopper) or citrate plasma (light-blue stopper). EDTA and citrate bind divalent cations that may serve as cofactors for enzymes used as reagents or labels in various assays. Additionally, liquid EDTA and citrate anticoagulants dilute the specimen. Serum or plasma separator tubes (identifiable by the separator gel in the tube) are also acceptable, provided that

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Part A

The General Approach to Medical Toxicology

prolonged gel contact before testing is avoided. Some hydrophobic drugs may diffuse slowly into the gel, leading to falsely low results after several hours. A random, clean urine specimen is generally preferred for toxicology screens because the higher drug concentrations usually found in urine can compensate for the lower sensitivity of the broadly focused screening techniques. A urine specimen of 20 mL is usually optimal. Requirements for all specimens may vary from laboratory to laboratory. When making a request for a screening test, an important—and often overlooked—item of communication is specifying any xenobiotics that are particularly suspected. This knowledge allows the laboratory to set up the tests for those drugs first and possibly adjust the protocols to increase sensitivity or specificity. This may save an hour or more in the time needed to receive the critical information. Consultation with the laboratory regarding puzzling cases or unusual needs may allow consensus on an effective and feasible testing strategy. The full capabilities of a toxicology laboratory are often not apparent from published lists of tests available. Most full-service laboratories devote substantial efforts to meeting reasonable requests and often provide consultations at no charge. The laboratory should also be contacted whenever results appear inconsistent or discrepant with the clinical presentation. The most common causes for this are interferences and preanalytical errors. Analytical interference is caused by materials in the specimen that interfere with the measurement process, leading to falsely high or low results. For example, hemoglobin may interfere with a variety of spectrophotometric tests by absorbing the light used to make the measurement. Preanalytical errors are events that occur before laboratory analysis and produce incorrect or misleading results, such as mislabeling, specimen contamination by intravenous solutions, and incorrect collection time or technique. The laboratory will be familiar with the common sources of discrepant results. If a discrepancy is the result of laboratory error, it is critical that the laboratory be informed so that steps can be taken to understand the source of the error and avoid a recurrence.

METHODS USED IN THE TOXICOLOGY LABORATORY Most tests in the toxicology laboratory are directed toward the identification or quantitation of xenobiotics. The primary techniques used include spot tests, spectrochemical tests, immunoassays, and chromatographic

techniques. Mass spectrometry may also be used, usually in conjunction with gas chromatography (GS) or liquid chromatography. Table 6–2 compares the basic features of these methodologies. Other methodologies include ion-selective electrode measurements of lithium, atomic absorption spectroscopy or inductively coupled plasma mass spectroscopy for lithium and heavy metals, and anodic stripping methods for heavy metals. Many adjunctive tests, including glucose, creatinine, electrolytes, osmolality, metabolic products, and enzyme activities, may also be useful in the management of poisoned patients. The focus here is on the major methods used for directly measuring xenobiotics.

■ SPOT TESTS The simplest tests are spot tests. These rely on the rapid reaction of a xenobiotic with a chemical reagent to produce a colored product (e.g., the formation of a colored complex between salicylate and ferric ions). Because the reagents may cause precipitation of serum proteins, spot tests are more commonly performed on urine specimens or gastric aspirates. Such tests were once a mainstay of toxicologic testing. Because of the poor selectivity of chemical reagents, as well as substantial variability in visual interpretation, these assays suffer from fairly frequent false-positive results and occasional false-negative results. As more sensitive and more specific methods have become available, spot tests have waned in popularity. Only a few are still in use, largely to fill gaps in testing menus or to rapidly exclude some common poisonings. The introduction of point-of-care testing devices that have better sensitivity and specificity and are designed to facilitate compliance with regulations is likely to further reduce the use of spot tests.

■ SPECTROCHEMICAL TESTS Spectrochemical tests are sophisticated versions of spot tests. They also rely on a chemical reaction to form a light-absorbing substance. They differ in that the reaction conditions and reagent concentrations are carefully controlled and the amount of light absorbed is quantitatively measured at one or more specific wavelengths. The use of specific wavelengths enhances the sensitivity and, particularly, the specificity of the detection, and the measurement of the amount of light absorbed under controlled conditions allows quantitation of the substance. When an analyte is intrinsically light absorbing, no reaction may be necessary. Cooximetry (also known as hemoximetry) represents

TABLE 6–2. Relative Comparison of Toxicology Methods Method

Sensitivity

Specificity

Quantitation

Analyte Range

Speed

Cost

Spot test Spectrochemical Immunoassay TLC HPLC GC GC/MS LC/MS/MS

+ + ++ + ++ ++ +++ +++

± + ++ ++ ++ ++ +++ +++

No Yes Yes No Yes Yes Yes Yes

Few Few Moderate Broad Broad Broad Broad Broad

Fast Medium Medium Slow Medium Medium Slow Medium

$ $ $$ $$ $$ $$ $$$ $$$$

GC, gas chromatography; GC/MS, gas chromatography/mass spectroscopy; HPLC, high-performance liquid chromatography; LC/MS/MS, liquid chromatography/tandem mass spectroscopy; TLC, thin-layer chromatography. $ = very low $$$$ = very high cost

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a sophisticated application of spectrophotometry to the measurement of various forms of hemoglobin in a hemolyzed blood sample. Measurement of light absorbance at multiple wavelengths allows several hemoglobin species to be simultaneously quantitated. For mathematical reasons, the number of wavelengths used must be greater than the number of different types of hemoglobin present. This is why classic pulse oximetry, which uses only two wavelengths, yields spurious results in the presence of significant amounts of methemoglobin or carboxyhemoglobin (Chaps. 21, 125, and 127). Most analytes are neither as deeply colored nor as highly concentrated as hemoglobin species. Their detection requires the generation of an intensely light-absorbing product, as is done in spot tests. The difference between a spot test and a spectrochemical one lies in whether the colored product is visually observed or quantitatively measured in a spectrophotometer. Because spectrophotometers can also measure ultraviolet and infrared light, it is not necessary for the product to have a visible color. Early spectrochemical assays typically measured the absorbance after conversion of all of the analyte to the light-absorbing product. Modern assays usually use rate spectrophotometry, taking multiple absorbance measurements over time to determine the rate of change in light absorbance as the reaction proceeds. During the initial phase of the reaction, this rate is constant and proportional to the initial concentration of the analyte. This significantly reduces the time needed to obtain a result because it is not necessary for the reaction to go to completion first, and it allows the averaging of multiple measurements, improving precision. Furthermore, it is unaffected by nonreacting substances that absorb light at the test wavelength because the absorbance of the nonreacting substances is constant and does not contribute to the rate of change in the absorbance. Rate spectrophotometry remains subject to interference by substances that react to produce a light-absorbing product, thereby falsely increasing the apparent concentration. Substances that inhibit the assay reaction or that consume reagents without producing a lightabsorbing product give falsely low results. For example, ascorbic acid produces negative interference in many spectrophotometric assays that use oxidation reactions to generate colored products. Cooximetry is relatively free of interferences because the concentrations of the hemoglobins are so much higher than other substances in the blood. However, the presence of intensely colored substances (e.g., methylene blue) may cause spurious increases or decreases in the apparent percentages of the hemoglobins. Modern instruments are often able to recognize a significantly atypical pattern of absorbance and generate an error message in addition to or instead of a result. One way to improve the selectivity of a spectrochemical assay is to increase the selectivity of the reaction that generates the light-absorbing product. Enzymes, which can catalyze highly selective reactions, are often used for this purpose. For example, many assays for ethanol use alcohol dehydrogenase to catalyze the oxidation of ethanol to acetaldehyde, with concomitant reduction of the cofactor NAD+ (oxidized form of nicotinamide adenine dinucleotide) to NADH (reduced form of nicotinamide adenine dinucleotide). The initial rate of increase in light absorption produced by the conversion of NAD+ to NADH is proportional to the concentration of ethanol. Although other alcohols, such as isopropanol and methanol, can also be oxidized by alcohol dehydrogenase, they are much poorer substrates with low rates of reaction and correspondingly low levels of interference. Many other enzymatic assays also rely on measuring the change in light absorption at 340 nm when NAD+ is converted to NADH or vice versa. These include enzymatic assays for ethylene glycol, as well as some enzyme-linked immunoassays, such as EMIT (enzymemultiplied immunoassay technique) assays. All such assays are potentially subject to interference by specimens with high concentrations of

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lactate. Lactate dehydrogenase, which is naturally present in serum, will oxidize this lactate to pyruvate if NAD+ becomes available for simultaneous reduction to NADH. When a serum specimen with high lactate is mixed with assay reagents that contain NAD+, oxidation of the lactate contributes to the total rate of NADH production. The increased rate of NADH production results in a false increase in the measured concentration of the target analyte.

■ IMMUNOASSAYS The need to measure very low concentrations of an analyte with a high degree of specificity led to the development of immunoassays. The combination of high affinity and high selectivity makes antibodies excellent assay reagents. There are two common types of immunoassays: noncompetitive and competitive. In noncompetitive immunoassays, the analyte is sandwiched between two antibodies, each of which recognizes a different epitope on the analyte. In competitive immunoassays, analyte from the patient’s specimen competes for a limited number of antibody binding sites with a labeled version of the analyte provided in the reaction mixture. Because most drugs are too small to have two distinct antibody binding sites, drug immunoassays are usually competitive. In competitive immunoassays, increasing the concentration of xenobiotic in the specimen results in increased displacement of labeled xenobiotic from the antibodies. The amount of xenobiotic in the specimen can be determined by measuring either the amount of label remaining bound to the assay antibodies or the amount of label free in solution. In the earliest immunoassays, the label was a radioisotope, typically iodine-125, tritium, or carbon-14. The bound and free radioactivity were physically separated, for example, by using a second antibody to cross-link and precipitate the assay antibody, along with its bound radioactivity (Fig. 6–1) or by adsorbing the free label with activated charcoal. Today, radioimmunoassays are relatively uncommon because of problems associated with handling and disposal of radioactivity. They are primarily used for xenobiotics with insufficient demand to justify the development costs of more sophisticated nonisotopic assays. Nonisotopic immunoassays are currently the most widely used methodologies for the measurement of drugs. They offer high selectivity and good precision and are readily adapted to automated analyzers, thereby decreasing both the cost and the turnaround time of the assays. The effort involved in developing these assays is substantial. Accordingly, the xenobiotics for which immunoassays are available are limited to those for which there is a high demand, such as widely monitored therapeutic drugs and the drugs of abuse included in workplace drug screening. However, after assay development is completed, production costs are relatively low, allowing the tests to be widely distributed at reasonable prices. The most widely used nonisotopic drug immunoassays are in the category of homogenous immunoassays. Homogenous immunoassays measure differences in the properties of bound and free labels, rather than directly measuring one or the other after their physical separation. Avoiding a separation step allows homogenous immunoassays to be readily adapted to automated analysis. Homogenous techniques that are in wide use include EMIT (Fig. 6–2), kinetic inhibition of microparticles in solution (KIMS), cloned enzyme donor immunoassay (CEDIA), and fluorescence polarization immunoassay (FPIA). Many of the newest automated immunoassays are again using physical separation techniques. In these assays, the detection antibody is physically attached to a solid support, and separation occurs by a simple wash step. This wash step removes the patient’s serum along with many potentially interfering substances. Newer solid supports

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FIGURE 6–1. Competitive radioimmunoassay. (A) No drug from the specimen is present to displace the I125 -labeled drug. Adding the cross-linking antibody precipitates the assay antibody, along with high amounts of bound radioactivity. (B) Unlabeled drug in the specimen displaces some of the labeled drug. The displaced label is left in solution when the cross-linking antibody is added, resulting in less radioactivity in the precipitate.

consist of fine glass fibers or latex microparticles. These have very high total surface areas that allow for rapid equilibration and short assay times. Older assays of this type used antibodies bound to large plastic beads or wells of microtiter plates and required long incubation steps because of substantial times required for diffusion of the reactants to the antibodies. Fig. 6–3 shows a schematic magnetic microparticle enzyme-labeled chemiluminescent competitive immunoassay. A single enzyme label can generate many photons, allowing high signal amplification. Coupled with a background luminescence that is essentially zero, such assays can measure concentrations below the nanomolar level. Many variations of this approach are in use. Enzyme substrates may be used that result in fluorescent or colored products. Enzymes other than alkaline phosphatase may be used as labels, or non-enzymatic fluorescent, chemiluminescent, or electroluminescent labels may be used. Non-magnetic microparticles may be captured in glass fiber filters

FIGURE 6–2. Enzyme-multiplied immunoassay technique (EMIT) immunoassay. The drug to be measured is labeled by being attached to the enzyme glucose-6-phosphate dehydrogenase (G6PD) near the active site. (A) Binding of the enzyme-labeled drug to the assay antibody blocks the active site, inhibiting conversion of NAD+ (oxidized form of nicotinamide adenine dinucleotide) to NADH (reduced form of nicotinamide adenine dinucleotide). (B) Unlabeled drug from the specimen can displace the drugenzyme conjugate from the antibody, thereby unblocking the active site and increasing the rate of reaction.

during the washing and signal generation steps. These new techniques are readily automated and have higher sensitivities than homogenous immunoassays. Microparticle capture assays are a type of competitive immunoassays that have become very popular, especially for urine drug-screening tests. The use of either latex or colloidal gold colored microparticles because the label enables the result to be read visually as the presence or absence of a colored band, with no special instrumentation required. Competitive binding occurs as the assay mixture is drawn by capillary action through a porous membrane. This design feature is responsible for alternate names for the technique: lateral flow immunoassay or immunochromatography. The simplest design uses an antidrug antibody bound to colored microparticles and a capture zone consisting of immobilized drug

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Magnetic microparticle coated with antidrug antibodies Unlabeled drug Alkaline phosphatase-labeled drug Stable dioxetane phosphate derivative Unstable dioxetane derivative

FIGURE 6–4. Microparticle capture immunoassay. (A) Diagram of a device before specimen addition. Colored microbeads (about the size of red blood cells) coated with antidrug antibodies ( ) are in the specimen well. At the far end of a porous strip are capture zones with immobilized drug molecules (•) and a control zone with antibodies recognizing the antibodies that coat the microbeads. (B) Adding the urine specimen suspends the microbeads, which are drawn by capillary action through the porous strip and into an absorbent reservoir (hatched area) at the far end of the strip. In the absence of drug in the urine, the antibodies will bind the beads to the capture zone containing the immobilized drug and form a colored band. Excess beads will be bound by antibody–antibody interactions in the control zone, forming a second colored band that verifies the integrity of the antibodies in the device. (C) If the urine contains the drug (•) in concentrations exceeding the detection limit, all of the antibodies on the microbeads will be occupied by drug from the specimen, and the microbeads will not be retained by the immobilized drug in the capture zone. No colored band will form. However, the beads will be bound and form a band in the control zone.

Emitted light FIGURE 6–3. Magnetic microparticle chemiluminescent competitive immunoassay. (A) Unlabeled drug from the specimen competes with alkaline phosphatase-labeled drug for binding to antibody-coated magnetic microparticles. The microparticles are then held by a magnetic field while unbound material is washed away. (B) A dioxetane phosphate derivative is added and is dephosphorylated by microparticle-bound alkaline phosphatase to give an unstable dioxetane product that spontaneously decomposes with emission of light. The rate of light production is directly proportional to the amount of alkaline phosphatase bound to the microparticles and inversely proportional to the concentration of competing unlabeled drug from the specimen.

(Fig. 6–4). If the specimen is xenobiotic free, the beads will bind to the immobilized analyte, forming a colored band. When the amount of drug in the patient specimen exceeds the detection limit, all of the antibody sites will be occupied by drug from the specimen, and no labeled antibody will be retained in the capture zone. The use of multiple antibodies and discrete capture zones with different immobilized analytes can allow several xenobiotics to be detected with a single device. A disadvantage of this design is the potential for causing confusion because a positive test result is indicated by the absence of a band. More complex (and more expensive) variations have been developed in which a colored band denotes a positive test result. Although immunoassays have a high degree of sensitivity and selectivity, they are also subject to interferences and problems with crossreactivity. Cross-reactivity refers to the ability of the assay antibody to bind to xenobiotics other than the target analyte. Xenobiotics with similar chemical structures may be efficiently bound, which can lead to falsely elevated results. In some situations, cross-reactivity can be beneficially exploited. For example, some immunoassays effectively detect classes of drugs rather than one specific drug. Immunoassays

for opiates use antibodies that recognize various xenobiotics that are structurally related to morphine, including codeine, hydrocodone, and hydromorphone. Oxycodone typically has less cross-reactivity, and higher concentrations are required to give a positive result. However, structurally unrelated synthetic opioids, such as meperidine and methadone, have little or no cross-reactivity and are not detected by opiate immunoassays. Immunoassays for the benzodiazepine class react with a wide variety of benzodiazepines but with varying degrees of sensitivity.10,17 Class specificity can be a two-edged sword. Assays for the TCA family have similar reactivity with amitriptyline, nortriptyline, imipramine, and desipramine and can be used to provide a semiquantitative estimate of the total concentration of any combination of these drugs. However, a large number of other drugs with tricyclic structures, including carbamazepine, many phenothiazines, and diphenhydramine, also crossreact and generate a signal, particularly at concentrations found in patients who overdose. Qualitative tests, such as microparticle capture assays, may then yield false-positive results if the signal generated by the cross-reacting drug (e.g., carbamazepine) exceeds the detection limit of the immunoassay. With quantitative or semiquantitative assays, however, the apparent concentration produced by a cross-reacting drug is generally well below TCA concentrations associated with toxicity. Even when an antibody is selected to be specific to a single drug, it is common that metabolites of the target drug show some cross-reactivity. This, too, may be beneficial. When the metabolite is an active one (e.g., carbamazepine epoxide), the contribution of its cross-reactivity may yield results that correlate better with the drug effect than the true concentration of the parent drug alone. Immunoassays are also subject to interference by substances that impair detection of the label. Elevated lactate concentrations may lead

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to spuriously increased drug concentrations in specimens tested by EMIT, as described above. Immunoassays that rely on enzyme labels are particularly sensitive to nonspecific interference because enzyme activity is highly dependent on reaction conditions. A number of substances that can inhibit the enzyme reaction in EMIT assays are used to adulterate urine submitted for drug abuse testing with the intent of producing false-negative results (see the discussion of drugabuse screening tests under “Special Considerations for Drug Abuse Screening Tests” below). Such adulteration may be detected when the rate of reaction is lower than the rate observed with a drug-free control.

■ CHROMATOGRAPHY Chromatography encompasses several related techniques in which analyte specificity is achieved by physical separation. The unifying mechanism for separation is the partition of the analytes between a stationary phase and a moving phase (mobile phase). In most instances, the stationary phase consists of very fine particles arranged in a thin layer or enclosed within a column. The mobile phase flows through the spaces between the particles. Analytes are in a rapid equilibrium between solution in the mobile phase and adsorption to the surfaces of the particles. They move when in the mobile phase and stop when adsorbed to the stationary phase. The average velocity of the analyte xenobiotics depends on the relative time spent in the moving versus stationary phase. Xenobiotics that partition primarily into the mobile phase have average velocities slightly lower than the mobile phase velocity. Average velocity decreases as the proportion of time adsorbed to the stationary phase increases. Under controlled conditions, these average velocities are highly reproducible. Xenobiotics may be provisionally identified based on their characteristic velocity. This is measured as the distance traveled relative to the solvent migration distance in thinlayer chromatography, or the amount of time required to traverse the length of a chromatography column. These characteristic parameters are referred to as the RF value and retention time, respectively. Chromatography is a separation method and must be combined with a detection method to allow identification and measurement of the separated substances. Chromatographic behavior is sufficiently reproducible that the failure to detect a signal at an RF value or retention time characteristic of a compound effectively excludes the presence of that compound in amounts greater than the detection limit. On the other hand, a number of different substances may have migration velocities that are identical or nearly so. A positive finding is therefore not completely specific. Definitive identification depends on having additional information, which may be obtained through selective detection techniques or by confirmatory testing using a second method. The sensitivity of chromatographic methods depends on both the amount of specimen available and the sensitivity of the detection method. The detection limit may range from less than 10 pg with mass spectrometric detection to more than 10 μg when detection is achieved by forming a colored product using a postchromatographic chemical reaction. A major advantage of chromatographic techniques is that multiple xenobiotics may be detected and measured in a single procedure. It is not always necessary to know in advance the specific xenobiotic to be looked for. For this reason, chromatographic techniques have a major role in screening for multiple xenobiotics. Most chromatographic procedures require extraction and concentration of the xenobiotics to be analyzed before the chromatography is done. Extraction results in removal of salts, proteins, and other materials that may exhibit unfavorable interactions with either of the chromatographic phases. Concentration allows the substances to be introduced in a narrow “band,” so that compounds with slightly different relative mobilities become completely resolved, or separated from one another,

rather than overlapping. This also results in a more intense signal as a band passes through the detector and increases sensitivity. Extraction of drugs is most commonly done with organic solvents, but “solid-phase extraction” is also very popular.9 Solid-phase extraction is a modified chromatographic procedure in which a urine or serum specimen is passed through a short chromatography column with a hydrophobic stationary phase. Most drugs are sufficiently hydrophobic so that they partition almost completely into the stationary phase and are retained on the column. Subsequently, the retained xenobiotics are eluted with an organic solvent. The organic solvents from either extraction technique are evaporated to concentrate the extracted xenobiotics. The extraction process allows the analyte from a large volume of specimen to be concentrated. Detection sensitivity can thereby be increased, provided large volume specimens can be readily obtained, as is true with urine. Often a preextraction treatment is used to increase the hydrophobicity of the substances to be extracted. The most common manipulation is pH adjustment, either upward or downward, to convert charged forms of drugs into uncharged, extractable ones. In other instances, enzymatic or chemical hydrolysis may be used to convert water-soluble glucuronide metabolites back to their more readily extracted parent compounds; for example, conversion of morphine glucuronide to morphine. In thin-layer chromatography (TLC), the concentrated extracts are redissolved in a small amount of solvent and spotted onto a thin layer of silica gel that is supported on a glass or plastic plate or embedded in a fiber matrix. A typical TLC plate has room for several different spots of extracts from samples and controls. The plates are placed vertically in closed tanks containing a shallow layer of an organic solvent mixture. As the solvent is drawn upward through the silica gel by capillary action, various xenobiotics are carried along at characteristic velocities determined by their partition between the moving organic solvent and the stationary silica gel (Fig. 6–5). Silica gel is

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FIGURE 6–5. Thin-layer chromatography. (A) Concentrated extracts from patient (P) and control (C) specimens are dried in small spots on a plate coated with a thin layer of silica gel particles. The plate is placed vertically into an organic solvent mixture, which is being drawn up the plate by capillary action. The leading edge (or solvent front, shown by the dotted line) reaches the extracts and begins to dissolve them. (B) Various substances are moving at different rates, depending on the relative proportion of time spent in the moving solvent (mobile phase) and adsorbed to the silica gel (stationary phase). (C) The development of the chromatogram is stopped when the solvent front nears the top. Various substances are seen at characteristic positions relative to the solvent front. The patient specimen contains a substance that can be tentatively identified as compound b in the control mixture based on its relative mobility. Although shown as shaded spots here for clarity, most drugs are colorless and are visualized at the end of the chromatography by being dipped or sprayed with reagents that form colored products. The tentative identification of the unknown drug as compound b requires that it show the predicted behavior with the visualizing reagents.

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polar, so hydrophobic xenobiotics migrate rapidly and hydrophilic ones more slowly. Adjusting the composition of the solvent mixture allows optimization of the migration rates. After sufficient solvent migration, the plates are removed from the tanks, dried, and sprayed with a series of reagents that convert the xenobiotics to be detected into various colored derivatives. The xenobiotics are thereby visualized as colored spots and identified by their migration distance (RF value), as well as by the various colors produced after each spray. Those that are metabolized can be further confirmed by the finding of additional spots corresponding to characteristic metabolites. Identifications can be most confidently made when an authentic sample of the xenobiotic has been included as a control on the plate. TLC has the ability to identify the presence of a large number of xenobiotics and is widely used in “drug screens.” Visualization as colored spots generally requires fairly large amounts of material. For this reason, TLC is usually used with urine and gastric aspirate specimens because they typically have higher concentrations of many drugs than do corresponding serum specimens and because they are readily available in large volumes. Drawbacks to TLC include the need for multiple steps—extraction, concentration, chromatography, and a series of detection reactions. This makes TLC a relatively slow and labor-intensive procedure. Interpretation of the spots requires a skilled technologist who knows the TLC behavior of commonly encountered xenobiotics. Quantitation is difficult and rarely attempted. Therefore, TLC is primarily used to demonstrate the presence of a drug. It is of limited value in identifying a drug not previously seen by the chromatographer unless a possible candidate is suggested to the laboratory and an authentic sample (i.e., a standard) can be obtained to verify its behavior in the TLC system. Also, drugs that have limited excretion in the urine might not be readily detected. In the past, full-service toxicology laboratories used classical TLC procedures to screen urine for a variety of drugs. The development of a commercial kit for TLC of drugs in urine (Toxilab, Varian, Inc., Palo Alto, CA) has reduced the time, labor, and expertise required and has extended its practicability to a broader range of laboratories.13 The use of a standardized procedure also allows tentative identification of a drug not previously encountered by comparing its characteristics with those of a broad range of drugs provided in a compendium by the manufacturer. Identifications made solely on the basis of agreement with characteristics described in the compendium should be considered provisional until confirmed by additional testing. In the related technique of high-performance liquid chromatography (HPLC), the stationary phase is packed into a column and the mobile phase is pumped through under high pressure (Fig. 6–6). This allows good flow rates to be achieved, even when solid phases with very small particle sizes are used. Smaller particle size increases surface area, decreases diffusion distances, and improves resolution, but the spaces between the particles are also smaller, increasing the resistance to flow. The use of high pressure and small particles allows better separations in a fraction of the time required for TLC. Another way that HPLC often differs from TLC is that HPLC typically uses “reverse-phase” chromatography. Reverse-phase chromatography uses stationary phases in which the silica gel particles have had hydrocarbon molecules covalently linked to the outer surface. This reduces the surface charge on the silica, thereby reducing its hydrophilicity, and simultaneously coats the particles with a permanently bonded oil-like layer. At the same time, solvent polarity is increased by using a primarily aqueous mobile phase with varying amounts of organic solvent. Because of these modifications, whereas hydrophobic xenobiotics are more strongly adsorbed by the stationary phase, hydrophilic ones tend to remain in the mobile phase. This results in

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FIGURE 6–6. High-performance liquid chromatography (HPLC). HPLC is schematically shown. (A) A mixture of three compounds ( ) ( ) ( ) is injected into a column filled with a spherical reversed-phase packing. (B) The compounds move through the column at characteristic speeds. The most hydrophilic compound ( ) moves most quickly, and the most hydrophobic compound ( ) moves most slowly. (C) The compound of intermediate polarity ( ) has reached the detection cell, where it absorbs light directed through the cell and generates a signal proportional to its concentration. (D) Illustration of the HPLC tracing that might result: 1 indicates the time of injection. The artifact at 2 results when the injection solvent reaches the detector and indicates the retention time of a completely unretained compound. The peaks at 3, 4, and 5 correspond to the separated compounds. For example, peak 4 might be amitriptyline, peak 3 might be the more polar metabolite, nortriptyline, and peak 5 could be the more hydrophobic internal standard N-ethylnortriptyline. Later-emerging peaks are typically wider and shorter because of more time for diffusive forces to spread out the molecules.

an order of elution from the column that is approximately the reverse of that seen with organic solvents and unmodified silica gel. Thus, the term reverse-phase chromatography is used. Both TLC and HPLC can be done using either “normal-phase” or “reverse-phase” conditions. However, TLC is more commonly done in normal phase and HPLC more commonly in reverse phase. A variety of hydrocarbons can be used to derivatize the silica gel. By far, the most common reverse phase columns use an octadecyl hydrocarbon as the outer coating and are often referred to as C-18 columns. In HPLC, the xenobiotics are detected after they exit the chromatographic column. In this case, they are identified by their retention time (the characteristic time required to traverse the column). Because most xenobiotics absorb ultraviolet light, detection is commonly by ultraviolet spectroscopy using specially designed flow-through cuvettes. Measuring light absorbance at a selected wavelength allows the amount of the xenobiotic to be determined. Accuracy is often enhanced by comparing the absorbance of the target analyte with absorbance of an internal standard (i.e., a compound with a different retention time that is added in a fixed amount to all specimens). The ratio of the drug absorbance to the internal standard absorbance is proportional to the drug concentration in the specimen.

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Although most HPLC detectors allow a selection of the detection wavelength, only one wavelength is commonly used during a given run. Some detectors, however, allow absorbance at multiple wavelengths to be determined, either by rapidly and repeatedly scanning through a range of wavelengths or by breaking white light into its component wavelengths only after it has passed through the detection cuvette and then using an array of photodiode detectors to make measurements at multiple wavelengths simultaneously. These techniques can allow the absorbance spectrum of a compound to be determined as it elutes from the column. This information can supplement the retention time and allow more specific identifications to be made. TLC generally requires one or more hours to complete and provides qualitative identification of xenobiotics present at concentrations of 1 mg/L or higher. In contrast, HPLC can routinely provide quantitation of xenobiotics at 10-fold lower concentrations in less than 1 hour (provided the calibration was done in advance). Thus, HPLC is often the method of choice for measuring serum concentrations of xenobiotics for which no immunoassay is available. Relative disadvantages of HPLC in comparison with TLC are the much higher costs of the equipment, the inability to analyze multiple samples simultaneously, and a relative inability to analyze drugs with a wide range of polarities with a single assay. The latter limitation inhibits the use of HPLC as a broad drug-screening technique. GC is similar in principle to HPLC, except that the moving phase is a gas, usually the inert gas helium but occasionally nitrogen. The schematic illustration of HPLC in Figure 6–6 is also applicable to GC. The low flow resistance of gas allows high flow rates that make possible substantially longer columns than are used in HPLC. This offers the dual advantages of high resolution and fast analysis. As was true in HPLC, most GC assays incorporate an internal standard to increase precision. Because the inert carrier gas does not engage in intermolecular interactions, partition of the analytes into the moving gas phase depends primarily on their natural volatility. Elevated column temperatures are required to achieve sufficient volatility for analysis of most xenobiotics. The use of a temperature gradient (the column temperature is programmed to increase throughout the course of the analysis) can allow xenobiotics with a wide range of volatility to be analyzed in a single run. This feature makes GC suitable for screening assays encompassing a broad range of drugs. GC is limited to xenobiotics that are reasonably volatile at temperatures below 572°F (300°C), above which the stationary phase may begin to break down. Two principal attributes of a xenobiotic limit its volatility: its size and its ability to form hydrogen bonds. Xenobiotics that form hydrogen bonds via amino, hydroxyl, and carboxylate moieties can be made more volatile by replacing hydrogens on oxygen and nitrogen atoms with a non-bonding, preferably large, substituent. (Large substituents sterically hinder access to the acceptor electron pairs on the nitrogen and oxygen atoms.) A number of derivatizing agents can be used to add appropriate substituents. The most common derivatives involve the trimethylsilyl (TMS) group. Although derivatization with TMS substantially increases the molecular weight, the resulting derivative is much more volatile as a consequence of the loss of hydrogen bonding. In traditional packed-column GC, the packing may consist of inert support particles with a thin coating of nonvolatile, high-molecularweight oil that comprises the stationary phase. It is increasingly common for the stationary phase to be covalently bonded to the support particles. A highly useful variant of GC is capillary chromatography. A long, thin capillary tube of fused silica is coated on the inside with a covalently bonded stationary phase. The mobile gas phase flows through the tiny channel in the middle. These capillaries are flexible, allowing very long columns (≥10 m) to be coiled into a small space.

The long column length, coupled with highly uniform conditions throughout the column, results in extremely high resolution. The small diameter of the column allows rapid thermal equilibration and the use of steep temperature gradients that can speed analysis. The major drawback to capillary chromatography is a very limited column capacity. Special techniques are needed to restrict the amount of material introduced into the column and thereby to avoid overloading it. Highsensitivity detectors are required to measure the small quantities that can be chromatographed. A number of detectors are available for GC. The most common detector, particularly for packed columns, is the flame ionization detector. This involves directing the outflow of the column into a hydrogen flame. Organic molecules emerging from the column are burned, creating charged combustion intermediates that can be measured as a current. The amount of current flow is largely determined by the mass of carbon that is being burned. Nitrogen–phosphorus detectors are also widely used in drug analysis. In this modification of a flame ionization detector, a heated bead coated with an alkali metal salt is used to selectively generate ions from xenobiotics containing nitrogen or phosphorus. These devices detect broad ranges of substances but do not identify them. The identity of the compounds detected must be inferred from the retention time. The mass spectrometer can serve as a highly sensitive GC detector and also possesses the ability to generate highly characteristic mass spectra from the compounds it is detecting. A special requirement of the mass spectrometer is that it requires a high vacuum to prevent the ionic particles that it creates from interacting with other molecules or ions. This requires removal of the inert carrier gas and is easiest when there is a low total gas flow, such as occurs with capillary GC. The mass spectrometer, in turn, provides good sensitivity for the small amounts of analyte that can be accommodated in capillary GC. This detection process also begins by generating ions from the analyte. This is usually done using electron impact ionization. The gas phase analyte is separated from the bulk of the carrier gas and introduced into an ionization chamber, where it is bombarded by a stream of electrons. Electron impact can dislodge an electron from the analyte, creating a positively charged ion and frequently imparting sufficient energy to the ion to break it into pieces. If fragmentation occurs, conservation of charge requires that one of the resulting fragments be a positively charged ion. The fragments into which a molecular ion can break are characteristic of the xenobiotics because is the relative probability that a given fragment will carry the positive charge. The mass spectrometer then uses electromagnetic filtering to direct only ions of a specified mass-to-charge (m/z) ratio to a detector. Because most of the ions produced have a single positive charge, the observed peaks generally correspond to the mass of the ions. The detector has sufficient electronic amplification that a single ion could theoretically be detected, accounting for the high sensitivity of mass spectrometric detection. By rapidly scanning through a range of masses that are sequentially allowed to reach the detector, a mass spectrum may be generated. The mass spectrum records the masses of the pieces produced by fragmentation of the parent ion, as well as the relative frequency with which these fragments are produced and detected. The highest mass observed in the spectrum usually corresponds to the mass of intact parent ions generated from collisions that were not energetic enough to cause fragmentation. Figure 6–7 shows the mass spectrum obtained from a gas chromatograph at a time when the TMS derivative of the cocaine metabolite benzoylecgonine was emerging from the capillary column. The mass spectrum of any compound is highly distinctive and usually unique. The primary exception involves optical enantiomers, both of which have the same mass spectrum. Toxicologically significant examples of

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FIGURE 6–7. Mass spectrum of the trimethylsilyl derivative of benzoylecgonine (TMS-BE). (A) Mass spectrum of effluent from a gas chromatography (GC) column at the retention time of TMS-BE. The unfragmented parent ion of TMS-BE is at a mass-to-charge (m/z) ratio of 361. The two fragment peaks at m/z 243 and 259 result from fracture of the bonds at X and Y, respectively, in structure of TMS-BE (inset in B). Additional peaks at m/z 243, 259, and 364 are derived from trideuterated TMS-BZE (d3-TMS-BE) added as an internal standard. The mass spectrometer can identify and quantify TMS-BE and d3-TMS-BE independently of one another by measuring the heights of the peaks unique for each compound. The peak at m/z 425 is from a coeluting contaminant. (B) Mass spectrum of pure TMS-BE.

enantiomers include d-methamphetamine, a drug of abuse; l-methamphetamine, which is found in decongestant inhalers; and dextrorphan, the major metabolite of the cough suppressant dextromethorphan, and levorphan (levorphanol), a controlled substance. To avoid the need to scan the full range of masses in a typical mass spectrum, selected ion monitoring is often used. Here, the mass spectrometer is typically programmed to filter and detect only three of the larger and more characteristic peaks in the spectrum. In the case of TMS benzoylecgonine (TMS-BE), the peaks at m/z 240, 256, and 361 are used. The concentration of TMS-BE in the specimen is determined

from the ratio of the peak height at m/z 240 to a peak height at m/z 243 that results from a corresponding fragment of a triply deuteriumlabeled internal standard, d3-TMS-BE (see Fig. 6-7). The specificity of the identification is verified by finding peaks at m/z 256 and m/z 361, with peak height ratios to the peak at m/z 240 comparable to the ratios seen with authentic TMS-BE. The detection at the correct retention time of a xenobiotic producing all three peaks in the correct ratios produces an extremely specific identification. The high sensitivity and specificity afforded by GS/mass spectrometry is being further extended by the related hybrid technique of liquid

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chromatography/tandem mass spectrometry, often abbreviated as LC/ MS/MS. Initially restricted to research settings, the technique is now becoming available in a few toxicology laboratories.19 In LC/MS/MS, a tandem mass spectrometer is used as the detector for liquid chromatography system. The initial ionization is done under conditions that do not promote fragmentation and is commonly achieved by adding or removing a proton rather than forcefully dislodging an electron. The resulting ions have a mass that differs from that of the parent molecule by 1 mass unit ([M+H]+ or [M–H]−) The first mass spectrometer is used to selectively filter only unfragmented ions with the expected molecular mass. As the selected ions exit the first mass spectrometer at high speed, they are allowed to collide with molecules of an inert gas. These collisions cause the ions to break apart to create the fragment mass spectrum that is detected by the second mass spectrometer. The additional selection step provided by the first mass spectrometer greatly enhances specificity and reduces background signal, enhancing sensitivity.

QUANTITATIVE DRUG MEASUREMENTS When properly used to guide dosing adjustments, drug concentration measurements improve medical outcomes.6 However, many therapeutic drug measurements are drawn at inappropriate times or are made without an appropriate therapeutic question in mind. An essential requirement for interpretation of xenobiotic concentrations is that the relationship between concentrations and effects must be known. Such knowledge is available for routinely monitored xenobiotics and is often encapsulated in published ranges of therapeutic concentrations and toxic concentrations. Concentrations designated as “toxic” are usually higher than the upper end of the therapeutic range and typically represent concentrations at which toxicity is acute and potentially serious (see back cover). For most xenobiotics, the relationships between toxic concentrations and effects cannot be systematically studied in humans and consequently are often incompletely defined. These relationships are largely inferred from data provided in overdose case reports and case

series. The measurement of xenobiotic concentrations in overdose cases in which concentration–effect relationships are not well defined may contribute more to the management of future overdosed patients than to the management of the patient in whom the measurements were made. For toxicologists, xenobiotic concentrations are especially useful in two ways. For xenobiotics whose toxicity is delayed or is clinically inapparent during the early phases of an overdose, concentrations may have substantial prognostic value and facilitate anticipatory management. These concentrations may also be used to make decisions regarding the use of antidotes or of interventions to hasten drug elimination, such as hemodialysis. Quantitative xenobiotic measurements are subject to various interferences, but these are less problematic than in qualitative assays. Signals generated by cross-reacting substances are weaker than those from the target analyte and are relatively unlikely to lead to a false diagnosis of toxicity, particularly if the target analyte is absent. Such cross-reactivity can be exploited in some instances to provide confirmatory evidence of a poison for which no specific assay is immediately available. For example, the immunoassay finding of apparent subtoxic levels of TCAs can help confirm a diphenhydramine overdose, and the finding of a measurable digoxin concentration in an unexposed patient may suggest poisoning with other cardioactive steroids of plant or animal origin. Negative interferences are much less frequent. Table 6–3 summarizes some of the more common interferences in quantitative assays for drugs and poisons. Extensive information on interferences with laboratory tests, including toxicology tests, may be found online. Interferences in chromatographic methods usually result from the presence of other compounds with migration rates similar to the target analyte. Because the migration rates are rarely exactly the same, the laboratory can often recognize the presence of the interference as an overlapping peak when both compounds are present. In such instances, the interference may impair accurate measurement of the drug concentration. When no target xenobiotic is present, misidentification of the interfering peak as the target becomes much more likely because a single peak is seen at approximately the expected position. Because

TABLE 6–3. Interferences in Quantitative Assays for Xenobiotics Analyte

Technique

Potential Interferences

Acetaminophen

Spectrochemical Immunoassay Spectrochemical Immunoassay

Bilirubin, phenacetin, renal failure, salicylates Phenacetin (clinically a true-positive test result) Fetal hemoglobin, hydroxocobalamin Other cardioactive steroids (found in oleander, red squill, Chan Su), endogenous digoxin-like substances (found in hepatic and renal failure, neonates, pregnancy), digoxin metabolites in renal failure, spironolactone, canrenone (spironolactone metabolite), human anti-mouse antibodies, digoxin immune Fab Citrate, deferoxamine, EDTA, gadolinium contrast agents, hemolysis, oxalate Hemolysis, lithium heparin (clinically a true positive result) abnormal serum sodium Lipemia, methylene blue, sulfhemoglobin Bilirubin, diflunisal, ketosis, salicylamide, salicylsalicylate Diflunisal Caffeine, lipemia

Carboxyhemoglobin Digoxin

Iron Lithium Methemoglobin Salicylate Theophylline

Spectrochemical Electrochemical Spectrochemical Spectrochemical Immunoassay Immunoassay

EDTA, ethylenediamine tetraacetic acid.

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interferences in chromatographic methods are generally unique to a specific method, information about these interferences should be obtained by asking the laboratory. Xenobiotic measurements are unlike most other laboratory measurements in that the concentrations are highly dependent on the timing of the measurement. Knowledge of the pharmacokinetics of a xenobiotic can substantially enhance the ability to draw meaningful conclusions from a measured concentration. Some xenobiotics alter their pharmacokinetic behavior at very high concentrations. These changes in pharmacokinetics may be predictable from the mechanisms of drug clearance and the extent of binding to plasma proteins and to tissues (Chap. 8). Knowledge of the relationship between xenobiotic concentrations and effects, or pharmacodynamics, is also important. Effects depend on local concentrations at the site of action, typically at cell membrane receptors or intracellular locations. Serum or plasma concentrations can be correlated with effects only when these concentrations are in equilibrium with concentrations at the site of action. Table 6–4 lists several circumstances that may alter the normal ratio of xenobiotic concentrations measured in serum or plasma to concentrations found at the site of action, thereby altering the usual concentration–effect relationships. During the absorption and distribution phases, the concentration ratio will be higher than its equilibrium value, yet often the only xenobiotic concentration measured after an acute overdose is one obtained while absorption and distribution are still ongoing. This effect may explain some observations of apparent poor correlation between measured concentrations and toxic effects. For xenobiotics that bind significantly to plasma proteins, it is the concentration of xenobiotic that is not bound to proteins (the freexenobiotic concentration) that is in equilibrium with concentrations at the site of action. For most drugs at therapeutic concentrations, the free-drug concentration is an approximately constant percentage of the total drug concentration. The total concentration is what is usually measured in the laboratory. Under these conditions, the ratio of total concentration to active site concentration is approximately constant, and a reasonable correlation between total concentration and effects can be expected. A major change in the free fraction occurs after treatment of digoxin toxicity with digoxin immune Fab, when the free digoxin concentration falls from approximately 75% of the total concentration to less than 1% as a consequence of digoxin binding by the antidigoxin antibody fragments. At the same time, there is extensive redistribution of digoxin from tissues to plasma, leading to substantial increases in total digoxin

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concentration. This situation may be further complicated by complex digoxin immune Fab interference in many digoxin immunoassays. Measurement of free-drug concentrations can clarify such situations.16 Assays for free phenytoin are available in many laboratories. Assays for other free-drug concentrations may require special arrangements. The availability and expected turnaround time can be provided by the laboratory. For example, for patients treated with digoxin immune Fab, newer immunoassays that use antibodies attached to microparticles or glass fibers give results that can be used to set an upper bound on free-digoxin concentrations and thereby verify adequacy of treatment.26

■ TOXICOLOGY SCREENING A test unique to the toxicology laboratory is the toxicology screen, or “tox screen.” Depending on the laboratory, this term may refer to a single testing methodology with the ability to detect multiple xenobiotics, such as a thin-layer or GS, it may refer to a panel of individual tests, such as a drug-abuse screen; or it may be a combination of broadspectrum and individual tests. The widespread use of the term “tox screen” is unfortunate because this inappropriately implies for many physicians the availability of a test that can confirm or exclude poisoning as a diagnosis. There are many more toxic xenobiotics in the world than there are named diseases. However, a relatively limited number of xenobiotics account for most serious poisonings. As a result, in one study, a comprehensive toxicology screening protocol using multiple detection methods applied to both serum and urine specimens was able to identify more than 98% of implicated xenobiotics.12 This suggests that a comprehensive “tox screen” can exclude poisoning with a substantial degree of reliability. However, this study was done some time ago, when the rate of introduction of new drugs was much slower than is currently the case. Many newer therapeutic drugs may not be identified even by “comprehensive” screens currently in use.36 Moreover, comprehensive toxicology screens typically do not detect elemental ions, including bromide, lithium, iron, lead, and other heavy metals, nor do they necessarily detect drugs that are toxic at extremely low concentrations, such as digoxin or fentanyl. Table 6–5 lists a number of xenobiotics encountered in emergency toxicology that may not be detected by routine toxicology screening. It should therefore be apparent that a negative toxicology screen result cannot exclude poisoning. It is equally true that a positive finding does not necessarily confirm a diagnosis of poisoning. For assays that detect only the presence of a xenobiotic, it is not possible to distinguish

TABLE 6–4. Factors that May Alter Concentration–Effect Relationships Factor

Effect

Examples

Measurement during absorption phase

Underestimation of eventual effects

Measurement during distribution phase Decreased binding to proteins Saturation of binding proteins Binding by antidote

Overestimation of effects Underestimation of effects Underestimation of effects Variable

Sustained-release preparations; large ingestions of poorly soluble xenobiotics (e.g., salicylates); xenobiotics that slow gastric emptying (e.g., TCAs) Lithium, digoxin, TCAs Phenytoin Salicylate, valproic acid Digoxin/digoxin immune Fab

TCA, tricyclic antidepressant.

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TABLE 6–5. Xenobiotics of Concern that are Often not Detected by Toxicology Screens Antidysrhythmics Anticholinergics Anticoagulants Anticonvulsants Antipsychotics β-Adrenergic agonists and antagonists Calcium channel blockers Carbon monoxide Clonidine Cyanide “Designer drugs” Digoxin Diphenhydramine Ethylene glycol Fentanyl

γ-Hydroxybutyrate Herbal preparations Hypoglycemics Iron Isopropanol Ketamine Lithium Lysergic acid diethylamide Methylene dioxyamphetamine Methylene dioxymethamphetamine Metals Methanol Methemoglobin Solvents Serotonin reuptake inhibitors Strychnine

benign or therapeutic levels from toxic ones. Quantitative tests may falsely suggest toxicity when drug concentrations are measured during the drug’s distribution phase, which may extend for several hours with drugs such as digoxin and lithium. Moreover, the phenomenon of tolerance may allow chronic drug users to be relatively unaffected by concentrations that would be quite toxic to a non-using individual. Because comprehensive drug screens may differ widely between institutions and patterns of exposure also show substantial regional variation, there is limited ability to draw meaningful conclusions from any study of the sensitivity and specificity of such screens for detecting or excluding poisoning. The predictive power of the result of a toxicology screen depends on a number of factors, including the likelihood of poisoning before receiving the test results (the prior probability or the prevalence), the range of xenobiotics effectively detected, and the frequency of false-positive results. It should be noted that false-positive and falsenegative results may be either analytical or clinical in origin. A clinical false-positive result occurs when a xenobiotic is detected that is not contributing to the medical problem (e.g., a therapeutic amount of acetaminophen). A clinical false-negative result may occur when the wrong test is ordered (e.g., a screen for drugs of abuse for a patient with acetaminophen poisoning). Table 6–6 explores the positive and negative predictive values of two hypothetical toxicology screens. The sensitivity of 98% and specificity of 98% in one scenario reflect the sensitivity of a broadly comprehensive toxicology screen12 and an achievable false-positive rate of 2%. The second scenario has a sensitivity of only 80% and a specificity of 95% and represents plausible but mediocre performance. Three sets of prior probabilities are considered: 10%, 50%, and 95%. A prior probability of 10% might be seen if screening were indiscriminately applied to all patients in an emergency department or in a scenario in which xenobiotics were being excluded as a secondary cause of lethargy in an older patient who fell and struck his head. Both screens do well at excluding xenobiotics when their presence is already unlikely. However, a positive finding from either does not yield a fully convincing diagnosis of

TABLE 6–6. Positive and Negative Predictive Values of Toxicology Screens Sensitivity/ Specificity (%/%)

10%

98/98 (excellent) 80/95 (mediocre)

84%/99.8% 64%/98%

Prior Probability 50% 98%/98% 94%/83%

95% 99.9%/72% 99.7%/20%

the presence of a xenobiotic. A prior probability of 50% falls into the range of prevalence actually observed in patients for whom toxicology screens were ordered (see below). In this scenario of maximum uncertainty, both screens do a good job of diagnosing poisoning, but xenobiotic exclusion by the mediocre screen will be incorrect in one of six instances. A prior probability of 95% represents testing in which the clinical presentation strongly suggests poisoning, as in the investigation of lethargy in a known regular drug user. Although positive findings in either screen raise the probability to almost complete certainty, negative findings from the excellent screen are incorrect one time out of four, whereas negative results from the mediocre screen are wrong four times out of five. Overall, toxicology screens have better positive predictive value than negative predictive value. This observation should give pause to those who primarily order toxicology screens “to rule out poisoning.” Although only approximately 2% of laboratories offer comprehensive toxicology screening,3 most laboratories offer some sort of testing in response to a request for a toxicology screen. This may consist of a panel of immunoassays for drugs of abuse or a urine TLC screen, or it may result in a comprehensive screening test performed at a reference laboratory. Other laboratories may offer a focused, rather than a comprehensive, screening panel. Larger laboratories may have several types of “tox screens” available for use in different situations. Among laboratories that do not limit their tests exclusively to commercially available methods, it is likely that no two will have exactly the same menu of drugs that can be reliably detected. Some laboratories address the issue of providing useful information in a timely fashion through the use of focused, rather than comprehensive, screening protocols.34 These screens include xenobiotics locally prevalent in overdose cases or drugs for which there are specific interventions. Table 6–7 suggests the possible composition of a focused screen. Given the trends toward increasing automation and decreasing personnel in clinical laboratories, it is relevant to ask what benefits may be derived from such testing. Studies show that comprehensive toxicologic screening has the potential to provide significant information, with utility varying with the indication for testing. The prevalence of positive results has ranged from 34% to 86% of specimens submitted for testing. When drug exposure, as predicted from the patient’s history and physical examination, was compared with screening results, clinically unsuspected substances were found in 7% to 48% of the cases, and clinically suspected xenobiotics were not found in 9% to 25%.11,12,15,24,25 However, limited utility is suggested by studies showing that the results of comprehensive screening affect management in fewer than 15% of cases,24 and in many instances, in fewer than 5% of cases.11,15,21,25,32 A survey of emergency physicians found that more than 75% were not fully aware of the range of drugs detected and not detected by their laboratory’s toxicology screen. The majority believed that the screen was more comprehensive than it actually was.7

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a

Urine Tests

Acetaminophen Ethanol Salicylates Tricyclic antidepressants (semiquantitative immunoassay) Consider including: Barbiturates Cooximetryb Iron Lithium Theophylline Valproic acid Volatile alcoholsc Other locally prevalent drugs

Cocaine metabolite Opiates TCAsa

Amphetamines Barbituratesa Benzodiazepines Methadone Phencyclidine Propoxyphene

BEDSIDE TOXICOLOGY TESTS

If not included in serum tests.

b

Requires whole-blood specimen.

c

Methanol, isopropanol (+ acetone).

83

only in major medical centers, where consultation from a medical or clinical toxicologist is more likely to be available. Such experts may be more able to make correct diagnoses and initiate appropriate management relying on clinical findings alone. Several recently introduced point-of-care devices are capable of rapidly screening urine for the presence of drugs of abuse, as well as TCAs. Results are typically available in 20 to 30 minutes. In a small study of one such device, diagnosis was believed to have been aided in 82% of cases, and clinical management was changed in 25%.2 Additional studies are needed to ascertain the utility of point-of-care drug screening in emergency toxicology.35 A useful alternative to the toxicology screen is the toxicology hold. This is a set of serum and urine specimens drawn at the time of presentation, when xenobiotic concentrations are likely to be near maximum concentrations, and initially held refrigerated or frozen without testing. This allows a specimen to remain available for subsequent testing if needed. Most laboratories hold such specimens for several days.

TABLE 6–7. Components of a Focused Toxicology Screen Serum Tests

Laboratory Principles

TCA, tricyclic antidepressant.

One reason for a limited effect on management is the substantial time delay before results of comprehensive screening are available. Generally, more than 3 hours is required for the report of a negative result, and an even longer time is required for confirmation of a positive finding. By this time, most consequential management decisions have been implemented. Another possible explanation for the limited utility of screening is that comprehensive screening is largely available

Testing at the bedside is attractive for emergency toxicology. When a specific diagnosis is being considered, a bedside test can provide confirmation or exclusion quickly and often inexpensively,18 enabling appropriate management to be initiated. This benefit must be balanced against the generally poorer sensitivity and specificity of bedside tests in comparison with testing in the clinical laboratory, the lack of quantitative information for most tests, the lack of laboratory support, the need to perform testing in accord with regulatory requirements (see below), record-keeping issues, and the erosion of the time advantage when multiple bedside tests are done on the same patient. Table 6–8 lists some tests that can be conveniently performed at the bedside. Spot tests can also be done at the bedside, although many spot tests use hazardous reagents that may not be suitable for use in many bedside settings. A major problem with bedside tests that are not done with commercial devices is that these are considered “highly complex” tests under federal regulations, although they may be very simple to perform. This classification results from the fact that they are not subject

TABLE 6–8. Bedside Toxicology Tests Test

Substrate

Drug or Poison

Comments

Alcohol dehydrogenase Breath analysis Breath analysis

Saliva Breath Breath

Ethanol Carbon monoxide Ethanol

Ferric chloride Meixner

Urine Mushroom

Salicylate Amatoxins

Microparticle agglutination

Urine

Drugs of abuse

Microparticle capture

Urine

Drugs of abuse

Oxalate crystals

Urine

Ethylene glycol

Other alcohols may interfere. Some tests only give concentration ranges. Ethanol may interfere. Good cooperation is required. Ethanol in the oral cavity interferes. Calibrated to give whole-blood rather than serum concentration. Acetaminophen and phenothiazines interfere (limited utilization). Paper must contain lignin (filter paper, which is lignin-free, must be used as a negative control). Requires strong acid. Some false-positives and false-negative test results have been seen KIMS variant with visual endpoint. Separate test for each drug. Single device detects one or more of the drugs listed in Table 6-10 in a variety of menus available from multiple manufacturers. Some multitest devices include TCAs. Higher false-positive and false-negative rates than for clinical laboratory testing. Metabolic end product. Not detected during early stages. Nonspecific.

KIMS, kinetic interaction of microparticles in solution; TCA, tricyclic antidepressant.

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to the validation processes required for Food and Drug Administration (FDA)–approved commercial devices. Meeting the regulations requires significant initial and ongoing investment of time. The Meixner test1 (for amatoxins in mushrooms) and breath analysis (for ethanol or carbon monoxide from human breath) are exempted from these regulations because they are not considered to involve human specimens (see Regulatory Issues Affecting Toxicology Testing below). In testing in overdose situations, most specimens will have either zero or very high concentrations of target analytes, and correct identification of the presence or absence of a substance is likely even with imprecise methods. Unfortunately, when point-of-care drug-screening devices have been compared with laboratory testing at concentrations near cutoff limits, performance has been variable.33,35 An extensive study using a more representative range of urine drug concentrations observed higher rates of correct results, but performance remained inferior to that of immunoassays conducted with laboratory instrumentation.8 A clinical and methodologic issue with bedside drug-screening assays is whether positive results will subsequently be subjected to confirmatory testing. The extra investment of labor needed to submit a specimen tends to discourage laboratory confirmation. The argument in favor of routine confirmation is that this is an accepted standard of practice, even for screening assays that have lower false-positive rates than the point-of-care devices (see Special Considerations for Drug Abuse Screening Tests below). The counterargument is that if testing is limited to populations with a high prior probability of drug exposure, the predictive value of a positive test result is high. The NACB guidelines actually recommend against routine confirmation of positive results of drug-screening immunoassays done solely for medical reasons but suggest that all such unconfirmed positive results be reported as being “presumptive.”37

REGULATORY ISSUES AFFECTING TOXICOLOGY TESTING Since 1992, medical laboratory testing has been governed by federal regulations (42 CFR part 405 et seq) issued under the authority of the Clinical Laboratory Improvement Amendments of 1988 (often referred to as CLIA-88 or simply CLIA). These regulations apply to all laboratory testing of human specimens for medical purposes, regardless of site. They include the universal requirement for possession of an appropriate certificate to perform even the simplest of tests. The remaining requirements depend on the complexity of the test. These regulations become important to the clinician whenever testing is done at the bedside, whether using spot tests or commercial point-of-care devices such as dipsticks, glucose meters, or urine drug-screening devices. The regulations divide testing into three categories: waived, moderate complexity, and high complexity. Waived tests include a number of specifically designated simple tests, including urine dipsticks, urine pregnancy tests, urine drug-screening immunoassay devices, and blood glucose measurements with a hand-held monitor. The only legal requirement for performing waived testing are the possession of an appropriate CLIA certificate (certificate of waiver or higher) and performance of the test in accordance with the manufacturer’s instructions. There are substantial additional requirements for both moderate and highly complex testing, most of which simply represent good laboratory practice. Table 6–9 lists the most significant of these requirements. Most assays performed with commercial kits or devices are classified as belonging to the moderately complex category. All tests not specifically classified as waived or moderately complex are considered highly complex. This includes essentially all noncommercial tests, including

TABLE 6–9. Major Clinical Laboratory Improvement Amendments (CLIA) Requirements for Laboratory Testing Waived Tests Certificate of waiver Follow manufacturer’s instructions exactly Moderate-Complexity Tests CLIA certificate Record keeping Test method verification Written procedures Qualified laboratory director Personnel educational requirements Documented training of all testing personnel Annual competency testing of all personnel Two levels of controls daily Participate in proficiency testing every 4 months Verify calibration and reportable range at least every 6 months Quality assessment program Biennial inspection and certification High-Complexity Tests All moderate-complexity requirements plus Qualified onsite supervisor or Daily review of all results by qualified supervisor

spot tests, because the testing materials have not been subject to review and approval by the FDA. These regulations have had a substantial impact in all areas of laboratory testing. Some of the most significant effects have been on bedside testing, including spot tests and point-of-care devices. Although clinical laboratories had been following most required practices before the implementation of the regulations, this was usually not the case for testing done at other sites. Most institutions have now established point-of-care testing programs to facilitate compliance with the regulations, as well as with additional requirements of accrediting agencies, such as the Joint Commission. Any toxicologic or other testing done at the point of care should be set up in consultation with the institutional program. Often, all point-of-care testing is done under a CLIA certificate held by the program. There is frequently a point-ofcare testing coordinator who may make recommendations or personally assist in efficiently addressing the assorted requirements. This table lists only the most significant requirements of the regulations implementing CLIA. These regulations continue to evolve. Accrediting agencies such as the Joint Commission may have additional requirements. Consultation with the clinical laboratory or with an institutional point-ofcare coordinator is recommended before implementing any testing. However, such testing may be covered by state laws or by institutional or accrediting agency policies. The NACB guidelines recommend that breath testing be overseen by the clinical laboratory and meet the same standards as other point-of-care testing.37 Personnel unaccustomed to quality control and assessment practices may find the CLIA requirements initially burdensome. Nonetheless, compliance is important. Following these practices may lead to a threefold reduction in incorrect results,31 thereby greatly improving the

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quality of care provided to the patient. Moreover, noncompliant testing is illegal under federal law and may also be illegal under state law. Any untoward outcome associated with illegal testing creates a major risk management liability for both the institution and the individual. Additionally, billing for any testing that is not CLIA compliant may be considered fraudulent. Another area in which the CLIA regulations have impacted toxicology testing is in the provision of infrequently requested tests. Meeting regulatory requirements involves a substantial labor investment even when few patient specimens are being tested. Mounting pressures to reduce laboratory costs make it less likely that laboratories will continue to maintain such assays. Another important regulation, although not part of CLIA regulations, requires that the medical reason for ordering a test be provided with the order. Federal regulations require that the ordering physician provide the diagnosis that establishes the medical necessity for the test, either by name or by diagnostic code (CPT code). Laboratories may not use a “best guess” to assign codes to undocumented test requests.

SPECIAL CONSIDERATIONS FOR DRUG ABUSE SCREENING TESTS Testing for drugs of abuse is a significant component of medical toxicology testing. These tests are widely used in the evaluation of potential poisonings and are assuming an increasing role is assuring the appropriate use of pain medications.28 Initial testing is usually done with a screening immunoassay. Although drug-screening immunoassays were initially developed for use in workplace drug-screening programs and are not always optimal for medical purposes, their wide availability low cost and ease of use formats led to their nearly universal adoption in clinical laboratories. Growth of the market for medical drug screening has led to the development of point-of-care tests specifically for medical use, but these devices largely retain the deficiencies of their predecessors. Drug abuse testing for nonmedical reasons is generally considered to be forensic testing, and confirmation of immunoassay results is considered mandatory in such circumstances. Confirmatory testing can compensate for some immunoassay shortcomings but is frequently not performed when screening tests are done for medical purposes. Despite the widespread use of drug-screening immunoassays in medical practice, studies suggest that many physicians do not fully understand the capabilities and limitations of these tests.28 The most commonly tested-for drugs are amphetamines, cannabinoids, cocaine, opiates, and phencyclidine. These are often referred to as the NIDA 5, because they are the five drugs that were recommended in 1988 by the National Institute on Drug Abuse (NIDA) for drug screening of federal employees. (Responsibility for recommendations for federal drug testing now lies with the Substance Abuse and Mental Health Services Administration [SAMHSA].) Drug-screening immunoassays are also frequently done for barbiturates and benzodiazepines and less frequently for meperidine, methadone, and propoxyphene. Drug-screening devices intended primarily for medical use may also include tests for acetaminophen or TCAs. Table 6–10 lists some of the general characteristics of these tests. Commercial urine immunoassays are also available for buprenorphine, lysergic acid diethylamide, methaqualone, methylenedioxymethamphetamine (MDMA), and oxycodone. Drug-screening immunoassays are available in a number of formats, which may differ in performance. Almost all of them are designed to be used with urine specimens because these can be obtained noninvasively and generally have higher concentrations than serum, enhancing the sensitivity of the test.

Laboratory Principles

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The drug-screening tests for cannabinoids and cocaine are directed toward inactive drug metabolites rather than the active parent compound. The parent drugs, cocaine and tetrahydrocannabinol, are both short lived and persist for no more than a few hours after use. The metabolites remain present substantially longer. Detection of the metabolites increases the ability to detect any recent drug use. However, this limits the utility of the assays for determining whether a patient is currently under the influence of the drug. Because the metabolites are rapidly formed, a negative test result generally excludes toxicity, but a positive test result indicates only use in the recent past, not current toxicity. To increase sensitivity for detection of less-recent drug use, substrates other than urine can be used for drug screening, including hair and meconium. The latter is used to document intrauterine drug exposure (Chap. 30). SAMHSA is planning to develop regulations governing the use of hair, saliva, and sweat specimens for federal workplace testing after their performance characteristics have been adequately studies. This can be expected to increase the availability of clinical testing using these substrates. However, testing performed on hair and sweat are unlikely to offer advantages over testing of serum and urine for the management of toxicologic emergencies. The stigma attached to a positive test result for an abused drug requires that special care be exercised in performing and reporting the test results. To protect citizens’ rights, many states have legislated specific requirements for workplace drug screening. In some states, the requirements apply only to screening in the workplace, exempting testing for medical purposes. Laws in other states might apply to all drug screening. Although they are not always legally required, some workplace drug-screening practices have been widely applied to all drug screening. The use of specific cutoff concentrations is nearly universal. Test results are considered positive only when the concentration of drugs in the specimen exceeds a predetermined threshold. This threshold should be set sufficiently high that false-positive results as a consequence of analytic variability or cross-reactivity are extremely infrequent. They should also be low enough to consistently give a positive result in persons who are using drugs. Cutoff concentrations used vary with the drug or drug class under investigation. In some drugscreening immunoassays, the laboratory has the option of selecting from several cutoff values. The use of cutoff values sometimes creates confusion when a patient who is known to have recently used a drug has a negative result reported on a drug screen. In such instances, the drug is usually present but at a concentration below the cutoff value. Another potential problem occurs when a patient’s drug-screening test result is positive after previously having become negative. This is usually interpreted as indicating renewed drug use, but it may actually be an artifact. Urine drug concentrations are directly proportional to the serum drug concentrations but inversely proportional to the rate of urine production. The rate of the urine flow may vary up to 100-fold, with a resulting possible 100-fold change in the urine drug concentration. This effect is often exploited by individuals who drink large quantities of water before taking a urine drug test to increase urine flow and decrease urine drug concentrations. In contrast, a decrease in the rate of urine production may result in a positive test result following a negative one despite no new drug exposure. A similar effect may be produced by changes in urine pH. Drugs containing a basic nitrogen may demonstrate ionic trapping, with increasing concentrations as urine pH decreases. Similarly, excretion of the phenobarbital anion may increase with increasing urine pH. This phenomenon is medically exploited by alkalinizing the urine to increase phenobarbital excretion.

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TABLE 6–10. Performance Characteristics of Common Drug Abuse Screening Immunoassaysa

a

Drug/Class

Detection Limitsb

Confirmation Limitsb

Detection Intervalc

Comments

Amphetamines

1000 ng/mL

500 ng/mL amphetamine or MDMA

1–2 d (2–4 d)

Barbiturates Benzodiazepines

200 ng/mL Secobarbital 100–300 ng/mL

Cannabinoids

50 ng/mL; 20ng/mL; 25 ng/mL; 100ng/mL THCA

15 ng/mL THCA

1–3 d (>1 mo)

Cocaine

300 ng/mL BE

150 ng/mL BE

2 d (1 wk)

Opiates

2000 ng/mL; 300 ng/mL

2000 ng/mL; morphine or codeine

1–2 d; 2–4 d (500 ng/mL with >200 ng/mL of metabolite, amphetamine. Phenobarbital may be detected for up to 4 weeks. Benzodiazepines vary in reactivity and potency. Hydrolysis of glucuronides increases sensitivity. False-positive test results maybe be seen with oxaprozin. Screening assays detect inactive and active cannabinoids; confirmatory assay detects inactive metabolite THCA. Duration of positivity is highly dependent on screening assay detection limits. Screening and confirmatory assays detect inactive metabolite BE. False-positive test results are unlikely. >10 ng/mL of heroin metabolite 6-monoacetyl morphine is also confirmatory. Semisynthetic opiates derived from morphine show variable cross-reactivity. Fully synthetic opioids (e.g., fentanyl, meperidine, methadone, propoxyphene, tramadol) have minimal cross-reactivity. Quinolones may cross-react. Doxylamine may cross-react. Dextromethorphan, diphenhydramine, ketamine, and venlafaxine may cross-react. Duration of positivity depends on cross-reactivity of metabolite norpropoxyphene.

2–4 d 1–30 d

25 ng/mL

1–4 d 4–7 d (>1 mo) 3–10 d

Performance characteristics vary with manufacturer and may change over time. for the most accurate information, consult the package insert of the current lot or contact the manufacturer.

b

Substance Abuse and Mental Health Services Administration recommendations5 are shown as the first value for amphetamines, cannabinoids, cocaine, opiates, and phencyclidine immunoassays and as only values for confirmatory assays. Other commercial immunoassay cutoffs are also listed. Other gas spectrometry cutoffs are set by the laboratory. c

Values are after typical use; values in parentheses are after heavy or prolonged use.

BE, benzoylecgonine; MDA, methylenedioxyamphetamine; MDMA, methylenedioxymethamphetamine; THCA, tetrahydrocannabinoic acid.

Another widely used practice is the confirmation of positive screening results using an analytical methodology different from that used in the screen, such as an immunoassay screen followed by chromatographic confirmation. The possibility of simultaneous false-positive results by two distinct methods is quite low. Clinical laboratories may differ in their policies with regard to confirmatory testing. Some may confirm all positive results from screening immunoassays, but others may not provide any confirmatory testing unless it is explicitly requested. The most common confirmatory method is gas chromatography/ mass spectrometry (GS/MS). The high specificity afforded by the combination of the retention time and the mass spectrum makes false-positive results extremely unlikely. GC/MS also has greater sensitivity than the screening immunoassays, minimizing failed confirmations because of drug concentrations below the sensitivity of the confirmatory assay. Some states require GC/MS confirmation for workplace drug screening, and it may be legally required for all drug screening. Immunoassay results can generally be obtained within 1 hour. Confirmatory testing usually requires at least several hours. This can

create a problem when confirmation of initial immunoassay results is considered mandatory. Most laboratories provide a verbal report of a presumptive positive result to facilitate medical management but may not enter the result into a permanent record, such as the laboratory computer, until after confirmation has been completed. The importance of confirmatory testing in workplace drug screening follows from the relatively low prevalence of positive results. A screening test with both sensitivity and specificity of 98% will produce two false-positive results per 100 subjects tested. A workforce with a 2% prevalence of illicit drug use will yield two true-positive results per 100 subjects. The predictive value of a positive test will only be 50% (two of four). This is an unacceptable level of certainty for results that might be used to terminate employment. Although the prevalence of recent drug use in the workforce is low, rates of positivity of 34% to 86% have been reported for selective drug screening of emergency department populations. Given a 50% prevalence of recent drug use, the positive predictive value of same screening test increases to 98% (see Table 6–6). A high prior probability of drug positivity for patients tested in medical settings results in a very high posterior probability after a

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Chapter 6

positive test result. Confirmatory testing is much less critical in such a setting, particularly because a positive finding infrequently has consequences that extend beyond the medical management of the patient. An exception may occur when results of testing performed on motor vehicle crash victims can be subsequently subpoenaed as evidence in legal proceedings. Confirmatory testing also becomes more important in drug abuse testing associated with chronic pain management programs, in which unexpected findings may result in termination of care. Chromatographic tests that identify individual opiates can distinguish between prescribed and nonprescribed drugs. One workplace drug-screening practice that is not widely followed in medical toxicology is maintenance of a chain of custody. Employers generally insist on chain of custody for workplace testing because actions taken in response to a positive result may be contested in court. A chain of custody provides results that are readily defended in court. Laboratories providing testing for medical purposes rarely keep a chain of custody because it is quite expensive and does not benefit the patient. Additionally, the medical personnel responsible for obtaining the specimens are rarely trained in collection requirements for a chain of custody. The lack of chain of custody may create problems when persons with no medical complaints present at an emergency department or other medical facility requesting the performance of a drug-screening test. Unless the facility is prepared to initiate the chain of custody at the time of specimen collection and the laboratory is prepared to maintain it, such persons should be redirected to a site maintained by a commercial laboratory that routinely performs workplace drug testing and has appropriate procedures in place. Many laboratories have had the experience of unwittingly performing drug abuse testing for nonmedical purposes because the reason for the testing is not always included on the test requisition. To avoid liability issues, the laboratory may choose to include a disclaimer with every drug-screening report indicating that the results are for purposes of medical management only. Another practice common in workplace testing but rare in medical laboratories is testing for specimen validity. It is common for individuals to try to “beat” a workplace drug test through a variety of means, including diluting the specimen (either physiologically by water ingestion or by direct addition of water to the specimen), substituting “clean” urine obtained from another individual, or adding various substances that will either destroy drugs in the specimen or inactivate the enzymes or antibodies used in the screening immunoassays. Such substances include acids, bases, oxidizing agents (bleach, nitrite, peroxide, peroxidase, iodine, chromate), glutaraldehyde, pyridine, niacin detergents, and soap. SAMHSA requires validity testing for all specimens in federal workplace testing, including measurement of urinary pH, specific gravity, and creatinine concentration, as well as tests for the presence of adulterants.5 Dipsticks are available that detect the most common adulterants. However, manipulation or adulteration is rarely a problem in medical specimens, and clinical laboratories infrequently provide validity testing.

PERFORMANCE CHARACTERISTICS OF COMMON DRUG-SCREENING ASSAYS Medical toxicologists, toxicology laboratory directors, and practicing physicians may frequently get questions about the significance of drugscreening assays, particularly about the causes of false-positive results. Often these questions come from an individual who recently had a positive test result. Table 6–10 summarizes drug-screening test performance characteristics, which are discussed in more detail below. Immunoassays for opiates are directed toward morphine but have good cross-reactivity with many (but not all) structurally similar

Laboratory Principles

87

natural and semisynthetic opiates. The extent of cross-reactivity may vary between manufacturers. For example, oxycodone exhibits approximately 30% cross-reactivity relative to morphine in a fluorescence polarization immunoassay but less than 5% cross-reactivity in a number of other screening assays.17,28 A failure to appreciate the poor detection of oxycodone can create problems when opiate-screening immunoassays are used to confirm that patients receiving prescription oxycodone for chronic pain are indeed taking it rather than diverting it for illicit sale. If a low cross-reactivity assay is used, a patient taking oxycodone as prescribed might have a negative result, but another patient who is selling the oxycodone and using the proceeds to buy heroin would have a positive result. To address this problem, assays specific for oxycodone have been introduced. These assays are sensitive to therapeutic amounts of oxycodone but relatively insensitive to other opiates. Synthetic opioids, such as dextromethorphan, fentanyl, meperidine, methadone, propoxyphene, and tramadol, show little or no crossreactivity in opiate immunoassays. Urine immunoassays specific for meperidine, methadone, and propoxyphene are available. Given the increasing importance of buprenorphine as maintenance therapy for opiate dependency, it is worth noting that the combination of high potency and low cross-reactivity means that buprenorphine will generally not be detected by opiate immunoassays. Immunoassays for detection of buprenorphine have therefore been developed. A positive immunoassay result may reflect multiple contributions from various opiates and opiate metabolites. Concentrations of morphine glucuronide in the urine may be up to 10-fold higher than the concentrations of unchanged morphine and can contribute substantially to positive results. A positive opiate result after the use of heroin (diacetylmorphine) is primarily a result of the morphine and morphine glucuronide that result from heroin metabolism. Distinguishing heroin from other opiates requires detection of 6-monoacetylmorphine, the heroin-specific metabolite. Small amounts of the metabolite may be detected by GC/MS for up to 24 hours after use. A half-life of 5 minutes means that unchanged heroin can only be found in the urine if sampling is done immediately after use. The duration of positivity of an opiate immunoassay after last use depends on the identity and amount of the opiate used, the specific immunoassay, the cutoff value, and the pharmacokinetics of the individual. Currently, SAMHSA recommends a cutoff equivalent to 2000 ng/mL of morphine for workplace screening because poppy seeds can rarely produce transient positive results with the previously recommended cutoff of 300 ng/mL. However, most toxicology laboratories continue to use a 300 ng/mL cutoff. Drug-screening assays for “cocaine” are actually assays for the inactive cocaine metabolite benzoylecgonine, which is eliminated more slowly than cocaine. This extends the duration of positivity after last use from a few hours to 2 days and sometimes to a week or longer after prolonged heavy use. Because the assay is directed toward an inactive metabolite, positive results do not equate with toxicity but merely indicate recent exposure. The assay is highly specific for benzoylecgonine, and false-positive results are extremely uncommon (Chap. 76). Immunoassays for cannabinoids are also directed toward an inactive metabolite, in this case tetrahydrocannabinoic acid. These immunoassays exhibit cross-reactivity with other cannabinoids but little else. Because cannabinoids are structurally unique and occur only in plants of the genus Cannabis, false–positive results are quite uncommon (Chap. 83) It is unusual, although possible, to become exposed to sufficient “second-hand” or sidestream marijuana smoke to develop a positive urine test result.4 Legal hemp products include fiber, oil, and seedcake derived from Cannabis varieties with low concentrations of cannabinoids. Hemp food products contain insufficient amounts of tetrahydrocannabinol to produce psychoactive effects and usually will

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not increase urinary cannabinoid concentrations above a 50 ng/mL screening threshold.10,28 Interpretation of a positive result for cannabinoids can be problematic. Urine may be positive for up to 3 days after occasional recreational use. However, with heavy or prolonged use, there may be significant accumulation of cannabinoids in adipose tissue. These stored cannabinoids are slowly released into the bloodstream and can produce positive findings for 1 month or more. Consequently, little can be concluded from a positive finding in terms of current toxicity. Because positive results in the absence of toxicity are very common and because tetrahydrocannabinol is rarely responsible for serious acute toxicity, NACB guidelines recommend against its routine inclusion in drug screening for patients with acute symptoms.37 Amphetamine-screening tests have the greatest problems with falsepositive results. A number of structurally related compounds may have significant cross-reactivity, including bupropion metabolites and nonprescription decongestants such as pseudoephedrine, as well as l-ephedrine, which is found in a variety of herbal preparations. Some over-the counter nasal inhalers contain l-methamphetamine, the less potent levorotary isomer of d-methamphetamine. It is particularly problematic because it not only cross-reacts in immunoassays but also cannot be distinguished from the d-isomer by mass spectrometry.10 This cross-reactivity is beneficial from the point of view of the medical toxicologist because all of these compounds may produce serious stimulant toxicity. But it is problematic in drug abuse screening because of the widespread legitimate use of cold medications. Assays with greater selectivity for amphetamine or methamphetamine have been developed. Although these assays produce fewer false-positive results caused by decongestant cross-reactivity, they are also less sensitive for the detection of other abused amphetamine-like compounds, including methylenedioxyamphetamine (MDA), MDMA, and phentermine. Cross-reactivity patterns vary from assay to assay.17 The manufacturer’s literature should be consulted for specific details. Testing for benzodiazepines is complicated by the wide array of benzodiazepines that differ substantially in their potency, cross-reactivity, and half-lives. There are also substantial differences in the detection patterns of the various immunoassays.10,17 This heterogeneity complicates the interpretation of benzodiazepine-screening assays. Screening results may be positive in persons using low therapeutic doses of diazepam but negative after an overdose of a highly potent benzodiazepine such as clonazepam. To improve the scope of detection, some assays use antibodies to oxazepam, which is a metabolite of a number of different benzodiazepines. These assays may have poor sensitivity to benzodiazepines that are not metabolized to oxazepam. False-negative results may occur for benzodiazepines that are excreted in the urine almost entirely as glucuronides that have poor cross-reactivity with antibodies directed toward an unmodified benzodiazepine. This is one reason for the poor detectability of lorazepam in some screening assays. The latter situation has led to the recommendation that specimens be treated with β-glucuronidase before analysis.20 Some assays now include β-glucuronidase in the reagent mixture or use antibodies directed toward glucuronidated metabolites. The frequency of falsenegative results, as well as the fact that benzodiazepines are relatively benign in overdose, have led the NACB guidelines to withhold recommendation for routine screening of urine for benzodiazepines until these problems with the immunoassays are addressed.37 Barbiturates are comparable to benzodiazepines in their heterogeneity of potency, cross-reactivity, and half-lives, although the differences are less substantial. Specific assays for serum phenobarbital can often help to clarify the significance of a positive barbiturate screen. Some phencyclidine screening assays may give positive results with dextromethorphan, ketamine, or diphenhydramine but only when

these are used in amounts above usual therapeutic quantities. A positive result may serve as a clue to a possible overdose with any of these substances. Furthermore, much of the illicit phencyclidine (PCP) actually consists of a mixture of various congers and byproducts of synthesis. The cross-reactivity of these xenobiotics with the assay varies significantly and may result in false-negative assay results in patients who use PCP.

MEASUREMENT OF ETHANOL CONCENTRATIONS Measuring ethanol may have ramifications beyond guiding medical management, particularly when performed on crash victims. Although testing for ethanol in urine is common in workplace drug screening, most testing in clinical laboratories is done using serum or plasma. Concentrations are most commonly measured enzymatically using alcohol dehydrogenase. In larger toxicology laboratories, ethanol measurements are often done using a GC assay that can also distinguish and measure isopropanol and methanol, as well as the isopropanol metabolite acetone. Alcohols with lower volatility, including ethylene and propylene glycol, are usually not detected by this assay. Because both enzymatic and chromatographic assays have substantial specificity for ethanol, confirmatory testing with a second method is uncommon. Breath alcohol analyzers may also be used in assessing ethanol intoxication, as may point-of-care devices that measure salivary ethanol. These measurements are less precise than laboratory assays14,30 and are more subject to interference by other alcohols and other organic solvents. Breath-alcohol analyzers require good cooperation from the patient to obtain an appropriate breath sample and are typically calibrated to give results approximating whole-blood alcohol concentrations. For the above reasons, confirmation of positive findings with a laboratory measurement may sometimes be desirable. Blood alcohol concentrations used legally to define driving under the influence have no particular clinical significance but may have risk management implications for patient discharge. Whereas legal standards are written in terms of whole-blood alcohol concentrations, clinical laboratories usually measure alcohol in serum or plasma. Serum and plasma alcohol concentrations are essentially identical, but both will be higher than the alcohol concentration measured in a whole-blood specimen obtained at the same time. This is a result of the lower concentration of alcohol in the red blood cells. The ratio of serum alcohol to whole-blood alcohol varies from individual to individual, with a median value of 1.15.27 It is more likely than not that an individual with a serum alcohol concentration of less than 92 mg/dL will have a whole-blood alcohol concentration of less than 80 mg/dL ( sublingual > intramuscular, subcutaneous, intranasal, oral > cutaneous, rectal. After the oral intake of 200 mg (0.59 mmol) of cocaine hydrochloride, the onset of action is 20 minutes, with an average peak concentration of 200 ng/ mL.71 In marked contrast, smoking 200 mg (0.66 mmol) of cocaine freebase results in an onset of action of 8 seconds and a peak level of 640 ng/mL. When administered IV as 200-mg cocaine hydrochloride, it then has an onset of action of 30 seconds and a peak level of 1000 ng/mL.71 A xenobiotic must diffuse through a number of membranes before it can reach its site of action. Figure 8–2 shows the number of membranes through which a xenobiotic typically diffuses. Membranes are predominantly composed of phospholipids and cholesterol in addition to other lipid compounds.54 A phospholipid is composed of a polar head and a fatty acid tail, which are arranged in membranes so that the fatty acid tails are inside and the polar heads face outward in a mirror image.58 Proteins are found on both sides of the membranes and may traverse the membrane.54 These proteins may function as receptors and channels. Pores are found throughout the membranes. The principles relating to diffusion apply to absorption, distribution, certain aspects of elimination, and each instance when a xenobiotic is transported through a membrane. Transport through membranes occurs via (1) passive diffusion; (2) filtration or bulk flow, which is most important in renal and biliary secretion as the mechanism of transport associated with the movement of molecules with a molecular weight less than 100 daltons, with water directly through aquapores; (3) carrier-mediated active or facilitated transport, which is saturable, and (4) rarely, endocytosis (see Fig. 8–2). Most xenobiotics traverse membranes via simple passive diffusion. The rate of diffusion is determined by the Fick law of diffusion (Eq. 8–1):

Mary Ann Howland Pharmacokinetics is the study of the absorption, distribution, metabolism, and excretion of xenobiotics. Xenobiotics are substances that are foreign to the body and include natural or synthetic chemicals, drugs, pesticides, environmental agents, and industrial agents.49 Mathematical models and equations are used to describe and to predict these phenomena. Pharmacodynamics is the term used to describe an investigation of the relationship of xenobiotic concentration to clinical effects. Toxicokinetics, which is analogous to pharmacokinetics, is the study of the absorption, distribution, metabolism, and excretion of a xenobiotic under circumstances that produce toxicity. Toxicodynamics, which is analogous to pharmacodynamics, is the study of the relationship of toxic concentrations of xenobiotics to clinical effect. Overdoses provide many challenges to the mathematical precision of toxicokinetics and toxicodynamics because many of the variables, such as dose, time of ingestion, and presence of vomiting, that affect the result are often unknown. In contrast to the therapeutic setting, atypical solubility characteristics are noted, and saturation of enzymatic processes occurs. Intestinal or hepatic enzymatic saturation or alterations in transporters may lead to enhanced absorption through a decrease in first-pass effect. Metabolism before the xenobiotic reaches the blood is referred to as the first-pass effect.2,76 Saturation of plasma protein binding results in more free xenobiotic available in the serum, plasma, and blood. Saturation of hepatic enzymes or active renal tubular secretion leads to prolonged elimination. In addition, age, obesity, gender, genetics, chronopharmacokinetics (diurnal variations), and the effects of illness and compromised organ perfusion all further inhibit attempts to achieve precise analyses.3,17,40,45,68,72 In addition, various treatments may alter one or more pharmacokinetic and toxicokinetic parameters. There are numerous approaches to recognizing these variables, such as obtaining historical information from the patient’s family and friends, performing pill counts, procuring sequential serum concentrations during the phases of toxicity, and occasionally repeating a pharmacokinetic evaluation during therapeutic dosing of that same agent to obtain comparative data. Despite all of the confounding and individual variability, toxicokinetic principles may nonetheless be applied to facilitate our understanding and to make certain predictions. These principles may be used to help evaluate whether a certain antidote or extracorporeal removal method is appropriate for use, when the serum concentration might be expected to decrease into the therapeutic range (if one exists), what ingested dose might be considered potentially toxic, what the onset and duration of toxicity might be, and what the importance is of a serum concentration. While considering all of these factors, the clinical status of the patient is paramount, and mathematical formulas and equations can never substitute for evaluating the patient. This chapter explains the principles and presents the mathematics in a user-friendly fashion.79 The application of these principles and mathematical approaches by example and case illustration are found on the website.

Rate  of diffu sion =

dQ DAK(C1 − C 2 ) = dt h

(Eq. 8–1)

D = diffusion constant A = surface area of the membrane h = membrane thickness K = partition coefficient C1 − C2 = difference in concentrations of the xenobiotic at each side of the membrane The driving force for passive diffusion is the difference in concentration of the xenobiotic on both sides of the membrane. D is

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The General Approach to Medical Toxicology

and RCOO− (A−), and RNH2 (B) (amphetamines, tricyclic antidepressants) are bases. The equilibrium dissociation constant Ka can then be described by Equations 8–2A and 8–2B:

A Toxic Concentration

For   weak  acids :  HA = H + + A − B

For   weak   bases :  BH + = B + H +

⎡H + ⎤ ⎡A − ⎤ Ka = ⎣ ⎦ ⎣ ⎦ ⎡⎣HA⎤⎦ ⎡H + ⎤ ⎡⎣B⎤⎦ Ka = ⎣ ⎦ ⎡⎣BH + ⎤⎦

(Eq. 8–2A) (Eq. 8–2B)

Therapeutic To work with these numbers in a more comfortable fashion, the negative log of both sides is determined. The results are given in Equations 8–3A and 8–3B.

C

0

⎡A − ⎤ For   weak  acids : − log K a = − log ⎡⎣H + ⎤⎦ − log ⎣ ⎦ (Eq. 8–3A) ⎡⎣H A⎤⎦

Time

0

I

Concentration

Toxic

By definition, the negative log of [H+] is expressed as pH, and the negative log of Ka is pKa. Rearranging the equations gives the familiar forms of the Henderson-Hasselbalch equations, as shown in Equations 8–4A, 8–4B, and 8–4C:

H Therapeutic G

0 0

⎡B⎤ For weak bases : − log K a = − log ⎡⎣H + ⎤⎦ − log ⎣ ⎦ ⎡⎣BH + ⎤⎦ (Eq. 8–3B)

Time

FIGURE 8–1. Effects of changes in ka (rate of absorption) and F (bioavailability) on the blood concentration time graph and achieving a toxic threshold. In curves A, B, and C, F is constant as ka decreases. In curves G, H, and I, ka is constant as F increases from G to I.48

a constant for each xenobiotic and is derived when the difference in concentrations between the two sides of the membrane is 1. The larger the surface area A, the higher the rate of diffusion. Most ingested xenobiotics are absorbed more rapidly in the small intestine than in the stomach because of the tremendous increase in surface area created by the presence of microvilli. The partition coefficient Ke represents the lipid-to-water partitioning of the xenobiotic. To a substantial degree, the more lipid soluble a xenobiotic is, the more easily it crosses membranes. Membrane thickness (h) is inversely proportional to the rate at which a xenobiotic diffuses through the membrane. Xenobiotics that are uncharged, nonpolar, of low molecular weight, and of the appropriate lipid solubility have the highest rates of passive diffusion. The extent of ionization of weak electrolytes (weak acids and weak bases) affects their rate of passive diffusion. Nonpolar and uncharged molecules penetrate faster. The Henderson-Hasselbalch relationship is used to determine the degree of ionization. An acid (HA), by definition, gives up a hydrogen ion, and a base (B) accepts a hydrogen ion. RCOOH (HA) (ie, aspirin, phenobarbital) and RNH3+ (BH+) are acids

Unprotonated species Protonated spec i es

(Eq. 8–4A)

⎡A − ⎤ For   weak  acids :  pH = pK a   +  log ⎣ ⎦ ⎡⎣HA⎤⎦

(Eq. 8–4B)

pH = pK a + log

For   weak   bases :  pH = pK a   +  log

[B] [BH+ ]

(Eq. 8–4C)

Because noncharged molecules traverse membranes more rapidly, it is understood that weak acids cross membranes more rapidly in an acidic environment and weak bases move more rapidly in a basic environment. When the pH equals the pKa, half of the xenobiotic is charged and half is noncharged. An acid with a low pKa is a strong acid, and a base with a low pKa is a weak base. For an acid, whereas a pH less than the pKa favors the protonated or noncharged species facilitating membrane diffusion, for a base, a pH greater than the pKa achieves the same result. Table 8–1 lists the pH of selected body fluids, and Figure 8–3 illustrates the extent of charged versus noncharged xenobiotic at different pH and pKa values. Lipid solubility and ionization each have a distinct influence on absorption. Figure 8–4 demonstrates these characteristics for three different xenobiotics. Although the three xenobiotics have similar pKa values, their different partition coefficients result in different degrees of absorption from the stomach. Specialized transport mechanisms are either adenosine triphosphate (ATP) dependent to transport xenobiotics against a concentration gradient (ie, active transport), or ATP independent and lack the ability to transport against a concentration gradient (ie, facilitated transport). These transport mechanisms are of importance in numerous parts of the body, including the intestines, liver, lungs, kidneys, and biliary system. These same principles apply to a small number of lipid-insoluble molecules that resemble essential endogenous agents.28,64 For example,

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Interstitial space

Environment

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Pharmacokinetic and Toxicokinetic Principles

Interstitial space

Blood

Cell

Organelle

Concentration gradiant Diffusion Filtration & Bulk flow

Endocytosis

Facilitated transport Active transport

Mucosa or skin

Capillary membranes

Cell membrane

Organelle membrane

FIGURE 8–2. Illustration of the number of membranes encountered by a xenobiotic in the process of absorption and distribution and the transport mechanisms involved in the passage of xenobiotics across membranes. Examples include diffusion: nonelectrolytes (ethanol) and unionized forms of weak acids (salicylic acid) and bases (amphetamines); endocytosis: Sabin polio virus vaccine; facilitated: 5-fluorouracil, lead, methyldopa, thallium; and active: thiamine and pyridoxine.

5-fluorouracil resembles pyrimidine and is transported by the same system, and thallium and lead are actively absorbed by the endogenous transport mechanisms that absorb and transport potassium and calcium, respectively. Filtration is generally considered to be of limited importance in the absorption of most xenobiotics but is substantially more important with regard to renal and biliary elimination. Endocytosis, which describes the encircling of a xenobiotic by a cellular

TABLE 8–1. pH of Selected Body Fluids Fluids

pH

Cerebrospinal Eye Gastric secretions Large intestinal secretions Plasma Rectal fluid: Infants and children Saliva Small intestinal secretions: Duodenum Small intestinal secretions: Ileum Urine Vaginal secretions

7.3 7–8 1–3 8 7.4 7.2–12 6.4–7.2 5–6 8 4–8 3.8–4.5

membrane, is responsible for the absorption of large macromolecules such as the oral Sabin polio vaccine.64 Gastrointestinal (GI) absorption is affected by xenobiotic-related characteristics such as dosage form, degree of ionization, partition coefficient, and patient factors (eg, GI blood flow; GI motility; and the presence or absence of food, ethanol, or other interfering substances such as calcium) (Fig. 8–5). The formulation of a xenobiotic is extremely important in predicting GI absorption. Disintegration and dissolution must precede absorption. Disintegration is usually much more rapid than dissolution except for modified-release products. Modified-release products include delayedrelease and extended-release formulations. By definition, extendedrelease formulations decrease the frequency of drug administration by 50% compared with immediate release-formulations, and they include controlled-release, sustained-release, and prolonged-release formulations. These modified-release formulations are designed to release the xenobiotic over a prolonged period of time to simulate the blood concentrations achieved with the use of a constant IV infusion. These formulations minimize blood level fluctuations, reduce peak-related side effects, reduce dosing frequency, and improve patient compliance. A variety of products use different pharmaceutical strategies, including dissolution control (encapsulation or matrix; Feosol), diffusion control (membrane or matrix; Slow K, Plendil ER), erosion (Sinemet CR), osmotic pump systems (Procardia XL, Glucotrol XL), and ion exchange resins (MS Contin suspension). Overdoses with modified-release formulations often result in a prolonged absorption phase, a delay to peak concentrations, and a prolonged duration of effect.7 Delayed-release preparations are enteric coated and designed to bypass the stomach and to release drug in the small intestine. Enteric-coated (acetylsalicylic acid [ASA], divalproex

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122

Part A

Aspirin (pKa =3.5)

pH O

2

C OH

3

O

O C

3.5 5 6

Methamphetamine (pKa =10)

% Nonioniz ed

% Nonioniz ed

99.7

1

4

The General Approach to Medical Toxicology

97 76

CH3

50

+

CH2

24

O C O-

O

O C

7

NH2

CH3

CH3

3 CH3

C

0.001

0.315

0.01

0.032

0.1

10

50

11

CH2

12

C

NH CH3

90.9 99

CH3 FIGURE 8–3. Effect of pH on the ionization of aspirin (pKa = 3.5) and methamphetamine (pKa = 10).

short GI transit times reduce absorption. This change in transit time is the unproven rationale for use of whole-bowel irrigation (WBI). Delays in emptying of the stomach impair absorption as a result of the delay in delivery to the small intestine. Delays in gastric emptying occur as a result of the presence of food, especially fatty meals; agents with anticholinergic, opioid, or antiserotonergic properties; ethanol; and any agent that results in pylorospasm (salicylates, iron). Bioavailability is a measure of the amount of xenobiotic that reaches the systemic circulation unchanged (Eq. 8–5).38 The fractional absorption (F) of a xenobiotic is defined by the area under the plasma drug concentration versus time curve (AUC) of the designated route of absorption compared with the AUC of the IV route. The AUC for each route represents the amount absorbed. F=

sodium) formulations resist disintegration and delay the time to onset of effect.6 Dissolution is affected by ionization, solubility, and the partition coefficient, as noted earlier. In the overdose setting, the formation of poorly soluble or adherent masses such as concretions of foreign material termed bezoars (verapamil, meprobamate, and bromide) significantly delay the time to onset of toxicity (Table 8–2).4,11,29,30,60 Most ingested xenobiotics are primarily absorbed in the small intestine as a result of the large surface area and extensive blood flow of the small intestines.59 Critically ill patients who are hypotensive, have a reduced cardiac output, or are receiving vasoconstrictors such as norepinephrine have a decreased perfusion of vital organs, including the GI tract, kidneys, and liver.3 Not only is absorption delayed, but elimination is also diminished.57 Total GI transit time can be from 0.4 to 5 days, and small intestinal transit time is usually 3 to 4 hours. Extremely

Absorbed from stomach in 1 hour (% of dose)

50

580

40 52

30

20

10 1 0

Barbital Secobarbital Thiopental (pKa 7.9) (pKa 7.6) (pKa 7.8)

FIGURE 8–4. Influence of increasing lipid solubility on the amount of xenobiotic absorbed from the stomach for three xenobiotics with similar pKa values. The number above each column is the oil/water equilibrium partition coefficient.

(AUC )route under study (AUC )IV

(Eq. 8–5)

Gastric emptying and activated charcoal are used to decrease the bioavailability of ingested xenobiotics. The oral administration of certain chelators (deferoxamine, D-penicillamine) actually enhances the bioavailability of the complexed xenobiotic. The net effect of some chelators, such as succimer, is a reduction in body burden via enhanced urinary elimination even though absorption is enhanced.31 Historically, the enteral administration of sodium bicarbonate was used to theoretically reduce the solubility of iron salts; unfortunately, this approach was ineffective and increased toxicity.15 Presystemic metabolism may decrease or increase the bioavailability of a xenobiotic or a metabolite.53 The GI tract contains microbial organisms that can metabolize or degrade xenobiotics such as digoxin and oral contraceptives and enzymes, such as peptidases, that metabolize insulin.54 However, in rare cases, GI hydrolysis can convert a xenobiotic into a toxic metabolite, as occurs when amygdalin is enzymatically hydrolyzed to produce cyanide, a metabolic step that is not produced after IV amygdalin administration.27 Xenobiotic metabolizing enzymes and transporters such as P-glycoprotein may also affect bioavailability. Xenobiotic-metabolizing enzymes are found in the lumen of the small intestine and can substantially decrease the absorption of a xenobiotic.44,73 Some of the xenobiotic that enters the cell can then be removed by the P-glycoprotein transporter out of the cell and back into the lumen to be exposed again to the metabolizing enzymes.44,73 Venous drainage from the stomach and intestine delivers orally (and intraperitoneally) administered xenobiotics to the liver via the portal vein and avoids direct delivery to the systemic circulation. This venous drainage allows hepatic metabolism to occur before the xenobiotic reaches the blood, and as previously mentioned, is referred to as the first-pass effect.2,76 The hepatic extraction ratio is the percentage of xenobiotic metabolized in one pass of blood through the liver.47 Xenobiotics that undergo significant first-pass metabolism (eg, propranolol, verapamil) are used at much lower IV doses than oral doses. Some drugs, such as lidocaine and nitroglycerin, are not administered by the oral route because of significant first-pass effect.4 Instead, sublingual (nitroglycerin), transcutaneous (topical), or rectal administration of drugs is used to bypass the portal circulation and avoid first-pass metabolism.

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Pharmacokinetic and Toxicokinetic Principles

Distribution

Absorption First-pass metabolism

Dissolution

Disintegration slowed by:product formulation such as sustained release, enteric coating

123

slowed by:acidic pH for weak acids,water insolubility,large particle siz e, concretions, bez oars

slowed by:decreased gastric emptying,increased ioniz ed drug, pylorospasm,fast small intestine transit time,decreased mesenteric blood flow

enzyme saturation, P450 or P glycoprotein inhibitors result in less first pass metabolism and increased bioavailability.

FIGURE 8–5. Determinants of absorption.

In the overdose setting, presystemic metabolism may be saturated, leading to an increased bioavailability of xenobiotics such as cyclic antidepressants, phenothiazines, opioids, and many β-adrenergic antagonists.56 Hepatic metabolism usually transforms the xenobiotic into a less-active metabolite but occasionally results in the formation of a more toxic agent such as occurs with the transformation of parathion to paraoxon.51 Biliary excretion into the small intestine usually occurs for these transformed xenobiotics of molecular weights greater than 350 daltons and may result in a xenobiotic appearing in the feces even though it had not been administered orally.34,54,67 Hepatic conjugated metabolites such as glucuronides may be hydrolyzed in the intestines to the parent form or to another active metabolite that can be reabsorbed by the enterohepatic circulation.41,49,52,54 The enterohepatic circulation may be responsible for what is termed a double-peak phenomenon after the administration of certain xenobiotics.64 The double-peak phenomenon is characterized as a serum concentration that decreases and then increases again as xenobiotic is reabsorbed from the GI tract. Other causes include variability in stomach emptying, presence of food, or failure of a tablet dosage form.64

DISTRIBUTION After the xenobiotic reaches the systemic circulation, it is available for transport to peripheral tissue compartments and to the liver and kidney for elimination. Both the rate and extent of distribution depend on many of the same principles discussed with regard to diffusion.

TABLE 8–2. Xenobiotics that Form Concretions or Bezoars, Delay Gastric Emptying, or Result in Pylorospasm Anticholinergics Barbiturates Bromides Enteric-coated tablets Glutethimide Iron

Meprobamate Methaqualone Opioids Phenytoin Salicylates Verapamil

Additional factors include affinity of the xenobiotic for plasma (plasma protein binding) and tissue proteins, acid–base status of the patient (which affects ionization), drug transporters, and physiologic barriers to distribution (blood–brain barrier, placental transfer, blood–testis barrier).23,35,58 Blood flow, the percentage of free drug in the plasma, and the activity of transporters account for the initial phase of distribution, and xenobiotic affinities determine the final distribution pattern. Whereas the adrenal glands, kidneys, liver, heart, and brain receive from 55 to 550 mL/min/100 g of tissue of blood flow, the skin, muscle, connective tissue, and fat receive 1 to 5 mL/min/100 g of tissue of blood flow.62 Hypoperfusion of the various organs in critically ill and injured patients affects absorption, distribution, and elimination.74 ABC transporters are active ATP-dependent transmembrane protein carriers of which P-glycoprotein was the initial example discovered.9 Approximately 50 ABC transporters exist, and they are divided into subfamilies based on their similarities. Several members of the ABC superfamily, including P-glycoprotein, are under extensive investigation because of their role in controlling xenobiotic entry into, distribution in, and elimination from the body as well as their contributions to drug interactions.21,32,73 The discovery of P-glycoprotein resulted from an investigation into why certain tumors exhibit multidrug resistance to many cancer chemotherapy agents. P-glycoprotein (ABCB1) as well as ABCC and ABCG2 are known to be efflux transporters located in the intestines, renal proximal tubules, hepatic bile canaliculi, placenta, and blood–brain barrier and are responsible for the intra- to extracellular transport of various xenobiotics.16 First-generation transport inhibitors such as amiodarone, ketoconazole, quinidine, and verapamil are responsible for increasing body levels of P-glycoprotein substrates such as digoxin, the protease inhibitors, vinca alkaloids, and paclitaxel. St. John’s wort is a transport inducer, and it lowers serum concentrations of these same xenobiotics. Second- and third-generation xenobiotics that will affect transport with a higher affinity and specificity are in development.18,65 Many of the same xenobiotics that affect cytochrome P450 (CYP) 3A4 also affect P-glycoprotein (Appendix Chapter 12: Cytochrome P450 Substrates Inhibitors and Inducers). Recently, the organic anion transporting polypeptides (OATPs) have been recognized as another group of transporters found in the liver, kidneys, intestines, brain, and placenta that are also responsible for affecting the absorption, distribution, and elimination of many xenobiotics and contributing to xenobiotic interactions. They include the organic anion transporters (OATs) and the organic cation transporters (OCTs).18 For example, probenecid increases the serum concentrations

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of penicillin by inhibiting the OAT responsible for the active secretion of penicillin by the renal tubular cells, and cimetidine inhibits the OCT responsible for the renal elimination of procainamide and metformin. A variety of OAT inhibitors are being investigated to decrease the hepatic uptake of amatoxins18 (Chap. 117). Plasma concentration and serum concentration are terms often used interchangeably by medical personnel. When a reference or calculation is made with regard to a concentration in the body, it is actually a plasma concentration. When concentrations are measured in the laboratory, a serum concentration (clotted and centrifuged blood) is often determined. In reality, the laboratory measurements of most xenobiotics in serum or plasma are nearly equivalent. Frequently, this is not the case for whole-blood determination if the xenobiotic distributes into the erythrocyte, such as lead and most other heavy metals. Volume of distribution (Vd) is the proportionality term used to relate the dose of the xenobiotic that the individual receives and the resultant plasma concentration. Vd is an apparent or theoretic volume into which a xenobiotic distributes. It is a measure of how much xenobiotic is located inside and outside of the plasma compartment because only the plasma compartment is routinely assayed. In a 70-kg man, the total body water (TBW) is 60% of total body weight, or 42 L, with two-thirds (28 L) of the fluid accounted for by intracellular fluid. Of the 14 L of extracellular fluid, 8 L is considered interstitial or between the cells; 3 L, or 0.04 L/kg, is plasma; and 6 L, or 0.08 L/kg, is blood. If 42 g of a xenobiotic is administered and remains in the plasma compartment (Vd = 0.04 L/kg), the concentration would be 15 g/L. If the distribution of the 42 g of xenobiotic approximated TBW (methanol; 0.6 L/kg), the concentration would be 100 mg/dL. These calculations can be performed by using Equation 8–6, where S equals the percent pure drug if a salt form is used. Vd =

S × F × Dose  (mg ) C0

(Eq. 8–6)

Experimental determination of Vd involves administering an IV dose of the xenobiotic and extrapolating the plasma concentration time curve back to time zero (C0). If the determination takes place after steady state has been achieved, the volume of distribution is then referred to as the Vdss. For many xenobiotics, the Vd is known and readily available in the literature (Table 8–3). When the Vd and the dose ingested are known, a maximum predicted plasma concentration can be calculated after assuming all of the xenobiotic is absorbed and no elimination occurred. This assumption usually overestimates the plasma concentration. Distribution is complex, and differential affinities for various storage sites, such as plasma proteins, liver, kidney, fat, and bone, in the body determine where a xenobiotic ultimately resides. For the purposes of determining the utility of extracorporeal removal of a xenobiotic, a low Vd is often considered to be less than 1 L/kg. For some xenobiotics, such as digoxin (Vd = 7 L/kg) and the cyclic antidepressants (Vd = 10–15 L/kg), the Vd is much larger than the actual volume of the body. A large Vd indicates that the xenobiotic resides outside of the plasma compartment, but again, it does not describe the site of distribution. The site of accumulation of a xenobiotic may or may not be a site of action or toxicity. If the site of accumulation is not a site of toxicity, then the storage depot may be relatively inactive, and the accumulation at that site may be theoretically protective to the animal or person.58 Selective accumulation of xenobiotics occurs in certain areas of the body because of affinity for certain tissue-binding proteins. For example, the kidney contains metallothionein, which has a high affinity for metals such as cadmium, lead, and mercury.23 The retina contains the pigment melanin, which binds and accumulates chlorpromazine, thioridazine,

and chloroquine.23 Other examples of xenobiotics accumulating at primary sites of toxicity are carbon monoxide binding to hemoglobin and myoglobin and paraquat distributing to type II alveolar cells in the lungs.55 Dichlorodiphenyltrichloroethane (DDT), chlordane, and polychlorinated biphenyls are stored in fat, which can be mobilized after starvation.77 Lead sequestered in bone33 is not immediately toxic, but mobilization of bone through an increase in osteoclastic activity58 (hyperparathyroidism, possibly pregnancy) may free lead for distribution to sites of toxicity in the central nervous system (CNS) or blood. Several plasma proteins bind xenobiotics and act as carriers and storage depots. The percentage of protein binding varies among xenobiotics, as do their affinities and potential for reversibility. After it is bound to plasma protein, a xenobiotic with high binding affinity will remain largely confined to the plasma until elimination occurs. However, dissociation and reassociation may occur if another carrier is available with a higher binding affinity. Most plasma measurements of xenobiotic concentration reflect total drug (bound plus unbound). Only the unbound drug is free to diffuse through membranes for distribution or for elimination. Albumin binds primarily to weakly acidic, poorly water-soluble xenobiotics, which include salicylates, phenytoin, and warfarin, as well as endogenous substances, including free fatty acids, cortisone, aldosterone, thyroxine, and unconjugated bilirubin.62 α1-Acid glycoprotein usually binds basic xenobiotics, including lidocaine, imipramine, and propranolol.62 Transferrin, a β1-globulin, transports iron, and ceruloplasmin carries copper. Phenytoin is an example of a xenobiotic whose effects are significantly influenced by changes in concentration of plasma albumin. Only free phenytoin is active. When albumin concentrations are in the normal range, approximately 90% of phenytoin is bound to albumin. As the albumin concentration decreases, more xenobiotic is free for distribution, and a greater clinical response to the same serum phenytoin concentration is often observed. The free plasma phenytoin concentration can be calculated based on the albumin concentration. This achieves an appropriate interpretation (adjusted) of total phenytoin within the conventional therapeutic range of 10 to 20 mg/L of free plus bound phenytoin (Eq. 8–7).

Adjusted   phenytoin  concentration =         

Ac t ual phenytoin  concentration   (0.25 × [albumin] ) + 0.1

(Eq. 8–7)

The clinical implications are that a malnourished patient with an albumin of 2 g/dL receiving phenytoin can manifest toxicity with a plasma phenytoin concentration of 14 mg/L. This measurement is total phenytoin (bound + unbound). Because the patient has a reduced albumin concentration, this actually represents a substantially higher proportion and absolute amount of active unbound phenytoin. Substitution into the above equation of 14 mg/L for actual plasma phenytoin concentration and 2 g/dL for albumin gives an adjusted plasma phenytoin concentration of 23.33 mg/L (therapeutic range, 10–20 mg/L). Although drug interactions are often attributed to the displacement of xenobiotics from plasma protein binding, concurrent metabolic interactions are usually more consequential. Displacement transiently increases the amount of unbound, active drug. This may result in an immediate increase in drug effect. This is followed by enhanced distribution and elimination of unbound drug. Gradually, the unbound plasma concentration returns to predisplacement concentrations.59 Saturation of plasma proteins may occur in the therapeutic range for a drug such as valproic acid. Acute saturation of plasma protein binding after an overdose often leads to consequential adverse effects. Saturation of plasma protein binding with salicylates and iron after

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Pharmacokinetic and Toxicokinetic Principles

TABLE 8–3. Pharmacokinetic Characteristics of Xenobiotics Associated with the Largest Number of Toxicologic Deaths Vd (L/kg)

Protein Binding (%)

Renal Elimination (% Unchanged)

Hepatic Metabolism (CYP)

Active Metabolite

Enterohepatic

Analgesics Acetaminophen

0.8–1.0

5–20

2

Aspirin

0.15–0.20

N-acetyl-pbenzoquinoneimine Salicylic acid

27%–42% excreted in bile None

Methadone Morphine

3.59 3–4

50–80 (salicylic 10 (pH dependent) acid) saturable 71–87 5–10 35 3A4)

Metabolized by microsomal enzymes Yes

None

Yes?

Yes

Yes

Yes

No

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overdose increase distribution to the CNS (salicylates) or to the liver, heart, and other tissues (iron), increasing toxicity. Specific therapeutic maneuvers in the overdose setting are designed to alter xenobiotic distribution by inactivating or enhancing elimination to limit toxicity. These therapeutic maneuvers include manipulation of serum or urine pH (salicylates), the use of chelators (lead), and the use of antibodies or antibody fragments (digoxin). The Vd permits predictions about plasma concentrations and assists in defining whether an extracorporeal method of removal is beneficial for a particular toxin. If the Vd is large (>1 L/ kg), it is unlikely that hemodialysis, hemoperfusion, or exchange transfusion would be effective because most of the xenobiotic is outside of the plasma compartment. Plasma protein binding also influences this decision. If the xenobiotic is more tightly bound to plasma proteins than to activated charcoal, then hemoperfusion is unlikely to be beneficial even if the Vd of the xenobiotic is small. In addition, high plasma protein binding limits the effectiveness of hemodialysis because only unbound xenobiotic will freely cross the dialysis membrane. Exchange transfusion can be effective for a xenobiotic with a small Vd and substantial plasma protein binding because both bound and free xenobiotic are removed simultaneously.

ELIMINATION Removal of a parent compound from the body (elimination) begins as soon as the xenobiotic is delivered to clearance organs such as the liver, kidneys, and lungs. Elimination begins immediately but may not be the predominant kinetic process until absorption and distribution are substantially completed. As expected, the functional integrity of the major organ systems, such as cardiovascular, pulmonary, renal, and hepatic systems, are major determinants of the efficiency of xenobiotic removal and of therapeutically administered antidotes. The xenobiotics themselves (eg, acetaminophen) may cause renal or hepatic failure, subsequently compromising their own elimination. Other factors that influence elimination include age (enzyme maturation), competition or inhibition of elimination processes by interacting xenobiotics, saturation of enzymatic processes, gender, genetics, obesity, and the physicochemical properties of the xenobiotic.46 Elimination can be accomplished by biotransformation to one or more metabolites or by excretion from the body of unchanged xenobiotic. Excretion may occur via the kidneys, lungs, GI tract, and body secretions (sweat, tears, milk).Because of their water solubility, hydrophilic (polar) or charged xenobiotics and their metabolites are generally excreted via the kidney. The majority of xenobiotic metabolism occurs in the liver, but it also commonly occurs in the blood, skin, GI tract, placenta, or kidneys. Lipophilic (noncharged or nonpolar) xenobiotics are usually metabolized in the liver to hydrophilic metabolites, which are then excreted by the kidneys.24,51 These metabolites are generally inactive, but if they are active, may contribute to toxicity. Examples of active metabolites include the metabolism of amitriptyline to nortriptyline, procainamide to N-acetylprocainamide, and meperidine to normeperidine. Metabolic reactions catalyzed by enzymes categorized as either phase I or phase II may result in pharmacologically active metabolites; frequently, the latter have different toxicities than the parent compounds. Phase I (asynthetic), or preparative metabolism, which may or may not precede phase II, is responsible for introducing polar groups onto nonpolar xenobiotics by oxidation (hydroxylation, dealkylation, deamination), reduction (alcohol dehydrogenase, azo reduction), and hydrolysis (ester hydrolysis). 22,49 Phase II, or synthetic reactions, conjugate the polar group with a glucuronide, sulfate, acetate, methyl or

glutathione; or amino acids such as glycine, taurine, and glutamic acid, creating less polar metabolites.14,22,49 Comparatively, phase II reactions produce a much larger increase in hydrophilicity than phase I reactions. The enzymes involved in these reactions have low substrate specificity, and those in the liver are usually localized to either the endoplasmic reticulum (microsomes) or the soluble fraction of the cytoplasm (cytosol).49 The location of the enzymes becomes important if they form reactive metabolites, which then concentrate at the site of metabolism and cause toxicity. For example, acetaminophen causes centrilobular necrosis because the CYP 2E1 enzymes, which form N-acetyl-p-benzoquinoneimine (NAPQI), the toxic metabolite, are located in their highest concentration in that zone of the liver. The enzymes that metabolize the largest variety of xenobiotics are heme-containing proteins referred to as CYP monooxygenase enzymes.28,49 This group of enzymes, formerly called the mixed function oxidase system, is found in abundance in the microsomal endoplasmic reticulum of the liver. These cytochrome P-450 metabolizing enzymes (CYPs) primarily catalyze the oxidation of xenobiotics. Cytochrome P450 in a reduced state (Fe2+) binds carbon monoxide. Its discovery and initial name resulted from spectral identification of the colored CO-bound cytochrome P450, which absorbs light maximally at 450 nm. The cytochrome P450 system is composed of many enzymes grouped according to their respective gene families and subfamilies, of which approximately 57 of these functional human genes have been sequenced. Members of a gene family have more than 40% similarity of their amino acid sequencing, and subfamilies have more than 55% similarity. For example, the CYP2D6*1a gene encodes wild-type protein (enzyme) CYP2D6, where 2 represents the family, D the subfamily and 6 the individual gene, and *1a the mutant allele; CYP2D6.1 represents the most common or wild-type allele. Toxicity may result from induction or inhibition of CYP enzymes by another xenobiotic, resulting in a consequential drug interaction (Chap. 12) Many of these interactions are predictable based on the known xenobiotic affinities and their capability to induce or inhibit the P450 system.12,42,49,50,66 However, polymorphism (individual genetic expression of enzymes),1 stereoisomer variability75(enantiomers with different potencies and isoenzyme affinities), and the capability to metabolize a xenobiotic by alternate pathways contribute to unexpected metabolic outcomes. The pharmaceutical industry is now exploiting the concept of chiral switching (marketing a single enantiomer instead of the racemic mixture) to alter efficacy or side effect profiles. Enantiomers are named either according to the direction in which they rotate polarized light (l or – for levorotatory, and d or + for dextrorotatory) or according to the absolute spatial orientation of the groups at the chiral center (S or R). Chiral means “hand” in Greek, and the latter designations refer to either sinister (left-handed) or rectus (right-handed). There is no direct correlation between levorotatory or dextrorotatory and S and R.70 The liver reduces the oral bioavailability of xenobiotics with high extraction ratios. The bioavailabilities of xenobiotics with high extraction ratios are greatly affected by enzyme induction and enzyme inhibition; the reverse is true for xenobiotics with a low extraction ratio. After the xenobiotic is in the blood, the hepatic elimination is affected by blood flow to the liver, the intrinsic hepatic metabolism, and plasma protein binding. If the hepatic metabolism of a xenobiotic is very high, then the only limit to hepatic clearance is blood flow to the liver, and protein binding is not an issue. However, if the intrinsic hepatic metabolism for a xenobiotic is low, then blood flow to the liver is not a consequential factor. Plasma protein binding becomes important because only unbound xenobiotics can be cleared by the liver. Because enzyme inhibition and induction greatly affect intrinsic hepatic metabolism, these factors are also important.

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Excretion is primarily accomplished by the kidneys, with biliary, pulmonary, and body fluid secretions contributing to lesser degrees. Urinary excretion occurs through glomerular filtration, tubular secretion, and passive tubular reabsorption. The glomerulus filters unbound xenobiotics of a particular size and shape in a manner that is not saturable (but is subject to renal blood flow and perfusion). Passive tubular reabsorption accounts for the reabsorption of noncharged, lipid-soluble xenobiotics and is therefore influenced by the pH of the urine and the pKa of the xenobiotic. The principles of diffusion discussed earlier permit, for example, the ion trapping of salicylate (pKa = 3.5) in the urine through urinary alkalinization. Tubular secretion is an active process carried out by drug transporters (OATs, OCTs) and subject to saturation and drug interactions (Table 8–4). Obesity is the accumulation of fat far in excess of that which is considered normal for a person’s age and gender. The National Institutes of Health defines obesity as a body mass index (BMI) greater than 30. The BMI is calculated by dividing a person’s weight in kilograms by the individual’s height in meters squared (m2). By this criterion, about one-third of the adult US population is obese. Obesity poses problems in determining the correct loading dose and maintenance dose for therapeutic xenobiotics and for the estimation of serum concentrations and elimination times in the overdose setting.10,26,39,48 A number of formulas have been proposed to classify body size in addition to BMI, but none have been tested adequately in the obese population. Obese patients have not only an increase in adipose tissue but also an increase in lean body mass of 20% to 55% which results in the alteration of the distribution of both lipophilic and hydrophilic xenobiotics. In general, the absorption of xenobiotics in obese patients does not appear to be affected, but distribution is affected. The effect of obesity on hepatic metabolism necessitates additional study, although some studies suggest a nonlinear increase in clearance. Glomerular filtration rate increases in obesity. For example, although aminoglycosides are hydrophilic, because of an increase in fat free mass in obese patients, a dosing weight correction of 40% is used to calculate both the loading dose and the maintenance dose (Dosing body weight = 0.4 × [Actual

TABLE 8–4. Xenobiotics Secreted by Renal Tubules Organic Anion Transport (OAT)

Organic Cation Transport (OCT)

Acetazolamide Bile salts Cephalosporins Indomethacin Hydrochlorothiazide Furosemide Methotrexate Penicillin G Probenecid Prostaglandins Salicylate

Acetylcholine Amiodarone Atropine Cimetidine Digoxin Diltiazem Dopamine Epinephrine Morphine Neostigmine Procainamide Quinidine Quinine Triamterene Trimethoprim Verapamil

Pharmacokinetic and Toxicokinetic Principles

127

TABLE 8–5. Equations for Determining Body Size BMI =

Weight (kg) Height (m 2 )

BSA (m 2 ) =

Height (cm) × Weight (kg) 3600

IBW: Males (kg) = 50 + 2.3 (Height > 60 inches) IBW: Females (kg) = 45.5 + 2.3 (Height > 60 inches) LBW2005: Males (kg) =

9270 × Weight (kg ) 6680 + [(216 × BMI(kg / m 2 )]

LBW2005: Females (kg) =

9270 × Weight (kg ) 8780 + [(244 × BMI(kg / m 2 )]

BMI, body mass index; BSA, body surface area; IBW, ideal body weight; LBW, lean body weight.

body weight – Ideal body weight] + Ideal body weight). Preliminary studies with propofol, a very lipophilic drug, suggest that induction and maintenance doses correlate better with actual body weight. These equations are found in Table 8–5. One recent hypothesis suggests using LBW2005 to simplify the calculation of maintenance doses.26

CLASSICAL VERSUS PHYSIOLOGIC COMPARTMENT TOXICOKINETICS Models exist to study and describe the movement of xenobiotics in the body with mathematical equations. Traditional compartmental models (one or two compartments) are data based and assume that changes in plasma concentrations represent tissue concentrations (Fig. 8–6).47 Advances in computer technology facilitate the use of the classic concepts developed in the late 1930s.69 Physiologic models consider the movement of xenobiotics based on known or theorized biologic processes and are unique for each xenobiotic. This allows the prediction of tissue concentrations while incorporating the effects of changing physiologic parameters and affording better extrapolation from laboratory animals.79 Unfortunately, physiologic modeling is still in its infancy, and the mathematical modeling it entails is often very complex.19 Regardless, the most commonly used mathematical equations are based on traditional compartmental modeling. The one-compartment model is the simplest approach for analytic purposes and is applied to xenobiotics that rapidly enter and distribute throughout the body. This model assumes that changes in plasma concentrations will result in and reflect proportional changes in tissue concentrations. Many xenobiotics, such as digoxin, lithium, and lidocaine, do not instantaneously equilibrate with the tissues and are better described by a two-compartment model. In the two-compartment model, a xenobiotic is distributed instantaneously to highly perfused tissues (central compartment) and then is secondarily, and more slowly, distributed to a peripheral compartment. Elimination is assumed to take place from the central compartment.

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Model 1. One-compartment open model, IV injection. ke 1 Model 2. One-compartment open model with first-order absorption. ka ke 1 Model 3. Two-compartment open model, IV injection. k12 1 2 k21 ke Model 4. Two-compartment open model with first-order absorption. k12 ka 1 2 k21 ke FIGURE 8–6. Various classical compartmental models. ke = pharmacokinetic rate constants; 1 = plasma or central compartment; 2 = tissue compartment; k12 = rate constant into tissue from plasma; k21 = rate constant into plasma from tissue; ka = absorption rate constant.

If the rate of a reaction is directly proportional to the concentration of xenobiotic, it is termed first order or linear. Processes that are capacity limited or saturable are termed nonlinear (not proportional to the concentration of xenobiotic) and are described by the Michaelis-Menten equation, which is derived from enzyme kinetics. Calculus is used to derive the first-order equation, as done by Yang and Andersen.79 Rate is directly proportional to concentration of xenobiotic, as in Equation 8–8.

Rate  α   concentration (C )

(Eq. 8–8)

An infinitesimal change in concentration of a xenobiotic (dC) with respect to an infinitesimal change in time (dt) is directly proportional to the concentration (C) of the xenobiotic as in Equation 8–9: dC   dt ∝ C

(Eq. 8–9)

The proportionality constant ke is added to the right side of the expression to mathematically allow the introduction of an equals sign. The constant ke represents all of the bodily factors, such as metabolism and excretion, that contribute to the determination of concentration (Eq. 8–10). dC = kC dt

(Eq. 8–10)

Introducing a negative sign to the left-hand side of the equation describes the “decay” or decreasing xenobiotic concentration (Eq. 8–11). −

dC = kC dt

(Eq. 8–11)

This equation is impractical because of the difficulty of measuring infinitesimal changes in C or t. Therefore, the use of calculus allows the integration or summing of all of the changes from one concentration to another beginning at time zero and terminating at time t. This relationship is mathematically represented by the integration sign (∫).∫ means to integrate the term from concentration at time zero (C0) to concentration at a given time t (Ct). ∫means the same with respect to time, where t0 = zero. Prior to this application, the previous equation is first rearranged (Eq. 8–12). dC = kdt C Ct t dC ∫C0 − C = k ∫t0 dt  −

(Eq. 8–12)

The integration of dC divided by C is the natural logarithm of C (ln C) and the integration of dt is t (Eq. 8–13). − In C

Ct t = kt t0 . C0

(Eq. 8–13)

The vertical straight lines proscribe the evaluation of the terms between those two limits. The following series of manipulations are then performed (Eq. 8–14A–D). −( InCt − InC0 ) = k(t − 0)

(Eq. 8–14A)

− InCt + InC0 = kt

(Eq. 8–14B)

− InCt = − InC0 + kt

(Eq. 8–14C)

InCt = InC0 − kt Ca n be Constant Ca n be mea sured selected

(Eq. 8–14D)

Equation 8–14D can be recognized as taking the form of an equation of a straight line (Eq. 8–15), where the slope is equal to the rate constant ke and the intercept is C0.

y = b + mx

(Eq. 8–15)

Instead of working with natural logarithms, an exponential form (the antilog) of Equation 8–14D may be used (Eq. 8–16).

Ct = C0e − kt

(Eq. 8–16)

Graphing the ln (natural logarithm) of the concentration of the xenobiotic at various times for a first-order reaction is a straight line. Equation 8–16 describes the events when only one first-order process occurs. This is appropriate for a one-compartment model (Fig. 8–7). In this model, regardless of the concentration of the xenobiotic, the rate (percentage) of decline is constant. The absolute amount of xenobiotic eliminated changes continuously while the percent eliminated remains constant. ke is reported in h−1. A ke of 0.10 h−1 means that the xenobiotic is being processed (eliminated) at a rate of 10% per hour. ke is often designated as ke and referred to as the elimination rate constant. The time necessary for the xenobiotic concentration to be reduced by 50% is called the half-life. The half-life is determined by

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Two-compartment model

B t (min)

ka

0 1 3 5 • • •

1 ke

C

In Ct

100 80 70 • • •

4.605 4.382 4.248 • • •

Ct = Ae-αt + Be-βt

D In Co

Co(or A)

4.6 4.4 4.2 4.0 5 t

k12 1

2

50 A B 10

Slope = -β

5 Slope = -α

k21

1

ke

Time

FIGURE 8–8. Mathematical and graphical forms of a two-compartment classical pharmacokinetic model. ka represents the absorption rate constant, ke represents the elimination rate constant, α represents the distribution phase, and β represents the elimination phase.

10 1

0

ka

100

ke = 2.303 × slope

100 Ct

In Ct

Ct (μg/mL)

Concentration

A

129

Pharmacokinetic and Toxicokinetic Principles

0

10

5 t

10

FIGURE 8–7. A one-compartment pharmacokinetic model demonstrating (A) graphical illustration, (B) hypothetical dataset, (C) linear plot, and (D) semilogarithmic plot.

equation used in enzyme kinetics (Eq. 8–20) in which v is the velocity or rate of the enzymatic reaction; C is the concentration of the xenobiotic; Vmax is the maximum velocity of the reaction between the enzyme and the xenobiotic; and Km is the affinity constant between the enzyme and the xenobiotic.79 V ×C v = max (Eq. 8–20) K +C m

a rearrangement of Equation 8–14D whereby C2 becomes C at time t2 and C1 becomes C at t1 and by rearrangement giving Equation 8–17:

(t1 − t2 ) =

(InC − InC ) 1

2

Application of this equation to toxicokinetics requires v to become the infinitesimal change in concentration of a xenobiotic (dC) with respect to an infinitesimal change in time (dt) as previously discussed (see Eq. 8–10). Vmax and Km both reflect the influences of diverse biologic processes. The Michaelis-Menten equation then becomes Equation 8–21, in which the negative sign again represents decay:

(Eq. 8–17)

dC Vmax × C = dt Km + C

ke

(Eq. 8–21)

Substitution of 2 for C1 and 1 for C2 or 100 for C1 and 50 for C2 gives Equations 8–18A and 8–18B:

t1/2 =

( In 2 − In1) ke

(Eq. 8–18A) 100 (Eq. 8–18B)

The use of semilog paper facilitates graphing the first-order equation. However, because semilog paper plots log (not ln) versus time, to retain appropriate mathematical relationships the rate constant or slope (k) must be divided by 2.303 (see Fig. 8–7). The mathematical modeling becomes more complex when more than one first-order process contributes to the overall elimination process. The equation that incorporates two first-order rates is used for a two-compartment model and is Equation 8–19. Ct = Ae − αt + Be −βt

Ct (mg/mL)

0.693 t1/2 = ke

Zero order dc - = Vmax dt

10

First order dC V - = max C Km dT

1

(Eq. 8–19)

Figure 8–8 demonstrates a two-compartment model where α often represents the distribution phase and β is the elimination phase. The rate of reaction of a saturable process is not linear (ie, not proportional to the concentration of xenobiotic) when saturation occurs (Fig. 8–9). This model is best described by the Michaelis-Menten

0.1 100

200 Time (min)

300

FIGURE 8–9. Concentration versus time curve for a xenobiotic showing nonlinear pharmacokinetics where concentrations below 10 mg/mL represent first-order elimination.

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TABLE 8–6A. Illustration of 1000 mg of Xenobiotic in Body After First-Order Elimination Time After Drug Administration (hour)

Amount of Drug in Body (mg)

Amount of Drug Eliminated Over Preceding Hour (mg)

Fraction of Drug Eliminated Over Preceding Hour

0 1 2 3 4 5 6

1000 850 723 614 522 444 377

— 150 127 109 92 78 67

— 0.15 0.15 0.15 0.15 0.15 0.15

When the concentration of the xenobiotic is very low (C Km), the rate becomes fixed at a constant maximal rate regardless of the exact concentration of the xenobiotic, termed a zero-order reaction. Tables 8–6A and 8–6B compare a first-order reaction with a zero-order reaction. In this particular example, zero order is faster, but if the fraction of xenobiotic eliminated in the first-order example were 0.4, then the amount of xenobiotic in the body would decrease below 100 before the

xenobiotic in the zero-order example. It is inappropriate to perform half-life calculations on a xenobiotic displaying zero-order behavior because the metabolic rates are continuously changing. After an overdose, enzyme saturation is a common occurrence because the capacity of enzyme systems is overwhelmed.

CLEARANCE Clearance (Cl) is the relationship between the rate of transfer or elimination of a xenobiotic from a reference fluid (usually plasma) to the plasma concentration of the xenobiotic and is expressed in units of volume per unit time mL/min (Eq. 8–23).25,47,61 Cl =

Rate  of  elimination Cp

(Eq. 8–23)

The determination of creatinine clearance is a well-known example of the concept of clearance. Creatinine clearance (ClCR) is determined by Equation 8–24: Clcreatinine =

U ×V Cp

(Eq. 8–24)

TABLE 8–6B. Illustration of 1000 mg of Xenobiotic in Body After Zero-Order Elimination Time After Drug Administration (hour)

Amount of Drug in Body (mg)

Amount of Drug Eliminated Over Preceding Hour (mg)

Fraction of Drug Eliminated Over Preceding Hour

0 1 2 3 4 5 6

1000 850 700 550 400 250 100

— 150 150 150 150 150 150

— 0.15 0.18 0.21 0.27 0.38 0.60

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in which U is the concentration of creatinine in urine (mg/mL); V is the volume flow of urine (mL/min); Cp is the plasma concentration of creatinine (mg/mL); and the units for clearance are millimeters per minute. A creatinine clearance of 100 mL/min means that 100 mL of plasma is completely cleared of creatinine every minute. Clearance for a particular eliminating organ or for extracorporeal elimination is calculated with Equation 8–25:

Pharmacokinetic and Toxicokinetic Principles

131

Compartment model ke

VD, CP

Static volume and first-order elimination is assumed. Plasma flow is not considered. ClT = ke VD. Physiologic model

Cl = Qb × ( ER ) = Qb × Cl Qb ER Cin

(Cin − Cout ) Cin

(Eq. 8–25)

= = = =

clearance for the eliminating organ or extracorporeal device blood flow to the organ or device extraction ratio xenobiotic concentration in fluid (blood or serum) entering the organ or device Cout = xenobiotic concentration in fluid (blood or serum) leaving the organ or device Clearance can be applied to any elimination process independent of the precise mechanisms (ie, first-order, Michaelis-Menten) and represents the sum total of all of the rate constants for xenobiotic elimination. Total body clearance (Cltotal body) is the sum of the clearances of all of the individual eliminating processes, as seen in Equation 8–26: Cltotal   body = Clrenal + Clhepatic + Clintestinal + Clchelation + ⋅⋅⋅

(Eq. 8–27)

Experimentally, the clearance can be derived by examining the IV dose of xenobiotic in relation to the AUC from time zero to time t (Eq. 8–28). The AUC is calculated using the trapezoidal rule or through integral calculus (units, eg, mg/mL) (Figs. 8–10 and 8–11). Cl =

doseIV

(Eq. 8–28)

AUC0−t

Qp Cv

Elimination Clearance is the product of the plasma flow (Qp) and the extraction ratio (ER). Thus, ClT = Qp ER. Model independent ?V, CP

ke

Volume and elimination rate constant not defined. ClT = Dose ÷ [AUC]∝ 0. FIGURE 8–11. General approaches to clearance.

(Eq. 8–26)

For a first-order process (one-compartment model), clearance is given by Equation 8–27: Cl = keVd

Qp Ca

STEADY STATE When exposure to a xenobiotic occurs at a fixed rate, the plasma concentration of the xenobiotic gradually achieves a plateau level at a concentration at which the rate of absorption equals the rate of elimination and is termed steady state. The time to achieve 95% of steady-state concentration for a first-order process is dependent on the half-life and usually necessitates 5 half-lives. The concentration achieved at steady state depends on the Vd, the rate of exposure, and the half-life. Iatrogenic toxicity may occur in the therapeutic setting when dosing decisions are based on plasma concentrations determined before achieving a steady state. This adverse event is particularly common when using xenobiotics with long half-lives such as digoxin78 and phenytoin.

Concentration

PEAK PLASMA CONCENTRATIONS

=AUC

Time FIGURE 8–10. The AUC profile obtained after extravascular administration of a xenobiotic.

Peak plasma concentrations (Cmax) of a xenobiotic occur at the time of peak absorption. At this point in time, the absorption rate is at least equal to the elimination rate. Thereafter, the elimination rate predominates, and plasma concentrations begin to decline. Whereas the Cmax depends on the dose, the rate of absorption (ka), and the rate of elimination (ke), the time to peak (tmax) is independent of dose and only depends on the ka and ke. For the same dose of xenobiotic, if the ke remains constant and the rate of absorption decreases, then the tmax (see Table 8–7) will occur later and the Cmax will be slightly lower. Controlled-release dosage forms and xenobiotics that form concretions and have a decreased rate of absorption may not achieve peak concentrations until many hours after an immediate-release preparation with rapid absorption. The AUC will remain the same. However if the ka remains constant and the ke is increased, then the tmax occurs sooner, the Cmax decreases, and the AUC decreases (Table 8–7).52 Values are based on a single oral dose (100 mg) that is 100% bioavailable (F = 1) and has an apparent Vd of 10 L. The drug follows a

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Vi TABLE 8–7. Pharmacokinetic Effects of the Absorption Rate Constant and Elimination Rate Constanta Absorption Rate Constant ka (h−1)

Elimination Rate Constant ke (h−1)

tmax (h)

Cmax (μg/mL)

AUC (μg·hr/mL)

0.1 0.2 0.3 0.4 0.5 0.6 0.3 0.3 0.3 0.3 0.3

0.2 0.1 0.1 0.1 0.1 0.1 0.1 0.2 0.3 0.4 0.5

6.93 6.93 5.49 4.62 4.02 3.58 5.49 4.05 3.33 2.88 2.55

2.50 5.00 5.77 6.26 6.69 6.69 5.77 4.44 3.68 3.16 2.79

50 100 100 100 100 100 100 50 33.3 25 20

A

10 ng/mL

B

5.5 ng/mL

C

3.25 ng/mL

D

2.125 ng/mL

E

1 ng/mL

AUC, area under the (plasma drug concentration versus time) curve; Cmax, peak xenobiotic concentration; tmax, time to peak plasma concentration; Reprinted with permission from Shargel L, Yu A: Pharmacokinetics of drug absorption. In: Applied Biopharmaceutics and Pharmacokinetics, 3rd ed. Norwalk, CT: Appleton & Lange; 1993:183.

one-compartment open model. The AUC is calculated by the trapezoidal rule from 0 to 24 hours. In the overdose setting, gastric emptying, single-dose activated charcoal, and WBI decrease ka. Multiple-dose activated charcoal, manipulation of pH to promote ion trapping to facilitate elimination, and certain chelators (ie, succimer, deferoxamine) increase ke and are likely to decrease Cmax, tmax, and AUC.

INTERPRETATION OF PLASMA CONCENTRATIONS For plasma concentrations to have significance, there must be an established relationship between effect and plasma concentration. Many medications, such as phenytoin, digoxin, carbamazepine, and theophylline, have an established therapeutic range. However, there are also many drugs (eg, diazepam, propranolol, verapamil) for which there is no established therapeutic range. Some xenobiotics (eg, physostigmine) exhibit hysteresis in which the effect increases as the plasma concentration decreases. For many xenobiotics, very little information on toxicodynamics is available. Sequential plasma concentrations often are collected for retrospective analysis in an attempt to correlate plasma concentrations and toxicity. Tolerance to drugs, such as ethanol, also influences the interpretation of plasma concentrations. Tolerance is an example of a pharmacodynamic or toxicodynamic effect as a result of cellular adaptation, and it occurs when larger doses of a xenobiotic are necessary to achieve the same clinical or pharmacologic result. Other factors that influence the interpretation of plasma concentrations include chronicity of dosing (a single dose versus multiple doses); whether absorption is still ongoing and therefore concentrations are still increasing; whether distribution is still ongoing and therefore concentrations are uninterpretable (Fig. 8–12); or whether the value is a peak, trough, or steady-state concentration. Clinical examples in

α t1/2 =35 min

Vt

t =0 0.0 ng/mL

t =35 min 0.5 ng/mL

t =70 min 0.75 ng/mL

t =105 min 0.875 ng/mL

t =3–4 hr 1 ng/mL

FIGURE 8–12. A theoretical two-compartment model for digoxin. Assume A-E represents the digoxin serum concentration equilibrium at different t (time) intervals between the plasma compartment and the tissue compartment. Vi (initial volume of distribution) is smaller than Vt (tissue volume of distribution). The myocardium sits in Vt. E represents distribution at 5 half lives and it is assumed that the plasma and tissue compartments are now in equilibrium.78 (Winter ME: Digoxin. In: Koda-Kimble MA, Young LY, eds. Basic Clinical Pharmacokinetics, 3rd ed. Vancouver, WA: Applied Therapeutics; 1994: 198-235.)

which interpretation is dependent on the dosing pattern of a single dose versus multiple doses include theophylline, digoxin, lithium, and acetaminophen. Controlled-release preparations and xenobiotics that delay gastric emptying or form concretions are expected to have prolonged absorptive phases and require serial plasma concentrations to obtain a meaningful analysis of plasma concentrations (Chap. 6). A combination of trough, peak, and minimum inhibitory concentrations is often consequential for monitoring antibiotics such as gentamicin.8,43 Pitfalls in interpretation arise when the units for a particular plasma concentration are not obtained or are unfamiliar (eg, mmol/L) to the clinician. In the overdose setting, the type of analysis used is not generally applied to such large concentrations, the laboratory may make errors in dilution, or errors can be inherent in the assay (Chap. 6). In these cases, the director of the laboratory should be consulted for advice with regard to the need for a reference laboratory. The type of collection tube (eg, plasma or serum instead of whole blood for certain metals), or receptacle, or the conditions during delivery of the sample may give rise to inaccurate or inadequate information. When in doubt, the laboratory should be called before sample collection. The laboratory usually measures total xenobiotic (free plus bound), and for agents

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that are highly plasma protein bound, reductions in albumin increase free concentrations and alter the interpretation of the reported value (see Eq. 8–7). Active metabolites may contribute to toxicity and may not be measured.37 Collection of accurate data for analysis requires at least 4 data points during 1 elimination half-life. During extracorporeal methods of elimination, ideal criteria for determining the amount removed require assay of the dialysate or charcoal cartridge or multiple simultaneous serum concentrations going into and out of the device rather than random serum concentrations. Clearance calculations for drugs such as lithium that partition significantly into the red cells are more accurate when measurements are taken on whole blood.13,20 The patient’s weight and height and, when indicated, hemoglobin, creatinine, albumin, and other parameters to assess elimination pathways, may be helpful.

REFERENCES 1. Bertilsson L: Geographical/interracial differences in polymorphic drug oxidation. Clin Pharmacokinet. 1995;29:192-209. 2. Blaschke TF, Rubin PC: Hepatic first-pass metabolism in liver disease. Clin Pharmacokinet. 1979;4:423-432. 3. Bodenham A, Shelly MP, Park GR: The altered pharmacokinetics and pharmacodynamics of drugs commonly used in critically ill patients. Clin Pharmacokinet. 1988;14:347-373. 4. Bosse GM, Matyunas NJ: Delayed toxidromes. J Emerg Med. 1999;17:679-690. 5. Boyes RN, Scott DB, Jebson PJ, et al: Pharmacokinetics of lidocaine in man. Clin Pharmacol Ther. 1971;12:105-116. 6. Brubacher J, Dahghani P, McKnight D: Delayed toxicity following ingestion of enteric-coated divalproex sodium. J Emerg Med. 1999;3:463-467. 7. Buckley N, Dawson A, Reith D: Controlled-release drugs in overdose. Drug Saf. 1995;12:73-84. 8. Burgess D: Pharmacodynamic principles of antimicrobial therapy in the prevention of resistance. Chest. 1999;115:19S-23S. 9. Calcagno A, Kim I, Wu C, et al: ABC drug transporters as molecular targets for the prevention of multidrug resistance and drug-drug interactions. Curr Drug Deliv. 2007;4:324-333. 10. Casati A, Putzu M: Anesthesia in the obese patient: pharmacokinetic considerations. J Clin Anesth. 2005;17:134-145. 11. Chaikin P, Adir J: Unusual absorption profile of phenytoin in a massive overdose case. J Clin Pharmacol. 1987;27:70-73. 12. Ciummo PE, Katz NL: Interactions and drug metabolizing enzymes. Am Pharm. 1995;9:41-51. 13. Clendenin N, Pond S, Kaysen G, et al: Potential pitfalls in the evaluation of the usefulness of hemodialysis for the removal of lithium. J Toxicol Clin Toxicol. 1982;19:341-352. 14. Dauterman WC: Metabolism of toxicants: phase II reactions. In: Hodgson E, Levi P, eds. Introduction to Biochemical Toxicology. Norwalk, CT: Appleton & Lange; 1994:113-132. 15. Dean B, Oehme FW, Krenzelok E: A study of iron complexation in a swine model. Vet Hum Toxicol. 1988;30:313-315. 16. de Boer AG, van der Sandt IC, Gaillard PJ: The role of drug transporters at the blood–brain barrier. Annu Rev Pharmacol Toxicol. 2003;43:629-656. 17. DeGeorge JJ: Food and drug administration viewpoints on toxicokinetics: the view from review. Toxicol Pathol. 1995;23:220-225. 18. Endres CJ, Hsiao P, Chung FS, et al: The role of transporters in drug interactions. Eur J Pharm Sci. 2006;27:501-517. 19. Engasser JM, Sarhan F, Falcoz C, et al: Distribution, metabolism and elimination of phenobarbital in rats: Physiologically based pharmacokinetic model. J Pharm Sci. 1981;70:1233-1238. 20. Ferron G, Debray M, Buneaux F, et al: Pharmacokinetics of lithium in plasma and red blood cells in acute and chronic intoxicated patients. Int J Clin Pharmacol Ther. 1995;33:351-355. 21. Fromm MF: Importance of P-glycoprotein at blood–tissue barriers. Trends Pharmacol Sci. 2004;25:423-429. 22. Gillette JR: Factors affecting drug metabolism. Ann N Y Acad Sci. 1971;179:43-66. 23. Gram TE: Drug absorption and distribution. In: Craig CR, Stitzel RE, eds. Modern Pharmacology with Clinical Applications. Boston: Little, Brown; 1997:13.

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24. Guengerich FP, Liebler DC: Enzymatic activation of chemicals to toxic metabolites. Crit Rev Toxicol. 1985;14:259-307. 25. Gwilt PR: Pharmacokinetics. In: Craig CR, Stitzel RE, eds. Modern Pharmacology with Clinical Applications. Boston: Little, Brown; 1997:49-58. 26. Han PY, Duffull SB, Kirkpatrick CMJ, et al: Dosing in obesity: a simple solution to a big problem. Clin Pharmacol Ther. 2007;82:505-508. 27. Hill HZ, Backer R, Hill GJ: Blood cyanide levels in mice after administration of amygdalin. Biopharm Drug Dispos. 1980;1:211-220. 28. Hodgson E, Levi PE: Metabolism of toxicants phase I reactions. In: Hodgson E, Levi P, eds. Introduction to Biochemical Toxicology. Norwalk, CT: Appleton & Lange; 1994:75-111. 29. Iberti T, Patterson B, Fisher C: Prolonged bromide intoxication resulting from a gastric bezoar. Arch Intern Med. 1984;144:402-403. 30. Jenis EH, Payne RJ, Goldbaum LR: Acute meprobamate poisoning: a fatal case following a lucid interval. JAMA. 1969;207:361-365. 31. Kapoor SC, Wielopolski L, Graziano JH, LoIacono NJ: Influence of 2,3-dimercaptosuccinic acid on gastrointestinal lead absorption and wholebody lead retention. Toxicol Appl Pharmacol. 1989;97:525-529. 32. Kivisto KT, Niemi M, Fromm MF: Functional interaction of intestinal CYP3A4 and P-glycoprotein. Fundam Clin Pharmacol. 2004;8:621-626. 33. Klaassen CD, Shoeman DW: Biliary excretion of lead in rats, rabbits and dogs. Toxicol Appl Pharmacol. 1974;29:436-446. 34. Klaassen CD, Watkins JB: Mechanisms of bile formation, hepatic uptake, and biliary excretion. Pharmacol Rev. 1984;36:1-67. 35. Klotz U: Pathophysiological and disease-induced changes in drug distribution volume: pharmacokinetic implications. Clin Pharmacokinet. 1976;1:204-218. 36. Koch-Weser J: Bioavailability of drugs. Part I. N Engl J Med. 1974;291:233-237. 37. Koch-Weser J: Bioavailability of drugs. Part II. N Engl J Med. 1974;291:503-506. 38. Kwan KC: Oral bioavailability and first-pass effects. Drug Metab Dispos. 1997;25:1329-1336. 39. Lee J, Winstead P, Cook A: Pharmacokinetic changes in obesity. Orthopedics. 2006;29:984-988. 40. Lemmer B, Bruguerolle B: Chronopharmacokinetics, are they clinically relevant? Clin Pharmacokinet. 1994;26:419-427. 41. Levine WG: Biliary excretion of drugs and other xenobiotics. Ann Rev Pharmacol. Toxicol 1978;18:81-96. 42. Levy R, Thummel K, Trager W, et al, eds. Metabolic Drug Interactions. Philadelphia: Lippincott Williams & Wilkins; 2000. 43. Li R, Zhu M, Shentag J: Achieving optimal outcome in the treatment of infections. Clin Pharmacokinet. 1999;37:1-16. 44. Lin JH, Yamazaki M: Role of P-glycoprotein in pharmacokinetics: Clinical implications. Clin Pharmacokinet. 2003;42:59-98. 45. Marik P, Varon J: The obese patient in the ICU. Chest. 1998;113:492-498. 46. McCarthy J, Gram TE: Drug metabolism and disposition in pediatric and gerontological stages of life. In: Craig CR, Stitzel RE, eds. Modern Pharmacology with Clinical Applications. Boston: Little, Brown; 1997:43-48. 47. Medinsky MA, Klaassen CD: Toxicokinetics. In: Klaassen CD, ed. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 5th ed. New York, McGraw-Hill; 1996:187-198. 48. Pai MP, Bearden DT: Antimicrobial dosing considerations in obese adult patients. Pharmacotherapy. 2007;27:1081-1091. 49. Parkinson A: Biotransformation of xenobiotics. In: Klaassen C, ed. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 5th ed. New York: McGraw-Hill; 1996:113-186. 50. Pharmacist’s Letter. Stockton, CA: Pharmacy Information Services, University of the Pacific, June 1985. 51. Pirmohamed M, Kitteringham NR, Park BK: The role of active metabolites in drug toxicity. Drug Saf. 1994;11:114-144. 52. Plaa OL: The enterohepatic circulation. In: Gillette JR, Mitchell JR, eds. Handbook of Experimental Pharmacology. New York: Springer; 1975:28, 130-140, 480. 53. Pond SM, Tozer TN: First-pass elimination: basic concepts and clinical consequences. Pharmacokinetics. 1984;9:1-25. 54. Riviere JE: Absorption and distribution. In: Hodgson E, Levi P, eds. Introduction to Biochemical Toxicology. Norwalk, CT: Appleton & Lange; 1994:11-48. 55. Rose MS, Lock EA, Smith LL, Wyatt I: Paraquat accumulation: tissue and species specificity. Biochem Pharmacol. 1976;25:419-423. 56. Rosenberg J, Benowitz NL, Pond S: Pharmacokinetics of drug overdose. Clin Pharmacokinet. 1981;6:161-192. 57. Rowland M, Tozer TN: Clinical Pharmacokinetics Concepts & Applications, 2nd ed. Philadelphia, Lea & Febiger; 1989.

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58. Rozman KK, Klaassen CD: Absorption, distribution and excretion of toxicants. In: Klaassen CD, ed. Casarett & Doull’s Toxicology: The Basic Science of Poisons. New York: McGraw-Hill; 1996:91-112. 59. Sansom LN, Evans AM: What is the true clinical significance of plasma protein binding displacement interactions? Drug Saf. 1995;12:227-233. 60. Schwartz MD, Morgan BW: Massive verapamil pharmacobezoar resulting in esophageal perforation. Int J Med Toxicol. 2004;7:4. 61. Shargel L, Wu-Pong S, Yu A: Drug elimination and clearance. In: Applied Biopharmaceutics and Pharmacokinetics, 5th ed. New York: McGraw-Hill; 2005:131-160. 62. Shargel L, Wu-Pong S, Yu A: Physiologic drug distribution and protein binding. In: Applied Biopharmaceutics and Pharmacokinetics, 5th ed. New York: McGraw-Hill; 2005:251-301. 63. Shargel L, Wu-Pong S, Yu A: Pharmacokinetics of oral absorption. In: Applied Biopharmaceutics and Pharmacokinetics, 5th ed. New York: McGraw-Hill; 2005:pp. 161-184. 64. Shargel L, Wu-Pong S, Yu A: Physiologic factors related to drug absorption. In: Applied Biopharmaceutics and Pharmacokinetics, 5th ed. New York: McGraw-Hill; 2005:371-408. 65. Silverman J: P-Glycoprotein. In: Levy R, Thummel K, Trager W, et al, eds. Metabolic Drug Interactions. Philadelphia: Lippincott Williams & Wilkins; 2000:135-144. 66. Slaughter RL, Edwards DJ: Recent advances: the cytochrome P450 enzymes. Ann Pharmacother. 1995;29:619-623. 67. Stowe CM, Plaa GL: Extrarenal excretion of drugs and chemicals. Annu Rev Pharmacol. 1968;8:337-356. 68. Sue Y, Shannon M: Pharmacokinetics of drugs in overdose. Clin Pharmacokinet. 1992;23:93-105.

69. Teorell T. Kinetics of distribution of substances administered to the body: I. The extravascular modes of administration. Arch Intern Pharmacodyn 1937;57:205–225. 70. Tucker G: Chiral switches. Lancet. 2000;355:1085-1087. 71. Verebey K, Gold MS: From coca leaves to crack: the effect of dose and routes of administration in abuse liability. Psychiatr Ann. 1988;18:513-520. 72. Vesell ES: The model drug approach in clinical pharmacology. Clin Pharmacol Ther. 1991;50:239-248. 73. von Richter O, Burk O, Fromm MF, et al: Cytochrome P450 3A4 and P-glycoprotein expression in human small intestinal enterocytes and hepatocytes: a comparative analysis in paired tissue specimens. Clin Pharmacol Ther. 2004;75:172-183. 74. Wagner B, O’Hara D: Pharmacokinetics and pharmacodynamics of sedatives and analgesics in the treatment of agitated critically ill patients. Clin Pharmacokinet. 1997;33:426-453. 75. Welling PG: Differences between pharmacokinetics and toxicokinetics. Toxicol Pathol. 1995;23:143-147. 76. Wilkinson GR: Influence of hepatic disease on pharmacokinetics. In: Evans WE, Schentag J, Justo W, eds. Applied Pharmacokinetics: Principles of Therapeutic Drug Monitoring. Spokane, WA: Applied Therapeutics; 1986:116-138. 77. Wilkinson GR: Plasma and tissue binding considerations in drug disposition. Drug Metab Rev. 1983;14:427-465. 78. Winter ME: Digoxin. In: Koda-Kimble MA, Young LY, eds. Basic Clinical Pharmacokinetics, 3rd ed. Vancouver, WA: Applied Therapeutics; 1994:198-235. 79. Yang R, Andersen M: Pharmacokinetics. In: Hodgson E, Levi P, eds. Introduction to Biochemical Toxicology. Norwalk, CT: Appleton & Lange; 1994:49-73.

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PRINCIPLES AND TECHNIQUES APPLIED TO ENHANCE ELIMINATION David S. Goldfarb Enhancing the elimination of a xenobiotic from a poisoned patient is a logical step after techniques to inhibit absorption such as orogastric lavage, activated charcoal, or whole-bowel irrigation have been considered. Table 9–1 lists methods that might be used to enhance elimination. Some of these techniques are described in more detail in chapters that deal with specific xenobiotics. In this chapter, hemodialysis, hemoperfusion, and hemofiltration are considered extracorporeal therapies because xenobiotic removal occurs in a blood circuit outside the body. Currently these methods are used infrequently as intensive supportive care because most poisonings are not amenable to removal by these methods. Because these elimination techniques have associated adverse effects and complications, they are indicated in only a relatively small proportion of patients.

EPIDEMIOLOGY Although undoubtedly an underestimate of true use, enhancement of elimination was used relatively infrequently in a cohort of more than 2.4 million patients reported by the American Association of Poison Control Centers (AAPCC) National Poison Data System (NPDS) in 2007 (Chap. 135)31. Alkalinization of the urine was reportedly used 9430 times, MDAC 3114 times, hemodialysis 2106 times, hemoperfusion 16 times, and “other extracorporeal procedures” (most likely continuous venovenous hemofiltration [CVVH]) 24 times. As in the past, there continue to be many instances of the use of extracorporeal therapies that are considered inappropriate, such as in the treatment of overdoses of cyclic antidepressants (CAs) or acetaminophen.31 Although data reporting remains important in comparing the most recent data with past reports (Table 9–2), there is a continued increase in the reported use of hemodialysis, paralleling a decline in reports of charcoal hemoperfusion (Chap. 135). Lithium and ethylene glycol were the most common xenobiotics for which hemodialysis was used between 1985 and 2005. Possible reasons for the decline in use of charcoal hemoperfusion are described in the Charcoal Hemoperfusion section below. Various resins and other sorbents once used for hemoperfusion are not currently available in the United States. Peritoneal dialysis (PD), a slower modality that should have little or no role in any poisonings, is no longer separately reported (Chap. 135). “Other extracorporeal procedures” in the AAPCC reports are probably continuous modalities (discussed below in the section Continuous Hemofiltration and Hemodiafiltration) and may include some cases in which PD was used. Very few prospective, randomized, controlled clinical trials have been conducted to determine which groups of patients actually benefit from enhanced elimination of various xenobiotics and which modalities are most efficacious. For most poisonings, it is unlikely that such studies will ever be performed, given the relative scarcity of appropriate cases of sufficient severity and because of the many variables that

would hinder controlled comparisons. Thus, limited evidence predominates. We must therefore rely on an understanding of the principles of these methods to identify the individual patients for whom enhanced elimination is indicated. Isolated case reports in which the kinetics are studied before, during, and after enhanced elimination are also very useful in establishing the efficacy of a method.

GENERAL INDICATIONS FOR ENHANCED ELIMINATION Enhanced elimination may be indicated for several types of patients: • Patients who fail to respond adequately to full supportive care. Such patients may have intractable hypotension, heart failure, seizures, metabolic acidosis, or dysrhythmias. Hemodialysis or hemoperfusion are much better tolerated than in the past and may represent potentially life-saving opportunities for patients with life-threatening toxicity caused by theophylline, lithium, salicylates, or toxic alcohols. • Patients in whom the normal route of elimination of the xenobiotic is impaired. Such patients may have renal or hepatic dysfunction, either preexisting or caused by the overdose. For example, a patient with chronic renal insufficiency associated with long-term lithium use is more likely to develop lithium toxicity and then require hemodialysis as therapy. • Patients in whom the amount of xenobiotic absorbed or its high concentration in serum indicates that serious morbidity or mortality is likely. Such patients may not appear acutely ill on initial evaluation. Xenobiotics in this group may include ethylene glycol, lithium, methanol, paraquat, salicylate, and theophylline. • Patients with concurrent disease or in an age group (very young or old) associated with increased risk of morbidity or mortality from the overdose. Such patients are intolerant of prolonged coma, immobility, and hemodynamic instability. An example is a patient with both severe underlying respiratory disease and chronic salicylate poisoning. • Patients with concomitant electrolyte disorders that could be corrected with hemodialysis. An example is the lactic acidosis associated with metformin toxicity discussed in the Hemodialysis section of this chapter. Ideally, these techniques will be applied to poisonings for which studies suggest an improvement in outcome in treated patients compared with patients not treated with extracorporeal removal. As previously mentioned, these data are rarely available.25 The need for extracorporeal elimination is less clear for patients who are poisoned with xenobiotics that are known to be removed by the various modalities of treatment but that cause limited morbidity if supportive care is provided. Relatively high rates of endogenous clearance would also make extracorporeal elimination redundant. Examples of such xenobiotics include ethanol and barbiturates. Both are subject to substantial rates of hepatic metabolism, and neither would be expected to lead to significant morbidity after the affected patient has been endotracheally intubated and is mechanically ventilated. There may be instances of severe toxicity from these two xenobiotics for which enhanced elimination will reduce the length of intensive care unit (ICU) stays and the associated nosocomial risks; extracorporeal elimination may then be a reasonable option.8,50 Dialysis should be avoided if other more effective modalities are available. For example, patients with acetaminophen overdoses should be treated with N-acetylcysteine instead of with hemodialysis.

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TABLE 9–1. Potential Methods of Enhancing Elimination of Xenobiotics Cerebrospinal fluid drainage and replacement Chelation Cholestyramine Colestipol Continuous hemo(dia)filtration Diuresis Exchange transfusion Hemodialysis Sodium polystyrene sulfonate (Kayexalate) Manipulation of urinary pH Multiple-dose activated charcoal Nasogastric suction Peritoneal dialysis Plasmapheresis Sorbent hemoperfusion (charcoal, others) Xenobiotic-specific antibody fragments Whole-bowel irrigation

CHARACTERISTICS OF XENOBIOTICS APPROPRIATE FOR EXTRACORPOREAL THERAPY The appropriateness of any modality for increasing the elimination of a given xenobiotic depends on various properties of the molecules in question. Effective removal by the extracorporeal procedures and other methods listed in Table 9–1 is limited by a large volume of distribution (Vd). The Vd relates the concentration of the xenobiotic in the blood or serum to the total body burden. The Vd can be envisioned as the apparent volume in which a known total dose of drug is distributed before metabolism and excretion occur: Vd (L/kg) × patient weight (kg) = Dose (mg)/Concentration (mg/L) The larger the Vd, the less the xenobiotic is available to the blood compartment for elimination. A xenobiotic with a relatively small Vd, considered amenable to extracorporeal elimination, would distribute

TABLE 9–2. Changes in Use of Extracorporeal Therapiesa

Hemodialysis Charcoal hemoperfusion Resin Peritoneal dialysis Other extracorporeal: CVVH, CVVHD, etc a

1986

1990

2001

2004

2007

297 99 23 62

584 111 37 27

1280 45

1726 20

2106 16

26

33

24

Data derived from American Association of Poison Control Centers annual reports (Chap. 135).

in an apparent volume not much larger than total body water (TBW). TBW is approximately 60% of total body weight, so a Vd equal to TBW is approximately 0.6 L/kg body weight. Ethanol is an example of a xenobiotic with a small Vd approximately equal to TBW. A substantial fraction of a dose of ethanol could be removed by hemodialysis. In contrast, an insignificant fraction of digoxin with a large Vd (5–12 L/kg of body weight) would be removed by this therapy. Lipid-soluble xenobiotics and those that are highly protein bound have large volumes of distribution, which can exceed TBW or even total body weight. These high apparent volumes of distribution imply that the xenobiotic is not available to extracorporeal removal because only a small portion would be in the blood and therefore the extracorporeal circuit. In addition to the alcohols, other xenobiotics with a relatively low Vd include phenobarbital, lithium, salicylates, bromide and fluoride ions, and theophylline. Conversely, those with a high Vd (≥1 L/kg of body weight), which would not be removed substantially by hemodialysis, include many β-adrenergic antagonists (with the possible exception of atenolol59), diazepam, organic phosphorus compounds, phenothiazines, quinidine, and the cyclic antidepressants. Pharmacokinetics also influence the ability to enhance elimination of a xenobiotic. Kinetic parameters after an overdose may differ from those after therapeutic or experimental doses. For instance, carrieror enzyme-mediated elimination processes may be overwhelmed by higher concentrations of the xenobiotic in question, making extracorporeal removal potentially more useful. Similarly, plasma protein- and tissue-binding sites may all be saturated at higher concentrations, making extracorporeal removal feasible in instances in which it would have no role in less significant overdoses. An example is valproic acid, which may be poorly dialyzed at nontoxic concentrations because of high rates of protein binding (although dialysis is rarely indicated). However, higher, potentially toxic concentrations saturate proteinbinding sites and lead to a higher proportion of the drug free in the serum, amenable to removal by hemodialysis at a clinically relevant rate.35 Estimates of the expected endogenous rates of elimination of a xenobiotic in the setting of an overdose should be made, wherever possible, from knowledge of the toxicokinetic characteristics derived from obtained in relevant models of toxicity, not after therapeutic doses. When assessing the efficacy of any technique of enhanced elimination, a generally accepted principle is that the intervention is worthwhile only if the total body clearance of the xenobiotic is increased by at least 30%.17 This substantial increase is easier to achieve when the xenobiotic has a low endogenous clearance. Examples of xenobiotics with low endogenous clearances (130 beat/min Sinus tachycardia without apparent identified cause Sinus bradycardia Respiratory rate Any unexplained depression or elevation in rate Temperature Elevation especially if > 106°F (> 41.1°C) Hypothermia Dissociation between typically paired changes, for example: Hypotension and bradycardia (tachycardia expected) Fever and dry skin (diaphoresis expected) Hypertension and tachycardia (reflex bradycardia anticipated) Depressed mental status and tachypnea (decreased respirations common) Relatively rapid changes in vital signs Initial hypertension becomes hypotension Increasing sinus tachycardia or hypertension General Alteration in consciousness, such as depressed mental status, confusion, or agitation Findings usually not associated with cardiovascular diseases Ataxia, bullae, dry mucous membranes, lacrimation, miosis or mydriasis, nystagmus, unusual odor, flushed skin, salivation, tinnitus, tremor, visual disturbances Findings consistent with a toxic syndrome Especially findings consistent with anticholinergics, sympathomimetics, or sedative hypnotics Laboratory tests Any unexpected or unexplained laboratory result, especially: Metabolic acidosis Respiratory alkalosis Hypokalemia or hyperkalemia

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SUMMARY Xenobiotics can interact with the heart or blood vessels to produce hypotension or hypertension, congestive heart failure, dysrhythmias (including bradycardias and tachycardias), or cardiac conduction delays. These toxic effects often occur through interactions with specific receptors or with the ion channels in the cell membrane. Disruption of the normal cellular regulation of metabolic processes or of the cellular ionic status leads to the cardiovascular and hemodynamic compromise. The occurrence of these abnormalities, individually or in combination, might suggest a particular xenobiotic or class of xenobiotics as the etiologic (toxic syndrome) and might dictate initial treatment. Often, however, significant abnormalities in vital signs must be corrected before the xenobiotic is identified. By understanding both the pharmacology of the xenobiotic and the physiology of the heart and vasculature, appropriately tailored treatment can be delivered. Definitive care of the poisoned patient with hemodynamic compromise or a dysrhythmia begins with recognition that a xenobiotic may be present. Infectious, cardiovascular disease, and other metabolic disorders must always be considered; however, the toxic effects of xenobiotics must be included in the differential diagnosis. A variety of clinical clues, when present, should heighten the clinician’s suspicion that a xenobiotic effect may be responsible for the hemodynamic or dysrhythmic problem (Table 23–9).

REFERENCES 1. Ahlquist RP. A study of the adrenotropic receptors. Am J Physiol. 1948;153:586-600. 2. Bailey B. Glucagon in beta-blocker and calcium channel blocker overdoses: a systematic review. J Toxicol Clin Toxicol. 2003;41:595-602. 3. Berridge MJ. Inositol trisphosphate and calcium signalling. Nature. 1993;361:315-325. 4. Berridge MJ. Smooth muscle cell calcium activation mechanisms. J Physiol. 2008; 586(Pt 21):5047-5061. 5. Blackshear PJ, Nairn AC, Kuo JF. Protein kinases 1988: a current perspective. FASEB J. 1988;2:2957-2969. 6. Brodde OE. The functional importance of beta 1 and beta 2 adrenoceptors in the human heart. Am J Cardiol. 1988;62:24C-29C. 7. Casey PJ, Gilman AG. G protein involvement in receptor-effector coupling. J Biol Chem. 1988;263:2577-2580. 8. Celi FS. Brown adipose tissue—when it pays to be inefficient. N Engl J Med. 2009;360:1553-1556. 9. Chakraborti S, Das S, Kar P, et al. Calcium signaling phenomena in heart diseases: a perspective. Mol Cell Biochem. 2007;298:1-40. 10. Chen-Izu Y, Xiao RP, Izu LT, et al. G(i)-dependent localization of beta(2)-adrenergic receptor signaling to L-type Ca(2+) channels. Biophys J. 2000;79:2547-2556. 11. Clapham DE, Neer EJ. G protein beta gamma subunits. Annu Rev Pharmacol Toxicol. 1997;37:167-203. 12. Dibb KM, Graham HK, Venetucci LA, Eisner DA, Trafford AW. Analysis of cellular calcium fluxes in cardiac muscle to understand calcium homeostasis in the heart. Cell Calcium. 2007;42:503-512. 13. Eisner DA, Choi HS, Díaz ME, O’Neill SC, Trafford AW. Integrative analysis of calcium cycling in cardiac muscle. Circ Res. 2000;87:1087-1094. 14. Enocksson S, Shimizu M, Lonnqvist F, et al. Demonstration of an in vivo functional beta 3-adrenoceptor in man. J Clin Invest. 1995;95:2239-2245. 15. Fant JS, James LP, Fiser RT, Kearns G. The use of glucagon in nifedipine poisoning complicated by clonidine ingestion. Pediatr Emerg Care. 1997;13:417-419. 16. Frank K, Kranias EG. Phospholamban and cardiac contractility. Ann Med. 2000;32:572-578. 17. Frank KF, Bolck B, Erdmann E, Schwinger RH. Sarcoplasmic reticulum Ca2+-ATPase modulates cardiac contraction and relaxation. Cardiovasc Res. 2003;57:20-27.

18. Gauthier C, Tavernier G, Charpentier F, Langin D, Le Marec H. Functional beta3-adrenoceptor in the human heart. J Clin Invest. 1996;98:556-562. 19. Gilman AG. The Albert Lasker Medical Awards. G proteins and regulation of adenylyl cyclase. JAMA. 1989;262:1819-1825. 20. Glick G, Parmley WW, Wechsler AS, Sonnenblick EH. Glucagon. Its enhancement of cardiac performance in the cat and dog and persistence of its inotropic action despite beta-receptor blockade with propranolol. Circ Res. 1968;22:789-799. 21. Gorgas DL. Vital sign measurement. In: Roberts JR, Hedges JR, eds. Clinical Procedures in Emergency Medicine. 4th ed. Philadelphia: WB Saunders; 2004. 22. Graham RM, Perez DM, Hwa J, Piascik MT. Alpha 1-adrenergic receptor subtypes. Molecular structure, function, and signaling. Circ Res. 1996;78:737-749. 23. Hartzell HC, Hirayama Y, Petit-Jacques J. Effects of protein phosphatase and kinase inhibitors on the cardiac L-type Ca current suggest two sites are phosphorylated by protein kinase A and another protein kinase. J Gen Physiol. 1995;106:393-414. 24. Hirayama Y, Hartzell HC. Effects of protein phosphatase and kinase inhibitors on Ca2+ and Cl- currents in guinea pig ventricular myocytes. Mol Pharmacol. 1997;52:725-734. 25. Jaken S. Protein kinase C isozymes and substrates. Curr Opin Cell Biol. 1996;8:168-173. 26. Katz AM. A growth of ideas: role of calcium as activator of cardiac contraction. Cardiovasc Res. 2001;52:8-13. 27. Katz AM, Lorell BH. Regulation of cardiac contraction and relaxation. Circulation. 2000;102:IV69-74. 28. Kuschel M, Zhou YY, Cheng H, Zhang SJ, Chen Y, Lakatta EG, Xiao RP. G(i) protein-mediated functional compartmentalization of cardiac beta(2)adrenergic signaling. J Biol Chem. 1999;274:22048-22052. 29. Lee J. Glucagon use in symptomatic beta blocker overdose. Emerg Med J. 2004;21:755. 30. Lennon NJ, Ohlendieck K. Impaired Ca2+-sequestration in dilated cardiomyopathy. Int J Mol Med. 2001;7:131-141. 31. Levitzki A, Marbach I, Bar-Sinai A. The signal transduction between betareceptors and adenylyl cyclase. Life Sci. 1993;52:2093-2100. 32. Limbird LE. Receptors linked to inhibition of adenylate cyclase: additional signaling mechanisms. FASEB J. 1988;2:2686-2695. 33. Love JN, Leasure JA, Mundt DJ, Janz TG. A comparison of amrinone and glucagon therapy for cardiovascular depression associated with propranolol toxicity in a canine model. J Toxicol Clin Toxicol. 1992;30:399-412. 34. Mader SL. Orthostatic hypotension. Med Clin North Am. 1989;73:1337-1349. 35. Marston S, El-Mezgueldi M. Role of tropomyosin in the regulation of contraction in smooth muscle. Adv Exp Med Biol. 2008;644:110-123. 36. Mery PF, Brechler V, Pavoine C, Pecker F, Fischmeister R. Glucagon stimulates the cardiac Ca2+ current by activation of adenylyl cyclase and inhibition of phosphodiesterase. Nature. 1990;345:158-161. 37. Neer EJ. Heterotrimeric G proteins: organizers of transmembrane signals. Cell. 1995;80:249-257. 38. Neer EJ, Clapham DE. Roles of G protein subunits in transmembrane signalling. Nature. 1988;333:129-134. 39. Oloizia B, Paul RJ. Ca2+ clearance and contractility in vascular smooth muscle: evidence from gene-altered murine models. J Mol Cell Cardiol. 2008;45:347-362. 40. Paakkari P, Paakkari I, Feuerstein G, Siren AL. Evidence for differential opioid mu 1- and mu 2-receptor-mediated regulation of heart rate in the conscious rat. Neuropharmacology. 1992;31:777-782. 41. Petrovic MM, Vales K, Putnikovic B, et al. Ryanodine receptors, voltagegated calcium channels and their relationship with protein kinase A in the myocardium. Physiol Res. 2008;57:141-149. 42. Rasmussen H. The calcium messenger system (1). N Engl J Med. 1986;314: 1094-1101. 43. Rasmussen H. The calcium messenger system (2). N Engl J Med. 1986;314: 1164-1170. 44. Rasmussen H, Barrett P, Smallwood J, Bollag W, Isales C. Calcium ion as intracellular messenger and cellular toxin. Environ Health Perspect. 1990;84:17-25. 45. Reuter H. Calcium channel modulation by beta-adrenergic neurotransmitters in the heart. Experientia. 1987;43:1173-1175. 46. Rivers EP, Coba V, Whitmill M. Early goal-directed therapy in severe sepsis and septic shock: a contemporary review of the literature. Curr Opin Anaesthesiol. 2008;21:128-140.

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47. Roden DM, Balser JR, George AL Jr, Anderson ME. Cardiac ion channels. Annu Rev Physiol. 2002;64:431-475. 48. Ruegg JC. Cardiac contractility: how calcium activates the myofilaments. Naturwissenschaften. 1998;85:575-582. 49. Ruegg JC. Pharmacological calcium sensitivity modulation of cardiac myofilaments. Adv Exp Med Biol. 2003;538:403-410. 50. Saunders C, Limbird LE. Localization and trafficking of alpha2-adrenergic receptor subtypes in cells and tissues. Pharmacol Ther. 1999;84:193-205. 51. Sperelakis N, Xiong Z, Haddad G, Masuda H. Regulation of slow calcium channels of myocardial cells and vascular smooth muscle cells by cyclic nucleotides and phosphorylation. Mol Cell Biochem. 1994;140:103-117. 52. Steinberg SF. The cellular actions of beta-adrenergic receptor agonists: looking beyond cAMP. Circ Res. 2000;87:1079-1082. 53. Steinberg SF. The molecular basis for distinct beta-adrenergic receptor subtype actions in cardiomyocytes. Circ Res. 1999;85:1101-1111. 54. Stinson J, Walsh M, Feely J. Ventricular asystole and overdose with atenolol. BMJ. 1992;305:693. 55. Sulakhe PV, Vo XT. Regulation of phospholamban and troponin-I phosphorylation in the intact rat cardiomyocytes by adrenergic and cholinergic stimuli: roles of cyclic nucleotides, calcium, protein kinases and phosphatases and depolarization. Mol Cell Biochem. 1995;149-150:103-126. 56. Sunahara RK, Beuve A, Tesmer JJ, Sprang SR, Garbers DL, Gilman AG. Exchange of substrate and inhibitor specificities between adenylyl and guanylyl cyclases. J Biol Chem. 1998;273:16332-16338. 57. Sunahara RK, Dessauer CW, Gilman AG. Complexity and diversity of mammalian adenylyl cyclases. Annu Rev Pharmacol Toxicol. 1996;36:461-480.

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58. Talosi L, Kranias EG. Effect of alpha-adrenergic stimulation on activation of protein kinase C and phosphorylation of proteins in intact rabbit hearts. Circ Res. 1992;70:670-678. 59. Tang WJ, Gilman AG. Type-specific regulation of adenylyl cyclase by G protein beta gamma subunits. Science. 1991;254:1500-1503. 60. Taussig R, Tang WJ, Hepler JR, Gilman AG. Distinct patterns of bidirectional regulation of mammalian adenylyl cyclases. J Biol Chem. 1994;269:60936100. 61. Travill CM, Pugh S, Noble MI. The inotropic and hemodynamic effects of intravenous milrinone when reflex adrenergic stimulation is suppressed by beta-adrenergic blockade. Clin Ther. 1994;16:783-792. 62. Walter FG, Frye G, Mullen JT, et al. Amelioration of nifedipine poisoning associated with glucagon therapy. Ann Emerg Med. 1993;22:1234-1237. 63. Whitehurst VE, Vick JA, Alleva FR, et al. Reversal of propranolol blockade of adrenergic receptors and related toxicity with drugs that increase cyclic AMP. Proc Soc Exp Biol Med. 1999;221:382-385. 64. Xiao RP. Cell logic for dual coupling of a single class of receptors to G(s) and G(i) proteins. Circ Res. 2000;87:635-637. 65. Xiao RP, Cheng H, Zhou YY, Kuschel M, Lakatta EG. Recent advances in cardiac beta(2)-adrenergic signal transduction. Circ Res. 1999;85: 1092-1100. 66. Yagami T. Differential coupling of glucagon and beta-adrenergic receptors with the small and large forms of the stimulatory G protein. Mol Pharmacol. 1995;48:849-854. 67. Zaugg M, Schaub MC. Cellular mechanisms in sympatho-modulation of the heart. Br J Anaesth. 2004;93:34-52.

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HEMATOLOGIC PRINCIPLES Marco L.A. Sivilotti Blood is rightfully considered the vital fluid, as every organ system depends on the normal function of blood. Blood delivers oxygen and other essential substances throughout the body, removes waste products of metabolism, transports hormones from their origin to site of action, signals and defends against threatened infection, promotes healing via the inflammatory response and maintains the vascular integrity of the circulatory system. It also contains the central compartment of classical pharmacokinetics, and thereby comes into direct contact with virtually every systemic toxin that acts on the organism.162 The ease and frequency with which blood is assayed, its central role in functions vital to the organism, and the ability to analyze its characteristics, at first by light microscopy and more recently with molecular techniques, have enabled a detailed understanding of blood that has advanced the frontier of molecular medicine. In addition to transporting xenobiotics throughout the body, blood and the blood-forming organs can at times be directly affected by these same xenobiotics. For example, decreased blood cell production, increased blood cell destruction, alteration of hemoglobin, and impairment of coagulation can all result from exposure to many xenobiotics. The response in many cases depends on the nature and quantity of the xenobiotic, and the capacity of the system to respond to the insult. In other cases, no clear and predictable dose–response relationship can be determined, especially when the interaction involves the immune system. These latter reactions are often termed idiosyncratic, reflecting an incomplete understanding of their causative mechanism. In general, such reactions can often be reclassified when advancing knowledge identifies the characteristics which render the individual vulnerable.

HEMATOPOIESIS Hematopoiesis is the development of the cellular elements of blood. The majority of the cells of the blood system may be classified as either lymphoid (B, T, and natural-killer lymphocytes) or myeloid (erythrocytes, megakaryocytes, granulocytes, and macrophages). All of these cells are descended from a small common pool of totipotent cells called hematopoietic stem cells.182 Indeed, the study of this process and its regulation has provided fundamental insight into embryogenesis, stem cell pluripotency, and complex cell-to-cell signaling and interaction.

■ BONE MARROW Marrow spaces within bone begin to form in humans at about the 5th fetal month and become the sole site of granulocyte and megakaryocyte proliferation. Erythropoiesis moves from the liver to the marrow by the end of the last trimester. At birth, all marrow contributes to blood cell formation and is red, containing very few fat cells. By adulthood, the same volume of hematopoietic marrow is normally restricted to the sternum, ribs, pelvis, upper sacrum, proximal femora and humeri, skull, vertebrae, clavicles and scapulae. So-called extramedullary hematopoiesis in the liver and spleen may reemerge as a compensatory mechanism under severe stimulation. Progenitor cells must interact with a supportive microenvironment to sustain hematopoiesis. The hematopoietic stroma consists

of macrophages, fibroblasts, adipocytes, and endothelial cells. The extracellular matrix is produced by the stromal cells and is composed of various fibrous proteins, glycoproteins, and proteoglycans, such as collagen, fibronectin, laminin, hemonectin, and thrombospondin. Hematopoietic progenitor cells have receptors to particular matrix molecules. The extracellular matrix provides a structural network to which the progenitors are anchored. As the cells approach maturity, they lose their surface receptors, allowing them to leave the hematopoietic space and enter the venous sinuses. Blood cell release depends upon the development of a pressure gradient that drives mature cells through channels in endothelial cell cytoplasm.191 Pressure within the marrow is increased by erythropoietin and by granulocyte colonystimulating factor (G-CSF). 83,84

■ STEM CELLS A stem cell is capable of self-renewal, as well as differentiating into a specific cell type. The pluripotent hematopoietic stem cells can therefore continuously replicate while awaiting the appropriate signal to differentiate into either a myeloid stem cell (for myelo-, erythro-, mono-, or megakaryopoiesis) or a lymphoid stem cell (for lymphopoiesis of T, B, null, and natural-killer cells) (Fig. 24–1). The stem cell pool represents approximately 1 in 100,000 of the nucleated cells of the bone marrow, and the majority of these stem cells are usually quiescent. Nevertheless, these relatively few cells are directly responsible for the estimated 3 billion red cells, 2.5 billion platelets, and 1.5 billion granulocytes per kilogram of body weight produced each day. In response to hemolysis or infection, substantially larger numbers of blood cells can be produced.130 Hematopoietic stem cells are found in umbilical cord blood, bone marrow, and peripheral blood.108 With subsequent division and maturation, these cells progressively display the antigenic, biochemical, and morphologic features characteristic of mature cells of the appropriate lineages, and lose their capacity for self-renewal. Multiple steps are involved in the commitment of less-differentiated cells to more mature cell lines. The final steps in the maturation of erythrocytes alone, for example, involve extensive remodeling, the restructuring of cellular membranes, the accumulation of hemoglobin, and the loss of nuclei and organelles. In the case of granulocytes, granules containing proteolytic enzymes are formed in cell cytoplasm, and the nucleus condenses to form the multilobulated nucleus of the mature cell. Megakaryocyte cytoplasm demarcates into units that are split off eventually as platelets. Multipotent mesenchymal stem cells capable of differentiating into other tissue lines including hepatic, renal, muscle and perhaps nerves are also found in the bone marrow.64 Furthermore, tissue-specific stem cells capable of self-renewal are believed to reside in numerous other organs and to play a fundamental role in repair and regeneration.35 A variety of strategies have likely evolved to protect the stem cell from injury due to xenobiotics and radiation, and a better understanding of these effects promises to improve our understanding of toxicity and treatment. The hematopoietic stem cell has provided fundamental insights into regenerative biology, and remains a focus of intense research given the profound implications for organ homeostasis, tissue repair and gene therapy.99,105

■ CYTOKINES Cytokines are soluble mediators secreted by cells for cell-to-cell communication. Initially termed growth factors, it is now recognized that not all cytokines are growth factors. Cytokines promote or inhibit the differentiation, proliferation, and trafficking of blood cells and their precursors. Importantly, they can also inhibit apoptosis, and their

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Chapter 24

Multipotential Hematopoietic stem cells

Lineage commitment stage

Maturation stages of committed progenitor cells

B-cell progenitors

Circulating mature blood cells

B-lymphocyte

Lymphoid T-cell progenitors

Granulocyte progenitors

T-lymphocyte

Granulocyte

Monocyte/ macrophage progenitors

Monocyte

Erythroid progenitors

Erythrocyte

Myeloid

Megakaryocyte progenitors Commitment

Differentiation

Platelets Release

FIGURE 24–1. Principles of hematopoiesis. Commitment refers to the apparent inability of progenitor cells to generate hematopoietic stem cells. Following differentiation, the various mature blood cells are released into the circulation.

absence therefore results in the self-destruction of unwanted cells. They include growth factors or colony-stimulating factors (CSFs), interleukins, monokines, interferons, and chemokines. At baseline, these act in concert to maintain normal blood counts. In response to antigens or other stimuli, cytokines are released to combat perceived infection. Recombinant cytokines are being developed for therapeutic use in immunocompromised patients, transplant recipients, sepsis, and cancer. They have also been used in clinical toxicology for the treatment of colchicine and podophyllum toxicity.45,69 The growth factors are glycoproteins necessary for the differentiation and maturation of individual or multiple cell lines.83,93,94,123 They fall into two families based on their target receptors. The ligands of the cytokine receptor family include growth hormone, interleukin-2 (IL-2), macrophage colony-stimulating factor-1 (CSF-1), granulocytemacrophage colony-stimulating factor (GM-CSF), γ-interferon, and granulocyte colony-stimulating factor (G-CSF), to name a few. The second group, the tyrosine kinase family, includes Kit ligand and insulinlike growth factor-I receptor (IGF-1R), a member of the insulin family. The complete development of all of the mature blood cells from stem cells or multilineage progenitors requires the action of growth factors, either alone or in combination, for successful differentiation and final maturation.

■ CELL SURFACE ANTIGENS Using monoclonal antibody technology, cell surface antigens are used to characterize cell types. The cluster designation (CD) nomenclature was introduced by immunologists to ensure a common language when confronted with multiple antibodies to the same leukocyte cell-surface molecule, and hundreds of such unique molecules have been classified.198 For example, the CD34 antigen is a 115-kilodalton (kDa) highly glycosylated transmembrane protein that is selectively expressed by primitive multipotent hematopoietic stem cells shortly after activation, but is absent from mature T and B lymphocytes.108 Advances in genomics and proteomics now complement the immunologic designation, but the ability to subtype blood cells phenotypically has transformed the approach to the leukemias, autoimmune disease, transplantation medicine and thromboembolic disease.

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■ APLASTIC ANEMIA Aplastic anemia is characterized by pancytopenia on peripheral smear, a hypocellular marrow, and delayed plasma iron clearance. Severe aplastic anemia denotes a granulocyte count of less than 500 cells/mm3, a platelet count of less than 20,000/mm3, and a reticulocyte count of less than 1% after correction for anemia. Following acute insult and depletion of extracirculatory reserves, cell line counts fall at a rate inversely proportional to their life span: granulocytes (half-life 6–12 hours in the circulation) disappear within days, platelets (life span of 7–10 days) decline by half in about one week, while erythrocytes (normal life span 120 days) decline over weeks in the absence of bleeding or hemolysis. Approximately 1000 new cases of aplastic anemia are diagnosed yearly in the United States. The incidence is two to three times higher in Asia, perhaps due to a combination of genetic, environmental and infectious factors.195 Aplastic anemia may be inborn (as in Fanconi anemia) or acquired. A variety of xenobiotics have been associated with acquired aplastic anemia, such as benzene, environmental pesticides and chloramphenicol (Table 24–1).32,196 However, much of this older literature is suspect given uncertain case ascertainment and other biases. More recent epidemiologic studies have shown that specific causes are identified in relatively few cases.82 Generally speaking, the majority of cases of so-called idiosyncratic aplastic anemia are caused by autoimmune attack on CD34+

TABLE 24–1. Xenobiotics Associated with Aplastic Anemia Analgesics Acetaminophen Acetylsalicylic acid Diclofenac Dipyrone Indomethacin Phenylbutazone Antibiotics Azidothymidine Chloramphenicol Mefloquine Penicillin Anticonvulsants Carbamazepine Felbamate Antidysrhythmics Tocainide Antihistamines Cimetidine Antiplatelets Ticlopidine Antipsychotics Chlorpromazine Clozapine

Antirheumatics Gold salts Methotrexate D-Penicillamine Antithyroids Propylthiouracil Antineoplasticsa Adriamycina Antimetabolites Colchicine Daunorubicina Mustards Vinblastine Vincristine Diuretics Acetazolamide Metolazone Occupational Arsenica Benzenea Cadmium Copper Pesticides Pesticides Radiationa

a Denotes agents that predictably result in bone marrow aplasia following a sufficiently large exposure.

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hematopoietic stem cells. Following an exposure to an inciting antigen, cytotoxic T cells secrete interferon-γ and tumor necrosis factor α which destroy progenitor cells, causing loss of circulating mature leukocytes, erythrocytes and platelets.196 As with other autoimmune diseases, certain histocompatibility antigen patterns are associated with the condition, namely the human leukocyte antigen (HLA) DR2, indicating a genetic predisposition. Clozapine-induced agranulocytosis is associated with the HLA B38, DR4, and DQ3 haplotypes.132 Immunosuppressive therapy or allogenic stem cell transplantation allow recovery of hematopoiesis, and survival is now expected.195 It is important to distinguish immunologic xenobiotic-induced aplastic anemia from the direct myelotoxic effects of radiation and chemotherapy. Following exposure to ionizing radiation, a pancytopenia ensues due to injury to both stem and progenitor cells. Nevertheless, atom bomb survivors rarely develop aplastic anemia.79 Vacuolated pronormoblasts can be found in the bone marrow when aplasia is due to a myelotoxic drug, and treatment consists of stopping the offending agent. Other nonimmunologic mechanisms of aplasia have also been identified in specific cases. For example, the severe pancytopenia seen following 5-fluorouracil therapy is caused by a deficiency of dihydropyrimidine dehydrogenase present in 3% to 5% of whites.187

THE ERYTHRON The erythron can be considered to be a single yet dispersed tissue, defined as the entire mass of erythroid cells from the first committed progenitor cell to the mature circulating erythrocyte. This functional definition emphasizes the integrated regulation of the erythron, both in health and disease. Homeostasis of the erythron is primarily maintained by the equilibrium between stimulation via the hormone erythropoietin, and apoptosis controlled by two receptors, Fas and FasL, expressed on the membranes of erythroid precursors. At the other extreme, erythrocytes are culled from the circulation at the end of their life span, primarily by the action of the spleen. Senescent erythrocytes less able to negotiate the narrow red pulp passages are phagocytosed by macrophages, thereby minimizing both entrapment in the microvasculature of other organs, and spillage of intracellular contents into the intravascular circulation. The primary function of the erythron is to transport molecular oxygen throughout the organism. To accomplish this, adequate number of circulating erythrocytes must be maintained. These erythrocytes must be able to preserve their structure and flexibility to circuit repeatedly through the microcirculation and to resist oxidant stress accumulated during their life span.150 The erythrocyte also plays a key role in modulating vascular tone. Interactions between oxyhemoglobin and nitric oxide help match vasomotor tone to local tissue oxygen demands.46,62,68,119,160

■ ERYTHROPOIETIN Erythropoietin (EPO) is a glycoprotein hormone of molecular weight 34,000 Da that is produced in the epithelial cells lining the peritubular capillaries in the normal kidney. Anemia and hypoxemia stimulate its synthesis.2,3 EPO receptors are found in human erythroid cells, megakaryocytes, and fetal liver. EPO promotes erythroid differentiation, the mobilization of marrow progenitor cells, and the premature release of marrow reticulocytes.2 The cell most sensitive to EPO is a cell between the erythroid colony-forming unit (CFU-E) and the proerythroblast.3 The absence of EPO results in DNA cleavage and erythroid cell death.

■ THE MATURE ERYTHROCYTE The mature erythrocyte (red blood cell) is a highly specialized cell, designed primarily for oxygen transport. Accordingly, it is densely

packed with hemoglobin, which constitutes approximately 90% of the dry weight of the erythrocyte. During maturation, the erythrocyte loses its nucleus, mitochondria and other organelles, rendering it incapable of synthesizing new protein, replicating, or using the oxygen being transported for oxidative phosphorylation. Its metabolic repertoire is also severely limited, and largely restricted to a few pathways described below under Metabolism. In general, the enzymatic pathways are those required for optimizing oxygen and carbon dioxide exchange, transiting the microcirculation while maintaining cellular integrity and flexibility, and resisting oxidant stress on the iron and protein of the cell. The characteristic biconcave discocyte shape is dynamically maintained, increasing membrane surface to cell volume.117 This shape both decreases intracellular diffusion distances to the extracellular membrane104 and allows plastic deformation when squeezing through the microcirculation.36,161 The shape is the net sum of elastic and electrostatic forces within the membrane, surface tension, and osmotic and hydrostatic pressures. The cell membrane contains globular proteins floating within the phospholipid bilayer. The major blood group antigens are carried on membrane ceramide glycolipids and proteins, particularly glycophorin A and the Rh proteins.40 Membrane proteins generally serve to maintain the structure of the cell, to transport ions and other substances across the membrane, or to catalyze a limited number of specific chemical reactions for the cell. Structural proteins The cell membrane is coupled to, and interacts dynamically with the cytoskeleton, allowing changes in cell shape such as tank treading or rotation of the membrane relative to the cytoplasm. This cytoskeleton consists of a hexagonal lattice of proteins, especially spectrin, actin, and protein 4.1, which interact with ankyrin and band 3 in the membrane to provide a strong but flexible structure to the membrane.21,101,159 Other essential structural proteins include tropomyosin, tropomodulin, and adducin. Absence or abnormalities of these proteins can result in abnormal erythrocyte shapes such as spherocytes and elliptocytes. Transport proteins Many specialized transport proteins are embedded in the erythrocyte membrane. These include anion and cation transporters, glucose and urea transporters, and water channels.177 The erythrocyte membrane is relatively impermeable to ion flux. Band 3 anionexchange protein plays an important role in the chloride-bicarbonate exchanges that occur as the erythrocyte moves between the lung and tissues. Glucose, the sole source of energy of the erythrocyte, crosses the membrane by facilitated diffusion mediated by a transmembrane glucose transporter. Sodium-potassium adenosine triphosphatase (Na+,K+-ATPase) maintains the primary cation gradient by pumping sodium out of the erythrocyte in exchange for potassium. Membrane-associated enzymes At least 50 membrane-bound or membrane-associated enzymes are known to exist in the human erythrocyte. Acetylcholinesterase is an externally oriented enzyme whose role in the function of the erythrocyte remains obscure.178 Its function is inhibited by certain xenobiotics, most notably the organic phosphorus insecticides, and it can be conveniently assayed as a marker for such exposures (Chap. 113). Metabolism Lacking mitochondria and the ability to generate adenosine triphosphate (ATP) using molecular oxygen, the mature erythrocyte has a severely limited repertoire of intermediary metabolism compared to most mammalian cells. Its metabolic capacity is also limited once its nucleus, ribosomes, and translational apparatus are lost. Unable to synthesize new enzymes, the capacity declines over the lifetime of the cell because of declining enzyme function with time. Fortunately, the metabolic demands of the erythrocyte are usually modest, but under conditions of stress the capacity can be overwhelmed, especially among senescent cells. The greatest expenditure of energy under physiologic

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conditions is for the maintenance of transmembrane gradients and for the contraction of cytoskeletal elements. However, oxidant stress can put severe strain on the metabolic reserves of the erythrocyte, and lead ultimately to the premature destruction of the cell, a process termed hemolysis. Figure 24–2 illustrates the main metabolic pathways and their purpose. The Embden-Meyerhof glycolysis is the only source of ATP for the erythrocyte, and consumes approximately 90% of the glucose imported by the cell. The reduced nicotinamide adenine dinucleotide (NADH) generated during glycolysis, which would ordinarily be used for oxidative phosphorylation in cells containing mitochondria, is directed toward the reduction of either methemoglobin to hemoglobin by cytochrome b5 reductase, or pyruvate to lactate. Both pyruvate and lactate are exported from the cell. During glycolysis, metabolism can be diverted into the Rapoport-Luebering shunt, generating 2,3-bisphosphoglycerate (2,3-BPG, formerly known as 2,3-diphosphoglycerate

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or 2,3-DPG) in lieu of ATP. 2,3-BPG binds to deoxyhemoglobin to modulate oxygen affinity and allow unloading of oxygen at the capillaries. In response to anemia, altitude, or changes in cellular pH, the activity of the shunt increases, thereby favoring synthesis of 2,3-BPG and increasing oxygen delivery considerably.42,113 Reduced levels of 2,3BPG in stored blood are believed to result in impaired oxygen delivery for approximately 12 hours following massive transfusion.183 As an alternative to glycolysis, glucose can be directed toward the hexose monophosphate shunt during times of oxidant stress. This pathway results in the generation of reduced nicotinamide adenine dinucleotide phosphate (NADPH), which the erythrocyte uses to maintain reduced glutathione which, in turn, inactivates oxidants and protects the sulfhydryl groups of hemoglobin and other proteins. The initial, rate-limiting step of this pathway is controlled by glucose-6phosphate dehydrogenase (G6PD). Accordingly, cells deficient in this enzyme are less able to maintain glutathione in a reduced state, and

Glycolysis Glucose ATP ADP Glucose-6-phosphate

Hexose monophosphate shunt Glucose-6-phosphate NADP+ Glucose-6-phosphate

GSH

dehydrogenase

Fructose-6-phosphate ATP ADP Fructose-1,6-biphosphate

NADPH GSSG 6-Phosphogluconolactone Glutathione reduction: Deficiency in RBC of reduced glutathione leads to oxidative 6-Phosphogluconate stress and hemolysis + NADP NADPH Ribulose-5-phosphate

Glyceraldehyde-3-phosphate (× 2) Fe2+ NAD+ Cyt b5 red NADH Fe3+ Ribose-5-phosphate 1,3-Biphosphoglycerate ADP NADH: Methemoglobin 2,3-Biphosphoglycerate reduction ATP 3-Phosphoglycerate Rapoport-Luebering shunt (2,3-BPG shunt) 2-Phosphoglycerate

2,3-BPG: Modulation of HbO2 affinity

Phosphoenolpyruvate ADP NAD+ NADH Lactate

ATP

ATP Synthesis: Source of cellular energy for metabloic and other critical functions

Pyruvate

FIGURE 24–2. Metabolic pathways of the erythrocyte. The main metabolic pathways available to the mature erythrocyte are shown (rectangles). Glucose is imported into the cell, while pyruvate, lactate, and oxidized glutathione (GSSG) are exported. 2,3-BPG = 2,3-Biphosphoglycerate; ADP = adenosine diphosphate; ATP = adenosine triphosphate; cyt b5 red = cytochrome b5 reductase; G6PD = glucose-6-phosphate dehydrogenase; GSH = reduced glutathione; Hb = hemoglobin; NADH reduced form of nicotinamide adenine dinucleotide (NAD+); NADPH = reduced form of nicotinamide adenine dinucleotide phosphate (NADP+); RBC = red blood cell (erythrocyte).

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are vulnerable to irreversible damage under oxidant stress. The consequences of this deficiency are discussed in greater detail below under Glucose-6-Phosphate Dehydrogenase Deficiencies. The erythrocyte also contains enzymes to synthesize glutathione (γ-glutamyl-cysteine synthetase and glutathione synthetase), to convert CO2 to bicarbonate ion (carbonic anhydrase I), to remove pyrimidines resulting from the degradation of RNA (pyrimidine 5′-nucleotidase), to protect against free radicals (catalase, superoxide dismutase, glutathione peroxidase), and to conjugate glutathione to electrophiles (ρ glutathione-S-transferase).

■ HEMOGLOBIN Hemoglobin, the major constituent of the cytoplasm of the erythrocyte, is a conjugated protein with a molecular weight of 64,500 Da. One molecule is composed of 4 protein or globin chains, each attached to a prosthetic group called heme. Heme contains an iron molecule complexed at the center of a porphyrin ring. The globin chains are held together by noncovalent electrostatic attraction into a tetrahedral array. Hemoglobin is so efficient at binding and carrying oxygen that it enables blood to transport 100 times as much oxygen as could be carried by plasma alone (Chap. 21). In addition, the capacity of hemoglobin to modulate oxygen binding under different conditions allows adaptation to a wide variety of environments and demands. Three complex and integrated pathways are required for the formation of hemoglobin: globin synthesis, protoporphyrin synthesis, and iron metabolism. Globin synthesis The protein chains of hemoglobin are produced with information from two different genetic loci. The α-globin gene cluster spans 30 kb on the short arm of chromosome 16, and codes for 2 identical adult α-chain genes, as well as the ζ -chain, an embryonic globulin. The β cluster is 50 kb on chromosome 11, and codes for the 2 adult globins β and δ, as well as 2 nearly identical γ chains expressed in the fetus and an embryonic globulin ε. The expression of genes in each family changes during embryonic, fetal, neonatal, and adult development. Until 8 weeks of intrauterine life, ε, ζ, γ, and α chains are produced and assembled in various combinations in yolk sac-derived erythrocytes. With the shift in erythropoiesis from yolk sac to fetal liver and spleen, embryonic hemoglobin is no longer detectable, and the α and γ globin chains are paired into fetal hemoglobin (HbF = α2γ2). Erythrocytes containing HbF have a higher O2 affinity than those containing adult hemoglobin, which is important for oxygen transfer across the placenta into the relatively hypoxic uterine environment. Beginning shortly before birth, expression shifts to the α and β globins, which constitute the predominant adult hemoglobin termed hemoglobin A (α2β2). Approximately 2.5% of normal adult hemoglobin is in the form of hemoglobin A2 (α2 δ2). The rate of globin synthesis is increased in the presence of heme, and inhibited in its absence.116 As the globin chains are released from the ribosomes, they spontaneously assemble into αβ dimers, and then into α2β2 tetramers. The thalassemias, a group of inherited disorders, result from defective synthesis of one or more of the globin chains. Clinically this results in a hypochromic, microcytic anemia.65,116 Heme synthesis Heme is the iron complex of protoporphyrin IX. Protoporphyrin IX is a tetramer composed of four porphyrin rings joined in a closed, flat-ring structure. The IX designation refers to the order in which it was first synthesized in Hans Fischer’s laboratory. Of the 15 possible isomers, only protoporphyrin IX occurs in living organisms. Technically, only iron complexes with the iron in the Fe2+ state can be called heme, but the term is commonly used to refer to the prosthetic group of metalloproteins such as peroxidase (ferric) and cytochrome c (both ferric and ferrous), whether the iron is in the

Fe2+ or Fe3+ state. The terms “hemiglobin” and “ferrihemoglobin” are synonymous with methemoglobin but rarely used. All animal cells can synthesize heme, with the notable exception of mature erythrocytes.143 Hemoproteins are involved in a multitude of biologic functions, including oxygen binding (hemoglobin, myoglobin), oxygen metabolism (oxidases, peroxidases, catalases, and hydroxylases), and electron transport (cytochromes), as well as metabolism of xenobiotics (cytochrome P450 family).144 Erythroid cells synthesize 85% of total body heme, with the liver synthesizing most of the balance. Hemoglobin is the most abundant hemoprotein, containing 70% of total body iron.143 The first step in the synthesis of heme takes place in the mitochondrion and is the condensation of glycine- and succinylcoenzyme A (CoA) to form 5-aminolevulinic acid (ALA) (Fig. 24–3).116 The formation of 5-ALA is catalyzed by aminolevulinic acid synthase (ALAS), the rate-limiting step of the pathway. The rate of heme synthesis is closely controlled, given that free intracellular heme is toxic and that this first step is essentially irreversible. Of the two isoforms of ALAS known to exist in mammals, erythroid cells express the ALAS 2 isoform which resides on the X chromosome. Comparatively more is known about ALAS 1 (chromosome 3), a housekeeping gene with a short half-life expressed ubiquitously allowing the synthesis of cellular and mitochondrial hemoproteins. ALAS 1 activity is induced by many factors, which can increase its expression by two orders of magnitude. Moreover, it is strongly inhibited by heme in a classical negative feedback fashion.143 ALAS 2 is constitutively expressed at very high levels in erythroid precursors, allowing sustained synthesis of heme during erythropoiesis. Pyridoxal phosphate (active vitamin B6) serves as a cofactor to both isoforms of ALAS. The clinical consequences of pyridoxine deficiency may include a hypochromic, microcytic anemia, iron overload, and neurologic impairment. The next step in the synthesis of hemoglobin is the formation of the monopyrrole porphobilinogen via the condensation of two molecules of ALA. The subsequent steps in heme synthesis involve the condensation of four molecules of porphobilinogen into a flat ring, which is transported back into the mitochondrion by an unknown mechanism. The final step is the insertion of iron into protoporphyrin IX, a reaction that is catalyzed by ferrochelatase (also known as heme synthase) to form heme. Understanding this carefully regulated synthetic pathway is relevant to understanding the laboratory evidence of lead exposure, and predicting the response of porphyric patients to a range of xenobiotics. Most steps in the heme biosynthetic pathway are inhibited by lead (see Fig. 24–3; Chap. 94). ALA dehydratase is the most sensitive, followed by ferrochelatase, coproporphyrinogen oxidase, and porphobilinogen (PBG) deaminase. As a consequence, ALA is increased in plasma and

Hemoglobin

Ferrochelatase∗

ALA synthase∗ 5-ALA Elevated in urine and plasma

Protoporphyrin IX + Iron Accumulates in RBCs Fluoresces

Succinyl CoA + Glycine Coproporphyrinogen oxidase∗

ALA dehydratase∗ Porphobilinogen

Uroporphyrinogen III

Coproporphyrinogen III Elevated in urine

FIGURE 24–3. The heme synthesis pathway. The enzymatic steps inhibited by lead are marked with an asterisk (∗) RBCs red blood cells; 5-ALA = 5-aminolevulinic acid.

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especially urine. With increasing exposure, ferrochelatase inhibition coupled with iron deficiency causes zinc protoporphyrin to accumulate in erythrocytes, which can easily be detected by fluorescence. Coproporphyrinogen III also appears in the urine. These effects have served as the basis for a number of tests of lead exposure. The porphyrias are a group of disorders resulting from an inherited deficiency of any given enzyme which follows ALAS on the heme biosynthetic pathway. As such, when ALAS activity outpaces the activity of this enzyme, the rate-limiting step shifts downstream, and intermediate metabolites accumulate. These metabolites can cause characteristic neuropsychiatric symptoms and palsies (due to 5-ALA and porphobilinogen), and cutaneous reactions including photosensitivity (caused by the fluorescence of the porphyrins). For example, porphobilinogen is excreted in large quantities by patients with acute intermittent porphyria (porphobilinogen deaminase deficiency), and the urine darkens with exposure to air and light due to oxidation to porphobilin and to non-enzymatic assembly into porphyrin rings. A variety of xenobiotics can precipitate a crisis in susceptible individuals, by inducing ALAS 1 and overloading the deficient enzyme.181 The molecular mechanisms which allow xenobiotics to induce the ALAS 1 gene closely resemble those accounting for induction of the cytochrome P450 (CYP) genes, not surprisingly since both components are required to form the hemoprotein. The xenobiotic typically interacts with either the constitutive androstane receptor (CAR) or the pregnane X receptor (PXR), the two main so-called orphan nuclear receptors.194 These transcriptional factors are DNA-binding proteins which induce the expression of a range of drug metabolizing and transporting genes in response to the presence of a xenobiotic, and have been termed “xenosensors.” When activated, they associate with the 9-cis retinoic acid xenobiotic receptor (RXR), and then attach to enhancer sequences near the apoCYP or ALAS1 genes to enhance transcription.142 The multifunctional inducers capable of activating a wide range of hepatic enzymes are therefore extremely porphyrogenic, and include phenobarbital, phenytoin, carbamazepine, and primidone. Furthermore, because CYP 3A4 and 2C9 represent nearly half of the hepatic CYP pool, inducers of these isoforms can also stimulate heme synthesis and induce a porphyric crisis. Examples of these agents included the anticonvulsants, nifedipine, sulfamethoxazole, rifampicin, ketoconazole, and the reproductive steroids progesterone, medroxyprogesterone and testosterone. Glucocorticoids, on the other hand, despite binding to PXR, suppress ALAS1 induction and translation, and are not porphyrogenic.181 Iron metabolism Unless appropriately chelated, free iron not bound by transport or storage proteins can generate harmful oxygen free radicals that damage cellular structures and metabolism (Chaps. 11 and 40).145 For this reason, serum iron circulates bound to a transfer protein, transferrin, and is stored in the tissues using ferritin. Although each molecule of transferrin can bind two iron atoms, ferritin has a large internal cavity, approximately 80 Å in diameter, that can hold up to 4500 iron atoms per molecule. The amount of iron transported through plasma depends on total-body iron stores and the rate of erythropoiesis. Only about one-third of the iron-binding sites of circulating transferrin are normally saturated, as demonstrated by the usual serum iron content of 60–170 μg/dL (10–30 μmol/L) as compared to the total iron-binding capacity of 280–390 μg/dL (50–70 μmol/L). Only transferrin can directly supply iron for hemoglobin synthesis.143 The iron–transferrin complex binds to transferrin receptors on the surface of developing erythroid cells in bone marrow. Iron in the erythroid cell is used for hemoglobin synthesis or is stored in the form of ferritin. The absorption of non-heme, free ferrous iron from the diet occurs via the divalent metal transporter of the duodenal enterocyte, which then passes it into the circulation via ferroportin. Oxidized to the ferric form, iron then circulates bound to transferrin.71 Dietary iron

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complexed with heme can also be absorbed via the recently discovered heme carrier protein 1, which transports either iron or zinc protoporphyrin into the erythrocyte.164 The iron may then be freed by microsomal heme oxygenase, and follow the transport of atomic iron, or perhaps heme itself can be transferred to the circulation via specific export proteins, and circulate bound to its carrier protein, hemopexin.9 The senescent erythrocyte is usually removed from the circulation by splenic macrophages. Heme is degraded by heme oxygenase to carbon monoxide and biliverdin, and the iron extracted.145 Some iron may remain in macrophages in the form of ferritin or hemosiderin. Most is delivered again by ferroportin back to the plasma, and bound to transferrin. Iron homeostasis is largely regulated at the level of absorption, with little physiologic control over its rate of loss. Excess absorption relative to body stores is the hallmark of hereditary hemochromatosis. The iron regulatory hormone hepcidin produced by the liver is now believed to play a central role in iron control, including the anemia of chronic disease caused by inflammatory signals.71 Hepcidin is a 25-amino acid peptide that senses iron stores, and controls the ferroportin-mediated release of iron from enterocytes, macrophages and hepatocytes. The liver is an important reservoir of iron as it can store considerable amounts of iron taken from portal blood, and release it when needed.

■ OXYGEN-CARBON DIOXIDE EXCHANGE The evolutionary transition of organisms from anaerobic to aerobic life allowed the liberation of 18 times more energy from glucose. Vertebrates have developed 2 important systems to overcome the relatively small quantities of oxygen dissolved in aqueous solutions under atmospheric conditions: the circulatory system and hemoglobin. The circulatory system allows delivery of oxygen and removal of carbon dioxide throughout the organism. Hemoglobin also plays an essential role in the transport and exchange of both gases.74 Moreover, the interactions between these gases and hemoglobin are directly linked in a remarkable story of molecular evolution. Understanding this interplay has allowed fundamental insight into protein conformation and the importance of allosteric interactions between molecules. The binding of oxygen to each of the 4 iron molecules in heme results in conformational changes that affect binding of oxygen at the remaining sites. This phenomenon is known as cooperativity, and is a fundamental property to allow both the transport of relatively large quantities of oxygen and the unloading of most of this oxygen at tissue sites. Cooperativity results from the intramolecular interactions of the tetrameric hemoglobin, and is expressed in the sigmoidal shape of the oxyhemoglobin dissociation curve (Chap. 21). Conversely, the monomeric myoglobin has a hyperbolic oxygen binding curve. The partial pressure of oxygen at which 50% of the oxygen bindings sites of hemoglobin are occupied is about 26 mm Hg, in contrast with about 1 mm Hg for myoglobin. Moreover, hemoglobin is nearly 100% saturated at partial oxygen pressures of about 100 mm Hg in the pulmonary capillaries, transporting 1.34 mL of oxygen per gram of hemoglobin A. About onethird of this oxygen can be unloaded under normal conditions at tissue capillaries with partial oxygen pressures around 35 mm Hg. The proportion rises during exercise and sepsis, and with poisons that uncouple oxidative phosphorylation. Elite athletes can extract up to 80% of the available oxygen under conditions of maximal aerobic effort. The oxygen reserve, however, is only one of the reasons for the large quantity of hemoglobin in circulation. The ability of hemoglobin to buffer the acid equivalent of CO2 in solution is equally vital to respiratory physiology, as it allows the removal of large quantities of CO2 from metabolically active tissues with minimal changes in blood pH. To put things in perspective, the typical adult male has approximately 75 mL/kg

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of blood containing 15 g/100 mL of hemoglobin, or nearly 1 kg of hemoglobin. His 0.3-kg heart must pump this entire mass of hemoglobin every minute at rest, a substantial work expenditure. This expenditure may be explained in part by the observation that hemoglobin is by far the largest buffer in circulation, accounting for nearly seven times the buffer capacity of the serum proteins combined (28 vs. 4 mEq H+/L of whole blood). For every 1 mol of oxygen unloaded in the tissue, about 0.5 mol of H+ is loaded onto hemoglobin. The linked interaction between oxygen and carbon dioxide transport can be first considered from the perspective of oxygen binding to hemoglobin. The affinity of oxygen for hemoglobin is directly affected by pH, which is a function of the CO2 content of the blood. The oxyhemoglobin dissociation curve shifts to the left in lungs, where the level of carbon dioxide, and thus carbonic acid, are kept relatively low as a result of ventilation, an effect that promotes oxygen binding. The curve shifts to the right in tissues where cellular respiration increases CO2 concentrations. This phenomenon, known as the Bohr effect, promotes the uptake of oxygen in the lungs and the release of oxygen at tissue sites. From the perspective of carbon dioxide transport, hemoglobin also plays an essential albeit indirect role. Carbon dioxide dissolves into serum, and is slowly hydrated to carbonic acid which dissociates to H+ and HCO3−(pKa 6.35). The hydration reaction is accelerated from about 40 seconds to 10 msec by the abundant enzyme carbonic anhydrase located within the erythrocyte. Most carbon dioxide collected at the tissues diffuses into erythrocytes where it becomes H+ and HCO3−. This HCO3− is then rapidly transported back to the serum in exchange for chloride ion via the band 3 anion exchange transporter located in the erythrocyte membrane, thereby shifting serum Cl− into the erythrocyte (the chloride shift).177 The hydrogen ion is accepted by hemoglobin, largely at the imidazole ring of histidine residues which have a pKa of about 7.0. A small amount of CO2 reacts directly with the amino terminal of the globin chains to form carbamino residues (HbNHCOO−). Thus, most of the transported carbon dioxide is transformed by the erythrocyte into bicarbonate ion that is returned to the serum, and hydrogen ion that is buffered by hemoglobin. Each liter of venous blood typically carries 0.8 mEq dissolved CO2 and 16 mEq HCO3− in the serum, and 0.4 mEq dissolved CO2, 4.6 mEq HCO3−, and 1.2 mEq HbNHCOO− in the erythrocyte (a total of 23 mEq CO2, equivalent to 510 mL CO2/L blood). Although two-thirds of the total CO2 content appears to be carried in the serum, all of the serum bicarbonate is originally generated within erythrocytes. In the capillaries of the lungs, the reverse reactions occur to eliminate CO2. Because deoxyhemoglobin is better able to buffer hydrogen ions, the release of oxygen from hemoglobin at the tissues facilitates the uptake of carbon dioxide into venous blood. This effect is known as the Haldane effect. In fact, 1 L of venous blood at 70% oxygen saturation can transport an additional 20 mL of CO2 compared to arterial blood. Both the Bohr and Haldane effects can have important consequences, either at the extremes of acid–base perturbations or because of interference with oxygen metabolism, as can occur in a number of poisonings. Finally, in addition to inactivating nitric oxide, hemoglobin can also reversibly bind it as S-nitrosohemoglobin, thereby playing an important role in the regulation of microvascular circulation and oxygen delivery. The ability of hemoglobin to vasodilate the surrounding microvasculature in response to oxygen desaturation using nitric oxide provides new insight into oxygen delivery, and may be pivotal in such disorders as septic shock, pulmonary hypertension, and senescence of stored red blood cells.167

■ ABNORMAL HEMOGLOBINS Several alterations of the hemoglobin molecule are encountered in clinical toxicology. A detailed understanding of their molecular basis,

clinical manifestations, and effects on gas exchange are essential. Unfortunately, the nomenclature can be ambiguous and overlap with distinct clinical entities such as oxidant injury and hemolysis. Therefore, although a detailed discussion of these abnormal hemoglobins appears elsewhere (Chaps. 125 and 127), an overview of the subject is presented here. It is helpful to recall that the iron atom has six binding positions. Four of these positions are attached in a single plane to the protoporphyrin ring to form heme. The remaining 2 binding positions lie on opposite sides of this plane. Iron is ordinarily bonded on one side to the F8 proximal histidine residue of the globin chain. The remaining site is available for binding molecular oxygen, but can also bind carbon monoxide, nitric oxide, cyanide, hydroxide ion, or water. The E7 distal histidine residue facilitates the binding of oxygen, while stearically hindering carbon monoxide binding. Methemoglobin Methemoglobin (ferrihemoglobin or hemiglobin) is the oxidized form of deoxyhemoglobin in which at least one heme iron is in the oxidized (Fe3+) valence state. A number of valency hybrids can occur depending on the number of ferric versus ferrous heme units within the tetramer. Methemoglobin therefore represents oxidation (loss of electrons) of the hemoglobin molecule at the iron atom. It occurs spontaneously as a consequence of interactions between the iron and oxygen. Normally, in deoxygenated hemoglobin, the heme iron is in the ferrous (Fe2+) valence state. In this state, there are 6 electrons in the outer shell, 4 of which are unpaired. When oxygen is bound, one of these electrons is partially transferred to it and the iron is reversibly oxidized. When O2 is released, the electron is usually transferred back to heme iron, yielding the normal reduced state. Sometimes, the electron remains with the O2 yielding a superoxide anion radical O2− rather than molecular oxygen. In this case, heme iron is left in the Fe3+, or oxidized, state and is unable to release another electron to bind oxygen. This oxidation is primarily reversed via the action of cytochrome b5 reductase, also known as NADH methemoglobin reductase, which uses the electron carrier NADH generated by glycolysis (“Metabolism” and Chap. 12).77,112 Minor pathways are also involved in methemoglobin reduction, including NADPH methemoglobin reductase, which normally reduces only approximately 5% of the methemoglobin, and vitamin C, a nonenzymatic reducing agent. The activity of NADPH methemoglobin reductase may be significantly accelerated by the presence of the electron donor methylene blue (Antidotes in Depth: Methylene Blue and Chap. 127) or riboflavin.91 Equilibrium is maintained with methemoglobin concentrations of 1% of total hemoglobin. Many xenobiotics are capable of increasing the rate of methemoglobin formation as much as 1000-fold. Nitrites, nitrates, chlorates, and quinones are capable of directly oxidizing hemoglobin.30 Certain individuals may be especially vulnerable because of deficient methemoglobin reduction.44 The fetus and neonate are more susceptible to methemoglobinemia than the adult, as HbF is more susceptible to oxidation of the heme iron than adult hemoglobin. The newborn also has a limited capacity to reduce methemoglobin, because levels of cytochrome b5 reductase only reach adult levels around 6 months of age. Carboxyhemoglobin Carbon monoxide (CO) can reversibly bind to heme iron in lieu of molecular oxygen. The affinity of CO for hemoglobin is 200–300 times that of oxygen, despite the stearic hindrance of the E7 distal histidine. The presence of CO thereby precludes the binding of oxygen. In addition, CO binding within any one heme subunit degrades the cooperative binding of oxygen at the remaining heme groups of the same hemoglobin molecule. The oxyhemoglobin dissociation curve is therefore shifted to the left, reflecting the fact that oxygen is more tightly bound by hemoglobin and less able to be unloaded to the tissues. In addition, CO binds to the heme group of myoglobin and the cytochromes, interfering with cellular respiration, exacerbating the clinical symptoms of hypoxia (Chap. 125).66

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Sulfhemoglobin Sulfhemoglobin is a bright green molecule in which the hydrosulfide anion HS− irreversibly binds to ferrous hemoglobin. The sulfur atom is probably attached to a β carbon in the porphyrin ring, and not at the normal oxygen-binding site.125 It has a spectrophotometric absorption band at approximately 618 nm,23 is ineffective in oxygen transport, and clinically resembles cyanosis. The oxygen affinity of sulfhemoglobin is approximately 100 times less than that of oxyhemoglobin, shifting the oxyhemoglobin dissociation curve to the right, in favor of O2 unbinding. Thus, the symptoms of hypoxia are not as severe with sulfhemoglobinemia as with carboxy- or methemoglobinemia.136 Oxidation of the globin chain Oxidation can also occur at the amino acid side chains of the globin protein. In particular, sulfhydryl groups can oxidize to form disulfide links between cysteine residues, which leads to the unfolding of the protein chain, exposure of other side chains and further oxidation. When these disulfide links join adjacent hemoglobin molecules, they cause the precipitation of the concentrated hemoglobin molecules out of solution. Covalent links can also form between hemoglobin and other cytoskeletal and membrane proteins.39 Eventually, aggregates of denatured and insoluble protein are visible on light microscopy as Heinz bodies. The distortion of the cellular architecture, and the loss of fluidity in particular, is a signal to reticuloendothelial macrophages to excise sections of erythrocyte membrane (“bite cells”) or to remove the entire erythrocyte from the circulation (“Hemolysis”). To guard against these oxidation reactions, the erythrocyte maintains a pool of reduced glutathione via the actions of the NADPH generated in the hexose monophosphate shunt (assuming adequate G6PD activity to initiate this pathway). This glutathione transfers electrons to break open disulfide links and to preserve sulfhydryl groups in their reduced state.

■ HEMOLYSIS Hemolysis is merely the acceleration of the normal process by which senescent or compromised erythrocytes are removed from the circulation.168 The normal life span of a circulating erythrocyte is approximately 120 days, and any reduction in this life span represents some degree of hemolysis. If sufficiently rapid, hemolysis can overwhelm the regenerative capacity of the erythron, resulting in anemia. Intravascular hemolysis occurs when the rate of hemolysis exceeds the capacity of the reticuloendothelial macrophages to remove damaged erythrocytes, and free hemoglobin and other intracellular contents of the erythrocyte appear in the circulation. Reticulocytosis, polychromasia, unconjugated hyperbilirubinemia, increased serum lactate dehydrogenase, and decreased serum haptoglobin are characteristic of hemolysis. A normal or elevated RBC distribution width and thrombocytosis are usually present on the automated complete blood count. The presence of spherocytes on peripheral blood smear suggests an autoimmune or hereditary process, and can be pursued with a Coombs’ test. Schistocytes suggest thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome, disseminated intravascular coagulation, or valvular hemolysis. TTP and hemolytic uremic syndrome are characterized by a microangiopathic anemia, thrombocytopenia and normal coagulation parameters (unlike disseminated intravascular coagulation). TTP is discussed under platelet disorders below. Hemoglobinemia, hemoglobinuria, and hemosiderinuria can occur with intravascular hemolysis. Specialized tests to measure hemolysis detect shortened erythrocyte survival, increased endogenous carbon monoxide generation from heme oxygenase, and increased fecal urobilinogen.175 Table 24–2 presents a brief classification of acquired causes of hemolysis relevant to toxicology. Oxidant injury following xenobiotic

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TABLE 24–2. Xenobiotics Causing Acquired Hemolysis Immune-mediated Type I: IgG against drug tightly bound to red cell Type II: Complement activated by antibodies against drug-membrane complex Type III: True autoimmune response to red cell membrane Nonimmune-mediated Oxidants Aniline107 Benzocaine52;103 Chlorates47;85 Dapsone88 Hydrogen peroxide Hydroxylamine174 Methylene blue166 Naphthalene184 Nitrites16;28;31;154 Nitrofurantoin Oxygen102;121 Phenacetin122 Phenazopyridine53;131 Phenol Platin salts109 Sulfonamides190 Nonoxidants Arsine (AsH3) Copper Lead Pyrogallic acid Stibine (SbH3) Microangiopathic (eg, ticlopidine, clopidogrel, cyclosporine, tacrolimus)(17;19;49;73;165;186) Venoms (snake, spider)(60;78;127;189) Osmotic agents (eg, water)(76;98) Hypophosphatemia(5;90;120)

exposure is one of the triggers of hemolysis, as it may cause irreversible changes in the erythrocyte. Xenobiotics can also interact with the immune system to cause hemolysis. Finally, erythrocytes deficient in G6PD by virtue of cell age or enzyme mutations are particularly vulnerable to hemolysis following oxidant stress due to limited capacity to generate NADPH and reduced glutathione.168

■ NONIMMUNE-MEDIATED CAUSES OF XENOBIOTIC-INDUCED HEMOLYSIS A number of xenobiotics or their reactive metabolites can cause hemolysis via oxidant injury; Table 24–2 provides a partial list. A Heinz-body hemolytic anemia can result, which typically resolves within a few weeks of drug discontinuation. Some xenobiotics cause hemolysis in the absence of overt oxidant injury (see Table 24–2). Copper sulfate

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hemolysis is described in Chap. 93, and the delayed hemolysis following exposure to arsine or stibine is described below. Arsine Arsine (AsH3) is a colorless, odorless, nonirritating gas that is 2.5 times denser than air (Chap. 88). Clinical signs and symptoms appear after a latent period of up to 24 hours after exposure to concentrations above 30 ppm, and may include headache, malaise, dyspnea, abdominal pain with nausea and vomiting, hepatomegaly, hemolysis with hemoglobinuric renal failure, and death.38,54,87,97,141 The mechanism of hemolysis is believed to involve the fixation of arsine by sulfhydryl groups of hemoglobin and other essential proteins.63,192 Interestingly, hemolysis is prevented in vitro by conversion to carboxyor methemoglobin.70 Impairment of membrane proteins including Na+-K+-ATPase is another potential mechanism for arsine-induced hemolysis.148 Chronic exposure to low levels of arsine can produce clinically significant disease.38 Stibine (SbH3) an antimony derivative likely causes hemolysis via similar mechanisms.

■ IMMUNE-MEDIATED HEMOLYTIC ANEMIA The immune-mediated hemolytic anemias occur when ingested xenobiotics trigger an antigen antibody reaction (see Table 24–2).138 In general, these molecules are too small to be sensitizing agents, but antigenicity can be acquired after binding to carrier proteins in blood. The particulars of the xenobiotic-carrier immune activation sequence form the basis for the classification of this group of hemolytic anemias.13 The first class of reaction (hapten model, or drug adsorption) occurs when the xenobiotic acts as a hapten and binds tightly to cell membrane glycoproteins on the surface of the erythrocyte. IgG antibodies develop against the bound drug, leading to removal of the erythrocyte by splenic macrophages. The prototype of this reaction is the hemolytic anemia observed following high dose penicillin therapy.55 Historically, approximately 3% of patients treated with megadose penicillin over weeks for infectious endocarditis developed a positive direct Coombs test, demonstrating erythrocytes become coated with IgG or complement. The positive direct Coombs test is a necessary, but insufficient, condition for the hemolytic reaction. The hemolysis is usually subacute, and requires at least a week to develop, but can become life threatening if the cause is not recognized. Discontinuation of the xenobiotic results in cessation of hemolysis, because its presence is needed for antibody binding. The second class of reaction (immune complex, or neoantigen) occurs with drugs that have low affinity for cellular membrane glycoproteins. Examples are quinine, quinidine, stibophen and newer-generation cephalosporins, such as cefotetan, cefotaxime, and ceftriaxone. Antibodies are formed against the joint drug-membrane complex (neoantigen), and erythrocyte injury is primarily mediated by complement. Unlike the hapten model, small doses of xenobiotics are sufficient to trigger sudden intravascular hemolysis and hemoglobinuria, leading to renal failure. The direct Coombs test is positive only for complement, but the presence of drug is again necessary. The third class of reaction (true autoimmune) occurs when the xenobiotic alters the natural suppressor system, allowing the formation of antibody to cellular components. This is a true autoantibody reaction directed against erythrocyte surface antigen rather than the drug.15 The classic example is α-methyldopa, but chlorpromazine, cladribine, cyclosporine, fludarabine, levodopa, and procainamide can also trigger autoimmune hemolysis.15,128,153 An indirect Coombs test that is positive in the absence of drug demonstrates the presence of IgG autoantibodies in the patient’s serum when incubated with normal erythrocytes. The severity of hemolysis is variable, and its onset insidious, but hemolysis can continue for weeks to months despite removal of the inciting agent. Glucose-6-phosphate dehydrogenase deficiencies (G6PD) G6PD is the enzyme that catalyzes the first step of the hexose monophosphate

shunt: the conversion of glucose-6-phosphate to phosphogluconolactone (see Fig. 12-5). In the process, NADP+ is reduced to NADPH, which the erythrocyte uses to maintain a supply of reduced glutathione and to defend against oxidation. It follows that erythrocytes deficient in G6PD activity are less able to resist oxidant attack and, in particular, to maintain sulfhydryl groups of hemoglobin in their reduced state, resulting in hemolysis. It is important to recognize that the term G6PD deficiency encompasses a wide range of differences in enzyme activities among individuals. These differences may result from decreased enzyme synthesis, altered catalytic activity, or reduced stability of the enzyme. Approximately 7.5% of the world population is affected to some degree, with more than 400 variants having been identified. Most cases involve relatively mild deficiency and minimal morbidity.25,37,114 Ethnic populations from tropical and subtropical countries (the socalled malaria belt) have a much higher prevalence of G6PD deficiency, possibly because that phenotype protects against malaria.129 The gene that encodes for G6PD resides near the end of the long arm of the X-chromosome. Most mutations consist of a single amino acid substitution, as complete absence of this enzyme is lethal. Although males hemizygous for a deficient gene are more severely affected, females randomly inactivate one X-chromosome during cellular differentiation according to the Lyon hypothesis. Thus, female carriers heterozygous for a deficient G6PD gene have a mosaic of erythrocytes, some proportion of which expresses the deficient gene during maturation. Accordingly, approximately 10% of carrier females may be nearly as severely affected as a male hemizygous for the same deficient gene. Because of the high gene frequency in certain ethnic groups, another approximately 10% of females may be homozygous for the deficient gene. Normal G6PD has a half-life of about 60 days. Because the erythrocyte cannot synthesize new protein, the activity of G6PD normally declines by approximately 75% over its 120-day life span. Consequently, even in unaffected individuals, susceptibility to oxidant stress varies based on the age mix of circulating erythrocytes. In all cases, older erythrocytes are less likely to recover following exposure to an oxidant and will hemolyze first. Moreover, after an episode of hemolysis following acute exposure to an oxidant stress, the higher G6PD activity of surviving erythrocytes will confer some resistance against further hemolysis in most individuals with relatively mild deficiency, even if the offending xenobiotic is continued. Phenotypic testing for G6PD deficiency is best done 2 to 3 months after a hemolytic crisis, after the reticulocyte count has normalized. The World Health Organization classification of G6PD is based on the degree of enzyme deficiency and severity of hemolysis.27 Both class I and class II patients are severely deficient, with less than 10% of normal G6PD activity. Class I individuals are prone to chronic hemolytic anemia, whereas class II patients experience intermittent hemolytic crises. Class III patients have only moderate (10%–60%) enzyme deficiency, and experience self-limiting hemolysis in response to certain drugs and infections. Approximately 11% of African Americans have a class III deficiency, traditionally termed type A−, and experience a decline of no more than 30% of the red blood cell mass during any single hemolytic episode. Another 20% of African Americans have type A+ G6PD enzyme, which is functionally normal, and therefore of no consequence despite a 1-base substitution compared to wild-type B. The Mediterranean type found in Sardinia, Corsica, Greece, the Middle East, and India is a class II deficiency, and hemolysis can occur spontaneously or in response to ingestion of oxidants, such as the β-glycosides found in fava (Vicia fava) beans. The most common clinical presentation of previously unrecognized G6PD deficiency is the acute hemolytic crisis. Typically, hemolysis begins 1 to 4 days following the exposure to an offending xenobiotic or infection (Table 24–3). Jaundice, pallor, and dark urine may occur

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TABLE 24–3. Representative Xenobiotics That Can Cause Hemolysis in Patients with Class I, II, or III G6PD Deficiency Doxorubicin Furazolidone Isobutyl nitrite Methylene blue Nalidixic acid Naphthalene Nitrofurantoin Phenazopyridine

Phenylhydrazine Primaquine Sulfacetamide Sulfamethoxazole Sulfanilamide Sulfapyridine Toluidine blue Trinitrotoluene

Data adapted from Beutler E: Glucose-6-phosphate dehydrogenase deficiency. N Engl J Med 1991;324:169–174, and Beutler E: G6PD deficiency. Blood 1994;84:3613–3636.

with abdominal and back pain. A decrease in the concentration of hemoglobin occurs. The peripheral smear demonstrates cell fragments and cells that have had Heinz bodies excised. Bone marrow stimulation results in a reticulocytosis by day 5 and an increased erythrocyte mass. In general, a normal bone marrow can compensate for ongoing hemolysis, and can return the hemoglobin concentration to normal. Most crises are self-limiting because of the higher G6PD activity of younger erythrocytes. Historically, the anemia observed when primaquine was administered to type A− military recruits for malaria prophylaxis resolved within 3 to 6 weeks in most patients.26 Some xenobiotics, including acetaminophen, vitamin C, and sulfisoxazole, are safe at therapeutic doses but can cause hemolysis in G6PD-deficient patients following overdose.24,170,193 Other presentations of more severe variants of G6PD include neonatal jaundice and kernicterus, chronic hemolysis with splenomegaly and black pigment gallstones, megaloblastic crisis caused by folate deficiency, and aplastic crisis after parvovirus B19 infection.

■ MEGALOBLASTIC ANEMIA Vitamin B12 and folate are essential for one-carbon metabolism in mammals. One-carbon fragments are necessary for the biosynthesis of thymidine, purines, serotonin and methionine, as well as the methylation of DNA, histones and other proteins, and the complete catabolism of branched chain fatty acids and histidine. Unable to synthesize vitamin B12 or folate, mammals are dependent on dietary sources and microorganisms for these cofactors. The hematologic manifestation of vitamin B12 or folate deficiency is a characteristic panmyelosis termed megaloblastic anemia. The hallmark nuclear-cytoplasmic asynchrony is due to disrupted DNA synthesis, halted interphase and ineffective erythropoiesis.146 The hyperplastic bone marrow contains precursor cells with abnormal nuclei filled with incompletely condensed chromatin. Among circulating blood cells, macrocytic anemia (macroovalocytes) without reticulocytosis is followed by the appearance of granulocytes with an abnormally large, distorted nucleus (hypersegmented neutrophils with six or more lobes). Lymphocytes and platelets may appear normal but are also functionally impaired. In addition to dietary deficiencies which have become less common, macrocytic anemia with or without megaloblastosis in adults is usually caused by chronic ethanol abuse, chemotherapy or antiretroviral agents, especially when mean corpuscular volumes are only moderately elevated (100–120 fL).158 The folate antagonists aminopterin, methotrexate, hydantoins, pyrimethamine, proguanil, sulfasalazine,

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trimethoprim-sulfamethoxazole and valproate can interfere with DNA synthesis. Ethanol affects folate metabolism and transport. Vitamin B12 deficiency can be induced by chronic exposure to nitrous oxide, biguanides, colchicine, neomycin, and the proton pump inhibitors. Purine analogs (eg, azathioprine, 6-mercaptopurine, 6-thioguanine, acyclovir) and pyrimidine analogs (eg, 5-fluorouracil, floxuridine, 5-azacitidine, and zidovudine) also disrupt nucleic acid synthesis. Hydroxyurea and cytarabine, which inhibit ribonucleotide reductase, also delay nuclear maturation and function and frequently cause megaloblastosis.

■ PURE RED CELL APLASIA Pure red cell aplasia is an uncommon condition in which erythrocyte precursors are absent from an otherwise normal bone marrow. It results in a normocytic anemia with inappropriately low reticulocyte count. The other blood cell lines are unaffected, unlike aplastic anemia. Drugs cause less than 5% of cases of this uncommon condition, having been implicated in fewer than 100 human reports.180 Only phenytoin, azathioprine, and isoniazid meet criteria for definite causality; chlorpropamide and valproic acid can only be considered as possible causes.180 Most other xenobiotics are cited only in single case reports, and drug rechallenge was not used, making the association uncertain. In part because of its rarity, a cluster of 13 cases in France of pure red cell aplasia in hemodialysis patients receiving subcutaneous recombinant erythropoietin ultimately led to an international effort by researchers, regulatory authorities and industry to identify the etiology.20,41 To reduce theoretical concerns regarding transmission of variant Creutzfeldt-Jakob disease, human serum albumin was replaced with polysorbate 80 as the stabilizer in a formulation used in Europe and Canada. It is suspected that this change allowed rubber to leach from the uncoated stopper of prefilled syringes, triggering an immune response against both recombinant and endogenous erythropoietin in some patients.118 This episode not only serves as a recent example of successful pharmacovigilence for rare adverse drug effects, but has also influenced safety assessments for an emerging class of biological therapies which include simple peptides, monoclonal antibodies and recombinant DNA proteins.18,118

■ ERYTHROCYTOSIS Erythrocytosis denotes an increase in the red cell mass, either in absolute terms or relative to a reduced plasma volume. An increasingly recognized cause of drug-induced absolute erythrocytosis is the abuse of recombinant human erythropoietin by athletes to enhance aerobic capacity.34,57,61,173 Autologous blood transfusions (doping) are also used in this population, and both can cause dangerous increases in blood viscosity. Cobalt was once considered for the treatment of chronic anemia50 because of its ability to cause a secondary erythrocytosis. The mechanism may involve impaired degradation of the transcription factor Hypoxia Inducible Factor 1α, thereby prolonging erythropeitin transcription. This effect is more pronounced in high altitude dwellers, in whom elevated serum erythropoietin concentrations despite hematocrits in excess of 75% and chronic mountain sickness have been associated with increased serum cobalt concentrations.86

THE LEUKON The leukon represents all leukocytes (white blood cells), including precursor cells, cells in the circulation, and the large number of extravascular cells. It includes the granulocytes (neutrophils, eosinophils, and basophils), lymphocytes, and monocytes. Neutrophils (polymorphonuclear leukocytes) are highly specialized mediators of the inflammatory response, and are a primary focus of concern regarding hematologic

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toxicity of xenobiotics. B and T lymphocytes are involved in antibody production and cell-mediated immunity. Monocytes migrate out of the vascular compartment to become tissue macrophages and to regulate immune system function. Immunity is generally divided into the innate and the adaptive responses. Innate immunity is an immediate but less specific defenses that is highly conserved in evolutionary terms. It is centered on the neutrophil response, and involves monocytes and macrophages as well as complement, cytokines and acute phase proteins. The innate system responds primarily to extracellular pathogens, especially bacteria, by recognizing structures commonly found on pathogens, namely lipopolysaccharide (Gram negative cell walls), lipotechoic acid (Gram positive) and mannans (yeast). Adaptive immunity is demonstrated only in higher animals, and is an antigen-specific response via T- and B-lympocytes after antigen presentation and recognition. While this reaction is more specific, it requires several days to develop, unless that antigen has previously triggered a response (so-called immune memory). This response can also at times be directed against self antigens, resulting in autoimmune disorders. The recruitment and activation of neutrophils provide the primary defense against the invasion of bacterial and fungal pathogens. They emerge from the bone marrow with the biochemical and metabolic machinery needed for the efficient killing of microorganisms. Activated macrophages release granulocyte and granulocyte-macrophage colony stimulating factors, which stimulate myeloid differentiation and can be recognized on blood testing as the classic neutrophil leucocytosis. Neutrophils are activated when circulating cells detect chemokines released from sites of inflammation. On activation, they undergo conformational and biochemical changes that transform them into powerful host defenders.115 These changes allow rolling along the endothelial lining of postcapillary venules, migration toward the site of inflammation, adherence to the endothelium, migration through the endothelium to tissue sites, ingestion, killing, and digestion of invading organisms.115 Neutrophils migrate to sites of infection along gradients of chemoattractant mediators. An acute inflammatory stimulus leads to the accumulation of neutrophils along the endothelium of postcapillary venules.33 The major molecules involved in this process are adhesion molecules, chemoattractants, and chemokines. Loose adhesions between neutrophils and endothelium are made and broken, resulting in the slow movement of leukocytes along endothelium and a more intense exposure of neutrophils to activating factors. Chemotaxis requires responses involving actin polymerization–depolymerization adhesion events mediated by integrins and involving microfilament– membrane interactions.29 All leukocytes including lymphocytes localize infection using these same mediators. Colchicine depolymerizes microfilaments, causing the dissolution of the fibrillar microtubules in granulocytes and other motile cells, impairing this response. Opsonized particles, immune complexes, and chemotactic factors activate neutrophils in tissues by binding to cell surface receptors. The neutrophil makes tight contact with its target, and the plasma membrane surrounds the organism completely enclosing it. Two mechanisms are then responsible for the destruction of the organism: the oxygen-dependent respiratory burst and the oxygen-independent response involving cationic enzymes found in cytoplasmic granules. The respiratory burst is caused by an NADPH oxidase complex that assembles at the phagosomal membrane. Electrons are transferred from cytoplasmic NADPH to oxygen on the phagosomal side of the membrane, generating superoxide, hydrogen peroxide, hydroxyl radical, singlet oxygen, hypochlorous acid, chloramines, nitric oxide, and peroxynitrite.67 Cytoplasmic granules within the neutrophil fuse with the phagosome and empty their contents into it. There are at least four different classes of granules.67 The components of these granules include myeloperoxidase (MPO), elastase, lipases, metalloproteinases, and a

pool of CD11b/CD18 proteins required for adhesion and migration.149 Finally, the phagocytized organism is digested and eliminated by the neutrophil. Overstimulation of this complex and highly regulated but somewhat non-specific system can at times become deleterious, as is postulated to occur with reperfusion injury or carbon monoxide poisoning, to cite two examples.179,188 Vasculitis and the systemic inflammatory response syndrome are further examples of excessive activation of the innate response.

■ NEUTROPENIA AND AGRANULOCYTOSIS Neutropenia is a reduction in circulating neutrophils at least two standard deviations below the norm, but the threshold of 1500/mm3 (1.5 × 109/L) is often used instead.75 Severe neutropenia is termed agranulocytosis, and is generally defined to be an absolute neutrophil count of less than 500/mm3 (0.5 × 109/L). Neutropenia can result from decreased production, increased destruction or retention of neutrophils in the various storage pools. Their high rate of turnover renders neutrophils vulnerable to any xenobiotic that inhibits cellular reproduction. As such, the various antineoplastic xenobiotics including antimetabolites, alkylating agents and antimitotics will predictably cause neutropenia. This predictable, dose-dependent reaction represents an important dose-limiting adverse effect of therapy. On the other hand, a number of xenobiotics are implicated in idiosyncratic neutropenia.7,8 The parent drug or a metabolite usually act as a hapten to trigger antineutrophil antibodies. Table 24–4 provides an abbreviated list.139,176 A recent

TABLE 24–4. Selected Causes of Idiosyncratic Drug-Induced Agranulocytosis Anticonvulsants Carbamazepine Phenytoin Antiinflammatory agents Aminopyrine Ibuprofen Indomethacin Phenylbutazone Antimicrobials β-Lactams, including penicillin G* Cephalosporins Chloramphenicol Dapsone* Ganciclovir Isoniazid Rifampicin Sulfonamides Vancomycin Antirheumatics Gold salts Levamisole197 Penicillamine Sulfasalazine∗

*

Antipsychotics Clozapine* Phenothiazines Antithyroid agents Methimazole* Propylthiouracil* Cardiovascular agents Hydralazine Lidocaine Procainamide* Quinidine Ticlopidine* Vesnarinone Diuretics Acetazolamide Hydrochlorothiazide Hypoglycemics Chlorpropamide Tolbutamide Sedative-hypnotics Barbiturates Flurazepam Other Deferiprone

denotes at least 10 cases reported6

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systematic review of published case reports identified a small subset of xenobiotics (denoted by an asterisk in the table) which were implicated in at least 10 cases and which account for the majority of reports deemed definitely or probably drug-induced. 6

■ EOSINOPHILIA Eosinophils are primarily responsible for protecting against parasitic infection. Allergic reactions and malignancies such as lymphoma are also common causes of eosinophilia, especially where nematode infection is rare.155 Eosinophils bind to antigen-specific IgE, and discharge their large granules which contain major basic protein, peroxidase, and eosinophil-derived neurotoxin onto the surface of the antibodycoated organism. Two unusual toxicologic outbreaks were characterized by eosinophilia, acute cough, fever, and pulmonary infiltrates, followed by severe myalgia, neuropathy, and eosinophilia. The first outbreak, called the toxic oil syndrome, took place in central Spain in 1981, when industrial-use rapeseed oil denatured with 2% aniline was fraudulently sold as olive oil by door-to-door salesmen.58 The precise causative agent remains uncertain, but may include fatty acid esters of 3-(N-phenylamino)-1,2-propanediol.58 The second outbreak, called the eosinophilia-myalgia syndrome, occurred during 1988 and 1989 in users of L-tryptophan supplements traced back to a single wholesaler in Japan.10 The causative contaminant has not been identified, but is believed to have been present in only trace quantities in the L-tryptophan purified from microbial culture. Both syndromes appear to be mediated by immunologic mechanisms.

■ LEUKEMIA The leukemias represent the malignant, unregulated proliferation of hematopoietic cells. Although monoclonal in origin, they affect all cell lines derived from the progenitor cell. Acute myeloid leukemia (AML) and the myelodysplastic syndromes are the most common leukemias associated with xenobiotics. The long-recognized association between AML and occupational benzene exposure, radiation, or treatment with alkylating antineoplastic agents has helped to advance understanding of the molecular mechanisms underlying leukemogenesis.22 The necessary events are believed to involve several sequential genetic and epigenetic alterations, as evidenced by a distinct pattern of chromosomal deletions preceding the development of AML.80,81 Other recognized xenobiotics that can cause leukemia include topoisomerase

Subendothelial collagen

II inhibitors, 1,3-butanediol, styrol, ethylene oxide, and vinyl chloride.92 In many cases, the latency period between exposure and illness is prolonged. For example, leukemia linked to benzene is preceded by several months of anemia, neutropenia, and thrombocytopenia. Benzene or other petroleum products are not believed to cause multiple myeloma.22

HEMOSTASIS In the absence of pathology, blood remains in a fluid form with cells in suspension. Injury triggers coagulation and thrombosis. The resulting clot formation, retraction, and dissolution involve an interaction between the vessel endothelium, soluble constituents of the coagulation system, and proteins located on and within platelets. Platelets respond to signals within their immediate environment and from injured components of the distant microcirculation. A dynamic balance must be maintained between coagulation and fibrinolysis to maintain the integrity of the circulatory system (Fig. 24–4).

■ COAGULATION Two basic pathways termed intrinsic and extrinsic are involved in the initiation of coagulation. Activation of the intrinsic system occurs when blood is exposed to tissue factor in damaged blood vessels or on the surface of activated leukocytes. Tissue factor binds factor VIIa, forming the intrinsic tenase complex, which activates factors IX and X. Factor IXa binds to the surface of activated platelets together with VIIIa and calcium, forming the extrinsic tenase complex. Factor X, which is activated by extrinsic and intrinsic tenase, binds to factor Va on the surface of activated platelets, forming the prothrombinase complex. The prothrombinase complex activates prothrombin, which results in the generation of thrombin activity. Thrombin activates platelets, promotes its own generation by activation of factors V, VIII, and XI, and converts fibrinogen to fibrin (Chap. 59).72

■ XENOBIOTIC-INDUCED DEFECTS IN COAGULATION Warfarin The recognition of a hemorrhagic disease in cattle in the 1920s and the isolation of the causative agent dicoumarol from spoiled sweet clover in the 1940s resulted in the development of the warfarintype anticoagulants (Chap. 59). This group of anticoagulants indirectly

Vessel injury

Von Willebrand factor

TF

VIIa

Platelet adhesion

Thrombin

Prothrombin

Xa Va

Hemostatic plug VII

APD EPI NO PGI2 TXA2

351

Hematologic Principles

X

Protein C/S

Plasmin D-dimers Platelet aggregates

Plasminogen

Thrombin + Heparin

Crosslinking

Fibrin

AT Fibrinogen

FIGURE 24–4. The general relationships between thrombosis, coagulation, and fibrinolysis. Although these pathways are shown independently, they are intricately linked as outlined in the text. Von Willebrand factor stabilizes factor VIII and platelets on the surface of exposed endothelium. The star indicates that plasminogen is activated by t-PA, which itself is inhibited by plasminogen activator inhibitor (PAI; not shown). Recombinant t-PA (rt-PA) is commercially available. ( ) indicate inhibition; ⊕ denotes activation of catalytic activity. For a more detailed version, see Figure 59–1. AT = antithrombin; t-PA = tissue plasminogen activator.

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inhibits hepatic synthesis of coagulation factors II, VII, IX, X, and proteins C and S.140 Hepatic γ-carboxylation of glutamic acid residues by vitamin K-dependent carboxylase results in the formation of the vitamin K-dependent clotting factors. Vitamin K must be available in its reduced form, vitamin K quinol, to effectively catalyze this reaction. The carboxylation reaction oxidizes vitamin K quinol to vitamin K2,3 epoxide, which must be reduced to vitamin K by reductase enzymes. The warfarin anticoagulants inhibit the reductase that is responsible for the regeneration of vitamin K quinone from vitamin K epoxide, impairing the synthesis of the vitamin K-dependent proteins.95,171 Heparin Heparin is a highly sulfated glycosaminoglycan that is normally present in tissues. Commercial unfractionated heparin is either bovine or porcine in origin, and consists of a mixture of polysaccharides with molecular weights ranging from 4000–30,000 Da. It is used extensively for the prophylaxis and treatment of venous thrombosis and thromboembolism. It is ineffective orally. This same property makes it safe for use during pregnancy because heparin cannot cross the placenta.157 The anticoagulant activity of heparin is through its catalytic activation of antithrombin III. Antithrombin III acts as a suicide inhibitor of the serine proteases thrombin and factors IXa, Xa, XIa and XIIa.126 The low-molecular-weight heparins (LMWHs) have a mean molecular weight of 4000–6000 Da.72 The pharmacokinetics and bioavailability of the LMWHs are more predictable, eliminating the need for close monitoring. They exhibit lower protein binding and a longer half-life than unfractionated heparin, making them more convenient to use.126 Other anticoagulants Heparinoids are glycosaminoglycans not derived from heparin with anticoagulant effects. This class includes dermatan sulfate, which activates the thrombin inhibitor heparin cofactor II, and danaparoid sodium, which inhibits factor Xa. Fondaparinux is a synthetic pentasaccharide that also inhibits factor Xa, and therefore acts upstream of thrombin. Several direct thrombin inhibitors are also in clinical use, including lepirudin, argatroban, bivalirudin, and dabigatran. These agents prolong the activated partial thromboplastin time and whole-blood activated clotting time, but also affect the INR.

■ FIBRINOLYSIS The coagulation system is opposed by three major inhibitory systems. Components of the fibrinolytic system circulate as zymogens, activators, inhibitors, and cofactors.51 Plasminogen can be activated to plasmin by an intrinsic pathway involving factor XII, prekallikrein, and highmolecular-weight kininogen. This produces the degradation products and fibrin monomers that are found in disseminated intravascular coagulation. The extrinsic pathway involves the release of tissue plasminogen activator (t-PA) from tissues and urokinase plasminogen activator (u-PA) from secretions.51 Once activated, plasmin can degrade fibrinogen, fibrin, and coagulation factors V and VIII. The degradation of cross-linked fibrin strands results in the formation of D-dimers. Several inhibitors oppose the fibrinolytic system, including α2antiplasmin, α2-macroglobulin, both of which oppose plasmin activity, and plasminogen activator inhibitor (PAI) types 1 and 2, which oppose t-PA. PAI-1 and PAI-2 are opposed by activated protein C and protein S. Activated protein C is activated by thrombin. Congenital deficiencies of proteins C and S may result in pathologic venous thrombosis. Decreased fibrinolytic activity may result from decreased synthesis, release of t-PA, or from an elevation of the PAI-1 level. Both conditions have been observed postoperatively, with the use of oral contraceptives, in the third trimester of pregnancy, and in obesity. The activity of α2antiplasmin and α2-macroglobulin are increased in pulmonary fibrosis, malignancy, infection, and myocardial infarction, and in thromboembolic disease.51

TABLE 24–5. Xenobiotics which impair Fibrinolysis Antineoplastics Anthracyclines L-Asparaginase Methotrexate Mithramycin Antifibrinolytics Aminocaproic acid Aprotinin Desmopressin Tranexamic acid Coagulation factors Cytokines Erythropoietin Thrombopoietin Hormones, including conjugated estrogens

■ XENOBIOTIC-INDUCED DEFECTS IN FIBRINOLYSIS. Table 24–5 lists xenobiotics associated with an acquired defect of fibrinolysis. The antitumor agents may result in a reduction in serine protease inhibitors such as antithrombin. L-Asparaginase is associated with a reduction in circulating t-PA levels. Methotrexate can damage vascular endothelium, which may trigger thrombosis (Chap. 53).51 Hemostatic drugs used therapeutically include the synthetic lysine derivatives aminocaproic acid and tranexamic acid, which bind reversibly to plasminogen; the bovine protease inhibitor aprotinin, which inhibits kallikrein; the vasopressin analog desmopressin, which increases plasma concentrations of factor VIII and vWF; and conjugated estrogens, which normalize bleeding times in uremia.111

■ PLATELETS In the resting state, platelets maintain a discoid shape. The platelet membrane is a typical trilaminal membrane with glycoproteins, glycolipids, and cholesterol embedded in a phospholipid bilayer. The plasma membrane is in direct continuity with a series of channels, the surfaceconnected canalicular system (SCCS), which is sometimes referred to as the open canalicular system. The SCCS provides a route of entry and exit for various molecules, a storage pool for platelet glycoproteins, and an internal reservoir of membrane that may be recruited to increase platelet surface area.133 This facilitates platelet spreading and pseudopod formation during the process of cell adhesion. The glycocalyx, or outer coat, is heavily invested with glycoproteins that serve as receptors for a wide variety of stimuli. The β1-integrin family includes receptors that mediate interactions between cells and mediators in the extracellular matrix, including collagen, laminin, and fibronectin.169 The β2-integrin receptors are present in inflammatory cells and platelets and are important in immune activation. The β3-integrin receptors (also known as cytoadhesins) include the glycoprotein (GP) IIb-IIIa fibrinogen receptor, as well as vitronectin.72 Vitronectin has binding sites for other integrins, collagen, heparin, and components of complement. All of the integrins are active in the process of platelet adhesion to surfaces. Platelet aggregation is mediated by the GP IIb-IIIa receptors.72

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The submembrane region contains actin filaments that stabilize the platelets’ discoid shape and are involved in the formation and stabilization of pseudopods. They also generate the force needed for the movement of receptor-ligand complexes from the outer plasma membrane to the SCCS. These mobile receptors are important in the spreading of platelets on surfaces, and for binding fibrin strands and other platelets. Platelet cytoplasm contains three types of membrane bound secretory granules.72 The α granules contain β-thromboglobulin, which mediates inflammation, binds and inactivates heparin, and blocks the endothelial release of prostacyclin. In addition, platelet factor-4, which inactivates heparin, and fibrinogen are contained within the α granules. Dense granules store adenine nucleotides, serotonin, and calcium, which are secreted during the release reaction. Platelet lysosomes contain hydrolytic enzymes. Stimulation by platelet agonists causes the granules to fuse with the channels of the SCCS, driving the contents out of the platelets and into the surrounding media. Platelet adhesion In the vessel wall, collagen, von Willebrand factor (vWF), and fibronectin are the adhesive proteins that play the most prominent role in the adhesion of platelets to vascular subendothelium.169 On the exposure of collagen (eg, following a laceration or the rupture of an atherosclerotic plaque), platelet adhesion is triggered. Under conditions of high shear (flowing blood), platelet adhesion is mediated by the binding of GP Ib-V-IX receptors on platelet membranes to vWF in the vascular subendothelium.72,169 Following adherence of platelets to subendothelial vWF, a conformational change in GP IIb-IIIa on platelet membrane occurs, activating this receptor complex to ligate vWF and fibrinogen. The result is the amplification of platelet adhesion and aggregation. An important interaction occurs between thrombosis and inflammation. Platelet-activating factor is synthesized and coexpressed with P-selectin on the surface of the endothelium in response to mediators such as hista-mine or thrombin. Plateletactivating factor interacts with a receptor on the surface of neutrophils that activates the CD11/CD18 adhesion complex, and results in adhesion of neutrophils to endothelium and to platelets. This results in the synthesis of leukotrienes and other mediators of inflammation. Platelet activation Thrombin, collagen, and epinephrine can activate platelets. In response to thrombin, granules fuse with each other and with elements of the SCCS to form secretory vesicles.133 These vesicles are believed to fuse with the surface membrane, releasing their contents into the surrounding medium. The membranes of the secretory granules become incorporated into the platelet surface membrane. Platelet aggregation Following activation, GP IIb-IIIa is expressed in active form on platelet surface, serving as the final common pathway for platelet aggregation regardless of inciting stimulus. This receptor binds exogenous calcium and fibrinogen. GP IIb-IIIa ligates fibrinogen along with fibronectin, vitronectin, and vWF, resulting in the binding of platelets to other platelets, and ultimately the formation of the platelet plug. Collagen-induced platelet aggregation is mediated by adenosine diphosphate (ADP) and thromboxane A2. ADP binds to the metabotropic purine receptors P2Y1 and P2Y12, leading to transient and sustained aggregation, respectively.56 Thromboxane A2 is formed from arachidonic acid by the action of cyclooxygenase 1. It is a potent vasoconstrictor and inducer of platelet aggregation and release reactions.72 Platelets participate in triggering the coagulation cascade by binding coagulation factors II, VII, IX, and X to membrane phospholipid, a calcium-dependent process.

■ ANTIPLATELET AGENTS Aspirin Aspirin inhibits prostaglandin H synthase (cyclooxygenase [COX]) by irreversibly acetylating a serine residue at the active site of the enzyme. Aspirin inhibition of the COX-1 isoform of this enzyme

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is 100–150 times more potent than its inhibition of the COX-2 isoform. The inhibition of COX-1 results in the irreversible inhibition of thromboxane A2 formation. Because platelets can be activated by other mechanisms including thrombin, thrombosis can develop despite aspirin therapy (Chap. 35).163 Selective COX-2 inhibitors Platelets express primarily COX-1 and use it to produce mostly thromboxane A2, which leads to platelet aggregation and vasoconstriction. Endothelial cells express COX-2 and use it to produce prostaglandin I2, an inhibitor of platelet aggregation and a vasodilator. Whereas aspirin and traditional (nonselective) nonsteroidal antiinflammatory medications inhibit the production of thromboxane A2 and prostaglandin I2 at both sites, the selective COX-2 inhibitors do not affect platelet derived thromboxane A2, perhaps accounting for the increase in cardiovascular events associated with long-term use of some of these xenobiotics.43,89,100,110,172,185 GP IIb-IIIa antagonists The GP IIb-IIIa antagonist abciximab is a chimeric human-murine monoclonal antibody that binds the GP IIb-IIIa receptor of platelets and megakaryocytes. Two synthetic ligand-mimetic antagonists have also been developed: eptifibatide and tirofiban. These parenteral agents are used primarily in patients undergoing percutaneous coronary interventions.72 By blocking the fibrogen binding site of IIb-IIIa, platelet aggregation is blocked and even reversed regardless of the inciting activation. Reversible thrombocytopenia can occur within hours of initiation of these xenobiotics.156 Thienopyridines The prodrugs clopidogrel and ticlopidine antagonize ADP-mediated platelet aggregation by noncompetitive inhibition of ADP binding to the P2Y12 receptor.137,147 Both prodrugs are associated with thrombotic thrombocytopenic purpura, as well as neutropenia and aplastic anemia.17,19,134,135,147 Dipyridamole The pyrimidopyrimidine derivative dipyridamole inhibits cyclic nucleotide phosphodiesterase in platelets, resulting in the accumulation of cyclic adenosine monophosphate and perhaps cyclic guanine monophosphate.

■ XENOBIOTIC-INDUCED THROMBOCYTOPENIA Multiple drugs are reported to cause thrombocytopenia, either via the formation of drug-dependent antiplatelet antibodies or as thrombotic thrombocytopenic purpura. Drug-induced platelet antibodies are estimated to occur in 1 in 100,000 drug exposures. Reversible drug binding to platelet epitopes such as GP Ib-V-IX, GP IIb-IIIa, and platelet– endothelial cell adhesion molecule-1, lead to a structural change that can form or expose a neoepitope target for antibody formation.11,152 The presence of the drug is required for antibody binding and increased platelet destruction, but there is no covalent bond (as occurs in the hapten model of penicillin binding to the erythrocyte membrane). Thrombocytopenia can also occur as a result of spurious clumping, pregnancy, hypersplenism with cirrhosis, idiopathic thrombocytopenic purpura, heparin-induced thrombocytopenia (Chap. 59), bone marrow toxicity, and thrombotic thrombocytopenic purpura. After excluding these conditions and nontherapeutic exposures, a systematic literature search updated annually lists more than 1000 cases reported in English involving more than 150 xenobiotics.1 Table 24–6 lists the xenobiotics appearing in multiple cases satisfying criteria for probable to definite causality including drug rechallenge. Nevertheless, a common clinical problem is to distinguish drug-induced thrombocytopenia from idiopathic thrombocytopenic purpura in a patient on multiple medications who develops thrombocytopenia. In the absence of validated laboratory assays for drug-dependent platelet antibodies other than heparin, diagnosis still depends on the clinical course following drug discontinuation and perhaps rechallenge. Large databases provide

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TABLE 24–6. Xenobiotics Reported to Cause Thrombocytopenia as a Result of Antiplatelet Antibodiesa Abciximab Acetaminophen Aminoglutethimide Aminosalicylic acid Amiodarone Amphotericin B Carbamazepine Cimetidine Danazol Diclofenac Digoxin Dipyridamole Eptifibatide Famotidine Furosemide Gold salts Heparin Imipenem-cilastatin

Indinavir Levamisole Linezolid Meclofenamic acid Nalidixic acid Orbofiban Oxprenolol Phenytoin Piperacillin Procainamide Quinidine Quinine Rifampin Tirofiban Trimethoprim-sulfamethoxazole Valproate Vancomycin

a Xenobiotics reported in at least 2 cases to have definitely caused immune thrombocytopenia, or in at least 5 cases to have probably caused immune thrombocytopenia following therapeutic use.

Data adapted from George JN, Raskob GE, Shah SR, et al: Drug-induced thrombocytopenia: A systematic review of published case reports. Ann Intern Med 1998;129:886–890; Li X, Swisher KK, Vesely SK, George JN: Drug-induced thrombocytopenia: an updated systematic review. Drug Safety 2007;30:185–186 and http://w3.ouhsc.edu/platelets. Accessed January 12, 2009.

some guidance regarding past reported experience.1,59,106,151 Severe (< 20,000 platelets/mm3), or acute transient thrombocytopenia are more likely to be drug-induced.14 In patients administered the sensitizing agent de novo, 5 to 7 days are typically required for the development of the immune response. During rechallenge, thrombocytopenia can develop within 12 hours.14 Interestingly, the unique ability of GP IIb/IIIa inhibitors such as abciximab to cause thrombocytopenia within hours of first use suggests the presence of preformed antibodies directed against platelet epitopes, perhaps accounting for ex vivo clumping of platelets observed in each of approximately 500 normal patients.152 Clinically, fever, chills, pruritus, and lethargy may occur. The onset of life-threatening bleeding may be abrupt. Hemorrhagic vesicles may be seen in the oral mucosa. Laboratory investigations will demonstrate an absence of platelets on peripheral smear, prolongation of the bleeding time, deficient clot retraction, and an abnormal prothrombin consumption test. Bone marrow aspiration will demonstrate normal or increased numbers of megakaryocytes and immature forms. Treatment includes the transfusion of blood products, glucocorticoids, and the withdrawal of the offending agent.14 Thrombotic thrombocytopenic purpura Thrombotic thrombocytopenic purpura (TTP) is characterized by the triad of microangiopathic hemolytic anemia, severe thrombocytopenia, and fluctuating neuro-

logic abnormalities.124 Fever and renal dysfunction are also common, although overt renal failure is rare. The hallmark is the presence of platelet aggregates throughout the microvasculature, without fibrin clot, unlike the fibrin-rich thrombi seen in disseminated intravascular coagulation or the hemolytic uremic syndrome. In the acquired form, drug-induced autoantibodies inactivate a circulating zinc metalloprotease ADAMTS13, thereby blocking its ability to depolymerize large multimers of vWF and leading to platelet clumping.11,12,17,186 Plasma exchange with fresh frozen plasma replensishes ADAMTS13 and removes the inhibitory antibodies. Prior to understanding of the molecular mechanism, other causes of microvascular hemolysis with thrombocytopenia were often confused with TTP. These causes included hemolytic uremic syndrome due to shiga toxin, the HELLP syndrome of pregnancy, Rocky Mountain spotted fever, and paroxysmal nocturnal hemoglobinuria. Also included were cases secondary to xenobiotics such as cyclosporine, cocaine, gemcitabine, mitomycin C and cisplatin, in which ADAMTS13 antibodies are not present.48,186 Heparin-induced thrombocytopenia An immune response to heparin, manifested clinically by the development of thrombocytopenia and, at times, venous thrombosis, is now recognized to result from antibodies to a complex of heparin and platelet factor 4.4 The diagnosis is confirmed by testing for these antibodies. The heparin–platelet factor 4 antibody complex can directly activate platelets, and is believed to be the mechanism for the paradoxical thrombosis associated with this condition, which can be limb- or life-threatening96 (Chap. 59).

SUMMARY The mechanisms of toxic injury to the blood are extremely varied, reflecting the complexity of this vital fluid. The response to injury may be idiosyncratic, as in many xenobiotic-related causes of agranulocytosis and aplastic anemia, or predictable, as in the case of significant exposures to ionizing radiation or to benzene. Injury may depend on the presence of certain host factors, such as G6PD deficiency. Xenobiotics may directly injure mature cells, or prohibit their development by injuring the stem cell pool. Toxicity may result from the amplification of a potentially therapeutic intervention, such as occurs with many chemotherapeutic agents and anticoagulants. A common theme in hematologic toxicity is the perturbation of homeostatic equilibria that exist between cell proliferation and apoptosis, between immune activation and suppression, or between thrombophilia and thrombolysis. An improved awareness of these complex pathways allows the toxicologist to better understand, diagnose, and treat toxic injury to the blood.

ACKNOWLEDGMENT Dr. Diane Sauter contributed to this chapter in previous editions.

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62. Gow AJ, Luchsinger BP, Pawloski JR, et al. The oxyhemoglobin reaction of nitric oxide. Proc Natl Acad Sci (USA). 1999;96(16):9027-9032. 63. Graham AF, Crawford TBB, Marian GF. The action of arsine on blood: Observations on the nature of the fixed arsenic. Biochem J. 1946;40:256-260. 64. Gregory CA, Prockop DJ, Spees JL. Non-hematopoietic bone marrow stem cells: Molecular control of expansion and differentiation. Exp Cell Res. 2005;306(2):330-335. 65. Grosveld F, DeBoer E, Dillon N, et al. The dynamics of globin gene expression and gene therapy vectors. Ann N Y Acad Sci. 1998;850:18-27. 66. Haab P. The effect of carbon monoxide on respiration. Experientia. 1990;46:1202-1203. 67. Hampton MB, Kettle AJ, Winterbourne CC. Inside the neutrophil phagosome: oxidants, myeloperoxidase, and bacterial killing. Blood. 1998;92:3007-3017. 68. Hare JM. Nitroso-redox balance in the cardiovascular system. N Engl J Med. 2004;351(20):2112-2114. 69. Harris R, Marx G, Gillett M, et al. Colchicine-induced bone marrow suppression: treatment with granulocyte colony-stimulating factor. J Emerg Med. 2000;18(4):435-440. 70. Hatlelid KM, Brailsford C, Carter DE. Reactions of arsine with hemoglobin. J Toxicol Environ Health. 1996;47(2):145-157. 71. Hentze MW, Muckenthaler MU, Andrews NC. Balancing acts: molecular control of mammalian iron metabolism. Cell. 2004;117(3):285-297. 72. Hirsh J, Weitz I. Thrombosis and anticoagulation. Semin Hematol. 1999;36:118-132. 73. Holman MJ, Gonwa TA, Cooper B, et al. FK506-associated thrombotic thrombocytopenic purpura. Transplantation. 1993;55(1):205-206. 74. Hsia CC. Respiratory function of hemoglobin. N Engl J Med. 1998;338(4):239-247. 75. Hsieh MM, Everhart JE, Byrd-Holt DD, et al. Prevalence of neutropenia in the U.S. population: age, sex, smoking status, and ethnic differences. Ann Intern Med. 2007;146(7):486-492. 76. Hulten JO, Tran VT, Pettersson G. The control of haemolysis during transurethral resection of the prostate when water is used for irrigation: monitoring absorption by the ethanol method. BJU International. 2000;86(9):989-992. 77. Hultquist DE, Passon PG. Catalysis of methaemoglobinemia reduction by erythrocyte cytochrome B5 and cytochrome B5 reductase. Nat New Biol. 1971;229:252-254. 78. Hung DZ, Wu ML, Deng JF, Lin-Shiau SY. Russell’s viper snakebite in Taiwan: differences from other Asian countries. Toxicon. 2002;40(9):12911298. 79. Ichimaru M, Ishimaru T, Tsuchimoto T, Kirshbaum JD. Incidence of aplastic anemia in A-bomb survivors. Hiroshima and Nagasaki, 19461967. Radiat Res. 1972;49(2):461-72. 80. Irons RD. Molecular models of benzene leukemogenesis. J Toxicol Environ Health A. 2000;61(5-6):391-397. 81. Irons RD, Stillman WS. The process of leukemogenesis. Environ Health Perspect. 1996;104Suppl6:1239-1246. 82. Issaragrisil S, Kaufman DW, Anderson T, et al. The epidemiology of aplastic anemia in Thailand. Blood. 2006;107(4):1299-1307. 83. Iversen PO, Nicolaysen G, Benestad HB. Blood flow to bone marrow during development of anemia or polycythemia in the rat. Blood. 1992;79(3):594-601. 84. Iversen PO, Nicolaysen G, Benestad HB. The leukopoietic cytokine granulocyte colony-stimulating factor increases blood flow to rat bone marrow. Exp Hematol. 1993;21(2):231-235. 85. Jackson RC, Elder WJ, McDonnell H. Sodium-chlorate poisoning complicated by acute renal failure. Lancet. 1961;2:1381-1383. 86. Jefferson JA, Escudero E, Hurtado ME, et al. Excessive erythrocytosis, chronic mountain sickness, and serum cobalt levels. Lancet. 2002;359(9304):407-408. 87. Jenkins GC, Ind JE, Kazantzis G, Owen R. Arsine poisoning: Massive haemolysis with minimal impairment of renal function. BMJ. 1965;5453:78-80. 88. Jollow DJ, Bradshaw TP, McMillan DC. Dapsone-induced hemolytic anemia. Drug Metab Rev. 1995;27(1-2):107-124. 89. Juni P, Nartey L, Reichenbach S, et al. Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet. 2004;364(9450):2021-2029. 90. Kaiser U, Barth N. Haemolytic anaemia in a patient with anorexia nervosa. Acta Haematologica. 2001;106(3):133-135. 91. Kaplan JC, Chirouze M. Therapy of recessive congenital methaemoglobinaemia by oral riboflavin. Lancet. 1978;2:1043-1044.

92. Karp JE, Smith MA. The molecular pathogenesis of treatment-induced (secondary) leukemias: foundations for treatment and prevention. Semin Oncol. 1997;24(1):103-113. 93. Kaushansky K. Thrombopoietin. N Engl J Med. 1998;339:746-754. 94. Kaushansky K. Thrombopoietin and hematopoietic stem cell development. Ann N Y Acad Sci.1999;872:314-319. 95. Keller C, Matzdorff AC, Kemkes-Matthes B. Pharmacology of warfarin and clinical implications. Semin Thromb Hemost. 1999;25:13-16. 96. Kelton JG, Warkentin TE. Heparin-induced thrombocytopenia: a historical perspective. Blood. 2008;112(7):2607-2616. 97. Kleinfeld MJ. Arsine poisoning. J Occup Med. 1980;22(12):820-821. 98. Knutsen OH, Jansson U. [Hemolysis and pulmonary edema after a neardrowning accident in chlorated water]. Lakartidningen. 1988;85(52): 4646-4647. 99. Korbling M, Estrov Z. Adult stem cells for tissue repair—a new therapeutic concept? N Engl J Med. 2003;349(6):570-582. 100. Krum H, Liew D, Aw J, Haas S. Cardiovascular effects of selective cyclooxygenase-2 inhibitors. Exp Rev Cardiovasc Ther 2004;2(2):265-270. 101. Lambert S, Bennett V. From anemia to cerebellar dysfunction. A review of the Ankyrin gene family. Eur J Biochem. 1993;211:1-6. 102. Larkin EC, Williams WT, Ulvedal F. Human hematologic responses to 4 hr of isobaric hyperoxic exposure (100 per cent oxygen at 760 mm Hg). J Appl Physiol. 1973;34(4):417-421. 103. Lee E, Boorse R, Marcinczyk M. Methemoglobinemia secondary to benzocaine topical anesthetic. Surg Laparosc Endosc. 1996;6(6):492-493. 104. Lenard JG. A note on the shape of the erythrocyte. Bull Math Biol. 1974;36(1):55-58. 105. Lennard AL, Jackson GH. Stem cell transplantation. BMJ. 2000;321(7258): 433-437. 106. Li X, Swisher KK, Vesely SK, George JN. Drug-induced thrombocytopenia: an updated systematic review, 2006. Drug Safety. 2007;30(2):185-186. 107. Lubash GD, Phillips RE, Shields JD, III, Bonsnes RW. Acute aniline poisoning treated by hemodialysis. Report of a case. Arch Intern Med. 1964;114:530-532. 108. Majeti R, Park CY, Weissman IL. Identification of a Hierarchy of Multipotent Hematopoietic Progenitors in Human Cord Blood. Cell Stem Cell. 2007;1(6):635-645. 109. Maloisel F, Kurtz JE, Andres E, et al. Platin salts-induced hemolytic anemia: cisplatin- and the first case of carboplatin-induced hemolysis. AntiCancer Drugs. 1995;6(2):324-326. 110. Mamdani M, Juurlink DN, Lee DS, et al. Cyclo-oxygenase-2 inhibitors versus non-selective non-steroidal anti-inflammatory drugs and congestive heart failure outcomes in elderly patients: a population-based cohort study. Lancet. 2004;363(9423):1751-1756. 111. Mannucci PM. Hemostatic drugs. N Engl J Med. 1998;339(4):245-253. 112. Mansouri A. Methemoglobin reduction under near physiological conditions. Biochem Med Metab Biol. 1989;42(1):43-51. 113. Marschner JP, Seidlitz T, Rietbrock N. Effect of 2,3-diphosphoglycerate on O2-dissociation kinetics of hemoglobin and glycosylated hemoglobin using the stopped flow technique and an improved in vitro method for hemoglobin glycosylation. Int J Clin Pharmacol Ther. 1994;32(3):116-121. 114. Mason PJ. New insights into G6PD deficiency. Br J Haematol. 1996;94(4):585-591. 115. Matzner Y. Acquired neutrophil dysfunction and diseases with an inflammatory component. Semin Hematol. 1997;34:291-302. 116. May BK, Bawden MJ. Control of heme biosynthesis in animals. Semin Hematol. 1989;26:150-156. 117. Mayhew TM, Mwamengele GL, Self TJ, Travers JP. Stereological studies on red corpuscle size produce values different from those obtained using haematocrit- and model-based methods. Br J Haematol. 1994;86(2):355-360. 118. McKoy JM, Stonecash RE, Cournoyer D, et al. Epoetin-associated pure red cell aplasia: past, present, and future considerations. Transfusion. 2008;48(8):1754-1762. 119. McMahon TJ, Moon RE, Luschinger BP, et al. Nitric oxide in the human respiratory cycle. Nat Med. 2002;8(7):711-717. 120. Melvin JD, Watts RG. Severe hypophosphatemia: a rare cause of intravascular hemolysis. Am J Hematol. 2002;69(3):223-224. 121. Mengel CE, Kann HE, Jr., Heyman A, Metz E. Effects of in vivo hyperoxia on erythrocytes. Ii. Hemolysis in a human after exposure to oxygen under high pressure. Blood. 1965;25:822-829. 122. Millar J, Peloquin R, De Leeuw NK. Phenacetin-induced hemolytic anemia. CMAJ. 1972; 106(7):770-775.

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123. Miyazaki H, Kato T. Thrombopoietin: biology and clinical potentials. Int J Hematol. 1999;70:216-225. 124. Moake JL. Thrombotic microangiopathies. N Engl J Med. 2002;347(8):589600. 125. Morell DB, Chang Y. The structure of the chromophore of sulphmyoglobin. Biochim Biophys Acta. 1967;136(1):121-130. 126. Mousa SA. Comparative efficacy of different low-molecular-weight heparins (LMWHs) and drug interactions with LMWH: Interactions for management of vascular disorders. Semin Thromb Hemost. 2000;26(Suppl1):1-46. 127. Mukherje AK, Ghosal SK, Maity CR. Some biochemical properties of Russell’s viper (Daboia russelli) venom from Eastern India: correlation with clinico-pathological manifestation in Russell’s viper bite. Toxicon. 2000;38(2):163-175. 128. Myint H, Copplestone JA, Orchard J, et al. Fludarabine-related autoimmune haemolytic anaemia in patients with chronic lymphocytic leukaemia. Br J Haematol. 1995; 91(2):341-344. 129. Nagel RL, Roth EF Jr. Malaria and red cell genetic defects. Blood. 1989;74(4):1213-1221. 130. Nardi NB, Alfonso ZZC. The hematopoietic stroma. Braz J Med Biol Res. 1999;32:601-609. 131. Nathan DM, Siegel AJ, Bunn HF. Acute methemoglobinemia and hemolytic anemia with phenazopyridine: possible relation to acute renal failure. Arch Intern Med. 1977;137(11):1636-1638. 132. Nimer SD, Ireland P, Meshkinpour A, Frane M. An increased HLA DTR2 frequency is seen in aplastic anemia patients. Blood. 1994;84:923-927. 133. Nurden P, Heilman E, Paponneau A, Nurden A. Two-way trafficking of membrane glycoproteins on thrombin-activated human platelets. Semin Hematol. 1994;31:240-250. 134. Paradiso-Hardy FL, Angelo CM, Lanctot KL, Cohen EA. Hematologic dyscrasia associated with ticlopidine therapy: evidence for causality. CMAJ. 2000;163(11):1441-1448. 135. Paradiso-Hardy FL, Papastergiou J, Lanctot KL, Cohen EA. Thrombotic thrombocytopenic purpura associated with clopidogrel: further evaluation. Can J Cardiol. 2002;18(7):771-773. 136. Park CM, Nagel RL. Sulfhemoglobinemia: Clinical and molecular aspects. N Engl J Med. 1984;310:1579-1584. 137. Patrono C, Coller B, Dalen JE, et al. Platelet-active drugs : the relationships among dose, effectiveness, and side effects. Chest. 2001;119(1Suppl):39S63S. 138. Petz LD. Drug-induced autoimmune hemolytic anemia. Transfus Med Rev. 1993;7(4):242-254. 139. Piga A, Roggero S, Vinciguerra T, et al. Deferiprone: new insight. Ann NY Acad Sci. 2005;1054:169-174. 140. Pindur G, Morsdorf S, Schenk JF, et al. The overdosed patient and bleedings with oral anticoagulation. Semin Thromb Hemost. 1999;25:85-88. 141. Pinto SS. Arsine poisoning: Evaluation of the acute phase. J Occup Med. 1976;18:633-635. 142. Podvinec M, Handschin C, Looser R, Meyer UA. Identification of the xenosensors regulating human 5-aminolevulinate synthase. Proc Natl Acad Sc U S A. 2004;101(24):9127-32. 143. Ponka P. Tissue-specific regulation of iron metabolism and heme synthesis: Distinct control mechanisms in erythroid cells. Blood. 1997;89:1-25. 144. Ponka P. Cell biology of heme. Am J Med Sci. 1999;318:241-256. 145. Ponka P, Beaumont C, Richardson DR. Function and regulation of transferrin and ferritin. Semin Hematol. 1998;35:35-54. 146. Provan D, Weatherall D. Red cells II: acquired anaemias and polycythaemia. Lancet. 2000;355(9211):1260-1268. 147. Quinn MJ, Fitzgerald DJ. Ticlopidine and clopidogrel. Circulation. 1999;100(15):1667-1672. 148. Rael LT, Ayala-Fierro F, Carter DE. The effects of sulfur, thiol, and thiol inhibitor compounds on arsine-induced toxicity in the human erythrocyte membrane. Toxicol Sci. 2000;55(2):468-477. 149. Rainger GE, Rowley AF, Nash GB. Adhesion-dependent release from human neutrophils in a novel flow-based model: specificity of different chemotactic agents. Blood. 1998;92:4819-4827. 150. Reiter CD, Wang X, Tanus-Santos JE, et al. Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease. Nat Med. 2002;8(12):13831389. 151. Rizvi MA, Kojouri K, George JN. Drug-induced thrombocytopenia: an updated systematic review. Ann Intern Med. 2001;134(4):346. 152. Rizvi MA, Shah SR, Raskob GE, George JN. Drug-induced thrombocytopenia. Curr Opin Hematol. 1999;6(5):349-353.

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153. Robak T, Blasinska-Morawiec M, Krykowski E, et al. Autoimmune haemolytic anaemia in patients with chronic lymphocytic leukaemia treated with 2-chlorodeoxyadenosine (cladribine). Eur J Haematol. 1997;58(2):109-113. 154. Romeril KR, Concannon AJ. Heinz body haemolytic anaemia after sniffing volatile nitrites. Med J Austral. 1981;1(6):302-303. 155. Rothenberg ME. Eosinophilia. N Engl J Med. 1998;338(22):1592-1600. 156. Said SM, Hahn J, Schleyer E, et al. Glycoprotein IIb/IIIa inhibitorinduced thrombocytopenia: diagnosis and treatment. Clin Res Cardiol. 2007;96(2):61-69. 157. Samama MM, Gerotziafas GT. Comparative pharmacokinetics of LMWHs. Semin Thromb Hemost. 2000;26(Suppl1):1-38. 158. Savage DG, Ogundipe A, Allen RH, et al. Etiology and diagnostic evaluation of macrocytosis. Am J Med Sci. 2000;319(6):343-352. 159. Schafer DA, Cooper JA. Control of actin assembly at filament ends. Annual Rev Cell Dev Biol. 1995;11:497-518. 160. Schechter AN, Gladwin MT. Hemoglobin and the paracrine and endocrine functions of nitric oxide. N Engl J Med. 2003;348(15):1483-1485. 161. Schmid-Schonbein H, Wells RE Jr. Rheological properties of human erythrocytes and their influence upon the “anomalous” viscosity of blood. Ergebnisse der Physiologie, Biologischen Chemie und Experimentellen Pharmakologie. 1971;63:146-219. 162. Schrijvers D. Role of red blood cells in pharmacokinetics of chemotherapeutic agents. Clin Pharmacokinet. 2003;42(9):779-791. 163. Schror K. Aspirin and platelets: the antiplatelet action of aspirin and its role in thrombosis and treatment prophylaxis. Semin Thromb Hemost. 1997;23:349-356. 164. Shayeghi M, Latunde-Dada GO, Oakhill JS, et al. Identification of an intestinal heme transporter. Cell. 2005;122(5):789-801. 165. Shitrit D, Starobin D, Aravot D, et al. Tacrolimus-induced hemolytic uremic syndrome case presentation in a lung transplant recipient. Trans Pros. 2003;35(2):627-628. 166. Sills MR, Zinkham WH. Methylene blue-induced Heinz body hemolytic anemia. Arch Pediatr Adolesc Med. 1994;148(3):306-310. 167. Singel DJ, Stamler JS. Chemical physiology of blood flow regulation by red blood cells: the role of nitric oxide and S-nitrosohemoglobin. Annual Rev Physiol. 2005;67:99-145. 168. Sivilotti MLA. Oxidant stress and hemolysis of the human erythrocyte. Toxicol Rev. 2004;23(3):169-188. 169. Sixma J, van Zanten H, Banga JD, et al. Platelet adhesion. Semin Hematol. 1995;32:89-98. 170. Sklar GE. Hemolysis as a potential complication of acetaminophen overdose in a patient with glucose-6-phosphate dehydrogenase deficiency. Pharmacotherapy. 2002;22(5):656-658. 171. Smith RE. The INR: a perspective. Semin Thromb Hemost. 1997;23:547549. 172. Solomon DH, Schneeweiss S, Glynn RJ, et al. Relationship between selective cyclooxygenase-2 inhibitors and acute myocardial infarction in older adults. Circulation. 2004;109(17):2068-2073. 173. Spivak JL. Erythropoietin use and abuse: when physiology and pharmacology collide. Adv Exp Med Biol. 2001;502:207-224. 174. Spooren AA, Evelo CT. Hydroxylamine treatment increases glutathioneprotein and protein-protein binding in human erythrocytes. Blood Cells Mol Dis. 1997;23(3):323-336. 175. Stevenson DK, Vreman HJ. Carbon monoxide and bilirubin production in neonates. Pediatrics. 1997;100(2:Pt 1):t-4. 176. Stock W, Hoffman R. White blood cells 1: non-malignant disorders. Lancet. 2000;355(9212):1351-1357. 177. Tanner MLA. Molecular and cellular biology of the erythrocyte anion exchanger (AE1). Semin Hematol. 1993;30:34-57. 178. Telen MJ. Erythrocyte blood group antigens: polymorphisms of functionally important molecules. Semin Hematol. 1996;33(4):302-314. 179. Thom SR. Leukocytes in carbon monoxide-mediated brain oxidative injury. Toxicol Applied Pharmacol. 1993;123:234-247. 180. Thompson DF, Gales MA. Drug-induced pure red cell aplasia. Pharmacotherapy. 1996;16(6):1002-1008 181. Thunell S, Pomp E, Brun A. Guide to drug porphyrogenicity prediction and drug prescription in the acute porphyrias. Br J Clin Pharmacol. 2007;64(5):668-679. 182. Till JE, McCulloch EA. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res. 1961;14:213-222. 183. Tinmouth A, Chin-Yee I. The clinical consequences of the red cell storage lesion. Transfus Med Rev. 2001;15(2):91-107.

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184. Todisco V, Lamour J, Finberg L. Hemolysis from exposure to naphthalene mothballs. N Engl J Med. 1991;325(23):1660-1661. 185. Topol EJ. Arthritis medicines and cardiovascular events—”house of coxibs”. JAMA. 2005;293(3):366-368. 186. Tsai HM. Current concepts in thrombotic thrombocytopenic purpura. Annual Rev Med. 2006;57:419-436. 187. Vandendries ER, Drews RE. Drug-associated disease: hematologic dysfunction. Crit Care Clin. 2006;22(2):347-355,viii. 188. VanUffelen BE, de Koster BM, VanStevenink J, et al. Carbon monoxide enhances human neutrophil migration in a cyclic GMP-dependent way. Biochem Biophys Res Commun. 1996;226:21-26. 189. Vetter RS, Visscher PK, Camazine S. Mass envenomations by honey bees and wasps. West J Med. 1999;170(4):223-227. 190. Ward PC, Schwartz BS, White JG. Heinz-body anemia: “bite cell” variant—a light and electron microscopic study. Am J Hematol. 1983;15(2):135-146. 191. Waugh RE, Sassi M. An in vitro model of erythroid egress in bone marrow. Blood. 1986;68:250-257.

192. Winski SL, Barber DS, Rael LT, Carter DE. Sequence of toxic events in arsine-induced hemolysis in vitro: implications for the mechanism of toxicity in human erythrocytes. Fundam Appl Toxicol. 1997;38(2):123-128. 193. Wright RO, Perry HE, Woolf AD, Shannon MW. Hemolysis after acetaminophen overdose in a patient with glucose-6-phosphate dehydrogenase deficiency. J Toxicol Clin Toxicol. 1996;34(6):731-734. 194. Xie W, Uppal H, Saini SP, et al. Orphan nuclear receptor-mediated xenobiotic regulation in drug metabolism. Drug Discovery Today. 2004;9(10):442-449. 195. Young NS, Kaufman DW. The epidemiology of acquired aplastic anemia. Haematologica. 2008;93(4):489-492. 196. Young NS, Scheinberg P, Calado RT. Aplastic anemia. Curr Opin Hematol. 2008;15(3):162-168. 197. Zhu NY, LeGatt DF, Turner AR. Agranulocytosis after consumption of cocaine adulterated with levamisole. Ann Intern Med. 2009;0000605200902170. 198. Zola H, Swart B, Nicholson I, et al. CD molecules 2005: human cell differentiation molecules. Blood. 2005;106(9):3123-3126.

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CHAPTER 25

GASTROINTESTINAL PRINCIPLES Richard G. Church and Kavita M. Babu Humans are constantly in contact with a variety of xenobiotics. The gastrointestinal (GI) tract forms an important initial functional barrier, in addition to its critical role in absorbing nutrients. An understanding of the structure, physiology, and enteric autonomic system is critical to toxicologic concepts of absorption, gastric motility and appreciating the unique vulnerabilities of the GI tract to xenobiotics. This chapter discusses the role of the GI tract and its relation to toxicology. Anatomic, pathologic, and microbiologic principles are discussed, including the role of the GI tract in the metabolism of xenobiotics. Examples of GI pathologies and their clinical manifestations are discussed.

STRUCTURE AND INNERVATION OF THE GASTROINTESTINAL TRACT The luminal gastrointestinal tract can be divided into five distinct structures: oral cavity and hypopharynx, esophagus, stomach, small intestine, and colon. These environments differ in luminal pH, specific epithelial cell receptors, and endogenous flora. The transitional areas between these distinct organs have specialized epithelia and muscular sphincters with specific functions and vulnerabilities. Knowledge of the anatomy of these transition zones is particularly important to the localization and management of foreign bodies. The functions of the pancreas and liver are closely integrated with those of the luminal organs, although they are not within the nutrient stream. The pancreas is discussed here; the liver and its metabolic functions are discussed in Chapters 12 and 26. The visceral structures of the GI tract are composed of several layers, including the epithelium, lamina propria, submucosa, muscle layers and serosa (the last only in intraperitoneal organs). As the transition is made throughout the GI tract differences in luminal pH, epithelial cell receptors, muscularity and endogenous flora are encountered, affecting absorption and metabolism of individual xenobiotics. The epithelium, the innermost layer of the GI tract, is the most specialized cell type in the intestine and is composed of epithelial, endocrine and receptor cells. Epithelial cells have polarity, with the basal surface facing the lamina propria and the apical surface facing the lumen. They are further specialized for specific functions of secretion or absorption. Additionally, the epithelial cell forms part of the mucosal immune defense, to detect the presence of microbial pathogens and down-regulate the immune system in the presence of nonpathogenic or probiotic microbes. The major barrier to penetration of xenobiotics and microbes is the GI epithelium, a single cell thick membrane.13 The cell membrane is a lipid bilayer that contains proteins, which act as aqueous pores through which certain materials can pass, dependent on size or molecular structure, providing the basis for semi-permeability. The membrane is not continuous as it consists of individual epithelial cells; however, these cells are joined to each other by structures known as tight junctions, which are located on the lateral surfaces of the cells, near the apical membranes. The tight junctions have a gap of about 8 angstroms, which allows passage only of water, ions, and low-molecular weight substances.

The muscle layer found beneath the lamina propria is made up of the muscularis mucosa, the circular muscles and the longitudinal muscles. Contraction of the muscularis mucosa causes a change in the surface area of the gut lumen that alters secretion or absorption of nutrients. Depolarization of circular muscle leads to contraction of a ring of smooth muscle and a decrease in the diameter of that segment of the GI tract whereas depolarization of longitudinal muscle leads to contraction in the longitudinal direction and a decrease in the length of that segment. The function of the muscle layers is integrated with the enteric nervous system to provide for a coordinated movement of luminal contents through the GI tract so as to maximize absorption and minimize bacterial growth. This integration facilitates the flow of chyme (undigested food) via a coordinated sequence of muscular contractions and relaxations, leading to segmentation of luminal contents, peristaltic movements, and unidirectional flow through the intestine. The GI tract is innervated by the autonomic nervous system via both extrinsic and intrinsic pathways. The extrinsic innervation permits communication between the brain, spinal cord, and chemoreceptors and mechanoreceptors located in the gut. Parasympathetic stimulation in the extrinsic pathway tends to be excitatory (“rest and digest”), and is carried via the vagus, splanchnic and pelvic nerves to the myenteric and submucosal plexuses. In contrast, increased sympathetic tone (“fight or flight”) inhibits digestive and peristaltic activity via fibers that originate in the thoracolumbar cord and terminate in the myenteric and submucosal plexuses. The intrinsic innervation of the GI tract, or enteric nervous system, is responsible for the determination of parasympathetic and sympathetic tone to the GI tract. The intrinsic innervation provides local control of peristalsis and endocrine secretions, via the myenteric (Auerbach) and submucosal (Meissner) plexuses, respectively.

THE IMMUNE SYSTEM AND MICROBIOLOGY OF THE GI TRACT An elaborate mucosal immune system has evolved to protect the GI tract from pathogens.38 Mucosal immunity can be divided into an afferent limb, which recognizes a pathogen and induces the proliferation and differentiation of immunocompetent cells, and an efferent limb, which coordinates and affects the immune response. The afferent system includes the lymphoid follicles, and specialized M-cells found therein, that promote transit of antigens to antigen-presenting cells.26 Once sensitized, immune cells undergo a complicated process of clonal expansion and differentiation, which occurs in mucosal and mesenteric lymphoid follicles, as well as in extraintestinal sites. Immunocompetent cells then return to the intestine and other mucous membranes, and are scattered diffusely within the epithelial and lamina propria compartments. The normal endogenous flora in the GI tract includes more than 400 species of bacteria; the intestinal mucosa is normally colonized by nonpathogenic strains of Esterichia coli, Proteus spp., Enterobacter spp., Serratia spp., and Klebsiella spp. En masse, these bacteria are more metabolically active than the liver. The concentration of luminal bacteria varies by site, from lowest in the proximal small intestine to highest in the large intestine. Endogenous bacteria occupy unique niches related to host physiology, environmental pressures, and microbial interactions, which result in long-term stability.17 The flora may be altered by various insults (particularly antibiotics), but usually returns to baseline once the insult is removed. The endogenous flora has multiple metabolic functions. A primary function in the colon is the salvage of malabsorbed carbohydrates by fermentation and production of short-chain fatty acids, which is a preferred substrate for colonic epithelial cells. Hydrolysis of urea occurs following its passive diffusion into the intestinal lumen, producing NH3

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and a carbon skeleton. Elevated concentrations of nitrogenous compounds, including ammonia, may result from increased dietary load, or from gastrointestinal hemorrhage, or by decreased clearance, as occurs in patients with end-stage liver disease and hepatic encephalopathy. Bacterial metabolism can significantly affect the disposition of enteral compounds. For example, the bacterial metabolism of digoxin contributes to its steady state concentrations, and antibiotic treatment may reduce or eradicate the intestinal flora, predisposing to digoxin toxicity.7 Bacterial contribution to vitamin K metabolism is also demonstrated, necessitating dose adjustments of warfarin during and after antibiotic therapy. The metabolic activity of intraluminal bacteria has been exploited in treatment strategies. For example, sulfasalazine, used in the treatment of ulcerative colitis is created through the linkage of 5-aminosalicylic acid to sulfapyridine. The azo bonds of the nonabsorbable sulfasalazine are broken by bacterial azoreductases, permitting the absorption of active metabolites in the colon at the site of inflammation.30 The normal flora of the gut consists of probiotics—live, nonpathogenic bacteria and fungi that can also be used as prophylactic or therapeutic agents. These bacteria compete for and displace pathogenic bacteria, directly modulate intestinal immune function and exert a trophic effect on the gastrointestinal tract. They are used to decrease traveler’s diarrhea, suppress antibiotic-induced diarrhea, and reduce inflammation in ileal pouches after colectomy in patients with ulcerative colitis.10,15

REGULATORY SUBSTANCES OF THE GASTROINTESTINAL TRACT There are three groups of regulatory materials that act on target cells within the GI tract. These gastrointestinal hormones are released from endocrine cells in the GI mucosa into the portal circulation, enter the systemic circulation with resultant physiologic actions on target cells. Gastrin, cholecystokinin (CCK), secretin, and gastric inhibitory peptide (GIP) are considered the primary GI hormones. Somatostatin and histamine make up the paracrines, hormones that are released from endocrine cells and diffuse over short distances to act on target cells located in the GI tract. Vasoactive intestinal peptide (VIP), GRP (bombesin) and enkephalins compose the last group known as neurocrines, substances that are synthesized in neurons of the GI tract, move by axonal transport down the axon, and are then released by action potentials in the nerves. Effects on these regulatory substances are in summarized Table 25–1.8

ANATOMIC AND PHYSIOLOGIC PRINCIPLES ■ OROPHARYNX AND HYPOPHARYNX The main functions of the mouth and oropharynx are chewing, lubrication of food with saliva, and swallowing. Saliva initiates digestion of

TABLE 25–1. Regulatory Substances of the GI Tract8 Substance

Site of Secretion/Release

Stimulus for Secretion/Release

Actions

Gastrin

G cells of gastric antrum

↑ gastric H+ secretion, ↑ growth of gastric mucosa

Cholecystokinin

I cells of duodenum and jejunum

Small peptides and amino acids Stomach distention Vagal stimulation (via GRP) Inhibited by H+ in stomach (negative feedback) Small peptides and amino acids Fatty acids and monoglycerides

Secretin

S cells of duodenum

H+ in duodenal lumen Fatty acids in duodenal lumen

Gastric Inhibitory Peptide

Duodenum and jejunum

Somatostatin

Throughout GI tract

Histamine Vasoactive Intestinal Peptide

Mast cells of gastric mucosa GI tract mucosa and smooth muscle neurons

Fatty acids, amino acids, oral glucose H+ in GI tract lumen Inhibited by vagal stimulation Vagal stimulation gastrin H+ in duodenal lumen

Bombesin

Vagus nerves that innervate G cells GI tract mucosa and smooth muscle neurons

Enkephalins (met-enkephalin, leu-enkephalin)

Vagal stimulation

↑ contraction of gallbladder and relaxation of sphincter of Oddi ↑ pancreatic enzyme and HCO3− secretion ↑ growth of exocrine pancreas/gallbladder ↓ gastric emptying (allow more time for digestion and absorption) Coordinated to reduce small intestinal H+ ↑ pancreatic HCO3− secretion ↑ biliary HCO3− secretion ↓ gastric H+ secretion ↑growth of exocrine pancreas ↓ H+ secretion by gastric parietal cells ↑ insulin release ↓ release of all GI hormones ↓ gastric H+ secretion ↑ gastric H+ secretion Smooth muscle relaxation ↑ pancreatic HCO3− secretion ↓ gastric H+ secretion ↑ gastrin release from G cells ↑ contraction of GI smooth muscle ↓ intestinal secretion of fluid and electrolytes

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starch by α-amylase (ptyalin), triglyceride digestion by lingual lipase, lubrication of ingested food by mucus, and protection of the mouth and esophagus by dilution and buffering of ingested foods. Saliva production is unique in that it is increased by both parasympathetic and sympathetic activity. Parasympathetic stimulation, via cranial nerves VII and IX acts on muscarinic cholinergic receptors on acinar and ductal cells, increases saliva production by causing vasodilation and increasing transport processes in the acinar and ductal cells. Parasympathetic pathways are stimulated by food in the mouth, smells, conditioned reflexes, and nausea, and are inhibited by sleep, dehydration, and fear. Sympathetic stimulation, originating from preganglionic nerves in the thoracic segments T1-3, requires receipt of norepinephrine by β-adrenergic receptors on acinar and ductal cells, leading to increases in the production of saliva, but at a rate less than that of parasympathetic stimulation.8 Dysfunction of saliva production can lead to dry mouth, or xerostomia.

■ ESOPHAGUS The normal esophagus is a distensible muscular tube that extends from the epiglottis to the gastroesophageal junction. The lumen of the esophagus narrows at several points along its course, first at the cricopharyngeus muscle, then midway down alongside the aortic arch and then distally where it crosses the diaphragm. The upper esophageal sphincter (UES) and lower esophageal sphincter (LES) are physiologic high-pressure regions that remain closed except during swallowing, and have no anatomic features to distinguish them from the intervening esophageal musculature. The wall of the esophagus reflects the general structural organization of the GI tract noted previously, consisting of mucosa, submucosa, muscularis propria, and adventitia. The mucosal layer has three components. The nonkeratinizing stratified squamous epithelial layer faces the lumen, provides protection for underlying tissue, and houses several specialized cell types such as melanocytes, endocrine cells, dendritic cells, and lymphocytes. The lamina propria is the nonepithelialized portion of the mucosa, and the muscularis mucosa, a layer of longitudinally oriented smooth-muscle bundles is the third component. The submucosa consists of loose connective tissue, and submucosal glands secrete a mucin-containing fluid via squamous epithelium-lined ducts which facilitates lubrication of the esophageal lumen. The muscularis propria consists of an inner circular and outer longitudinal coat of smooth muscle; this layer also contains striated muscle fibers in the proximal esophagus that is responsible for voluntary swallowing. The esophagus has no serosal lining. Only small segments of the intraabdominal esophagus are covered by adventitia, a sheath-like structure that also surrounds the adjacent great vessels, tracheobronchial tree, and other structures of the mediastinum. The esophagus provides a conduit for food and fluids from the pharynx to the stomach, and the sphincters generally prevent reflux of gastric contents into the esophagus. Normal transit of food involves coordinated motor activity including a wave of peristaltic contraction, relaxation of the LES (facilitated by nitric oxide and VIP), and subsequent closure of the LES (facilitated by several hormones and neurotransmitters such as gastrin, acetylcholine, serotonin, and motilin). Because of the rapid transit time of swallowed substances through this portion of the GI tract, digestion does not take place and passive diffusion of substances from the food into the bloodstream is prevented.8,24

■ STOMACH The stomach is a saccular organ covered entirely by peritoneum that has a capacity greater than 3 liters. The stomach is divided into five anatomic regions: the cardia, fundus, corpus or body, antrum, and pyloric

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sphincter. The gastric wall consists of mucosa, submucosa, muscularis propria, and serosa. The interior surface of the stomach is marked by coarse rugae, or longitudinal folds. The mucosa is made up of a superficial epithelial cell compartment and a deep glandular compartment. The glandular compartment consists of gastric glands, which vary between regions of the stomach. The mucus glands of the cardia, fundus and body secrete mucus and pepsinogen. Oxyntic, or acid-forming glands, found in the fundus and body contain parietal, chief, and endocrine cells. The parietal cells contain vesicles that house hydrochloric acidsecreting proton pumps and also secrete intrinsic factor, a substance necessary for the ileal absorption of vitamin B12. Chief cells secrete the proteolytic proenzyme pepsinogen which is cleaved to its active form, pepsin, upon exposure to the low luminal gastric pH of 3 to 4. Pepsin is subsequently inactivated in the duodenum when the pH increases to 6.0. The endocrine, or enterochromaffin-like (ECL), cells found in the mucosa of the body of the stomach produce histamine, which increases acid production and decreases gastric pH by stimulating H2 receptors on the parietal cells. Somatostatin and endothelin, both modulators of acid production, are also produced in ECL cells (Fig. 50–3). Hydrochloric acid is secreted when cephalic, gastric and intestinal signals converge on the gastric parietal cells to activate proton pumps and release hydrochloric acid in an ATP-dependent process. During the cephalic phase, or the preparatory phase of the brain for eating and digestion, acetylcholine is released from vagal afferents in response to sight, smell, taste, and chewing. Acetylcholine stimulates the parietal cells via muscarinic receptors, resulting in an increase in cytosolic calcium and activation of the proton pump. G cells, located in the antrum of the stomach, produce and release gastrin in response to luminal amino acids and peptides. Gastrin activates receptors within parietal cells, leading to a similar increase in cytosolic calcium. Additionally, gastrin and vagal afferents induce the release of histamine from ECL cells, which stimulates parietal cell H2 receptors. Lastly, the intestinal phase is initiated when food containing digested protein enters the proximal small intestine and involves gastrin as well as a number of other polypeptides in the secretion of hydrochloric acid from the stomach.24 See Fig 25–1. The gastric mucosa is protected from the acidic secretions of the stomach by several mechanisms, including a thin layer of surface mucus, and channels that allow acid- and pepsin- containing fluids to exit glands without contact with the surface epithelium. Additionally, the surface epithelium secretes bicarbonate, creating a more neutral pH at the cell surface. Prostaglandins produced in the mucosal cells stimulate production of bicarbonate and mucus, and inhibit parietal cell production of acid; prostaglandin inhibition plays an important role in the pathogenesis of peptic ulcer disease.24 In the stomach, ingested products are ground to particle sizes of less than 0.2 mm, which are then further processed and digested in preparation for absorption of nutrients in the small intestine.25 Many xenobiotics are weak acids that are no longer ionized in the acidic environment of the stomach, facilitating absorption through the lipid bilayer at the level of the stomach. Other factors that affect xenobiotic absorption include particle size, transit time, and type of drug delivery system. Different types of drug formulations, such as time-release, enteric coating, slowly dissolving matrices, dissolution control via osmotic pumps, ion exchange resins, and pH-sensitive mechanisms can affect bioavailability, as well as the site of maximal release within the GI tract. Following processing, the stomach delivers the products to the small intestine. The time required for gastric emptying is determined by the complex interplay of GI innervation, muscle action, underlying illness, and xenobiotic exposure. Digestion and absorption are time-dependent

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Food

[Proton pump + inhibitors] H

[Antacids] H+

Stomach lumen

H+ H+ [Caustics]

H+ Parietal cell

Gastrin

ATPase K+

Ulcer bed

cAMP

G M3

H2

(CCK-B)

Stom

ach w all

[H2 blockers] [Muscarinic antagonists]

H H

ECL cell

Enteric nervous system

H

G M1

G(CCK-B)

ST2 [Somatostatin]

FIGURE 25–1. Effects of various xenobiotics on the gastrointestinal tract. ECL cell, enterochromaffin-like cell; CCK-B, cholecystokinin receptor B; H, histamine; H2, histamine-2 (H2) receptor; M1, M3; muscarinic receptors; ST2, somatostatin-2 receptor.

processes and optimal absorption requires adjustment of the luminal environment through secretion of ions and water, to accommodate meals that vary considerably in nutrient composition and density. Osmoreceptors and chemoreceptors in the GI tract fine-tune the digestive and absorptive processes by regulating transit and secretion, using a variety of neurocrine, paracrine and endocrine mechanisms. Interference with this integrated response may lead to stasis and bacterial overgrowth, or rapid transit with decreased absorption and development of diarrhea. A large number of mediators affect motility, including common neurotransmitters, such as acetylcholine and norepinephrine, hormones, cytokines, inflammatory compounds, and others. In general, parasympathetic impulses promote motility, whereas sympathetic stimulation inhibits motility. Other transmitters, such as serotonin, promote transit, whereas dopamine and enkephalins can slow motility.

■ SMALL AND LARGE INTESTINES In the average adult, the small intestine is approximately 6 meters in length, and begins retroperitoneally as the duodenum, becoming peritoneal at the jejunum and ileum. Small intestine transitions to large intestine at the ileocecal valve, and the large intestine typically measures 1.5 meters in an adult. The large intestine or colon is further divided into cecal, ascending, transverse, descending, and sigmoid segments. The sigmoid colon transitions to the rectum, and terminates at the anus. Anterograde and retrograde peristalsis occurs in the small intestine, whereas anterograde peristalsis predominates in the large

intestine. This movement allows for mixing of food, maximizes contact with the mucosa, and is mediated by both the extrinsic and intrinsic nervous systems. The remarkable absorptive capacity of the small intestine is created by innumerable villi of the intestinal wall, which are small epithelial-lined “fingers” that extend into the lumen. The epithelial border of the small intestine also contains mucin-secreting goblet cells, endocrine cells, and specialized absorptive cells; functionally, these cells create an ideal environment for maximal nutrient absorption. The mucosa of the large intestine is devoid of villi. The large intestine functions primarily to absorb electrolytes and water, secrete potassium, salvage any remaining nutrients, and to store and release waste. Intestinal epithelial cells also have the ability to metabolize xenobiotics, a function typically attributed to the liver. Epithelial cells contain many of the same metabolic enzymes as the liver and are capable of performing multiple types of reactions including hydroxylation, sulfation, acetylation, and glucuronidation. These metabolic processes affect the amount of orally administered xenobiotic that enters the body and contributes to the first-pass effect, or presystemic disposition. Variations in intestinal metabolism also may influence the pharmacokinetics of a xenobiotic. Regeneration of injured or senescent intestinal epithelial cells begins in the crypts, with differentiation occurring as these cells migrate towards to the intestinal lumen. This process occurs rapidly, with turnover of the small intestinal epithelium occurring every 4 to 6 days, and large intestinal epithelium every 3 to 8 days. This rapid regeneration leaves the intestinal epithelium vulnerable to processes that interfere

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with cell replication. The sloughing of GI epithelium, typically manifested by hemorrhagic enteritis, is subsequently a valuable marker for xenobiotic insults that lead to mitotic arrest.

■ PANCREAS The pancreas is a retroperitoneal organ that serves dual exocrine and endocrine functions. The exocrine portion of the gland produces digestive enzymes and occupies more than 80%–85% of the mass of the pancreas. The exocrine pancreas is comprised of acinar cells, specialized epithelial cells housing zymogen granules that release digestive enzymes and proenzymes on secretion. The digestive enzymes enter the duodenum, while columnar epithelial cells produce mucin and ductal cuboidal epithelial cells secrete a bicarbonate-rich fluid that neutralizes gastric acids. The pancreas secretes 2–2.5 liters per day of this mixed solution. Typically, the digestive enzymes are released as proenzymes, such as trypsinogen, chymotrypsinogen, and procarboxypeptidase, are activated upon contact with the higher pH of the duodenum; this process helps to prevent autodigestion of the pancreas itself. Enzymes on the brush border of the duodenum, including enteropeptidase, cleave proenzymes to their active forms. Only pancreatic amylase and lipase are secreted in their active forms. Secretion of pancreatic enzymes is regulated by multiple factors, the most important of which are cholecystokinin and secretin, both produced in the duodenum. Cholecystokinin is released from the duodenum in response to fatty acids and the products of protein catabolism such as peptides and amino acids. Cholecystokinin stimulates acinar cells to release digestive enzymes and proenzymes. Secretin is released by the duodenum in the presence of lowered pH caused by gastric acids and luminal fatty acids. Secretin triggers ductal cells to secrete bicarbonate and water. Acetylcholine also plays a role in the regulation of pancreatic exocrine function, by stimulating digestive enzyme secretion from the acinus and potentiating the effects of secretin. Vagal reflexes increase acetylcholinergic tone in the setting of decreased pH, protein breakdown products, and fatty acids in the duodenal lumen. The endocrine portion of the pancreas is comprised of approximately one million clusters of cells known as the islets of Langerhans which secrete insulin, glucagons, and somatostatin. Other products of the endocrine pancreas include serotonin and VIP. Injury to the endocrine pancreas can result in impaired glucose homeostasis.

XENOBIOTIC METABOLISM Although the liver is usually identified as the site of xenobiotic metabolism, similar functions occur in the luminal GI tract. Biotransformation is a property both of luminal bacteria and enterocytes. Metabolism by the intestine affects the amount of orally administered xenobiotic that actually enters the body and therefore contributes to the first-pass effect, or presystemic disposition. One of the most well-described families of export proteins, P-glycoprotein (PGP), is found in the mucosa of the small and large intestines, hepatocytes, the adrenal cortex, renal tubules, and the capillary cells lining the blood-brain barrier.43 The PGPs are susceptible to induction and inhibition in a manner similar to hepatic cytochrome oxidase enzymes. Many of the substrates of CYP3A have inhibitory effects on PGPs. Inhibitors of PGPs may raise serum concentrations of the parent drug or metabolite, although inducers of PGPs may prevent therapeutic drug concentrations from ever reaching the target cell. The PGP system is important in drug interactions and drug resistance (Chap. 8).

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TABLE 25–2. Xenobiotics Causing Discoloration of the Teeth and Gums1 Areca catecha leaves Cadmium Ciprofloxacin Doxycycline Fluoride Chlorhexidine oral rinse Tetracycline

Red Yellow Green Yellow White flecking Brown Yellow to brown-grey

■ PATHOLOGIC CONDITIONS OF THE GI TRACT Oral Pathology Discoloration of the teeth has been reported with a number of medications, most notably tetracyclines. Medications known to cause dental pigmentation are listed in Table 25–2. Gingival hyperplasia in an uncommon, but reported adverse effect of the chronic use of several xenobiotics, including multiple anticonvulsants. Gingival hyperplasia describes overgrowth of the gums around the teeth which can result in loosening of teeth and severe periodontal disease. Some medications implicated in causing gingival hyperplasia include calcium channel blockers, cyclosporine, lithium, phenobarbital, phenytoin, topiramate, and valproic acid.1 Xerostomia, or pathologic dryness of the mouth, is an uncomfortable adverse effect of many xenobiotics that can lead to increased dental decay. Xenobiotics that can cause xerostomia is extensive, and the most commonly implicated classes of xenobiotics causing xerostomia are listed in Table 25–3. Chronic methamphetamine use has been linked to characteristic oral pathology known as “meth mouth.” This condition is characterized by extensive and severe tooth decay, and has been linked to poor hygiene, bruxism, and xerostomia associated with methamphetamine use.9 Esophagitis and Dysphagia Xenobiotic-induced esophageal injury includes esophagitis, ulceration, perforation, and stricture. The most common presenting complaint is a foreign body sensation in the throat.5,18 Xenobiotics commonly implicated in the causation of esophagitis or esophageal ulcerations are listed in Table 25–4. Patient features that predict likelihood of esophageal pathology include preexisting esophageal motility disorderts. Conditions like Parkinsonism, cerebrovascular accidents, scleroderma, and myasthenia gravis can contribute to dysphagia. Xenobiotics with a gelatin matrix, rapid dissolvability, and large size predispose to esophageal injury. Although most symptoms resolve with withdrawal of the offending xenobiotics, patients with persistent or severe odynophagia should be evaluated with endoscopy to identify pathology and prevent perforation caused by retained pills.11

TABLE 25–3. Xenobiotics that Commonly Cause Xerostomia1,40 α1-adrenergic receptor antagonists α2-adrenergic receptor agonists Anticholinergics Antidepressants (CAs, maprotiline) Antihistamines Antipsychotics (phenothiazines) Protease inhibitors

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TABLE 25–4. Xenobiotics Implicated in Esophagitis and Esophageal Ulcerations28 Antipsychotics Bisphosphonates NSAIDs Potassium chloride Quinine Tetracycline

Webs, strictures, and esophageal malignancy Caustic injury is one of the most common causes of esophageal strictures. Some authors have also postulated the role of pill esophagitis in the evolution of esophageal strictures.4 Caustic injury is also implicated in the causation of esophageal malignancy. As great as 4% of patients with esophageal cancer report a history of caustic injury and patients with a prior history of caustic ingestion may have more than a 1000-fold higher risk of developing an esophageal malignancy than the general population.19,20 Other xenobiotics known to cause esophageal strictures include aluminum phosphide and ionizing radiation.37 Gastritis/Peptic Ulcer Disease Gastritis, or inflammation of the gastric mucosa, and peptic ulcer disease (PUD) are commonly related to xenobiotic exposure (Table 25–5). Symptoms of gastritis and PUD include epigastric pain, nausea and vomiting, but may include hematemesis and melena.29 The primary distinction between gastritis and peptic ulcer disease is appearance at endoscopy where gastritis is characterized by diffuse inflammation of the gastric mucosa, whereas an ulcer is a discrete lesion of the mucosa. Nonsteroidal antiinflammatory drugs (NSAIDs) remain an important part of the pathogenesis of gastric and PUD by decreasing prostaglandin secretion and subsequently affecting the integrity of the gastric mucosal barrier to acid. Cyclooxygenase-2 (COX-2) selective inhibitors promised to decrease the incidence of gastric pathology caused by chronic NSAID use; however, the available COX-2 inhibitors now carry a black box warning in the United States that desribe an increased risk of significant adverse cardiovascular events.14 Chronic treatment of peptic ulcer disease with antacids, H2 blockers, or proton pump inhibitors can lead to hypochlorhydria or achlorhydria, the reduction or absence of gastric acid, respectively. These conditions increase risk of bacterial overgrowth, atrophic gastritis, hip fracture (possibly caused by impaired calcium absorption), Salmonella and Vibrio cholerae infection, and gastric carcinoma.32,42

TABLE 25–5. Xenobiotics Commonly Implicated in Gastritis and Peptic Ulcer Disease Aspirin Corticosteroids Ethanol Isopropyl alcohol Nicotine NSAIDs Radiation (Ionizing)

TABLE 25–6. Xenobiotic-induced Enteritis Mechanism

Xenobiotic

Mechanical irritation

Aloe Bacterial food poisoning Laxatives Mushrooms Carbamates Neostigmine, physostigmine Nicotine Organic Phosphorous compounds Arsenic Colchicine Mercuric salts Iron Monochloroacetic acid Podophyllin Pokeweed (Phytolacca americana) Radiation (ionizing) Thallium

Cholinergic stimulation

Inhibitors of mucosal regeneration (Hemorrhagic enteritis)

Enteritis The symptoms of GI distress are nonspecifically associated with xenobiotic exposure, as well as a myriad of infectious etiologies. However, certain xenobiotics that increase gastric emptying and peristalsis can result in significant diarrhea. Opioid withdrawal and serotonin syndrome are important toxidromes that may feature diarrhea as a prominent symtom. Additionally, the rapid turnover of the GI mucosa makes it uniquely susceptible to xenobiotics that cause cell death and mitotic arrest. Hemorrhagic enteritis, manifested by hematochezia, can be a characteristic finding of certain xenobiotic exposures (Table 25–6). Pancreatitis Pancreatitis is an acute inflammatory process that results in autolysis of the pancreas from digestive enzymes.41 Cases range from mild to severe, with mortality of 5%.16 The most common causes of pancreatitis are alcohol abuse and gallbladder disease; however, xenobiotic-induced pancreatitis accounts for 0.1%–2% of cases of acute pancreatitis.2 Populations at higher risk of drug-induced pancreatitis include children, women, the elderly, and patients with HIV and inflammatory bowel disease.2 In acute pancreatitis, the most common diagnostic criterion is elevation of serum pancreatic enzymes, amylase or lipase, to more than three times the upper limit of the reference range. The diagnosis of xenobiotic-induced pancreatitis can be impossible to confirm, as no diagnostic test or pattern of injury distinguishes xenobiotic-induced pancreatitis from other etiologies. However, the symptoms and laboratory abnormalities associated with xenobiotic-induced pancreatitis tend to resolve shortly after withdrawal of the offending xenobiotic; again, this can be challenging to differentiate from the natural course of mild to moderate disease. It is unclear whether rechallenge with a culprit xenobiotic will cause pancreatitis again; however, any xenobiotic suspected of causing pancreatitis should be withheld unless the benefits outweigh this risk. The management of xenobiotic-induced pancreatitis does not differ from other causes, and hinges on aggressive volume resuscitation, bowel rest, and careful monitoring. Patients at the extremes of age, manifesting end organ dysfunction, acute lung injury, or signs of shock are at greatest risk of death. There are numerous xenobiotics associated with pancreatitis, and the strength of that association has been described as definite, likely, or possible; representative xenobiotics are listed in Table 25–7. The pathogenic mechanism varies with the specific xenobiotic. The nucleoside reverse transcriptase inhibitor, didanosine, and exposure to dioxin,

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■ FOREIGN BODIES TABLE 25–7. Xenobiotics Commonly Associated with Pancreatitis2 Alcohols: Ethanol and methanol Analgesics: Acetaminophen, NSAIDs Antibiotics: Clarithromycin, isoniazid, metronidazole, sulfonamides, tetracycline Anticonvulsants: Valproic acid Antihyperlipidemics: HMG-CoA reductase inhibitors Cardiovascular: ACE inhibitors Diuretics: Furosemide, thiazides HIV medications: Didanosine, lamivudine, nelfinavir Hormones: Corticosteroids, estrogens Immunosuppressants: Azathioprine, corticosteroids Pesticides: Organic Phosphorous compounds Sitagliptin Venoms: Buthus quiquestriatus, Tityus discrepans

may promote pancreatitis as a result of mitochondrial injury.27,33,34 Cholinergic xenobiotics, like parathion and certain scorpion venoms, may result in pancreatitis caused by overstimulation.21,31 Vasospasm and ischemia are also purported as a mechanism, as in cases of pancreatitis secondary to ergot alkaloids.12 The endocrine pancreas is also susceptible to injury from pancreatitis or toxic insult. Typically, dysfunction of the endocrine pancreas results from injury to pancreatic beta cells and impaired glucose homeostasis, similar to diabetes. There are rare xenobiotics that can cause damage to alpha cells in animal models; however, they do not consistently cause hypoglycemia (Table 25–8).

TABLE 25–8. Xenobiotics Associated with Endocrine Pancreatic Dysfunction Alpha cells Cobalt salts Decamethylene diguanidine Phenylethylbiguanide Beta cells Alloxan Androgens Cyclizine Cyproheptadine Diazoxide Dihydromorphanthridine Epinephrine Glucagon Glucorticoids Growth hormone Pentamidine Streptozocin Sulfonamides Vacor

The esophagus is the most common site of symptomatic foreign bodies. They tend to be found in the cervical esophagus, at the level of the aortic notch, just above the gastroesophageal junction, or just proximal to an esophageal narrowing.6 The likelihood that a foreign object will lodge in the esophagus is related to its size and shape. The major complications of foreign bodies in the esophagus include pain, bleeding, obstruction or perforation, which may lead to subsequent mediastinitis or fistula. The general rule is that conservative means can be employed for up to 12 hours after ingestion of the esophageal foreign body. If serial radiographs demonstrate no movement after 12 hours, endoscopic retrieval or surgery should be considered, as the risk of perforation increases after that time; some authors will extend this observation period to 24 hours.3,35 Ingestion of button batteries proves an important exception to this rule. Esophageal button batteries can cause significant mucosal injury in four hours, with perforation in as little as 6 hours.22 Proposed mechanisms for the rapid development of esophageal injury include alkaline burn, local current and pressure necrosis.23,36 As a result, all suspected esophageal button batteries should undergo immediate endoscopic removal, and success rates with this modality have been reported as excellent.23 Foreign bodies are also commonly found in the stomach. Many small foreign bodies will pass through the stomach and the remainder of the GI tract without difficulty. Objects greater than 5 cm in length or 2 cm in diameter may be unable to traverse the duodenum, and may require endoscopic or surgical removal. Foreign bodies beyond the duodenum may not require any intervention except observation; however, some objects may become stuck at the ileocecal valve. Serial examinations and radiographs can be appropriate for asymptomatic patients; however, increasing abdominal pain or tenderness may mandate further imaging and surgical consultation. Body packers represent an unusual exception to these rules. Patients who are discovered to be internally concealing large quantities of illicit drugs may require whole bowel irrigation to facilitate transit of colonic packets, and even emergency laparotomy for obstruction or suspected packet rupture in cases of cocaine or methamphetamine smuggling.39

SUMMARY The GI tract is vulnerable to a wide variety of pathogenic agents with diverse physical, chemical, and biologic forms. Understanding the effects of such xenobiotics on the GI tract requires an appreciation of its normal anatomy and physiology. Because of its potential as a site of severe local or systemic effects, and the role that GI signs and symptoms play in various toxic syndromes, the GI tract is an important consideration in many toxicologic emergencies.

ACKNOWLEDGMENT Donald P. Kotler and Neal E. Flomenbaum contributed to this chapter in previous editions.

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4. Bonavina L, DeMeester TR, McChesney L, Schwizer W, Albertucci M, Bailey RT. Drug-induced esophageal strictures. Ann Surg. 1987;206:173-183. 5. Carlborg B, Densert O, Lindqvist C. Tetracycline induced esophageal ulcers. a clinical and experimental study. Laryngoscope. 1983;93:184-187. 6. Chaikhouni A, Kratz JM, Crawford FA. Foreign bodies of the esophagus. Am Surg. 1985;51:173-179. 7. Constantine PA. Antibiotic therapy and serum digoxin toxicity. Am Fam Physician. 1998;57:1239-1240. 8. Costanzo L. Physiology. Philadelphia: Saunders; 2002. 9. Curtis EK. Meth mouth: a review of methamphetamine abuse and its oral manifestations. Gen Dent. 2006;54:125-129; quiz 130. 10. D’Souza AL, Rajkumar C, Cooke J, Bulpitt CJ. Probiotics in prevention of antibiotic associated diarrhoea: meta-analysis. BMJ. 2002;324:1361. 11. de Groen PC, Lubbe DF, Hirsch LJ, et al. Esophagitis associated with the use of alendronate. N Engl J Med. 1996;335:1016-1021. 12. Deviere J, Reuse C, Askenasi R. Ischemic pancreatitis and hepatitis secondary to ergotamine poisoning. J Clin Gastroenterol. 1987;9:350-352. 13. Diamond JM. Channels in epithelial cell membranes and junctions. Fed Proc. 1978;37:2639-2643. 14. Flower RJ. The development of COX2 inhibitors. Nat Rev Drug Discov. 2003;2:179-191. 15. Gionchetti P, Rizzello F, Helwig U, et al. Prophylaxis of pouchitis onset with probiotic therapy: a double-blind, placebo-controlled trial. Gastroenterology. 2003;124:1202-1209. 16. Granger J, Remick D. Acute pancreatitis: models, markers, and mediators. Shock. 2005;24 Suppl 1:45-51. 17. Hooper LV, Gordon JI. Commensal host-bacterial relationships in the gut. Science. 2001;292:1115-1118. 18. Kikendall JW. Pill esophagitis. J Clin Gastroenterol. 1999;28:298-305. 19. Kiviranta. U. Corrosion carcinoma of the esophagus. Cancer. 1953;6:11591164. 20. Kochhar R, Sethy PK, Kochhar S, Nagi B, Gupta NM. Corrosive induced carcinoma of esophagus: report of three patients and review of literature. J Gastroenterol Hepatol. 2006;21:777-780. 21. Lankisch PG, Muller CH, Niederstadt H, Brand A. Painless acute pancreatitis subsequent to anticholinesterase insecticide (parathion) intoxication. Am J Gastroenterol. 1990;85:872-875. 22. Litovitz T, Schmitz BF. Ingestion of cylindrical and button batteries: an analysis of 2382 cases. Pediatrics. 1992;89:747-757. 23. Litovitz TL. Button battery ingestions. A review of 56 cases. JAMA. 1983;249:2495-2500. 24. Liu C, Crawford J., The gastrointestinal tract. In: Kumar V, Abbas AK, Fausto N, editors. In: Robbins and Cotran, Pathologic Basis of Disease. 7th ed. . Philadelphia: Elsevier Saunders; 2005:799-875.

25. Meyer J, ed. Motility of the Stomach and Gastroduodenal Junction. 2nd ed. New York: Raven; 1987:613. 26. Neutra MR. M cells in antigen sampling in mucosal tissues. Curr Top Microbiol Immunol. 1999;236:17-32. 27. Nyska A, Jokinen MP, Brix AE, et al. Exocrine pancreatic pathology in female Harlan Sprague-Dawley rats after chronic treatment with 2,3,7,8tetrachlorodibenzo-p-dioxin and dioxin-like compounds. Environ Health Perspect. 2004;112:903-909. 28. O’Neill JL, Remington TL. Drug-induced esophageal injuries and dysphagia. Ann Pharmacother. 2003;37:1675-1684. 29. Parfitt JR, Driman DK. Pathological effects of drugs on the gastrointestinal tract: a review. Hum Pathol. 2007;38:527-536. 30. Peppercorn MA. Sulfasalazine. Pharmacology, clinical use, toxicity, and related new drug development. Ann Intern Med. 1984;101:377-386. 31. Possani LD, Martin BM, Fletcher MD, Fletcher PL Jr. Discharge effect on pancreatic exocrine secretion produced by toxins purified from Tityus serrulatus scorpion venom. J Biol Chem. 1991;266:3178-3185. 32. Recker RR. Calcium absorption and achlorhydria. N Engl J Med. 1985;313:70-73. 33. Rozman K, Pereira D, Iatropoulos MJ. Histopathology of interscapular brown adipose tissue, thyroid, and pancreas in 2,3,7,8-tetrachlorodibenzop-dioxin (TCDD)-treated rats. Toxicol Appl Pharmacol. 1986;82:551-559. 34. Seidlin M, Lambert JS, Dolin R, Valentine FT. Pancreatitis and pancreatic dysfunction in patients taking dideoxyinosine. Aids. 1992;6:831-835. 35. Silverberg M, Tillotson R. Case report: esophageal foreign body mistaken for impacted button battery. Pediatr Emerg Care. 2006;22:262-265. 36. Studley JG, Linehan IP, Ogilvie AL, Dowling BL. Swallowed button batteries: is there a consensus on management? Gut. 1990;31:867-870. 37. Talukdar R, Singal DK, Tandon RK. Aluminium phosphide-induced esophageal stricture. Indian J Gastroenterol. 2006;25:98-99. 38. Tomasi TB Jr, Tan EM, Solomon A, Prendergast RA. Characteristics of an immune system common to certain external secretions. J Exp Med. 1965;121:101-124. 39. Traub SJ, Hoffman RS, Nelson LS. Body packing—the internal concealment of illicit drugs. N Engl J Med. 2003;349:2519-2526. 40. Tredwin CJ, Scully C, Bagan-Sebastian JV:. Drug-induced disorders of teeth. J Dent Res. 2005;84:596-602. 41. Whitcomb DC. Clinical practice. Acute pancreatitis. N Engl J Med. 2006;354:2142-2150. 42. Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA. 2006;296:2947-2953. 43. Yu DK. The contribution of P-glycoprotein to pharmacokinetic drug-drug interactions. J Clin Pharmacol. 1999;39:1203-1211.

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HEPATIC PRINCIPLES Kathleen A. Delaney The liver plays an essential role in the maintenance of metabolic homeostasis. Hepatic functions include the synthesis, storage, and breakdown of glycogen. In addition, the liver is important in the metabolism of lipids; the synthesis of albumin, clotting factors, and other important proteins; the synthesis of the bile acids necessary for absorption of lipids and fat-soluble vitamins; and the metabolism of cholesterol.20,54 Hepatocytes facilitate the excretion of metals, most importantly iron, copper, zinc, manganese, mercury, and aluminum; and the detoxification of products of metabolism, such as bilirubin and ammonia.29,62 Generalized disruption of these important functions results in manifestations of liver failure: hyperbilirubinemia, coagulopathy, hypoalbuminemia, hyperammonemia, and hypoglycemia.41,74 The hepatic functions can also be selectively altered by exposure to hepatotoxins.54 Disturbances of more specific functions result in accumulation of fat, metals, and bilirubin, and the development of fatsoluble vitamin deficiencies.20,54 The liver is also the primary site of biotransformation and detoxification of xenobiotics.46,133 Its interposition between the gut and systemic circulation makes it the first-pass recipient of xenobiotics absorbed from the gastrointestinal tract into the portal vein. The liver also receives blood from the systemic circulation and participates in the detoxification and elimination of xenobiotics that reach the bloodstream through other routes, such as inhalation or cutaneous absorption.20,118 Many xenobiotics are lipophilic inert substances that require chemical activation followed by conjugation to make them sufficiently soluble to be eliminated. The liver contains the highest concentration of enzymes involved in phase I oxidation-reduction reactions, the first stage of detoxification for many lipophilic xenobiotics.46,133 Conjugation of the reactive products of phase I biotransformation with molecules such as glucuronide facilitates excretion.133 (Chap. 12) Although many xenobiotics that are detoxified in the liver are subsequently excreted in the urine, the biliary tract provides a second essential route for the elimination of detoxified xenobiotics and products of metabolism.20,29

MORPHOLOGY AND FUNCTION OF THE LIVER Two pathologic concepts are used to describe the appearance and function of the liver; a structural one represented by the hepatic lobule, and a functional one represented by the acinus. The basic structural unit of the liver characterized by light microscopy is the hepatic lobule, a hexagon with the central hepatic vein at the center and the portal triads at the angles. The portal triad consists of the portal vein, the common bile duct, and the hepatic artery. Cords of hepatocytes are oriented radially around the central hepatic vein, forming sinusoids. The acinus, or “metabolic lobule” is a functional unit of the liver. Located between two central hepatic veins, it is bisected by terminal branches of the hepatic artery and portal vein that extend from the bases of the acini toward hepatic venules at the apices. The acinus is subdivided into three metabolically distinct zones. Zone 1 lies near the portal triad, zone 3 near the central hepatic vein, and zone 2 is intermediate.20,54 Figure 26–1 illustrates the relationship of the structural and functional concepts of the liver.

Approximately 75% of the blood supply to the liver is derived from the portal vein, which drains the alimentary tract, spleen, and pancreas. The blood is enriched with nutrients and other absorbed xenobiotics and is poor in oxygen. The remainder of the hepatic blood flow comes from the hepatic artery, which delivers well-oxygenated blood from the systemic circulation.20 Blood from the hepatic artery and portal vein mixes in the sinusoids, coming in close contact with cords of hepatocytes before it exits through small holes in the wall of the vein. Oxygen content diminishes several fold as blood flows from the portal area to the central hepatic vein.54,118 There are six types of cells in the liver. Hepatocytes and bile duct epithelia make up the parenchyma. Cells found in the vicinity of the sinusoids include endothelial cells, fixed macrophages (Kupffer cells), hepatic stellate cells (Ito cells) that store fat, and large lymphocytic “pit cells” that roam the sinusoids.118 The sinusoidal lining formed by endothelial cells is thin and fenestrated, allowing transfer of fluid, chylomicrons, and proteins across the space of Disse, an extrasinusoidal space filled with microvilli.20,54,118 Kupffer cells scavenge particulate materials and cell debris within the sinusoids. When immunologically activated by xenobiotics, Kupffer cells contribute to the generation of oxygen free radicals115,144 and may also participate in the production of autoimmune injury to hepatocytes.33,61,115 Hepatic stellate cells (Ito cells) are primary sites for the storage of fat and vitamin A.43 In a quiescent state they spread out between the sinusoidal endothelium and hepatic parenchymal cells. Filled with microtubules and microfilaments, they project cytoplasmic extensions that contact several cell types.54,118 Activated stellate cells produce collagen, proteoglycans, and adhesive glycoproteins, which are crucial to the development of hepatic fibrosis.118 Kupffer cells also contribute to the activation of hepatic stellate cells.118 “Pit cells” are antigenically related to circulating natural killer cells. They actively lyse tumor cells and cells infected by virus118 (Fig. 26–2). Bile acids, organic anions, bilirubin, phospholipids, xenobiotics, and other molecules excreted in bile are actively transported across the hepatocyte plasma membrane into the bile canaliculi at sites that have specificity for acids, bases, and neutral compounds.20,54 Tight junctions separate the contents of the bile canaliculi from the sinusoids and hepatocytes, maintaining a rigid and functionally necessary compartmentalization. Bile acids use three active transport systems: a sodium-dependent bile salt transporter in the sinusoidal membrane; an adenosine triphosphate (ATP)-dependent bile salt carrier in the canalicular membrane; and a canalicular membrane transport site driven by the membrane voltage potential.54,67,118 Glucuronidated xenobiotics are substrates for the bile acid transport systems and are actively secreted into bile. Xenobiotics with molecular weights greater than 350 daltons are also preferentially secreted into bile. Like the transport and concentration of constituents from the sinusoids and hepatocytes, the flow of bile through the canaliculi is also an active process facilitated by ATP-dependent contractions of actin filaments that encircle the canaliculi.67,139 The enterohepatic circulation of bile acids and some vitamins plays a crucial role in their conservation. Unfortunately, this physiologically important process impedes the fecal elimination of some xenobiotics by reabsorbing and returning them back into the systemic circulation, prolonging their half lives and toxicity. Xenobiotics that have low molecular weights and are not ionized at intestinal pH, such as methyl mercury, phencyclidine, and nortriptyline, are most likely to be reabsorbed.29,114 The liver is especially vulnerable to toxic injury, due to its location at the end of the portal system and its substantial complement of biotransformation enzymes. Although phase I activation of xenobiotics is usually followed by phase II conjugation that results in detoxification, it can also lead to the production of xenobiotics with increased toxicity, which is often manifest at the site of their synthesis.46,82,133

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Zone 1 Periportal parenchyma

Hepatic artery

Bile duct

Zone 2 Midzonal parenchyma

Zone 3 Centrilobar parenchyma

Portal vein

Hepatic vein

Characteristic:

Zone 1

Zone 3

O2

O2

Glutathione

Glucuronidation, Sulfation Alcohol dehydrogenase CYP2E1

During injury:

O2 free-radical mediated necrosis

Necrosis by ethanol, CCl4 CYP2E1 metabolites

FIGURE 26–1. The acinus is defined by three functional zones. Specific contributions of each zone to the biotransformation of xenobiotics reflect various metabolic factors that include differences in oxygen content of blood as it flows from the oxygen-rich portal area to the central hepatic vein; differences in glutathione content; different capacities for glucuronidation and sulfation; and variations in content of metabolic enzymes such as CYP2E1.The hepatic lobule (not shown) is a structural concept, a hexagon with the central vein at the center surrounded by 6 portal areas that contain branches of the hepatic artery, bile duct, and portal vein. Injury to hepatocytes that is confined to zone 3 is called “centrilobular” because in the structure of the lobule, zone 3 encircles the central vein, which is the center of the hepatic lobule.

FACTORS THAT AFFECT THE ANATOMIC LOCALIZATION OF HEPATIC INJURY Hepatocellular injury that occurs near the portal vein is called periportal, or zone 1 necrosis. The terms centrilobular or zone 3 necrosis refer to injury that surrounds the central hepatic vein.20 Figure 26–3 shows centrilobular necrosis caused by exposure to bromobenzene. Metabolic characteristics of the zones of the acinus have important relevance to the anatomic distribution of toxic liver injury. Because of its location in the periportal area, zone 1 has a two-fold higher oxygen content than zone 3. Hepatic injury that results from the metabolic production of oxygen free radicals predominates in zone 1. Allyl alcohol, an industrial chemical that is metabolized to a highly reactive aldehyde, is associated with

oxygen dependent lipid peroxidation injury to hepatocytes in zone 1.8 The tendency for centrilobular or zone 3 accumulation of fat in patients with alcoholic steatosis is attributed to the effect of relative hypoxia in the central vein area on the oxidation potential of the hepatocyte.80 The availability of substrates for detoxification and the localization of enzymes involved in biotransformation also affect the site of injury. Zone 1 has a higher concentration of glutathione, whereas zone 3 has a greater capacity for glucuronidation and sulfation.134 Zone 3 has higher concentrations of alcohol dehydrogenase, which may lead to increased production of toxic acetaldehyde at centrilobular sites.28,54,80,84 Zone 3 also has high concentrations of cytochrome oxidase CYP2E1, which converts many xenobiotics including acetaminophen, nitrosamines, benzene, and carbon tetrachloride (CCl4) to reactive intermediates that may cause centrilobular injury. Although CCl4 can be metabolized to a

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Pit (NK) cell

Kupffer cell

Endothelial cells

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injury caused by CCl4, possibly by increasing the formation of CCl3OO. in zone 3, which is then efficiently detoxified by glutathione.16,133 The observed effects of isoniazid (an inhibitor of the enzyme CYP2E1) and chronic ethanol intake (an inducer of the CYP2E1 gene) on injury in cell cultures from periportal and centrilobular areas exposed to CCl4 support the association of CCl4 injury with the localization of CYP2E1 activity. Acute exposure to isoniazid significantly decreases the injury associated with exposure of zone 3 cells to CCl4, whereas chronic treatment with ethanol significantly enhances it.81

HOST FACTORS THAT AFFECT THE DEVELOPMENT OF HEPATOTOXICITY Hepatocytes Bile Caniculi

Stellate (Ito) cells

FIGURE 26–2. Blood flowing through the hepatic sinusoids is separated from hepatocytes by fenestrated endothelium that allows passage of many substances across the Space of Disse. This figure shows 6 types of cells found in the liver and their localization in relation to the sinusoid. Stellate cells are fat storage cells that promote fibrosis when activated. Kupffer cells are fixed macrophages that participate in immune surveillance and are a source of free radicals when activated. Pit cells float freely in the sinusoids and have activities similar to natural killer (NK) cells. Hepatocytes and bile epithelial cells form the hepatic parenchyma.

highly reactive oxygen free radical in zone 1, it primarily injures zone 3 for the following reasons:16 CCl4 is metabolized by CYP2E1 in zone 3 to a trichloromethyl free radical (·CCl3) that can form covalent bonds with cellular proteins, cause lipid peroxidation, or spontaneously react with oxygen to form the more highly reactive trichloromethyl peroxy radical (CCl3OO·).16,33,81 Higher oxygen tension in zone 1 fosters the formation of CCl3OO· which is rapidly detoxified by glutathione. Since the less reactive ·CCl3 that predominates in zone 3 is not readily detoxified by glutathione, zone 3 incurs the greater amount of injury. Hyperbaric oxygen increases the oxygen tension throughout the liver and decreases liver

Xenobiotics that produce liver damage in all humans in a predictable and dose-dependent manner are called intrinsic hepatotoxins. They include acetaminophen, CCl4, and yellow phosphorous. Those that cause liver damage in a small number of individuals and whose effect is not apparently dose dependent or predictable are called idiosyncratic hepatotoxins. Some idiosyncratic hepatotoxins cause hepatotoxicity very rarely, whereas others produce it commonly. The majority of hepatotoxins fall into the category of idiosyncratic xenobiotics.75,82 The inhaled anesthetic halothane is both an intrinsic and an idiosyncratic hepatotoxin. A mild degree of hepatitis occurs in as great as 20% of patients exposed to halothane.32 This form of halothane hepatitis, which can be reliably induced in animals, is likely caused by direct toxicity.117 A more severe idiosyncratic form appears to be caused by an autoimmune response induced by halothane that targets liver proteins13,127 (Chap. 67). Sporadic unpredicted hepatotoxicity is not idiosyncratic, but is more likely a result of the combined effects of genetic and other factors that result in the overproduction or decreased clearance of toxic metabolites. Idiosyncratic toxicity may be related to individual variability in the capacity to metabolize a specific xenobiotic and would most likely be predictable, rather than “idiosyncratic,” if the exposed individual’s metabolic capabilities could be prospectively defined (Chap. 12). An individual’s susceptibility to a hepatotoxin depends on numerous factors, including the activity of biotransformation enzymes, the availability of substrates such as glutathione, and the immune competence of the individual. In turn, these are affected by age, sex, diet, underlying diseases, concurrent exposure to other xenobiotics, and genetic factors. Many enzymes involved in biotransformation show genetic polymorphism.46,51,75,82 The susceptibility to toxic effects of a xenobiotic may be determined by inherited variations in CYP enzymes. For example, approximately 8% of whites are deficient in CYP2D6, which is responsible for the metabolism of a number of xenobiotics, including debrisoquine (an antihypertensive first identified as the substrate of this enzyme), several antidepressants and antidysrhythmics, some opioids, and phenformin.75,125 Perhexiline, an antianginal agent marketed in Europe in the 1980s, caused severe liver disease and peripheral neuropathy in persons with a demonstrated inability to metabolize debrisoquine.125 The congenital disorder that results in Gilbert syndrome is characterized by impaired glucuronyltransferase. Patients demonstrate decreased glucuronidation and increased bioactivation of acetaminophen during chronic therapeutic dosing, suggesting an increased risk of hepatic injury following ingestions of acetaminophen.25

■ EFFECTS OF XENOBIOTICS ON ENZYME FUNCTION FIGURE 26–3. Centrilobular necrosis in a rat liver caused by bromobenzene administration. Note the polymorphonuclear leukocyte infiltration surrounded by vacuolated hepatocytes in the necrotic area. (Reprinted, with permission, from Hetu C, Dumont A, Joly JG, et al. Effect of chronic ethanol administration on bromobenzene liver toxicity in the rat. Toxicol Appl Pharm. 1983;676:166.)

Changes in the activities of biotransformation enzymes that result in increased formation of hepatotoxic metabolites increase susceptibility to hepatic injury. Chronic administration of isoniazid (INH) induces CYP2E1 activity.145 During chronic ethanol exposure proliferation of the smooth endoplasmic reticulum in the centrilobular areas is associated with increased activity of CYP2E1.23,65,81,83,99 In one rat study, the

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administration of an average of 9.2 gm/kg of ethanol in increasing doses for 4 weeks resulted in a significant increase in the extent of injury to cultured zone 3 hepatocytes when exposed to CCl4. This was associated with a higher expression of CYP 2E1 in the livers of ethanol treated rats.81 Bromobenzene is a xenobiotic whose metabolism and hepatotoxicity are similar to that of acetaminophen. When administered to rats chronically exposed to ethanol, the onset of hepatotoxicity occurs more rapidly in study animals, with only a small increase in the extent of hepatic necrosis. The dose of bromobenzene required for hepatic injury to occur is not altered by pretreatment with ethanol.48 Chronic administration of phenobarbital to rats results in a very significant increase in the hepatotoxic effects of bromobenzene.98,109 Hepatic toxicity caused by solvents such as CCl4, dimethylformamide, and bromobenzene may be exacerbated by chronic exposure to ethanol.48,81,86,107 Whether ethanol increases the clinical risk of acetaminophen hepatotoxicity in humans is debated.68,103,120,124,148 There is no evidence that the chronic use of ethanol increases the risk of liver injury due to therapeutic doses of acetaminophen.54 Some xenobiotic combinations increase the possibility of hepatotoxic reactions because one xenobiotic alters the metabolism of the other, leading to the production of toxic metabolites.102 This is the case with combinations of rifampin and isoniazid;55 amoxicillin and clavulanic acid;72,106 and trimethoprim and sulfamethoxazole.3 Immune Mediated Hepatic Injury Immune-mediated liver injury is an idiosyncratic and host-dependent hypersensitivity response to exposure to xenobiotics.9,82 It is differentiated from liver injury caused by other autoimmune disorders by the absence of self-perpetuation, that is, there is a need for continuous exposure to the xenobiotic to perpetuate the injury.82 Hypersensitivity reactions result in forms of liver injury that include hepatitis, cholestasis, and mixed disorders. Drugs with hypersensitivity reactions that typically present with hepatitis include halothane,13,59,127 trimethoprim-sulfamethoxazole,3,98 anticonvulsants,77 and allopurinol.4,126 Drugs that typically present with cholestatic signs and symptoms (pruritus, jaundice, insignificant elevations of aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) include chlorpromazine, erythromycin, penicillins, rifampin, and sulfonamides.67,137 Signs of injury typically begin 1 to 8 weeks following the initiation of the drug, although they may begin as late as 20 weeks for drugs such as isoniazid or dantrolene. The onset of signs of injury associated with the oxypenicillins may occur as great as 2 weeks after the drug is stopped.82 In all cases, the onset is earlier when the patient is rechallenged with the drug. Although eosinophilia, atypical lymphocytosis, fever, and rash are common clinical manifestations of hypersensitivity, their absence does not exclude an autoimmune mechanism of drug-associated liver injury.64,82 How the immune response ultimately leads to cell injury is not well defined. Damage to the hepatocyte may be mediated by complement- or antibody-directed lysis; by specific cell-mediated cytotoxicity; or by an inflammatory response stimulated by immune complexes and complement.10,14,31,59,61,92 The covalent binding of a reactive electrophilic metabolite with a hepatocellular protein resulting in the formation of a neoantigen is a well-defined first step in the development of xenobioticrelated autoimmune liver injury. This covalent binding creates an “adduct” that is perceived as foreign by the immune system and induces an immune response. In cases where the metabolite is highly unstable, the electrophilic attack may be directed against the CYP enzyme at the site of formation of the metabolite.13,77,82 Adducts and associated autoantibodies have been demonstrated for acetaminophen,18 minocycline,10 halothane,13,31,127 dihydralazine,14 phenytoin,77 and germander.71 The most severe form of idiosyncratic halothane liver injury is manifest as fulminant hepatic failure associated with formation of adducts of its trifluoroacetyl chloride (TFA) metabolite with numerous hepatoproteins that include CYP2E1 and pyruvate dehydrogenase.9,31,59,127 Autoantibodies against the CYP2E1 enzyme have been demonstrated in halothane liver injury (Chap. 67).13,59 Autoantibodies specifically directed against CYP

enzymes have also been demonstrated for dihydralazine,14 and phenytoin.77 A trifluoroacetyl protein adduct similar to that associated with halothane hepatitis was detected in workers who developed hepatic necrosis following exposure to hydrochlorofluorocarbons.49 Whether autoantibodies stimulated by the xenobiotic-protein adducts are the actual mediators of cell injury is not clear. Early reports of lymphocyte sensitization in cases of xenobioticmediated liver toxicity suggested that cell-mediated immunity may play a role.137 Cell-mediated autoimmune mechanisms are implicated in the idiosyncratic type of halothane hepatitis and are suspected in an increasing number of models of experimental xenobiotic-mediated liver injury.32 Polymorphonucleocyte (PMN) activation and infiltration appear to be important factors in the production of cholangitis in a rat model of α-naphthyl-isothiocyanate (ANIT) liver injury. ANIT stimulates the release of cytotoxic lysosomal enzymes and oxygen free radicals by activated PMNs.92 Antibodies directed against circulating neutrophils to decrease the extent of liver damage caused by ANIT.22 Natural killer T cells are ubiquitous in the liver and their possible role in the facilitation of cell-mediated autoimmune liver injury is being investigated.21,45 Availability of Substrates The availability of substrates for detoxification may significantly affect both the likelihood and localization of hepatic injury.73 The metabolism of acetaminophen illustrates the effect of glutathione concentration on the delicate balance between detoxification and the production of injurious metabolites. In healthy adults taking therapeutic amounts of acetaminophen, approximately 90% of hepatic metabolism results in formation of glucuronidated or sulfated metabolites.25,133 Most of the remainder undergoes oxidative metabolism to the toxic electrophile N-acetyl-p-benzoquinoneimine (NAPQI) and is rapidly detoxified by conjugation with glutathione.18,54 Glutathione may be depleted during the course of metabolism of acetaminophen by otherwise normal livers, or it may be decreased by inadequate nutrition or liver disease.73,75 Excessive amounts of acetaminophen result in increased synthesis of NAPQI, which, in the absence of glutathione, reacts avidly with hepatocellular macromolecules. The cellular concentration of glutathione correlates inversely with the demonstrable covalent binding of NAPQI to liver cells.18 Centrilobular (zone 3) necrosis predominates in acetaminophen induced hepatic injury, possibly related to the centrilobular localization of CYP2E1 and the relatively low glutathione concentrations compared to the periportal areas (zone 1).54

MORPHOLOGIC AND BIOCHEMICAL MANIFESTATIONS OF HEPATIC INJURY The liver responds to injury in a limited number of ways.57 Cells may swell (ballooning degeneration) and accumulate fat (steatosis) or biliary material. They may necrose and lyse or undergo the slower process of apoptosis, forming shrunken, nonfunctioning, eosinophilic bodies. Necrosis may be focal or bridging, linking the periportal or centrilobular areas; zonal or panacinar; or it may be massive. An inflammatory cell response may precede or follow necrosis.20,75 Injury to the bile ducts results in cholestasis. Vascular injuries may cause obstruction to venous flow.69,143 The vascular effects of cocaine may cause ischemic liver injury.75,135 The variety and spectrum of injury caused by NSAIDS illustrates the difficulty in categorizing and characterizing all of the forms and causes of xenobiotic hepatic injury. These xenobiotics are associated with most forms of injury including asymptomatic aminotransferase elevations, simple cholestasis, hepatitis, bile duct injury, fulminant necrosis, and steatosis.57 Both azathioprine27 and ethanol54,80,84 are associated with a multitude of histopathologic manifestations of hepatocellular injury. Table 26–1 lists characteristic morphologies of hepatic injury and associated xenobiotics.

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Table 26–1. Morphology of Liver Injury by Selected Xenobiotics Acute Hepatocellular Necrosis Acetaminophena Allopurinol Amatoxina Arsenic Carbamazepine Carbon tetrachloridea Chlordecone (less severe) Hydralazine Iron Isoniazid Methotrexatea Methyldopa Nitrofurantoin Phenytoin Phosphorus (yellow)a Procainamide Propythiouracil Quinine Propythiouracil Quinine Sulfonamides Tetrachlorethane Tetracycline Trinitrotoluene Troglitazone Vinyl Chloride Steatohepatitis Amiodarone Dimethyl formamide Microvesicular Steatosis Aflatoxin Cerulide Fialuridine Hypoglycin Margosa oil Nucleoside analogs (Antiretrovirals) Tetracycline Valproic acid a

Granulomatous Hepatitis Allopurinol Aspirin Beryllium Carbamazepine Copper Salts Diltiazem Halothane Hydralazine Isoniazid Metolazone Methyldopa Nitrofurantoin Penicillins Phenytoin Procainamide Quinidine Quinine Sulfonamides Sulfonylureas Cholestasis Allopurinol Amoxacillin/clavulanic acid Androgens Chlorpromazine Chlorpropamide Erythromycin estolate Hydralazine Nitrofurantoin Oral contraceptives Rifampin Tetracycline Trimethaprimsulfamethoxazole

Fibrosis and Cirrhosis Ethanol Methotrexate Vitamin A Neoplasms Androgens Contraceptive steroids Vinyl chloride Venoocclusive Disease Cyclophosphamide Pyrrozolidine alkaloids Cannicular Cholestasis Chlorpromazine Cyclosporine Estrogens Methylene dianiline Bile Duct Damage α-napthylisothiocyanate Amoxicillin Carbamazepine Nitrofurantoin Oral contraceptives Autoimmune Hepatitis Dantrolene Diclofenac Methyldopa Methyldopa Nafcillin Nitrofurantoin Methyldopa Nafcillin Nitrofurantoin Propylthiouracil

Intrinsic hepatotoxin.

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■ ACUTE HEPATOCELLULAR NECROSIS Numerous xenobiotics have been associated with hepatocellular necrosis (see Table 26–1). Acetaminophen is a common cause, as are herbal remedies, whose risks are increasingly recognized.34,50,52,71,97 Many halogenated hydrocarbons that include carbon tetrachloride,16,81 bromobenzene,48,109 hydrochlorofluorocarbons,49 halothane13,59,127 and antituberculous drugs93,94,101 also produce hepatocellular necrosis. A study of greater than 11,000 patients exposed to isoniazid during preventive treatment showed that hepatocellular necrosis occurred in 0.10% of those starting treatment, and in 0.15% of those completing treatment.94 Risk factors for the development of hepatotoxicity from isoniazid exposure are female sex, increasing age, coadministration with rifampin, and alcoholism101 (Chap. 57). The thiazolidinedione agents troglitazone and rosiglitazone, marketed for the treatment of type 2 diabetes, are associated with acute hepatocellular necrosis.5,44 The much greater incidence of liver injury attributed to troglitazone led to its withdrawal from the market in March 2000.79 Occupational exposure to solvents that include dimethylformamide and CCl4 cause dose-related hepatocellular necrosis.86,107,108 Acute necrosis of a hepatocyte disrupts all aspects of its function. Because there is a great deal of functional reserve in the liver, hepatic function may be preserved despite the development of focal necrosis. Extensive necrosis results in functional liver failure. The processes that lead to cell necrosis are not well known. Cell lysis is preceded by the formation of blebs in the lipid membrane and leakage of cytosolic enzymes, primarily aminotransferases and lactate dehydrogenase. Coalescence of blebs leads to rupture of the cellular membrane and acute irreversible cell death, with disintegration of the nucleus and termination of all cellular function. Prior to membrane rupture, this injury is reversible by membrane repair processes.92 The release of intracellular constituents attracts circulating leukocytes and results in an inflammatory response in the hepatic parenchyma. A proposed mechanism of rapid injury to the cell membrane is the initiation of a cascading lipid peroxidation reaction following attack by a free radical. The CYP2E1 enzyme has a significant potential to produce oxygen free radicals, as do activated PMNs and Kupffer cells.23,33,92,115,144 Oxidant stress is an important cause of liver injury during the metabolism of ethanol by CYP2E1.28 This results in cell death and the stimulation of stellate cells, which promotes fibrosis.28 In addition to peroxidation of membrane lipids, the oxidation of proteins, phospholipid fatty acyl side chains, and nucleosides appear to be widespread. Mitochondrial injury and resultant ATP depletion may also be associated with necrosis.58,85 Acetaminophen is the commonest xenobiotic cause of fulminant hepatic failure and NAPQI, its reactive metabolite of acetaminophen, may target mitochondrial enzymes.79 Other xenobiotics known to cause mitochondrial injury include antiviral drugs,19,24,79,88,90 tetracycline,122 valproic acid,11 hypoglycin, margosa oil, and cerulide.85,119

increased uptake of circulating lipids; increased triglyceride production; decreased binding of triglycerides to lipoprotein; and decreased release of very-low-density lipoproteins from the hepatocytes.7,54,70,80 There are two light microscopic manifestations of steatosis: macrovesicular steatosis, in which the nucleus is displaced by large droplets of intracellular fat, and microvesicular steatosis, which is characterized by tiny cytoplasmic fat droplets that do not displace the nucleus. Xenobiotics associated with macrovesicular steatosis include ethanol and amiodarone. Ethanol increases the uptake of fatty acids into hepatocytes and decreases lipoprotein secretion. In addition, the increased ratio of the reduced form of nicotinamide adenine dinucleotide (NADH) to the oxidized form of nicotinamide adenine dinucleotide (NAD+), associated with hepatic metabolism of ethanol, decreases oxidation of fatty acids and promotes fatty acid synthesis.54,80 An early pathologic lesion that occurs in alcoholic liver disease is reversible macrovesicular steatosis. Mallory bodies, eosinophilic cytoplasmic deposits of keratin filaments in degenerating hepatocytes, are also common microscopic findings in alcoholic liver disease.20,54,80,84 Amiodarone hepatic toxicity resembles that of alcoholic hepatitis, with steatosis, Mallory bodies, and potential for progression to cirrhosis.75 Lamellated intralysosomal phospholipid inclusion bodies are specific for amiodarone toxicity.112 Figure 26–4 shows macrovesicular steatosis with Mallory bodies caused by amiodarone. Steatosis Associated with Mitochondrial Dysfunction Microvesicular steatosis is caused by severe impairment of β-oxidation of fatty acids. The β-oxidation of fatty acids depends on a steady synthesis of cellular energy in the form of ATP and takes place in the mitochondia. Mechanisms of impaired β-oxidation of fatty acids include direct inhibition or sequestration of critical cofactors such as coenzyme-A and L-carnitine.70 An association between deficiency of carnitine, microsteatosis, and the development of hyperammonemia is observed in children treated with valproic acid.11,104,136 Valproic acid causes mild elevations of aminotransferases in approximately 11% of patients, usually during the first few months of therapy. The earliest pathologic

■ STEATOSIS Steatosis is the abnormal accumulation of fat in hepatocytes. It reflects abnormal cellular metabolism in conditions that include responses to xenobiotics. Cell injury depends on the severity of the underlying metabolic disturbance, steatosis per se is normally well tolerated and reversible in many cases although approximately one-third of patients with nonalcoholic steatosis may develop steatohepatitis.37,54,70 Nonalcoholic steatosis associated with obesity, insulin resistance, and the metabolic syndrome may account for many cases of cryptogenic cirrhosis.37 Intracellular fat accumulation may occur as a result of any one or more of the following mechanisms: impaired synthesis of lipoproteins; increased mobilization of peripheral adipose stores;

FIGURE 26–4. Macrovesicular steatosis associated with administration of amiodarone. The small arrow indicates the presence of Mallory bodies. The large arrow points to accumulated intracellular fat. (Note that the nuclei are displaced.) Polymorphonuclear leukocytes (P) are also present. (Reprinted, with permission, from Lee WM. Druginduced hepatotoxicity. N Engl J Med. 1995;333:1118.)

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lesion that signals progression of liver injury is microvesicular steatosis, which occurs in the absence of necrosis. A small percentage of patients progress to fulminant hepatic failure characterized by centrilobular necrosis.146 The incidence of fatal hepatocellular injury is highest in children, approaching 1 in 800 children younger than age 2 years.104 Other mechanisms of impairment of β-oxidation of fatty acids include processes that disrupt cellular ATP production, either directly by xenobiotics such as sodium azide or cyanide that inhibit electron transport in the respiratory chain; by xenobiotics that increase permeability of mitochondrial membranes and degrade the proton gradient that is critical to ATP synthesis; or by xenobiotics that uncouple oxidative ph osphorylation.7,42,78,90,119,122 Nucleoside analogs that inhibit viral reverse transcriptase also inhibit mitochondrial DNA synthesis, leading to depletion of mitochondria.19,70,90,119 Microvesicular steatosis is described in patients taking antiretrovirals such as zidovudine, zalcitabine, and didanosine.24,88,128,131 Failure of the mitochondrial power supply may or may not be associated with hepatocyte necrosis and elevation of hepatocellular enzymes.85,90,119 In all cases, metabolic acidosis with elevated lactate is a prominent biochemical feature.24,42,119 The nucleoside analog fialuridine caused severe hepatotoxicity during a study of its use in the treatment of chronic hepatitis B infection. Microscopic examinations of liver specimens in these cases showed marked accumulation of fat with minimal necrosis or structural injury. Severe acidosis and failure of hepatic synthetic function suggested failure of cellular energy production. Mitochondria examined under the electron microscope were demonstrably abnormal.90 Figure 26–5 demonstrates microvesicular steatosis in a patient with fialuridine hepatotoxicity. High doses of tetracycline produce microvesicular steatosis associated with moderate elevations of aminotransferases, markedly prolonged prothrombin time, and progression to fulminant hepatic failure.122 Microvesicular steatosis attributed to failure of mitochondrial energy production was reported in a fatal case of Bacillus cereus food poisoning, where high concentrations of the bacterial emetic toxin cereulide were found in the bile and liver. In this case, microvesicular steatosis was associated with extensive hepatocellular necrosis.85 Other xenobiotics that cause

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mitochondrial failure are hypoglycin, the cause of Jamaican vomiting sickness, aflatoxin, and margosa oil.119 Steatosis is also observed following exposure to the industrial solvent dimethylformamide. Liver biopsies in patients with acute illness show focal hepatocellular necrosis and microvesicular steatosis. More prolonged, less symptomatic exposures result in significant macrovesicular steatosis with mild aminotransferase elevations.107,108

■ CHOLESTASIS Xenobiotics induce cholestasis by targeting specific mechanisms of bile synthesis and flow or by damaging canicular cells.54,67 Cholestasis may occur with or without associated hepatitis. The development of jaundice following hepatic necrosis is a manifestation of general failure of liver function. More discrete mechanisms that result in intrahepatic cholestasis include (a) impairment of the integrity of tight membrane junctions that functionally isolate the canaliculus from the hepatocyte and sinusoids; (b) failure of transport of bile components across the hepatocytes; (c) blockade of specific membrane active transport sites; (d) decreased membrane fluidity resulting in altered transport; and (e) decreased canalicular contractility resulting in decreased bile flow.12,54,67,121 Estrogens cause intrahepatic cholestasis by altering the composition of the lipid membrane and inhibiting the rate of secretion of bile into the canaliculi.67,79,121 Rifampin impedes the uptake of bilirubin into hepatocytes. Methyltestosterone and C-17 alkylated anabolic steroids impair the secretion of bilirubin into canaliculi.79 Exposure to chlorpromazine is associated with cholestasis and periductal inflammation. This may be caused by inhibition of Na+, K+-adenosine triphosphatase (ATPase), which results in decreased canalicular contractility.116 Cyclosporine inhibits sodium-dependent uptake of bile salts across the sinusoidal membrane and blocks ATPdependent bile salt transport across the canalicular membrane.12 Floxacillin causes cholestasis with minimal inflammation or evidence of hepatocellular injury.137 Exposure of rats to ANIT causes a specific injury localized to the tight junctions that separate the hepatocyte from the canaliculi. This results in reflux of bile constituents into the sinusoidal space and increased access of sinusoidal molecules to the biliary tree.22,67,92

■ VENOOCCLUSIVE DISEASE Hepatic venoocclusive disease is caused by toxins that injure the endothelium of terminal hepatic venules, resulting in intimal thickening, edema, and nonthrombotic obstruction. Central and sublobular hepatic veins may also become edematous and fibrosed. There is intense sinusoidal dilation in the centrilobular areas that is associated with liver cell atrophy and necrosis.142 The gross pathologic appearance is that of a “nutmeg” liver.69,143 Massive hepatic congestion and ascites ensue.69,111 Hepatic venoocclusive disease is rapidly fatal in 15% to 20% of cases. It is associated with exposure to pyrrolizidine alkaloids found in many plant species including Symphytum (comfrey tea),140,143 Heliotrope, Senecio, and Crotalaria.69 It has occurred in epidemic proportions; in South Africa after the ingestion of flour contaminated with ragwort (Senecio); in Jamaica after the ingestion of “bush teas” (Crotalaria spp); and in India and Afghanistan when food was contaminated with Heliotropium lasiocarpine and Crotalaria.15,95,132 A rapidly progressive form has been reported in bone marrow transplant patients following high-dose treatment with cyclophosphamide.89 FIGURE 26–5. This figure shows severe microvesicular steatosis in a patient treated with fialuridine. Note the central location of the nuclei. (Reprinted, with permission, from McKenzie R, Fried MW, Sallie R, et al. Hepatic failure and lactic acidosis due to fialuridine, an investigational nucleoside analogue for chronic hepatitis B. N Engl J Med. 1995;333:1099.)

■ CHRONIC HEPATITIS A form of hepatitis that clinically resembles nontoxic autoimmune hepatitis occurs with the chronic administration of drugs such as

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methyldopa, nitrofurantoin, propylthiouracil, nafcillin, dantrolene, and diclofenac.4,60,76,88,110,123,130 Many cases are associated with positive antinuclear antibody (ANA), smooth muscle antibody (SMA), and hyperglobulinemia. Jaundice is prominent and hepatocellular enzymes are elevated 5- to 60-fold. Liver biopsy commonly reveals intrahepatic cholestasis, as well as centrilobular inflammation.82 Granulomatous hepatitis is characterized by infiltration of the hepatic parenchyma with caseating granulomata. As great as 60 drugs are associated with this disorder. Fever and systemic symptoms are common, 25% have splenomegaly. Liver enzymes are mixed, reflecting variable degrees of cholestasis and hepatocellular injury. Eosinophilia occurs in 30% as an extrahepatic manifestation of drug hypersensitivity. Continued exposure may result in a more severe form of liver disease. Small vessel vasculitis, which may involve the skin, lungs, and kidney, is a disturbing sign associated with increased mortality.75,91,147 Table 26–1 lists a number of the xenobiotics that have been implicated in this disorder.

CLINICAL PRESENTATION OF TOXIC LIVER INJURY

■ CIRRHOSIS

■ FULMINANT HEPATIC FAILURE

Cirrhosis is caused by progressive fibrosis and scarring of the liver, which results in irreversible hepatic dysfunction and portal hypertension. This causes shunting of blood away from hepatocytes and subsequent hepatocellular dysfunction. Activated stellate cells produce collagen, proteoglycans, and adhesive glycoproteins, which are deposited in the space of Disse and are crucial to the development of hepatic fibrosis.118 Kupffer cells contribute to the activation of hepatic stellate cells.118 In alcoholic cirrhosis, acetaldehyde also stimulates collagen production by hepatic stellate cells, as do other aldehydes that are products of lipid peroxidation.54,80 Alcoholic hepatitis generally precedes cirrhosis, although cirrhosis may develop in its absence.84 Chronic ingestion of excessive amounts of vitamin A (25,000 U/d for 6 years or 100,000 U/d for 2.5 years) results in cirrhosis. An increase in the fat content of the sinusoidal stellate cells with increasing degrees of collagen formation are characteristic lesions that occur early in vitamin A toxicity (Chap. 41). Portal hypertension may be early and striking.43 Like vitamin A, methyldopa and methotrexate also cause a slow progressive development of cirrhosis with few clinical symptoms.76,141 Methotrexate-induced hepatic fibrosis is dose dependent. Risk factors include associated alcohol intake and preexisting liver disease. Reduced dosing has largely eliminated the risk of the development of cirrhosis in patients receiving methotrexate.58,141

Fulminant hepatic failure (FHF) is defined as liver injury that progresses to coagulopathy and encephalopathy within 8 weeks of the onset of illness in a patient without preexisting liver disease.41,74 Complications from FHF include encephalopathy, cerebral edema, coagulopathy, renal dysfunction, hypoglycemia, hypotension, acute lung injury, sepsis, and death. In some cases, a patient may progress from health to death in as little as 2-10 days.17,39,40,41,74,85,100 Table 26–2 shows the clinical progression of encephalopathy as hepatic failure develops. The prognosis of FHF is related to the time that passes between the onset of jaundice and the onset of encephalopathy. Perhaps surprisingly, a better prognosis is associated with shorter (2-4 weeks) jaundice-toencephalopathy intervals.113 Most cases of FHF are caused by xenobiotics or viral hepatitis. FHF is usually associated with extensive necrosis,

Clinical presentations of toxic liver injury range from indolent, often asymptomatic progression of impairment of hepatic function to rapid development of hepatic failure. Jaundice and pruritis are due to increased concentrations of bile acids and bilirubin in the blood. Failure of hepatocellular synthetic function results in bleeding due to coagulopathy and edema due to hypoalbuminemia. Encephalopathy may be due to hypoglycemia, impaired neurotransmission, or accumulation of toxic products of metabolism such as ammonia. Fever may occur with autoimmune mediated liver injury. Impaired hepatic blood flow results in familiar manifestations of portal hypertension such as caput medusa, splenomegaly, ascites and varices. Spider angiomata and gynecomastia also occur due to altered estrogen metabolism.20

TABLE 26–2. Stages of Hepatic Encephalopathy Clinical Stage Mental Status

Neuromotor Function

Subclinical

Normal physical examination

I

Euphoric, irritable, depressed, fluctuating mild confusion, poor attention, sleep disturbance Impaired memory, cognition, or simple mathematical tasks Difficult to arouse, persistent confusion, incoherent Coma; may respond to noxious stimuli

Subtle impairment of neuromotor function → driving or work injury hazard Poor coordination; may have asterixis alone

■ HEPATIC TUMORS There is persuasive evidence that the use of oral contraceptive steroids increases the risk of hepatic adenomas.63 There is also evidence that oral contraceptives increase the overall risk of hepatocellular carcinoma; however, the number of cases associated with estrogen therapy is low.53 Anabolic steroids are rarely associated with the development of both benign and malignant hepatic tumors.38 Angiosarcoma is strongly associated with exposure to vinyl chloride, in addition to arsenic, thorium dioxide, and steroid hormones.36

II

III

■ HEPATIC INJURY ASSOCIATED WITH PLANTS AND HERBS In addition to the venoocclusive disease associated with pyrrolizidine alkaloids described above, herbal remedies are increasingly recognized as a cause of acute hepatocellular injury. Numerous plants or plant products are known or suspected to cause hepatic injury (Chaps. 43 and 118).30,34,50,52,71,97

IV

Slurred speech, tremor, ataxia

Hyperactive reflexes, clonus, nystagmus May have decerebrate posturing; Cheyne-Stokes respirations; pupils are reactive and the oculocephalic reflex is intact; may have signs of ↑ intracranial pressure

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although it may occur in the absence of demonstrable necrosis following exposures to xenobiotics that injure mitochondria.85,90,131 Some xenobiotics that are associated with fulminant hepatic necrosis are clove oil, amanitin cyclopeptides, acetaminophen, tetracycline, yellow phosphorus, halogenated hydrocarbons, isoniazid, methyldopa, and valproic acid.30,74,96,107,108,113,122

■ HEPATIC ENCEPHALOPATHY Hepatic encephalopathy (HE) is a severe manifestation of liver failure that is potentially fully reversible, even in cases of deep coma.39,40,41 HE is associated with a fluctuating sensorium that ranges from barely discernible confusion to coma. Neuromotor signs such as asterixis and rigidity are common.17 Table 26–2 lists the clinical stages of acute HE. Ammonia is produced in the colon by bacterial breakdown of ingested proteins then transported to the liver via the portal circulation where it is detoxified to glutamine and urea.40 Ammonia concentrations are elevated in 60% to 80% of patients with HE.40 Processes that raise CNS ammonia concentrations include infection, hypokalemia, alkalosis, increased muscle wasting, volume depletion, azotemia, or gastrointestinal bleeding.40 Alkalosis and hypokalemia facilitate conversion of NH4+ to NH3, which moves more easily across the blood–brain barrier. The demonstration that ammonia is not elevated in many cases suggests that there are other pathogenic etiologies and the etiology is multifactorial. Disruption of central neurotransmitter regulation including dopamine receptor binding may contribute.138 There is evidence that liver failure is associated with the accumulation of substances that stimulate central benzodiazepine receptors, leading to inhibition of γ-aminobutyric acid (GABA) transmission.6 Nonnitrogenous HE is precipitated by sedatives, especially benzodiazepines, hypoxia, hypoglycemia, hypothyroidism, and anemia.40 Although it is clear that sedatives that depress GABAergic transmission can make encephalopathy worse, studies of the use of flumazenil to reverse encephalopathy show conflicting results.6 Significant short-term improvement was demonstrated in some patients who already have a highly favorable prognosis. Although there is no clear evidence that all patients will benefit from flumazenil, some individuals may benefit for a short time. Certainly, the administration of benzodiazepines should be avoided.6

EVALUATION OF THE PATIENT WITH LIVER DISEASE The history is critical in establishing the diagnosis of the patient with liver disease. A medication history should include careful investigation of nonprescription xenobiotics, especially acetaminophen and the possible use of alternative or complementary therapies including herbal therapies. Nearly all chronically used medications should be suspect. An occupational history may indicate exposure to vinyl chloride (plastics industry), dimethylformamide (leather industry), or other industrial solvents. Table 26–3 lists occupational exposures that result in liver injury. Alcohol abuse is a common cause of acute hepatitis and the most common cause of cirrhosis in this country.80,84 A history of male homosexual contacts, healthcare occupation, or intravenous drug use indicates the possibility of hepatitis B and C. Recent travel to an underdeveloped country suggests the possibility of hepatitis A. In patients with significant pain, the possibility of cholelithiasis should be considered.

■ BIOCHEMICAL PATTERNS OF LIVER INJURY There are two basic biochemical patterns associated with liver injury induced by xenobiotics. The hepatocellular pattern is characterized by elevation of liver transaminases due to the injury of hepatocytes

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TABLE 26–3. Occupational Exposures Associated with Liver Injury Xenobiotic

Type of Injury

Arsenic Beryllium Carbon tetrachloride Chlordecone Copper salts Dimethylformamide Methylenedianiline Phosphorus Tetrachloroethane Tetrachloroethylene Toluene Trichloroethane Trinitrotoluene Vinyl chloride Xylene

Cirrhosis, angiosarcoma Granulomatous hepatitis Acute necrosis Minor hepatocellular injury Granulomatous hepatitis, angiosarcoma Steatohepatitis Acute cholestasis Acute necrosis Acute, subacute necrosis Acute necrosis Steatosis, minor hepatocellular injury Steatosis, minor hepatocellular injury Acute necrosis Acute necrosis, fibrosis, angiosarcoma Steatosis, minor hepatocellular injury

by apoptosis or necrosis. The cholestatic pattern is characterized by elevation of the serum alkaline phosphatase concentration and usually results from injury or functional impairment of the bile ductules.1 Processes associated with intrahepatic cholestasis in the absence of hepatitis may not lead to significant aminotransferase elevation.98,106,147 Aminotransferases Laboratory tests are helpful and certain patterns may be suggestive of specific etiologies (Table 26–4). Elevation of hepatocellular enzymes, especially the AST and ALT, indicates hepatocellular injury, and within a given clinical context, has useful diagnostic significance. Aminotransferases may be increased up to 500 times normal when hepatic necrosis is extensive, such as in severe acute viral or toxic hepatitis.2,74 The degree of elevation does not always reflect the severity of injury as concentrations may decline as FHF progresses. Only moderately elevated, or occasionally normal aminotransferase concentrations occur in some patients with hepatic failure caused by mitochondrial failure, cirrhosis, or venoocclusive disease.43,69,90,146 Aminotransferase concentrations may be normal or only slightly elevated in processes associated with intrahepatic cholestasis in the absence of hepatitis.98,106,147 In alcoholic liver disease, in contrast to other forms of hepatitis, the AST concentration is typically two to three times greater than the ALT. This is attributed to impairment of ALT synthesis because of pyridine-5ʹ-phosphate deficiency in alcoholics. This effect is reversed by pyridoxine supplementation. Elevation of either of these enzymes greater than 300 IU/L is inconsistent with injury caused by ethanol.2 During acute extrahepatic obstruction of the biliary tract, the AST or ALT may be as high as 1000 IU/L, indicating inflammation caused by reflux of bile acids into the biliary tree.2 The measurement of γ-glutamyl transpeptidase (GGTP) is not very useful as it is present throughout the liver and its elevation is often nonspecific.2 Alkaline Phosphatase In patients with cholestasis, bile acids stimulate the synthesis of alkaline phosphatase by hepatocytes and biliary epithelium in response to a number of pathologic processes in the liver. Elevations of the alkaline phosphatase as great as 10-fold may occur with infiltrative liver diseases, but are most commonly associated with extrahepatic obstruction.2 Although the alkaline phosphatase may be normal or elevated only minimally in hepatocellular injury, it is

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TABLE 26–4. Laboratory Tests that Evaluate the Liver Disorder

Alkaline Phosphatase

AST, ALT

Albumin

Prothrombin Time

Bilirubin

Ammonia

Anion Gap

Hepatocellular necrosis, acute focal (hepatitis) Hepatocellular necrosis, acute massive Chronic infiltrative disease (tumor, fatty liver) Acute mitochondrial failure Cholelithiasis Cholestasis Chronic hepatitis Cirrhosis

N or ↑

↑↑↑

N

N or ↑

↑↑

N

N

N or ↑

↑↑↑

N

↑↑

↑↑↑

↑↑

↑

↑↑↑

↑

N

N

N

N

N

N or ↑

N or ↑

N

↑↑

↑

↑↑

↑↑↑

↑ ↑↑ N or ↑ N or ↑

N or ↑ N or ↑ ↑ ↑

N N N or ↓ ↓

N N N N or ↑

N or ↑ ↑ N or ↑ N or ↑

N N N or ↑ N or ↑

N N N N

↑ = increase; ↓ = decrease; N = normal.

unusual for obstruction to occur without some elevation of the alkaline phosphatase. Elevations of alkaline phosphatase and GGTP parallel each other in disease of the biliary tract.2 Bilirubin Elevation of conjugated, or direct, bilirubin implies impairment of secretion into bile while elevation of unconjugated, or indirect, bilirubin implies impairment of conjugation. Unconjugated hyperbilirubinemia also occurs during hemolysis and in rare disorders of hepatic conjugation such as Gilbert or Crigler-Najjar syndromes. Except in cases of pure unconjugated hyperbilirubinemia, the fractionation of bilirubin in the case of hepatobiliary disorders does not have any important diagnostic utility, and will not distinguish patients with parenchymal disorders of the liver from intrinsic or extrinsic cholestasis. The presence of bilirubin in the urine implies elevation of conjugated (direct) bilirubin which is water soluble and filtered by the glomerulus obviating the need for laboratory fractionation.2 Urobilinogen is produced by the bacterial metabolism of bilirubin in the bowel lumen. It is absorbed and excreted in the urine. Its presence in the urine indicates the normal excretion of bilirubin in bile, while its absence is associated with complete biliary obstruction. As a result of more modern methods of detection of complete obstruction of the biliary tract, this test is mainly of historical interest. Serum Albumin Quantitatively, albumin is the most important protein that is made in the liver. With a half-life as great as 20 days, the albumin is usually normal in the previously healthy patient with acute liver injury. In the absence of disorders that affect albumin, such as nephrotic syndrome, protein-losing enteropathy, or starvation, a low serum albumin is a useful marker for the severity of chronic liver disease.2 Coagulation Factors Impairment of coagulation is a marker of the severity of hepatic dysfunction in both acute and chronic liver disease. Unlike the case with serum albumin, with its half-life of 20 days, the onset of coagulopathy as a consequence of impaired synthesis of the short-lived vitamin K-dependent clotting factors II, VII, IX, and X is rapid. Very acute changes in coagulation reflect the concentration of

factor VII, which has the shortest half life.56 The extrinsic coagulation pathway, as measured by the prothrombin time (PT) or the international normalized ratio (INR), is affected by reductions in factors II, VII, and X. Elevation of the INR or PT in acute hepatitis is associated with a higher risk of FHF.47,74,90 In addition to failure of hepatic synthesis, inadequate levels of factors II, VII, IX, and X may also result from ingestion of warfarin anticoagulants or malabsorption of vitamin K (Chap. 59).2 Because different thromboplastin reagents give different PT values on the same sample, the INR was developed to normalize PT measurements in patients treated with warfarin, allowing comparisons of therapeutic outcomes across different care settings and across the literature. The INR uses the International Sensitivity Index (ISI) that is derived from a cohort of patients on stable anticoagulant therapy. It normalizes the responsiveness of a given thromboplastin reagent in comparison to a WHO reference standard that is assigned a value of 1.0.66 There is little controversy regarding the value of the INR in comparison with the PT ratio for measuring the extent of warfarininduced anticoagulation. Because factor deficiencies in patients with liver disease are different from those in patients on warfarin, there is considerable controversy regarding which measurement is best for patients with liver disease.2,26,66 Although comparison of factor levels in warfarin-treated patients with those with liver disease showed no difference in factor VII, there are significant differences in factors II, V, X, and fibrinogen. Comparison of the PT with INR in the evaluation of test results with three different thromboplastin reagents showed consistency among the control groups of warfarin-treated patients, but no consistency among PT or INR measurements using the same thromboplastin reagents in patients with liver disease.66 Because of a failure to demonstrate an advantage, liver specialists who have expressed an opinion support the continued use of the PT to describe the degree of liver injury, lacking the availability of a single reliable standard that would help predict operative risk.2,26,66 In patients with liver disease, use of the INR implies a normalized correlation that does not exist and is therefore potentially misleading. The implication for toxicologists is that caution should be exercised in relying too heavily on published

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INR values that purportedly predict the severity of illness in patients with acute liver failure. Ammonia Severe generalized impairment of hepatic function leads to a rise in the serum ammonia concentration as a result of impairment of detoxification of ammonia produced during catabolism of proteins. The absolute concentration is not clearly associated with mental status alteration. Elevations of serum ammonia concentrations occur in 60% to 80% of patients with hepatic encephalopathy, suggesting that hyperammonemia is not the only cause of hepatic encephalopathy.40 Some patients treated with valproic acid have developed alterations in mental status associated with elevated ammonia concentrations, sometimes in the absence of other laboratory indicators of hepatic injury, and without demonstrable toxic concentrations of valproic acid. This has been attributed to selective impairment of urea cycle enzymes ornithine transcarbamylase or carbamyl phosphate synthetase by pentanoic acid metabolites (Chap. 47).35,105 As noted above, an association between deficiency of carnitine, microsteatosis, and the development of hyperammonemia is observed in children treated with valproic acid. This is attributed to impairment of carnitinedependent beta-oxidation of sodium valproate and free fatty acids in the mitochondria.11,104,136

■ OTHER LABORATORY TESTS Serologic Studies for the Presence of Markers of Hepatitis A, B, and C Should be Done Routinely in Patients with Hepatitis. In the patient with severe liver injury, hypoglycemia is a major concern because of impairment of glycogen storage and gluconeogenesis. Hyperglycemia also occurs as a result of the liver’s inability to handle a large glucose load. The arterial blood-gas value commonly shows a respiratory alkalosis. Severe metabolic acidosis with elevated lactate occurs in patients with hepatic failure caused by mitochondrial injury. Measurements of serum lactate concentration may be useful in identifying the cause of acidosis in a patient with suspected toxic liver injury.85,90,119 The CT and MRI scans are useful tests for evaluation of parenchymal disease of the liver. An ultrasound examination reliably demonstrates dilation of the extrahepatic bile ducts. Liver biopsy may be helpful but is not specifically diagnostic of xenobiotic-induced hepatic injury.

MANAGEMENT In many patients, toxic liver injury resolves with simple withdrawal of the offending xenobiotic. In patients with severe injury, significant improvement in survival is associated with good supportive care in an intensive care environment.74 Early referral to a transplant center for patients with evidence of severe or rapidly progressive toxic injury is indicated. For discussion of indications for the use of N-acetylcysteine and discussion of indications for transplantation, see Antidotes in Depth A4: N-Acetylcysteine.

SUMMARY The primary role of the liver in the biotransformation of xenobiotics results in an increased risk of hepatotoxicity. Xenobiotic-induced liver injury can be dose-dependent and predictable or idiosyncratic and unpredictable. Idiosyncratic injury is affected by host characteristics that include genetic makeup, concomitant or previous exposure to drugs and toxins, and the underlying condition of the liver. The spectrum of liver injury includes combinations of cholestasis, steatosis, hepatocellular necrosis, apoptosis, and fibrosis. Injury may be a result

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of cellular or antibody-mediated immune mechanisms; free radical initiation of lipid peroxidation; mitochondrial injury; formation of adducts with critical cellular enzymes; and other, less-well-defined mechanisms.

ACKNOWLEDGMENT Charles Maltz and Todd Bania contributed to this chapter in a previous edition.

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22. Dahm LJ, Schultze AE, Roth RA. An antibody to neutrophils attenuates alpha-naphthylisothiocyanate–induced liver injury. J Pharmacol Exp Ther. 1991;256:412-420. 23. Dai Y, Rashba-Step J, Cederbaum AI. Stable expression of human cytochrome P450 2E1 in HepG2 cells: characterization of catalytic activities and production of reactive oxygen intermediates. Biochemistry. 1993;32:6928-6937. 24. Day L, Shikuma C, Gerschenson M. Mitochondrial injury in the pathogenesis of antiretroviral-induced hepatic steatosis and lactic acidemia. Mitochondrion. 2004;4:95-109. 25. de Morais SM, Uetrecht JP, Wells PG. Decreased glucuronidation and increased bioactivation of acetaminophen in Gilbert’s syndrome. Gastroenterology. 1992;102:577-586. 26. Denson KW, Reed SV, Haddon ME. Validity of the INR system for patients with liver impairment. Thromb Haemost. 1995;73:162. 27. DePinho RA, Goldberg CS, Lefkowitch JH. Azathioprine and the liver. Evidence favoring idiosyncratic, mixed cholestatic-hepatocellular injury in humans. Gastroenterology. 1984;86:162-165. 28. Dey A, Cederbaum AI. Alcohol and oxidative liver injury. Hepatology. 2006;43:S63-S74. 29. Dutczak WJ, Clarkson TW, Ballatori N. Biliary-hepatic recycling of a xenobiotic: gallbladder absorption of methyl mercury. Am J Physiol. 1991;260:G873-G880. 30. Eisen JS, Koren G, Juurlink DN, et al. N-Acetylcysteine for the treatment of clove oil-induced fulminant hepatic failure. J Toxicol Clin Toxicol. 2004;42:89-92. 31. Eliasson E, Kenna JG. Cytochrome P450 2E1 is a cell surface autoantigen in halothane hepatitis. Mol Pharmacol. 1996;50:573-582. 32. Elliott RH, Strunin L. Hepatotoxicity of volatile anaesthetics. Br J Anaesth. 1993;70:339-348. 33. El-Sisi AE, Earnest DL, Sipes IG. Vitamin A potentiation of carbon tetrachloride hepatotoxicity: role of liver macrophages and active oxygen species. Toxicol Appl Pharmacol. 1993;119:295-301. 34. Estes JD, Stolpman D, Olyaei A, et al. High prevalence of potentially hepatotoxic herbal supplement use in patients with fulminant hepatic failure. Arch Surg. 2003;138:852-858. 35. Eze E, Workman M, Donley B. Hyperammonemia and coma developed by a woman treated with valproic acid for affective disorder. Psychiatr Serv. 1998;49:1358-1359. 36. Falk H, Thomas LB, Popper H, et al. Hepatic angiosarcoma associated with androgenic-anabolic steroids. Lancet. 1979;2:1120-1123. 37. Farrell GC, Larter CZ. Non-alcoholic fatty liver disease. Hepatology. 2006;43:S99-S112. 38. Farrell GC, Joshua DE, Uren RF, et al. Androgen-induced hepatoma. Lancet. 1975;1:430-432. 39. Ferenci P. Brain dysfunction in fulminant hepatic failure. J Hepatol. 1994;21:487-490. 40. Fitz JG. Hepatic encephalopathy. In: Feldman M, Friedman L, Sleisenger M, et al., eds. Sleisenger & Fordtran’s Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management. 8th ed. Philadelphia: Saunders; 2006:1966-1971. 41. Fontana RJ. Acute liver failure. In: Feldman M, Friedman L, Sleisenger M, et al., eds. Sleisenger & Fordtran’s Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management. 8th ed. Philadelphia: Saunders; 2006:1993-2003 . 42. Fromenty B, Pessayre D. Inhibition of mitochondrial β-oxidation as a mechanism of hepatotoxicity. Pharmacol Ther. 1995;67:101-154. 43. Geubel AP, de Galoscy C, Alves N, et al. Liver damage caused by therapeutic vitamin A administration: estimate of dose-related toxicity in 41 cases. Gastroenterology. 1991;100:1701-1709. 44. Gitlin N, Julie NL, Spurr CL, et al. Two cases of severe clinical and histologic hepatotoxicity associated with troglitazone. Ann Intern Med. 1998;129:36-38. 45. Godfrey DI, Hammond KJ, Poulton LD, et al. NKT cells: facts, functions and fallacies. Immunol Today. 2000;21:573-583. 46. Guegenrich F. Catalytic selectivity of human cytochrome P450 enzymes: relevance to drug metabolism and toxicity. Toxicol Lett. 1994;70:133-138. 47. Harrison PM, O’Grady JG, Keays RT, et al. Serial prothrombin time as prognostic indicator in paracetamol induced fulminant hepatic failure. BMJ. 1990;301:964-966. 48. Hetu C, Dumont A, Joly JG. Effect of chronic ethanol administration on bromobenzene liver toxicity in the rat. Toxicol Appl Pharmacol. 1983;67:166-177.

49. Hoet P, Graf ML, Bourdi M, et al. Epidemic of liver disease caused by hydrochlorofluorocarbons used as ozone-sparing substitutes of chlorofluorocarbons. Lancet. 1997;350:556-559. 50. Horowitz RS, Feldhaus K, Dart RC, et al. The clinical spectrum of Jin Bu Huan toxicity. Arch Intern Med. 1996;156:899-903. 51. Huang YS, Chern HD, Su WJ, et al. Cytochrome P450 2E1 genotype and the susceptibility to antituberculous drug-induced hepatitis. Hepatology. 2003;37:924-930. 52. Humberston CL, Akhtar J, Krenzelok EP. Acute hepatitis induced by kava kava. J Toxicol Clin Toxicol. 2003;41:109-113. 53. Ishak KG. Hepatic lesions caused by anabolic and contraceptive steroids. Semin Liver Dis. 1981;1:116-128. 54. Jaeschke H. Toxic responses of the liver. In: Klaassen CD, ed. Casarett and Doull’s Toxicology The Basic Science of Poisons. 7th ed. New York: McGraw Hill Medical; 2007:557-582. 55. Jenner PJ, Ellard GA. Isoniazid-related hepatotoxicity: a study of the effect of rifampicin administration on the metabolism of acetyl isoniazid in man. Tubercle. 1989;7093-101. 56. Johnston M, Harrison L, Moffat K, et al. Reliability of the international normalized ratio for monitoring the induction phase of warfarin: comparison with the prothrombin time ratio. J Lab Clin Med. 1996;128:214-217. 57. Kanel GC. Histopathology of drug-induced liver disease. In: Kaplowitz N, DeLeve LD, eds. Drug-Induced Liver Disease. 2nd ed. Informa Health Care; New York, NY. 2007:237. 58. Kaplowitz N. Mechanisms of liver cell injury. J Hepatol. 2000;32:39-47. 59. Kenna JG: Immunoallergic drug-induced hepatitis: lessons from halothane. J Hepatol. 1997;26(Suppl1):5-12. 60. Kim HJ, Kim BH, Han YS, et al. The incidence and clinical characteristics of symptomatic propylthiouracil-induced hepatic injury in patients with hyperthyroidism: a single-center retrospective study. Am J Gastroenterol. 2001;96:165-169. 61. Kita H, Mackay IR, Van De Water J, et al. The lymphoid liver: considerations on pathways to autoimmune injury. Gastroenterology. 2001;120:1485-1501. 62. Klaassen CD. Biliary excretion of metals. Drug Metab Rev. 1976;5:165-193. 63. Knowles DM 2nd, Casarella WJ, Johnson PM, et al. The clinical, radiologic, and pathologic characterization of benign hepatic neoplasms. Alleged association with oral contraceptives. Medicine.1978;57:223-237. 64. Knudtson E, Para M, Boswell H, et al. Drug rash with eosinophilia and systemic symptoms syndrome and renal toxicity with a nevirapine-containing regimen in a pregnant patient with human immunodeficiency virus. Obstet Gynecol. 2003;101:1094-1097. 65. Konishi M. Ishii H. Role of microsomal enzymes in development of alcoholic liver diseases. J Gastroenterol Hepatol. 2007;22(Suppl1):S7-S10. 66. Kovacs MJ, Wong A, MacKinnon K, et al. Assessment of the validity of the INR system for patients with liver impairment. Thromb Haemost. 1994;71:727-730. 67. Krell H, Metz J, Jaeschke H, et al. Drug-induced intrahepatic cholestasis: characterization of different pathomechanisms. Arch Toxicol. 1987;60:124130. 68. Kuffner EK, Dart RC, Bogdan GM, et al. Effect of maximal daily doses of acetaminophen on the liver of alcoholic patients: a randomized, doubleblind, placebo-controlled trial. Arch Intern Med. 2001;161:2247-2252. 69. Kumana CR, Ng M, Lin HJ, et al. Herbal tea induced hepatic venoocclusive disease: quantification of toxic alkaloid exposure in adults. Gut. 1985;26:101-104. 70. Labbe G, Pessayre D, Fromenty B. Drug-induced liver injury through mitochondrial dysfunction: mechanisms and detection during preclinical safety studies. Fundam Clin Pharmacol. 2008;22:335-53. 71. Laliberte L, Villeneuve JP. Hepatitis after the use of germander, a herbal remedy. CMAJ. 1996;154:1689-1692. 72. Larrey D, Vial T, Micaleff A, et al. Hepatitis associated with amoxicillinclavulanic acid combination. Report of 15 cases. Gut. 1992;33:368-371. 73. Lauterburg BH, Velez ME. Glutathione deficiency in alcoholics: risk factor for paracetamol hepatotoxicity. Gut. 1988;29:1153-1157. 74. Lee WM. Acute liver failure. N Engl J Med. 1993;329:1862-1872. 75. Lee WM. Drug-induced hepatotoxicity. N Engl J Med. 1995;333:1118-1127. 76. Lee WM, Denton WT. Chronic hepatitis and indolent cirrhosis due to methyldopa: the bottom of the iceberg? J S C Med Assoc. 1989;85:75-79. 77. Leeder JS, Lu X, Timsit Y, et al. Non-monooxygenase cytochromes P450 as potential human autoantigens in anticonvulsant hypersensitivity reactions. Pharmacogenetics. 1998;8:211-225.

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78. Leverve XM. Mitochondrial function and substrate availability. Crit Care Med. 2007;35(Suppl):S454-S460. 79. Lewis JH. Drug-induced liver disease. Med Clin North Am. 2000;84:12751311. 80. Lieber CS. Alcohol and the liver: 1994 update. Gastroenterology. 1994;106:1085-1105. 81. Lindros KO, Cai YA, Penttila KE. Role of ethanol-inducible cytochrome P-450 IIE1 in carbon tetrachloride-induced damage to centrilobular hepatocytes from ethanol-treated rats. Hepatology. 1990;12:1092-1097. 82. Liu ZX, Kaplowitz N. Immune-mediated drug-induced liver disease. Clin Liver Dis. 2002;6:467-486. 83. Lu Y, Cederbaum AI. CYP2E1 and oxidative liver injury by alcohol. Free Radical Biol Med. 2008;44:723-738. 84. Maddrey WC. Alcohol-induced liver disease. Clin Liver Dis. 2000;4:116130. 85. Mahler H, Pasi A, Kramer JM, et al. Fulminant liver failure in association with the emetic toxin of Bacillus cereus. N Engl J Med. 1997;336:1142-1148. 86. Manno M, Rezzadore M, Grossi M, et al. Potentiation of occupational carbon tetrachloride toxicity by ethanol abuse. Hum Exp Toxicol. 1996;15:294300. 87. Mazuryk H, Kastenberg D, Rubin R, et al. Cholestatic hepatitis associated with the use of nafcillin. Am J Gastroenterol. 1993;88:1960-1962. 88. McComsey GA, Libutti DE, O’Riordan M, et al. Mitochondrial RNA and DNA alterations in HIV lipoatrophy are linked to antiretroviral therapy and not to HIV infection. Antiviral Therapy. 2008;13:715. 89. McDonald GB, Hinds MS, Fisher LD, et al. Venoocclusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med. 1993;118:255-267. 90. McKenzie R, Fried MW, Sallie R, et al. Hepatic failure and lactic acidosis due to fialuridine (FIAU), an investigational nucleoside analogue for chronic hepatitis B. N Engl J Med. 1995;333:1099-1105. 91. McMaster KR 3rd, Hennigar GR. Drug-induced granulomatous hepatitis. Lab Invest. 1981;44:61-73. 92. Mehendale HM, Roth RA, Gandolfi AJ, et al. Novel mechanisms in chemically induced hepatotoxicity. FASEB J. 1994;8:1285-1295. 93. Mitchell I, Wendon J, Fitt S, et al. Anti-tuberculous therapy and acute liver failure. Lancet. 1995;345:555-556. 94. MMWR. Centers for Disease Control and Prevention: severe isoniazidassociated hepatitis—New York, 1991–1993. Morb Mortal Wkly Rep. 1993;42:545-547. 95. Mohabbat O, Younos MS, Merzad AA, et al. An outbreak of hepatic venoocclusive disease in north-western Afghanistan. Lancet. 1976;2:269271. 96. Moses PL, Schroeder B, Alkhatib O, et al. Severe hepatotoxicity associated with bromfenac sodium. Am J Gastroenterol. 1999;94:1393-1396. 97. Nadir A, Agrawal S, King PD, et al. Acute hepatitis associated with the use of a Chinese herbal product, ma-huang. Am J Gastroenterol. 1996;91:14361438. 98. Nair SS, Kaplan JM, Levine LH, et al. Trimethoprim-sulfamethoxazoleinduced intrahepatic cholestasis. Ann Intern Med. 1980;92:511-512. 99. Nakajima T, Okino T, Sato A. Kinetic studies on benzene metabolism in rat liver—Possible presence of three forms of benzene metabolizing enzymes in the liver. Biochem Pharmacol. 1987;36:2799-2804. 100. Nicolas F, Rodineau P, Rouzioux JM, et al. Fulminant hepatic failure in poisoning due to ingestion of T 61, a veterinary euthanasia drug. Crit Care Med. 1990;18:573-575. 101. Nolan CM, Goldberg SV, Buskin SE. Hepatotoxicity associated with isoniazid preventive therapy: a 7-year survey from a public health tuberculosis clinic. JAMA. 1999;281:1014-1018. 102. Peck CC, Temple R, Collins JM. Understanding consequences of concurrent therapies. JAMA. 1993;269:1550-1552. 103. Prescott LF. Paracetamol, alcohol and the liver. Br J Clin Pharmacol. 2000;49:291-301. 104. Raskind JY, El-Chaar GM. The role of carnitine supplementation during valproic acid therapy. Ann Pharmacother. 2000;34:630-638. 105. Rawat S, Borkowski WJ, Jr., Swick HM. Valproic acid and secondary hyperammonemia. Neurology. 1981;31:1173-1174. 106. Reddy KR, Brillant P, Schiff ER. Amoxicillin-clavulanate potassiumassociated cholestasis. Gastroenterology. 1989;96:1135-1141. 107. Redlich CA, Beckett WS, Sparer J, et al. Liver disease associated with occupational exposure to the solvent dimethylformamide. Ann Intern Med. 1988;108:680-686.

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108. Redlich CA, West AB, Fleming L, et al. Clinical and pathological characteristics of hepatotoxicity associated with occupational exposure to dimethylformamide. Gastroenterology. 1990;99:748-757. 109. Reid WD, Christie B, Krishna G, et al. Bromobenzene metabolism and hepatic necrosis. Pharmacology. 1971;6:41-55. 110. Reinhart HH, Reinhart E, Korlipara P, et al. Combined nitrofurantoin toxicity to liver and lung. Gastroenterology. 1992;102:1396-1399. 111. Ridker PM, Ohkuma S, McDermott WV, et al. Hepatic venoocclusive disease associated with the consumption of pyrrolizidine-containing dietary supplements. Gastroenterology. 1985;88:1050-1054. 112. Rigas B, Rosenfeld LE, Barwick KW, et al. Amiodarone hepatotoxicity. A clinicopathologic study of five patients. Ann Intern Med. 1986;104:348-351. 113. Riordan SM, Williams R. Fulminant hepatic failure. Clin Liver Dis. 2000;4:25-45. 114. Roberts MS, Magnusson BM, Burczynski FJ, et al. Enterohepatic circulation: physiological, pharmacokinetic and clinical implications. Clin Pharmacokinet. 2002;41:751-790. 115. Roberts RA, Ganey PE ,Ju C, et al. Role of the Kupffer cell in mediating hepatic toxicity and carcinogenesis. Toxicol Sci. 2007;96:2-15. 116. Ros E, Small DM, Carey MC. Effects of chlorpromazine hydrochloride on bile salt synthesis, bile formation and biliary lipid secretion in the rhesus monkey: a model for chlorpromazine-induced cholestasis. Eur J Clin Invest. 1979;9:29-41. 117. Ross WT Jr, Daggy BP, Cardell RR Jr. Hepatic necrosis caused by halothane and hypoxia in phenobarbital-treated rats. Anesthesiology. 1979;51:321-326. 118. Roy-Chowdhury N, Roy-Chowdhury J. Liver physiology and energy metabolism. In: Feldman M, Friedman L, Sleisenger M, et al., eds. Sleisenger & Fordtran’s Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management. 7th ed. Philadelphia: Saunders; 2006:1551-1565. 119. Schafer DF, Sorrell MF. Power failure, liver failure. N Engl J Med. 1997;336:1173-1174. 120. Schiodt FV, Rochling FA, Casey DL, Lee WM. Acetaminophen toxicity in an urban county hospital. N Engl J Med. 1997;330:1907. 121. Schreiber AH, Simon FR. Estrogen-induced cholestasis. Clues to pathogenesis and treatment. Hepatology. 1983;3:607-613. 122. Schultz JC, Adamson JS Jr, Workman WW, et al. Fatal liver disease after intravenous administration of tetracycline in high dosage. N Engl J Med. 1963;269:999-1004. 123. Scully LJ, Clarke D, Barr RJ. Diclofenac induced hepatitis. 3 cases with features of autoimmune chronic active hepatitis. Dig Dis Sci. 1993;38:744-751. 124. Seeff LB, Cuccherini BA, Zimmerman HJ, et al. Acetaminophen hepatotoxicity in alcoholics. Ann Intern Med. 1986;104:399-404. 125. Shah RR, Oates NS, Idle JR, et al. Impaired oxidation of debrisoquine in patients with perhexiline neuropathy. Br Med J (Clin Res Ed). 1982;284:295-299. 126. Simmons F, Feldman B, Gerety D. Granulomatous hepatitis in a patient receiving allopurinol. Gastroenterology. 1972;62:101-104. 127. Smith GC, Kenna JG, Harrison DJ, et al. Autoantibodies to hepatic microsomal carboxylesterase in halothane hepatitis. Lancet. 1993;342:963-964. 128. Soriano V, Puoti M, Garcia-Gasco P, et al. Antiretroviral drugs and liver injury. AIDS. 2008;22:1-13. 130. Stricker BH, Blok AP, Claas FH, et al. Hepatic injury associated with the use of nitrofurans: a clinicopathological study of 52 reported cases. Hepatology. 1988;8:599-606. 131. Sundar K, Suarez M, Banogon PE, et al. Zidovudine-induced fatal lactic acidosis and hepatic failure in patients with acquired immunodeficiency syndrome: report of two patients and review of the literature. Crit Care Med. 1997;25:1425-1430. 132. Tandon BN, Tandon HD, Tandon RK, et al. An epidemic of venoocclusive disease of liver in central India. Lancet. 1976;2:271-272. 133. Timbrell J. Factors affecting toxic responses: metabolism. In: Principles of Biochemical Toxicology. 3rd ed. London: Taylor and Francis Ltd; 2000:65-110. 134. Tsutsumi M, Lasker JM, Shimizu M, et al. The intralobular distribution of ethanol-inducible P450IIE1 in rat and human liver. Hepatology. 1989;10:437-446. 135. Van Thiel DH, Perper JA. Hepatotoxicity associated with cocaine abuse. Recent Dev Alcohol. 1992;10:335-341. 136. Verrotti A, Greco R, Morgese G, et al. Carnitine deficiency and hyperammonemia in children receiving valproic acid with and without other anticonvulsant drugs. Int J Clin Lab Res. 1999;29:36-40. 137. Victorino RM, Maria VA, Correia AP, et al. Floxacillin-induced cholestatic hepatitis with evidence of lymphocyte sensitization. Arch Intern Med. 1987;147:987-989.

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138. Watanabe Y, Kato A, Sawara K, et al. Selective alterations of brain dopamine D(2) receptor binding in cirrhotic patients: results of a (11)C-Nmethylspiperone PET study. Metabol Br Dis. 2008;23:265-74. 139. Watanabe N, Tsukada N, Smith CR, et al. Permeabilized hepatocyte couplets. Adenosine triphosphate-dependent bile canalicular contractions and a circumferential pericanalicular microfilament belt demonstrated. Lab Invest. 1991;65:203-213. 140. Weston CF, Cooper BT, Davies JD, et al. Veno-occlusive disease of the liver secondary to ingestion of comfrey. Br Med J (Clin Res Ed). 1987;295:183. 141. Whiting-O’Keefe QE, Fye KH, Sack KD. Methotrexate and histologic hepatic abnormalities: a meta-analysis. Am J Med. 1991;90:711-716. 142. Williams DE, Reed RL, Kedzierski B, et al. Bioactivation and detoxication of the pyrrolizidine alkaloid senecionine by cytochrome P-450 enzymes in rat liver. Drug Metab Dispos. 1989;17:387-392.

143. Yeong ML, Swinburn B, Kennedy M, et al. Hepatic venoocclusive diseaseassociated with comfrey ingestion. J Gastroenterol Hepatol. 1990;5:211-214,144. 144. Younis HS, Parrish AR, Sypes IG, et al. The role of hepatocellular oxidative stress in Kuppfer cell activation during 1-2 dichlorobenzene-induced hepatocellular toxicity. Toxicol Sci. 2003;76:201-211. 145. Zand R, Nelson SD, Slattery JT, et al. Inhibition and induction of cytochrome P4502E1-catalyzed oxidation by isoniazid in humans. Clin Pharmacol Ther. 1993;54:142-149. 146. Zimmerman HJ, Ishak KG. Valproate-induced hepatic injury: analyses of 23 fatal cases. Hepatology. 1982;2:591-597. 147. Zimmerman HJ, Lewis JH. Chemical- and toxin-induced hepatotoxicity. Gastroenterol Clin North Am. 1995;24:1027-1045. 148. Zimmerman HJ, Maddrey WC. Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol: analysis of instances of therapeutic misadventure. Hepatology. 1995;22:767-773.

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CHAPTER 27

RENAL PRINCIPLES Donald A. Feinfeld and Nikolas B. Harbord

OVERVIEW OF RENAL FUNCTION ■ ANATOMIC CONSIDERATIONS The kidneys lie in the paravertebral grooves at the level of the T12-L3 vertebrae. The medial margin of each is concave whereas the lateral margins are convex, giving the organ a bean-shaped appearance. In the adult, each kidney measures 10 to 12 cm in length, 5 to 7.5 cm in width, and 2.5 to 3.0 cm in thickness. In an adult man, each kidney weighs 125 to 170 g; in an adult woman, each kidney weighs 115 to155 g. On the concave surface of the kidney is the hilum, through which the renal artery, vein, renal pelvis, a nerve plexus, and numerous lymphatics pass. On the convex surface, the kidney is surrounded by a fibrous capsule, which protects it, and a fatty capsule with a fibroareolar capsule called the renal fascia, which offers further protection and serves to anchor it in place. The arterial supply begins with the renal artery, which is a direct branch of the aorta. On entering the hilum, this artery subdivides into branches supplying the five major segments of each kidney: the apical pole, the anterosuperior segment, the anteroinferior segment, the posterior segment, and the inferior pole. These arteries subsequently divide within each segment to become lobar arteries. In turn, these vessels give rise to arcuate arteries that diverge into the sharply branching interlobular arteries, which directly supply the glomerular tufts. The cut surface of the kidney reveals a pale outer rim and a dark inner region corresponding to the cortex and medulla, respectively. The cortex is 1 cm thick and surrounds the base of each medullary pyramid. The medulla consists of between 8 and 18 cone-shaped areas called medullary pyramids; the apex of each area forms a papilla containing the ends of the collecting ducts. Urine empties from these ducts into the renal pelvis, flows into the ureters, and, subsequently, into the urinary bladder. The kidneys maintain the constancy of the extracellular fluid by creating an ultrafiltrate of the plasma that is virtually free of cells and larger macromolecules, and then processing that filtrate, reclaiming what the body needs and letting the rest escape as urine. Every 24 hours, an adult’s kidneys filter nearly 180 L of water (total body water is ∼ 25–60 L), and 25,000 mEq of sodium (total body Na+ is 1200–2800 mEq). Under normal circumstances, the kidneys regulate these two substances independent of each other, depending on the body’s needs. Approximately 1% of the filtered water and 0.5% to 1% of the filtered Na+ are excreted. Renal function begins with filtration at the glomerulus, a highly permeable capillary network stretched between two arterioles in series. The relative constriction or dilation of these vessels normally controls the glomerular filtration rate (GFR). Under normal circumstances, approximately 20% of the plasma water in the blood entering the glomeruli goes through the filter, carrying with it electrolytes, small metabolites such as glucose, amino acids, lactate, and urea, and leaving behind the blood cells and nearly all the larger proteins, including albumin and globulins. The filtrate then enters a series of tubules that reabsorb and secrete certain substances, such as organic acids and bases, into the urinary space. The proximal tubule performs

bulk reabsorption, isotonically reclaiming 65% to 70% of the filtrate. Distal to the proximal tubule is the loop of Henle, which controls concentration and dilution of the urine, and the distal nephron, which does the fine-tuning in the balance between excretion and reclamation. Reabsorption of sodium is controlled proximally by hydrostatic and oncotic pressures in the peritubular capillaries, and distally by hormones such as aldosterone. Control of water reclamation depends first on function of the ascending limb of the loop of Henle, which absorbs solute without water. This produces a dilute tubular fluid and at the same time makes the medullary interstitium hypertonic. Final regulation of water reabsorption is related to the concentration of antidiuretic hormone (ADH), which opens waterreabsorbing channels (aquaporins) into the membranes of the final nephron segments (collecting ducts). The kidneys also regulate balance for potassium and hydrogen ion (both of which are influenced by the effect of aldosterone on the distal nephron), and calcium and phosphate (both of which are influenced by the blood concentration of parathormone). Injury to the vasculature, glomeruli, tubules, or interstitium can lead to renal dysfunction; that is, to a decrease in glomerular filtration. As the kidneys fail, serum concentrations of the marker substances urea and creatinine increase. However, the relationship between these concentrations and the level of GFR is hyperbolic, not linear, therefore a small initial elevation in serum concentrations of these substances denotes a large decrease in renal function. By the time blood urea nitrogen (BUN) or serum creatinine exceeds the upper limit of normal, GFR is reduced by more than 50%. Many xenobiotics cause or aggravate renal dysfunction. The kidneys are particularly susceptible to toxic injury for four reasons:151 (a) they receive 20% to 25% of cardiac output yet make up less than 1% of total body mass implying a relatively large renal exposure in almost all circumstances; (b) they are metabolically active, and thus vulnerable to xenobiotics that disrupt metabolism or are activated by metabolism such as acetaminophen; (c) they remove water from the filtrate and may build up a high concentration of xenobiotics; and (d) the glomeruli and interstitium are susceptible to attack by the immune system. Many factors, such as renal perfusion, can affect an individual’s reaction to a particular nephrotoxin.10 The clinician should be aware of these factors and, when possible, alter them to minimize the adverse effect after a toxic exposure.

■ FUNCTIONAL TOXIC RENAL DISORDERS Although most toxic renal injury results in decreased renal function, there are three functional disorders that upset body balance despite normal GFR in anatomically normal kidneys: renal tubular acidosis, syndrome of inappropriate secretion of ADH, and nephrogenic diabetes insipidus. Renal tubular acidosis (RTA) is a loss of ability to reclaim the filtered bicarbonate (proximal RTA) or a decreased ability to generate new bicarbonate to replace that lost in buffering the daily acid load (distal RTA). In either case, there is a nonaniongap metabolic acidosis, usually accompanied by hypokalemia. The primary defect in distal RTA involves the decreased secretion of hydrogen (H+) from the intercalated cells of the distal tubule. This most often denotes a defect in the H+-translocating adenosine triphosphatase (ATPase) on the luminal surface of these cells. Less frequently occurring mechanisms include abnormalities of the chloride-bicarbonate exchanger, which is responsible for returning bicarbonate generated within the cell to the systemic circulation. Also, given the voltage dependence of hydrogen secretion, if there is a decrease in the degree of luminal electronegative charge, there will be a decrease in this secretion. Most of this voltage is created

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by the activity of the Na+-K+-ATPase on the peritubular capillary side of the adjacent cell. (Note: Cells adjacent to the intercalated cells are called principal cells and primarily control K+ secretion.) As this pump malfunctions, less sodium is returned to the capillaries, creating a decreased gradient from the lumen to the cell. Thus, the lumen becomes more electropositive, diminishing the transmembrane potential. Amphotericin causes distal RTA by allowing secreted H+ to leak back into the tubular cells.38 The primary defect in proximal RTA is incompletely understood. Normally, the Na+-H+ exchanger in the luminal membrane, the Na+-K+-ATPase in the basolateral membrane, and the enzyme carbonic anhydrase, are the key systems necessary for proximal tubular bicarbonate reabsorption. If one or more of these mechanisms becomes disordered, the resorptive capacity of the proximal tubule is diminished. Proximal RTA often occurs as part of the Fanconi syndrome, a generalized failure of proximal tubular transport (proximal RTA plus aminoaciduria, renal glycosuria, and hyperphosphaturia), which may occur during treatment with some chemotherapy agents or antiretroviral drugs. Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) occurs when the body produces ADH despite a fall in plasma osmolality, which normally inhibits ADH secretion. ADH primarily affects the collecting tubule and causes increased water reabsorption by increasing the aquaporin channels in this segment. There are three common patterns of altered physiology: altered secretion of ADH; a resetting of the osmostat (ie, the threshold for ADH secretion); and the inability to decrease ADH secretion in the face of a water load. The increased hormonal effect of ADH serves to augment normal free water retention, which subsequently leads to the main clinical manifestations of SIADH: concentrated urine (as reflected in a relative increase in urine osmolality) and hyponatremia in the setting of euvolemia. Although this manifestation most often occurs as a complication of intracranial lesions or from ectopic ADH production by a tumor or in a diseased lung, many xenobiotics (eg, chlorpropamide, antidepressants, vincristine, opioids, and methylenedioxymethamphetamine [MDMA or Ecstasy]) can also cause inappropriate ADH release (Chap. 16). Nephrogenic diabetes insipidus (NDI) is the reverse of SIADH and is the inability of the kidneys to respond to ADH stimulation despite severe losses of body water in urine. NDI will typically present with polyuria, or hypernatremia if water intake is limited or insufficient. Although genetic disorders, disease states, or electrolyte perturbations are usually implicated, several xenobiotics also cause NDI. Lithium, demeclocycline, foscarnet and clozapine are drugs that can cause this syndrome (Chap. 16). NDI from lithium toxicity is thought to result from impaired aquaporin-2 channel synthesis and transport despite normal ADH binding to vasopressin type-2 receptors at the collecting tubule.199

MAJOR TOXIC SYNDROMES OF THE KIDNEY Most nephrotoxicity involves histologic renal injury. Although xenobiotics can affect any part of the nephron (Fig. 27–1), there are three major syndromes of toxic renal injury: (a) chronic kidney disease; (b) nephrotic syndrome; and, especially, (c) acute kidney injury (Table 27–1). For purposes of continuity, acute kidney injury is discussed last. Because nephrotoxins usually affect the tubules, the most metabolically active segment of the nephron, most nephrotoxicity involves either acute or chronic tubular injury, although glomerular injury sometimes results from xenobiotics. The processes are not mutually exclusive, and toxic nephropathy may impinge on more than one part of the nephron (eg, nonsteroidal antiinflammatory drug [NSAID]-induced acute kidney injury and nephrotic syndrome). When one of these patterns of renal injury occurs, the clinician should consider possible toxic etiologies. Chronic kidney disease refers to a disease process that causes progressive decline of renal function over a period of months to years. There is usually a gradual rise in BUN and serum creatinine concentration as glomerular filtration falls; often there are no symptoms other than nocturia (indicating loss of urinary concentrating ability). The most common lesion of nephrotoxic chronic kidney disease is chronic interstitial nephritis (Fig. 27–2), which involves destruction of tubules over a prolonged period,75 with tubular atrophy, fibrosis, and a variable cellular infiltrate (see Fig. 27–2), sometimes accompanied by papillary necrosis. Acute interstitial nephritis may progress to chronic interstitial nephritis, if exposure to xenobiotics is prolonged.217 The onset is usually insidious and relatively asymptomatic, often presenting as secondary hypertension or unexplained chronic azotemia. The major symptom is nonspecific nocturia. Papillary necrosis may lead to ureteral colic via papillary sloughing. There is mild to moderate proteinuria that remains well under the nephrotic range. Unlike other chronic renal disorders, interstitial nephritis is characterized by failure of the diseased tubules to adapt to the renal impairment, resulting in metabolic imbalances such as hyperchloremic metabolic acidosis, sodium wasting, and hyperkalemia early in the disease course.71 Injury to erythropoietinsecreting cells may produce a disproportionate anemia. Nephrotic syndrome is characterized by massive proteinuria (>3 g/d, in the adult), hypoalbuminemia, hyperlipidemia, and the edema that usually prompts the patient to seek medical attention. Although the relationships among these findings are not completely understood, the underlying event is injury to the glomerular barrier that normally prevents macromolecules from passing from the capillary lumen into the urinary space. Xenobiotics induce nephrotic syndrome (Table 27–2) in two ways. First, they may release hidden antigens into the blood, which leads to antigen–antibody complex formation after the immune response is elicited. These complexes subsequently deposit in the

TABLE 27–1. Major Nephrotoxic Syndromes Chronic Renal Disease (slowly increasing azotemia)

Nephrotic Syndrome (proteinuria, hypoalbuminemia, edema)

Acute Renal Injury (rapidly increasing azotemia)

Chronic interstitial nephritis Papillary necrosis Chronic glomerulosclerosis

Minimal glomerular change Membranous nephropathy Focal segmental glomerulosclerosis

Acute prerenal failure Acute urinary obstruction Acute tubular necrosis Acute interstitial nephritis Acute vasculitis or glomerular injury (rare)

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Chapter 27

Acute Tubular Necrosis (proximal): Aminoglycosides Antineoplastics Fluorinated anesthetics Glycols Metals(As, Bi, Cr, Hg, U) Myoglobin/hemoglobin Pigments Radiocontrast agents

Nephrotic syndrome: Metals(Au,Hg) NSAIDs Penicillamine Bowman capsule

Proximal tubule

Distal tubule

Renal Principles

383

Acute Tubular Necrosis (distal): Amphotericin Cisplatin Glycols

CORTEX Vasculitis (hypersensitivity): Amphetamines NSAIDs Penicillins Sulfonamides

INNER MEDULLA

Prerenal: Amphotericin Antihypertensives Cathartics Cyclosporine Diuretics Doxorubicin Iron Methotrexate NSAIDs

OUTER MEDULLA

Loop of Henle

Acute interstitial nephritis: Allopurinol Antimicrobials β-Lactams Rifampin Sulfonamides Vancomycin NSAIDs

Collecting duct

Obstruction: Acyclovir Anticholinergics Bromocriptine Ergot alkaloids Fluoroquinolones Methotrexate Sulfonamides

Chronic interstitial nephritis: Analgesic combinations Cyclosporine Metals (Pb, Cd, Be, Li, Ge) Methyl-CCNU Nephrotoxic herbals

FIGURE 27–1. Schematic showing the major nephrotoxic processes and the sites on the nephron that they chiefly affect.

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FIGURE 27–3. Membranous glomerulonephropathy (secondary to gold), a cause of nephrotic syndrome. Globally thickened glomerular capillaries ( ) and interstitial foam cells ( ) are seen. H&E × 450. (Image contributed by Dr. Rabia Mir.) FIGURE 27–2. Chronic interstitial nephritis (secondary to NSAIDs). Interstitial fibrosis ( ), lymphocytic infiltration ( ), and tubular atrophy ( ). H&E × 225. (Image contributed by Dr. Rabia Mir.)

glomerular basement membrane, thereby changing its consistency (eg, gold) (Fig. 27–3). Second, they can upset the immunoregulatory balance (eg, NSAIDs). A less-common glomerular lesion is hypersensitivity vasculitis. The pathologic appearance of the glomeruli may be described as secondary minimal glomerular change, membranous glomerulopathy, or focal segmental glomerulosclerosis. Albumin loss usually exceeds urinary excretion as a result of renal tubular catabolism of filtered protein. The tubules also retain sodium, causing expansion of the extracellular space and edema. The glomerular lesion may progress to renal failure if the pathologic process continues. Acute kidney injury (formerly called “acute renal failure”) is defined as an abrupt decline in renal function that impairs the capacity of the kidney to maintain metabolic balance. The three main categories of acute kidney injury are prerenal, postrenal, and intrinsic renal failure.

TABLE 27–2. Xenobiotics that Cause Nephrotic Syndrome Antimicrobials (rifampicin, cefixime) Captopril Drugs of abuse (heroin, cocaine) Insect venom Interferon α Metals (gold, mercury, lithium) NSAIDs Penicillamine

Prerenal failure involves impaired renal perfusion, which can occur with volume depletion, systemic vasodilatation, heart failure, or preglomerular vasoconstriction. Hence, toxic events that cause bleeding (overdose of anticoagulants), volume depletion (diuretics, cathartics, or emetics), cardiac dysfunction (β-adrenergic antagonists), or hypotension from any cause can lead to acute prerenal failure.67 An example of vascular constriction is the hepatorenal syndrome, or renal hypoperfusion caused by liver failure. This syndrome is characterized by impaired renal function and marked constriction of the renal arterial vasculature associated with severe chronic or acute hepatic failure. Many neurohumoral disturbances lead to the renal and systemic hemodynamic changes that occur in the syndrome. Splanchnic and systemic vasodilation- likely secondary to portal hypertension decrease mean arterial pressure and compromise renal blood flow. Circulating mediators of vasoconstriction are subsequently increased, resulting in hepatorenal syndrome. Angiotensin, norepinephrine, vasopressin, endothelin, and isoprostane F2 all contribute to an extreme cortical vasoconstriction. That this renal insufficiency is extrarenal is best illustrated by the fact that when a kidney from a patient with hepatorenal syndrome is transplanted into a uremic patient, the function of the graft promptly returns to normal. Postrenal failure, such as urinary tract obstruction, may result from crystalluria (eg, oxalosis in ethylene glycol poisoning) or blocked urinary flow (eg, retroperitoneal fibrosis from methysergide; bladder dysfunction from anticholinergic drugs). Regardless of the cause of urinary tract obstruction, there are characteristic histologic and pathophysiologic alterations in the kidney. Microscopically, tubular dilation, predominantly in the distal nephron segments (ie, the collecting ducts and distal tubules), occurs initially and glomerular structure is preserved, subsequently dilation of the Bowman space occurs, and finally periglomerular fibrosis develops. Pathophysiologically, GFR falls as tubule pressure counteracts the capillary hydraulic pressure gradient. Subsequently there is a fall in

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TABLE 27–3. Xenobiotics that Cause Acute Tubular Necrosis Acetaminophen Antimicrobials Aminoglycosides Amphotericin Pentamidine Tenofovir, cidofovir, adefovir Polymyxins

Halogenated hydrocarbons Metals Arsenic Bismuth Chromium Mercury Uranium

Antineoplastics Cisplatin Ifofamide Methotrexate Mithramycin Streptozotocin

Mushrooms Cortinarius spp Amanita smithiana

Fluorinated anesthetics Foscarnet Glycols Ethylene glycol Diethylene glycol

Radiocontrast agents Those that cause hypotension or hypovolemia

Pigments Myoglobin Hemoglobin

renal perfusion leading to ischemic damage to nephrons. Tubular function is impaired such that concentrating ability, potassium secretory function, and urinary acidification mechanisms are all altered. Acute tubular necrosis (Table 27–3), the most common nephrotoxic event,4 is characterized pathologically by patchy necrosis of tubules, usually the proximal segments (Fig. 27–4). The lesion is associated with three different processes: direct toxic injury, ischemic injury from renal hypoperfusion, and pigmenturia.181 Direct toxicity accounts for approximately 35% of all cases of acute tubular necrosis.130,235 Direct acting xenobiotics affect different segments of the renal tubules; for example, uranium attacks the proximal tubule and amphotericin the distal tubule (see Fig. 27–1). However, the clinical pattern of rapidly declining renal function, often accompanied by oliguria, is identical in all forms of tubular necrosis. Poisoning may also lead to ischemic tubular necrosis if hypotension or cardiac failure causes ischemia of nephron segments (proximal straight tubule and inner medullary collecting duct) that are particularly vulnerable to hypoxia. Pigmenturia refers either to myoglobinuria from rhabdomyolysis (skeletal muscle necrosis) or to hemoglobinuria from massive hemolysis.61 Either pigment may cause tubular injury and necrosis by precipitating in the tubular lumen.73,181 Myoglobinuria follows necrosis of striated muscle. Alcohol and cocaine can be directly myotoxic in some individuals,190 as can the β-hydroxy-β-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) used to lower blood cholesterol.107 Rhabdomyolysis causing myoglobinuric acute tubular necrosis can occur after extensive bee or wasp stings128 or fire ant bites.134 Xenobiotics that produce hypokalemia (eg, diuretics and laxatives) or predispose to hyperthermia (antipsychotics) can cause muscle necrosis on this basis. Most often, poisoning leads to muscle breakdown from pressure necrosis following prolonged unconsciousness (opioids and sedative-hypnotics), excessive muscle contraction (cocaine), or grand

FIGURE 27–4. Acute tubular necrosis (secondary to mercury). Proximal tubular epithelial necrosis ( ) and sloughing are associated with interstitial edema ( ). H&E × 450. (Photo contributed by Dr. Rabia Mir.)

mal seizures (alcohol withdrawal, theophylline).82 Pigmenturic acute renal failure may also complicate poisoning with carbon monoxide, copper sulfate, and zinc phosphate.34,130,259 Myoglobin is normally excreted without causing toxicity. A study of patients with rhabdomyolysis suggests that the concentration of myoglobin in the urine may affect the development of renal failure.73 If myoglobin inspissates in the tubular lumen because of renal hypoperfusion and high water absorption, it dissociates in the relatively acidic environment as H+ is secreted, releasing tubulotoxic hematin.61 This toxicity may stem from the iron-catalyzing production of oxygen free radicals. Myoglobinuric acute tubular necrosis is diagnosed when acute kidney injury occurs following muscle breakdown. There is a simultaneous elevation of concentration of serum muscle enzymes such as creatinine kinase and aldolase. A positive urine orthotolidine test, with no erythrocytes in the sediment, and urine myoglobin may be measured. However, because primary renal failure may cause detectable myoglobinuria that does not worsen renal function,71 finding myoglobin in the urine does not prove the diagnosis. Myoglobinuric acute tubular necrosis can be prevented by early volume expansion if renal injury has not yet occurred.200 Alkalinizing the urine may prevent dissociation of myoglobin and minimize tubular necrosis. However, massive rhabdomyolysis can lead to severe hypocalcemia resulting from the release of large amounts of phosphate into the blood. Alkalemia in this setting can cause tetany or seizures, worsening muscle injury.130 Hence, the risk of alkalinization must be weighed against the benefit. Hemoglobinuria follows hemolysis, which can be caused by a number of xenobiotics, including snake and spider venoms, cresol, phenol, aniline, arsine, stibine, naphthalene, dichromate, and methylene chloride. Sensitivity reactions to drugs (hydralazine, quinine) can also cause hemolysis.61 The pathophysiology of hemoglobinuric acute tubular necrosis resembles that of myoglobinuria. The pigment deposits in the tubules and dissociates, causing necrosis to occur.181 Volume depletion and acidosis precipitate the disorder, so volume expansion and alkalinization may help prevent kidney injury. Although there is controversy about how a tubular lesion leads to glomerular shutdown, it is generally felt that tubular obstruction,

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TABLE 27–4. Xenobiotics that Cause Acute Interstitial Nephritis More Common

Less Common

Allopurinol Antimicrobials β-Lactams, especially ampicillin, methicillin, penicillin Moxifloxacin Rifampin Sulfonamides (including mesalamine) Vancomycin Proton-pump inhibitors Azathioprine NSAIDs

Anticonvulsants Carbamazepine Phenobarbital Phenytoin Captopril Diuretics Furosemide Thiazides Zoledronate

back-leak of filtrate across injured epithelium, renal hypoperfusion, and decreased glomerular filtering surface combine to impair glomerular filtration.232 Additionally, filtration pressure is diminished by neutrophil infiltration and status in the vasa recta.239 Recent evidence suggests that prolonged medullary ischemia, perhaps caused by an imbalance in the production of vasoconstrictors such as endothelin and vasodilators such as nitric oxide, is important in prolonging the renal dysfunction after the tubular injury develops.142 Clinically, acute tubular necrosis presents as a rapid deterioration of renal function, usually first noted as azotemia. Muddy brown casts or renal tubular cells may be seen in the urinary sediment, but hematuria and leukocyturia are unusual. Disorders of metabolic balance, such as hyperkalemia and metabolic acidosis, are also common. Although tubular sodium reabsorption is decreased, the fall in glomerular

A

filtration usually leads to positive sodium and water balance, as renal output of these substances is fixed.159 Acute interstitial nephritis (Table 27–4) is clinically similar to acute tubular necrosis and often must be diagnosed by renal biopsy, which shows a cellular infiltrate separating tubular structures (Fig. 27–5). Nearly all acute interstitial nephritis is caused by hypersensitivity.238 In many patients, the renal failure is accompanied by manifestations of systemic allergy such as fever, rash, or eosinophilia. Finding eosinophils in the urine is consistent with this disorder.177 However, approximately 25% of patients with xenobiotic-induced interstitial nephritis have no signs of hypersensitivity. Unlike those with tubular necrosis, most patients with acute interstitial nephritis have hematuria and leukocyturia,9 particularly eosinophiluria.10 Secondary fever at the onset of azotemia is common, and flank pain or arthralgia may be present. The lesion usually improves after the xenobiotic is removed. Corticosteroids may hasten recovery;89,147 many physicians use this treatment only if the renal failure does not improve promptly when the xenobiotic exposure is stopped.

DIFFERENTIAL DIAGNOSIS OF ACUTE KIDNEY INJURY Patients who present with acutely deteriorating renal function often represent a difficult diagnostic challenge. Not only are there three major etiologic categories, but each category has several subdivisions; and more than one factor may be present. For example, a patient with an opioid overdose may have neurogenic hypotension (prerenal), together with muscle necrosis causing myoglobinuric renal failure (intrinsic renal), and opioid-induced urinary retention (postrenal). Because renal, prerenal, and postrenal processes are not mutually exclusive and require different interventions, all three should always be considered, even when one appears to be the most obvious cause of the renal failure. Prerenal failure (renal hypoperfusion) initiates a sequence of events leading to renal salt and water retention.12 Renin is released, causing

B

FIGURE 27–5. Acute interstitial nephritis (secondary to rifampin). Interstitial edema and patchy lymphocyte, plasma cell, and eosinophil infiltration occurs without fibrosis ( ). Tubular epithelium shows degenerative and regenerative changes ( ) and mononuclear cell infiltration (tubulitis) ( )(A) H&E × 112; (B) H&E × 450. (Images contributed by Dr. Rabia Mir.)

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TABLE 27–5. Tests of Renal Function Acute

Chronic

To differentiate prerenal failure from acute tubular necrosis: 1. BUN-to-creatinine ratio; usually > 20:1 in prerenal failure 2. Urine Na+ usually < 20 mEq/L in prerenal failure; usually > 40 mEq/L in acute tubular necrosis 3. Fractional Na+ excretion (FENa) is most reliable test:,

Creatinine clearance (Ccr) = U × V/P (normal range 90–130 mL/min), where U is urine creatinine concentration, V is urine flow in mL/min, and P is plasma creatinine concentration. Urine collection must be complete (not necessarily 24 hours), and U and P must be in the same units. In steady states, Ccr in adults can be approximated by dividing the patient’s weight in kilograms by the serum creatinine in mg/dL (multiply by 0.8 in women);3 from the Cockroft-Gault equation,44

FENa =

Urine[Na]/Plasma [Na+ ] × 100 Urine[Creatinine ]/Plasma [Creatinine]

FENa < 1% (ie, normal) in prerenal failure, if the patient has not received diuretics or large infusions of sodium, which increase Na+ excretion despite normal tubular function. In tubular necrosis or interstitial nephritis, renal Na+ absorption is decreased, and FENa > 1%. This is useful except in pigmenturic or iodinated radiocontrast-associated renal failure, when the test is of no benefit.

C cr =

(140 − age) × ideal body weight (kg) ( × 0.85 for women) 72 × serum creatinine

or more formally, GFR can be estimated from the MDRD formula, 186 × serum creatinine–1.154 × age–0.203 (× 0.742 if female); × (1.21 if African-American).140

Go to website http://www.nephron.com/MDRD_GFR.cgi N.B. If renal function is unstable, these formulae are meaningless.

production of angiotensin, which enhances proximal tubular sodium reabsorption and stimulates adrenal aldosterone release, thus increasing distal sodium reabsorption. Prerenal failure is, therefore, accompanied by low urinary sodium excretion (Table 27–5). Release of ADH increases water and urea retention. Unresolving renal hypoperfusion may cause ischemic tubular necrosis. Xenobiotics may decrease renal blood flow without causing intrinsic renal injury (see Fig. 27–1). Diuretics or cathartics can decrease blood volume and antihypertensive agents can excessively reduce blood pressure. Some xenobiotics (eg, cyclosporine, tacrolimus, amphotericin, methotrexate) cause prerenal vasoconstriction. NSAIDs lower filtration rate by inhibiting production of vasodilatory prostaglandins in the afferent arteriole. Finally, cardiotoxins, such as doxorubicin, can cause severe heart failure. Some xenobiotics cause a hypersensitivity vasculitis (see Fig. 27–1). Although it is not a renal injury, the clinician should bear in mind that an estimated creatinine clearance (Ccr) or GFR < 40 carries the risk of nephrogenic systemic fibrosis in patients exposed to gadolinium for contrast MRI studies.236 Urinary tract obstruction should always be considered when the kidneys fail rapidly. Although complete obstruction leads to anuria, partial obstruction, which is more common, is usually associated with alternating oliguria and polyuria. Continued production of urine in the presence of obstruction leads to distension of the urinary tract above the blockage. Calyceal dilatation is common. Obstruction of the bladder outlet or urethra may distend the bladder. Obstruction may be caused by xenobiotics (Table 27–6).75 Most do so by impairing contraction of the bladder through anticholinergic action (atropine, antidepressants). Rarely, certain xenobiotics, particularly methysergide,230 cause retroperitoneal fibrosis and ureteral constriction. Finally, a few xenobiotics lead to crystalluria and intratubular obstruction. Sometimes the xenobiotic itself forms precipitates (sulfonamides,48 indinavir, or methotrexate) or causes excretion of a precipitating chemical such as oxalate (ethylene glycol and fluorinated anesthetics).

PATIENT EVALUATION Evaluation of a patient with suspected toxic renal injury should include extrarenal as well as renal factors. The kidney’s response to xenobiotics is affected by previous renal function, renal blood flow, and the presence of urinary tract obstruction that can exert back-pressure on the nephrons, all of which must be considered.

■ HISTORY A past history of renal disease or conditions that can affect the kidney (eg, diabetes, hypertension, cardiovascular disease) should be noted. Flank pain, hematuria, or an abnormal pattern of urine output are important findings. The patient’s intravascular volume status affects renal perfusion. Thus, a history of heart disease or a disorder that

TABLE 27–6. Xenobiotics that Cause Urinary Obstruction Bladder Dysfunction Anticholinergics Antihistamines Atropine Cyclic Antidepressants Scopolamine Antipsychotics Butyrophenones Phenothiazines Atypicals Bromocriptine CNS depressants

Crystal Deposition Acyclovir (intravenous) Ethylene glycol Fluorinated anesthetics Fluoroquinolones Heme pigments Indinavir Methotrexate Phenylbutazone Sulfonamides Retroperitoneal Fibrosis Ergotamines (Methysergide, LSD) Chinese herbs (Stephania spp, Aristolochia spp)

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TABLE 27–7. Nephrotoxic Effects of Metals Toxic Acute Tubular Necrosis Antimony35 Arsenic137,167,243,245 Barium204,255 Beryllium16 Bismuth20,21,211 Cadmium124,254,121 Chromium181,250 Copper210,180 Gadolinium87,106,216 Germanium149,179 Gold7,56,173,241 Iron41,153,240 Lead6,19,34,39,45,50,113,145,14,6,178,253 Lithium30,53,78,104,221,156 Mercury25,83,166,diamond, stachiatti Platinum (cisplatin)90,95,206,224,258 Silicon122 Silver150,153 Thallium215 Uranium181,186

+ +++ +

Shock Acute Tubular Necrosis

Hemolysis

Acute Interstitial Nephritis

+++

++

+

Chronic Interstitial Nephritis

Tubular Dysfunction

Nephrotic Syndrome

Glomerulonephritis

+ ++

++

+ +++

+ +++

+

+++ +

+

+ + +

+++ ++

+ + +++ ++

+ +++ ++

+ +

++

+++ ++ + ++

+ + +

+ + +

+

+++ = common; + = uncommon.

lowers plasma volume such as vomiting or diarrhea is important. Prior cancer chemotherapy with drugs such as cisplatin or methylCCNU (methyl-1-[2-chloroethyl]-3-cyclohexyl-1-nitrosourea) should be noted. All current xenobiotics should be evaluated for potential

renal effects, both those with direct and indirect nephrotoxic effects.92 The patient’s intake of alcohol and drugs of abuse should be explored. A careful occupational history and assessment of hobbies and lifestyle are crucial, with emphasis on exposure to nephrotoxic xenobiotics.

■ PHYSICAL EXAMINATION TABLE 27–8. Nephrotoxic Hydrocarbons and Mechanisms of Toxicity Solvents

Glycols 153,181,222,223

Carbon tetrachloride Hepatic failure leading to hepatorenal syndrome Occasional acute nephrotoxic renal failure Tetrachloroethylene215 Hepatic failure leading to hepatorenal syndrome Occasional acute nephrotoxic renal failure Trichloroethylene13 Acute tubular necrosis Toluene198 Hippuric acidosis

Ethylene glycol37,135 Metabolized to glycolic acid (metabolic acidosis) Further metabolized to oxalic acid (acute tubular necrosis) Diethylene glycol96,181 Direct tubular toxin (acute tubular necrosis) Hyperoxaluria may add to renal injury Propylene glycol261,262 Metabolic acidosis and acute kidney injury May cause hemolysis and hemoglobinuric renal failure

The patient’s hemodynamic status should be carefully assessed. Postural changes in pulse and blood pressure, and either engorgement or decreased filling of the neck veins, give important information about the intravascular volume. The skin should be examined for lesions. Funduscopy may reveal evidence of chronic hypertension or diabetes. All aspects of cardiac function should be noted, including presence or absence of edema. Injuries or scars in the suprapubic area or evidence of past urologic or retroperitoneal surgery may suggest obstruction, as may a palpable or percussible bladder.

■ LABORATORY EVALUATION Nephrotoxic injury is not always apparent clinically, so the laboratory is exceedingly important. Acute loss of renal function may be suspected if urine output decreases, but oliguria is not universal. The most important parameter of renal function is glomerular filtration. Because urea and creatinine are largely excreted by this route, serum concentrations of these substances are used as markers of renal function. However, the concentration of any substance depends on both production and excretion. Azotemia—elevation of BUN or creatinine—is a standard

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TABLE 27–9. Nephrotoxic Antimicrobials Acute glomerular Injury

Acute Tubular Necrosis

Acute Interstitial Nephritis

Hypersensitivity Vasculitis

Obstruction (Crystalluria)

Tubular Dysfunction

Crystalline deposits Foscarnet260 Nephrotic syndrome Cefixime114 Rifampicin237

Aminoglycosides27,54,184,205,220 Gentamicin,111 tobramycin,226 amikacin138 Amphotericin5,17,38,98,244 Fluoroquinolones (ciprofloxacin, levofloxacin)88,227 Polymyxins B and E131 Pentamidine229 Acyclovir22 Foscarnet32 Ritonavir55 Phenazopyridine77 Tenofovir, cidofovir, adefovir154

β-Lactams (penicillins,9,169 cephalosporins10,129) Sulfonamides162 (including cotrimoxazole147) Vancomycin8,64 Rifampin and Rifampicin174,197,47 Nitrofurantoin168 Aminoglycosides (rare)164,207 Tetracyclines (rare)251 Polymyxins24

Penicillins169 Sulfonamides169

Acyclovir (IV)22 Indinavir120 Sulfonamides162

Aminoglycosides (K+ and Mg2+ wasting)111 Amphotericin Renal tubular acidosis100 K+ and Mg2+ wasting18 Nephrogenic diabetes insipidus81 Tetracyclines (Fanconi syndrome,80 hypercatabolism192)

indication of renal insufficiency. However, BUN or creatinine in the normal range does not exclude a substantial degree of renal impairment because of the previously discussed hyperbolic relationship between these parameters and GFR. In addition, decreased production of urea (starvation or liver failure) or creatinine (amputation, muscle wasting) may result in a normal BUN or creatinine in the presence of significant renal impairment. Conversely, decreased renal perfusion (prerenal failure) is often associated with a disproportionate rise in BUN in comparison with the rise in creatinine, because urea is partially reabsorbed along with salt and water, whose reabsorption is increased when the kidneys are underperfused. Thus, a BUN-to-creatinine ratio > 20 is suggestive of prerenal failure (see Table 27–5). Because many

TABLE 27–10. Nephrotoxic Effects of Antiarthritic Drugs40,43,62,188,213 Acute tubular necrosis Colchicine231 Acetaminophen33,52 Acute interstitial nephritis Allopurinol85 Sulfinpyrazone109,147 Acute worsening of kidney function (prerenal)84 Indomethacin and other NSAIDS Chronic interstitial nephritis31 5-Aminosalicylate2 Aspirin/phenacetin or aspirin/acetaminophen “analgesic nephropathy”66,101,153,209,213 Hyperkalemia213 Hyponatremia43 Nephrotic syndrome31,76,252 Penicillamine202 Probenecid103

nephrotoxic xenobiotics are associated with nonoliguric acute renal failure (urine volume > 400 mL/d), progressive azotemia without oliguria should always raise suspicion of a drug-related cause. Tubular injury, especially in lead poisoning and myoglobinuria, can cause hyperuricemia from decreased tubular secretion of uric acid. Certain xenobiotics alter measured concentrations of urea and creatinine in the absence of any change in renal function.171 The most obvious is exogenous creatine taken to build muscle mass. Cefoxitin, nitromethane, and ketones absorb light at the same frequency as the creatinine reaction product, thus artifactually increasing the measured level. Drugs that block renal creatinine secretion, such as cimetidine and trimethoprim, may also increase serum creatinine. BUN may be raised independently of renal function by tetracycline or corticosteroids, which increase protein catabolism. In patients with chronic kidney disease it is necessary to assess the remaining renal function to manage the patient properly. Clearance measurements are generally used to determine glomerular filtration rate. The most common is endogenous Ccr (see Table 27–5). Determining Ccr in acute kidney injury is not helpful, as the accuracy of a clearance implies a steady state. Changing GFR during a clearance time period distorts the resulting estimation. There is also a lag period between changes in kidney function and changes in BUN or creatinine concentrations. In general, a patient with acute kidney injury should be treated as if glomerular filtration were < 10 mL/min. In patients with acute kidney injury, a random sample of urine may be sent promptly to the laboratory for sodium and creatinine measurements to determine fractional sodium excretion, which may help discriminate prerenal azotemia from tubular necrosis (see Table 27–5). Examination of the urine is essential in cases of poisoning. Although urine is sent to the laboratory, it can also be examined carefully by the physician. Standard dipsticks will detect albumin and glucose. The dipstick test for blood is useful for confirming the presence of small amounts of blood or myoglobin, but is not a substitute for careful microscopic examination of the sediment. Clinicians should look not only for red or white cells but also for crystals, tubular elements, casts, and bacteria. If acute interstitial nephritis is a consideration, a fresh urine sample should be stained for eosinophils.164

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TABLE 27–11. Nephrotoxic Medications

TABLE 27–12. Nephrotoxicity of Miscellaneous Xenobiotics

Antineoplastics Diuretics Acute tubular necrosis Prerenal failure (volume depletion) Cisplatin90,206 Acute interstitial nephritis147,151,152 28,93 Methotrexate46,99,193,116 Acute renal failure (mannitol) + 72 Mithramycin126 Hyperkalemia (K -sparing diuretics) Ifosfamide219 Hyponatremia Streptozotocin214 Antihypertensives Chronic interstitial nephritis Prerenal failure (excessive dosage) Cisplatin95 Acute interstitial nephritis Nitrosoureas64,217 Methyldopa256 Thrombotic microangiopathy Captopril233 Mitomycin C139,187 Nephrotic syndrome Immunosuppressants Captopril196 Acute tubular necrosis and/or Obstruction (retroperitoneal fibrosis) chronic interstitial nephritis Methyldopa141 Cyclosporine74,110,158,172,189 Anticonvulsants Tacrolimus173,235 Acute interstitial nephritis Acute interstitial nephritis Carbamazepine108 Azathioprine225 182 Phenobarbital Renal tubular acidosis Phenytoin9,112 Tacrolimus97 Nephrotic syndrome Radiocontrast agents Trimethadione15 Acute renal failure, especially the Paramethadione high osmolal and ionic Anesthetics agents11,28,68,123,165,166,179,195,249 Acute tubular necrosis Osmotic nephropathy and renal Methoxyflurane185 vasoconstriction [gadolinium] Halothane86 Enflurane63

Acute glomerular injury Focal segmental glomerulosclerosis Pamidronate (collapsing type)155 Interferon alpha176,257 Acute tubular necrosis Aluminum phosphide127 Deferoxamine41 Epinephrine (in neonate)141 Etidronate183 Mycotoxins57 Paraquat, diquat248 Acute interstitial nephritis Cimetidine147,157 Clofibrate51 Phenylpropanolamine26 Proton-pump inhibitors84A Ranitidine79 Ticlopidine201

Renal stones and aminoaciduria Worcestershire sauce170 Thrombotic microangiopathy Clopidogrel25 Cyclosporine246 Mitomycin C139 Possible (IL-2, Interferon alpha, imatinib, gemcitabine) Quinine132 Tacrolimus144 Ticlopidine36

Acute renal failure Mushrooms Amanita(especially A. smithiana)172 Cortinarius spp136 Pigments67 Hemoglobin Myoglobin Obstruction (retroperitoneal fibrosis) Bromocriptine29

TABLE 27–13. Nephrotoxicity of Drugs of Abuse Nephrotic Syndrome Adulterated heroin119,60,148,161 Adulterated cocaine119

Amyloidosis

Obstruction (Retroperitoneal Fibrosis)

Acute Renal Failure (Myoglobinuria)

Chronic Renal Failure (Vasculitis)

Adulterated heroin (injection use)49,117

Lysergic acid diethylamide (LSD)230

Amphetamines102,125 Cocaine203

Amphetamines42

TABLE 27–14. Nephrotoxicity of “Complementary” Medical Treatments Acute Interstitial Nephritis

Acute Tubular Necrosis

Obstruction (Retroperitoneal Fibrosis)

Stephania tetrandra, Grass carp Stephania tetrandra, Magnolia officinalis69,247 Magnolia officinalis69,247 gallbladder143 (Chinese herbs, Disodium edetate45,183 often irreversible) Hypericum69 Ledum69

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Further evaluation of the patient with acute renal failure should include tests for obstruction, which can be caused by a number of substances (see Table 27–6). Renal ultrasonography should be performed to look for hydronephrosis. Postvoiding residual urine volume may be measured as appropriate by catheterization; if the volume is in excess of 75 to 100 mL, suspect bladder dysfunction or obstruction. Nephrotoxic complications of specific xenobiotics are found in Tables 27–7 through 27–14.

SUMMARY The kidneys are exposed to exogenous or endogenous xenobiotics in their role as primary defenders against harmful xenobiotics entering the bloodstream. The environment, the workplace, and, especially, the administration of medications, represent potential sources of nephrotoxicity. Consequently, it is important to determine, by history and observation, to which xenobiotics a patient may have been exposed and to be aware of their potential to harm the kidneys. It is equally crucial to work the other way when a patient presents with renal dysfunction: review all xenobiotics, both conventional and complementary, all xenobiotic exposures, and any conditions that can adversely affect the kidneys.

ACKNOWLEDGMENT Vincent L. Anthony contributed to this chapter in a previous edition.

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136. Lampe KF. Toxic effects of plant toxins. In: Klaassen CD, Amdur MO, Doull J, eds. Casarett and Doull’s Toxicology. 3rd ed. New York: Macmillan; 1986:757-770. 137. Landrigan PJ. Arsenic. In: Rom WN, ed. Environmental and Occupational Medicine. Boston: Little, Brown; 1983:473-480. 138. Lerner SA, Schmitt B, Seligsohn R, et al. Comparative study of ototoxicity and nephrotoxicity in patients randomly assigned to treatment with amikacin or gentamicin. Am J Med. 1986;80:90-104. 139. Lesesne JB, Rothschild N, Erickson B, et al. Cancer-associated hemolyticuremic syndrome: analysis of 85 cases from a national registry. J Clin Oncol. 1989;7:781-789. 140. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130:461-470. 141. Levine DH, Levkoff AH, Pappu LD, et al. Renal failure and other serious sequelae of epinephrine toxicity in neonates. South Med J. 1985;78:874-877. 142. Lieberthal W. Biology of acute renal failure: therapeutic implications. Kidney Int. 1997;52:1102-1115. 143. Lim PS, Lin JL, Hu SA, et al. Acute renal failure due to ingestion of the gallbladder of grass carp: report of 3 cases with review of literature. Ren Fail. 1993;15:639-644. 144. Lin CC, King KL, Chao YW, et al. Tacrolimus-associated hemolytic uremic syndrome: a case analysis. J Nephrol. 2003;16:580-585. 145. Lin JL, Tan DT, Ho HH, et al. Environmental lead exposure and urate excretion in the general population. Am J Med. 2002;113:563-568. 146. Lin JL, Yu CC, Lin-Tan DT, et al. Lead chelation therapy and urate excretion in patients with chronic renal diseases and gout. Kidney Int. 2001;60:266-271. 147. Linton AL, Clark WF, Drieger AA, et al. Acute interstitial nephritis due to drugs: review of the literature with a report of nine cases. Ann Intern Med. 1980;93:735-741. 148. Llach F, Descoeudres C, Massry SG. Heroin-associated nephropathy: clinical and histological studies in 19 patients. Clin Nephrol. 1979;11:7-12 149. Luck BE, Mann H, Melzer H, Dunemann L, Begerow J. Renal and other organ failure caused by germanium intoxication. Nephrol Dial Transplant. 1999;14:2464-2468. 150. Lucké B. Lower nephron nephrosis: the renal lesions of crush syndrome of burns, transfusions and other conditions affecting the lower segment of the nephrons. Mil Surg. 1946;99:371-396. 151. Lyons H, Pinn VW, Cortell S, et al. Allergic interstitial nephritis causing reversible renal failure in four patients with idiopathic nephrotic syndrome. N Engl J Med. 1973;288:124-128. 152. Magil AB, Ballon HS, Cameron ECC, et al. Acute interstitial nephritis associated with thiazide diuretics: clinical and pathological observations in three cases. Am J Med. 1980;69:939-943. 153. Maher JF. Toxic nephropathy. In: Brenner BM, Rector FC Jr, eds. The Kidney. Philadelphia: WB Saunders; 1976:1355-1395. 154. Malik A, Abraham P, Malik N. Acute renal failure and Fanconi syndrome in an AIDS patient on tenofovir treatment: case report and review of literature. J Infect. 2005;51:E61-E65. 155. Markowitz GS, Appel GB, Fine PL, et al. Collapsing focal segmental glomerulosclerosis following treatment with high-dose pamidronate. J Am Soc Nephrol. 2001;12:1164-1172. 156. Markowitz GS, Radhakrishnan J, Kambham N, et al. Lithium nephrotoxicity: a progressive combined glomerular and tubulointerstitial nephropathy. J Am Soc Nephrol. 2000;11:1439-1448. 157. McGowan WR, Vermillion SE. Acute interstitial nephritis related to cimetidine therapy. Gastroenterology. 1980;79:746-749. 158. Mihatsch MJ, Thiel G, Spichtin HD, et al. Morphological findings in kidney transplants after treatment with cyclosporine. Transplant Proc. 1983;15:2821-2835. 159. Miller TJ, Anderson RJ, Linas SL, et al. Urinary diagnostic indices in acute renal failure: A prospective study. Ann Intern Med. 1978;89:47-50. 160. Mitchel DH Amanita mushroom poisoning. Annu Rev Med. 1980; 31:51-57. 161. Moody C, Kaufman R, McGuire D, et al. The role of adulterants in heroin nephropathy (abstract). Natl Kidney Found. 1985;15:A12. 162. More RH, McMillan GC, Duff GL. The pathology of sulfonamide allergy in man. Am J Pathol. 1946;22:703-705. 163. Moreau JF, Droz D, Noel LH. Tubular nephrotoxicity of water soluble iodinated contrast media. Invest Radiol. 1980;15(Suppl 6):S54-S60.

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164. Morin JP, Viotte G, Vandewalle A, et al. Gentamicin-induced nephrotoxicity: A cell biology approach. Kidney Int. 1980;18:583-590. 165. Mudge GH, Meier FA, Ward KK. Pathogenesis of renal impairment induced by radiocontrast drugs. In: Solez K, Whelton A, eds. Acute Renal Failure. New York: Marcel Dekker; 1984:361-388. 166. Mudge GH. Nephrotoxicity of urographic radiocontrast drugs. Kidney Int. 1980;18:540-552. 167. Muehrcke RC, Pirani CL. Arsine induced anuria: a correlative clinicopathologic study with electron microscopic observations. Ann Intern Med. 1968;68:853-866. 168. Muehrcke RC, Pirani CL, Kark RM. Interstitial nephritis: a clinico-pathological renal biopsy study. Ann Intern Med. 1967;66:1052. 169. Mullick FG, McAllister HA Jr, Wagner BM, et al. Drug-related vasculitis: clinicopathologic correlations in 30 patients. Hum Pathol. 1979;10:313325. 170. Murphy KJ. Bilateral renal calculi and aminoaciduria after excessive intake of Worcestershire sauce. Lancet. 1967;2:401-403. 171. Muther RS. Drug interference with renal function tests. Am J Kidney Dis. 1983;3:118-120. 172. Myers BD, Ross J, Newton L, et al. Cyclosporine-associated chronic nephropathy. N Engl J Med. 1984;311:699-705. 173. Nagi AH, Alexander F, Barbas AZ. Gold nephropathy in rats: light and electron microscopic studies. Exp Mol Pathol. 1971;15:354-362. 174. Nessi R, Bonoldi GL, Redaelli B, et al. Acute renal failure after rifampicin: a case report and survey of the literature. Nephron. 1976;16:148-159. 175. Neylan J, Whelchel J, Laskow D, et al. Adverse events in the comparative dose finding trial of FK-506 in primary renal transplantation. Am Soc Transplant Phys. 1993;12:154. 176. Nishimura S, Miura H, Yamada H, et al. Acute onset of nephrotic syndrome during interferon-alpha retreatment for chronic active hepatitis C. J Gastroenterol. 2002;37:854-858. 177. Nolan CR, Anger MS, Kelleher SP. Eosinophiluria: a new method of detection and definition of the clinical spectrum. N Engl J Med. 1986;315:15161519. 178. Nolan CV, Shaikh ZA. Lead nephrotoxicity and associated disorders: biochemical mechanisms. Toxicology. 1992;73:127-146. 179. Obara K, Saito T, Sato H, et al. Germanium poisoning: clinical symptoms and renal damage caused by long-term intake of germanium. Jpn J Med. 1991;30:67-72. 180. Oldenquist G, Salem M. Parenteral copper sulfate poisoning causing acute renal failure. Nephrol Dial Transplant. 1999;14:441-443. 181. Oliver J, MacDowell M, Tracy A. The pathogenesis of acute renal failure associated with traumatic and toxic injury: renal ischemia, nephrotoxic damage and the ischemuric episode. J Clin Invest. 1951;30:1307-1351. 182. Ooi BS, First MR, Pesce AJ, et al. IgE levels in interstitial nephritis. Lancet. 1974;1:1254-1256. 183. O’Sullivan TL, Akbari A, Cadnapaphornchai P. Acute renal failure associated with the administration of parenteral etidronate. Ren Fail. 1994;16:767-773. 184. Paller MS. Drug-induced nephropathies. Med Clin North Am. 1990;74:909916. 185. Panner BJ, Freeman, RB, Roth-Mayo VA, et al. Toxicity following methoxyflurane anesthesia. JAMA. 1970;214:86-90. 186. Pavlakis N, Pollack CA, McLean G, et al. Deliberate overdose of uranium: toxicity and treatment. Nephron. 1996;72:313-317. 187. Pavy MD, Wiley EL, Abeloff MD. Hemolytic-uremic syndrome associated with mitomycin therapy. Cancer Treat Rep. 1982;66:457-461. 188. Perazella MA, Eras J. Are selective COX-2 inhibitors nephrotoxic? Am J Kidney. Dis 2000;35:937-940. 189. Perico N, Ruggenenti P, Gaspari P, et al. Daily renal hypoperfusion induced by cyclosporine in patients with renal transplantation. Transplantation. 1992;54:56-60. 190. Perkoff GT, Dioso MM, Bleisch V, et al. A spectrum of myopathy associated with alcoholism. I. Clinical and laboratory features. Ann Intern Med. 1967;67:493-510. 191. Peterson BA, Collins AJ, Vogelzang NJ, et al. 5-Azacytidine and renal tubular dysfunction. Blood. 1981;57:182-185. 192. Phillips ME, Eastwood JB, Curtis JR, et al. Tetracycline poisoning in renal failure. Br Med J. 1974;2:149-151. 193. Pitman SW, Parker LM, Tattersall MHN, et al. Clinical trials of high-dose methotrexate with citrovorum factor: toxicologic and therapeutic observations. Cancer Chemother Rep. 1975;6:43-49.

194. Poole G, Stradling P, Worlledge S. Potentially serious side effects of highdose twice-weekly rifampicin. Br Med J. 1971;3:343-347. 195. Porter GA. Radiocontrast-induced nephropathy. Nephrol Dial Transplant. 1994;9(Suppl 4):146-156. 196. Prins EJL, Hoorntje SJ, Weening JJ, et al. Nephrotic syndrome in patients on captopril. Lancet. 1979;2:306-307. 197. Qunibi WY, Godwin J, Eknoyan G. Toxic nephropathy during continuous rifampin therapy. South Med J. 1980;73:791-792. 198. Reisin E, Teicher A, Jaffe R, et al. Myoglobinuria and renal failure in toluene poisoning. Br J Ind Med. 1975;32:163-164. 199. Robben JH, Knoers NV, Deen PM. Cell biological aspects of the vasopressin type-2 receptor and aquaporin 2 water channel in nephrogenic diabetes insipidus. Am J Physiol Renal Physiol. 2006;291:F257-F270 200. Ron D, Taitelman MD, Michaelson MD, et al. Prevention of acute renal failure in traumatic rhabdomyolysis. Arch Intern Med. 1984;144:277-280. 201. Rosen H, El-Hennawy AS, Greenberg S, et al. Acute interstitial nephritis associated with ticlopidine. Am J Kidney Dis. 1995;25:934-936. 202. Ross JH, McGinty F, Brewer DG. Penicillamine nephropathy. Nephron. 1980;26:184-186. 203. Roth D, Alarcon FJ, Fernandez JA, et al. Acute rhabdomyolysis associated with cocaine intoxication. N Engl J Med. 1988;319:673-677. 204. Roza O, Berman LB. The pathophysiology of barium: hypokalemic and cardiovascular effects. J Pharmacol Exp Ther. 1971;177:433-439. 205. Rybak MJ, Abate BJ, Kang SL, et al. Prospective evaluation of the effect of an aminoglycoside-dosing regimen on rates of observed nephrotoxicity and ototoxicity. Antimicrob Agents Chemother. 1999;43:1549-1555. 206. Safirstein R, Winston J, Goldstein M, et al. Cisplatin nephrotoxicity. Am J Kidney Dis. 1986;8:356-367. 207. Saltissi D, Pulsey CD, Rainford DJ. Recurrent acute renal failure due to antibiotic-induced interstitial nephritis. Br Med J. 1979;1:1182-1183. 208. Sandhu JS, Sood A, Midha V, et al. Non-traumatic rhabdomyolysis with acute renal failure. Ren Fail. 2000;22:81-86. 209. Sandler DP, Smith JC, Weinberg CR, et al. Analgesic use and chronic renal disease. N Engl J Med. 1989;320:1238-1243. 210. Sanghvi LM, Sharma R, Mirsa SN, et al. Sulfhemoglobinemia and acute renal failure after copper sulfate poisoning: report of two fatal cases. Arch Pathol. 1957;63:172-175. 211. Sarikaya M, Sevinc A, Ulu R, et al. Bismuth subcitrate nephrotoxicity. a reversible cause of acute oliguric renal failure. Nephron. 2002;90:501-502. 212. Schacht RG, Feiner HD, Gallo GR, et al. Nephrotoxicity of nitrosoureas. Cancer. 1981;38:1328-1334. 213. Scharschmidt LA, Feinfeld DA. Renal effects of nonsteroidal antiinflammatory drugs. Hosp Physician. 1989;25:29-33. 214. Schein PS, O’Connell MJ, Blom J, et al. Clinical antitumor activity and toxicity of streptozotocin. Cancer. 1974;34:993-1000. 215. Schreiner GE, Maher JF. Toxic nephropathy. Am J Med. 1965;38:409-449. 216. Schuhmann-Giamperi G, Krestin G. Pharmacokinetics of Gd-DTPA in patients with chronic renal insufficiency. Invest Radiol. 1991;26:975-979. 217. Schwarz A, Krause PH, Kunzendorf U, et al. The outcome of acute interstitial nephritis: risk factors for the transition from acute to chronic interstitial nephritis. Clin Nephrol. 2000;54:179-190. 218. Shils ME. Renal disease and the metabolic effects of tetracycline. Ann Intern Med. 1963;58:389-408. 219. Shore R, Greenberg M, Geary D, et al. Iphosphamide-induced nephrotoxicity in children. Pediatr Nephrol. 1992;6:162-165. 220. Simmons CF, Bogusky RT, Humes HD. Inhibitory effects of gentamicin on renal mitochondrial oxidative phosphorylation. J Pharmacol Exp Ther. 1980;214:709-715. 221. Singer I. Lithium and the kidney. Kidney Int. 1981;19:374-387. 222. Sinicrope RA, Gordon JA, Little JR, et al. Carbon tetrachloride nephrotoxicity: a reassessment of pathophysiology based upon the urinary diagnostic indices. Am J Kidney Dis. 1984;3:362-365. 223. Sipes IG, Krishna G, Gillette JR. Bioactivation of carbon tetrachlo-ride, chloroform, and bromotrichloromethane: role of cytochrome. Life Sci. 1977;20:1541-1548. 224. Sleijfer DTH, Smit EF, Meijer S, et al. Acute and cumulative effects of carboplatin on renal function. Br J Cancer. 1989;60:116-120. 225. Sloth K, Thomsen AC. Acute renal insufficiency during treatment with azathioprine. Act Med Scand. 1971;189:145-148. 226. Smith CR, Lipsky JJ, Laskin OL, et al. Double-blind comparison of the nephrotoxicity and auditory toxicity of gentamicin and tobramycin. N Engl J Med. 1980;302:1106-1109.

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227. Solomon NM, Mokrzycki MH. Levofloxacin-induced allergic interstitial nephritis. Clin Nephrol. 2000;54:356. 228. Stacchiotti A, Borsani E, Rodella L, et al. Dose-dependent mercuric chloride tubular injury in rat kidney. Ultrastruct Pathol. 2003;27:253-259. 229. Stahl-Bayliss CM, Kalman CM, Laskin OL. Pentamidine-induced hypoglycemia in patients with the acquired immune deficiency syndrome. Clin Pharmacol Ther. 1986;39:271-275. 230. Stecker JF Jr, Rawls HP, Devine CJ, et al. Retroperitoneal fibrosis and ergot derivatives. J Urol. 1974;112:30-32. 231. Stefanidis I, Bohm R, Hagel J, et al. Toxic myopathy with kidney failure as a colchicine side effect in familial Mediterranean fever. Dtsch Med Wochenschr. 1992;117:1237-1240. 232. Stein JH, Lifschitz MD, Barnes LD. Current concepts of the pathophysiology of acute renal failure. Am J Physiol. 1978;234:F171-F181. 233. Steinman TI, Silva P. Acute renal failure, skin rash, and eosinophilia associated with captopril therapy. Am J Med. 1983;75:154-156. 234. Sterne TL, Whitaker C, Webb CH. Fatal cases of bismuth intoxication. J La State Med Soc. 1955;107:332-335. 235. Su Q, Weber L, Lettir M, et al. Nephrotoxicity of cyclosporin A and FK-506: inhibition of calcineurin phosphatase. Ren Physiol Biochem. 1995;18:128-139. 236. Swaminathan S, Shah SV. New insights into nephrogenic systemic fibrosis. J Am Soc Nephrol. 2007;18:2636-2643. 237. Tada T, Ohara A, Nagai Y, et al. A case report of nephrotic syndrome associated with rifampicin therapy. Nippon Jinzo Gakkai Shi. 1995;37:145-150. 238. Ten RM, Torres VE, Milliner DS, et al. Acute interstitial nephritis: immunologic and clinical aspects. Mayo Clin Proc. 1988;63:921-930. 239. Thadhani R, Pascual M, Bonventre J. Medical progress: Acute renal failure. N Engl J Med. 1996;334:1448-1460. 240. Thompson J. Ferrous sulfate poisoning: its incidence, symptomatology, treatment, and prevention. Br Med J. 1950;1:645-646. 241. Tornroth T, Skrifvars B. Gold nephropathy prototype of membranous glomerulonephritis. Am J Pathol. 1974;75:573-590. 242. Tubbs RR, Gephardt GN, McMahon JT, et al. Membranous glomerulonephritis associated with industrial mercury exposure. Am J Clin Pathol. 1982;77:409-413. 243. Uldall PR, Khan HA, Ennis JE, et al. Renal damage from industrial arsine poisoning. Br J Ind Med. 1970;27:372-377. 244. Ullmann AJ, Sanz MA, Tramarin A, et al. Prospective study of amphotericin B formulations in immunocompromised patients in 4 European countries. Clin Infect Dis. 2006;43:e29-e38. 245. Vallee BL, Ulmer DD, Wacker WEC. Arsenic toxicology and biochemistry. Arch Ind Health. 1960;21:132-151.

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246. Van Buren D, Van Buren CT, Flechner SM, et al. De novo hemolytic uremic syndrome in renal transplant recipients immunosuppressed with cyclosporine. Surgery. 1985;98:54-62. 247. Vanherweghem JL, Depierreux M, Tielemans C, et al. Rapidly progressive interstitial renal fibrosis in young women: association with slimming regimen including Chinese herbs. Lancet. 1993;341:387-391. 248. Vanholder R, Colardyn F, De Reuck J, et al. Diquat intoxication: report of two cases and review of the literature. Am J Med. 1981;70:1267-1271. 249. VanZee BE, Hoy WE, Talley TE, et al. Renal injury associated with intravenous pyelography in nondiabetic and diabetic patients. Ann Intern Med. 1978;89:51-54. 250. Varma A, Jha V, Ghosh AK, et al. Acute renal failure in a case of fatal chromic acid poisoning. Ren Fail. 1994;16:653-657. 251. Walker RG, Thomson NM, Dowling JP, Ogg CS. Minocycline-induced acute interstitial nephritis. Br Med J. 1979;1:524. 252. Warren GV, Korbet SM, Schwartz MM, et al. Minimal change glomerulopathy associated with nonsteroidal anti-inflammatory drugs. Am J Kidney Dis. 1989;13:127-130. 253. Weaver VM, Jaar BG, Schwartz BS, et al. Associations among lead dose biomarkers, uric acid, and renal function in Korean lead workers. Environ Health Perspect. 2005;113:36-42. 254. Wedeen RP, Batuman V. Tubulo-interstitial nephritis induced by heavy metals and metabolic disturbances. Contemp Issues Nephrol. 1983;10:211241. 255. Wetherill SF, Guarine MJ, Cox RW. Acute renal failure associated with barium chloride poisoning. Ann Intern Med. 1981;95:187-188. 256. Wilson M, Brown DJ, Brown RW, et al. Renal failure from alpha-methyldopa therapy. Aust N Z J Med. 1974;4:415-416. 257. Willson RA. Nephrotoxicity of interferon alfa-ribavirin therapy for chronic hepatitis C. J Clin Gastroenterol. 2002;35:89-92. 258. Woolf AD, Ebert TH. Toxicity after self-poisoning by ingestion of potassium chloroplatinite. J Toxicol Clin Toxicol. 1991;29:467-472. 259. Wolff E. Carbon monoxide poisoning with severe myonecrosis and acute renal failure. Am J Emerg Med. 1994;12:347-349. 260. Zanetta G, Maurice-Estepa L, Mousson C, et al. Foscarnet-induced crystalline glomerulonephritis with nephrotic syndrome and acute renal failure after kidney transplantation.Transplantation. 1999;67:1376-1378. 261. Zar T, Graeber C, Perazella MA. Recognition, treatment, and prevention of propylene glycol toxicity. Semin Dial. 2007;20:217-219. 262. Zar T, Yusufzai I, Sullivan A, et al. Acute kidney injury, hyperosmolality and metabolic acidosis associated with lorazepam. Nat Clin Pract Nephrol. 2007;3:515-520.

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CHAPTER 28

GENITOURINARY PRINCIPLES Jason Chu The genitourinary system encompasses two major organ systems: the reproductive and the urinary systems. Successful reproduction requires interaction between two sexually mature individuals. Xenobiotic exposures to either individual can have an adverse impact on fertility, which is the successful production of children, and fecundity, which is an individual’s or a couple’s capacity to produce children. The role of occupational and environmental exposures in the development of infertility is difficult to define.10,37,89,93 Well-designed and conclusive epidemiologic studies are lacking due to the following factors: laboratory tests used to evaluate fertility are relatively unreliable; clinical endpoints are unclear; xenobiotic exposure is difficult to monitor; and indicators of biologic effects are imprecise. The negative impact on fertility as an adverse effect of xenobiotics is often ignored, but the evaluation of infertility is incomplete without a thorough xenobiotics and occupational history. Differences in the toxicity of xenobiotics in individuals may be sex- and/or age-related. Xenobiotic-related, primary infertility may be the result of effects on the hypothalamic-pituitary-gonadal axis or of a direct toxic effect on the gonads.78 Fertility is also affected by exposures that cause abnormal sexual performance. Table 28–1 lists xenobiotics associated with infertility. Aphrodisiacs are used to heighten sexual desire and to counteract sexual dysfunction. Historically, humans have continued to search for the perfect aphrodisiac. Efficacy is variable, and toxic consequences occur commonly. Various treatments have been available for male sexual dysfunction, or erectile dysfunction. Although many people search for a cure for impotence or infertility, others explore xenobiotics that can be used as abortifacients. Routes of administration used include oral, parenteral, and intravaginal, with an end result of pregnancy termination. Toxicity results not only in the termination of pregnancy but also from the systemic effects of the various xenobiotics. This chapter examines these issues, as well as the impact of xenobiotics on the urinary system, specifically, urinary retention and incontinence, and abnormalities detected in urine specimens. Renal (Chap. 27), teratogenic, (Chap. 30), and carcinogenic principles are discussed elsewhere in this text.

MALE FERTILITY Male fertility is dependent on a normal reproductive system and normal sexual function. The male reproductive system is comprised of the central nervous system (CNS) endocrine organs and the male gonads. The hypothalamus and the anterior pituitary gland form the CNS portion of the male reproductive system. Both organs begin low-level hormone secretion as early as in utero gestation. At puberty, the hypothalamus begins pulsatile secretion of gonadotropin-releasing hormone (GnRH). This stimulates the anterior pituitary gland to release follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in a pulsatile fashion. The hormones exert their effects on the male target

organs, inducing spermatogenesis and secondary body sexual characteristics (Fig. 28–1). Disruption of normal function at any part of the system affects fertility. There are a number of xenobiotics that can adversely affect the male reproductive system and sexual function.

■ SPERMATOGENESIS Central to the male reproductive system is the process of spermatogenesis, which occurs in the testes. The bulk of the testes consist of seminiferous tubules with germinal spermatogonia and Sertoli cells. The remainder of the gonadal tissue is interstitium with blood vessels, lymphatics, supporting cells, and Leydig cells. Spermatogenesis begins with the maturation and differentiation of the germinal spermatogonia. The process is controlled by the secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus, which stimulates the pituitary to release follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Follicle-stimulating hormone stimulates the development of Sertoli cells in the testes, which are responsible for the maturation of spermatids to spermatozoa. Luteinizing hormone promotes production of testosterone by Leydig cells. Testosterone concentrations must be maintained to ensure the formation of spermatids.19 Both FSH and testosterone are required for initiation of spermatogenesis, but testosterone alone is sufficient to maintain the process. Testicular Xenobiotics Xenobiotics can affect any part of the male reproductive tract, but, invariably, the end result is decreased sperm production defined as oligospermia, or absent sperm production, azoospermia. In contrast to oogenesis in women, spermatogenesis is an ongoing process throughout life but can be inhibited by decreases in FSH and/or LH or Sertoli cell toxicity. Spermatogenic capacity is evaluated by semen analysis, including sperm count, motility, sperm morphology, and penetrating ability. Normal sperm count is greater than 40 million sperm/mL semen, and a count less than 20 million/mL is indicative of infertility.19 Decreased motility (asthenospermia) less than 40% of normal or abnormal morphology (teratospermia) of greater than 40% of the total number of sperm also indicates infertility.19,101 Physiology of Erection The penis is composed of two corpus cavernosa and a central corpus spongiosum. The internal pudendal arteries supply blood to the penis via four branches. Blood outflow is via multiple emissary veins draining into the dorsal vein of the penis and plexus of Santorini. Within the penis, the corpora cavernosa share vascular supply and drainage due to extensive arteriolar, arteriovenous, and sinusoidal anastomoses.120 When penile blood flow is greater than 20–50 mL/min, erection occurs. Maintenance of tumescence occurs with flow rates of 12 mL/min. The tunica albuginea limits the absolute size of erection. In the flaccid state, sympathetic efferent nerves maintain helicine resistance arteriole constriction primarily through norepinephrine induced α-adrenergic agonism. α-Adrenergic receptor agonism in the erectile tissues decreases cAMP to produce flaccidity, while α-Adrenergic antagonism can result in pathologic erection (priapism) as a consequence of parasympathetic dominance.120 Other vasoconstrictors, such as endothelin, prostaglandin F2a, and thromboxane A2 play a role in maintaining corpus cavernosal smooth muscle tone in contraction, which results in a flaccid state.84 Normal penile erection is a result of both neural and vascular effects. Psychogenic neural stimulation arising from the cerebral cortex inhibits norepinephrine release from thoracolumbar sympathetic pathways, stimulates nitric oxide (NO) and acetylcholine release from sacral parasympathetic tracts, and stimulates acetylcholine release from somatic pathways. In animals, dopamine and NO play a role in erection.84 Reflex stimulation can also occur from the sacral spinal cord. The

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Chapter 28

TABLE 28–1. Xenobiotics Associated with Infertility

Genitourinary Principles

397

CNS Hypothalamus GnRH

Men Xenobiotic

Effects

Anabolic steroids Androgens Antineoplastics Cyclophosphamide Chlorambucil Methotrexate Combination chemotherapy (COP, CVP, MOPP, MVPP) Carbon disulfide Cimetidine Chlordecone Dibromochloropropane (DBCP) Diethylstilbestrol Ethanol

↓ LH, oligospermia ↓ testosterone production Gonadal toxicity Oligospermia Oligospermia Oligospermia Oligospermia

Ethylene oxide Glycol ethers Ionizing radiation Opioids Lead Nitrofurantoin Sulfasalazine Tobacco

↓ FSH, ↓ LH, ↓ spermatogenesis Oligospermia Asthenospermia, oligospermia Azoospermia, oligospermia Testicular hypoplasia ↓ Testosterone production, Leydig cell damage, asthenospermia, oligospermia, teratospermia Asthenospermia (in monkeys), oligospermia Azoospermia, oligospermia, testicular atrophy ↓ Spermatogenesis ↓ LH, ↓ testosterone ↓ Spermatogenesis, asthenospermia, teratospermia ↓ Spermatogenesis ↓ Spermatogenesis ↓ Testosterone Women

Xenobiotic

Effects

Antineoplastics Cyclophosphamide Busulphan Combination chemotherapy (MOPP, MVPP) Diethylstilbestrol Ethylene oxide Lead Oral contraceptives

Gonadal toxicity Ovarian failure Amenorrhea Amenorrhea

Thyroid hormone

Spontaneous abortions Spontaneous abortions Spontaneous abortions, still births Affect hypothalamic-pituitary axis, end-organ resistance to hormones, amenorrhea ↓ Ovulation

afferent limb of the reflex arc is supplied by the pudendal nerves and the efferent limb by the nervi erigentes (pelvic splanchnic nerves). The central impulses stimulate various neurotransmitters to be released by peripheral nerves in the penis. Nonadrenergicnoncholinergic nerves and endothelial cells produce NO, which is the

Anterior Pituitary FSH LH

Testes

Leydig cells Testosterone

Sertoli cells Spermatozoa

Decrease FSH or LH Anabolic steroids Carbon disulfide Opioids

Decrease sperm

Decrease testosterone

Anabolic steroids Antineoplastics Carbon disulfide Chlordecone Cimetidine DBCP Ethanol Ethylene oxide Glycol ethers Lead Nitrofurantoin Radiation (ionizing) Sulfasalazine

Androgens Digoxin Ethanol Ketoconazole Opioids Spironolactone Tobacco

FIGURE 28–1. A schematic of the male reproductive axis and sites of xenobiotic effects. FSH = follicle stimulating hormone; GnRH = Gonadotropin releasing hormone; LH = Luteinizing hormone.

principal neurotransmitter mediating erection. Nitric oxide activates guanylate cyclase conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). Increasing concentrations of cGMP act as a second messenger, mediating arteriolar and trabecular smooth-muscle relaxation to enable increased cavernosal blood flow and penile erection.84 Both cGMP and cyclic adenosine

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Part B

The Fundamental Principles of Medical Toxicology

CNS

Spinal cord

Thoracolumbar tracts (sympathetic)

Bicalutamide Cimetidine Dutasteride Finasteride Flutamide Spironolactone Increase prolactin Antipsychotics Digoxin Methyldopa Metoclopramide Spironolactone

Erection

Cholinergic ACH

Decreases cAMP Smooth muscle contraction Decreased blood vessel filling

Erectile dysfunction

Amphetamines Antiandrogens Anticholinergics Antihypertensives Cocaine Cyclic antidepressants

receptors

Penis

Adrenergic NE

antagonists

Block androgen

Anabolic steroids Antineoplastics Antipsychotics β-adrenergic antagonists Benzodiazepines Barbituates Clonidine Cyclic antidepressants Ethanol MAO inhibitors Methyldopa Protease inhibitors SSRIs

Sacral tracts (parasympathetic)

Flaccidity

β-adrenergic

Decrease libido

NANC NO

VIPergic VIP

Increase cGMP and cAMP Smooth muscle relaxation Increased blood vessel filling

Improve erection Estrogens

α1-adrenergic antagonists

Ketamine

α2-adrenergic antagonists (Yohimbine)

Lithium Opioids Thiazides

Angiotensin receptor blockers Dopamine agonists Phosphodiesterase-5 inhibitors

FIGURE 28–2. A schematic of the erection and xenobiotics that cause sexual dysfunction. NE = norepinephrine; ACH = acetylcholine; NANC = nonadrenergic-noncholinergic; NO = nitric oxide; VIP = vasoactive intestinal peptide.

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monophosphate (cAMP) pathways mediate smooth-muscle relaxation. Cholinergic nerves release acetylcholine, which stimulates endothelial cells via M3 receptors to produce NO and prostaglandin E2 (PGE). Prostaglandin E2 and nerves containing vasoactive intestinal peptide (VIP) and calcitonin gene-related peptide (CGRP) increase cellular cAMP to potentiate smooth-muscle relaxation. Penile corpus cavernosal smooth muscle relaxation allows increased blood flow into the corpus cavernosal sinusoids. Expansion of the sinusoids compresses the venous outflow and enables penile erection (Fig. 28–2).

Antihypertensives Erectile dysfunction is reported as an adverse effect with all antihypertensives and may be caused, in part, by a decrease in hypogastric artery pressure, which impairs blood flow to the pelvis.117 Methyldopa and clonidine both are centrally acting α2-adrenergic agonists that inhibit sympathetic outflow from the brain. Sexual dysfunction is reported in 26% of patients receiving methyldopa and in 24% of patients receiving clonidine.14,87 Erectile dysfunction associated with thiazide diuretics may be related to decreased vascular resistance, diverting blood from the penis.20 Spironolactone acts as an antiandrogen by inhibiting the binding of dihydrotestosterone to its receptors. Impotence related to use of β-adrenergic antagonists, is well documented1,57,114 and may be caused by unopposed α-mediated vasoconstriction resulting in reduced penile blood flow. Ethanol Ethanol is directly toxic to Leydig cells. Chronic alcohol abuse causes decreased libido, erectile dysfunction, and is associated with testicular atrophy. In alcoholics liver disease contributes to sexual dysfunction resulting from decreased testosterone and increased estrogen production. Alcoholics can have autonomic neuropathies affecting penile nerves and subsequent erection. Heavy drinkers suffer more from erectile dysfunction than episodic drinkers.116 Antipsychotics Individuals who take antipsychotics therapeutically have varying degrees of sexual dysfunction related to their underlying disease and their medications. All psychoactive medications are associated with sexual dysfunction to some degree. Monoamine oxidase inhibitors

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TABLE 28–2. Xenobiotics Associated with Sexual Dysfunction (Particularly Diminished Libido and Impotence) α1-Adrenergic antagonists α2-Adrenergic agonists β-Adrenergic antagonists∗ Anabolic Steroids Anticholinergics∗ Anticonvulsants Antiestrogens Benzodiazepines Calcium channel blockers Cimetidine Clonidine Cyclic Antidepressants

■ SEXUAL DYSFUNCTION Sexual dysfunction can result from decreased libido (sexual desire), impotence, diminished ejaculation, and erectile dysfunction. Dopamine, norepinephrine, oxytocin, and adrenocorticotrophic hormone (ACTH) are central neurotransmitters and hormones which facilitate sexual function. Serotonin, prolactin, endogenous opioids and GABA inhibit sexual function centrally.6 Libido can be decreased by xenobiotics that block central dopaminergic or adrenergic pathways or by xenobiotics that increase serotonin or prolactin levels. Conversely, xenobiotics that increase dopamine can improve sexual function. Sexual dysfunction can also be caused by xenobiotics that decrease testosterone production and by xenobiotics that produce dysphoria. Xenobiotics that affect spinal reflexes can cause diminished ejaculation and erectile dysfunction.118 Approximately 30 million men in the United States suffer from erectile dysfunction, with an increased prevalence in older men.53 Erectile dysfunction is defined as the inability to achieve and/or maintain an erection for a sufficiently long period of time to permit satisfactory sexual intercourse3 and is divided into the following classifications: psychogenic, vasculogenic, neurologic, endocrinologic, and xenobioticinduced. Xenobiotic-induced erectile dysfunction is associated with the following categories of xenobiotics: antidepressants, antipsychotics, centrally and peripherally-acting antihypertensives, CNS depressants, anticholinergics, exogenous hormones, antibiotics, and antineoplastics.74,100,118 Treatment of this disorder is varied and includes vacuum-constriction devices, penile prostheses, vascular surgery, and medications (intracavernosal, transdermal, and oral agents).

Genitourinary Principles

Diuretics Ethanol Lead Lithium Methyldopa Monamine oxidase inhibitors∗ Opioids Oral contraceptives Phenothiazines Selective serotonin reuptake inhibitors Spironolactone

∗

Associated with erectile dysfunction

(MAOIs), cyclic antidepressants (CAs), antipsychotics, and selective serotonin reuptake inhibitors (SSRIs) are associated with decreased libido and erectile dysfunction in men.31 Thioridazine is associated with significantly lower LH and testosterone levels in men in comparison with other antipsychotics.19 Antidepressants such as bupropion, nefazodone, mirtazapine, and duloxetine have lower incidences of sexual dysfunction in comparison with other antidepressants.102 Table 28–2 lists xenobiotics associated with sexual dysfunction.

■ XENOBIOTICS USED IN THE TREATMENT OF ERECTILE DYSFUNCTION Intracavernosal Agents. The three most commonly used intracavernosal agents used for erectile dysfunction are papaverine, prostaglandin E1, and phentolamine. Papaverine is a benzylisoquinoline alkaloid derived from the poppy plant Papaver somniferum. It exerts its effects through nonselective inhibition of phosphodiesterase, leading to increased cAMP and cGMP levels and subsequent cavernosal vasodilation. Papaverine was used for the treatment of cardiac and cerebral ischemia but had limited efficacy. Presently, it is used as intracavernosal therapy for erectile dysfunction alone or in conjunction with phentolamine. Systemic side effects include dizziness, nausea, vomiting, hepatotoxicity, lactic acidosis with oral administration, and cardiac dysrhythmias with intravenous use. Intracavernosal administration is associated with penile fibrosis which is usually dose-related phenomenon, although fibrosis can also occur with limited use.33 More concerning is the development of priapism with papaverine use. Prostaglandin E1 (Alprostadil) is a nonspecific agonist of prostaglandin receptors resulting in increased concentrations of intracavernosal cAMP, cavernosal smooth muscle relaxation and penile erection. It is effective via intracavernosal administration as a single agent. Other preparations include an intraurethral preparation, which is less effective, and a topical gel formulation.54 Penile fibrosis can occur but the incidence is lower compared to papaverine. Other adverse effects include penile pain, secondary to its effects as a nonspecific prostaglandin receptor agonist, and priapism. Phentolamine is a competitive α-adrenergic antagonist at α1 and α2 receptors. It effects erection by inhibiting the normal resting adrenergic

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tone in cavernosal smooth muscle, thus allowing increased arterial blood flow and erection. Intracavernosal use can cause systemic hypotension, reflex tachycardia, nasal congestion, and gastrointestinal upset. Penile fibrosis and priapism are also reported. Oral Agents Since the development of the phosphodiesterase 5 inhibitors, oral therapy has replaced intracavernosal injections as the mainstay for treatment of erectile dysfunction. Sildenafil was the first agent developed, followed by vardenafil and tadalafil. These medications are pharmacodynamically similar but differ in their pharmacokinetics. Phosphodiesterase 5 inhibitors increase NO-induced cGMP concentrations by preventing phosphodiesterase breakdown of cGMP, enhancing NO-induced vasodilation to promote penile vascular relaxation and erection.18 After oral administration, sildenafil is rapidly absorbed with a bioavailability of 40% and a median peak serum concentration of 60 minutes. Its mean volume of distribution is 105 L, and its elimination half-life is 3 to 5 hours. Metabolism is primarily by the CYP3A4 pathway with some minor metabolic activity via the CYP2C9 pathway. Serum concentrations of sildenafil are increased in patients older than 65 years as well as those with hepatic dysfunction, severe renal dysfunction (creatinine clearance 0.5 cm in diameter Pustule: a circumscribed collection of leukocytes and free fluid that vary in size Tumor: an elevation of > 0.5 cm in diameter Vesicle: a circumscribed collection of free fluid ≥ 0.5 cm in diameter Wheal: a firm edematous plaque resulting from infiltration of the dermis with fluid

Erosion: a loss of the epidermis up to the full thickness of the epidermis but not through the basement membrane Hypertrophy: a thickening of the skin Lichenification: a secondary process with noted accentuation of skin surface markings Scale: flaking that is separate from the original surface of a lesion Scar: a thickened, often discolored, surface Ulcer: a loss of full-thickness epidermis and papillary dermis, reticular dermis, or subcutis

The apocrine glands consist of secretory coils and intradermal ducts ending in the follicular canal. The secretory coil is located in the subcutis and consists of a large lumen surrounded by columnar to cuboidal cells with eosinophilic cytoplasm.12 Apocrine glands, which are located in select areas of the body such as the axilla, produce secretions that are rendered odoriferous by cutaneous bacterial flora.

The eccrine glands, in contrast, produce an isotonic to hypotonic secretion that is modified by the ducts and emerges on the skin surface as sweat. The eccrine unit consists of a secretory gland as well as intradermal and intraepidermal ducts. The coiled secretory gland is located in the area of the deep dermis and subcutis. Xenobiotics can be concentrated in the sweat and increase the intensity of the local skin reactions.

Toxic epidermal necrolysis Pemphigus foliaceous Pemphigus vulgaris Horny layer Granular layer Spinous layer Basal layer Basement membrane

Epidermis

Dermis

HF

Basal layer Lamina lucida Lamina densa

Subcutis

Anchoring fibrils Anchoring plaque

FIGURE 29–1. Skin histology and pathology. Intraepidermal cleavage sites in various xenobiotic-induced blistering diseases. In pemphigus foliaceous, the cleavage is below or within the granular layer, whereas in pemphigus vulgaris, it is suprabasilar. This accounts for the differing types of blisters found in the two diseases. HF = Hair Follicle

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Certain antineoplastics, such as cytarabine or bleomycin, directly damage the eccrine sweat glands, resulting in anhidrosis. Sebaceous glands also reside in the dermis. They produce an oily, lipid-rich secretion that functions as an emollient for the hair and skin, and can be a reservoir of noxious environmental xenobiotics. Pilosebaceous follicles, which are present all over the body, consist of a hair shaft, hair follicle, sebaceous gland, sensory end organ, and erector pili. Certain halogenated aromatic chemicals, such as polychlorinated biphenyls (PCBs), dioxin, and 2,4-dichlorophenoxyacetic acid, are excreted in the sebum and cause hyperkeratosis of the follicular canal. This produces a syndrome, chloracne, that looks like acne vulgaris, because of plugging of the ducts. Similar syndromes result from exposure to brominated and iodinated compounds, and are known as bromoderma and ioderma, respectively.40 The tissues of the hypodermis or subcutaneous tissue, serves to insulate, cushion, and allow for mobility of the overlying skin structures. Adipocytes represent the majority of cells found in this layer. Leptin, an adipose-derived hormone responsible for long-term feedback of appetite and satiety signaling, is synthesized and regulates fat mass (adiposity) in this layer. The hair follicle is divided into three portions.34 The deepest portion of the hair follicle contains the bulb with matrix cells. The matrix cells are highly mitotically active and often are the target of cytotoxic xenobiotics. The rate of growth and the type of hair are unique for different body sites. Hair growth proceeds through three distinct phases: the active prolonged growth phase (anagen phase) during which matrix cell mitotic activity is high; a short involutional phase (catagen phase); and a resting phase (telogen phase). Understanding the phases and biochemical structure of hair growth is important because hair growth can be used to identify clues regarding the timing and mechanism of action of a xenobiotic. The nail, which is often considered analogous to the hair, is also a continuously growing structure. Fingernails grow at average of 0.1 mm/d and toenails grow at about one-third that rate. The mitotically active cells of the nail matrix are subject to both traumatic and xenobiotic injury that affects the appearance and growth of the nail plate. Because nail growth is consistent, location of an abnormality in the plate can predict the timing of exposure, such as Mees lines.

TOPICAL TOXICITY ■ TRANSDERMAL XENOBIOTIC ABSORPTION Although there is no active uptake mechanism for xenobiotics by the skin, many undergo percutaneous absorption by passive diffusion. Lipid solubility, concentration gradient, molecular weight, and certain specific skin characteristics are important determinants of dermal absorption. Absorption is generally considered to occur though intercellular movement, requiring that the xenobiotic dissolve in the ceramides. This accounts for the importance of lipid solubility of the xenobiotic in transdermal absorption. However, excessive lipid solubility limits the partitioning of the xenobiotic from the stratum corneum into the aqueous dermis, a critical requirement since the blood vessels are in this deeper layer.13,14,31,32 The relationship between lipid and water solubility is often described by the octanol-water partition coefficient. Xenobiotics with values between 10 and 1000 have sufficient lipid and water solubility to permit skin permeation. For example, morphine sulfate, with an octanol water partition coefficient of approximately 1, is not absorbed when applied topically, whereas fentanyl, with a coefficient of approximately 700, is widely used as a transdermally delivered medication. The dermal toxicity of the various organic phosphorus compounds may be

predicted based on this coefficient.9 Although metal ions such as Hg+ have limited skin penetration, the addition of a methyl group, to form methylmercury, increases its lipophilicity and its systemic absorption. Dimethylmercury, has even better absorption and may produce life-threatening systemic effects with a minute amount applied to the skin (Chap. 96). Similarly, the nonionized component of the weakly acidic hydrofluoric (HF) acid is able to penetrate deeply through skin and even bone. The proton (H+) and fluoride ion (F−) are unable to penetrate the lipids of the skin individually because of their charged nature; however, once in the dermis, the HF acid may ionize and cause both acid-induced tissue necrosis and fluoride-induced toxicity (Chap. 105).4 Children appear particularly at risk for toxicity from percutaneous absorption because their skin is more penetrable than an adult’s and specific anatomic sites, such as the face, often represent larger percentage of body surface areas than in the adult.37 Furthermore, there is enhanced absorption on anatomic parts of the body with thinner skin, such as the mucous membranes, eyelids, and intertriginous areas (axillae, groin, inframammary, and intergluteal). Under certain circumstances, such as with more highly lipophilic xenobiotics, the stratum corneum may serve a depot function leading to slow onset and continued systemic exposure despite apparent removal of the xenobiotic. For example, applied topically in the form of a transdermal device, fentanyl does not result in peak concentration for 24 to 72 hours after initial application. When removed, the serum fentanyl concentrations fall with an average half-life of 17 hours, which is substantially longer than when administered intravenously.18 The vehicle of a xenobiotic may also influence absorption; indeed, transdermal drug-delivery systems are based on their ability to alter the skin partition coefficient through the use of an optimized vehicle. Similarly, through localized dermal occlusion, transdermal systems hydrate the skin and raise its temperature to increase absorption. Despite these techniques to enhance drug delivery, transdermal systems require that large amounts of drug be present externally to maximize the transcutaneous gradient. Much of the drug typically remains in the patch when it is removed following its intended course of therapy, raising concerns for safe disposal, especially for children.13,14,31,32 Transdermal drug delivery has several therapeutic advantages, such as continuous dosing resulting in more stable pharmacokinetics, prolonged drug delivery resulting in a more convenient dosing schedule (eg, weekly device changes), and the avoidance of first pass hepatic metabolism. These delivery devices, familiarly called “patches,” are highly developed and crafted to deliver their content at a specified rate. Some variability occurs related to skin thickness, dermal barrier damage (eg, dry skin, rashes), or external factors, such as ambient temperature. As with any route of administration, adverse effects and toxicity caused by excessive absorption following patch application may occur following therapeutic use and misuse. For example, this is reported with nicotine, fentanyl, NSAIDS, and lidocaine transdermal delivery devices. Other xenobiotics, topically applied without a specific delivery device, may be associated with systemic morbidity and mortality, including podophyllin, camphor, phenol, organic phosphorus compounds, ethanol, organochlorines, and nitrates.

■ CONTACT DERMATITIS Allergic contact dermatitis from plants and dyes such as fragrances and paraphenylenediamine (henna) is increasing in frequency. Miconidin and miconidin methyl ester were isolated from Primula obconica (primrose). Parthenolide is an ingredient in feverfew and can cause an airborne contact dermatitis. Triethanolamine polyethylene glycol-3

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(TEA-PEG-3) cocamide sulfate was identified recently to cause allergic reactions in coconut oil.

■ DIRECT DERMAL TOXICITY Exposure to any of a myriad of industrial and environmental xenobiotics can result in dermal “burns.” Although the majority of these xenobiotics injure the skin through chemical reactivity rather than thermal damage, the clinical appearances of the two are often identical. Injurious xenobiotics may act as oxidizing or reducing agents, corrosives, protoplasmic poisons, desiccants, or vesicants. Often an injury may initially appear to be mild or superficial with only faint erythema, blanching, or discoloration of the skin. Over the subsequent 24 to 36 hours there may be progression to extensive necrosis of the skin and its underlying tissues. Acids are water soluble and many readily penetrate into the subcutaneous tissue. The damaged tissue coagulates and forms a thick leathery eschar that limits the spread of the xenobiotic. The histopathologic finding following acid injury is termed coagulative necrosis. Alkali exposures characteristically produce a liquefactive necrosis, which allows continued penetration of the corrosive xenobiotic; consequently, dermal injury following alkali exposure is typically more severe than after an acid exposure of an equivalent magnitude.7 Thermal damage can also be the result of a toxicologic exposure. For example, the exothermic reaction generated by the wetting of elemental phosphorus or sodium may result in a thermal burn. In these circumstances, the products of reactivity, phosphoric acid and sodium hydroxide respectively, may produce secondary chemical injury. Alternatively, skin exposure to a rapidly expanding gas, such as nitrous oxide from a whipped cream cartridge or compressed liquefied nitrogen, or to frozen substances, such as dry ice, can produce a freezing injury, or frostbite. Hydrocarbon-based solvents are typically liquids that are capable of dissolving non–water-soluble solutes.7 Although the most prominent effect is a dermatitis due to loss of ceramides from the stratum corneum, prolonged exposure can result in deeper dermal irritation and destruction.

PRINCIPLES OF DERMAL DECONTAMINATION On contact with xenobiotics, the skin should be thoroughly cleansed to prevent direct effects and systemic absorption. In general, a copious amount of water is the decontamination agent of choice for skin irrigation. Soap should be used when adherent xenobiotics are involved. Following exposures to airborne xenobiotics, the mouth, nasal cavities, eyes, and ear canals should be irrigated with appropriate solutions such as water or a 0.9% NaCl solution. For nonambulatory patients, the decontamination process may need to be conducted using special collection stretchers if available.6 There are a few situations in which water should not be used for skin decontamination. The situations include contamination involving the reactive metallic forms of the alkali metals, sodium, potassium, lithium, cesium, and rubidium, which react with water to form strong bases. The dusts of pure magnesium, sulfur, strontium, titanium, uranium, yttrium, zinc, and zirconium will ignite or explode on contact with water. Following exposure to these metals, any residual metal should be removed mechanically with forceps, gauze, or towels and stored in mineral oil. Additionally, phenol has a tendency to thicken and become difficult to remove following exposure to water. Suggestions for phenol decontamination include high-flow water or low-molecular-weight polyethylene glycol solution. Lime, or CaO, thickens and forms Ca(OH)2 following wetting, suggesting that mechanical removal is appropriate.6

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DERMATOLOGIC SIGNS OF SYSTEMIC DISEASES ■ CYANOSIS Normal cutaneous and mucosal pigmentation is caused by several factors, one of which is the visualization of the capillary beds through the translucent dermis and epidermis. Cyanosis manifests as a blue or violaceous appearance of the skin, mucous membranes, and nailbeds. It occurs when excessive concentrations of reduced hemoglobin (>5g/dL) are present, as in hypoxia or polycythemia, or when oxidation of the iron moiety of heme to the ferric state forms methemoglobin, which is deeply pigmented (Chap. 127). The presence of the more deeply colored hemoglobin moiety within the dermal plexus results in cyanosis that is most pronounced on the skin surfaces with the least overlying tissue, such as the mucous membranes or fingernails.

■ XANTHODERMA Xanthoderma is a yellow to yellow-orange macular discoloration of skin.16 Xanthoderma can be caused by xenobiotics such as carotenoids, which deposit in the stratum corneum, and causes carotenoderma. Carotenoids are lipid soluble and consist of α-carotene, β-carotene, β-cryptoxanthin, lycopene, lutein, and zeaxanthan, and serve as precursors of vitamin A (retinol). The carotenoids are excreted via sweat, sebum, urine, and GI secretions. Jaundice is typically a sign of hepatocellular failure or hemolysis and is caused by hyperbilirubinemia either conjugated or unconjugated, a condition in which the yellow pigment deposits in the subcutaneous fat. True hyperbilirubinemia is differentiated from hypercarotenemia by the presence of scleral icterus in patients with the former which is absent in patients with the latter. In addition, the cutaneous discoloration seen in hypercarotenemia can be removed by wiping the skin with an alcohol swab. Lycopenemia, an entity similar to carotenemia, is caused by the excessive consumption of tomatoes. Additionally, topical exposure to dinitrophenol or picric acid or stains from cigarette use produces localized yellow discoloration of the skin.

■ URTICARIAL DRUG REACTIONS Urticarial drug reactions are characterized by transient, pruritic, edematous, pink papules, or wheals that arise in the dermis, which blanch on palpation and are frequently associated with central clearing. Approximately 40% of patients with urticaria experience angioedema and anaphylactoid reactions as well.1 The reaction pattern is representative of a type I, or IgE-dependent, immune reaction and commonly occurs as part of clinical anaphylaxis or anaphylactoid (non–IgE-mediated) reactions. Widespread urticaria may occur following systemic absorption of an allergen or following a minimal localized exposure in patients highly sensitized to the allergen. Following limited exposure, a localized form of urticaria also may occur. Regardless of the specific clinical presentation, the reaction occurs when immunologic recognition occurs between IgE molecules and a putative antigen triggering the immediate degranulation of mast cells, which are distributed along the dermal blood vessels, nerves, and appendages. The release of histamine, complements C3a and C5a, and other vasoactive mediators result in leakage of fluid from dermal capillaries as their endothelial cells contract. This produces the characteristic urticarial lesions described above. Activation of the nearby sensory neurons produces pruritus. Nonimmunologically mediated mast cell degranulation producing an identical urticarial syndrome may also occur, following exposure to any xenobiotic.8

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Pruritus is a common manifestation of urticarial reactions, but it may also be of nonimmunologic origin. Patients with hepatocellular disease frequently suffer from pruritus, which is mediated by the release of bile acids. In addition, in patients with chronic liver disease and obstructive jaundice, pruritus can be caused by central mechanisms, as suggested by elevated central nervous system (CNS) endogenous opioid concentrations. Pruritus can also be caused by topical exposure to the urticating hairs of Tarantula spiders, spines of the stinging nettle plant (Urtica spp), or via stimulation of substance P by certain xenobiotics such as capsaicin.15 Xenobiotics can also evoke a type III immune reaction that causes mast cells to degranulate. The cellular inflammatory response to released chemotactic factors leads to increased vascular permeability.

■ FLUSHING Vasodilation of the dermal arterioles leads to flushing. Flushing can occur following autonomically-mediated vasodilation, as occurs with stress, anger, or exposure to heat, or it can be chemically induced by vasoactive xenobiotics. Those xenobiotics that cause histamine release through a type I hypersensitivity reaction are the most frequent cause of xenobiotic-induced flush. Histamine and saurine poisoning can result from the consumption of scombrotoxic fish, and can produce flushing. Flushing after the consumption of ethanol is common in patients of Asian and Inuit descent and is similar to the reaction following ethanol consumption in patients exposed to disulfiram or similar agents (Chap. 79). The increased production of and inability to efficiently metabolize acetaldehyde, the initial metabolite of ethanol, results in the characteristic syndrome of vomiting, headache, and flushing. Niacin causes flushing through an arachidonic acid–mediated pathway that is generally prevented by aspirin.5,38 Vancomycin if too rapidly infused causes a transient bright red flushing, mediated by histamine. This reaction typically occurs during and immediately after the infusion, and is termed “red man syndrome.” Other nontoxicologic causes of flushing including carcinoid syndrome, pheochromocytoma, mastocytosis, anaphylaxis, medullary carcinoma of the thyroid, pancreatic cancer, and renal carcinoma must be entertained in the flushed patient.17

■ SKIN MOISTURE Xenobiotic-induced diaphoresis may be part of a physiologic response to heat generation or may be pharmacologically mediated following parasympathetic or sympathomimetic xenobiotic use. Because the postsynaptic receptor on the eccrine glands is muscarinic, most muscarinic agonists stimulate sweat production. Sweat most commonly occurs following exposure to cholinesterase inhibitors, such as organic phosphorus compounds, but it may also occur with direct-acting muscarinic agonists such as pilocarpine. Alternatively, antimuscarinic agents, such as belladonna alkaloids or antihistamines, reduce sweating and produce dry skin.

■ METALLIC PIGMENTATION Pigmentary changes can result from the deposition of fine metallic particles. The particles can be ingested and carried to the skin by the blood, or may permeate the skin from topical applications. Argyria, a slate-colored pigmentation of the skin resulting from the systemic deposition of silver particles in the skin, can be localized or widespread. The discoloration tends to be most prominent in areas exposed to sunlight, probably secondary to the fact that silver stimulates melanocyte proliferation. Histologically, fine black granules are found in the basement membrane zone of the sweat glands, blood

vessel walls, the dermoepidermal junction, and along the erector pili muscles (Chap. 99). Gold, which was historically used parenterally in the treatment of rheumatoid arthritis, caused a blue or slate-gray pigmentation known as chrysiasis. The pigmentation is also accentuated in light-exposed areas but, unlike in argyria, sun-protected areas do not histologically demonstrate gold. Also, melanin is not increased in the areas of hyperpigmentation. The hyperpigmentation is probably secondary to the gold itself, but the cause of its distribution pattern remains unknown. Histologically, the gold is distributed in a perivascular pattern in the dermis with granules accentuated at the basement membrane zone of sweat glands. Bismuth produces a characteristic oral finding of the metallic deposition in the gums and tongue known as bismuth lines. Arsenic, which is found in certain pesticides and in contaminated well water, causes cutaneous hyperpigmentation with areas of scattered hypopigmentation. Chronic lead poisoning can produce a characteristic “lead hue” with pallor. Lead also deposits in the gums, causing the characteristic “lead line.” Intramuscular injection of iron can cause staining of the skin, resulting in pigmentation similar to that seen in tattoos, and iron storage problems, known as hemochromatosis, can result in a bronze appearance of the skin.11

SPECIFIC SYNDROMES Dermatology is a specialty whereby visual inspection may allow a rapid diagnosis. Some authors suggest a brief examination prior to a lengthy history due to some of the classic skin conditions with such obvious morphologies that a “doorway diagnosis” can be made. Irrespective of the initial complaint a total body examination with proper lighting needs to be accomplished on all patients. The tools the physician needs are readily available: magnifying glass, glass slide (diascopy), flashlight, alcohol pad to remove scale or makeup, scalpel, and at times a Wood lamp. Universal precautions should always be used. The ability to describe lesions accurately is an important skill, as is the ability to recognize specific patterns. Such abilities help clinicians in their approach to the patient with a rash. Several cutaneous reaction patterns account for the majority of clinical presentations occurring in patients with xenobiotic-induced dermatotoxicity (Table 29–2). Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) (Fig. 29–2) are considered to be related disorders that belong to a spectrum of increasingly severe skin failure.27 Toxic epidermal necrosis is often considered to be the most severe manifestation of the spectrum of syndromes represented by erythema multiforme. Erythema multiforme is characterized by target-shaped, erythematous macules and patches on the palms and soles, as well as the trunk and extremities. The Nikolsky sign, consisting of sloughing of the epidermis when direct pressure is exerted on the skin lesion, is absent. Contact sensitization to sulfonamides, phenytoin, antihistamines, many antibiotics, dinitrochlorobenzene (DNCB), diphenylcyclopropenone (DPCP), isopropyl-p-phenylenediamine (IPPD), rosewood, and urushiol can elicit erythema multiforme. The Stevens-Johnson syndrome is considered to be an overlap reaction with erythema multiforme major when greater than 30% of body surface area is involved. However, although erythema multiforme shares many clinical characteristics with SJS/TEN, many now consider it as a distinct disease. It should also be noted that SJS occurs predominantly in children and TEN occurs in all age groups. Toxic epidermal necrolysis is a rare, life-threatening dermatologic emergency with a 30% mortality. Its incidence is estimated at 0.4 to 1.2 cases per 1 million population, and xenobiotics are causally implicated in 80% to 95% of the cases. The cutaneous reaction pattern is characterized by tenderness and erythema of the skin and mucosa, followed by

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TABLE 29–2. Xenobiotics Commonly Associated with Various Cutaneous Reaction Patterns Acneiform ACTH Amoxapine Androgens Azathioprine Bromides Corticosteroids Danazol Dantrolene Halogenated hydrocarbons Iodides Isoniazid Lithium Oral contraceptives Phenytoin Alopecia Anticoagulants Antineoplastics Hormones NSAIDs Phenytoin Radiation Retinoids Selenium Thallium Contact dermatitis Bacitracin Balsam of Peru Benzocaine Carba mix Catechol Cobalt Diazolidinyl urea Ethylenediamine dihydrochloride Formaldehyde Fragrance mix Imidazolidinyl urea Lanolin Methylchloroisothiazolinone/ methylisothiazolinone Neomycin sulfate Nickel

p-Tert-butylphenol formaldehyde resin p-Phenylenediamine Quaternium-15 Rosin (colophony) Sesquiterpene lactones Thimerosal Erythema multiforme Antimicrobials Allopurinol Barbiturates Carbamazepine Cimetidine Codeine Gold Glutethimide Ethinyl estradiol Furosemide Ketoconazole Methaqualone NSAIDs Nitrogen mustard Phenolphthalein Phenothiazines Phenytoin Sulfonamides Thiazides Exfoliative Dermatitis Allopurinol Anticonvulsants Calcium channel blockers Cimetidine Dapsone Gold Lithium Penicillins Quinidine Sulfonamides Vancomycin Fixed drug eruptions Acetaminophen Allopurinol

Barbiturates Captopril Carbamazepine Chloral hydrate Chlordiazepoxide Chlorpromazine Erythromycin D-Penicillamine Fiorinal Gold Griseofulvin Lithium Phenacetin Phenolphthalein Methaqualone Metronidazole Minocycline Naproxen NSAIDs Oral contraceptives Salicylates Sulindac Maculopapular reactions Antimicrobials Anticonvulsants Antihypertensive agents Antiinflammatory agents Photosensitivity reactions Amiodarone Benoxaprofen Chlorpromazine Ciprofloxacin Dacarbazine 5-Fluorouracil Furosemide Griseofulvin Hydrochlorothiazide Hematoporphyrin (Porphyria) Levofloxacin Nalidixic acid Naproxen Piroxicam

Psoralen Sulfanilamide Tetracyclines Tolbutamide Vinblastine Photoirritant contact dermatitis Celery Dispense blue 35 Eosin Fig Fragrance materials Lime Parsnip Pitch Toxic epidermal necrolysis Allopurinol L-Asparaginase Amoxapine Bactrim Mithramycin Nitrofurantoin NSAIDs Penicillin Phenytoin Prazosin Pyrimethamine–sulfadoxine Streptomycin Sulfonamides Sulfasalazine Vasculitis Allopurinol Cefaclor Cimetidine Gold Hydralazine Levamisole Minocycline NSAIDs Penicillamine Penicillin Phenytoin Propylthiouracil

Vesiculobullous Amoxapine Barbiturates Captopril Carbon monoxide Chemotherapeutics Dipyridamole Furosemide Griseofulvin Penicillamine Penicillin Rifampin Sulfonamides Xanthoderma Generalized Hepatic jaundice (Acetominophen, isoniazid) Hemolytic jaundice Carotenoderma Canthaxanthin (tanning pills) Dipyridamole (yellow compound) Quinacrine Localized Dihydroxyacetone (spray tanning) Picric acid Methylenedianiline Phenol, topical Nail changes Beau lines (Onychodystrophy) & Mees lines (Leukonychia) Cyclophosphamide Doxorubicin Hydroxyurea Paclitaxel

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B

C

FIGURE 29–2. Toxic Epidermal Necrolysis (A) Early eruption. Erythematous dusky red macules (flat atypical target lesions) that progressively coalesce and show epidermal detachment. (B) Advanced eruption. Blisters and epidermal detachment have led to large confluent erosions. (C) Full-blown epidermal necrolysis characterized by large erosive areas reminiscent of scalding. (Reproduced, with permission, from Wolff K, Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Lefferell DJ. Fitzpatrick’s Dermatology in General Medicine., 7th ed. McGraw-Hill, 2008.)

extensive cutaneous and mucosal exfoliation. The incidence is higher in HIV-infected patients with advanced disease. 27,36 There is general agreement that the keratinocyte cell death in TEN is the result of apoptosis not necrosis. Furthermore, apoptosis is suggested based on electronic microscopic studies with DNA fragmentation analysis.27 Greater than 220 xenobiotics are implicated in causing TEN. Classically, the eruption is painful and occurs within days of the exposure to the implicated xenobiotic(s). The eruption is preceded by malaise, headache, abrupt onset of fever, myalgia, arthralgia, nausea, vomiting, diarrhea, chest pain, or cough. Initially, a macular erythema develops that subsequently becomes raised and morbilliform (“measles-like”). The face, neck, and central trunk are usually the initial areas affected. The disease generally progresses to involve the extremities and with the remainder of the body the lesions progress over a period of 2 to 15 days. Individual lesions are reminiscent of target lesions because of their dusky centers. The entire thickness of the epidermis, including the nails, becomes necrotic and may slough off. The mucosal surfaces of the lips, oropharynx, conjunctivae, vagina, urethra, and anus may show erythema and sloughing. This mucositis precedes the skin lesions by a few days.30 A Nikolsky sign may occur,3 and although suggestive, is not pathognomonic of TEN as it occurs in a variety of other dermatoses, including pemphigus vulgaris. If the diagnosis is suspected, a biopsy should be performed and treatment initiated immediately. The histopathology typically shows partial- or full-thickness epidermal necrosis, with subepidermal bullae with a sparse infiltrate, and vacuolization with numerous dyskeratotic keratinocytes along the dermoepidermal junction adjacent to the necrotic epidermis. Cytotoxic T lymphocytes are the main effector cells and experimental evidence points to involvement of both the Fas-Fas ligand and perforin/granzyme pathways. Anemia and lymphopenia are common, neutropenia portends a poor prognosis. Early stages consist mainly of CD8 lymphocytes in the epidermis and blisters containing CD4 lymphocytes in dermis. Removal of the inciting xenobiotic as soon as possible is critical to survival. Patients with TEN related to a xenobiotic with a long half-life have poorer prognosis, and should be transferred to a burn or other specialized center for sterile wound care. The use of porcine xenografts or human skin allografts including amniotic membrane transplantation

has been utilized and is a widely accepted therapy.29 Although glucocorticoids are not generally recommended, there is emerging support for the use of immunosuppressive or immunomodulatory agents, such as intravenous immunoglobulins, cyclophosphamide, and cyclosporine.29 Reported mortality is as great as 30%, particularly in patients with gastrointestinal and tracheobronchial involvement.36 The “acute skin failure” patients have metabolic abnormalities, sepsis, multiorgan failure, pulmonary emboli and gastrointestinal hemorrhages. The major causes of sepsis is S. aureus and P. aerogenosa. In a patient with SJS/TEN with ophthalmologic complications early ophthalmologic consultation is necessary because blindness is a potential complication. Simulators of TEN include staphylococcal scalded skin syndrome; linear IgA dermatosis: paraneoplastic pemphigus; acute graft versus host disease; drug-induced pemphigoid and pemphigus vulgaris and acute generalized exanthematous pustulosis; discussion of these entities is beyond the scope of the chapter.

■ BLISTERING REACTIONS Xenobiotic-related cutaneous blistering reactions may be clinically indistinguishable from autoimmune blistering reactions, such as pemphigus vulgaris or bullous pemphigoid (Fig. 29–3). Certain topically-applied xenobiotics cause blistering by disrupting the anchoring filaments of basal cell desmosomes at the dermal–epidermal junction. In high concentrations, the xenobiotics can lead to necrosis of both skin and mucous membranes. Other xenobiotics cause a similar reaction pattern mediated by the production of antibody directed against the cells at the dermal–epidermal junction (Table 29–3). A number of medications, many of which contain a “thiol group” such as penicillamine and captopril, can induce either pemphigus, a superficial blistering disorder in which the blister is at the level of the stratum corneum, or pemphigus vulgaris, in which blistering occurs at the suprabasilar level (see Fig. 29–1). Other xenobiotics, such as diuretics, produce the tense bullae that resemble pemphigoid. Immunofluorescence studies might show epidermal intracellular immunoglobulin deposits at the dermal–epidermal junction. Treatment options include immunosuppressants. The reaction may persist for up to 6 months after the offending xenobiotic is withdrawn.

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FIGURE 29–3. Pemphigus vulgaris. (A) Flaccid blisters. (B) Oral erosions. (Part A, contributed by Lawrence Lieblich, MD. Part B, reproduced, with permission, from Wolff K, Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Lefferell D. Fitzpatrick’s Dermatology in General Medicine, 7th ed. McGraw-Hill, 2008.)

“Coma bullae” are flaccid bullae that occur occasionally in patients with sedative-hypnotic overdoses, particularly phenobarbital, or carbon monoxide poisoning. Although these blisters are thought to result predominantly from pressure-induced epidermal necrosis, they occasionally occur in non–pressure-dependent areas, suggesting a systemic mechanism. An intraepidermal or subepidermal blister may occur. There is accompanying eccrine duct and gland necrosis.

■ BULLOUS DRUG ERUPTIONS Multiple, large, ill-defined, dull, purplish-livid patches sometimes accompanied by large flaccid blisters characterize these eruptions. Typical locations include acral extremities, genitals, and intertriginous sites, and

this process may be confused with TEN if widely confluent. However, bullous drug eruptions spare the mucous membranes. This reaction pattern is generally not life-threatening. Bullous fixed-drug reactions result from exposure to diverse medications such as angiotensin converting enzyme inhibitors and a multitude of antibiotics. The drug hypersensitivity syndrome known as drug rash with eosinophilia and systemic symptoms (DRESS) can be severe and potentially life threatening. The skin may be involved with systemic xenobioticinduced immunologic diseases. The hypersensitivity syndromes are characterized by the triad of fever, skin eruption, and internal organ involvement.20 The frequency has been estimated between 1 in 1000 to 1 in 10,000 with anticonvulsants or sulfonamide antibiotic exposures and usually begins within 2 to 6 weeks after the initial exposure.

TABLE 29–3. Differential Diagnosis of Xenobiotic-induced Blistering Disorders Disease

Fever

Mucositis

Morphology

Onset

Miscellaneous

Xenobiotic-induced pemphigoid

No

Rare

Acute

Staphylococcal scalded skin syndrome Xenobiotic-induced pemphigus

Yes

Absent

No

Usually absent

Xenobiotic-triggered pemphigus

No

Present

Tense bullae (sometimes hemorrhagic) Erythema, skin tenderness, periorificial crusting Erosions, crusts, patchy erythema (resembles pemphigus foliaceous) Mucosal erosions, flaccid bullae

Paraneoplastic pemphigus

No Yes

Polymorphous skin lesions, flaccid bullae Morbilliform rash, bullae and erosions Superficial pustules Tense, subepidermal bullae

Gradual

Acute graft-versus host disease

Present (usually severe) Present

Diuretics a common cause, especially spironolactone; often pruritic Affects children < 5 years, adults on dialysis, and those on immunosuppressive therapy Commonly caused by penicillamine and other ‘’thiol’’ drugs; resolves after inciting inciting agent is discontinued Caused by ‘’non-thiol’’ drugs; persists after discontinuation of drug; may require long-term immunosuppressive therapy Resistant to treatment; associated with malignancy, especially lymphoma Closely resembles TEN

Acute generalized exanthematous Yes Xenobiotic-induced linear IgA No bullous dermatosis

Rare Rare

Acute Gradual

Gradual

Acute Acute Acute

Self-limiting on discontinuation of drug Vancomycin is most commonly implicated

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FIGURE 29–4. A patient with a hypersensitivity syndrome associated with phenytoin. He has a symmetric, bright red, and exanthematous eruption, confluent in some sites. The patient had associated lymphadenopathy. (Reproduced with permission from Klaus Wolff; Richard Allen Johnson. Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology, 6e, p. 22-10. McGraw-Hill, 2009.)

Fever, malaise, pharyngitis and cervical lymphodenpathy are the usual presenting clinical findings. Atypical lymphocytes and eosinophilia, occur initially. The exanthem is generalized and conjunctivitis and angioedema may occur. One-half of these patients have hepatitis, interstitial nephritis, vasculitis, CNS manifestations (including encephalitis, aseptic meningitis), interstitial pneumonitis, ARDS, and autoimmune hypothyroidism. Colitis with bloody diarrhea and abdominal pain may occur. The aromatic anticonvulsants, allopurinol, sulfonamide antibiotics, and dapsone are the common xenobiotics that induce this syndrome. Treatment is supportive.26,39 Although the role of systemic corticosteroids is controversial; most clinicians start prednisone at a dose of 1–2 mg/kg/d if symptoms are severe.

■ EXFOLIATIVE ERYTHRODERMAS Exfoliative erythrodermic eruptions (Fig. 29–4) can result from any xenobiotic and are characterized by widespread erythema and scale with the potential for multisystem organ failure. The process may persist for months. Such patients require aggressive fluid and electrolyte repletion and nutritional support. Boric acid toxicity causes a bright red eruption (“lobster skin”), followed usually within 1 to 3 days by a generalized exfoliation.

■ VASCULITIS Xenobiotic-induced vasculitis (Fig. 29–5) comprises 10% of acute cutaneous vasculitides. It generally occurs from 7 to 21 days after exposure to the xenobiotic and is a small vessel disease. Hypersensitivity vasculitis is characterized by purpuric, nonblanching macules that usually become raised and palpable. The purpura tends to occur predominantly on gravity-dependent areas, including the lower extremities, feet, and buttocks. Sometimes the reaction pattern can have edematous purpuric wheals (urticarial vasculitis), hemorrhagic bullae, or ulcerations. The

FIGURE 29–5. Leukocytoclastic vasculitis in a patient with mixed cryoglobulinemia manifested as palpable purpura and acrocyanosis. Patient with tuberculosis, positive antinuclear antibody, and hepatitis.(Reproduced, with permission, from Wolff K, Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Lefferell DJ. Fitzpatrick’s Dermatology in General Medicine, 7th ed. McGraw-Hill, 2008.)

underlying cytopathology consistently shows a leukocytoclastic vasculitis, which is characterized by fibrin deposition in the vessel walls. There is a perivascular infiltrate with intact and fragmented neutrophils that appear as black dots, known as “nuclear dust,” visible only by electron microscopy. This reaction pattern may be limited to the skin, or may be more serious and involve other organ systems, particularly the kidneys, joints, liver, lungs, and brain. The purpura results from circulating immune complexes, which form as a result of a hypersensitivity to a xenobiotic. Treatment consists of withdrawing the putative agent and systemic corticosteroid therapy. Purpura Purpura is the multifocal extravasation of blood into the skin or mucous membranes (Fig. 29–6). Ecchymoses are, therefore, considered to be purpuric lesions. Cytotoxic medications that either diffusely suppress the bone marrow or specifically depress platelet counts below 30,000/mm3, predispose to purpuric macules. Xenobiotics that interfere with platelet aggregation, such as, aspirin, clopidogrel, ticlopidine, and valproic acid, may cause purpura, as may thrombolytics. Anticoagulants, such as heparin and warfarin, may also result in purpura (Chaps. 24 and 59). Anticoagulant Skin Necrosis Skin necrosis from warfarin, low molecular weight heparin, or unfractionated heparin usually begins 3 to 5 days after the initiation of treatment (Fig. 29–7). The estimated risk is 1 in 10,000 persons. It is four times higher in women especially if obese with peaks in sixth to seventh decades. The necrosis is secondary to thrombus formation in vessels of the dermis and subcutaneous fat. There may be blisters, ecchymosis, ulcers, and massive subcutaneous necrosis, usually in areas of abundant subcutaneous fat, such as the breasts, buttocks, abdomen, thighs, and calves. It may be associated with protein C or S deficiency, anticardiolipin antibody syndrome, as well as Factor V Leiden mutations.28 Of note is acute generalized exanthematous pustulosis from dalteparin is reported.21 Treatment involves stopping the medication, administration of vitamin K and, if coumarin induced, changing to heparin. Treatment may include fresh frozen plasma and Protein C. Skin grafting may be necessary if full thickness necrosis occurs.

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FIGURE 29–7. Skin necrosis in a patient after 4 days of warfarin therapy. (Reproduced, with permission, from Wolff K, Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Lefferell DJ. Fitzpatrick’s Dermatology in General Medicine, 7th ed. McGraw-Hill, 2008.) FIGURE 29–6. Purpura. Non-blanching red erythematous papules and plaques (palpable purpura) on the legs, representing leukocytoclastic vasculitis. (Reproduced, with permission, from Wolff K, Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Lefferell DJ. Fitzpatrick’s Dermatology in General Medicine, 7th ed. McGraw-Hill, 2008.)

■ CONTACT DERMATITIS When a xenobiotic comes in contact with the skin, it can result in either an allergic contact dermatitis or an irritant dermatitis. Contact dermatitis is characterized by inflammation of the skin with spongiosis (intercellular edema) of the epidermis that results from the interaction of a xenobiotic with the skin. Erythema, induration, pruritus, or blistering may be noted on areas in direct contact with the xenobiotic, while the remaining areas are spared. Allergic contact dermatitis fits into the classic delayed hypersensitivity, or type IV, immunologic reaction. The development of this reaction requires prior sensitization to an allergen, which, in most cases, acts as a hapten by binding with an endogenous molecule that is then presented to an appropriate immunologic T cell. Upon reexposure, the hapten diffuses to the Langerhans cell, is chemically altered, bound to an HLA-DR, and the complex is expressed on the Langerhans cell surface. This complex interacts with primed T cells either in the skin or lymph nodes, causing the Langerhans cells to make interleukin-1 and the activated T cells to make interleukin-2 and interferon. This subsequently activates the keratinocytes to produce cytokines and eicosanoids that activate mast cells and macrophages, leading to an inflammatory response (Fig. 29–8).19 Many allergens are associated with contact dermatitis; a complete list is beyond the scope of this chapter. Among the most common plantderived sensitizers are urushiol (poison ivy), sesquiterpene lactone (ragweed), and tuliposide A (tulip bulbs). Metals, particularly nickel, are commonly implicated in contact dermatitis. Several industrial chemicals, such as the thiurams (rubber) and urea formaldehyde resins

(plastics), account for the majority of occupational contact dermatitis. Medications, particularly topical medications such as neomycin, commonly cause contact dermatitis. Management strategies commonly employed are outlined in Table 29–4. Irritant dermatitis, although clinically indistinguishable, results from direct damage to the skin and does not require prior antigen sensitization. Still, the inflammatory response to the initial mild insult is the cause of the majority of the damage. Irritant xenobiotics include acids, bases, solvents, and detergents, many of which, in their concentrated form or following prolonged exposure, can cause direct cellular injury. The specific site of damage varies with the chemical nature of the xenobiotic. Many xenobiotics can affect the lipid membrane of the keratinocyte, whereas others can diffuse through the membrane, injuring the lysosomes, mitochondria, or nuclear components. When the cell membrane is injured, phospholipases are activated and affect the release of arachidonic acid and the synthesis of eicosanoids. The second-messenger system is then activated, leading to the expression of genes and the synthesis of various cell surface molecules and cytokines. Interleukin-1 is secreted, which can activate T cells directly and indirectly by stimulation of granulocytemacrophage colony-stimulating factor production. Treatment is similar to contact dermatitis.

■ PHOTOSENSITIVITY REACTIONS Photosensitivity may be caused by topical or systemic xenobiotics. Nonionizing radiation, particularly to ultraviolet A (320–400 nm) and less often to ultraviolet B (280–320 nm) are the wavelengths that commonly cause the photosensitivity diagnosis. There are generally two types of xenobiotic related reaction patterns: phototoxic and photoallergic.25 Phototoxic drug reactions occur within 24 hours of the first dose and are dose-related. These reactions result from direct tissue injury caused by the absorption by the xenobiotics of activating

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(4) Secondary exposure (1) Primary exposure

Sensitized T-cell

therapy, including topical or, if needed, systemic corticosteroids. The patient should be advised to avoid sun exposure or wear a sunscreen that blocks both ultraviolet A and ultraviolet B with a sun protection factor (SPF) of 15 or greater and is devoid of para-aminobenzoic acid (PABA), a sensitizing agent to many patients.

■ SCLERODERMA-LIKE REACTIONS A number of environmental xenobiotics are associated with a localized or diffuse scleroderma-like reactions. Sclerodermatous LC changes refer to a tightened indurated surMacrophage face change of the skin. These typically occur MH (2) on the face, hands, forearms, and trunk and C II are three times more common in women. This may be accompanied by facial telangiLymphocytes ectasias and Raynaud syndrome. Raynaud syndrome consists of skin color changes of white, blue, and red accompanied by intense pain with exposure to cold, and can cause (3) T cell response acral ulcerations, if untreated. The fibrotic creates sensitized T-cell process usually does not remit with removal FIGURE 29–8. Contact dermatitis. (1) Causative xenobiotic, typically a hapten of < 500 daltons, diffuses through stratum of the external stimulus. The association corneum and binds to receptor on Langerhans cell (LC). (2) The antigen is processed with major histocompatibility comof scleroderma-like reactions with polyviplex II (MHC II) receptor site, presented to T-helper lymphocytes, and carried through the lymphatics to regional lymph nyl chloride manufacture is likely related to nodes. (3) There it undergoes the sensitization phase by producing memory, effector, and suppressor T lymphocytes. exposure to vinyl chloride monomer. Similar (4) On reexposure to the same, or to a cross-reactive antigen, the LC represents the antigen to T lymphocytes ( ), reports of this syndrome are associated with which are now sensitized. This initiates an inflammatory process that appears as indurated, scaly patches. NK, Natural Killer. exposure to trichloroethylene and perchlorethylene, which are structurally similar to vinyl chloride. Epoxy resins, silica, and organic solvents have been implicated as environmental causes. The xenobiotics bleomycin, carbidopa, pentazocine are causative. wavelengths of nonionizing radiation. The clinical findings include In Spain, patients exposed to imported rapeseed oil mixed with an erythema, edema, and vesicles in a light-exposed distribution, and aniline denaturant developed widespread cutaneous sclerosis. This resemble an exaggerated sunburn that can last for days to weeks became known as the “toxic oil syndrome.” A similar syndrome, fol(Fig. 29–9). Photoallergic reactions occur less commonly, may occur lowing ingestion of impure L-tryptophan as a dietary supplement, used following even small exposures, and are characterized by lichenoid as a sleeping aid resulted in the eosinophilia myalgia syndrome, which papules or eczematous changes on exposed areas. These are type IV is characterized by myalgia, paralysis, edema, arthralgias, alopecia, urtihypersensitivity reactions that develop in response to a xenobiotic caria, mucinous yellow papules, and erythematous plaques.33 that has been altered by absorption of nonionizing radiation, acting as a hapten and eliciting an immune response on first exposure. Only on recurrent exposure do to the lesions typically develop. Photoallergic ■ HAIR LOSS reactions can be diagnosed by the use of patch tests. Both photoAnagen effluvium, hair loss during the anagen stage of the growth toxic and photoallergic reactions are managed with symptomatic cycle, is caused by interruption of the rapidly dividing cells of the hair matrix producing rapid hair loss. Telogen effluvium, or toxicity during the resting stage of the cycle, might not produce hair loss for 2 to 4 weeks. Anagen toxicity is the most common mechanism and occurs with chemotherapeutics such as doxorubicin, cyclophosphamide, TABLE 29–4. Overview of Treatment of Acute Contact Dermatitis vincristine, and thallium exposures.35 Many antineoplastics reduce the mitotic activity of the rapidly dividing hair matrix cells, leading to Avoidance the formation of a thin shaft that breaks easily topical minoxidil may hasten resolution of the alopecia. Thallium, a toxin classically associDrying agents, such as topical aluminum sulfate/calcium acetate: if weeping ated with hair loss, causes alopecia by two mechanisms. Thallium Emollients: lichenified lesions distributes intracellularly, like potassium, altering potassium-mediated Corticosteroids, topical, rarely systemic: for severe reactions processes and thereby disrupting protein synthesis. By binding sulfhyCalcineurin inhibitiors dryl groups, thallium also inhibits the normal incorporation of cysteine Cyclosporin (oral) into keratin. Selenium may produce alopecia by similar mechanisms. Thallium toxicity results in alopecia 1 to 4 weeks after exposure. Within Tacrolimus or picrolimus 4 days of exposure a hair mount observed using light microscopy will Phototherapy, UVA or UVB demonstrate tapered or bayonet anagen hair with a characteristic

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FIGURE 29–10. Presence of proximal indented Beau line and distal band of leukonychia due to cyclophosphamide 3 months after bone marrow transplantation. (Reproduced, with permission, from Wolff K, Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Lefferell DJ. Fitzpatrick’s Dermatology in General Medicine, 7th ed. McGraw-Hill, 2008.)

FIGURE 29–9. Phototoxicity associated with a heterocyclic antidepressant. Note erythema and edema on sun-exposed areas and sparing of sun-protected chest and shaded upper lip and neck. (Photo contributed by Dr. Adrian Tanew. Reproduced, with permission, from Wolff K, Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Lefferell DJ. Fitzpatrick’s Dermatology in General Medicine, 7th ed. McGraw-Hill, 2008.)

bandlike black pigmentation at the base. Seeing this anagen effect can reveal the timing of exposure (Chap. 100). Soluble barium salts, such as barium sulfide, are applied topically as a depilatory to produce localized hair loss. The mechanism of hair loss is undefined.

■ NAILS The nail consists of a horny layer the “nail plate” and four specialized epithelia: proximal nail fold, nail matrix, nail bed and hyponychium. The nail matrix consists of keratinocytes, melanocytes, Langerhans cells and Merkel cells. Nail hyperpigmentation occurs for unclear reasons, but may be caused by focal stimulation of melanocytes in the nail matrix. The pigment deposition can be longitudinal, diffuse, or perilunar in orientation, and typically develop several weeks after chemotherapy.35 Black darkskinned patients are more commonly affected due to a higher concentration of melanocytes. Cyclophosphamide, doxorubicin, hydroxyurea, and bleomycin are most often implicated in nail hyperpigmentation, and the pigmentation generally resolves with cessation of therapy. Nail findings may serve as important clues to xenobiotic exposures that have occurred in the recent past. Matrix keratinization in a programmed and scheduled pattern, leads to the formation of the nail plate. Certain changes in nails, such as Mees lines and Beau lines, result from a temporary arrest of the proximal nail matrix proliferation. These lines can be used to predict the timing of a toxic exposure because of the reliability of rate of growth of the nails at approximately 0.1 mm per day. Mees lines, first described in 1919 in the setting of

arsenic poisoning, can be used to approximate the date of the insult by the position of growth of the Mees line a patterned leukonychia (not indentation) causing transverse white lines.23 Multiple Mees lines suggests multiple exposures. Arsenic, thallium, doxorubicin, vincristine, cyclophosphamide, methotrexate, and 5 fluorouracil are examples of xenobiotics that cause Mees lines, but Mees lines may be noted after any period of critical illness such as sepsis or trauma. Beau lines, or onychodystrophy, are transverse grooves or indentations that are similar to Mees lines in origin and etiology (Fig. 29–10).

SUMMARY The integument is constantly exposed to both topical and systemic xenobiotics and the exposure may result in reactive dermatoses. Prompt attention and diagnosis is imperative in treating such exposures. The skin, hair, and nails may provide invaluable clues about the route and nature of the xenobiotic. With a careful history, clinical examination, and appropriate biopsy when indicated the etiology and nature of the reaction can be ascertained and treatment initiated in a timely and an effective manner.

ACKNOWLEDGMENT Dr. Dina Began contributed to this chapter in previous editions.

REFERENCES 1. Amar SM, Dreskin SC. Urticaria. Prim Care. 2008;35:141-57, vii–viii. 2. Baden HP. Biology of the epidermis and pathophysiology of psoriasis and certain ichthyosiform dermatoses. In: Soter, Nicholas A and Baden, Howard P. eds. Pathophysiology of Dermatologic Diseases. 2nd ed. New York: McGraw-Hill; 1991:131-158. 3. Bastuji-Garin S, Rzany B, Stern RS, Shear NH, Naldi L, Roujeau JC. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol. 1993;129:92-96. 4. Bertolini JC. Hydrofluoric acid: a review of toxicity. J Emerg Med. 1992;10:163-168.

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5. Brown BG. Expert commentary: niacin safety. Am J Cardiol. 2007;99:32C-34C. 6. Burgess JL, Kirk M, Borron SW, Cisek J. Emergency department hazardous materials protocol for contaminated patients. Ann Emerg Med. 1999;34: 205-212. 7. Cartotto RC, Peters WJ, Neligan PC, Douglas LG, Beeston J. Chemical burns. Can J Surg. 1996;39:205-211. 8. Clark S, Camargo CA Jr. Epidemiology of anaphylaxis. Immunol Allergy Clin North Am. 2007;27:145-63,v. 9. Czerwinski SE, Skvorak JP, Maxwell DM, Lenz DE, Baskin SI. Effect of octanol: water partition coefficients of organophosphorus compounds on biodistribution and percutaneous toxicity. J Biochem Mol Toxicol. 2006; 20:241-246. 10. Fartasch M, Diepgen TL: The barrier function in atopic dry skin. Disturbance of membrane-coating granule exocytosis and formation of epidermal lipids? Acta Derm Venereol Suppl (Stockh). 1992;176:26-31. 11. Granstein RD, Sober AJ. Drug- and heavy metal-induced hyperpigmentation. J Am Acad Dermatol. 1981;5:1-18. 12. Groscurth P. Anatomy of sweat glands. Curr Probl Dermatol. 2002;30:1-9. 13. Guy RH, Hadgraft J. Physicochemical aspects of percutaneous penetration and its enhancement. Pharm Res. 1988;5:753-758. 14. Hadgraft J, Lane ME. Skin permeation: the years of enlightenment. Int J Pharm. 2005;305:2-12. 15. Harvell J, Bason M, Maibach H. Contact urticaria and its mechanisms. Food Chem Toxicol. 1994;32:103-112. 16. Haught JM, Patel S, English JC 3rd. Xanthoderma: a clinical review. J Am Acad Dermatol. 2007;57:1051-1058. 17. Izikson L, English JC 3rd, Zirwas MJ. The flushing patient: differential diagnosis, workup, and treatment. J Am Acad Dermatol. 2006;55:193-208. 18. Duragesic [package insert]. Janssen, division of Ortho-McNeil-Janssen Pharmaceuticals. Titusville, New Jersey. 2008. 19. Kligman AM. The spectrum of contact urticaria. Wheals, erythema, and pruritus. Dermatol Clin. 1990;8:57-60. 20. Knowles SR, Shear NH. Recognition and management of severe cutaneous drug reactions. Dermatol Clin. 2007;25:245-53,viii. 21. Komericki P, Grims R, Kranke B, Aberer W. Acute generalized exanthematous pustulosis from dalteparin. J Am Acad Dermatol. 2007;57:718-721. 22. Lebwohl M, Herrmann LG. Impaired skin barrier function in dermatologic disease and repair with moisturization. Cutis. 2005;76:7-12. 23. Mees RA. Een verschijnsel bij polyneuritis arsenicosa. Ned Tijdsch Geneeskd. 1919;1:391-396.

24. Mihm MC, Kibbi AG, Wolff K. Basic Pathologic Reactions of the Skin. In: Fitzpatrick TB, Wolff K, eds. Fitzpatrick’s Dermatology in General Medicine. 7th ed. New York: McGraw-Hill Medical; 2008. 25. Morison WL. Clinical practice. Photosensitivity. N Engl J Med. 2004;350:1111-1117. 26. Morkunas AR, Miller MB. Anticonvulsant hypersensitivity syndrome. Crit Care Clin. 1997;13:727-739. 27. Pereira FA, Mudgil AV, Rosmarin DM. Toxic epidermal necrolysis. J Am Acad Dermatol. 2007;56:181-200. 28. Peterson CE, Kwaan HC. Current concepts of warfarin therapy. Arch Intern Med. 1986;146:581-584. 29. Prasad JK, Feller I, Thomson PD. Use of amnion for the treatment of Stevens-Johnson syndrome. J Trauma. 1986;26:945-946. 30. Revuz J, Roujeau JC, Guillaume JC, Penso D, Touraine R. Treatment of toxic epidermal necrolysis. Creteil’s experience. Arch Dermatol. 1987;123: 1156-1158. 31. Riviere JE, Brooks JD. Prediction of dermal absorption from complex chemical mixtures: incorporation of vehicle effects and interactions into a QSPR framework. SAR QSAR Environ Res. 2007;18:31-44. 32. Scheindlin S. Transdermal drug delivery: past, present, future. Mol Interv. 2004;4:308-312. 33. Silver RM, Heyes MP, Maize JC, Quearry B, Vionnet-Fuasset M, Sternberg EM. Scleroderma, fasciitis, and eosinophilia associated with the ingestion of tryptophan. N Engl J Med. 1990;322:874-881. 34. Stenn KS, Paus R. Controls of hair follicle cycling. Physiol Rev. 2001;81: 449-494. 35. Susser WS, Whitaker-Worth DL, Grant-Kels JM. Mucocutaneous reactions to chemotherapy. J Am Acad Dermatol. 1999;40:367-98. 36. Viard I, Wehrli P, Bullani R, et al. Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science. 1998;282:490-493. 37. Wester RC, Maibach HI. Percutaneous absorption of drugs. Clin Pharmacokinet. 1992;23:253-266. 38. Wilkin JK. The red face: flushing disorders. Clin Dermatol. 1993;11: 211-223. 39. Wolverton SE. Update on cutaneous drug reactions. Adv Dermatol. 1997;13:65-84. 40. Zugerman C. Chloracne. Clinical manifestations and etiology. Dermatol Clin. 1990;8:209-213.

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REPRODUCTIVE AND PERINATAL PRINCIPLES Jeffrey S. Fine Reproductive and perinatal principles in toxicology are derived from many areas of basic science and are applied to many aspects of clinical practice. This chapter reviews several principles of reproductive medicine that have implications for toxicology: the physiology of pregnancy and placental xenobiotic transfer, the effects of xenobiotics on the developing fetus and the neonate, and the management of overdose in the pregnant woman. One of the most dramatic effects of exposure to a xenobiotic during pregnancy is the birth of a child with congenital malformations. Teratology, the study of birth defects, has principally been concerned with the study of physical malformations. A broader view of teratology includes “developmental” teratoge ns—agents that induce structural malformations, metabolic or physiologic dysfunction, or psychological or behavioral alterations or deficits in the offspring, either at or after birth.245 Only 4% to 6% of birth defects are related to known pharmaceuticals or occupational and environmental exposures.41,245 Reproductive effects of xenobiotics may occur before conception. Female germ cells are formed in utero; adverse effects from xenobiotic exposure can theoretically occur from the time of a woman’s own intrauterine development to the end of her reproductive years. An example of a xenobiotic that had both teratogenic and reproductive effects is diethylstilbestrol (DES), which caused vaginal and/or cervical adenocarcinoma in some women who had been exposed to DES in utero and also had effects on fertility and pregnancy outcome.23,31 Men generally receive less attention with respect to reproductive risks. Male gametes are formed after puberty; only from that time on are they susceptible to xenobiotic injury. An example of a toxin affecting male reproduction is dibromochloropropane, which reduces spermatogenesis and, consequently, fertility. In general, much less is known about the paternal contribution to teratogenesis.301 Occupational exposures to xenobiotics are potentially important but are often poorly defined. In 2004, it was estimated that there were 41 million women of reproductive age in the workforce.281 Although approximately 90,000 chemicals are used commercially in the United States, only a few thousand industrial and pharmaceutic agents have been specifically evaluated for reproductive toxicity. Many xenobiotics have teratogenic effects when tested in animal models, but relatively few well-defined human teratogens have been identified (Table 30–1).256 Thus, most tested xenobiotics do not appear to present a human teratogenic risk, but most xenobiotics have not been tested.

Some of the presumed safe xenobiotics may have other reproductive, nonteratogenic toxicities. Several excellent reviews and online resources are available.93,209,218,219,245,256 Another type of xenobiotic exposure for a pregnant woman is intentional overdose. Although a xenobiotic taken in overdose may have direct toxicity to the fetus, fetal toxicity frequently results from maternal pulmonary and/or hemodynamic compromise, such as hypoxia or shock, further emphasizing the critical nature of the maternal–fetal dyad. Xenobiotic exposures before and during pregnancy can have effects throughout gestation and may extend into and beyond the newborn period. In addition, the effects of xenobiotic administration in the perinatal period and the special case of delivering xenobiotics to an infant via breast milk deserve special consideration.

PHYSIOLOGIC CHANGES DURING PREGNANCY THAT AFFECT DRUG PHARMACOKINETICS Many physical and physiologic changes that occur during pregnancy affect both absorption and distribution of xenobiotics in the pregnant woman and consequently affect the amount of xenobiotics delivered to the fetus.278 During pregnancy there is delayed gastric emptying, decreased gastrointestinal (GI) motility, and increased transit time through the GI tract. These changes result in delayed but more complete GI absorption of xenobiotics and, consequently, lower peak plasma concentrations. Because blood flow to the skin and mucous membranes is increased, absorption from dermal exposure may be increased. Similarly, absorption of inhaled xenobiotics may be increased because of increased tidal volume and decreased residual lung volume. An increased free xenobiotic concentration in the pregnant woman can be caused by several factors, including decreased plasma albumin, increased binding competition, and decreased hepatic biotransformation, during the later stages of pregnancy. Fat stores increase during the early stages of pregnancy; free fatty acids are released during the later stages and, with them, xenobiotics that are lipophilic and may have accumulated in the lipid compartment. The increased concentration of free fatty acids can compete with circulating free xenobiotic for binding sites on albumin. Other factors may lead to decreased free xenobiotic concentrations. Early in pregnancy, increased fat stores, as well as the increased plasma and extracellular fluid volume, lead to a greater volume of distribution. Increased renal blood flow and glomerular filtration may result in increased renal elimination. Cardiac output increases throughout pregnancy, with the placenta receiving a gradually increasing proportion of total blood volume. Xenobiotic delivery to the placenta may therefore increase over the course of pregnancy. These processes interact dynamically, and it is difficult to predict their net effect. The concentrations of many xenobiotics, such as

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424

Part B

The Fundamental Principles of Medical Toxicology

Table 30–1. Known and Probable Human Teratogens Xenobiotic Amiodarone

Androgens (eg, methyltestosterone, danazol) Alkylating agents (eg, busulfan, chlorambucil, cyclophosphamide, mechlorethamine, nitrogen mustard) Angiotensin converting enzyme inhibitors/angiotensin II type 1 receptor inhibitors (sartans) Carbamazepine

Carbon monoxide Cocaine

Corticosteroids Coumadin (Warfarin)

Diazepam

Diethylstilbestrol (DES)

Ethanol

Fluconazole

Reported Effects

Comments

Transient neonatal hypothyroidism, with or without goiter; hyperthyroidism

Amiodarone contains 39% iodine by weight. Small to moderate risk from 10 weeks to term for thyroid dysfunction. Virilization of the female external genitalia: clitoromegaly, Effects are dose dependent. Stimulates growth of sexlabioscrotal fusion steroid-receptor–containing tissue. Growth retardation, cleft palate, microphthalmia, hypoplastic A 10%–50% malformation rate, depending on the ovaries, cloudy corneas, renal agenesis, malformations of agent. Cyclophosphamide-induced damage requires digits, cardiac defects, other anomalies cytochrome P450 oxidation. Fetal/neonatal death, prematurity, oligohydramnios, neonatal Do not interfere with organogenesis. Significant risk of effects related to chronic fetal hypotension during anuria, IUGR, secondary skull hypoplasia, limb contractures, second/third trimester. If used during early pregnancy, pulmonary hypoplasia can be switched during first trimester.9,10,41 Upslanting palpebral fissures, epicanthal folds, short nose 1% risk for NTD. Risk of other malformations is with long philtrum, fingernail hypoplasia, developmental unquantified, but may be significant for minor delay, NTD128 anomalies. Risk is increased in setting of therapy with multiple anticonvulsants, particularly valproic acid. Mechanism may involve an epoxide intermediate. Highdose folate is recommended to prevent NTD. Cerebral atrophy, mental retardation, microcephaly, With severe maternal poisoning, high risk for neurologic convulsions, spastic disorders, intrauterine/death sequelae; no increased risk in mild exposures. IUGR, microcephaly, neurobehavioral abnormalities, vascular Vascular disruptive effects because of decreased uterine disruptive phenomenon (limb amputation, cerebral blood flow and fetal vascular effects from first trimester infarction, visceral/urinary tract abnormalities) through the end of pregnancy. Risk for major disruptive effects is low (see text). Cleft palate, decreased birth weight (up to 9%) and head Low risk. Most information related to prednisone or circumference (up to 4%) methylprednisolone. Fetal warfarin syndrome: nasal hypoplasia, chondrodysplasia A 10%–25% risk of malformation for first-trimester exposure, 3% risk of hemorrhage, 8% risk of stillbirth. punctata, brachydactyly, skull defects, abnormal ears, Bleeding is an unlikely explanation for effects produced in malformed eyes, CNS malformations, microcephaly, the first trimester. CNS defects may occur during second/ hydrocephalus, skeletal deformities, mental retardation, third trimesters and may be related to bleeding.128,289 spasticity Cleft palate, other anomalies Controversial association, probably low risk.42,77,93 Risk may extend to other benzodiazepines. Also risk for neonatal sedation or withdrawal following maternal use near delivery. A synthetic nonsteroidal estrogen that stimulates estrogen Female offspring: vaginal adenosis, clear cell carcinoma, receptor–containing tissue and may cause misplaced irregular menses, reduced pregnancy rates, increased rate genital tissue with propensity to develop cancer. A of preterm deliveries, increased perinatal mortality and 40%–70% risk of morphologic changes in vaginal spontaneous abortion Male offspring: epididymal cysts, cryptorchidism, hypogonadism, diminished spermatogenesis epithelium. Risk of carcinoma approximately 1/1000 for exposure before the 18th week. Most patients exposed to DES in utero can conceive and deliver normal children. FAS in 4% of offspring of alcoholic women consuming Fetal alcohol syndrome (FAS): pre-/postnatal growth ethanol above 2 g/kg/d (6 oz/d) over the first trimester. retardation, mental retardation, fine motor dysfunction, There may be a threshold for effects, but a safe dose has hyperactivity, microcephaly, maxillary hypoplasia, short not been identified. Can see partial expression or other palpebral fissures, hypoplastic philtrum, thinned upper lips, congenital anomalies (see text). Other effects: increased joint, digit anomalies incidence of spontaneous abortion, premature delivery, and stillbirth; neonatal withdrawal. Brachycephaly, abnormal facies, abnormal calvarial Risk related to high dose (400–800 mg/d), chronic, development, cleft palate, femoral bowing, thin ribs and parenteral use. Single 150-mg oral dose probably safe. long bones, arthrogryposis, and congenital heart disease

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Reproductive and Perinatal Principles

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Table 30–1. Known and Probable Human Teratogens (Continued ) Xenobiotic

Reported Effects

Comments

Indomethacin

Premature closure of the ductus arteriosus; in premature infants, oligohydramnios, anuria, intestinal ischemia

Iodine and iodine-containing products

Thyroid hypoplasia after the 8th week of development

Lead Lithium carbonate Methimazole

Lower scores on developmental tests Ebstein anomaly Aplasia cutis, skull hypoplasia, dystrophic nails, nipple abnormalities, hypo- or hyperthyroidism Hydro-/microcephaly; meningoencephalocele; anencephaly; abnormal cranial ossification; cerebral hypoplasia; growth retardation; eye, ear, and nose malformations; cleft palate; malformed extremities/fingers; reduction in derivatives of first branchial arch; developmental delay288 Normal appearance at birth; cerebral palsy–like syndrome after several months; microcephaly, mental retardation, cerebellar symptoms, eye/dental anomalies

NSAIDs generally labeled as category B. However, there is concern when used after 34 weeks’ gestation and for more than 48 hours and/or immediately prior to delivery. Risk may extend to other NSAIDs. High doses of radioiodine isotopes can additionally produce cell death and mitotic delay. Tissue and organ-specific damage is dependent on the specific radioisotope, dose, distribution, metabolism, and localization. Higher risk when maternal lead is >10 μg/dL. Low risk. Small risk of anomalies or goiter with first-trimester exposure. Hypothyroidism risk after 10 weeks’ gestation. These folate antagonists inhibit dihydrofolate reductase. High rate of malformations. Methotrexate is used to terminate ectopic pregnancies.

Methotrexate, Aminopterin (amethopterin)

Methyl mercury, mercuric sulfide

Methylene blue (intraamniotic injection) Misoprostol

Oxazolidine-2,4-diones (trimethadione, paramethadione)

Penicillamine Phenytoin

Polychlorinated biphenyls

Inhibits enzymes, particularly those with sulfhydryl groups. Of 220 babies born following the Minamata Bay exposure, 13 had severe disease. Mothers of affected babies ingested 9–27 ppm mercury; greater risk with ingestion at 6–8 months’ gestation. In acute poisoning, the fetus is 4–10 times more sensitive than an adult. Pathologically, there is atrophy and hypoplasia of the brain cortex and abnormalities in cytoarchitecture.110,294 Intestinal atresia, hemolytic anemia, neonatal jaundice This xenobiotic was used to identify twin amniotic sacs during amniocentesis.63 Vascular disruptive phenomena (eg, limb reduction defects); Synthetic prostaglandin E1 analog. Effects mostly observed Moebius syndrome (paralysis of 6th and 7th facial nerves) in women after unsuccessful attempts to induce abortion. An 83% risk of at least one major malformation with any Fetal trimethadione syndrome: V-shaped eyebrows; lowexposure; 32% die. Characteristic facial features are set ears with anteriorly folded helix; high-arched palate; associated with chronic exposure. irregular teeth; CNS anomalies; severe developmental delay; cardiovascular, genitourinary, and other anomalies Cutis laxa, hyperflexibility of joints Copper chelator—copper deficiency inhibits collagen synthesis/maturation. Few case reports; low risk. Fetal hydantoin syndrome: microcephaly, mental retardation, Phenytoin has a direct effect on cell membranes and on folate and vitamin K metabolism. May reduce cleft lip/palate, hypoplastic nails/phalanges, characteristic the availability of retinoic acid derivatives or alter the facies—low nasal bridge, inner epicanthal folds, ptosis, genetic expression of retinoic acid. Epoxide intermediate strabismus, hypertelorism, low-set ears, wide mouth may play a role in teratogenesis. Effects seen with chronic exposure. A 5%–10% risk of typical syndrome, 30% risk of partial syndrome. Risks confounded by those associated with epilepsy itself and use of other anticonvulsants. Possible increased risk of developing tumors, in particular, neuroblastoma, although absolute risk is very low. Cola-colored children; pigmentation of gums, nails, and Cytotoxic agent. Body residue can affect subsequent groin; hypoplastic, deformed nails; IUGR; abnormal skull offspring for up to 4 years after exposure. Most cases calcifications followed high consumption of PCB-contaminated rice oil; 4%–20% of offspring were affected.125 (Continued )

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Part B

The Fundamental Principles of Medical Toxicology

Table 30–1. Known and Probable Human Teratogens (Continued ) Xenobiotic

Reported Effects

Comments

Progestins (eg, ethisterone, norethindrone)

Masculinization of female external genitalia

Quinine Radiation, ionizing

Hypoplasia of 8th nerve, deafness, abortion Microcephaly, mental retardation, eye anomalies, growth retardation, visceral malformations

Retinoids (isotretinoin, etretinate, high-dose vitamin A)

Spontaneous abortions; micro-/hydrocephalus; deformities of cranium, ears, face, heart, limbs, liver

Smoking

Placental lesions, IUGR, increased perinatal mortality, increased risk of SIDS, neurobehavioral effects such as learning deficits and hyperactivity.121,230

Streptomycin

Hearing loss

Tetracycline

Yellow, gray-brown, or brown staining of deciduous teeth, hypoplastic tooth enamel

Thalidomide

Limb phocomelia, amelia, hypoplasia, congenital heart defects, renal malformations, cryptorchidism, abducens paralysis, deafness, microtia, anotia NTD, oral clefts, hypospadias, and cardiovascular defects

Progestogens are converted into androgens or may have weak androgenic activity. Stimulates or interferes with sex-steroid receptors. Effects occur only after exposure to high doses of some testosterone-derived progestins and may be at the rate of 40 mm Hg) or metabolic acidosis without an apparently appropriate degree of respiratory compensation (PCO2 100 mg/dL (in the absence of the above)a a Hemodialysis for patients with chronic poisoning is indicated for those with concerning symptoms regardless of salicylate concentrations.

salicylate but also to rapidly correct fluid, electrolyte, and acid–base disorders that will not be corrected by hemoperfusion (HP) alone. The combination of HD and HP in series is feasible and theoretically may be useful for treating patients with severe or mixed overdoses,35 but it is rarely used. Rapid reduction of serum salicylate concentrations in severely poisoned patients has been described with the use of continuous venovenous hemodiafiltration, a technique that may be especially valuable for patients who are too unstable to undergo HD or when HD is unavailable146 (see Chap. 9). A combination of therapies that is both useful and practical is to ensure effective alkalinization with sodium bicarbonate while the patient is waiting for and then while undergoing HD. In one unique case report, a patient who overdosed twice on salicylates within a 2-month period was treated in the first instance with 4 hours of HD but no effective alkalinization and in the second instance with sodium bicarbonate alkalinization but no HD. In both instances, blood concentrations of salicylates were above 65 mg/dL. Although similar decreases in salicylate concentrations were achieved with each technique, the rate of decline during the first 4 hours was faster with alkalinization and HD.63 Combining the two therapies makes sense even if part of the reason for the increased early effectiveness of sodium bicarbonate treatment is related to the rapidity with which it can be achieved compared with the 2 to 4 hours required to institute HD after a patient presents under even the most favorable circumstances.63 Peritoneal dialysis (PD) was sometimes suggested in the past as a simpler extracorporeal procedure for eliminating salicylates in the setting of hemodynamic compromise, coagulopathy, or inability to perform HP or HD. However, PD is only 10% to 25% as efficient as HP or HD and not even as efficient as renal excretion itself. The 24-hour clearance of salicylates with PD is less than the 4-hour clearance of salicylates by HP or HD; therefore, PD is not recommended (see Chap. 9). In a recent animal model of salicylate poisoning, IV infusion of 1.25 g/kg of albumin was accompanied by a 14% decline in median brain salicylate concentration.31 If this effect is achievable in humans, it could (along with rapid NaHCO3 infusions) allow additional time for HD to be instituted.

■ OTHER FORMS OF SALICYLATE Topical Salicylate Methyl Salicylate (Oil of Wintergreen) and Salicylic Acid Topical salicylates, which are used as keratolytics (salicylic acid) or as rubifacients (≤30% methyl salicylate) are rarely responsible for

salicylate poisoning when used in their intended manner because absorption through normal skin is very slow. However, particularly in children, extensive application of topical preparations containing methyl salicylate may result in consequential poisoning.17,143 After 30 minutes of contact time, only 1.5% to 2.0% of a dose is absorbed, and even after 10 hours of contact with methyl salicylate, only 12% to 20% of the salicylates is systemically absorbed.18,120 Heat, occlusive dressings, young age, inflammation, and psoriasis all increase topical salicylate absorption.24 Ingestion of methyl salicylate may be disastrous, but its highly irritating characteristics probably limit most ingestions. When ingested, 1 mL of 98% oil of wintergreen contains an equivalent quantity of salicylate as 1.4 g of aspirin. In a 10-kg child, the minimum toxic salicylate dose of approximately 150 mg/kg body weight can almost be achieved with 1 mL of oil of wintergreen, which contains 140 mg/kg of salicylates for the child (see Chap. 42). In Hong Kong, medicated oils containing methyl salicylate accounted for 48% of acute salicylate poisoning cases treated in one hospital.23 Methyl salicylate is rapidly absorbed from the GI tract and much, but not all, of the ester is rapidly hydrolyzed to free salicylates. Despite rapid and complete absorption, serum concentrations of salicylates are much less than predicted after ingestion of methyl salicylate containing liniment compared with oil of wintergreen.143 Vomiting is common, along with abdominal discomfort. Onset of symptoms usually occurs within 2 hours of ingestion.24 Patients with methyl salicylate exposure have died in less than 6 hours, emphasizing the need for early determinations of salicylate concentrations in addition to frequent testing after such exposures. Bismuth Subsalicylate Bismuth subsalicylate, which is found in the popular medication Pepto Bismol, releases the salicylate moiety in the GI tract, which is subsequently absorbed. Each milliliter of bismuth subsalicylate contains 8.7 mg of salicylic acid.46 After a large therapeutic dose (60 mL), peak salicylate concentrations may reach 4 mg/dL at 1.8 hours after ingestion.46 Patients with diarrhea and infants with colic using large quantities of this antidiarrheal agent may develop salicylate toxicity.91,137 Chronic use should raise concerns for bismuth toxicity (see Chap. 89).

■ PREGNANCY Considered a rare event, salicylate poisoning during pregnancy poses a particular hazard to the fetus because of the acid–base and hematologic characteristics of the fetus and placental circulation. Salicylates cross the placenta and are present in higher concentrations in the fetus than in the mother. The respiratory stimulation that occurs in the mother after toxic exposures does not occur in the fetus, which has a decreased capacity to buffer acid. The ability of the fetus to metabolize and excrete salicylates is also less than in the mother. In addition to its toxic effects on the mother, including coagulation abnormalities, acid– base disturbances, tachypnea, and hypoglycemia, repeated exposure to salicylates late in gestation displaces bilirubin from protein-binding sites in the fetus, causing kernicterus. A case report described fetal demise in a woman who claimed to ingest 50 aspirin tablets per day for several weeks during the third trimester of pregnancy. This raises concerns that the fetus is at greater risk from salicylate exposures than is the mother. Emergent delivery of near-term fetuses of salicylate-poisoned mothers should be considered on a case-by-case basis102 (see Chap. 30).

SUMMARY The initial assessment of a patient who has ingested excessive amounts of salicylates includes a determination of the vital signs, particularly

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Chapter 35

the depth and frequency of respiration as well as the temperature. The clinical presentation of a patient with a salicylate overdose may be characterized by an early onset of nausea, vomiting, abdominal pain, blood-tinged vomitus or gross hematemesis, tinnitus, and lethargy. The presence of hyperventilation, hyperthermia, confusion, coma, seizures, and any other nonspecific neurologic presentation should heighten suspicion of salicylate poisoning (see Tables 35–1 and 35–2). Using a combination of symptoms, signs, and characteristic ABG findings along with the results of point-of-care testing and laboratory studies, the clinician can rapidly confirm a significant salicylate ingestion and then institute immediate alkalinization with sodium bicarbonate; achieve gastric decontamination by orogastric lavage (if indicated), AC, or MDAC (if indicated); and consider the need for HD (or perhaps hemodiafiltration) early in the course of management. In patients with pulmonary and CNS manifestations of salicylate toxicity, the protective nature of hyperventilation in maintaining alkalemia may be disastrously compromised by assisted ventilation unless the clinician is extremely skilled at adjusting the ventilator to ensure hyperventilation, decreased PCO2, and high pH (7.5) at all times. Moreover, any unnecessary delays to HD places the patient at greater risk for morbidity or mortality. Serum and urinary alkalinization with sodium bicarbonate to eliminate salicylates is important even though use of sodium bicarbonate may further complicate electrolyte abnormalities. Maintenance of eukalemia is important to ensure success, and fluid and electrolyte replacement is essential.

ACKNOWLEDGMENT Eddy A. Bresnitz, MD, Donald Feinfeld, MD and Lorraine Hartnett, MD, contributed to this chapter in a previous edition.

REFERENCES 1. Abdallah HY, Mayersohn M, Conrad KA. The influence of age on salicylate pharmacokinetics in humans. J Clin Pharmacol. 1991;31:380-387. 2. Alvan G, Bergman V, Gustafsson L. High unbound fraction of salicylate in plasma during intoxication. Br J Clin Pharmacol. 1981;11:625-626. 3. American Academy of Clinical Toxicology and European Association of Poisons Centers and Clinical Toxicologists. Position statement and practice guidelines on the use of multi-dose activated charcoal in the treatment of acute poisoning. J Toxicol Clin Toxicol. 1999;37:731-751. 4. Anderson RJ, Potts DE, Gabow PA, et al. Unrecognized adult salicylate intoxication. Ann Intern Med. 1976;85:745-748. 5. Arena FP, Dugowson C, Saudek CD. Salicylate-induced hypoglycemia and ketoacidosis in a nondiabetic adult. Arch Intern Med. 1978;138:1153-1154. 6. Armstrong CP, Blower AL. Non-steroidal anti-inflammatory drugs and life-threatening complications of peptic ulceration. Gut. 1987;28:527-532. 7. Arrowsmith JB, Kennedy DL, Kuritsky JN, et al. National patterns of aspirin use and Reye syndrome reporting. United States 1980 to 1985. Pediatrics. 1987;79:858-863. 8. Bailey RB, Jones SR. Chronic salicylate intoxication: a common cause of morbidity in the elderly. J Am Geriatr Soc. 1989;37:556-561. 9. Barone J, Raia J, Huang YC. Evaluation of the effects of multiple-dose activated charcoal on the absorption of orally administered salicylate in a simulated toxic ingestion model. Ann Emerg Med. 1988;17:34-37. 10. Belay ED, Bresee JJ, Holman RC, et al. Reye’s syndrome in the United States from 1981 through 1997. N Engl J Med. 1999;340:1377-1382. 11. Berk WA, Anderson JC. Salicylate associated asystole: report of two cases. Am J Med. 1989;86:505-506. 12. Bertolini A, Ottani A, Sandrini A. Dual acting anti-inflammatory drugs: a reappraisal. Pharmacol Res. 2001;44:437-450. 13. Bhutta AT, Squell VH, Schexnayder SM. Reye’s syndrome: down but not out. South Med J. 2003;96:43-45. 14. Bogazc K, Caldron P. Enteric-coated aspirin bezoar: elevation of serum salicylate level by barium study. Am J Med. 1981;83:783-786.

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15. Borga O, Odar-Cederlof I, Ringberger VA, et al. Protein binding of salicylate in uremic and normal plasma. Clin Pharmacol Ther. 1976;20:464-475. 16. Brien J. Ototoxicity associated with salicylates. Drug Saf. 1993;9:143-148. 17. Brubacher JR, Hoffman RS. Salicylism from topical salicylates: review of the literature. J Toxicol Clin Toxicol. 1996;34:431-436. 18. Brubacher JR, Purssell R, Kent DA. Salty broth for salicylate poisoning? Adequacy of overdose management advice in the 2001 compendium of pharmaceuticals and specialties. CMAJ. 2002;167:992-996. 19. Burke A, Smyth E, FitzGerald GA. Analgesic-antipyretic agents; pharmacotherapy of gout. In: Brunton LL, Lazo JS, Parker KL, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 11th ed. New York: McGraw-Hill; 2006:671-715. 20. Cazals Y. Auditory sensorineural alterations induced by salicylate. Prog Neurobiol. 2000;62:583-631. 21. Cazals Y, Li XQ, Aurousseau C, et al. Acute effects of noradrenaline related vasoactive agents on the ototoxicity of aspirin: an experimental study in guinea pigs. Heart Res. 1988;36:89-96. 22. Centers for Disease Control and Prevention. Reye’s syndrome surveillance— United States 1989. MMWR Morb Mortal Wkly Rep. 1991;40:88-89. 23. Chan TYK. Medicated oils and severe salicylate poisoning: quantifying the risk based on methyl salicylate content and bottle size. Vet Human Toxicol. 1996;38:133-134. 24. Chan TYK. Potential dangers from topical preparations containing methyl salicylate. Hum Exp Toxicol. 1996;15:747-750. 25. Chan TYK, Chan AYW, Ho CS. The clinical value of screening for salicylates in acute poisoning. Vet Human Toxicol. 1995;37:37-38. 26. Childs C. Human brain temperature: regulation, measurement and relationship with cerebral trauma: part 1. Br J Neurosurg. 2008;22:486-496. 27. Chow EL, Cherry JD. Reassessing Reye syndrome. Arch Pediatr Adolesc Med. 2003;157:1241-1242. 28. Chui PT. Anesthesia in a patient with undiagnosed salicylate poisoning presenting as intraabdominal sepsis. J Clin Anesth. 1999;11:251-253. 29. Chyka PA, Erdman AR, Christianson G, et al. Salicylate poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol. 2007;45:95-131. 30. Coggon D, Langman MJS, Spiegelhalter D. Aspirin, paracetamol, hematemesis and melena. Gut. 1982;23:340-344. 31. Curry SC, Pizon AF, Riley BD, et al. Effect of intravenous albumin infusion on brain salicylate concentration. Acad Emerg Med. 2007;14:508-514. 32. D’Agati V. Does aspirin cause acute or chronic renal failure in experimental animals and in humans? Am J Kidney Dis. 1996;28(1 suppl 1):S24-S29. 33. Davis JE: Are one or two dangerous? Methyl salicylate exposure in toddlers. J Emerg Med. 2007;32:63-69. 34. Davison C. Salicylate metabolism in man. Ann N Y Acad Sci. 1971;179: 249-268. 35. DeBroe ME, Verpooten GA, Christiaens ME, et al. Clinical experience with prolonged combined hemoperfusion-hemodialysis treatment of severe poisoning. Artif Organs. 1981;5:59-66. 36. Dinis-Oliveira RJ, de Pinho PG, Ferreira AC, et al. Reactivity of paraquat with sodium salicylate: formation of stable complexes. Toxicology. 2008;249:130-139. 37. Done AK: Salicylate intoxication: significance of measurements of salicylate in blood in cases of acute ingestion. Pediatrics. 1960;26:800-807. 38. Done AK, Temple AR. Treatment of salicylate poisoning. Mod Treat. 1971;8:528-551. 39. Dugandzic RM, Tierney MG, Dickinson GE, et al. Evaluation of the validity of the Done nomogram in the management of acute salicylate intoxication. Ann Emerg Med. 1989;18:1186-1190. 40. Durnas C, Cusack BJ. Salicylate intoxication in the elderly. Recognition and recommendations on how to prevent it. Drugs Aging. 1992;2:20-34. 41. Ekstrand R, Alvan A, Borga O. Concentration dependent plasma protein binding of salicylate in rheumatoid patients. Clin Pharmacokinet. 1979;4:137-143. 42. Elseviers MM, DeBroe ME. Combination analgesic involvement in the pathogenesis of analgesic nephropathy: the European perspective. Am J Kidney Dis. 1996;28(suppl 1):S48-S55. 43. Emkey RD. Aspirin and renal disease. Am J Med. 1983;74:97-101. 44. English M, Marsh V, Amukoye E, et al. Chronic salicylate poisoning and severe malaria. Lancet. 1996;347:1736-1737. 45. Escoubet B, Amsallem P, Ferrary E, et al. Prostaglandin synthesis by the cochlea or the guinea pig. Influence of aspirin, gentamicin, and acoustic stimulation. Prostaglandins. 1985;29:589-599.

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Part C

The Clinical Basis of Medical Toxicology

46. Feldman S, Chen SL, Pickering LK. Salicylate absorption from bismuth subsalicylate preparation. Clin Pharmacol Ther. 1981;29:788-792. 47. Fertel BS, Nelson LS, Goldfarb DS. The underutilization of hemodialysis in patients with salicylate poisoning. Kidney Int. 2009;75(12):1349-1353. 48. Feuerstein RC, Finberg L, Fleishman BS. The use of acetazolamide in the therapy of salicylate poisoning. Pediatrics. 1960;25:215-227. 49. Fillippone G, Fish S, Lacouture P, et al. Reversible adsorption (desorption) of aspirin from activated charcoal. Arch Intern Med. 1987;147:1390-1392. 50. Fisher CJ, Albertson TE, Foulke GE. Salicylate induced pulmonary edema. Clinical characteristics in children. Am J Emerg Med. 1985;3:33-37. 51. Ford M, Tomaszewski C, Kerns W, et al. Bedside ferric chloride urine test to rule out salicylate intoxication [abstract]. Vet Hum Toxicol. 1994;36:364. 52. Fox GN. Hypocalcemia complicating bicarbonate therapy for salicylate poisoning. West J Med. 1984;141:108-109. 53. Gabow PA. How to avoid overlooking salicylate intoxication. J Crit Illness. 1986;1:77-85. 54. Gabow PA, Anderson RJ, Potts DE, Schrier RW. Acid-base disturbances in the salicylate poisoning in adults. Arch Intern Med. 1978;138:1481-1484. 55. Gaudreault P, Temple AR, Lovejoy FH Jr. The relative severity of acute versus chronic salicylate poisoning in children: a clinical comparison. Pediatrics. 1982;70:566-569. 56. Goldberg MA, Barlow CF, Roth LJ. The effects of carbon dioxide on the entry and accumulation of drugs in the central nervous system. J Pharmacol Exp Ther. 1961;131:308-318. 57. Graham CA, Irons AJ, Munro PT. Paracetamol and salicylate testing: routinely required for all overdose patients? Eur J Emerg Med. 2006;13:26-28. 58. Hahn IH, Chu J, Hoffman RS, Nelson LS. Errors in reporting salicylate levels. Acad Emerg Med. 2000;7:1336-1337. 59. Halla JT, Atchison SL, Hardin JG. Symptomatic salicylate ototoxicity: a useful indicator of serum salicylate concentration? Ann Rheum Dis. 1991;50:682-684. 60. Hamdan JA, Manasra K, Ahmed M. Salicylate-induced hepatitis in rheumatic fever. Am J Dis Child. 1985;139:453-455. 61. Harris FC. Pyloric stenosis: holdup of enteric-coated aspirin tablets. Br J Surg. 1973;60:979-981. 62. Heller I, Halevy J, Cohen S, et al. Significant metabolic acidosis induced by acetazolamide: not a rare complication. Arch Intern Med. 1985;145:1815-1817. 63. Higgins RM, Connolly JO, Hendry BM. Alkalinization and hemodialysis in severe salicylate poisoning: comparison of elimination techniques in the same patient. Clin Nephrol. 1998;50:178-183. 64. Hill JB. Salicylate intoxication. N Engl J Med. 1973;288:1110-1113. 65. Hill JB. Experimental salicylate poisoning: observations on the effects of altering blood pH on tissue and plasma salicylate concentrations. Pediatrics. 1971;47:658-665. 66. Hillman RJ, Prescott LF. Treatment of salicylate poisoning with repeated oral charcoal. Br Med J. 1986;291:1472. 67. Hogben CAM, Schanker LS, Jocco DJ, Brodie BB. Absorption of drugs from the stomach. II: the human. J Pharmacol Exp Ther. 1957;120:540-545. 68. Hoffman RJ, Nelson LS, Hoffman RS. Use of ferric chloride to identify salicylate-containing poisons. J Toxicol Clin Toxicol. 2002;40:547-549. 69. Hormaechea E, Carlson RW, Rogove H, et al. Hypovolemia, pulmonary edema and protein changes in severe salicylate poisoning. Am J Med. 1979;66:1046-1050. 70. Hrnicek G, Skelton J, Miller W. Pulmonary edema and salicylate intoxication. JAMA. 1974;230:866-867. 71. Huff RW, Fred HL. Postictal pulmonary edema. Arch Intern Med. 1966;117:824-828. 72. Hurwitz ES, Barrett MJ, Bregman D, et al. Public Health Service study on Reye’s syndrome and medications: report of the pilot phase. N Engl J Med. 1985;313:849-857. 73. Johnson D, Eppler J, Giesbrecht E, et al. Effect of multiple-dose activated charcoal on the clearance of high-dose intravenous aspirin in a porcine model. Ann Emerg Med. 1995;26:569-574. 74. Jung TTK, Rhee CK, Lee CS, et al. Ototoxicity of salicylate, nonsteroidal anti-inflammatory drugs, and quinine. Otolaryngol Clin North Am. 1993;26:791-810. 75. Juurlink DN, McGuigan MA. Gastrointestinal decontamination for entericcoated aspirin overdose: what to do depends on who you ask. J Toxicol Clin Toxicol. 2000;38:465-470. 76. Juurlink DN, Szalai JP, McGuigan MA. Discrepant advice from poison centres and their medical directors. Can J Clin Pharmacol. 2002;9: 101-105.

77. Kaplan E, Kennedy J, David J. Effects of salicylate and other benzoates on oxidative enzymes of the tricarboxylic acid cycle in rat tissue homogenates. Arch Biochem Biophys. 1954;51:47-61. 78. Karliner J. Noncardiogenic forms of pulmonary edema. Circulation. 1972;46:212-215. 79. Karsh J. Adverse reactions and interactions with aspirin—considerations in the treatment of the elderly patient. Drug Saf. 1990;5:317-327. 80. Keller RE, Schwab RA, Krenzelok EP. Contribution of sorbitol combined with activated charcoal in prevention of salicylate absorption. Ann Emerg Med. 1990;19:654-656. 81. King JA, Storrow AB, Finkelstein JA. Urine Trinder spot test: a rapid salicylate screen for the emergency department. Ann Emerg Med. 1995;26:330-333. 82. Kirshenbaum LA, Mathews SC, Sitar DS, Tenenbein M. Does multipledose charcoal therapy enhance salicylate excretion? Arch Intern Med. 1990;150:1281-1283. 83. Krebs HG, Woods HG, Alberti KG. Hyperlactatemia and lactic acidosis. Essays Med Biochem. 1975;1:81-103. 84. Lawson AAH, Proudfoot AT, Brown SS, et al. Forced diuresis in the treatment of acute salicylate poisoning in adults. Q J Med. 1969;38:31-48. 85. Lemesh RA. Accidental chronic salicylate intoxication in an elderly patient: major morbidity despite early recognition. Vet Hum Toxicol. 1993;35:34-36. 86. Leventhal LJ, Kuritsky L, Ginsburg R, et al. Salicylate-induced rhabdomyolysis. Am J Emerg Med. 1989;7:409-410. 87. Levy G. Clinical pharmacokinetics of salicylates: a reassessment. Br J Clin Pharmacol. 1980;10:285S-290S. 88. Levy G. Clinical pharmacokinetics of aspirin. Pediatrics. 1978;62(suppl): 867-872. 89. Levy G. Pharmacokinetics of salicylate elimination in man. J Pharm Sci. 1965;54:959-967. 90. Levy G, Tsuchiya T. Effect of activated charcoal on aspirin absorption in man. Clin Pharmacol Ther. 1972;13:317-322. 91. Lewis TV, Badillo R, Schaeffer S, Hagemann TM, McGoodwin L. Salicylate toxicity associated with administration of Percy medicine in an infant. Pharmacotherapy. 2006;26:403-109. 92. Macpherson CR, Milne MD, Evans BM. The excretion of salicylate. Br J Pharmacol. 1955;10:484-489. 93. Manso C, Taranta A, Nydick I. Effect of aspirin administration on serum glutamic oxaloacetic and glutamic pyruvic transaminases in children. Proc Soc Exp Biol Med. 1956;93:84-88. 94. Mayer AL, Sitar DS, Tenenbein M. Multiple-dose charcoal and wholebowel irrigation do not increase clearance of absorbed salicylate. Arch Intern Med. 1992;152:393-396. 95. McGuigan MA. A two year review of salicylate deaths in Ontario. Arch Intern Med. 1987;147:510-512. 96. Miyahara JT, Karler R. Effect of salicylate on oxidative phosphorylation and respiration of mitochondrial fragments. Biochem J. 1965;97:194-198. 97. Montgomery H, Porter JC, Bradley RD. Salicylate intoxication causing a severe systemic inflammatory response and rhabdomyolysis. Am J Emerg Med. 1994;12:531-532. 98. Montgomery PR, Berger LG, Mitenko PA, Sitar DS. Salicylate metabolism: effects of age and sex in adults. Clin Pharmacol Ther. 1986;39:571-576. 99. Morgan AG, Polak A. The excretion of salicylate in salicylate poisoning. Clin Sci. 1971;41:475-484. 100. Myers EN, Bernstein JM, Fostiropolous G. Salicylate ototoxicity. N Engl J Med. 1965;273:587-590. 101. Neuvonen PJ, Elfving SM, Elonen E. Reduction of absorption of digoxin, phenytoin, and aspirin by activated charcoal in man. Eur J Clin Pharmacol. 1978;13:213-218. 102. Palatnick W, Tenenbien M. Aspirin poisoning during pregnancy: increased fetal sensitivity. Am J Perinatol. 1998;15:39-41. 103. Park BK, Leck JB. On the mechanism of salicylate-induced hypothrombinaemia. J Pharm Pharmacol. 1981;33:25-28. 104. Partin JS, Partin JC, Schubert WK, Hammond JG. Serum salicylate concentration in Reye’s disease: a study of 130 biopsy proven cases. Lancet. 1982;1:191-194. 105. Patrono C, Baigent C, Hirsh J, Roth G. Antiplatelet drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008;133(6 suppl):199S-233S. 106. Phillips BM, Hartnagel RE, Leeling JL, Gurtoo HL. Does aspirin play a role in analgesic nephropathy? Aust NJ Med. 1976;6(suppl 1):48-53. 107. Porter GA. Acetaminophen/aspirin mixtures: experimental data. Am J Kidney Dis. 1996;28(suppl 1):S30-S33.

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108. Prescott LF, Balali-Mood M, Critchley JA, et al. Diuresis or urinary alkalinization for salicylate poisoning? Br Med J. 1982;285:1383-1386. 109. Proudfoot AT, Brown SS. Acidaemia and salicylate poisoning in adults. Br Med J. 1969;2:547-550. 110. Proudfoot AT, Krenzelok EP, Brent J, Vale JA. Does urine alkalinization increase salicylate elimination? If so, why? Toxicol Rev. 2003;22:129-136. 111. Proudfoot AT, Krenzelok EP, Vale JA. Position paper on urine alkalinization. J Toxicol Clin Toxicol. 2004;42:1-26. 112. Puel JL. Cochlear NMDA receptor blockade prevents salicylate-induced tinnitus. B-ENT 2007;3(suppl 7):19-22. 113. Puel JL, Guitton MJ. Salicylate-induced tinnitus: molecular mechanisms and modulation by anxiety. Prog Brain Res. 2007;166:141-146. 114. Pugliese A, Beltramo T, Torre D. Reye’s and Reye’s-like syndromes. Cell Biochem Funct. 2008;26:741-746. 115. Ramsden RT, Latif A, O’Malley S. Electrocochleographic changes in acute salicylate overdosage. J Laryngol Otol. 1985;99:1269-1273. 116. Rao P, Knaus EE. Evolution of nonsteroidal anti-inflammatory drugs (NSAIDs): cyclooxygenase (COX) inhibition and beyond. J Pharm Sci. 2008;11:81s-110s. 117. Raschke R, Arnold-Capell P, Richeson R, Curry SC. Refractory hypoglycemia secondary to topical salicylate intoxication. Arch Intern Med. 1991;151:591-593. 118. Rivera W, Kleinschmidt KC, Velez LI, et al. Delayed salicylate toxicity at 35 hours without early manifestations following a single salicylate ingestion. Ann Pharmacother. 2004;38:1186-1188. 119. Roberts MS, Cossum PA, Kilpatrick DO. Implications of hepatic and extrahepatic metabolism of aspirin in selective inhibition of platelet cyclooxygenase. N Engl J Med. 1985;312:1388-1389. 120. Roberts MS, Favretto WA, Meyer A, et al. Topical bioavailability of methyl salicylate. Aust N Z J Med. 1982;12:303-305. 121. Romankiewicz JA, Reidenberg MM. Factors that modify drug absorption. Ration Drug Ther. 1978;12:1-6. 122. Rothschild BM. Hematologic perturbations associated with salicylate. Clin Pharmacol Ther. 1979;26:145-150. 123. Ruel J, Chabbert C, Nouvian R, et al. Salicylate enables cochlear arachidonicacid-sensitive NMDA receptor responses. J Neurosci. 2008;28:7313-7323. 124. Schaller JG. Chronic salicylate administration in juvenile rheumatoid arthritis: Aspirin “hepatitis” and its clinical significance. Pediatrics. 1978;62(suppl):916-925. 125. Schanker LS, Tocco DJ, Brodie BB, Hogben CAM. Absorption of drugs from the rat’s small intestine. J Pharmacol Exp Ther. 1958;123:81-88. 126. Sogge MR, Griffith JL, Sinar DR, Mayes GR. Lavage to remove enteric-coated aspirin and gastric outlet obstruction. Ann Intern Med. 1977;87:721-722. 127. Sporer KA, Khayam-Bashi H. Acetaminophen and salicylate serum levels in patients with suicidal ingestion or altered mental status. Am J Emerg Med. 1996;14:443-447. 128. Stolbach AI, Hoffman RS, Nelson LS. Mechanical ventilation was associated with acidemia in a case series of salicylate-poisoned patients. Acad Emerg Med. 2008;15:866-869.

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129. Sweeney KR, Chapron DJ, Brandt JL, et al. Toxic interaction between acetazolamide and salicylate: case reports and a pharmacokinetic explanation. Clin Pharmacol Ther. 1986;40:518-524. 130. Swintosky JV. Illustrations and pharmaceutical interpretations of firstorder drug elimination rate from the bloodstream. J Am Pharm Assoc. 1956;45:395-400. 131. Temple AR. Acute and chronic effects of aspirin toxicity and their treatment. Arch Intern Med. 1981;141:364-369. 132. Temple AR, George DJ, Done AK, Thompson JA. Salicylate poisoning complicated by fluid retention. Clin Toxicol. 1976;9:61-68. 133. Tenenbein M. Whole-bowel irrigation as a gastrointestinal decontamination procedure after acute poisoning. Med Toxicol. 1988;3:77-84. 134. Tenney SM, Miller RM. The respiratory and circulatory action of salicylate. Am J Med. 1955;19:498-508. 135. Thurston JH, Pollock PG, Warren SK, Jones EM. Reduced brain glucose with normal plasma glucose in salicylate poisoning. Clin Invest. 1970;49:2139-2145. 136. Vane JR, Botting RM. The mechanism of action of aspirin. Thromb Res. 2003;110:255-258. 137. Vernace MA, Bellucci AG, Wilkes BM. Chronic salicylate toxicity due to consumption of over-the-counter bismuth subsalicylate. Am J Med. 1994;97:308-309. 138. Vertrees JE, McWilliams BC, Kelly HW. Repeated oral administration of activated charcoal for treating aspirin overdose in young children. Pediatrics. 1990;85:594-597. 139. Vree TB, Van Ewijk-Beneken Kolmer EWJ, Verwey-Van Wissen CPWGM, Hekster YA. Effect of urinary pH on the pharmacokinetics of salicylate acid, with its glycine and glucuronide conjugates in humans. Int J Clin Pharmacol Ther. 1994;32:550-558. 140. Waldman RJ, Hall WN, McGee H, Van Amburg G. Aspirin as a risk factor in Reye’s syndrome. JAMA. 1982;247:3089-3094. 141. Walters JS, Woodring JH, Stelling CB, et al. Salicylate-induced pulmonary edema. Radiology. 1983;146:289-293. 142. Weisberg HF. Water and electrolytes. In: Davidsohn I, Wells BB, eds. Clinical Diagnosis by Laboratory Methods. Philadelphia: WB Saunders; 1962:500. 143. Wolowich WR, Hadley CM, Kelley MT, et al. Plasma salicylate from methyl salicylate cream compared to oil of wintergreen. J Toxicol Clin Toxicol. 2003;41:353-358. 144. Wood DM, Dargan PI, Jones AL. Measuring plasma salicylate concentrations in all patients with drug overdose or altered consciousness: is it necessary? Emerg Med J. 2005;22:401-403. 145. Wortzman DJ, Grunfeld A. Delayed absorption following enteric-coated aspirin overdose. Ann Emerg Med. 1987;16:434-436. 146. Wrathall G, Sinclair R, Moore A, Pogson D. Three case reports of the use of haemodiafiltration in the treatment of salicylate overdose. Hum Exp Toxicol. 2001;20:491-495. 147. Zenser TV, Mattammal MB, Rapp NS, Davis BB. Effect of aspirin on metabolism of acetaminophen and benzidine by renal inner medulla prostaglandin hydroperoxidase. J Lab Clin Med. 1983;101:58-65.

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ANTIDOTES IN DEPTH (A5) SODIUM BICARBONATE Paul M. Wax Sodium bicarbonate is a nonspecific antidote effective in the treatment of a variety of poisonings by means of a number of distinct mechanisms (Table A5–1). However, the support for its use in these settings is predominantly based on animal evidence, case reports, and consensus.9 It is most commonly used in the treatment of patients with cyclic antidepressant (CA) and salicylate poisonings. Sodium bicarbonate also has a role in the treatment of phenobarbital, chlorpropamide, and chlorophenoxy herbicide poisonings and wide-complex tachydysrhythmias induced by type IA and IC antidysrhythmics and cocaine. Correcting the life-threatening acidosis generated by methanol and ethylene glycol poisoning and enhancing formate elimination are other important indications for sodium bicarbonate. Use of sodium bicarbonate in the treatment of rhabdomyolysis, metabolic acidosis with elevated lactate, cardiac resuscitation, and diabetic ketoacidosis is controversial and is not addressed in this Antidote in Depth.1,4,15,45,91,92

ALTERED XENOBIOTIC IONIZATION RESULTING IN ALTERED XENOBIOTIC DISTRIBUTION ■ CYCLIC ANTIDEPRESSANTS The most important role of sodium bicarbonate in toxicology appears to be its ability to reverse potentially fatal cardiotoxic effects of the CAs and other type IA and IC antidysrhythmics. Use of sodium bicarbonate for CA overdose developed as an extension of sodium bicarbonate use in the treatment of patients with other cardiotoxic exposures. Noting similarities in electrocardiographic (ECG) findings between hyperkalemia and quinidine toxicity (ie, QRS widening), investigators in the 1950s began to use sodium lactate (which is rapidly metabolized in the liver to sodium bicarbonate) for the treatment of quinidine toxicity.3,8,95 In a canine model, quinidine-induced ECG changes and hypotension were consistently reversed by infusion of sodium lactate.7 Clinical experience confirmed this benefit.8 Similar efficacy in the treatment of patients with procainamide cardiotoxicity was also reported.95 With the introduction of the CAs during the late 1950s, conduction disturbances, dysrhythmias, and hypotension occurring after overdose were soon reported. Extending the use of sodium lactate from the type I antidysrhythmics to the CAs, uncontrolled observations in the early 1970s showed a decrease in mortality from 15% to less than 3% when sodium lactate was administered to patients with CA poisoning.29 In 1976, the first report of successful use of sodium bicarbonate in the treatment of a series of CA-induced dysrhythmias in children was reported.17 In this series, nine of 12 children who had developed multifocal premature ventricular contractions (PVCs), ventricular tachycardia, or heart block reverted to normal sinus rhythm

with sodium bicarbonate therapy alone. An early canine experiment of amitriptyline-poisoning demonstrated resolution of dysrhythmias upon alkalinization of the blood to a pH above 7.40.17 Other methods of alkalinization, including hyperventilation and administration of the nonsodium buffer tris (hydroxymethyl) aminomethane (THAM), were also effective in reversing the dysrhythmias.18,42 A better understanding of the mechanism and utility of sodium bicarbonate has come from a series of animal experiments during the 1980s. In amitriptyline-poisoned dogs, sodium bicarbonate reversed conduction slowing and ventricular dysrhythmias and suppressed ventricular ectopy.62 When comparing sodium bicarbonate, hyperventilation, hypertonic sodium chloride, and lidocaine, sodium bicarbonate and hyperventilation proved most efficacious in reversing ventricular dysrhythmias and narrowing QRS prolongation. Although lidocaine transiently antagonized dysrhythmias, this antagonism was demonstrable only at nearly toxic lidocaine concentrations and was associated with hypotension. Furthermore, prophylactic alkalinization protected against the development of dysrhythmias in a pH-dependent manner. In desipramine-poisoned rats, the isolated use of either sodium chloride or sodium bicarbonate was effective in decreasing QRS duration.69 Both sodium bicarbonate and sodium chloride also increased mean arterial pressure, but hyperventilation or direct intravascular volume repletion with mannitol did not. In further studies both in vivo and on isolated cardiac tissue, alkalinization and increased sodium concentration improved CA effects on cardiac conduction.79,80 Although respiratory alkalosis and sodium chloride each independently improved conduction velocity, this effect was greater when sodium bicarbonate was administered. Another study on amitriptyline-poisoned rats demonstrated that treatment with sodium bicarbonate was associated with shorter QRS interval, longer duration of sinus rhythm, and increased survival rates.44 Sodium bicarbonate seems to work independently of initial blood pH. Animal studies show that cardiac conduction improves after treatment with sodium bicarbonate or sodium chloride in both normal pH and acidemic animals.69 Clinically, TCA-poisoned patients who already were alkalemic also responded to repeat doses of sodium bicarbonate.59 Although several authors suggest that the efficacy of sodium bicarbonate is modulated via a pH-dependent change in plasma protein binding that decreases the proportion of free drug,18,49 further study failed to support this hypothesis.72 The administration of large doses of a binding protein α1-acid glycoprotein (AAG) (to which CAs show great affinity) to desipramine-poisoned rats only minimally decreased cardiotoxicity. Although the addition of AAG increased the concentrations of total desipramine and protein-bound desipramine in the serum, the concentration of active free desipramine did not decline significantly. A redistribution of CA from peripheral sites may have prevented lowering of free desipramine concentration. The persistence of other CA-associated toxicity, such as the anticholinergic effects and seizures, also argues against changes in protein-binding modulating toxicity. In vitro studies performed in plasma protein-free bath further support that the efficacy of sodium bicarbonate is independent of plasma protein binding.79 Sodium bicarbonate has a crucial antidotal role in CA poisoning by increasing the number of open sodium channels, thereby partially

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Antidotes in Depth

TABLE A5–1. Sodium Bicarbonate: Mechanisms, Site of Action, and Uses in Toxicology Mechanism

Site of Action

Uses

Altered interaction between xenobiotic and sodium channel

Heart

Altered xenobiotic ionization leads to altered tissue distribution Altered xenobiotic ionization leads to enhanced xenobiotic elimination

Brain

Correct life-threatening acidosis

Metabolic

Increase xenobiotic solubility Neutralization Maintenance of chelator effect Reduce free radical formation

Kidneys

Amantadine Carbamazepine Cocaine Diphenhydramine Flecainide Mesoridazine Procainamide Propoxyphene Quinidine Quinine Thioridazine cyclic antidepressants Formic acid Phenobarbital Salicylates Chlorophenoxy herbicides Chlorpropamide Formic acid Methotrexate Phenobarbital Salicylates Cyanide Ethylene glycol Methanol Metformin Methotrexate

Lungs Kidneys

Chlorine gas, HCI Dimercaprol (BAL)–metal

Kidneys

Contrast media

Kidneys

BAL, British anti-Lewisite.

reversing fast sodium channel blockade. This decreases QRS prolongation and reduces life-threatening cardiovascular toxicity such as ventricular dysrhythmias and hypotension.62,69,79 The animal evidence supports two distinct and additive mechanisms for this effect: a pHdependent effect and a sodium-dependent effect. The pH-dependent effect increases the fraction of the more freely diffusible nonionized xenobiotic. Both the ionized xenobiotic and the nonionized forms are able to bind to the sodium channel, but assuming CAs act like local anesthetics, it is estimated that 90% of the block results from the ionized form. By increasing the nonionized fraction, less xenobiotic is available to bind to the sodium channel binding site. The sodiumdependent effect increases the availability of sodium ions to pass through the open channels. Decreased ionization should not significantly decrease the rate of CA elimination because of the small contribution of renal pathways to overall CA elimination (7.55) and hypernatremia should be avoided. Because sodium bicarbonate has a brief duration of effect, a continuous infusion usually is required after the IV bolus. Three 50-mL ampules should be placed in 1 L of 5% dextrose in water (D5W) and run at twice maintenance with frequent checks of QRS and pH depending on the fluid requirements and blood pressure of the patient. Frequent evaluation of the fluid status should be performed to avoid precipitating pulmonary edema. An optimal duration of therapy has not been established. The time to resolution of conduction abnormalities during

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Part C

The Clinical Basis of Medical Toxicology

continuous bicarbonate infusion varies significantly, ranging from several hours to several days.50 In a case of prolonged clinical effects from modified-release amitriptyline poisoning, sodium bicarbonate was administered on multiple occasions over 110 hours after the initial ingestion to reverse ongoing sodium channel conduction disturbances.64 Sodium bicarbonate infusion usually is discontinued as soon as there is improvement in hemodynamics and cardiac conduction and resolution in altered mental status, although controlled data supporting such an approach are lacking.

■ OTHER SODIUM CHANNEL BLOCKING XENOBIOTICS Sodium bicarbonate is useful in treating patients with cardiotoxicity from other xenobiotics, with sodium channel blocking effects manifested by widened QRS complexes, dysrhythmias, and hypotension. Isolated case reports provide the bulk of the evidence in these situations. The utility of sodium bicarbonate in treating patients with type IA and IC antidysrhythmics, diphenhydramine, propoxyphene, and quinine has been demonstrated.7,11,77,84,88,95 Use of sodium bicarbonate in the treatment of patients with amantadine overdose manifested by prolongation of the QRS and QT intervals was associated with narrowing of the QT but not the QRS interval.25 Although the usefulness of sodium bicarbonate in reversing QT prolongation occasionally observed during fluoxetine and citalopram overdose has been reported,19,24,30 sodium channel disturbances are uncommon in most cases of selective serotonin reuptake inhibitor (SSRI) overdose, and routine use of alkalinization therapy in this setting is unwarranted. Sodium bicarbonate may help in the management of patients with other ingestions associated with type IA-like cardiac conduction abnormalities and dysrhythmias, such as carbamazepine and the phenothiazines thioridazine and mesoridazine, but documentation of such benefit is lacking. The role of sodium bicarbonate as an antidote has been studied in experimental models of calcium channel blocker toxicity and β-adrenergic antagonist toxicity. In the calcium channel blocker study, hypertonic sodium bicarbonate increased mean arterial pressure and cardiac output in verapamil-poisoned swine.89 Possible explanations for this beneficial effect include the increase in serum pH, reversal of a sodium channel effect, lowering of serum potassium concentration, or volume expansion. In a canine model of propranolol toxicity, sodium bicarbonate failed to increase heart rate or blood pressure.51 Cocaine, a local anesthetic with membrane-stabilizing properties resembling other type I antidysrhythmics may cause similar conduction disturbances. In several canine models of cocaine toxicity, 2 mEq/kg of sodium bicarbonate successfully reversed cocaine-induced QRS prolongation6,68 and improved myocardial function.97 Of interest, sodium loading by itself (2 mEq/kg of sodium chloride) failed to produce a benefit. Similar findings were demonstrated in cocaine-treated guinea pig hearts.98 Patients with cocaine-induced cardiotoxicity responded to treatment with sodium bicarbonate.41,66,94 In many of these cases, simultaneous treatment with sedation, active cooling, and hyperventilation confounds the contribution of the sodium bicarbonate to overall recovery.

ALTERED XENOBIOTIC IONIZATION RESULTING IN ENHANCED ELIMINATION ■ SALICYLATES Although there is no known specific antidote for salicylate toxicity, judicious use of sodium bicarbonate is an essential treatment modality of salicylism. Through its ability to change the concentration gradient of

the ionized and nonionized fractions of salicylates, sodium bicarbonate is useful in decreasing tissue (eg, brain) concentrations of salicylates and enhancing urinary elimination of salicylates.74 This therapy may limit the need for more invasive treatment modalities, such as hemodialysis. Salicylate is a weak acid with a pKa of 3.0. As pH increases, more of the xenobiotic is in the ionized form. Ionized molecules penetrate lipidsoluble membranes less rapidly than do nonionized molecules because of the presence of polar groups on the ionized form. Consequently, when the ionized forms predominate weak acids, such as salicylates, may accumulate in an alkaline milieu, such as an alkaline urine.56,86 Although alkalinizing the urine to increase salicylate elimination is an important intervention in the treatment of patients with salicylate poisoning, increasing the serum pH in patients with severe salicylism may prove even more consequential by protecting the brain from a lethal central nervous system (CNS) salicylate burden. Using sodium bicarbonate to “trap” salicylate in the blood (ie, keeping it out of the brain) may prevent clinical deterioration of salicylate-poisoned patients. Salicylate lethality is directly related to primary CNS dysfunction, which, in turn, corresponds to a “critical brain salicylate level.”35 At physiologic pH, at which a very small proportion of the salicylate is in the nonionized form, a small change in pH is associated with a significant change in amount of nonionized molecules (eg, at a pH of 7.4, 0.004% of the salicylate molecules is in the nonionized form; at a pH of 7.2, 0.008% of the salicylate is in the nonionized form). In experimental models, lowering the blood pH produces a shift of salicylate into the tissues.20 Hence, acidemia that is observed in significant salicylate poisonings can be devastating. In salicylate-poisoned rats, increasing the blood pH with sodium bicarbonate produced a shift in salicylate out of the tissues and into the blood.34 This change in salicylate distribution did not result from enhanced urinary excretion because occlusion of the renal pedicles failed to alter these results. Enhancing the urinary elimination of salicylate by trapping ionized salicylate in the urine also provides great benefit. Salicylate elimination at low therapeutic concentrations consists predominantly of first-order hepatic metabolism. At these low concentrations, without alkalinization, only approximately 10% to 20% of salicylate is eliminated unchanged in the urine. With increasing concentrations, enzyme saturation occurs (Michaelis-Menten kinetics); thus, a larger percentage of elimination occurs as unchanged free salicylate. Under these conditions, in an alkaline urine, urinary excretion of free salicylate becomes even more significant, accounting for 60% to 85% of total elimination.31,75 The exact mechanism of pH-dependent salicylate elimination has generated controversy. The pH-dependent increase in urinary elimination initially was ascribed to “ion trapping,” which is the filtering of both ionized and nonionized salicylate while reabsorbing only the nonionized salicylate.82 However, limiting reabsorption of the ionizable fraction of filtered salicylate cannot be the primary mechanism responsible for enhanced elimination produced by sodium bicarbonate.52 Because the quantitative difference between the percentage of molecules trapped in the ionized form at a pH of 5.0 (99% ionized) and a pH of 8.0 (99.999% ionized) is small, decreases in tubular reabsorption cannot fully explain the rapid increase in urinary elimination seen at a pH above 7.0. “Diffusion theory” offers a reasonable alternative explanation. Fick’s law of diffusion states that the rate of flow of a diffusing substance is proportional to its concentration gradient. A large concentration gradient between the nonionized salicylate in the peritubular fluid (and blood) and the tubular luminal fluid is found in alkaline urine. Because at a higher urinary pH, a greater proportion of secreted nonionized molecules quickly becomes ionized upon entering the alkaline environment, more salicylate (ie, nonionized salicylate) must

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pass from the peritubular fluid into the urine in an attempt to reach equilibrium with the nonionized fraction. In fact, as long as nonionized molecules are rapidly converted to ionized molecules in the urine, equilibrium in the alkaline milieu will never be achieved. The concentration gradient of peritubular nonionized salicylates to urinary nonionized salicylates continues to increase with increasing urinary pH. Hence, increased tubular diffusion, not decreased reabsorption, probably accounts for most of the increase in salicylate elimination observed in the alkaline urine.52 Controversies regarding the indications for alkalinization in the treatment of patients with salicylism persist. Although urinary alkalinization undoubtedly works to lower serum salicylate concentrations and enhance urinary elimination, the risks associated with alkalinization in the management of salicylism are of concern. Concerns regarding excessive alkalemia, hypernatremia, fluid overload, hypokalemia, and hypocalcemia, as well as the potential delay in achieving alkalinization with sodium bicarbonate (as opposed to more rapid response achieved with hyperventilation), have all been raised.27,48,70,75,82 Early on, patients with pure respiratory alkalosis often have alkaluria, as well as alkalemia, and do not require urinary alkalinization. In the more common scenario in which patients present with a mixed respiratory alkalosis and metabolic acidosis, sodium bicarbonate must be administered cautiously. Young children who rapidly develop metabolic acidosis often require alkalinization but should be at less risk for complications of this therapy.65 Sodium bicarbonate is indicated in the treatment of salicylate poisoning for most patients with evidence of significant systemic toxicity. Although some authors have suggested alkali therapy for asymptomatic patients with concentrations above 30 mg/dL,96 limited data support this approach. For patients with chronic poisoning, concentrations are not as helpful and may be misleading; clinical criteria remain the best indicators for therapy. Patients with contraindications to sodium bicarbonate use, such as renal failure and acute lung injury, should be considered candidates for intubation and subsequent hyperventilation, but extracorporeal removal is often required because of the difficulty and danger of intubation. Dosing recommendations depend on the acid–base status of the patient. For patients with acidemia, rapid correction is indicated with IV administration of 1 to 2 mEq of sodium bicarbonate per kilogram of body weight.90 After the blood is alkalinized or if the patient has already presented with an alkalemia, continued titration with sodium bicarbonate over 4 to 8 hours is recommended until the urinary pH reaches 7.5 to 8.0.87,90 Alkalinization can be maintained with a continuous sodium bicarbonate infusion of 100 to 150 mEq in 1 L of D5W at 150 to 200 mL/hr (or about twice the maintenance requirements in a child). Obtaining a urinary pH of 8.0 is difficult but is considered to be the goal. Fastidious attention to the patient’s changing acid–base status is required. Systemic pH should not go above 7.55 to prevent complications of alkalemia. Hypokalemia can make urinary alkalinization particularly problematic.48,81 In hypokalemic patients, the kidneys preferentially reabsorb potassium in exchange for hydrogen ions. Urinary alkalinization will be unsuccessful as long as hydrogen ions are excreted into the urine. Thus, appropriate potassium supplementation to achieve normokalemia may be required to alkalinize the urine.99 In the past, proper urinary alkalinization was thought to require forced diuresis to maximize salicylate elimination.23,48 Suggestions included administering enough fluid (2 L/h) to produce a urine output of 500 mL/h. Because forced alkaline diuresis appears unnecessary and is potentially harmful as a result of its unnecessarily large fluid load, the goal is alkalinization at a rate of approximately twice maintenance requirements to achieve a urine output of 3 to 5 mL/kg/h.

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■ PHENOBARBITAL Although cardiopulmonary support is the most critical intervention in the treatment of patients with severe phenobarbital overdose, sodium bicarbonate may be a useful adjunct to general supportive care. The utility of sodium bicarbonate is particularly important considering the long plasma half-life (~100 hours) of phenobarbital. Phenobarbital is a weak acid (pKa, 7.24) that undergoes significant renal elimination. As in the case of salicylates, alkalinization of the blood and urine may reduce the severity and duration of toxicity. In a study of mice, the median anesthetic dose for mice receiving phenobarbital increased by 20% with the addition of 1 g/kg of sodium bicarbonate (increasing the blood pH from 7.23 to 7.41), demonstrating decreased tissue concentrations associated with increased pH.93 Extrapolating the animal evidence to humans has suggested that phenobarbital-poisoned patients in deep coma might develop a respiratory acidosis secondary to hypoventilation, with the acidemia enhancing the entrance of phenobarbital into the brain, thus worsening CNS and respiratory depression. Alternatively, increasing the pH with bicarbonate, ventilatory support, or both would enhance the passage of phenobarbital out of the brain, thus lessening toxicity. Given the relatively high pKa of phenobarbital, significant phenobarbital accumulation in the urine is evident only when urinary pH is increased above 7.5.10 As the pH approaches 8.0, a threefold increase in urinary elimination occurs. The urine-toserum ratio of phenobarbital, although much higher in alkaline urine than in acidic urine, remains less than unity, thereby suggesting less of a role for tubular secretion than in salicylate poisoning. Clinical studies examining the role of alkalinization in phenobarbital poisoning have been inadequately designed. Many are poorly controlled and fail to examine the effects of alkalinization, independent of coadministered diuretic therapy. In one uncontrolled study, a 59% to 67% decrease in the duration of unconsciousness in patients with phenobarbital overdoses occurred in patients administered alkali compared with nonrandomized control subjects.58 In other older studies, treatment with sodium lactate and urea reduced mortality and frequency of tracheotomy to 50% of control subjects, enhanced elimination, and shortened coma.47,61 In a later human volunteer study, urinary alkalinization with sodium bicarbonate was associated with a decrease in phenobarbital elimination half-life from 148 to 47 hours.28 However, this beneficial effect was less than the effect achieved by multiple-dose activated charcoal (MDAC), which reduced the half-life to 19 hours.28 In a nonrandomized study of phenobarbital-poisoned patients comparing urinary alkalinization alone, MDAC alone, and both methods together, both the phenobarbital half-life decreased most rapidly and the clinical course improved most rapidly in the group of patients who received MDAC alone.57 Interesting, the combination approach proved inferior to MDAC alone but was better than alkalinization alone. The authors speculated that when both treatments were used together, the increased ionization of phenobarbital resulting from sodium bicarbonate infusion may have decreased the efficacy of MDAC. These studies suggest that MDAC is more efficacious than urinary alkalinization in the treatment of phenobarbital-poisoned patients, although both approaches are beneficial and indicated. Sodium bicarbonate therapy does not appear warranted in the treatment of patients with ingestions of other barbiturates, such as pentobarbital and secobarbital, most of which have a pKa above 8.0 or are predominantly eliminated by the liver.

■ CHLORPROPAMIDE Chlorpropamide is a weak acid (pKa, 4.8) and has a long half-life (30–50 hours). In a human study using therapeutic doses of chlorpropamide, urinary alkalinization with sodium bicarbonate significantly increased

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renal clearance of the drug.63 This study showed that whereas nonrenal clearance was the more significant route of elimination at a urinary pH of 5 to 6 (only slightly above pKa), at a pH of 8.0, renal clearance was 10 times that of nonrenal clearance. Alkalinization reduced the area under the curve (AUC) almost fourfold and shortened the elimination halflife from 50 to 13 hours. Acidification increased the AUC by 41% and increased the half-life to 69 hours. Although not a study in overdose patients, this report suggests that sodium bicarbonate may be useful in the management of patients with chlorpropamide overdose. The effect of urinary alkalinization on elimination of other sulfonylureas is unnecessary because the benefit presumably is limited as these agents are largely metabolized in the liver.

■ CHLOROPHENOXY HERBICIDES Alkalinization is indicated in the treatment of patients with poisonings from weed killers that contain chlorophenoxy compounds, such as 2,4dichlorophenoxyacetic acid (2,4-D) or 2-(4-chloro-2-methylphenoxy) propionic acid (MCPP).73 Poisoning results in muscle weakness, peripheral neuropathy, coma, hyperthermia, and acidemia. These compounds are weak acids (pKa 2.6 and 3.8 for 2,4-D and MCPP, respectively) that are excreted largely unchanged in the urine. In an uncontrolled case series of 41 patients poisoned with a variety of chlorophenoxy herbicides, 19 of whom received sodium bicarbonate, alkaline diuresis significantly reduced the half-life of each by enhancing renal elimination.26 In one patient, resolution of hyperthermia and metabolic acidosis and improvement in mental status were associated with a transient elevation of serum concentration, perhaps reflecting chlorophenoxy compound redistribution from the tissues into the more alkalemic blood. The limited data suggest that the increased ionized fractions of the weak-acid chlorophenoxy compounds produced by alkalinization is trapped in both the blood and the urine (as demonstrated with salicylates and phenobarbital); thus, its use ameliorates toxicity and shortens the duration of effect.

CORRECTING METABOLIC ACIDOSIS ■ TOXIC ALCOHOLS Sodium bicarbonate has two important roles in treating patients with toxic alcohol ingestions. As an immediate temporizing measure, administration of sodium bicarbonate may reverse the life-threatening acidemia associated with methanol and ethylene glycol ingestions. In rats poisoned with ethylene glycol, the administration of sodium bicarbonate alone resulted in a fourfold increase in the median lethal dose.13 Clinically, titrating the endogenous acid with bicarbonate greatly assists in reversing the consequences of severe acidemia, such as hemodynamic instability and multiorgan dysfunction. The second role of bicarbonate in the treatment of toxic alcohol poisoning involves its ability to favorably alter the distribution and elimination of certain toxic metabolites.76 In cases of methanol poisoning, the proportion of ionized formic acid can be increased by administering bicarbonate, thereby trapping formate in the blood compartment.40,53 Consequently, decreased visual toxicity results from removal of the toxic metabolite from the eyes. In cases of formic acid (pKa of 3.7) ingestion, sodium bicarbonate decreases tissue penetration of the formic acid and enhances urinary elimination.60 Further investigation is required to delineate the beneficial effects of sodium bicarbonate in the treatment of patients with toxic alcohol ingestions. Early treatment of acidemia with sodium bicarbonate is strongly recommended in cases of methanol and ethylene glycol poisoning.33 Sodium bicarbonate should be administered to toxic alcohol-poisoned patients with an arterial pH below 7.30.46 More than 400 to 600 mEq of

sodium bicarbonate may be required in the first few hours.39 In cases of ethylene glycol toxicity, sodium bicarbonate administration may worsen hypocalcemia, so the serum calcium concentration should be monitored. Combating the acidemia, however, is not the mainstay of therapy, and concurrent administration of IV fomepizole or ethanol and preparation for possible hemodialysis are almost always indicated.

■ METFORMIN Metformin toxicity, either from overdose or therapeutic use in the setting of renal failure, may cause severe, life-threatening lactic acidosis. The use of high-dose sodium bicarbonate to correct the metabolic acidosis, as well as extracorporeal removal of the metformin, has been recommended in these cases.32

INCREASING XENOBIOTIC SOLUBILITY: METHOTREXATE Urinary alkalinization with sodium bicarbonate is routinely used during high-dose methotrexate cancer chemotherapy therapy. Methotrexate is predominantly eliminated unchanged in the urine. Unfortunately, it is poorly water soluble in acidic urine. Under these conditions, tubular precipitation of the methotrexate may occur, leading to nephrotoxicity and decreased elimination, increasing the likelihood of methotrexate toxicity. Administration of sodium bicarbonate (as well as intensive hydration) during high-dose methotrexate infusions increases methotrexate solubility and the elimination of methotrexate.22,78

NEUTRALIZATION: CHLORINE GAS Nebulized sodium bicarbonate serves as a useful adjunct in the treatment of patients with pulmonary injuries resulting from chlorine gas inhalation.2,21 Inhaled sodium bicarbonate neutralizes the hydrochloric acid that is formed when the chlorine gas reacts with the water in the respiratory tree. Although oral sodium bicarbonate is not recommended for neutralizing acid ingestions because of the problems associated with the exothermic reaction and production of carbon dioxide in the relatively closed gastrointestinal tract, the rapid exchange in the lungs of air with the environment facilitates heat dissipation. In a chlorine-inhalation sheep model, animals treated with 4% nebulized sodium bicarbonate solution demonstrated higher PO2 and lower PCO2 than did the normal, saline-treated animals.21 There was no difference, however, in 24-hour mortality or pulmonary histopathology. In a retrospective review, 86 patients with chlorine gas inhalation were treated with nebulized sodium bicarbonate.14 Sixty-nine patients were sent home from the emergency department, 53 of whom had clearly improved. In a more recent study, 44 patients who were diagnosed with reactive airway dysfunction syndrome after an acute exposure to chlorine gas were randomized to receive either nebulized sodium bicarbonate (4 mL of 4.2% NaHCO3 solution) or nebulized placebo.2 Both groups also received IV corticosteroids and inhaled β2 agonists. Compared with the placebo group, the nebulized sodium bicarbonate group had significantly higher forced expiratory volume in 1 second (FEV1) values at 120 and 240 minutes and scored significantly higher on a posttreatment quality of life questionnaire.

MAINTENANCE OF CHELATION EFFECT: DIMERCAPROL–METAL CHELATION Adverse effects and safety concerns may be associated with the dissociation of the dimercaprol (British anti-Lewisite [BAL]) metal binding

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that occurs in acid urine. Because dissociation of the BAL-metal chelate occurs in acidic urine, the urine of patients receiving BAL should be alkalinized with hypertonic NaHCO3 to a pH of 7.5 to 8.0 to prevent renal liberation of the metal.43

REDUCTION IN FREE RADICAL FORMATION: CONTRAST MEDIA Recent studies have suggested that sodium bicarbonate may be beneficial in preventing contrast-induced nephropathy (CIN).55 A randomized trial of 119 patients compared an infusion of 154 mEq/L of either sodium bicarbonate or sodium chloride before (3 mL/kg for 1 hour) and after (1 mL/kg/h for 6 hours) iopamidol administration. CIN, defined as a 25% or greater increase in serum creatinine concentration within 2 days of contrast, occurred in eight patients in the sodium chloride group and one patient in the sodium bicarbonate group. In another study comparing sodium bicarbonate with sodium chloride before emergency coronary angiography or intervention, the incidence of CIN was also significantly lower in the sodium bicarbonate group than in the sodium chloride group (7% vs. 35%).54 It is suggested that increasing medullary pH with sodium bicarbonate infusion might protect the kidneys from oxidant injury by slowing free radical production. The addition of N-acetylcysteine to a sodium bicarbonate hydration regimen to prevent CIN does not appear to offer any benefit compared with the use of only sodium bicarbonate hydration.67 Further study to define the optimal hydration strategy is recommended.38

SUMMARY Despite the increasing tendency to avoid sodium bicarbonate administration in critically ill acidemic patients, sodium bicarbonate remains an important antidote in the treatment of a wide variety of xenobiotic exposures. In fact, its utility in poisoned patients continues to expand. Sodium bicarbonate is effective in the treatment of patients with poisonings by CAs16 and other sodium channel blockers through its effects on drug ionization and subsequent diffusion from the sodium channel binding site. Sodium bicarbonate is effective for salicylates, phenobarbital, and other weak acids because of its ability to ion trap in the blood or brain and keep toxins away from the target organ.68 Sodium bicarbonate is effective as a neutralizing agent for inhaled acids such as chlorine gas. In the more common causes of metabolic acidosis with elevated lactate, specific therapy such as antibiotics, volume resuscitation, and inotropic support usually takes precedence over bicarbonate administration.

REFERENCES 1. Aschner JL, Poland RL, Aschner JL, Poland RL. Sodium bicarbonate: basically useless therapy. Pediatrics. 2008;122:831-835. 2. Aslan S, Kandis H, Akgun M, et al. The effect of nebulized NaHCO3 treatment on “RADS” due to chlorine gas inhalation. Inhal Toxicol. 2006;18:895900. 3. Bailey D. Cardiotoxic effects of quinidine and their treatment. Arch Intern Med. 1960;105:37-46. 4. Bar-Joseph G, Abramson NS, Kelsey SF, et al. Improved resuscitation outcome in emergency medical systems with increased usage of sodium bicarbonate during cardiopulmonary resuscitation. Acta Anaesthesiol Scand. 2005;49:6-15. 5. Bebarta VS, Waksman JC, Bebarta VS, Waksman JC. Amitriptylineinduced Brugada pattern fails to respond to sodium bicarbonate. Clin Toxicol (Phila). 2007;45:186-188.

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6. Beckman KJ, Parker RB, Hariman RJ, et al. Hemodynamic and electrophysiological actions of cocaine. Effects of sodium bicarbonate as an antidote in dogs. Circulation. 1991;83:1799-1807. 7. Bellet S, Hamdan G, Somiyo A, Lara R. The reversal of cardiotoxic effects of quinidine by molar sodium lactate: an experimental study. Am J Med Sci. 1959;237:165-176. 8. Bellet S, Wasserman F. The effects of molar sodium lactate in reversing the cardiotoxic effect of hyperpotassemia. Arch Intern Med. 1957;100:565-581. 9. Blackman K, Brown SG, Wilkes GJ. Plasma alkalinization for tricyclic antidepressant toxicity: a systematic review. Emerg Med (Fremantle). 2001;13:204-210. 10. Bloomer HA. A critical evaluation of diuresis in the treatment of barbiturate intoxication. J Lab Clin Med. 1966;67:898-905. 11. Bodenhamer JE, Smilkstein MJ. Delayed cardiotoxicity following quinine overdose: a case report. J Emerg Med. 1993;11:279-285. 12. Boehnert MT, Lovejoy FH Jr. Value of the QRS duration versus the serum drug level in predicting seizures and ventricular arrhythmias after an acute overdose of tricyclic antidepressants. N Engl J Med. 1985;313:474-479. 13. Borden TA, Bidwell CD. Treatment of acute ethylene glycol poisoning in rats. Invest Urol. 1968;6:205-210. 14. Bosse GM. Nebulized sodium bicarbonate in the treatment of chlorine gas inhalation. J Toxicol Clin Toxicol. 1994;32:233-241. 15. Boyd JH, Walley KR, Boyd JH, Walley KR. Is there a role for sodium bicarbonate in treating lactic acidosis from shock? Curr Opin Crit Care. 2008;14:379-383. 16. Bradberry SM, Thanacoody HK, Watt BE, et al. Management of the cardiovascular complications of tricyclic antidepressant poisoning: role of sodium bicarbonate. Toxicol Rev. 2005;24:195-204. 17. Brown TC. Sodium bicarbonate treatment for tricyclic antidepressant arrhythmias in children. Med J Aust. 1976;2:380-382. 18. Brown TC, Barker GA, Dunlop ME, Loughnan PM. The use of sodium bicarbonate in the treatment of tricyclic antidepressant-induced arrhythmias. Anaesth Intensive Care. 1973;1:203-210. 19. Brucculeri M, Kaplan J, Lande L, et al. Reversal of citalopram-induced junctional bradycardia with intravenous sodium bicarbonate. Pharmacotherapy. 2005;25:119-122. 20. Buchanan N, Kundig H, Eyberg C. Experimental salicylate intoxication in young baboons. A preliminary report. J Pediatr. 1975;86:225-232. 21. Chisholm C, Singletary E, Okerberg C, Langlinais P. Effect of hydration on sodium bicarbonate therapy for chlorine inhalation injuries [abstract]. Ann Emerg Med. 1988;18:466. 22. Christensen ML, Rivera GK, Crom WR, et al. Effect of hydration on methotrexate plasma concentrations in children with acute lymphocytic leukemia. J Clin Oncol. 1988;6:797-801. 23. Dukes D, Blainey J, Cumming G, Widdowson G. The treatment of severe aspirin poisoning. Lancet. 1963;2:329-331. 24. Engebretsen KM, Harris CR, Wood JE. Cardiotoxicity and late onset seizures with citalopram overdose. J Emerg Med. 2003;25:163-166. 25. Farrell S, Lee D, McNamara R. Amantadine overdose: considerations for the treatment of cardiac toxicity [abstract]. J Toxicol Clin Toxicol. 1995;33:516-517. 26. Flanagan RJ, Meredith TJ, Ruprah M, et al. Alkaline diuresis for acute poisoning with chlorophenoxy herbicides and ioxynil. Lancet. 1990;335:454-458. 27. Fox GN. Hypocalcemia complicating bicarbonate therapy for salicylate poisoning. West J Med. 1984;141:108-109. 28. Frenia ML, Schauben JL, Wears RL, et al. Multiple-dose activated charcoal compared to urinary alkalinization for the enhancement of phenobarbital elimination. J Toxicol Clin Toxicol. 1996;34:169-175. 29. Gaultier M. Sodium bicarbonate and tricyclic-antidepressant poisoning [letter]. Lancet. 1976;2:1258. 30. Graudins A, Vossler C, Wang R. Fluoxetine-induced cardiotoxicity with response to bicarbonate therapy. Am J Emerg Med. 1997;15:501-503. 31. Gutman A, Sirota J. A study by simultaneous clearance techniques of salicylate excretion in man: effects of alkalinization of the urine by bicarbonate administration: effect of probenecid. J Clin Invest. 1955;34:711-722. 32. Harvey B, Hickman C, Hinson G, et al. Severe lactic acidosis complicating metformin overdose successfully treated with high-volume venovenous hemofiltration and aggressive alkalinization. Pediatr Crit Care Med. 2005;6:598-601. 33. Herken W, Rietbrock N. The influence of blood-pH on ionization, distribution, and toxicity of formic acid. Naunyn Schmiedebergs Arch Exp Pathol Pharmakol. 1968;260:142-143.

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34. Hill JB. Experimental salicylate poisoning: observations on the effects of altering blood pH on tissue and plasma salicylate concentrations. Pediatrics. 1971;47:658-665. 35. Hill JB. Salicylate intoxication. N Engl J Med. 1973;288:1110-1113. 36. Hoffman JR, McElroy CR. Bicarbonate therapy for dysrhythmia and hypotension in tricyclic antidepressant overdose. West J Med. 1981;134:60-64. 37. Hoffman JR, Votey SR, Bayer M, Silver L. Effect of hypertonic sodium bicarbonate in the treatment of moderate-to-severe cyclic antidepressant overdose. Am J Emerg Med. 1993;11:336-341. 38. Hogan SE, L’Allier P, Chetcuti S, et al. Current role of sodium bicarbonatebased preprocedural hydration for the prevention of contrast-induced acute kidney injury: a meta-analysis. Am Heart J. 2008;156:414-421. 39. Jacobsen D, McMartin KE. Methanol and ethylene glycol poisonings. Mechanism of toxicity, clinical course, diagnosis and treatment. Med Toxicol. 1986;1:309-334. 40. Jacobsen D, Webb R, Collins TD, McMartin KE. Methanol and formate kinetics in late diagnosed methanol intoxication. Med Toxicol Adverse Drug Exp. 1988;3:418-423. 41. Kerns W 2nd, Garvey L, Owens J. Cocaine-induced wide complex dysrhythmia. J Emerg Med. 1997;15:321-329. 42. Kingston ME. Hyperventilation in tricyclic antidepressant poisoning. Crit Care Med. 1979;7:550-551. 43. Klaassen CD. Heavy metals and heavy metal antagonist. In: Hardman JG, Limbird LE, eds. The Pharmacological Basis of Therapeutics, 10th ed. New York: Macmillan; 2001:1851-1875. 44. Knudsen K, Abrahamsson J. Epinephrine and sodium bicarbonate independently and additively increase survival in experimental amitriptyline poisoning. Crit Care Med. 1997;25:669-674. 45. Kraut JA, Kurtz I. Use of base in the treatment of severe acidemic states. Am J Kidney Dis. 2001;38:703-727. 46. Kulig K, Duffy J, Linden C, Rumack B. Toxic effects of methanol, ethylene glycol, and isopropyl alcohol. Top Emerg Med. 1984;6:14-28. 47. Lassen N. Treatment of severe acute barbiturate poisoning by forced diuresis and alkalinization of the urine. Lancet. 1960;2:338-342. 48. Lawson AA, Proudfoot AT, Brown SS, et al. Forced diuresis in the treatment of acute salicylate poisoning in adults. Q J Med. 1969;38:31-48. 49. Levitt MA, Sullivan JB Jr, Owens SM, et al. Amitriptyline plasma protein binding: effect of plasma pH and relevance to clinical overdose. Am J Emerg Med. 1986;4:121-125. 50. Liebelt EL, Ulrich A, Francis PD, Woolf A. Serial electrocardiogram changes in acute tricyclic antidepressant overdoses. Crit Care Med. 1997;25:17211726. 51. Love JN, Howell JM, Newsome JT, et al. The effect of sodium bicarbonate on propranolol-induced cardiovascular toxicity in a canine model. J Toxicol Clin Toxicol. 2000;38:421-428. 52. Macpherson C, Milne MD, Evans B. The excretion of salicylate. Br J Pharmacol. 1955;10:484-489. 53. Martin-Amat G, McMartin KE, Hayreh SS, et al. Methanol poisoning: ocular toxicity produced by formate. Toxicol Appl Pharmacol. 1978;45:201-208. 54. Masuda M, Yamada T, Mine T, et al. Comparison of usefulness of sodium bicarbonate versus sodium chloride to prevent contrast-induced nephropathy in patients undergoing an emergent coronary procedure. Am J Cardiol. 2007;100:781-786. 55. Merten GJ, Burgess WP, Gray LV, et al. Prevention of contrast-induced nephropathy with sodium bicarbonate: a randomized controlled trial. JAMA. 2004;291:2328-2334. 56. Milne M, Scribner B, Crawford M. Non-ionic diffusion and the excretion of weak acids and bases. Am J Med. 1958;24(5):709-729. 57. Mohammed Ebid AH, Abdel-Rahman HM. Pharmacokinetics of phenobarbital during certain enhanced elimination modalities to evaluate their clinical efficacy in management of drug overdose. Ther Drug Monit. 2001;23:209-216. 58. Mollaret P, Rapin M, Pocidalo J, Monsallier J. Treatment of acute barbiturate intoxication through plasmatic and urinary alkalinization. Presse Med. 1959;67:1435-1437. 59. Molloy DW, Penner SB, Rabson J, Hall KW. Use of sodium bicarbonate to treat tricyclic antidepressant-induced arrhythmias in a patient with alkalosis. Can Med Assoc J. 1984;130:1457-1459. 60. Moore DF, Bentley AM, Dawling S, et al. Folinic acid and enhanced renal elimination in formic acid intoxication. J Toxicol Clin Toxicol. 1994;32:199-204. 61. Myschetzky A, Lassen N. Urea-induced, osmotic diuresis and alkalization of urine in acute barbiturate intoxication. JAMA. 1963;185:936-942.

62. Nattel S, Mittleman M. Treatment of ventricular tachyarrhythmias resulting from amitriptyline toxicity in dogs. J Pharmacol Exp Ther. 1984;231:430-435. 63. Neuvonen PJ, Karkkainen S. Effects of charcoal, sodium bicarbonate, and ammonium chloride on chlorpropamide kinetics. Clin Pharmacol Ther. 1983;33:386-393. 64. O’Connor N, Greene S, Dargan P, et al. Prolonged clinical effects in modified-release amitriptyline poisoning. Clin Toxicol (Phila). 2006;44:77-80. 65. Oliver T, Dyer M. The prompt treatment of salicylism with sodium bicarbonate. Am J Dis Child. 1960;99:553-564. 66. Ortega-Carnicer J, Bertos-Polo J, Gutierrez-Tirado C. Aborted sudden death, transient Brugada pattern, and wide QRS dysrrhythmias after massive cocaine ingestion. J Electrocardiol. 2001;34:345-349. 67. Ozcan EE, Guneri S, Akdeniz B, et al. Sodium bicarbonate, N-acetylcysteine, and saline for prevention of radiocontrast-induced nephropathy. A comparison of 3 regimens for protecting contrast-induced nephropathy in patients undergoing coronary procedures. A single-center prospective controlled trial. Am Heart J. 2007;154:539-544. 68. Parker RB, Perry GY, Horan LG, Flowers NC. Comparative effects of sodium bicarbonate and sodium chloride on reversing cocaine-induced changes in the electrocardiogram. J Cardiovasc Pharmacol. 1999;34:864-869. 69. Pentel P, Benowitz N. Efficacy and mechanism of action of sodium bicarbonate in the treatment of desipramine toxicity in rats. J Pharmacol Exp Ther. 1984;230:12-19. 70. Pentel PR, Benowitz NL. Tricyclic antidepressant poisoning. Management of arrhythmias. Med Toxicol. 1986;1:101-121. 71. Pentel PR, Goldsmith SR, Salerno DM, et al. Effect of hypertonic sodium bicarbonate on encainide overdose. Am J Cardiol. 1986;57:878-880. 72. Pentel PR, Keyler DE. Effects of high dose alpha-1-acid glycoprotein on desipramine toxicity in rats. J Pharmacol Exp Ther. 1988;246:1061-1066. 73. Prescott LF, Park J, Darrien I. Treatment of severe 2,4-D and mecoprop intoxication with alkaline diuresis. Br J Clin Pharmacol. 1979;7:111-116. 74. Proudfoot AT, Krenzelok EP, Brent J, Vale JA. Does urine alkalinization increase salicylate elimination? If so, why? Toxicol Rev. 2003;22:129-136. 75. Reimold EW, Worthen HG, Reilly TP Jr. Salicylate poisoning. Comparison of acetazolamide administration and alkaline diuresis in the treatment of experimental salicylate intoxication in puppies. Am J Dis Child. 1973;125:668-674. 76. Roe O. Methanol poisoning: its clinical course, pathogenesis, and treatment. Acta Med Scand. 1946;126(suppl 182):1-253. 77. Salerno DM, Murakami MM, Johnston RB, et al. Reversal of flecainideinduced ventricular arrhythmia by hypertonic sodium bicarbonate in dogs. Am J Emerg Med. 1995;13:285-293. 78. Sand TE, Jacobsen S. Effect of urine pH and flow on renal clearance of methotrexate. Eur J Clin Pharmacol. 1981;19:453-456. 79. Sasyniuk BI, Jhamandas V. Mechanism of reversal of toxic effects of amitriptyline on cardiac Purkinje fibers by sodium bicarbonate. J Pharmacol Exp Ther. 1984;231:387-394. 80. Sasyniuk BI, Jhamandas V, Valois M. Experimental amitriptyline intoxication: treatment of cardiac toxicity with sodium bicarbonate. Ann Emerg Med. 1986;15:1052-1059. 81. Savege TM, Ward JD, Simpson BR, Cohen RD. Treatment of severe salicylate poisoning by forced alkaline diuresis. Br Med J. 1969;1:35-36. 82. Segar WE. The critically ill child: salicylate intoxication. Pediatrics. 1969;44:440-444. 83. Seger DL, Hantsch C, Zavoral T, Wrenn K. Variability of recommendations for serum alkalinization in tricyclic antidepressant overdose: a survey of U.S. Poison Center medical directors. J Toxicol Clin Toxicol. 2003;41:331-338. 84. Sharma AN, Hexdall AH, Chang EK, et al. Diphenhydramine-induced wide complex dysrhythmia responds to treatment with sodium bicarbonate. Am J Emerg Med. 2003;21:212-215. 85. Smilkstein MJ. Reviewing cyclic antidepressant cardiotoxicity: wheat and chaff. J Emerg Med. 1990;8:645-648. 86. Smith P, Gleason H, Stoll C. Studies on the pharmacology of salicylates. J Pharmacol Exp Ther. 1946;87:237-255. 87. Snodgrass W, Rumack BH, Peterson RG, Holbrook ML. Salicylate toxicity following therapeutic doses in young children. Clin Toxicol. 1981;18:247-259. 88. Stork CM, Redd JT, Fine K, Hoffman RS. Propoxyphene-induced wide QRS complex dysrhythmia responsive to sodium bicarbonate—a case report. J Toxicol Clin Toxicol. 1995;33:179-183. 89. Tanen DA, Ruha AM, Curry SC, et al. Hypertonic sodium bicarbonate is effective in the acute management of verapamil toxicity in a swine model. Ann Emerg Med. 2000;36:547-553.

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90. Temple AR. Acute and chronic effects of aspirin toxicity and their treatment. Arch Intern Med. 1981;141:364-369. 91. Viallon A, Zeni F, Lafond P, et al. Does bicarbonate therapy improve the management of severe diabetic ketoacidosis? Crit Care Med. 1999;27:26902693. 92. Vukmir RB, Katz L, Sodium Bicarbonate Study Group. Sodium bicarbonate improves outcome in prolonged prehospital cardiac arrest. Am J Emerg Med. 2006;24:156-161. 93. Waddell W, Butler T. The distribution and excretion of phenobarbital. J Clin Invest. 1957;36:1217-1226. 94. Wang RY. pH-dependent cocaine-induced cardiotoxicity. Am J Emerg Med. 1999;17:364-369.

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95. Wasserman F, Brodsky L, Dick M, et al. Successful treatment of quinidine and procainamide intoxication. N Engl J Med. 1958;259:797-802. 96. Whitten C, Kesaree N, Goodwin J. Managing salicylate poisoning in children. Am J Dis Child. 1961;101:178-194. 97. Wilson LD, Shelat C. Electrophysiologic and hemodynamic effects of sodium bicarbonate in a canine model of severe cocaine intoxication. J Toxicol Clin Toxicol. 2003;41:777-788. 98. Winecoff AP, Hariman RJ, Grawe JJ, et al. Reversal of the electrocardiographic effects of cocaine by lidocaine. Part 1. Comparison with sodium bicarbonate and quinidine. Pharmacotherapy. 1994;14:698-703. 99. Yip L, Dart RC, Gabow PA. Concepts and controversies in salicylate toxicity. Emerg Med Clin North Am. 1994;12:351-364.

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CHAPTER 36

NONSTEROIDAL ANTIINFLAMMATORY DRUGS William J. Holubek Nonsteroidal antiinflammatory drugs (NSAIDs) comprise a class of xenobiotics with analgesic, antipyretic, and antiinflammatory properties. These desirable clinical effects account for the extensive list of approved clinical uses, including the treatment of pain, inflammation, and fever, as well as the management of connective tissue, immunologic, and rheumatologic diseases.55 In addition to the countless benefits of NSAIDs, some deleterious and life-threatening effects are associated with both their therapeutic use and overdose. In an attempt to circumvent some of these adverse effects, selective cyclooxygenase-2 (COX-2) inhibitors were introduced to the market but one was withdrawn because of their own toxicity profiles. The term NSAID used in this chapter does not refer to salicylates, which are unique members of the NSAID class and are covered in Chapter 35.

HISTORY AND EPIDEMIOLOGY The discovery of NSAIDs began with the creation of acetyl salicylic acid (aspirin) by Felix Hoffman in 1897.59 Searching for an antirheumatic xenobiotic with less adverse gastrointestinal (GI) effect than aspirin, Stewart Adams and John Nicholson discovered and developed 2-(4-isobutylphenyl) propionic acid, now known as ibuprofen, in 1961. Ibuprofen was initially marketed under the trade name Brufen in the United Kingdom in 1969 and was introduced to the U.S. market in 1974. Ibuprofen became available without a prescription in the United States by 1984. More than a decade later, in 1999, the first selective COX-2 inhibitor, rofecoxib, was approved by the U.S. Food and Drug Administration (FDA), but it was withdrawn in 2004 after increased myocardial infarctions and cerebrovascular accidents were associated with its use. The American Association of Poison Control Centers (AAPCC) compiles data from participating poison centers throughout the United States using the National Poison Data System (NPDS), formerly known as the Toxic Exposure Surveillance System (TESS). Approximately 4% of all human exposures reported to the AAPCC from 2003 to 2007 were to NSAIDs (including COX-2 inhibitors, ibuprofen, ibuprofen with hydrocodone, indomethacin, ketoprofen, naproxen, and others), which translates to about 90,000 to 100,000 calls annually. In 2006, the AAPCC introduced a Fatality Review Team, which attempts to determine the relationship between exposure and death. The 2006 and 2007 annual reports assigned five deaths and 107 life-threatening manifestations to NSAID exposure (see Chap. 135). Ibuprofen, naproxen, and ketoprofen are currently the only nonprescription NSAIDs in the United States. NSAIDs are also contained in cough and cold preparations and in prescription combination drugs (eg, ibuprofen with hydrocodone) and have occasionally been found as adulterants in herbal preparations.64 NSAIDs are considered among the most commonly used and prescribed medications in the world.10,75 An estimated one in seven

patients with rheumatologic diseases is given a prescription for NSAIDs, and another one in five U.S. citizens uses NSAIDs for acute common complaints.99

PHARMACOLOGY These chemically heterogeneous compounds can be divided into carboxylic acid and enolic acid derivatives and COX-2 selective inhibition (Table 36–1). They all share the ability to inhibit prostaglandin (PG) synthesis. PG synthesis begins with the activation of phospholipases (commonly, phospholipase A2 or PLR) that cleave phospholipids in the cell membrane to form arachidonic acid (AA). AA is metabolized by PG endoperoxide G/H synthase, otherwise known as COX, to form many eicosanoids, including PGs and the prostanoids, prostacyclin (PGI2) and thromboxane (TXA2). AA can also be metabolized by lipoxygenase (LOX) to form hydroperoxy eicosatetraenoic acid (HPETE), which is converted to many different leukotrienes (LTs) that are involved in creating a proinflammatory environment (Fig. 36–1). The COX enzyme responsible for PG production exists in two isoforms termed COX-1 and COX-2. COX-1 is constitutively expressed by virtually all cells throughout the body but is the only isoform found within platelets. This enzyme produces eicosanoids that govern “housekeeping” functions, including vascular homeostasis and hemostasis, gastric cytoprotection, and renal blood flow and function.11,79 COX-2, on the other hand, is rapidly induced (within 1 to 3 hours) in inflammatory tissue by laminar shear (or mechanical) forces and cytokines, producing PGs involved in the inflammatory response. COX-2 is also upregulated by several cytokines, growth factors, and tumor promoters involved with cellular differentiation and mitogenesis, suggesting a role in cancer development.11,31,85 Glucocorticoids can both inhibit PLA and downregulate the induced expression of COX-2, which decreases the production of eicosanoids and PGs, respectively. Most NSAIDs nonselectively inhibit the COX enzymes in a competitive or time-dependent, reversible manner, unlike salicylates which irreversibly acetylate COX (see Chap. 35). Inhibiting COX-1 can interrupt tissue homeostasis, leading to deleterious clinical effects. In what may seem advantageous, some NSAIDs (eg, etodolac, meloxicam, and nimesulide) preferentially inhibit COX-2 over COX-1; others were specifically designed to selectively inhibit COX-2 (eg, celecoxib).97 As will be discussed later in this chapter, many of the selective COX-2 inhibitors (sometimes referred to as coxibs) were removed from the market in the United States because of their increased risk of adverse cardiovascular events. NSAIDs do not directly affect the LOX enzyme and the production of LTs; however, some data suggest that blocking the COX enzymes allows AA to be shunted toward the LOX pathway, increasing the production of proinflammatory and chemotactic-vasoactive LTs.55,99

PHARMACOKINETICS AND TOXICOKINETICS Most NSAIDs are organic acids with extensive protein binding (>90%) and small volumes of distribution of approximately 0.1 to 0.2 L/kg. Oral absorption of most NSAIDs occurs rapidly, resulting in bioavailabilities above 80%. Time to peak plasma concentrations achieved by NSAIDs can differ widely (see Table 36–1).17 NSAIDs differ with regard to their sites of both action and accumulation within the body. For example, significant synovial concentrations are attained by indomethacin, tolmetin, diclofenac, ibuprofen, and piroxicam.17 Some NSAIDs cross the blood–brain barrier, achieving significant cerebrospinal fluid (CSF) concentrations. The mechanism and chemical properties related to these properties are not well defined, but evidence suggests that NSAIDs with either very high or very low lipophilicity do

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Nonsteroidal Antiinflammatory Drugs

529

TABLE 36–1. Classes and Pharmacology of Selected Nonsteroidal Antiinflammatory Drugs8,17,18,29,56,65 Time to Peak Plasma Concentration (h)

Half-Life (h)

Pharmacokinetics

Unique Features

CARBOXYLIC ACIDS Acetic Acids Diclofenaca,e

2–3

1–2

Etodolac Indomethacin Ketorolac Sulindac

1 1–2 90 95 15 >90∗∗ 0 40–60

1–2 100 40 10 95 1 27 80 μg/dL or >35 μmol/L) occurs in 16%–52% of patients receiving chronic VPA therapy.33,127,184

■ MANAGEMENT Supportive management is sufficient to ensure complete recovery in most patients with VPA overdoses. Discontinuation of all medications that likely affect VPA metabolism is also recommended (Table 47-2). MDAC is useful in preventing absorption of VPA, especially in overdoses of enteric-coated or extended-release preparations.3,49 As expected, naloxone is not effective in VPA-induced CNS or respiratory depression.26,77,180 L-Carnitine should be administered if evidence indicates the presence of hyperammonemia or hepatotoxicity.36,80 Intravenous carnitine is preferred in symptomatic patients whereas oral L-carnitine is sufficient in asymptomatic patients. The intravenous loading dose is 100 mg/kg over 30 minutes (maximum 6 g) followed by 15 mg/kg IV over 10– 30 minutes every 4 hours until clinical improvement occurs (Antidotes in Depth A9: l-Carnitine). Published data on extracorporeal removal of VPA are limited. Hemodialysis alone reduced the elimination half-life of VPA to 2.2–2.9 hours.18,39,68,74,78,159 Charcoal hemoperfusion alone and in combination with hemodialysis were not superior to hemodialysis alone.52,63,161,176 Continuous venovenous hemodialfiltration did not significantly improve elimination in one patient with a serum valproic acid concentration of 1402 mg/L.82 Since hemodialysis will additionally remove ammonia it is also recommended for hemodynamically or neurologically unstable patients or patients who have severe metabolic disturbances such as lifethreatening hyperammonemia following VPA overdose.4

■ VIGABATRIN Vigabatrin, or vinyl GABA, is a stereospecific irreversible inhibitor of GABA-transaminase. Although vigabatrin has a short elimination halflife, its duration of action is 24 hours. Dosage adjustments are necessary in patients with impaired renal function.113 Agitation, coma, and long-term psychosis are reported after acute ingestion.35,99 Chronic toxicity may result in psychosis, dizziness, vision loss and tremor, which usually is mild and transient, as well as depression and psychosis.99 Treatment of vigabatrin toxicity is largely supportive. Severe agitation is best treated with IV benzodiazepines. Some cases of mild vigabatrin-induced psychosis resolve simply by withdrawal of the medication.99

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Chapter 47

■ ZONISAMIDE Zonisamide is a sulfonamide derivative that inhibits sodium channels, low-voltage T-type calcium channels, and possibly also inhibits carbonic anhydrase similarly to topiramate.113 Somnolence is a commonly reported adverse effect. Overdose experience with zonisamide is limited. In one case report, status epilepticus, coma, and death were attributed to zonisamide overdose despite a minimally elevated concentration of 44 mg/L (therapeutic 10–40 mg/L).175 Activated charcoal should be considered. Supportive care is recommended.

DRESS SYNDROME OR ANTICONVULSANT HYPERSENSITIVITY SYNDROME Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome, previously named “drug hypersensitivity syndrome,” is a severe adverse drug event that was first described in 1950.177 DRESS syndrome is a distinct severe adverse drug reaction triad characterized by fever, rash, and internal organ involvement. DRESS occurs in approximately 1 of every 1000–10,000 uses of anticonvulsants, usually aromatic anticonvulsants such as phenytoin, carbamazepine, phenobarbital, primidone, and lamotrigine. Literature also supports the inclusion of oxcarbazepine as a causative agent. The incidence remains the same regardless of the patient’s gender and ethnic origin. Data suggest a genetic defect in drug metabolism as the causative lesion. First-degree relatives of patients with DRESS have a 25% risk of developing this syndrome.92,185 DRESS occurs most frequently within the first 2 months of therapy and is not related to dose or serum concentration. The pathophysiology is related to the accumulation of reactive arene oxide metabolites resulting from decreased epoxide hydrolase enzyme activity. These metabolites bind to macromolecules and cause cellular apoptosis and necrosis. They also form neoantigens that may trigger immunologic responses. Interestingly, the same metabolite is believed to cause other serious dermatologic reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis (see Chap. 29 and Figure 29–4). Initial symptoms also include malaise and pharyngitis (including tonsillitis). A skin eruption characterized by macular erythema evolves into a pruritic and confluent papular rash primarily involving the face, trunk, and later the extremities. A tender lymphadenopathy usually follows. The rash usually spares the mucous membranes but severely affected cases develop toxic epidermal necrolysis. Multiorgan involvement usually occurs 1–2 weeks into the syndrome. The liver is the most frequently affected organ, although involvement of the CNS (encephalitis), cardiac muscle (myocarditis), lungs (pneumonitis), renal system (nephritis), and thyroid (hyperthyroid thyroiditis followed by hypothyroidism) are possible. Eosinophilia and mononucleosis-type atypical lymphocytosis are common. Liver disturbances range from mildly elevated aminotransferase concentrations to fulminant hepatic failure.92,185 Fatality rates are reportedly as high as 10%.177 Skin biopsies reveal nonspecific perivascular lymphocytic infiltration, spongiotic or lichenoid dermatitis, and variable degrees of edema.185 Lymph node histology reveals benign hyperplasia, atypical lymphoid cells, or lymphoma. Other laboratory abnormalities include a positive rheumatoid factor, antinuclear antibodies, anti– double-stranded DNA smooth muscle antibodies, cold agglutinins, and hypogammaglobinemia or hypergammaglobulinemia. A novel, easy, fast, objective lymphocyte toxicity assay is being studied.124 Prompt discontinuation of the offending agent is essential to prevent symptom progression. Patients should be admitted to the hospital and receive methylprednisolone 0.5–1 mg/kg/d divided in four doses.27,185 Other promising therapies include use of IV immunoglobulin.111,149,185

Anticonvulsants

707

In one case series, 90% of patients with DRESS showed in vitro crossreactivity to other aromatic antiepileptics.1 Based on this evidence, avoidance of phenytoin, carbamazepine, phenobarbital, primidone, lamotrigine, and oxcarbazepine is recommended whereas benzodiazepines, levetiracetam, VPA, gabapentin, topiramate, and tiagabine are safe alternatives.158

SUMMARY All anticonvulsant drugs produce CNS symptoms when taken in overdose and therefore differentiation based on clinical findings is difficult. Lethargy, sedation, ataxia, and nystagmus occur following overdoses of almost all the anticonvulsants. Coma occurs following substantial overdose of all anticonvulsants with the exception of gabapentin. Seizures, including status epilepticus, may occur with carbamazepine, lamotrigine, tiagabine, topiramate and zonisamide overdoses. Hemodynamic instability and abnormal electrocardiograms are rare findings. Carbamazepine, lamotrigine, and possibly topiramate can cause QRS prolongation. Electrolyte abnormalities occur following overdoses with carbamazepine, oxcarbezipine, VPA and topiramate. Topiramate is uniquely associated with hyperchloremic metabolic acidosis. Except for VPA overdoses there are no specific antidotes or overdoses of anticonvulsants. Supportive care alone usually yields beneficial outcomes. Administration of activated charcoal is generally recommended because of its safety and efficacy. Anticonvulsant-induced seizures are treated with benzodiazepines, barbiturates, or propofol. Patients with severe VPA overdoses or VPA-induced hyperammonemia should be treated with carnitine. Extracorporeal drug removal is rarely necessary and should be reserved for severe carbamazepine, VPA, or topiramate overdose patients with concurrent electrolyte abnormalities, hemodynamic instability, and/or clinical deterioration. Data on overdoses with the newer anticonvulsants are limited.

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14. Brahmi K, Kouraic N, Thabet N, Amamou N. Influence of activated charcoal on pharmacokinetics and clinical features of carbamazepine poisoning. Am J Emerg Med. 2006;24:440-443. 15. Briassoulis G, Kalabalikis P, Tamiolaki M. Lamotrigine childhood overdose. Pediatr Neurol. 1998;19:239-242. 16. Bridge TA, Norton RL, Robertson WO. Pediatric carbamazepine overdoses. Pediatr Emerg Care. 1994;10:260-263. 17. Browne TR, Kugler AR, Eldon MA. Pharmacology and pharmacokinetics of fosphenytoin. Neurology. 1996;46:S3-S7. 18. Brubacher JR, Dahghani P, McKnight D. Delayed toxicity following ingestion of enteric-coated divalproex sodium (Epival). J Emerg Med. 1999;17:463-467. 19. Bryant AE, Dreifuss FE. Valproic acid hepatic fatalities: US experience since 1986. Neurology. 1996;46:465-469. 20. Buckley NA, Whyte IM, Dawson AH. Self-poisoning with lamotrigine. Lancet. 1993;342:1552-1553. 21. Butler TC, Rosen RM, Wallace AL, Amsden G. Flumazenil and dialysis for gabapentin-induced coma. Ann Pharmacother. 2003;37:74-76. 22. Cameron RJ, Hungerford P, Dawson AH. Efficacy of charcoal hemoperfusion in massive carbamazepine poisoning, J Toxicol Clin Toxicol. 2002;40:507-512. 23. Camilleri C, Albertson T, Offerman S. Fatal cerebral edema after moderate valproic acid overdose. Ann Emerg Med. 2005;45:337-338. 24. Cantrell FL, Ritter M, Himes E. Intentional overdose with tiagabine: an unusual clinical presentation. J Emerg Med. 2004;27:271-272. 25. Chaikin P, Adir J. Unusual absorption profile of phenytoin in a massive overdose case. J Clin Pharmacol. 1987;27:70-73. 26. Chan YC, Tse ML, Lau FL. Two cases of valproic acid poisoning treated with L-carnitine. Hum Exp Toxicol. 2007;26:967-969. 27. Chopra S, Levell NJ, Cowley G, et al. Systemic corticosteroids in the phenytoin hypersensitivity syndrome. Br J Dermatol. 1996;134:1109-1112. 28. Chua HC, Venketasubramanian N, Tjia H, et al. Elimination of phenytoin in toxic overdose. Clin Neurol Neurosurg. 2000;102:6-8. 29. Chung AM, Reed MD. Intentional topiramate ingestion in an adolescent female. Ann Pharmacother. 2004;38:1439-1442. 30. Comer JB. Extravasation from intravenous phenytoin. Intrav Ther Clin Nutr. 1984;11:23-29. 31. Connacher AA, Macnab JP, Jung RT. Fatality due to massive overdose of sodium valproate. Scott Med J. 1987;32:85-86. 32. Corday E, Enescu V, Vyden JK, et al. Antiarrhythmic properties of carbamazepine. Geriatrics. 1971;26:78-81. 33. Coulter DL, Allen RJ. Secondary hyperammonemia: a possible mechanism for valproate encephalopathy. Lancet. 1980;1:1310-1311. 34. Craig S. Phenytoin poisoning. Neurocrit Care. 2005;3:161-170. 35. Davie MB, Cook MJ, Ng C. Vigabatrin overdose. Med J Aust. 1996;165:403. 36. DeVivo DC, Bohan TP, Coulter DL, et al. L-Carnitine supplementation in childhood epilepsy: current perspectives. Epilepsia. 1998;39:1216-1225. 37. De Schoenmakere G, De Waele J, Terryn W, et al. Phenytoin intoxication in critically ill patients. Am J Kidney Dis. 2005;45:189-192. 38. De Zeuw R, Westemberg H, Van der Kleijn E. An unusual case of carbamazepine poisoning with a near fatal relapse after two days. J Toxicol Clin Toxicol. 1979;14:263-269. 39. Dharnidherka VR, Fennell RS 3rd, Richard GA. Extracorporeal removal of toxic valproic acid levels in children. Pediatr Nephrol. 2002;17:312-315. 40. Dodgson SJ, Shank RP, Maryanoff BE. Topiramate as an inhibitor of carbonic anhydrase isoenzymes. Epilepsia. 2000;41:S35-S39. 41. Dogukan A, Aygen B, Berilgen MS. Gabapentin-induced coma in a patient with renal failure. Hemodial Int. 2006;10:168-169. 42. Dreifuss FE, Langer DH, Moline KA, et al. Valproic acid hepatic fatalities. Neurology. 1989:39:201-207. 43. Drenck NE, Risbo A. Carbamazepine poisoning, a surprisingly severe case. Anesth Intens Care. 1980;8:203-204. 44. Durelli L, Massazza V, Cavallo R. Carbamazepine toxicity and poisoning. Incidence, clinical features and management. Med Toxicol Adv Drug Exp. 1989;4:95-107. 45. Earnest MP, Marx JA, Drury LR. Complications of intravenous phenytoin for acute treatment of seizures. JAMA. 1983;249:762-765. 46. Evers ML, Ishar A, Agil A. Cardiac monitoring after phenytoin overdose. Heart Lung. 1997;26:325-328. 47. Eyer F, Flegenhauer N, Gempel K, et al. Acute valproate poisoning: pharmacokinetics, alterations of fatty acid metabolism and changes during therapy. J Clin Psychopharmacol. 2005;25:376-380.

48. Farrar HC, Harold DA, Reed MD. Acute valproic acid intoxication: enhanced drug clearance with oral-activated charcoal. Crit Care Med. 1993;21:299-301. 49. Fakhoury T, Murray L, Seger D, et al. Topiramate overdose: clinical and laboratory features. Epilepsy Behav. 2002:3:185-189. 50. Fischer JH, Patel TV, Fischer PA. Fosphenytoin clinical pharmacokinetics and comparative advantages in acute treatment of seizures. Clin Pharmacol. 2003;42(1):33-58. 51. Fleishman A, Chiang VW. Carbamazepine overdose recognized by a tricyclic antidepressant assay. Pediatrics. 2001;107:176-177. 52. Franssen EJ, van Essen GG, Portman AT, et al. Valproic acid toxicokinetics serial hemodialysis and hemoperfusion. Ther Drug Monit. 1999;21: 289-292. 53. French JA, Pedley TA. Initial management of epilepsy. N Engl J Med. 2008;359:166-176. 54. Fulton JA, Hoffman RS, Nelson LS. Tiagabine overdose: a case of status epilepticus in a non-epileptic individual. Clin Toxcol. 2005;43:869-871. 55. Furlanat M, Franceshi L, Poz D, et al. Acute oxcarbazepine, benazepril and hydrochlorothiazide overdose with alcohol. Ther Drug Monit. 2006;28:267-268. 56. Gandelman MS. Review of carbamazepine-induced hyponatremia. Prog Neuropsychopharmacol Biol Psychiatry. 1994;18:211-233. 57. Garnett WR. Clinical pharmacology of topiramate: a review. Epilepsia. 2000;41:61-65. 58. Gary NE, Byra WM, Eisinger RP. Carbamazepine poisoning: treatment by hemoperfusion. Nephron. 1981;27:202-203. 59. Gee NS, Brown JP, Dissanayake VU, et al. The novel anticonvulsant drug gabapentin (Neurontin) binds to the alpha-2-delta subunit of a calcium channel. J Biol Chem. 1996;271:5768-5776. 60. Gilman JT. Lamotrigine: an antiepileptic agent for the treatment of partial seizures. Ann Pharmacother. 1993;29:144-151. 61. Goldschlager AW, Karliner JS. Ventricular standstill after intravenous diphenylhydantoin. Am Heart J. 1967;74:410-412. 62. Gordon MF, Gerstenblitt D. The use of free phenytoin levels in averting phenytoin toxicity. N Y State J Med. 1990;90:469-470. 63. Graudins A, Aaron CK. Delayed peak serum valproic acid in massive divalproex overdose: treatment with charcoal hemoperfusion. J Toxicol Clin Toxicol. 1996;34:335-341. 64. Graudins A, Peden GD, Owsett RP. Massive overdose with controlledrelease carbamazepine resulting in delayed peak serum concentrations and life-threatening toxicity. Emerg Med. 2002;14:89-94. 65. Graves NM. Felbamate. Ann Pharmacother. 1993;27:1073-1081. 66. Grunewald R. Levetiracetam in treatment of idiopathic epilepsies. Epilepsia. 2005;46(Suppl9):154-160. 67. Heckman JG, Ultrich K, Dutsch M, et al. Pregabalin associated asterixis. Am J Phys Med Rehabil. 2006;84:724. 68. Hicks LK, McFarlane PA. Valproic acid overdose and haemodialysis. Nephrol Dial Transplant. 2001;16:1483-1486. 69. Hojer J, Malmlund HO, Berg A. Clinical features in 28 consecutive cases of laboratory confirmed massive poisoning with carbamazepine alone. J Toxicol Clin Toxicol. 1993;31:449-458. 70. Hung TY, Seow VK, Chong CF, et al. Gabapentin toxicity: an important cause of altered consciousness in patients with uraemia. Emerg Med J. 2008;25:178-179. 71. Isacsson G, Holmgren P, Druid H, Bergman U. Psychotropics and suicide prevention. Implication from toxicological screening of 5281 suicides in Sweden 1992–1994. Br J Psychiatry. 1999;174:259-265. 72. Jette N, Cappell J, VanPassel L, et al. Tiagabine-induced nonconvulsive status epilepticus in an adolescent without epilepsy. Neurology. 2006;67:1514-1515. 73. Johannessen SI, Battino D, Berry DJ, et al. Therapeutic drug monitoring of the newer antiepileptic drugs. Ther Drug Monit. 2003;25:347-363. 74. Johnson LZ, Martinez I, Fernandez MC, et al. Successful treatment of valproic acid overdose with hemodialysis. Am J Kidney Dis. 1999;33:786-789. 75. Jolliff Ha, Fehrenbacher N, Dart RC. Bradycardia, hypotension and tinnitus after accidental oxcarbazepine overdose. Clin Toxicol. 2001;39:316-317 [abstract]. 76. Jones AL, Proudfoot AT. Features and management of poisoning with modern drugs used to treat epilepsy. Q J Med. 1998;91:325-332. 77. Jung J, Eo E, Ahn K. A case of hemoperfusion and L-carnitine management in valproic acid overdose. Am J Emerg Med. 2008;26:388e3-388e4. 78. Kane SL, Constantine M, Staubus AE, et al. High flux hemodialysis without hemoperfusion is effective in acute valproic acid overdose. Ann Pharmacother. 2000;34:1146-1151.

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79. Karsarkis EJ, Kuo CS, Berger R, et al. Carbamazepine-induced cardiac dysfunction. Characterization of two distinct clinical syndromes. Arch Intern Med. 1992;152:186-191. 80. Katiyar A, Aaron C. Case files of the Children’s Hospital of Michigan Regional Poison Control Center: the use of carnitine for the management of acute valproic acid toxicity. J Med Toxicol. 2007;3:129-138. 81. Kawasaki C, Nishi R, Vekihara S, et al. Charcoal hemoperfusion in the treatment of phenytoin overdose. Am J Kidney Dis. 2000;35:323-326. 82. Kay TD, Playford HR, Johnson DW. Hemodialysis versus continuous venovenous hemodialfiltration in the management of severe valproate overdose. Clin Nephrol. 2003;59(1):56-58. 83. Kazzi Z, Jones C, Morgan B. Seizures in a pediatric patient with tiagabine overdose. J Med Toxicol. 2006;2:160-162. 84. Keegan MT, Bondy LR, Blackshear JL, et al. Hypocalcemia-like electrocardiographic changes after administration of intravenous fosphenytoin. Mayo Clinic Proc. 2002;77:584-586. 85. Kerr BM, Thummel KE, Wurden CJ, et al. Human liver carbamazepine metabolism. Role of CYP3A4 and CYP2C8 in 10,11epoxide formation. Biochem Pharmacol. 1994;47:1969-1979. 86. Kesterson JW, Granneman GR, Machinist JM. The hepatotoxicity of valproic acid and its metabolites in rats: I. Toxicologic, biochemical and histopathologic studies. Hepatology. 1984,4:1143-1152. 87. Khan E, Huggan P, Celi L, et al. Sustained low-efficiency dialysis with filtration (SLEDD-f) in the management of acute sodium valproate intoxication. Hemodial Inter. 2008;12:211-214. 88. Khoo SH, Layland MJ. Cerebral edema following acute sodium valproate overdose. J Toxicol Clin Toxicol. 1992;30:209-214. 89. Kilarski DJ, Buchanan C, Von Behren L. Soft-tissue damage associated with intravenous phenytoin. N Engl J Med. 1984;311:1186-1187. 90. Kilvienen R. Long-term safety of tiagabine. Epilpesia. 2001;42:46-48. 91. Klein-Scwartz W, Shepherd JG, Gorman S, Dahl B. Characterization of gabapentin overdose using a poison center case series. J Toxicol Clin Toxicol. 2003;41:11-15. 92. Knowles SR, Shapiro LE, Shear NH. Anticonvulsant hypersensitivity syndrome: incidence, prevention and management. Drug Saf. 1999;21:489-501. 93. Kuz GM, Manssourian A. Carbamazepine-induced hyponatremia: assessment of risk factors. Ann Pharmacother. 2005;39:1943-1945. 94. Langman LJ, Kaliciak HA, Boone SA. Fatal acute topiramate toxicity. J Anal Toxicol. 2003;27:323-324. 95. Larsen JR, Larsen LS. Clinical features and management of poisoning due to phenytoin. Med Toxicol Adv Drug Exp. 1989;4:229-245. 96. Leach JP, Brodie MJ. Tiagabine. Lancet. 1998;351:203-207. 97. Leiber BL, Snodgrass WR. Cardiac arrest following large intravenous fosphenytoin overdose in an infant [abstract]. J Toxicol Clin Toxicol. 1998:36:473. 98. Leslie PJ, Heyworth R, Prescott LF. Cardiac complications of carbamazepine intoxication: treatment by haemoperfusion. Br Med J. 1983;286:1018. 99. Levinson DF, Devinsky O. Psychiatric adverse events during vigabatrin therapy. Neurology. 1999;53:1503-1511. 100. Levy RH, Pitlick WHJ, Troupin AS, et al. Pharmacokinetics of carbamazepine in normal man. Clin Pharmacol Ther. 1975;17:657–668. 101. Li J, Norwood DL, Li-Feng M, Schulz H. Mitochondrial metabolism of valproic acid. Biochemistry. 1991;30:388–394. 102. Lofton AL, Klein-Schwartz W. Evaluation of lamotrigine toxicity reported to poison centers. Ann Pharmacother. 2004;38:1-5. 103. Lofton Al, Klein-Schwartz W. Evaluation of toxicity of topiramate exposures reported to poison centers. Hum Exp Toxicol. 2005;24:591-595. 104. Lowry JA, Vandover JC, DeGreeff J, et al. Unusual presentation of iatrogenic phenytoin toxicity in a newborn. J Med Toxicol. 2005;1:26-29. 105. Luer MS, Rhoney DH. Tiagabine: a novel antiepileptic drug. Ann Pharmacother. 1998;32:1173-1180. 106. Lukyanetz EA, Shryl VM, Kostyuk PG. Selective blockade of N type calcium channels by levetiracetam. Epilepsia. 2002;43:9-18. 107. Lurie Y, Bentur Y, Levy Y, et al. Limited efficacy of gastrointestinal decontamination in severe slow-release carbamazepine overdose. Ann Pharmacother. 2007;41:1539-1543. 108. Mackey FJ, Wilton GL, Pearce SN, et al. Safety of long-term lamotrigine in epilepsy. Epilepsia. 1997;38:881-886. 109. Marini H, Costa C, Passaniti M. Levetiracetam protects against kainic acidinduced toxicity. Life Sci. 2004;74:1253-1264. 110. Mauro LS, Mauro V, Brown D, et al. Enhancement of phenytoin elimination by multiple-dose activated charcoal. Ann Emerg Med. 1987;16:1132-1135.

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111. Mayorga C, Torres MJ, Corzo JL, et al. Improvement of toxic epidermal necrolysis after the early administration of a single high dose of intravenous immunoglobulin. Ann Allergy Asthma Immunol. 2003; 91:86-91. 112. McBride KD, Wilcox J, Kher KK. Hyperphosphatemia due to fosphenytoin in a pediatric ESRD patient. Pediatr Nephrol. 2005;20:1182-1185. 113. McNamara JO. Pharmacotherapy of the Epilepsies. Brunton LL, Lazo JS, Parker KL, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 11th ed. New York: McGraw-Hill; 2005;501-525. 114. Merritt HH, Putnam TJ. Sodium diphenylhydantoinate in treatment of convulsive disorders. JAMA. 1938;111:1068-1073. 115. Mellick LB, Morgan JA, Mellick GA. Presentations of acute phenytoin overdose. Ann Emerg Med. 1989;7:61-67. 116. Meyer S, Kuhlmann MK, Peters FT, et al. Severe valproic acid intoxication is associated with atrial tachycardia: secondary detoxification by hemoperfusion. Klin Pediatr. 2005;217:82-85. 117. Miller MA, Crystal CS, Patel MM. Hemodialysis and hemoperfusion in a patient with an isolated phenytoin overdose. Am J Emerg Med. 2006;24:748-749. 118. Mixter CG, Moran JM, Austen WG. Cardiac and peripheral vascular effects of diphenylhydantoin sodium. Am J Cardiol. 1966;17:332-338. 119. Mortensen PB, Hansen HE, Pedersen B, et al. Acute valproate intoxication: biochemical investigations and hemodialysis treatment. Int J Clin Pharmacol Ther Toxicol. 1983;21:64-68. 120. Murakami K, Sugimoto T, Woo M, et al. Effect of L-carnitine supplementation on acute valproate intoxication. Epilepsia. 1996;37:687-689. 121. Mylonakis E, Vittorio CC, Hollick DA, et al. Lamotrigine overdose presenting as anticonvulsant hypersensitivity syndrome. Ann Pharmacother. 1999;33:557-559. 122. Nagel TR, Schunk JE. Felbamate overdose: a case report and discussion of a new antiepileptic drug. Pediatr Emerg Care. 1995;11:369-371. 123. Neels HM, Sierens AC, Naelerts K, et al. Therapeutic drug monitoring of old and newer anti-epileptic drugs. Clin Chem Lab Med. 2004;42:1228-1255. 124. Neuman MG, Mlakiewicz IM, Shear NH. A novel lymphocyte assay to assess drug hypersensitivity syndromes. Clin Biochem. 2000;33:517-524. 125. Neuvonen PJ, Elonen E. Effect of activated charcoal on absorption and elimination of phenobarbitone, carbamazepine and phenylbutazone in man. Eur J Clin Pharmacol. 1980;17:51-57. 126. O’Donnell John, Bateman ND. Lamotrigine overdose in an adult. J Toxicol Clin Toxicol. 2000;38:659-660. 127. Ohtani Y, Endo F, Matsuda I. Carnitine deficiency and hyperammonemia associated with valproic acid therapy. J Pediatr. 1982;101:782-785. 128. Olaizola I, Ellger T, Young P, et al. Pregabalin-associated acute psychosis and epileptiform EEG-changes. Seizure. 2006;15:208-210. 129. Ostovskiy D, Spanaki MV, Morris GL. Tiagabine overdose can induce convulsive status epilepticus. Epilepsia. 2002;43:773-774. 130. Paopairochanakorn C, White S, Malafa MJ. Cardiac and neurologic toxicity from lamortigine ingestion. J Toxicol Clin Toxciol. 2002;40:620-621. 131. Perucca E, Gram L, Avanzini G, Dulac O. Antiepileptic drugs as a cause of worsening seizures. Epilepsia. 1998;39:5-17. 132. Philippi H, Boor R, Reitter B. Topiramate and metabolic acidosis in infants and toddlers. Epilepsia. 2002;43:744-747. 133. Pilapil M, Petersen J. Efficacy of hemodialysis and charcoal hemoperfusion in carbamazepine overdose. Clin Toxicol. 2008;46:342-343. 134. Potter JM, Donnelly A. Carbamazepine-10,11-epoxide in therapeutic drug monitoring. Ther Drug Monit. 1998;20:652-657. 135. Privitera MD. Topiramate: a new antiepileptic drug. Ann Pharmacother. 1997;31:1164-1173. 136. Raju PM, Waller RW, Lee MA. Dyskinesia induced by gabapentin in idiopathic Parkinson’s disease. Mov Disord. 2007;22:288-289. 137. Randinitis EJ, Posvar EL, Alvey CW, et al. Pharmacokinetics of pregabalin in subjects with various degrees of renal function. J Clin Pharmacol. 2003;43:277-283. 138. Raskind JY, EI-Chaar GM. The role of carnitine supplementation during valproic acid therapy. Ann Pharmacother. 2000;34:630-638. 139. Reimers A, Reinholt G. Acute lamotrigine overdose in an adolescent. Ther Drug Monit. 2007;29:669-670. 140. Rengstroff DS, Milstone AP, Seger DL, et al. Felbamate overdose complicated by massive crystalluria and acute renal failure. J Toxicol Clin Toxicol. 2000;38:666-667. 141. Richards DA, Lemos T, Whitton PS, et al. Extracellular GABA in the ventrolateral thalamus of rats exhibiting spontaneous absence epilepsy: a microdialysis study. J Neurochem. 1995;65:1674-1680.

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Part C

The Clinical Basis of Medical Toxicology

142. Rogawski MA, Loscher W. The neurobiology of antiepileptic drugs. Nat Rev Neurosci. 2004;5:553-564. 143. Roodhooft AM, Van Dam K, Haentjens D, et al. Acute sodium valproate intoxication: occurrence of renal failure and treatment with haemoperfusionhaemodialysis. Eur J Pediatr. 1990;149:363-364. 144. Rose R, Cisek J, Michell J. Fosphenytoin-induced bradyasystole arrest in an infant treated with charcoal hemofiltration [abstract]. J Toxicol Clin Toxicol. 1998;36:473. 145. Rosebush PI, MacQueen GM, Mazurek MF. Catatonia following gabapentin withdrawal. J Clin Psychopharmacol. 1999;19:188-189. 146. Rush JA, Beran RG. Leucopenia as an adverse reaction to carbamazepine therapy. Med J Aust. 1984;140:426-428. 147. Russell MA, Bousvaros G. Fatal results from diphenylhydantoin administered intravenously. JAMA. 1968;20:2118-2119. 148. Schaub JEM, Williamson PJ, Barnes EW, Trewby PN. Multisystem adverse reaction to lamotrigine. Lancet. 1994;344:481. 149. Scheuerman O, Nofech-Moses Y, Rachmel A, et al. Successful treatment of antiepileptic drug hypersensitivity with intravenous immune globulin. Pediatrics. 2000;107:E14. 150. Schlienger RG, Knowles SR, Shear NH. Lamotrigine-associated anticonvulsant hypersensitivity syndrome. Neurology. 1998;51:1172-1175. 151. Schmidt S, Schmitz-Buhl M. Signs and symptoms of carbamazepine overdose. J Neurol. 1995;242:169-173. 152. Sen S, Ratnaraj N, Davies NA, et al. Treatment if phenytoin toxicity by the molecular adsorbents recirculating system (MARS). Epilepsia. 2003;44:265-267. 153. Schwartz MD, Geller RJ. Seizures and altered mental status after lamotrigine overdose. Ther Drug Monit. 2007;29:843-844. 154. Schuerer DJE, Brophy PD, Maxvold NJ, et al. High-efficiency dialysis for carbamazepine overdose. J Toxicol Clin Toxicol. 2000;38:321-323. 155. Seymour JF. Carbamazepine overdose. Features of 33 cases. Drug Saf. 1993;8:81-88. 156. Shank RP, Gardocki JF,Vaught JL, et al. Topiramate: preclinical evaluation of structurally novel anticonvulsant. Epilepsia. 1994;35:450-460. 157. Sharma P, Gupta RC, Bhardwaja B, et al. Status epilepticus and death following acute carbamazepine poisoning. J Assoc Physicians India. 1992;40:561-562. 158. Shear N, Spielberg S. Anticonvulsant hypersensitivity syndrome, in vitro assessment of risk. J Clin Invest. 1988;82:1826-1832. 159. Shih VE. Alternative-pathway therapy for hyperammonemia. N Engl J Med. 2007;356:2321-2322. 160. Sikma M, Mier JC, Meulenbelt J. Massive valproic acid overdose a misleading case. Am J Emerg Med. 2008;26:110e3-6. 161. Singh SM, McCormick BB, Mustata S, et al. Extracorporeal management of valproic acid overdose: a large regional experience. J Nephrol. 2004;17:43-49. 162. Smith AG, Brauer HR, Catalano G, Catalano MC. Topiramate overdose: a case report and literature review. Epilepsy Behav. 2001;2: 603-607. 163. Soman P, Jain S, Rajsekhar V, et al. Dystonia—a rare manifestation of carbamazepine toxicity. Postgrad Med J. 1994;70:54-56. 164. Spiller HA, Carlisle RD. Status epilepticus after massive carbamazepine overdose. J Toxicol Clin Toxicol. 2002;40:81-90. 165. Spiller HA, Winter ML, Ryan M, et al. Retrospective evaluation of tiagabine overdoses. Clin Toxicol. 2005;43:855-859. 166. Spiller HA, Krenzelok P, Klein-Schwartz W, et al. Multicenter case series of valproic acid ingestion: serum concentrations and toxicity. J Toxicol Clin Toxicol. 2000;38:755-760. 167. Steiner C, Wit AL, Weiss MB, et al. The antiarrhythmic actions of carbamazepine. J Pharmacol Exp Ther. 1970;173:323-335.

168. Stevenson CM, Kim J, Felischer D. Colonic absorption of antiepileptic agents. Epilepsia. 1997;38:63-67. 169. Stilman N, Masdeu JC. Incidence of seizures with phenytoin toxicity. Neurology. 1985;35:1769-1772. 170. Stremski ES, Brady W, Prasad K, et al. Pediatric carbamazepine intoxication. Ann Emerg Med. 1995;25:624-630. 171. Sullivan JB, Rumack BH, Peterson RG. Acute carbamazepine toxicity resulting from overdose. Neurology. 1981;31:621-624. 172. Sung SF, Chiang PC, Tung HH, Ong CT. Charcoal hemoperfusion in an elderly man with life-threatening adverse reactions due to poor metabolism of phenytoin. J Formos Med Assoc. 2004;103:648-652. 173. Swadron SP, Rudis MI, Azimian K et al. A comparison of phenytoinloading techniques in the emergency department. Acad Emerg Med. 2004;11:244-252. 174. Sztajnkrycer MD. Valproic acid toxicity: overview and management. J Toxicol Clin Toxicol. 2002;40:789-801. 175. Sztajinkrycer MD, Huang EE, Bond GR. Acute zonisamide overdose: a death revisited. Vet Hum Toxicol. 2003;45:154-156. 176. Tank JE, Palmer BF. Simultaneous “in series” hemodialysis and hemoperfusion in the management of valproic acid overdose. Am J Kidney Dis. 1993;22:341-344. 177. Tas S, Simonart T. Management of drug rash with eosinophilia and systemic symptoms (DRESS syndrome): an update. Dermatology. 2003;206:353-356. 178. Thundiyil JG, Anderson I, Stewart PJ, et al. Lamotrigine-induced seizures in a child: case report and literature review. Clin Toxicol. 2007:45:169-172. 179. Traub SJ, Howland MA, Hoffman RS, Nelson LS. Acute topiramate toxicity. J Toxicol Clin Toxicol. 2003;41:987-990. 180. Unal E, Kaya U, Aydin K. Fatal valproate overdose in a newborn baby. Human Exp Toxicol. 2007;26:453-456. 181. VanOpstal M, Jankneg TR, Cilissen J. Severe overdosage with the antiepileptic drug oxcarbazepine. Br J Pharmacol. 2004;58:329-31. 182. Vale JA. Carbamazepine overdose. J Toxicol Clin Toxicol. 1992;30:481-482. 183. Verma A, St Clair EW, Radtke RA. A case of sustained massive gabapentin overdose without serious side effects. Ther Drug Monit. 1999;21:615-617. 184. Verrotti A, Trotta D, Morgese G, et al. Valproate-induced hyperammonemic encephalopathy. Metab Brain Dis. 2002;17:367-373. 185. Verrotti A, Trotta D, Salladini C, Chiarelli F. Anticonvulsant hypersensitivity syndrome in children. CNS Drugs. 2002;16:197-205. 186. Voigt GC. Death following intravenous sodium diphenylhydantoin (Dilantin). Johns Hopkins Med J. 1968;123:153-157. 187. Wang SY, Wang GK. Voltage-gated sodium channels as primary targets of diverse lipid soluble neutotoxins. Cell Signal. 2003;15:151-159. 188. Weaver DF, Camfield P, Fraser A. Massive carbamazepine overdose: clinical and pharmacologic observation in five episodes. Neurology. 1988;38:755-759. 189. Willow M, Gonoi R, Catterall WA. Voltage clamp analysis of the inhibitory actions of diphenylhydantoin and carbamazepine on voltage sensitive sodium channels in neuroblastoma cells. Mol Pharmacol. 1985;27: 549-558. 190. Winnicka RI, Lopacinski B, Szymczak WM, Szymanska B. Carbamazepine poisoning: elimination kinetics and quantitative relationship with carbamazepine 10,11 epoxide. J Toxicol Clin Toxicol. 2002;40:759-765. 191. Wyte CD, Berk WA. Severe oral phenytoin overdose does not cause cardiovascular morbidity. Ann Emerg Med. 1991;20:508-512. 192. Yildiz TS, Toprak GD, Arisoy ES, Solak M, Toker K. Continuous venovenous hemodialfiltration to treat controlled-release carbamazepine overdose in a pediatric patient. Ped Anes. 2006;16:1176-1178. 193. Zoneraich S, Zoneraich O, Seigel J. Sudden death following intravenous sodium diphenylhydantoin. Am Heart J. 1976;91:375-377.

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ANTIDOTES IN DEPTH (A9) carbon.15 The l-carnitine regenerated in the mitochondrial matrix can also translocate in the opposite direction, from the matrix and through the inner membrane back to the space between the outer and inner membrane. Acyl-coenzyme A (CoA) is transported by carnitine from the cytosol to the mitochondria and undergoes β-oxidation in the mitochondrial matrix, generating acetyl-CoA, which then enters the citric acid cycle for the generation of adenosine triphosphate (ATP).

L-CARNITINE Mary Ann Howland CH3 H3C

N+

OH CH2-CH

O CH2-C

CH3

O–

L-Carnitine

l-Carnitine (levocarnitine) is an amino acid that is vital to mitochondrial utilization of fatty acids. It is an orphan drug approved by the Food and Drug Administration for treatment of l-carnitine deficiency that results from inborn errors of metabolism, is associated with hemodialysis, occurs secondary to valproic acid toxicity, and for zidovudine (AZT)induced mitochondrial myopathy10,11,20 and pediatric cardiomyopathy.17 l-Carnitine decreases valproic acid–induced hyperammonemia and limits valproic acid–induced hepatic toxicity. l-Carnitine should be administered intravenously (IV) to symptomatic patients because of the limited bioavailability after oral (PO) administration.

HISTORY l-Carnitine is found in mammals, in many bacteria, and in very small amounts in most plants.37 Carnitine was first discovered in 1905 in extracts of muscle, and its name is derived from carnis, the Latin word for flesh.21 Over the next 25 years, its chemical formula and structure were identified, and in 1997, its enantiomeric properties were confirmed.37 Carnitine was formerly known as vitamin BT.

CHEMISTRY Carnitine is a water-soluble amino acid that can exist as either the d or l form; however, the l isomer, which is found endogenously, is active and should be used therapeutically. l-Carnitine (C7H15NO3) has a molecular weight of 161 daltons. At physiologic pH, l-carnitine contains both a positively charged quaternary nitrogen ion and a negatively charged carboxylic acid group.15 Fatty acids provide 9 kcal/g and are an important source of energy for the body, especially for the liver, heart, and skeletal muscle. The utilization of fatty acids as an energy source requires l-carnitine– mediated passage through both the outer and inner mitochondrial membranes to reach the mitochondrial matrix where β-oxidation occurs (see Figs. 47-2 and 12-8). Enzymes in the outer and inner mitochondrial membranes (carnitine palmitoyltransferase and carnitine acylcarnitine translocase) catalyze the synthesis, translocation, and regeneration of l-carnitine.33 Binding of l-carnitine to fatty acids occurs through esterification at the hydroxyl group on the chiral

L-CARNITINE

HOMEOSTASIS

Approximately 54% to 87% of the body stores of l-carnitine is derived primarily from meat and dairy products in the diet; the remainder is synthesized.37 Although most plants supply very little l-carnitine, avocado and fermented soy products are exceptionally rich in this amino acid. The remainder of the carnitine needed by the body is synthesized from trimethyllysine. This amino acid, found largely in skeletal muscle, is converted to trimethylammoniobutanoate (γ-butyrobetaine) and then carried to the liver and kidney for hydroxylation to l-carnitine.21 Synthesis of l-carnitine in the liver and kidney occurs at a rate of approximately 2 μmol/kg/d and is regulated by the amount of dietderived trimethyllysine.21,37 l-Carnitine is filtered by the kidneys, and tubular reabsorption maintains serum l-carnitine concentrations in the normal range.

PHARMACOKINETICS OF EXOGENOUS L-CARNITINE Our current understanding of l-carnitine pharmacokinetics is largely derived from three major studies.9,19,43 l-Carnitine is not bound to plasma proteins. Its volume of distribution of the central compartment (Vc) is 0.15 L/kg, approximating extracellular fluid volume. Its volume of distribution (Vd) is 0.7 L/kg. Both vary depending on the compartment model analyzed. The α half life is 0.6 to 0.7 hours with a terminal elimination half-life of 10 to 23 hours but may be 25% to 50% shorter. Baseline serum concentrations for l-carnitine are 40 μmol/L but increase to 1600 μmol/L after administration of 40 mg/kg IV over 10 minutes. Whereas 2 g of l-carnitine administered IV produces a peak plasma concentration of 1000 μmol/L, PO administration of 2 g produces peaks of only 15 to 70 μmol/L. The time to peak concentrations after PO administration occurs at 2.5 to 7.0 hours, indicating slow uptake by intestinal mucosal cells. After a 2-g carnitine dose, PO absorption is rapidly saturated, and no further absorption occurs after administration of 6 g PO. After a radiolabeled dose, most l-carnitine is metabolized to trimethylamine N-oxide and butyrobetaine, with only approximately 4% to 8% remaining unchanged. The metabolites trimethylamine and trimethylamine N-oxide may accumulate after chronic high-dose PO therapy in patients with severely compromised renal function.9 Fecal excretion of l-carnitine is less than 1% of the total dose. Carnitor (levocarnitine) tablets are bioequivalent to the Carnitor PO solution, with an absolute bioavailability of approximately 15%. After 4 days of dosing at 1980 mg (6 × 330-mg tablets) twice daily or 2 g twice daily of the PO solution, the maximum serum concentration was 80 μmol/L.

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712

Part C

The Clinical Basis of Medical Toxicology

VALPROIC ACID AND HYPERAMMONEMIA

L-CARNITINE

Valproic acid may cause hyperammonemia (defined as serum ammonia concentration >80 μg/dL or >35 μmol/L) regardless of symptoms or liver function. Hyperammonemia and hepatic toxicity may be associated either with therapeutic dosing or an acute overdose. Approximately 35% of patients receiving valproic acid demonstrate hyperammonemia, often with corresponding reduced serum l-carnitine concentrations.7 In the absence of hepatic dysfunction, the postulated mechanisms for hyperammonemia are unclear but may result from interference with hepatic synthesis of urea or a small increase in ammonia production by the kidney.27,45 Valproic acid induces both carnitine and acetyl-CoA deficiencies by combining with l-carnitine as valproylcarnitine and with acetyl CoA as valproyl-CoA. Ultimately, β-oxidation of all fatty acids is reduced, resulting in decreased energy production. Valproylcarnitine formation may inhibit the renal reabsorption of l-carnitine.32 Valproic acid stimulates glutaminase, favoring glutamate uptake and ammonia release from the kidney. Reduced glutamate concentrations lead to impaired production of N-acetylglutamate (NAGA), a cofactor for carbamoyl phosphate synthetase I (CPS I), which is used in the liver to synthesize urea from ammonia. In humans taking valproic acid, l-carnitine supplementation reduces ammonia concentrations.1,3,5,7,18,25,31,34,35,39,46 The exact time frame for normalization of ammonia concentrations is unknown, but a preliminary report suggests hastening of ammonia elimination with l-carnitine (3–15 h) compared with published controls (11–90 h), although the difference was not statistically significant.41,42

In the serum, 80% of l-carnitine is free, and the rest is acylated.14 In adults who eat all food groups and children older than 1 year of age, the normal serum concentrations of free l-carnitine are 22 to 66 μmol/L and of total l-carnitine concentrations are 28 to 84 μmol/L. Vegetarians have l-carnitine concentrations 12% to 30% lower than omnivores.36 Studies in patients taking valproic acid demonstrate decreases in both free and total serum l-carnitine concentrations35 and decreases in both total and free muscle carnitine concentrations.2 Case studies demonstrate reduced serum free l-carnitine concentrations and abnormal valproic acid metabolite profiles that normalize with l-carnitine supplementation.22,28,29 All of these data support the use of l-carnitine and provide a potential mechanism for its beneficial effects in valproic acid–induced hepatotoxicity.

VALPROIC ACID AND HEPATOTOXICITY Valproic acid therapy is commonly associated with a transient doserelated asymptomatic increase in liver enzyme concentrations and a rare symptomatic, life-threatening, idiosyncratic hepatotoxicity similar to Reye syndrome.4 Liver histology of the latter demonstrates microvesicular steatosis, similar to that described in both hypoglycin-induced Jamaican vomiting sickness (see Chap. 118) and Reye syndrome. This occurrence presumably results from l-carnitine and acetyl-CoA deficiency, which inhibits mitochondrial β-oxidation of valproic acid and other fatty acids, causing them to accumulate in the hepatocyte. One study compared valproic acid administration in mice bred to have decreased carnitine stores with normal mice and found that the mice with decreased carnitine stores developed microvesicular steatosis of the liver. In addition, evaluation of their isolated liver mitochondria demonstrated decreased oxidative capacity.23 Evidence for the benefit of l-carnitine treatment in improving survival from valproic acid–induced hepatotoxicity comes from the retrospective analysis of patients identified by the International Registry for Adverse Reactions to valproic acid.6 When 50 patients with acute, symptomatic hepatic dysfunction who were not treated with l-carnitine were compared with 42 similar patients treated with l-carnitine, only 10% of the untreated patients survived but 48% of the l-carnitine–treated patients survived.6 Early diagnosis of patients, prompt discontinuance of valproic acid, and administration of IV rather than PO l-carnitine resulted in the greatest survival.6 Most patients received 50 to 100 mg/kg/d of l-carnitine regardless of the route of administration.6 Additionally, case reports and animal studies40 offer both support38,44 and lack of support for the beneficial effects of l-carnitine in the presence of valproic acid–induced hepatotoxicity.24,25,30,41

CONCENTRATIONS

ADVERSE EFFECTS AND CONTRAINDICATIONS TO L-CARNITINE l-Carnitine administration is well tolerated.26 Transient nausea and vomiting are the most common side effects reported, with diarrhea and a fishy body odor noted at higher doses.9 After chronic high doses of l-carnitine in patients with severely compromised renal function, the potentially toxic l-carnitine metabolites trimethylamine and methylamine N-oxide accumulate. The importance of this accumulation is unknown. Trimethylamine and its metabolite dimethylamine may contribute to cognitive abnormalities and the fishy odor.13 In a pharmacokinetic study after IV administration of 6 g of l-carnitine over 10 minutes, two of six subjects complained of transient visual blurring; one subject also complained of headache and lightheadedness. The manufacturer of l-carnitine has received case reports of convulsive episodes after l-carnitine use by patients with or without a preexisting seizure disorder. These reports are currently noted in the package insert. No reports of seizures related to l-carnitine use can be found in the human literature. The only data suggesting carnitine-related seizures are found in a rat model.16 There are no known contraindications to the use of l-carnitine. However, only the l isomer and not the racemic mixture should be used because the dl mixture may interfere with mitochondrial utilization of l-carnitine. l-carnitine is considered FDA pregnancy Category B.

OVERDOSE OF L-CARNITINE No cases of toxicity from overdose have been reported, although large PO doses may cause diarrhea.9 The LD50 in rats is 5.4 g/kg IV and 19.2 g/kg PO.9

DOSAGE AND ADMINISTRATION The optimal dosing of l-carnitine for valproic acid–induced hyperammonemia or hepatotoxicity has not been established. Recommendations for IV l-carnitine administration to patients with acute metabolic disorders resulting from l-carnitine deficiency range from 50 to 500 mg/ kg/d.9,12 A loading dose equal to the daily dose may be given initially, followed by the daily dose divided into every 4 hourly doses. The 500-mg/kg/d dose was intended for children8 and did not list a maximum dose After the loading dose, we suggest a maximal daily dose of 6 g . The PO dosing of l-carnitine usually is 50 to 100 mg/kg/d up to 3 g/d and should be reserved for patients who are not acutely ill.

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For patients with end-stage renal disease undergoing hemodialysis, the package insert recommends an IV starting dose of 10 to 20 mg/kg dry body weight as a slow IV bolus over 2 to 3 minutes after completion of dialysis followed by a dose adjustment according to l-carnitine trough (predialysis) serum concentrations (normal, 40–50 μmol/L). For patients with an acute overdose of valproic acid and without hepatic enzyme abnormalities or symptomatic hyperammonemia, l-carnitine administration can be considered prophylactic, and enteral doses of 100 mg/kg/d divided every 6 hours up to 3 g/d are appropriate. For patients with valproic acid–induced symptomatic hepatotoxicity or symptomatic hyperammonemia, IV l-carnitine should be administered. We suggest a dose of 100 mg/kg IV up to 6 g administered over 30 minutes as a loading dose followed by 15 mg/kg every 4 hours administered over 10 to 30 minutes.

AVAILABILITY l-Carnitine (Carnitor) is available as a sterile injection for IV use in 1 g/5 mL single-dose vials.9 l-Carnitine is supplied without a preservative. After the vial is opened, the unused portion should be discarded. Carnitor injection is compatible with and stable when mixed with normal saline or lactated Ringer solution in concentrations as high as 8 mg/mL for as long as 24 hours.9 l-Carnitine (Carnitor) is also available as a 330-mg tablet; as an PO solution with artificial cherry flavoring, malic acid, sucrose syrup, and methylparaben and propylparaben as preservatives; and as a sugar-free PO solution (Carnitor SF) at a concentration of 100 mg/mL.8 The PO solution may be consumed without diluting, or it may be dissolved in other drinks to mask the taste. Slow consumption reduces gastrointestinal side effects.9

REFERENCES 1. Altunbasak S, Baytok V, Tasouji M, et al. Asymptomatic hyperammonemia in children treated with valproic acid. J Child Neurol. 1997;12:461-463. 2. Anil M, Helvaci M, Ozbal E et al. Serum and muscle carnitine levels in epileptic children receiving sodium valproate. J Child Neurol. 2009;24:80-86. 3. Barrueto F Jr, Hack JB. Hyperammonemia and coma without hepatic dysfunction induced by valproate therapy. Acad Emerg Med. 2001;8:999-1001. 4. Berthelot-Moritz F, Chadda K, Chanavaz I, et al. Fatal sodium valproate poisoning. Intensive Care Med. 1997;23:599. 5. Beversdorf D, Allen C, Nordgren R. Valproate induced encephalopathy treated with carnitine in an adult. J Neurol Neurosurg Psychiatry. 1996;61:211. 6. Bohan TP, Helton E, McDonald I, et al. Effect of l-carnitine treatment for valproate-induced hepatotoxicity. Neurology. 2001;56:1405-1409. 7. Böhles H, Sewell AC, Wenzel D. The effect of carnitine supplementation in valproate-induced hyperammonaemia. Acta Paediatr. 1996;85:446-449. 8. Carnitor (levocarnitine) tablets, Carnitor Oral Solution, and Carnitor SF Sugar Free Oral solution (package insert). Gaithersburg, MD: Sigma-Tau; June 2006. 9. Carnitor® (levocarnitine) Injection (product information). Gaithersburg, MD: Sigma-Tau; March 2004. 10. Carter R, Singh J, Archambault C, et al. Severe lactic acidosis in association with reverse transcriptase inhibitors with potential response to l-carnitine in a pediatric HIV positive patient. AIDS Patient Care. 2004;18:131-134. 11. Claessens Y, Chiche J, Mira J, et al. Bench to bedside review: severe lactic acidosis in HIV patients treated with nucleoside analogue reverse transciptase inhibitors. Crit Care. 2003;7:226-232. 12. De Vivo DC, Bohan TP, Coulter DL, et al. l-carnitine supplementation in childhood epilepsy: current perspectives. Epilepsia. 1998;39:1216-1225. 13. Eknoyan G, Latos DL, Lindberg J. Practice recommendations for the use of l-carnitine in dialysis-related carnitine disorder. National Kidney Foundation Carnitine Consensus Conference. Am J Kidney Dis. 2003;41:868-876. 14. Evangeliou A, Vlassopoulos D. Carnitine metabolism and deficit—when supplementation is necessary? Curr Pharm Biotechnol. 2003;4:211-219. 15. Evans A. Dialysis-related carnitine disorder and levocarnitine pharmacology. Am J Kidney Dis. 2003;41(suppl):S13-S26. 16. Fariello RG, Zeeman E, Golden GT, et al. Transient seizure activity induced by acetylcarnitine. Neuropharmacology. 1984;23:585-587.

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17. Ferrari R, Cicchitelli D, Fucili M, et al. Therapeutic effects of l-carnitine and propionyl-l-carnitine on cardiovascular disease: a review. Ann NY Acad Sci. 2004;1033:79-91. 18. Gidal BE, Inglese CM, Meyer JF, et al. Diet- and valproate-induced transient hyperammonemia: effect of l-carnitine. Pediatr Neurol. 1997;16: 301-305. 19. Harper P, Elwin CE, Cederblad G. Pharmacokinetics of intravenous and oral bolus doses of l-carnitine in healthy subjects. Eur J Clin Pharmacol. 1988;35:555-562. 20. Hoffman R, Currier J. Management of antiretroviral treatment related complications Infect Dis Clinics North Am. 2007;21:103-132. 21. Hoppel C. The role of carnitine in normal and altered fatty acid metabolism. Am J Kidney Dis. 2003;41:S4-S12. 22. Ishikura H, Matsue N, Matsubara M, et al. Valproic acid overdose and l-carnitine therapy. J Anal Toxicol. 1996;20:55-58. 23. Knapp A, Todesco L, Beier K, et al. Toxicity of valproic acid in mice with decreased plasma and tissue carnitine stores. J Pharm Exp Ther. 2008;324:568-575. 24. Laub MC, Paetzke-Brunner I, Jaeger G. Serum carnitine during valproic acid therapy. Epilepsia. 1986;27:559-562. 25. Lheureux P, Hantson P. Carnitine in the treatment of valproic acid induced toxicity. Clin Toxicol. 2009;47:101-111. 26. LoVecchio F, Shriki J, Samaddar R. l-carnitine was safely administered in the setting of valproic acid toxicity. Am J Emerg Med. 2005;23: 321-322. 27. Marini AM, Zaret BS, Beckner RR. Hepatic and renal contributions to valproic acid-induced hyperammonemia. Neurology. 1988;38:365-371. 28. Murakami K, Sugimoto T, Nishida, et al. Alterations of urinary acetylcarnitine in valproate-treated rats: the effect of l-carnitine supplementation. J Child Neurol. 1992;7:404-407. 29. Murakami K, Sugimoto T, Woo M, et al. Effect of l-carnitine supplementation on acute valproate intoxication. Epilepsia. 1996;37:687-689. 30. Murphy JV, Groover RV, Hodge C. Hepatotoxic effects in a child receiving valproate and carnitine. J Pediatr. 1993;123:318-320. 31. Ohtani Y, Endo F, Matsuda I. Carnitine deficiency and hyperammonemia associated with valproic acid. J Pediatr. 1982;101:782-785. 32. Okamura N, Ohnishi S, Shimaoka H et al. Involvement of recognition and interaction of carnitine transporter in the decrease of l-carnitine concentration induced by pivalic acid and valproic acid. Pharm Res. 2006;23:1729-1735. 33. Pande SV. Carnitine-acylcarnitine translocase deficiency. Am J Med Sci. 1999;318:22-27. 34. Raby WN. Carnitine for valproic acid-induced hyperammonemia. Am J Psychiatry. 1997;154:158. 35. Raskind JY, El-Chaar M. The role of carnitine supplementation during valproic acid therapy. Ann Pharmacother. 2000;34:630-638. 36. Rebouche CJ. Carnitine function and requirements during the life cycle. FASEB J. 1992;6:3379-3386. 37. Rebouche CJ, Seim H. Carnitine metabolism and its regulation in microorganisms and mammals. Annu Rev Nutr. 1998;18:39-61. 38. Romero-Falcón A, de la Santa Belda E, García-Contreras R, Varela JM. A case of valproate-associated hepatotoxicity treated with l-carnitine. Eur J Intern Med. 2003;14:338-340. 39. Segura-Bruna N, Rodriguez-Campello A, Puente V et al. Valproate induced hyperammonemic encephalopathy. Acta Neurol Scand. 2006;114:1-7. 40. Sugimoto T, Araki A, Nishida N, et al. Hepatotoxicity in rat following administration of valproic acid: effect of l-carnitine supplementation. Epilepsia. 1987;28:373-377. 41. Sztajnkrycer M. Valproic acid toxicity: overview and management. J Toxicol Clin Toxicol. 2002;40:789-801. 42. Sztajnkrycer MD, Scaglione JM, Bond GR. Valproate-induced hyperammonemia: preliminary evaluation of ammonia elimination with carnitine administration. J Toxicol Clin Toxicol. 2001;39:497. 43. Uematsu T, Itaya T, Nishimoto M, et al. Pharmacokinetics and safety of l-carnitine infused I.V. in healthy subjects. Eur J Clin Pharmacol. 1988;34:213-216. 44. Vance CK, Vance WH, Winter SC, et al. Control of valproate-induced hepatotoxicity with carnitine. Ann Neurol. 1989;26:456. 45. Verrotti A, Trotta D, Morgese G, Chiarelli F. Valproate-induced hyperammonemic encephalopathy. Metab Brain Dis. 2002;17:367-373. 46. Wadzinski J, Franks R, Roane D, et al. Valproate associated hyperammonemic encephalopathy. J Am Board Fam Med. 2007;20:499-502.

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CHAPTER 48

ANTIDIABETICS AND HYPOGLYCEMICS George M. Bosse Glucose MW Normal fasting range (blood)

= 180 daltons = 60–100 mg/dL = 3.3–5.6 mmol/L

Although various xenobiotics and medical conditions may cause hypoglycemia, this chapter focuses on the medications used for treatment of diabetes mellitus. These medications include insulin, incretin mimetics, and oral agents: the sulfonylureas, biguanides, α-glucosidase inhibitors, thiazolidinediones, meglitinides, and gliptins. Some of the medications in these chemically heterogeneous groups of xenobiotics can cause unique toxic effects in addition to hypoglycemia. In general, neurohormonal control of glucose production in healthy individuals maintains a fasting serum glucose concentration in the range of 60–100 mg/dL. In diabetes mellitus, the body fails to maintain normal blood glucose concentrations. The two glycemic complications of diabetes mellitus and its therapy are hyperglycemia and hypoglycemia. Most patients with diabetes mellitus are classified as having either insulin-dependent diabetes mellitus (IDDM), also known as type I diabetes, or non–insulin-dependent diabetes mellitus (NIDDM), also known as type II diabetes. This classification scheme for diabetes mellitus is not perfect. For example, some patients with type II diabetes may require insulin in addition to oral hypoglycemics. Early in the course of type I diabetes, patients may enter a remission period during which exogenous insulin is not required.

HISTORY AND EPIDEMIOLOGY Insulin first became available for use in 1922 after Banting and colleagues successfully treated diabetic patients with pancreatic extracts.10 In an attempt to more closely simulate physiologic conditions, additional “designer” insulins with unique kinetic properties have been developed, including an ultrashort-acting preparation known as lispro.62,130 Several oral delivery systems for insulin have been studied.87 Development of an oral delivery system for use in humans has not been successful because of poor intestinal absorption and degradation of the oral form of insulin by digestive enzymes. Using zonula occludens toxin, modulation of intestinal tight junctions in animal models has resulted in significant increases in enteral absorption of insulin.38 An inhaled form of insulin had recently become available, but has been withdrawn from the market due to poor sales.83 The hypoglycemic activity of a sulfonamide derivative used for typhoid fever was noted during World War II.70 This discovery was verified later in animals. The sulfonylureas in use today are chemical modifications of that original sulfonamide compound. In the mid-1960s, the first-generation sulfonylureas were widely used. Newer second-generation drugs differ primarily in their potency. Although insulin is widely used for treating diabetes mellitus, sulfonylurea exposures are much more commonly reported to poison

centers than are insulin exposures, based on 15 years of data from 1993 to 2007 (Chap. 135). These data likely reflect a significant percentage of intentional overdose cases. In a review of 1418 medication-related cases of hypoglycemia, sulfonylureas (especially the long-acting chlorpropamide and glyburide) alone or with a second hypoglycemic accounted for the largest percentage of cases (63%).120 Only 18 of the sulfonylurea cases in this series involved overdose with suicidal intent. However, hypoglycemia is reported in as many as 20% of patients using sulfonylureas.55 Despite the lack of evidence reported in the literature, we speculate that insulin-induced hypoglycemia occurs frequently in settings other than volitional overdose. Besides sulfonylurea use, advanced age and fasting are identified as major risk factors for hypoglycemia. Other causes of hypoglycemia are listed in Table 48–1. The biguanides metformin and phenformin were developed as derivatives of Galega officinalis, the French lilac, recognized in medieval Europe as a treatment for diabetes mellitus.8 Phenformin was used in the United States until 1977, when it was removed from the market because of its association with life-threatening metabolic acidosis with hyperlactatemia (64 cases/100,000 patient-years). However, phenformin still is available outside the United States.101 Development of the α-glucosidase inhibitors began in the 1960s when an α-amylase inhibitor was isolated from wheat flour.116 Acarbose was discovered more than 10 years later and approved for use in the United States in 1995. Troglitazone and repaglinide were approved for use in the United States in 1997. The FDA subsequently directed the manufacturer of troglitazone to withdraw the product from the US market in 2000 because of associated liver toxicity. Exenatide, a synthetic form of a compound found in the saliva of the Gila monster, is an incretin mimetic. Incretins are endogenous compounds in humans which stimulate insulin secretion in response to an oral glucose load. Most recently, the gliptins, which inhibit the enzyme responsible for the inactivation of incretins, have been introduced.

PHARMACOLOGY Insulin is synthesized as a precursor polypeptide in the β-islet cells of the pancreas. Proteolytic processing results in the formation of proinsulin, which is cleaved, giving rise to C-peptide and insulin itself, a double-chain molecule containing 51 amino acid residues. Glucose concentration plays a major role in the regulation of insulin release.107 Glucose is phosphorylated after transport into the β-islet cell of the pancreas. Further metabolism of glucose-6-phosphate results in the formation of ATP. ATP inhibition of the K+ channel results in cell depolarization, inward calcium flux, and insulin release. After release, insulin binds to specific receptors on cell surfaces in insulin-sensitive tissues, particularly the hepatocyte, myocyte, and fat cells. The action of insulin on these cells involves various phosphorylation and dephosphorylation reactions. Figure 48–1 depicts the chemical structures of oral agents representing the major classes of antidiabetic and hypoglycemic agents. The sulfonylureas stimulate the β cells of the pancreas to release insulin; therefore, they are ineffective in type I diabetes mellitus resulting from islet cell destruction (Fig. 48–2). This stimulatory effect diminishes with chronic therapy. All the sulfonylureas bind to high-affinity receptors on the pancreatic β-cell membrane, resulting in closure of K+ channels.36,43,44 Inhibition of potassium ion efflux mimics the effect of naturally elevated intracellular ATP and results in insulin release. High-affinity sulfonylurea receptors also present within pancreatic β cells are postulated to be either located on granular membranes or part of a regulatory exocytosis kinase. Binding to these receptors promotes exocytosis by direct interaction with secretory machinery not involving closure of the plasma membrane K+ channels.36,43,44

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Antidiabetics And Hypoglycemics

TABLE 48–1. Causes of Hypoglycemia Artifactual Chronic myelogenous leukemia Polycythemia vera Endocrine disorders Addison disease Glucagon deficiency Panhypopituitarism (Sheehan syndrome) Hepatic disease Acute hepatic atrophy Alcoholism Cirrhosis Galactose or fructose intolerance Glycogen storage disease Neoplasia

Reactive hypoglycemia Renal disease Chronic hemodialysis Chronic renal insufficiency Xenobiotics β-Adrenergic antagonists Alloxan Antidiabetics (insulin, sulfonylureas, miglitinides)

Biguanides NH

Sulfonylureas O SO2

CI

NH

C

NH

CH2

CH2

CH2

CH2

CH3

NH

NH

C

NH

C

NH2

Chlorpropamide

CI

O

CH3

O NH

C

CH2

CH2

NH

SO2

OCH3

C

NH

C

NH NH

C

NH2

CH3 Metformin

O C

NH N

Glyburide

N H3C

Disopyramide Ethanol Hypoglycin (Ackee) Pentamidine Propoxyphene Quinidine Quinine Ritodrine Salicylates Streptozocin Sulfonamides Vacor Valproic acid

Neoplasms Carcinomas (diverse extrapancreatic) Hematologic Insulinoma Mesenchymal Multiple endocrine adenopathy type 1 (Werner syndrome)

Miscellaneous Acquired immunodeficiency syndrome (AIDS) Anorexia nervosa Autoimmune disorders Burns Diarrhea (childhood) Graves disease Leucine sensitivity Muscular activity (excessive) Postgastric surgery (including gastric bypass) Pregnancy Protein calorie malnutrition Rheumatoid arthritis Septicemia Shock SLE

O NH

N

CH2

SO2

CH2

NH

C

NH

Glipizide Thiazolidinedione N

α-Glucosidase inhibitor

NH HO

S

O

N

C CO2H

O Rosiglitazone maleate

H3C OH

CO2H C

N

OH HO HO

O

CH3

O OH OH

O

O HO

Acarbose

O HO

O

H3C

OH OH

Meglitinide

H3C

OH

NH

O OH OH

O

N

O Repaglinide CH3

FIGURE 48–1. Chemical structures of representative oral antidiabetics.

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FIGURE 48–2. Under normal conditions, cells release insulin in response to elevation of intracellular ATP concentrations. Sulfonylureas potentiate the effects of ATP at its “sensor” on the ligand-gated K+ channels and prevent efflux of K+. The subsequent rise in intracellular potential opens voltage-gated Ca2+ channels, which increases intracellular calcium concentration through a series of phosphorylation reactions. The increase in intracellular calcium results in the release of insulin. Release of insulin is also caused by binding of sulfonylureas to postulated receptor sites on regulatory exocytosis kinase and insulin granular membranes.

Repaglinide and nateglinide are oral agents of the meglitinide class and differ structurally from the sulfonylureas.111 However, they also bind to K+ channels on pancreatic cells, resulting in increased insulin secretion. Compared to the sulfonylureas, the hypoglycemic effects of the meglitinides are shorter in duration. The linkage of two guanidine molecules forms the biguanides. Metformin is an oral compound approved for treatment of type II diabetes mellitus. Its glucose-stabilizing effect is caused by several mechanisms, the most important of which appears to involve inhibition of gluconeogenesis and subsequent decreased hepatic glucose output. Enhanced peripheral glucose uptake also plays a significant role in maintaining euglycemia. Metformin’s ability to lower blood glucose concentrations also occurs as a result of decreased fatty acid oxidation and increased intestinal use of glucose.9,132 In skeletal muscle and adipose cells, metformin causes enhanced activity and translocation of glucose transporters. Although the details are unclear, the mechanism by which this process occurs involves an interaction between metformin and tyrosine kinase on the intracellular portion of the insulin receptor. Figure 48–3 depicts the mechanism of action of metformin. Insulin resistance in patients with type II diabetes mellitus may occur because of secretion of biologically defective insulin molecules, circulating insulin antagonists, or target tissue defects in insulin action.96 The thiazolidinedione derivatives decrease insulin resistance by potentiating insulin sensitivity in the liver, adipose tissue, and skeletal muscle. Uptake of glucose into adipose tissue and skeletal muscle is enhanced, while hepatic glucose production is reduced.17,54 Acarbose and miglitol are oligosaccharides that inhibit α-glucosidase enzymes such as glucoamylase, sucrase, and maltase in the brush border of the small intestine. As a result, postprandial elevations in blood glucose concentrations after carbohydrate ingestion are blunted.139 Delayed gastric emptying may be another mechanism for the antihyperglycemic effect of these oligosaccharides.110 Exenatide is structurally similar to glucagon-like peptide-1 (GLP-1), a human gut hormone that is released in response to an oral glucose

Tyrosine kinase

Phos

phor

–

ylatio

n

PC-1

–

Glucose

Metformin

Glucose

Skeletal muscle/ adipocyte

Metformin

Glucose –

Gluconeogenesis

Glycolysis ATP

Hepatocyte = GLUT

Pyruvate = Insulin receptor

FIGURE 48–3. Under normal conditions, insulin binding to its receptor on myocytes and adipocytes activates tyrosine kinase, resulting in phosphorylation and activation of the membrane-bound glucose transporter GLUT. Non–insulin-dependent diabetes mellitus is causally associated with an increased activity of PC-1, a glycoprotein that inhibits tyrosine kinase activity and thus reduces myocyte and adipocyte glucose uptake. Metformin reduces PC-1 activity in these cells, enhancing peripheral glucose utilization. In addition, gluconeogenesis in hepatic cells is reduced through interference with pyruvate carboxylase, the enzyme responsible for conversion of pyruvate to oxaloacetate.

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load. GLP-1 enhances the release of insulin, delays gastric emptying, and reduces food intake. GLP-1 is metabolized very rapidly, rendering it ineffective as a therapeutically administered agent. Exenatide has a much longer half-life, rendering it useful in the treatment of type II diabetes mellitus.136 Sitagliptin and saxagliptin inhibit dipeptidyl peptidase-4 (DPP-4), the enzyme responsible for the inactivation of GLP-1.1

PHARMACOKINETICS AND TOXICOKINETICS Pharmacokinetic parameters of the hypoglycemics are given in Tables 48–2 and 48–3. Insulin is a peptide that is poorly absorbed and degraded in the gut and therefore is not active by the oral route. The onset and duration of action in therapeutic doses varies considerably among preparations. Insulin overdose usually occurs after administration by the subcutaneous or intramuscular route. As might be predicted based on slow onset and prolonged duration of action of some of the preparations, insulin overdose may result in delayed and prolonged hypoglycemia. However, hypoglycemia may also occur with shortacting forms because of some unusual toxicokinetic features. Some of these unpredicted responses may be caused by a depot effect following intramuscular or subcutaneous administration, and poor absorption may be further potentiated by the poor perfusion that can occur during periods of hypoglycemia.88,129 Further complicating the prediction of the clinical course is the delayed release of insulin from adipose tissue at the injection site(s). In diabetics, the presence of insulin antibodies may explain a patient’s recovery in spite of massive overdoses.117 Because there are a finite number of insulin receptors, insulin overdoses of varying amounts probably are equivalent in terms of the degree of resultant hypoglycemia once receptor saturation occurs, but not in terms of its duration. A comparison can be made with the current treatment of diabetic ketoacidosis, in which lower doses of insulin are as effective as the higher doses used in the past.61 Many of the sulfonylureas have a long duration of action, which may explain the unusually long period of hypoglycemia that can occur in both therapeutic use and overdose. The first-generation sulfonylureas (acetohexamide, chlorpropamide, tolazamide, tolbutamide) reduce hepatic clearance of insulin and produce active metabolites via hepatic metabolism. These drugs are dependent on their effective urinary excretion to maintain euglycemia and prevent hypoglycemia. Second-generation sulfonylureas (glimepiride, glipizide, glyburide) have half-lives that approach 24 hours and are characterized by substantial fecal excretion of the parent drug. These drugs frequently cause hypoglycemia (Table 48–2). Like insulin, the sulfonylureas may cause delayed onset of hypoglycemia following overdose.98,108 The reason for the potential delayed onset of effects with sulfonylureas cannot be simply explained by known kinetic principles, but may be related to effective counter regulatory mechanisms that fail over time. Metformin metabolism is negligible, and the majority of an absorbed dose is actively secreted in the urine unchanged. Plasma protein binding also is negligible.9 The kinetics of acarbose are notable for minimal systemic absorption and metabolism that occurs in the gastrointestinal tract. As a result, serious systemic toxicity is not expected.118 Despite extensive gastrointestinal absorption of miglitol, serious toxicity is unlikely. Adverse clinical effects due to α-glucosidase inhibitors are usually gastrointestinal. Repaglinide and nateglinide are prandial glucose regulators characterized by short onset and short duration of action. Overdose experience and toxicokinetic data for repaglinide are lacking. Whether after-overdose hypoglycemia would be prolonged or delayed in onset is not clear. In one case of nateglinide overdose, hypoglycemia occurred early and was short lived.89 Exenatide is available only for parenteral (subcutaneous) injection.

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Both sitagliptin and saxagliptin have long half-lifes and cause pronounced inhibition of DPP-4, resulting in a long duration of action (approximately 24 hours) after therapeutic doses.68

PATHOPHYSIOLOGY OF HYPOGLYCEMIA To varying degrees, the antidiabetics may all produce a nearly identical clinical condition of hypoglycemia. The etiologies of hypoglycemia are divided into three general categories:40 physiologic or pathophysiologic conditions (Table 48–1), direct effects of various hypoglycemics (Tables 48–2 and 48–3), and potentiation of hypoglycemics by interactions with other xenobiotics (Table 48–4). Central nervous system (CNS) symptoms predominate in hypoglycemia because the brain relies almost entirely on glucose as an energy source. However, during prolonged starvation, the brain can utilize ketones derived from free fatty acids. In contrast to the brain, other major organs such as the heart, liver, and skeletal muscle often function during hypoglycemia because they can use various fuel sources, particularly free fatty acids.122 Emphasis on tighter diabetic control as a means of preventing microvascular effects carries with it an increased risk for hypoglycemia.30,31 Regulation of glucose control to near-normal glucose concentrations, the characteristics of each individual’s awareness of hypoglycemia, and the individual counterregulatory mechanisms define the frequency and intensity of hypoglycemia.121 The Diabetic Control and Complications Trial (DCCT) research group reported 62 episodes of blood glucose concentration less than 50 mg/dL with CNS manifestations requiring assistance for every 100 patient-years in patients undergoing an intensive insulin therapy regimen. This was in comparison to a conventional therapy group, which had 19 such episodes per 100 patient-years.30,31 The intensive therapy group received three or more insulin injections per day or used a pump in an effort to achieve a glucose concentration as close to normal as possible, whereas the conventional therapy group received 1 or 2 daily insulin injections. There has also been a recent emphasis in tighter control of glucose in critically ill patients, even when they are not known to have diabetes mellitus. Hyperglycemia occurs in critically ill patients due to several mechanisms, and is associated with increased mortality in patients with a variety of medical and surgical diagnoses.63 In a study of critically ill surgical patients tight control of glucose was associated with decreased morbidity and mortality.141 However, such benefits in other studies are not always clearly replicated, and significant hypoglycemia has been reported.37,140 Further large studies are ongoing and will hopefully clarify the risks and benefits of tight control. The autonomic nervous system regulates glucagon and insulin secretion, glycogenolysis, lipolysis, and gluconeogenesis. β-Adrenergic antagonists affect all of these mechanisms and can result in hypoglycemia. In the presence of chronic renal failure, β-adrenergic antagonist–induced hypoglycemia is a particular risk47 secondary to increased insulin half-life and reduced renal gluconeogenesis.99 In addition, the clinical presentation of hypoglycemia may be muted when β-adrenergic antagonists are present because the expected autonomic responses of tachycardia, diaphoresis, and anxiety may not occur. Although this is assumed to be true, an adverse effect on hypoglycemic awareness could not be demonstrated in healthy volunteers given metoprolol, atenolol, and propranolol.60 The concept of hypoglycemia-associated autonomic failure in diabetes mellitus is well described.28 Recent episodes of hypoglycemia result in autonomic failure by causing defective glucose counterregulation and hypoglycemic awareness. As glucose concentrations fall, normal sensing mechanisms result in decreased insulin secretion and increased

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TABLE 48–2. Characteristics of Noninsulin Hypoglycemics and Antidiabetics

Xenobiotic I. Sulfonylureas First generation Acetohexamide (Dymelor) Chlorpropamide (Diabinese) Tolazamide (Tolinase) Tolbutamide (Orinase) Second generation Glimepiride (Amaryl) Glipizide (Glucotrol, Glucotrol XL) Glyburide (Micronase, Glynase, DiaBeta)

Duration of Action (h)

Active Hepatic Metabolite

Active Urinary Excretory Product (% of Dose)

Fecal Frequency of Severe Excretion Hypoglycemia (Other (% of Dose) Complications)

12–18

Hydroxyhexamide (+++)

Negligible

~1%

24–72

2-Hydroxychlorpropamide (+) 3-Hydroxychlorpropamide (+)

Negligible

4%–6%

16–24

Hydroxytolazamide (++)

Negligible

~1%

6–12

Hydroxytolbutamide (+)

Hydroxyhexamide (65%) Acetohexamide (2%) Chlorpropamide (20%) 2-Hydroxychlorpropamide (55%) 3-Hydroxychlorpropamide (2%) Hydroxytolazamide (35%) Tolazamide (7%) Hydroxytolbutamide (30%) Tolbutamide (2%)

Negligible

1 hour) and is directly related to the duration of cholinesterase inhibition.2 After reversal of anticholinergic symptoms is achieved, additional doses may be required if clinical relapse occurs. The effective dose depends upon the ingested dose and duration of action of the antimuscarinic xenobiotic. Although a total of 4 mg in divided doses usually is sufficient in most clinical situations,16 significant interindividual variability exists. Atropine should be available at the bedside and titrated to effect should excessive cholinergic toxicity develop. A dose of atropine administered at half the physostigmine dose is often recommended. Physostigmine is available as an ophthalmic ointment that can be applied topically to the conjunctival sac to produce miosis as treatment of acute angle-closure glaucoma. Miosis occurs within 10 to 30 minutes and persists for 12 to 48 hours.31

AVAILABILITY Physostigmine is available in 2-mL ampules, with 1 mL containing 1 mg physostigmine salicylate. The vehicle contains sodium metabisulfite and benzyl alcohol.36

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SUMMARY Physostigmine has been used extensively in the fields of anesthesiology, emergency medicine, and medical toxicology. The only evidence-based use of physostigmine is for the management of patients with an anticholinergic syndrome, particularly those without cardiovascular compromise who have an agitated delirium and a normal QRS duration. In this population, physostigmine has an excellent risk-to-benefit profile.

REFERENCES 1. Aquilonius S, Hartvig P: Clinical pharmacokinetics of cholinesterase inhibitors. Clin Pharmacokinet. 1986;11:236-249. 2. Asthana S, Greig NH, Hegedus L, et al: Clinical pharmacokinetics of physostigmine in patients with Alzheimer’s disease. Clin Pharmacol Ther. 1995;58:299-309. 3. Atack JR, Yu Q-S, Soncrant TT, Brossi I, Rapoport SI: Comparative inhibitory effects of various physostigmine analogs against acetyl and butyrocholinesterases. J Pharmacol Exp Ther. 1989;249:194-202. 4. Bania TC, Chu J: Physostigmine does not effect arousal but produces toxicity in an animal model of severe -hydroxybutyrate intoxication. Acad Emerg Med. 2005;12:185-189. 5. Beaver KM, Gavin TJ: Treatment of acute anticholinergic poisoning with physostigmine. Am J Emerg Med. 1998;16:505-507. 6. Burns MJ, Linden CH, Graudins A, Brown RM, Fletcher KE: A comparison of physostigmine and benzodiazepines for the treatment of anticholinergic poisoning. Ann Emerg Med. 2000;35:374-381. 7. Caldicott DGE, Kuhn M: Gamma-hydroxybutyrate overdose and physostigmine: teaching new tricks to an old drug? Ann Emerg Med. 2001;37:99-102. 8. Chin RL, Sporer KA, Cullison B, Dyer JE, Wu TD: Clinical course of γ-hydroxy-butyrate overdose. Ann Emerg Med. 1998;31:716-722. 9. Crowell EB, Ketchum JS: The treatment of scopolamine-induced delirium with physostigmine. Clin Pharmacol Ther. 1967;8:409-414. 10. Cumming G, Harding LK, Prowse K: Treatment and recovery after massive overdose of physostigmine. Lancet. 1968;20:147-149. 11. Darreh-Shori T, Hellström-Lindahl E, Flores-Flores C, et al: Longlasting acetylcholinesterase splice variations in anticholinesterase-treated Alzheimer’s disease patients. J Neurochem. 2004;88:1102-1113. 12. Daunderer M: Physostigmine salicylate as an antidote. Int J Clin Pharmacol Ther Toxicol. 1980;18:523-535. 13. Duvoisin R, Katz R: Reversal of central anticholinergic syndrome in man by physostigmine. JAMA. 1968;206:1963-1965. 14. Eckstein M, Henderson SO, DelaCruz P, Newton E: Gamma-hydroxybutyrate (GHB): report of a mass intoxication and review of the literature. Prehosp Emerg Care. 1999;3:357-361. 15. El-Yousef MK, Janowsky D, Davis JM, Sekerke HJ: Reversal of antiparkinsonian drug toxicity by physostigmine: a controlled study. Am J Psychiatry. 1973;130:141-145. 16. Forrer GR, Miller JJ: Atropine coma—a somatic therapy in psychiatry. Am J Psychiatry. 1958;115:455-458. 17. Fraser TR: On the characters, action and therapeutic uses of the bean of Calabar. Edinburgh Med J. 1863;9:36-56; 235-245. 18. Giannini AJ, Castellani S: A case of phenylcyclohexylpyrolidine (PHP) intoxication treated with physostigmine. J Toxicol Clin Toxicol. 1982;19: 505-508. 19. Henderson RS, Holmes CM: Reversal of the anaesthetic action of sodium gamma-hydroxybutyrate. Anaesth Intensive Care. 1976;4:351-354. 20. Holmstedt BO: The ordeal bean of old Calabar: the pageant of Physostigmine venenosum in medicine. In: Swain T, ed. Plants in the Development of Modern Medicine. Cambridge, MA: Harvard University Press; 1975:303-360. 21. Holzgrate RE, Vondrell JJ, Mintz SM: Reversal of postoperative reactions to scopolamine with physostigmine. Anesth Analg. 1973;52:921-925. 22. Isbister GK, Oakley P, Whyte I, Dawson A: Treatment of anticholinergicinduced ileus with neostigmine. Ann Emerg Med. 2001;38:689-693. 23. Karczmar AG: History of the research with anticholinesterase agents. In: Karczmar AG, ed. International Encyclopedia of Pharmacology and Therapeutics, Vol. I. Oxford: Pergamon Press; 1970:1-44. 24. Karczmar AG: Pharmacology of anticholinesterase agents. In: Karczmar AG, ed. International Encyclopedia of Pharmacology and Therapeutics, Vol. I. Oxford: Pergamon Press; 1970:45, 363.

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25. Knapp S, Wardlow ML, Albert K, Waters D, Thal LJ: Correlation between plasma physostigmine concentrations and percentage of acetylcholinesterase inhibition over time after controlled release of physostigmine in volunteer subjects. Drug Metab Dispos. 1991;19:400-404. 26. Krall WJ, Sramck JJ, Cutler NR: Cholinesterase inhibitors: a therapeutic strategy for Alzheimer disease. Ann Pharmacother. 1999;33:441-450. 27. Larson GF, Hurbert BJ, Wingard DW: Physostigmine reversal of diazepaminduced depression. Anesth Analg. 1977;56:348-351. 28. Li J, Stokes SA, Woeckener A: A tale of novel intoxication: seven cases of γ-hydroxybutyric acid overdose. Ann Emerg Med. 1998;31:723-728. 29. Longo VG: Behavioral and electroencephalographic effects of atropine and related compounds. Pharmacol Rev. 1966;18:965-996. 30. Manoguerra AS: Poisoning with tricyclic antidepressant drugs. Clin Toxicol. 1977;10:149-158. 31. Physostigmine sulfate. In: McEvoy CK, ed. American Hospital Formulary Service (AHFS). Bethesda, MD: American Society of Health-System Pharmacists; 2004:2705. 32. Nattel S, Bayne L, Ruedy J: Physostigmine in coma due to drug overdose. Clin Pharmacol Ther. 1979;25:96-102. 33. Nickalls RWD, Nickalls EA: The first use of physostigmine in the treatment of atropine poisoning. Anesthesiology. 1988;43:776-779. 34. Nilsson E: Physostigmine treatment in various drug-induced intoxications. Ann Clin Res. 1982;14:165-172. 35. Pentel P, Peterson CD: Asystole complicating physostigmine treatment of tricyclic antidepressant overdose. Ann Emerg Med. 1980;9:588-590. 36. Physostigmine Salicylate Injection [package insert]. Decatur, IL: Taylor Pharmaceuticals; 2006. 37. Rumack BH: 707 cases of anticholinergic poisoning treated with physostigmine [abstract]. Presented at: Annual Meeting of American Academy of Clinical Toxicology; 1975; Montreal, Quebec, Canada. 38. Rupreht J, Dworacek B, Oosthoek H, et al: Physostigmine versus naloxone in heroin overdose. J Toxicol Clin Toxicol. 1983-1984;21:387-397. 39. Shepherd G, Klein-Schwartz W, Edwards R: Donepezil overdose: a tenfold dosing error. Ann Pharmacother. 1999;33:812-815.

40. Smiler BG, Bartholomew EG, Sivak BJ, Alexander GD, Brown EM: Physostigmine reversal of scopolamine delirium in obstetric patients. Am J Obstet. 1973;116:326-329. 41. Smilkstein MJ: Physostigmine [editorial]. J Emerg Med. 1991;9:275-277. 42. Somani SM, Dube SN: Physostigmine—an overview as pretreatment drug for organophosphate intoxication. Int J Clin Pharmacol Ther Toxicol. 1989;27:367-387. 43. Sopchak CA, Stork CM, Cantor RM, O’Hara PE: Central anticholinergic syndrome due to Jimson Weed physostigmine: therapy revisited? J Toxicol Clin Toxicol. 1998;36:42-45. 44. Suchard JR: Assessing physostigmine’s contraindication in cyclic antidepressant ingestions. J Emerg Med. 2003;25:185-191. 45. Taylor P: Anticholinesterase agents. In: Hardman JG, Limbird CE eds. Goodman and Gilman’s The Pharmacologic Basis of Therapeutics. 10th ed. New York: McGraw-Hill; 2001:175-191. 46. Titier K, Girodet PO, Verdoux H, et al: Atypical antipsychotics: from potassium channels to torsade de pointes and sudden death. Drug Saf. 2005;28:35-51. 47. Traub SJ, Nelson LS, Hoffman RS: Physostigmine as a treatment for gammahydroxybutyrate toxicity: a review. J Toxicol Clin Toxicol. 2002;40:781-787. 48. Viera AJ, Yates SW: Toxic ingestion of gamma-hydroxybutyric acid. South Med J. 1999;92:404-405. 49. Walker WE, Levy RC, Hanenson IB: Physostigmine—its use and abuse. JACEP. 1976;5:436-439. 50. Weinstock M, Davidson JT, Rosin AJ, Schnieden H: Effect of physostigmine on morphine-induced postoperative pain and somnolence. Br J Anesth. 1982;54:429-443. 51. Weiss S: Persistence of action of physostigmine and the atropinephysostigmine antagonism in animals and in man. J Pharmacol Exp Ther. 1925;27:181-188. 52. Weizberg M, Su M, Mazzola J, et al: Altered mental status from olanzapine overdose treated with physostigmine. Clin Tox. 2006;44:319-325. 53. Young SE, Ruiz RS, Falletta J: Reversal of systemic toxic effects of scopolamine with physostigmine salicylate. Am J Ophthalmol. 1971;72:1136-1138. 54. Zvosec D, Smith S, Litonjua R, et al: Physostigmine for gamma-hydroxybutyrate coma: inefficacy, adverse events, and review. Clin Tox. 2007;l45:261-265.

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ANTIMIGRAINE MEDICATIONS Jason Chu A migraine headache is a neurovascular disorder often initiated by a trigger and characterized by a headache, which 20% of the time is preceded by a visual aura. The headache may be accompanied by a variety of multiple organ system symptoms, such as allodynia, nausea, vomiting and urinary frequency. There are various types of migraine, the diagnostic criteria for which have been established by the International Headache Society.77 The types of migraine are divided into two groups: migraine without aura (“common migraine”) and migraine with aura (“classic migraine”). Further subdivisions include migraine with typical aura with or without headache, familial hemiplegic migraine, sporadic hemiplegic migraine, basilar type migraine, and retinal migraine.77 Treatment of migraines encompasses a wide variety of xenobiotics and can be broadly classified as prophylactic or abortive therapies (Table 51–1).

PATHOPHYSIOLOGY OF MIGRAINE HEADACHES The initiation of migraines is not fully understood, but likely involves genetic abnormalities in central nervous system (CNS) ion channels that predispose sufferers to specific triggers. Patients with familial hemiplegic migraine, an autosomal dominant disorder, have missense mutations in the α1 subunit of brain specific P/Q voltage gated calcium channels resulting in altered function of these channels. During migraines, the upper brainstem has increased blood flow and is implicated as a “migraine generator.” After activation, a wave of cortical depression spreads across the cortex from a caudal to rostral fashion followed by a spreading wave of oligemia, which can produce the auras that occur in 20% of migraineurs.23,34,83 Current theories suggest that this spreading wave occurs in patients who do not experience visual auras and spares the visual cortex. Cephalagia begins during vasoconstriction prior to vasodilation unlike previous vascular theory suggested prior to cerebral blood flow studies. Antidromic activation of the afferent neurons of the ophthalmic division of the trigeminal nerve and branches of the C1 and C2 nerves (first order neurons) located on dural arteries at the base of the brain releases inflammatory neuropeptides such as calcitonin gene related polypeptide, VIP and neurokinase A. Vasoactive neuropeptides, including serotonin, vasoactive intestinal peptide, nitric oxide, substance P, neurokinin A, and calcitonin gene-related peptide (CGRP), are released during this process, which exacerbates the vasodilation and irritates the meninges at the base of the brain, causing further pain. CGRP from trigeminal Aδ-fibers produces dural vasodilation, while substance P and neurokinin A from trigeminal C-fibers increase dural vessel permeability.23,33 Pain impulses are relayed orthodromically to the trigeminal nucleus caudalis (second order neurons) in the lower medulla and upper cervical spinal cord, then to the thalamus (third order neurons) via the quintothalamic tract, and finally to higher cortical areas (fourth order neurons probably located in the limbi cortex).23,31 The trigeminocervical complex also produces retrograde parasympathetic impulses from sphenopalatine ganglion and the superior salivatory nucleus in the pons through the

pterygopalatine, otic, and carotid ganglia to the cerebral vessels.31 abort migraines when administered intravenously, but it is too dangerous to utilize clinically. Migraineurs have increased serotonin release during migraine attacks.23,83 Abortive and prophylactic therapy ideally target these processes (see Table 51–1). Current abortive therapies include analgesics (nonsteroidal anti-inflammatory drugs [NSAIDs], acetaminophen, opioids), antiemetics, ergots alkaloids, triptans, oxygen, magnesium sulfate and intranasal lidocaine. Triptans are considered the drugs of choice for migraine therapy. Newer therapies such as CGRP antagonists are currently in phase 2 and 3 trials. Toxicity of many of these xenobiotics is discussed in depth elsewhere in the text (see Table 51–1).

ERGOT ALKALOIDS ■ HISTORY AND EPIDEMIOLOGY Ergot is the product of Claviceps purpurea, a fungus that contaminates rye and other grains. The spores of the fungus are both wind borne and transported by insects to young rye, where they germinate into hyphal filaments. When a spore germinates, it destroys the grain and hardens into a curved body called the sclerotium, which remains the major commercial source of ergot alkaloids.68 The C. purpurea fungus can elaborate diverse substances, including ergotamine, histamine, lysergic acid, tyramine, isomylamine, acetylcholine, and acetaldehyde. In 600 bc, an Assyrian tablet mentioned grain contamination believed to be by C. purpurea. In the Middle Ages, epidemics causing gangrene of the extremities, with mummification of limbs, were depicted in the literature as blackened limbs resembling the charring from fire and caused a burning sensation expressed by its victims. The disease was called holy fire or St. Anthony’s fire, but the improvement that reportedly occurred when victims went to visit the shrine of St. Anthony were probably the result of a diet free of contaminated grain on the journey.35 Abortion and seizures were also reported to result from this poisoning. On the other hand, as early as 1582, midwives used ergot to assist in the childbirth process. In 1818, Desgranges was the first physician to use ergot for obstetric care, and in 1822 Hosack reported that ergot could be used for the control of postpartum hemorrhage.81 Since 1950, the clinical use of ergot derivatives is almost entirely limited to the treatment of vascular headaches. Ergonovine, another ergot derivative, is used in obstetric care for its stimulant effect on uterine smooth muscle and was used in cardiac stress tests. Methylergonovine is used for postpartum uterine atony and hemorrhage. Ergot derivatives have also been used as “cognition enhancers,”84 to help manage orthostatic hypotension,74 and to prevent the secretion of prolactin.68 Currently in the United States, ergot grain infections are prevented by government inspections of grain fields. If a grain field contains more than 0.3% infected grain, it is rejected for commercial sale; in some years as much as 36% of the grain was rejected.68 However, elsewhere in the world ergot toxicity remains a problem predominantly in animals.7,45

■ PHARMACOLOGY AND PHARMACOKINETICS All ergot alkaloids are derivatives of the tetracyclic compound 6-methylergoline.They can be divided into three groups: amino acid alkaloids (ergotamine, ergotoxine), dihydrogenated amino acid alkaloids, and amine alkaloids (Fig. 51–1). The pharmacokinetics of the ergot alkaloids are well defined by controlled human volunteer studies, whereas the toxicokinetics are essentially unknown (Table 51–2). Almost all of the ergots are poorly absorbed orally and there is considerable first-pass hepatic

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Amine alkaloids ∗

TABLE 51–1. Xenobiotics Used in Migraine Treatment Prophylactic

Abortive

β adrenergic antagonists Butterbur root Calcium channel blockers Candesartan Coenzyme Q10 Cyclic antidepressants Enalapril Feverfew Flunarizine Gabapentin Isometheptene/dichloraphenazone/ acetaminophen (midrin)

Acetaminophen Antiemetics: metoclopramide, ondansetron, prochlorperazine

Lamotrigine Levetiracetam Lisinopril Magnesium (oral) MAO inhibitors Memantine Nefazadone Onabotulinumtoxin/A (Botox A) Pizotifen Riboflavin Selective serotonin reuptake inhibitors Topiramate Valproic acid

Aspirin Butalbital Caffeine Corticosteroids Ergots Lidocaine (intranasal) Magnesium (IV) Metoclopramide NSAIDs Opioids Oxygen Sedative-hypnotics Triptans Valproic acid

MAO, monoamine oxidase; NSAIDs, nonsteroidal anti-inflammatory drugs. ∗ Prophylatic xenobiotics are usually taken to prevent triggering of migraines, and abortive xenobiotics are usually taken to stop the clinical manifestations of migraines once they are triggered. However, the separation between the two groups of xenobiotics is not strict, and some xenobiotics may be used in both roles. Triptans are currently considered the drug class of choice for migraine treatment.

metabolism, resulting in highly variable bioavailability. Intramuscular absorption is unpredictable and actions are often delayed.60 Peak plasma concentrations with oral ergotamine occur within 45 to 60 minutes.60 The volume of distribution of ergotamine is approximately 2 L/kg and the half-life varies from 1.4 to 6.2 hours. Ergot alkaloids are metabolized in the liver, probably by CYP3A4, and the metabolites are excreted in the bile.6,68 The pharmacologic effects of the ergot alkaloids are complex and can be mutually antagonistic.68 These actions can be subdivided into central and peripheral effects (Table 51–3). In the CNS, ergotamine stimulates serotonergic (tryptaminergic) receptors, potentiates serotonergic effects, blocks neuronal serotonin reuptake, and has central sympatholytic actions.35,68 The ergot alkaloids interact with all known 5-HT1 and 5-HT2 receptor subtypes. 68 The result is increased intrasynaptic serotonin activity in the median raphe neurons of the brainstem.65 Ergotamine and dihydroergotamine are thought to decrease the neuronal firing rate and stabilize the cerebrovascular smooth musculature, which make them useful drugs for both acute and prophylactic treatment of migraine headaches.

O

NH

CH3

OH N CH3 H HN Methylergonovine Amino acid alkaloids H3C O

OH O

NH

H O

N O

N CH3 H HN Ergotamine FIGURE 51–1. Chemical structures of 2 ergot derivatives representative of the amine and amino acid alkaloids.

Peripherally, ergotamine acts as a partial α-adrenergic agonist or as an antagonist at adrenergic, dopaminergic, and serotonergic (tryptaminergic) receptors.68 The amino acid ergot alkaloids (ergotamine, ergotoxine) exhibit α-adrenergic agonism, and dehydrogenation (dihydroergotamine) of the lysergic acid nucleus increases the potency of this effect.68 However, the peripheral vasoconstrictive effects predominate over the α-adrenergic antagonist effects, and there may be an additional vasoconstrictive effect caused by the direct action of ergotamine on the media of the arterioles.68 Table 51–3 summarizes the pharmacologic actions of selected ergot alkaloids currently used in clinical medicine. The spectrum of effects depends on dosage, host response, and physiologic conditions. The clinical effects following overdose are an extension of the therapeutic effects. At toxic doses, extreme vasoconstriction produces the characteristic ischemic changes that occur in ergotism. The cerebrovascular effects of ergot alkaloids are not as clearly understood. In migraine treatment, for example, therapeutic doses of ergotamine produce mild vasoconstriction via α-adrenergic agonism. This may be more pronounced in intracranial vessels that are already dilated during a migraine. In toxic doses cephalic vasodilation may occur, but the mechanism for this effect is unknown. One hypothesis is that toxic doses of the drug initially produce cerebral vasoconstriction and ischemia, just as it does in the periphery, but since the cerebral vasculature cannot tolerate hypoxia and hypercapnia, rapid vasodilation then ensues to improve local perfusion. Also α-adrenergic receptors in the CNS function differently from those in the periphery, and it may be that CNS vascular tone cannot be maintained in the setting of local tissue hypoxia.

■ CLINICAL MANIFESTATIONS Ergotism, a toxicologic syndrome resulting from excessive use of ergot alkaloids, is characterized by intense burning of the extremities, hemorrhagic vesiculations, pruritus, formications, nausea, vomiting,

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Antimigraine Agents

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TABLE 51–2. Pharmacokinetics of Ergots Ergot Derivative

Clinical Use

t ½ (hours)

Bromocriptine

Parkisonism, amenorrhea/ prolactinemia syndrome Migraine

60 (PO)

Dihydroergotamine

Ergonovine

Duration of Action (hours)

2.4

1 week (suppression of prolactin) 3–4 (IM)

1.9

3

Ergotamine

Testing for coronary vasospastic angina Migraine

2 (1.4–6.2)

22 (IV)

Methylergonovine

Postpartum hemorrhage

1.4–2.0

3

Methysergide

Migraine

1 (PO)

—

and gangrene (Table 51–4). Headache, fixed miosis, hallucinations, delirium, cerebrovascular ischemia, and convulsions are also associated with this condition, which has been called “convulsive” ergotism.35 Chronic ergotism usually presents with peripheral ischemia of the lower extremities, although ischemia of cerebral, mesenteric, coronary, and renal vascular beds are well documented.3,24,25,66,67 Ergotism can also result from interactions of ergot derivatives with P450 CYP3A4

Bioavailability (%)

Metabolism/ Elimination

28 (PO)

Liver

100 (IM) 40 (Nasal) 1000 IU/L), and hyperbilirubinemia, can be observed with both acute and chronic therapy.42,44 It is usually associated with high-dosage regimens. Laboratory abnormalities improve within 1 to 2 weeks of discontinuation of MTX. The mechanism is incompletely understood, but toxicity is attributed to reduced liver folate stores.6 Factors associated with hepatotoxicity are sustained high serum concentrations, increased cumulative dosages, chronic therapy, and host factors such as increase in age, obesity, diabetes, and alcoholism.66 Pancytopenia usually occurs within the first 2 weeks after an acute exposure. There are several reports demonstrating the occurrence of pancytopenia in individuals receiving chronic MTX therapy for rheumatoid arthritis and psoriasis.14,36,42,52

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Chapter 53

2-deoxyuridine monophosphate Folate Dihydrofolate reductase –

Thymidylate synthetase

N5, 10-10-methylene FH4 (Tetrahydrofolate) N10-formyl FH4

MTX

N5-formyl FH4 (Leucovorin)

Purines

Thymidylate

DNA/RNA synthesis

FIGURE 53–1. Mechanism of MTX toxicity. Methotrexate inhibits DHFR activity, which is necessary for DNA and RNA synthesis. Leucovorin bypasses blockade to allow for continued synthesis.

When used in low-dose intravenous (IV) doses of 40 to 60 mg/m2, MTX is not associated with appreciable nephrotoxicity. However, at doses greater than 5000 mg/m2 (approximately 130 mg/kg for an adult), several investigators report severe kidney damage, with oliguria, azotemia, and renal failure.7 The renal function can normalize over time. Patients at risk for nephrotoxicity include the elderly, those with underlying renal disease defined as a glomerular filtration rate of less than 50 mL/min, and those who receive concurrent drug therapy that can delay MTX excretion, which includes agents that reduce renal blood flow such as NSAIDs, the nephrotoxins such as cisplatin, and the aminoglycosides, or weak organic acids such as salicylates and piperacillin which inhibit renal secretion.28,60 The neurologic complications associated with either high-dose systemic MTX therapy or intrathecal administration are the most consequential manifestations. The incidence of neurologic toxicity from high-dose MTX therapy is approximately 5% to 15%.31 The manifestations usually occur from hours to days after the initiation of therapy and include hemiparesis, paraparesis, quadraparesis, seizures, and dysreflexia.15,41,64,61 These events are reversible to varying degrees.1 Clinical findings occurring within several hours (usually within 12 hours) of therapy are attributed to chemical arachnoiditis, and they include acute onset of fever, meningismus, pleocytosis, and increased cerebrospinal fluid (CSF) protein concentration.26 Leukoencephalopathy is associated with the onset of behavioral disorders and progressive dementia from months to years after treatment and is irreversible, although manifestations presenting soon after treatment can be reversible depending on the extent of involvement.4,69 Patients with increased age and prior cranial radiation are at risk for this disorder.21 They have findings consistent with edema, and demyelination or necrosis of the white matter on computed tomography (CT) and magnetic resonance imaging (MRI) of the brain.4

DIAGNOSTIC TESTING Serum methotrexate concentrations are monitored during therapy to help limit clinical toxicity. For example, patients with a serum concentration greater than 1.0 μmol/L at 48 hours posttreatment are considered at risk for bone marrow and gastrointestinal mucosal toxicity.60 The measurement of methotrexate concentrations in the clinical setting is routinely conducted using an immunoassay

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technique, such as enzyme immunoassay or fluorescence polarization immunoassay (FPIA). These measurements can be performed on serum, plasma, and cerebrospinal fluid. The presence of MTX metabolites, such as 7-OH-MTX and DAMPA (2,4-diamino-N10methylpteroic acid), folic acid, and certain drugs, such as trimethoprim and aminopterin, can diminish the specificity of the method for MTX.3,9,17,48,55 The amount by which these xenobiotics affect the MTX concentration depends on the assay. The advantages of the high performance liquid chromatography (HPLC) method over these other methods include improved sensitivity, specificity, and ability to detect metabolites; however, it takes longer to run than the routine clinical methods because it is not an automated procedure. When patients are treated with carboxypeptidase G2, (see Antidote in Depth A-14) it is preferable to use the HPLC method to measure MTX because of the presence of metabolites during therapy. The FPIA method with monoclonal antibodies is not recommended for use in patients who have developed antibodies to mouse monoclonal antibodies or elevated concentrations of DAMPA. An elevated serum methotrexate concentration (greater than 100 μmol/L) is indicative of an excessive intrathecal dose or delayed cerebrospinal fluid outflow obstruction.46 Radiological imaging of the brain, such as computed tomography and magnetic resonance imaging, can be obtained to evaluate for meningeal inflammation, demyelination and necrosis of the white matter, or other pathologies such as a cerebrovascular accident.

MANAGEMENT In the event of an oral overdose of methotrexate, the initial concern should be gastrointestinal decontamination. Activated charcoal adsorbs methotrexate and should be administered as soon as possible to limit absorption.22 The administration of multiple-dose activated charcoal and cholestyramine15,57 can significantly decrease the elimination halflife of methotrexate by interrupting the enterohepatic circulation.19,22 This approach can increase MTX clearance but is of most benefit to patients with diminished creatinine clearance. Adequate hydration with 0.9% sodium chloride solution as well as urinary alkalinization with IV sodium bicarbonate (to urine pH 7 to 8) (see Antidotes in Depth A 5: Sodium Bicarbonate) is also important to prevent renal failure from the precipitation of drug and metabolites in patients who receive inadvertent high doses.11 The complete blood count (CBC) should be monitored on days 7, 10, and 14 to assess the impact on the bone marrow.38 Granulocyte-macrophage colonystimulating factor (GM-CSF) was used in a patient with a chronic MTX overdose and pancytopenia.59 The patient had a serum MTX concentration of 1.25 μmol/L on admission and was in renal failure. Bone marrow biopsy showed promyelocytes, but no mature white cells, and a marked reduction of megakaryocytes. Because of deteriorating conditions, GM-CSF (125 μg/m2/d) was administered when the MTX concentration fell below the reference limit for toxicity. Seven days after the initiation of GM-CSF, the white blood cell (WBC) count rose and reached normal values within 10 days. Patients presenting with meningismus or altered mental status following MTX therapy require an initial MRI of the brain and then CSF analysis for infection.34 Although not considered standard, the CSF may be assayed for MTX if excessive exposure to this compartment is suspected. The CSF methotrexate concentration is about 0.1 mol/L (1 × 105 μmol/L) and lasts for 48 hours after an IV MTX dose of 1500 mg/m2, and 100 mol/L (1 × 108 μmol/L) for the peak therapeutic concentration after a 12-mg intrathecal MTX dose.45 MRI of the brain may demonstrate a high signal throughout the pachymeningeal (dura mater) region, which is consistent with a chemical meningitis,18

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or a high signal of the white matter with a decreased diffusion coefficient in a diffusion weighted image to indicate the presence of edema, which is an early finding of leukoencephalopathy.

ANTIDOTES The available rescue agents for methotrexate toxicity include folinic acid (leucovorin) (see Antidotes in Depth A–13: Leucovorin [Folinic Acid] and Folic Acid) and glucarpidase (carboxypeptidase G2) (see Antidotes in Depth A–14: Glucarpidase [Carboxypeptidase G2]). The effectiveness of these therapies depends on both the timing of administration and the dose, which warrants the monitoring of serum MTX concentrations during the use of these antidotes. Folinic acid rescue therapy limits methotrexate bone marrow and gastrointestinal toxicity by allowing for the continuation of essential biochemical processes that are dependent on reduced folates. The purpose of the initial dose of leucovorin is to achieve a serum concentration equal to the MTX and subsequent doses should be adjusted according to serum MTX concentrations at 12, 24, and 48 hours postexposure (see Fig. A13–1).35,55 Leucovorin treatment is continued until the MTX concentration is less than 0.01 μmol/L.10 In patients with marrow toxicity and no cancer, leucovorin therapy should be considered until marrow recovery occurs, even if serum MTX is no longer detectable,40 because intracellular MTX activity may still be ongoing because of the presence of cytosolic MTX polyglutamates. Among 71 patients undergoing MTX therapy for rheumatoid arthritis (average 6.1 mg MTX per week), 75% of these patients had indirectly detectable MTX polyglutamates in red blood cells and nondetectable MTX in the serum (FPIA, monoclonal antibody). Glucarpidase (carboxypeptidase G2, Voraxaze™) is a recombinant bacterial enzyme that is used as a rescue therapy to inactivate MTX. Glucarpidase is available for use as an adjunctive therapy in patients receiving high dose MTX and experiencing MTX toxicity, or are at risk for MTX toxicity: diminished renal function or delayed MTX clearance based on serum MTX concentrations (Clinicaltrials.gov Identifier: NCT00481559; http://clinicaltrials.gov/ct2/show/NCT00481559). Following glucarpidase therapy, serum MTX concentrations need to be monitored because residual levels of MTX in the blood after initial enzymatic therapy can result from an inadequate dose of glucarpidase in patients with large MTX exposures or the redistribution of MTX from tissue stores to the blood compartment.9,55,67 Glucarpidase has been successfully administered intrathecally to reduce elevated MTX concentrations in the cerebrospinal space (see SC Intrathecal Administration of Xenobiotics).68

EXTRACORPOREAL ELIMINATION There are several reports of the use of hemodialysis and/or hemoperfusion for patients with MTX toxicity.33,43,51,62,65 Although the volume of distribution (0.6 to 0.9 L/kg) and protein binding (50%) suggest that methotrexate is dialyzable, older clinical evidence suggests otherwise.59 In one report, less than 10% of an initial 0.7 g dose of methotrexate was cleared in 12 sessions of hemodialysis.62 The measured clearance was only 38 mL/min, which can be compared to 5 mL/min for peritoneal dialysis,23 0.28 to 24 mL/min for continuous venovenous hemodiafiltration,32,35 and 180 mL/min for normal renal clearance.39 Using plasma exchange transfusion to remove MTX is not recommended because of the drug’s low degree of protein binding, which limits the efficacy of this procedure.7,35,47,62 Acute intermittent hemodialysis with a high-flux dialyzer membrane yielded an effective mean serum MTX clearance of 92 mL/min in six patients with renal failure that was a result of either chronic disease

or high-dose MTX therapy.65 These patients received high-dose MTX therapy and had predialysis plasma MTX concentrations ranging from 1.45 to 1813 μmol/L. The time of dialysis initiation after MTX treatment was from 1 hour to 6 days in this patient population. A serum MTX concentration of 0.3 μmol/L was used as an end point for dialysis. The reported serum MTX clearance by this technique closely approximates normal renal MTX clearance and is indicated to enhance the clearance of MTX in patients with diminished renal clearance and an elevated serum MTX concentration when it is available.53 Charcoal hemoperfusion removed more than 50% of methotrexate in four patients with impaired renal MTX clearance during high-dose MTX therapy.13 This was thought to have prevented severe skin and mucosal toxicity. Sequential hemodialysis and hemoperfusion were used for a patient with substantial MTX toxicity.22 These procedures decreased the half-life of elimination from 45 hours to 7.6 hours. In experimental animals, hemoperfusion significantly reduced the terminal half-life of methotrexate. In surgically anephric dogs, hemoperfusion decreased the half-life from more than 20 hours to 1.3 hours.27 Consequently, hemoperfusion is recommended over hemodialysis when it is available; otherwise, high-flux hemodialysis is preferred.51 In vitro studies indicate that the toxic effects of 100 μmol/L of MTX cannot be reversed by 1000 μmol/L of folinic acid.49 This suggests the need for extracorporeal elimination, such as high-flux hemodialysis, and enzymatic cleavage to lower persistent serum MTX concentrations of greater than 100 mol/L.51 It is important to perform high-flux hemodialysis early, prior to distribution into tissues. Rebound of MTX concentrations from tissues may be expected after hemodialysis, which can begin at 2 hours postdialysis and plateau at 16 hours.20,23,65 Patients who are at the greatest risk for developing MTX toxicity despite folinic acid treatment should be considered for glucarpidase therapy and extracorporeal elimination because they are most likely to benefit from this procedure. This includes patients with progressively diminishing renal clearance.60 High-flux hemodialysis can offer the additional benefit of correcting fluid and electrolyte disorders resulting from renal failure. Other treatment options to limit additional organ toxicity, including leucovorin and urinary alkalinization, should be continued during extracorporeal MTX removal. Folic acid is water-soluble and can be removed by hemodialysis.12,51,56,58 This is probably also applicable for folinic acid, and replacement doses of leucovorin postdialysis should be considered.

SUMMARY The number of patients with methotrexate exposures and resultant toxicity is anticipated to increase due to the expanding therapeutic indications and available multiple formulations of this antineoplastic. Thus, clinicians need to understand the clinical presentations, acute and chronic, and management of methotrexate toxicity to improve the patient’s outcome. Patients with associated chronic illnesses, diminished renal clearance, and chronic toxicity are at greatest risk for increased morbidity from overwhelming sepsis. Management includes supportive care, monitoring serum methotrexate concentrations, enhanced elimination (urinary alkalinization), and antidotal therapy with leucovorin and enzymatic cleavage. The early recognition of these patients and institution of these therapies can offer the patient the best outcome.

ACKNOWLEDGMENT This chapter was written by Richard Y. Wang in his private capacity. No official support or endorsement by the Centers for Disease Control and Prevention is intended or should be inferred. Paul Calabresi contributed to this chapter in a previous edition.

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Chapter 53

REFERENCES 1. Abelson HT. Methotrexate and central nervous system toxicity. Cancer Treat Rep. 1978;62:1999-2001. 2. Abelson HT, Fosburg MT, Beardsley GP, et al. Methotrexate-induced renal impairment: clinical studies and rescue from systemic toxicity with highdose leucovorin and thymidine. J Clin Oncol. 1983;1:208-216. 3. Albertioni F, Rask C, Eksborg S, et al. Evaluation of clinical assays for measuring high-dose methotrexate in plasma. Clin Chem. 1996;42:39-44. 4. Allen JC, Rosen G, Mehta BM, Horten B. Leukoencephalopathy following high-dose IV methotrexate chemotherapy with leucovorin rescue. Cancer Treat Rep. 1980;64:1261-1273. 5. Atherton LD, Leib ES, Kaye MD. Toxic megacolon associated with methotrexate therapy. Gastroenterology. 1984;86:1583-1588. 6. Barak AJ, Tuma DJ, Beckenhauer HC. Methotrexate hepatotoxicity. J Am Coll Nutr. 1984;3:93-96. 7. Benezet S, Chatelut E, Bagheri H, et al. Inefficacy of exchange-transfusion in case of a methotrexate poisoning. Bull Cancer. 1997;84:788-790. 8. Bleyer WA. The clinical pharmacology of methotrexate: new applications of an old drug. Cancer. 1978;41:36-51. 9. Buchen S, Ngampolo D, Melton RG, et al. Carboxypeptidase G2 rescue in patients with methotrexate intoxication and renal failure. Br J Cancer. 2005;92:480-487. 10. Chabner BA, Young RC. Threshold methotrexate concentration for in vivo inhibition of DNA synthesis in normal and tumorous target tissues. J Clin Invest. 1973;52:1804-1811. 11. Christensen ML, Rivera GK, Crom WR, Hancock ML, Evans WE. Effect of hydration on methotrexate plasma concentrations in children with acute lymphocytic leukemia. J Clin Oncol. 1988;6:797-801. 12. Cunningham J, Sharman VL, Goodwin FJ, Marsh FP. Do patients receiving haemodialysis need folic acid supplements? Br Med J (Clin Res Ed). 1981;282:1582. 13. Djerassi I, Ciesielka W, Kim JS. Removal of methotrexate by filtrationadsorption using charcoal filters or by hemodialysis. Cancer Treat Rep. 1977;61:751-752. 14. Doolittle GC, Simpson KM, Lindsley HB. Methotrexate-associated, earlyonset pancytopenia in rheumatoid arthritis. Arch Intern Med. 1989;149: 1430-1431. 15. Erttmann R, Landbeck G. Effect of oral cholestyramine on the elimination of high-dose methotrexate. J Cancer Res Clin Oncol. 1985;110:48-50. 16. Fong CM, Lee AC. High-dose methotrexate-associated acute renal failure may be an avoidable complication. Pediatr Hematol Oncol. 2006;23:51-57. 17. Fotoohi K, Skarby T, Soderhall S, Peterson C, Albertioni F. Interference of 7-hydroxymethotrexate with the determination of methotrexate in plasma samples from children with acute lymphoblastic leukemia employing routine clinical assays. J Chromatogr B Analyt Technol Biomed Life Sci. 2005;817:139-144. 18. Fukushima T, Sumazaki R, Koike K, et al. A magnetic resonance abnormality correlating with permeability of the blood-brain barrier in a child with chemical meningitis during central nervous system prophylaxis for acute leukemia. Ann Hematol. 1999; 78:564-567. 19. Gadgil SD, Damle SR, Advani SH, Vaidya AB. Effect of activated charcoal on the pharmacokinetics of high-dose methotrexate. Cancer Treat Rep. 1982;66:1169-1171. 20. Gibson TP, Reich SD, Krumlovsky FA, Ivanovich P, Gonczy C. Hemoperfusion for methotrexate removal. Clin Pharmacol Ther. 1978;23: 351-355. 21. Gowan GM, Herrington JD, Simonetta AB. Methotrexate-induced toxic leukoencephalopathy. Pharmacotherapy. 2002;22:1183-1187. 22. Grimes DJ, Bowles MR, Buttsworth JA, et al. Survival after unexpected high serum methotrexate concentrations in a patient with osteogenic sarcoma. Drug Saf. 1990;5:447-454. 23. Hande KR, Balow JE, Drake JC, Rosenberg SA, Chabner BA. Methotrexate and hemodialysis. Ann Intern Med. 1977;87:495-496. 24. Harned TM, Mascarenhas L. Severe methotrexate toxicity precipitated by intravenous radiographic contrast. J Pediatr Hematol Oncol. 2007;29:496-499. 25. Huang KC, Wenczak BA, Liu YK. Renal tubular transport of methotrexate in the rhesus monkey and dog. Cancer Res. 1979;39:4843-4848. 26. Hughes PJ, Lane RJ. Acute cerebral oedema induced by methotrexate. BMJ. 1989;298:1315. 27. Isacoff W. Effects of extracorporeal charcoal hemoperfusion on plasma methotrexate [abstract]. Proc Am Assoc Cancer Res. 1977;18:1.

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28. Iven H, Brasch H. The effects of antibiotics and uricosuric drugs on the renal elimination of methotrexate and 7-hydroxymethotrexate in rabbits. Cancer Chemother Pharmacol. 1988;21:337-342. 29. Jackson RC GG. The biochemical basis for methotrexate cytotoxicity. In: Sirotnak FM, ed. Folate Antagonists as Therapeutic Agents. New York: Academic Press; 1984:289-315. 30. Jacobs SA, Stoller RG, Chabner BA, Johns DG. 7-Hydroxymethotrexate as a urinary metabolite in human subjects and rhesus monkeys receiving high dose methotrexate. J Clin Invest. 1976;57:534-538. 31. Jaffe N, Takaue Y, Anzai T, Robertson R. Transient neurologic disturbances induced by high-dose methotrexate treatment. Cancer. 1985;56:1356-1360. 32. Jambou P, Levraut J, Favier C, et al. Removal of methotrexate by continuous venovenous hemodiafiltration. Contrib Nephrol. 1995;116:48-52. 33. Kawabata K, Makino H, Nagake Y, et al. A case of methotrexate-induced acute renal failure successfully treated with plasma perfusion and sequential hemodialysis. Nephron. 1995;71:233-234. 34. Kelkar R, Gordon SM, Giri N, et al. Epidemic iatrogenic Acinetobacter spp. meningitis following administration of intrathecal methotrexate. J Hosp Infect. 1989;14:233-243. 35. Kepka L, De Lassence A, Ribrag V, et al. Successful rescue in a patient with high dose methotrexate-induced nephrotoxicity and acute renal failure. Leuk Lymphoma. 1998;29:205-209. 36. Kevat SG, Hill WR, McCarthy PJ, Ahern MJ. Pancytopenia induced by lowdose methotrexate for rheumatoid arthritis. Aust N Z J Med. 1988;18:697-700. 37. Kremer JM, Hamilton RA. The effects of nonsteroidal antiinflammatory drugs on methotrexate (MTX) pharmacokinetics: impairment of renal clearance of MTX at weekly maintenance doses but not at 7.5 mg. J Rheumatol. 1995;22:2072-2077. 38. Langslow A. Nursing and the law. Deadly doses of methotrexate. Aust Nurs J. 1995;2:32-34. 39. Liegler DG, Henderson ES, Hahn MA, Oliverio VT. The effect of organic acids on renal clearance of methotrexate in man. Clin Pharmacol Ther. 1969;10:849-857. 40. MacKinnon SK, Starkebaum G, Willkens RF. Pancytopenia associated with low dose pulse methotrexate in the treatment of rheumatoid arthritis. Semin Arthritis Rheum. 1985;15:119-126. 41. Massenkeil G, Spath-Schwalbe E, Flath B, et al. Transient tetraparesis after intrathecal and high-dose systemic methotrexate. Ann Hematol. 1998;77:239-242. 42. McIntosh S, Davidson DL, O’Brien RT, Pearson HA. Methotrexate hepatotoxicity in children with leukemia. J Pediatr. 1977;90:1019-1021. 43. Molinari A, Oliva A, Aguilera N, et al. New antineoplastic prenylhydroquinones. Synthesis and evaluation. Bioorg Med Chem. 2000;8:1027-1032. 44. Nesbit M, Krivit W, Heyn R, Sharp H. Acute and chronic effects of methotrexate on hepatic, pulmonary, and skeletal systems. Cancer. 1976;37: 1048-1057. 45. Olver IN, Aisner J, Hament A, et al. A prospective study of topical dimethyl sulfoxide for treating anthracycline extravasation. J Clin Oncol. 1988;6:1732-1735. 46. O’Marcaigh AS, Johnson CM, Smithson WA, et al. Successful treatment of intrathecal methotrexate overdose by using ventriculolumbar perfusion and intrathecal instillation of carboxypeptidase G2. Mayo Clin Proc. 1996;71:161-165. 47. Park ES, Han KH, Choi HS, Shin HY, Ahn HS. Carboxypeptidase-G2 resuce in a patient with a high dose methotrexate-induced nephrotoxicty. Cancer Res Treat. 2005;37:2. 48. Pesce MA, Bodourian SH. Enzyme immunoassay and enzyme inhibition assay of methotrexate, with use of the centrifugal analyzer. Clin Chem. 1981;27:380-384. 49. Pinedo HM, Zaharko DS, Bull JM, Chabner BA. The reversal of methotrexate cytotoxicity to mouse bone marrow cells by leucovorin and nucleosides. Cancer Res. 1976;36:4418-4424. 50. Reggev A, Djerassi I. The safety of administration of massive doses of methotrexate (50 g) with equimolar citrovorum factor rescue in adult patients. Cancer. 1988;61:2423-2428. 51. Relling MV, Stapleton FB, Ochs J, et al. Removal of methotrexate, leucovorin, and their metabolites by combined hemodialysis and hemoperfusion. Cancer. 1988;62:884-888. 52. Roenigk HH Jr, Maibach HI, Weinstein GP. Methotrexate therapy for psoriasis. Guideline revisions. Arch Dermatol. 1973;108:35. 53. Saland JM, Leavey PJ, Bash RO, et al. Effective removal of methotrexate by high-flux hemodialysis. Pediatr Nephrol. 2002;17:825-829.

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Part C

The Clinical Basis of Medical Toxicology

54. Sasaki K, Tanaka J, Fujimoto T. Theoretically required urinary flow during highdose methotrexate infusion. Cancer Chemother Pharmacol. 1984;13:9-13. 55. Schwartz S, Borner K, Muller K, et al. Glucarpidase (carboxypeptidase G2) intervention in adult and elderly cancer patients with renal dysfunction and delayed methotrexate elimination after high-dose methotrexate therapy. Oncologist. 2007;12:1299-1308. 56. Sheikh-Hamad D, Timmins K, Jalali Z. Cisplatin-induced renal toxicity: possible reversal by N-acetylcysteine treatment. J Am Soc Nephrol. 1997;8: 1640-1644. 57. Shinozaki T, Watanabe H, Tomidokoro R, et al. Successful rescue by oral cholestyramine of a patient with methotrexate nephrotoxicity: nonrenal excretion of serum methotrexate. Med Pediatr Oncol. 2000;34:226-228. 58. Skoutakis VA, Acchiardo SR, Meyer MC, Hatch FE. Folic acid dosage for chronic hemodialysis patients. Clin Pharmacol Ther. 1975;18:200-204. 59. Steger GG, Mader RM, Gnant MF, et al. GM-CSF in the treatment of a patient with severe methotrexate intoxication. J Intern Med. 1993;233:499-502. 60. Stoller RG, Hande KR, Jacobs SA, Rosenberg SA, Chabner BA. Use of plasma pharmacokinetics to predict and prevent methotrexate toxicity. N Engl J Med. 1977;297:630-634. 61. Teh HS, Fadilah SA, Leong CF. Transverse myelopathy following intrathecal administration of chemotherapy. Singapore Med J. 2007;48:e46-49.

62. Thierry FX, Vernier I, Dueymes JM, et al. Acute renal failure after highdose methotrexate therapy. Role of hemodialysis and plasma exchange in methotrexate removal. Nephron. 1989;51:416-417. 63. Von Hoff DD, Penta JS, Helman LJ, Slavik M. Incidence of drug-related deaths secondary to high-dose methotrexate and citrovorum factor administration. Cancer Treat Rep. 1977;61:745-748. 64. Walker RW, Allen JC, Rosen G, Caparros B. Transient cerebral dysfunction secondary to high-dose methotrexate. J Clin Oncol. 1986;4:1845-1850. 65. Wall SM, Johansen MJ, Molony DA, et al. Effective clearance of methotrexate using high-flux hemodialysis membranes. Am J Kidney Dis. 1996; 28:846-854. 66. Weinstein GD. Methotrexate. Ann Intern Med. 1977;86:199-204. 67. Widemann BC, Balis FM, Murphy RF, et al. Carboxypeptidase-G2, thymidine, and leucovorin rescue in cancer patients with methotrexate-induced renal dysfunction. J Clin Oncol. 1997;15:2125-2134. 68. Widemann BC, Balis FM, Shalabi A, et al. Treatment of accidental intrathecal methotrexate overdose with intrathecal carboxypeptidase G2. J Natl Cancer Inst. 2004;96:1557-1559. 69. Ziereisen F, Dan B, Azzi N, et al. Reversible acute methotrexate leukoencephalopathy: atypical brain MR imaging features. Pediatr Radiol. 2006; 36:205-212.

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A N T I D O T E S I N D E P T H ( A 13 ) LEUCOVORIN (FOLINIC ACID) AND FOLIC ACID Mary Ann Howland

many folate congeners that exist in nature and perform essential cellular metabolic functions. After absorption, folic acid is reduced by dihydrofolic acid reductase (DHFR) to tetrahydrofolic acid, which accepts one-carbon groups. Tetrahydrofolic acid serves as the precursor for several biologically active forms of folic acid, including 5-formyltetrahydrofolic acid, which is best known as folinic acid, leucovorin, and citrovorum factor. These biologically active forms of folate are enzymatically interconvertible and function as cofactors, providing the one-carbon groups necessary for many intracellular metabolic reactions, including the synthesis of thymidylate and purine nucleotides, which are essential precursors of DNA.23,25,29,31,36 The minimum daily requirement of folate is normally 50 μg, but in pregnant women and nutritionally deprived, acutely ill patients, 100 to 200 μg may be required.7,8

ROLE IN METHOTREXATE TOXICITY Methotrexate, an antimetabolite, is a structural analog of folic acid, differing only in the substitution of an amino group for a hydroxyl group at the number 4 position of the pteridine ring (see Chap. 53). Methotrexate binds to the active site of DHFR, rendering it incapable of reducing folic acid to its biologically active forms, and incapable of regenerating the necessary active forms required for the synthesis of purine nucleotides and thymidylate.30 At physiologic pH the binding between methotrexate and DHFR is competitive, with an inhibition constant of about 1 μmol/L.27 Leucovorin is a reduced, active form of folate. As such, it does not require DHFR for enzymatic interconversion to the form required for purine nucleotide and thymidylate formation. Folic acid is unable to counteract methotrexate toxicity because following methotrexate therapy, DHFR is unavailable to convert folic acid to the active reduced forms. Leucovorin rescue is the term used to describe the practice of limiting the toxic effects of high-dose methotrexate therapy.

ROLE IN METHANOL TOXICITY

Leucovorin (folinic acid) is the primary antidote for a patient who receives an overdose of methotrexate. Methotrexate prevents the conversion of inactive folic acid to the biologically active reduced form of folic acid, known as leucovorin or folinic acid. Only leucovorin is an acceptable antidote for a patient with methotrexate toxicity. Following a methanol overdose, folic acid enhances the metabolism of formate. Since methanol does not interfere with the synthesis of folinic acid, either folic acid or leucovorin is acceptable for a patient poisoned by methanol.

PHARMACOLOGY Folic acid, an essential water-soluble vitamin, consists of a pteridine ring joined to PABA (para-aminobenzoic acid) and glutamic acid.7 Folic acid is the most common pharmaceutical preparation of the

Monkeys experimentally made folate deficient develop methanol toxicity at lower methanol concentrations.19 Administering folic acid to normal monkeys accelerates formate metabolism.19 Pretreatment with folic acid or leucovorin decreased both formate concentrations and the accompanying metabolic acidosis, without affecting the rate of methanol elimination.19 Leucovorin remained effective in hastening the metabolism of formate when given 10 hours after methanol administration.21 The hepatic concentrations of total folate, leucovorin, and folate dehydrogenase (which increases leucovorin concentrations) are all diminished in methanol-poisoned humans.12 In an analysis of a single methanol-poisoned patient who was given folate and ethanol and hemodialyzed, the half-life of formate was 1.1 hours.22 In another methanol-poisoned patient treated without folate, the formate half-life was 2.8 hours.9 These comparative data are inadequate to draw definitive conclusions, but may support the therapeutic role of folate, in addition to that of fomepizole and hemodialysis.

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Part C

The Clinical Basis of Medical Toxicology

LEUCOVORIN PHARMACOKINETICS Leucovorin is naturally formed in the body as the active (l or −) isomer, whereas the commercial preparation is the racemic mixture, which means it consists of equal amounts of the inactive (d or +) and active (l or −) isomers. The pharmacokinetics of the racemic mixture of leucovorin and its active metabolite were studied after intravenous (IV) infusion, and as a constant infusion in normal human volunteers.32,33 During constant infusion of 500 mg/m2/d, the steady-state concentration for the active isomer was 2.33 μM, the half-life was 35 minutes, and the volume of distribution was 13.6 L. The active isomer is metabolized to an active metabolite (l-5-CH3-THF) that achieved a steady-state concentration of 4.85 μM and a half-life of 227 minutes. Similar values were achieved for half-life and volume of distribution after single IV doses ranging from 25 to 100 mg. The inactive d isomer achieved higher concentrations and had a much longer half-life with oral administration which is saturable and stereoselective, resulting in absorption of the active isomer that is four to five times greater than that of the inactive isomer. Studies of stereospecific oral absorption demonstrate that 100% of the l-leucovorin is absorbed whereas only 20% of the d-leucovorin is absorbed at this dose.15 One study detected no adverse effects of the inactive isomer on the intracellular uptake of the active isomer and concluded that giving the active isomer provided no pharmacokinetic advantage over the racemic mixture.28 The pharmacokinetics of IV leucovorin was compared to intramuscular (IM) and oral administration in male volunteers given 25 mg. The mean peak of the active l-5-CH3-THF concentration was 258 ng/mL at 1.3 hours after IV administration compared with 226 ng/mL at 2.8 hours for IM and 367 ng/mL at 2.4 hours for oral administration. The pharmacokinetics of orally administered leucovorin was studied in healthy, fasted, male volunteers in single doses ranging from 20 to 100 mg, and 200 mg IV over 5 minutes as compared with 200 mg orally.18,24 Bioavailability decreased from 100% for the 20-mg dose to 78% for the 40-mg dose, and ultimately to 31% for the 200-mg dose. A microbiologic assay was used to measure total tetrahydrofolates (reduced and active folates). Normal serum folate concentrations are approximately 0.05 μmol/L.10 The 200-mg oral dose produced a peak serum concentration of 1.82 μmol/L, compared to 0.66 μmol/L for the 20-mg oral dose and 27.1 μmol/L for the 200-mg IV dose.18,24

LEUCOVORIN DOSING FOR METHOTREXATE OVERDOSES When a patient overdoses on methotrexate, a dose of leucovorin estimated to produce the same plasma concentration as the methotrexate dose should be given as soon as possible and, preferably, within 1 hour. One mole of methotrexate weighs 455 D and 1 mol of leucovorin calcium weighs 511 D, with the molecular weight of the leucovorin portion equal to 471 D. Because of the safety of leucovorin and because of the toxicity of methotrexate, underdosing leucovorin should be avoided. Although serum methotrexate concentrations are often closely followed in patients on diverse oncologic regimens,2,3 in the overdose setting, or in the treatment of methotrexate toxicity related to treatment for tubal pregnancies, it is inappropriate to wait for a serum methotrexate concentration before initiating treatment with leucovorin.1 The toxic threshold for methotrexate is reported to be 1 × 10−8 mol/L (0.01 μmol/L or 10 nmol/L).4 Normal serum folate concentrations are in the range of 13 to 43 nmol/L. In a patient who is not receiving methotrexate therapeutically, there is no need to permit any methotrexate to remain unantagonized by leucovorin. For example, if a child unintentionally ingests one hundred 2.5-mg methotrexate tablets for a total dose of 250 mg, only part of this dose

is absorbed because methotrexate absorption is saturable.6 The bioavailability of methotrexate decreases from 100% with doses less than 30 mg/m2 to approximately 10% to 20% with doses greater than 80 mg/m2. In this case, it is safe to assume that a bioavailability of 50% would result in an absorbed dose of methotrexate of less than 125 mg. For this substantial exposure an IV dose of 125 mg of leucovorin could be given over 15 to 30 minutes. This dose of IV leucovorin would be expected to produce serum concentrations in excess of that of the methotrexate, given that the volume of distribution of leucovorin is about 25% less than methotrexate and the molecular weights are similar. This dose of IV leucovorin should be repeated every 3 to 6 hours until the serum methotrexate concentration is less than 1 × 10−8 mol/L, and preferably zero. The methotrexate half-life may vary from 5 to 45 hours, depending on the dose and the patient’s renal function. For this reason, leucovorin therapy should be continued for 12 to 24 doses (3 days) or longer if methotrexate concentrations are unavailable. Patients who may develop third-space storage in ascites or pleural effusions may also require leucovorin dosing for an extended period of time. Patients with bone marrow toxicity require more prolonged dosing because plasma half-lives of methotrexate do not reflect persistent intracellular concentrations. Unintentional overdose with intrathecal methotrexate is potentially quite serious and is dose dependent.11,16 In these cases, IV leucovorin should be administered. Intrathecal leucovorin was considered a major factor in the death of a child given a slightly higher dose of intrathecal methotrexate than was prescribed.14 Not all intrathecal methotrexate overdoses require aggressive intervention, but consultation with experienced hematologists/oncologists and medical toxicologists is warranted (see Special Considerations SC2: Intrathecal Administration of xenobiotics).13 An IV leucovorin dose of 100 mg/m2 every 3 to 6 hours should be effective, in all but the most severe overdoses. A constant intravenous infusion of 21 mg/m2/h has been safely administered for 5 days. See Figure A13-1, which offers a nomogram for pharmacokinetically guided rescue after high-dose methotrexate.2 A transition to the oral administration of leucovorin depends on the serum concentration of the methotrexate and whether adequate serum concentrations of leucovorin can be achieved by that route. In adults, a 200-mg oral dose of leucovorin produces a peak serum concentration of 1.82 μmol/L as compared with 27.1 μmol/L with a 200-mg IV dose. Levoleucovorin, the active l isomer of folinic acid, is available and should be dosed at half the dose of the racemate leucovorin.5 Administration of activated charcoal precludes the subsequent administration of oral leucovorin. In addition to leucovorin, other

Leucovorin dose Plasma MTX concentration (mM)

784

1,000 100

1000 mg/m2 q 6 hr

10

100 mg/m2 q 3 hr

1.0

10 mg/m2 q 3 hr 10 mg/m2 q 6 hr

0.1 0.01 0

20 40 60 80 100 120 Time after start of MTX infusion (hr)

140

FIGURE A13–1. Example of a nomogram developed by Bleyer2 for pharmacokineti-

cally guided leucovorin rescue after high-dose methotrexate (MTX) administration.

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Antidotes in Depth

modalities to treat patients with methotrexate overdoses include activated charcoal and urinary alkalinization, and glucarpidase (carboxypeptidase G) and extracorporeal removal should be considered (see Chap. 53).

ADVERSE EFFECTS AND SAFETY ISSUES Reports of adverse reactions to parenteral injections of folic acid or leucovorin are uncommon; however, adverse reactions may include allergic or anaphylactoid reactions.7 Seizures are rarely associated with leucovorin administration.20 The calcium content of leucovorin warrants a slow intravenous infusion at a rate not faster than 160 mg/min in adults. Leucovorin should never be administered intrathecally.11,14,26,35 Leucovorin is not an antidote to 5-fluorouracil (5-FU) and can enhance the therapeutic and toxic effects of fluoropyrimidines such as 5-FU.15,17 Many protocols recommended separating leucovorin from glucarpidase by 2 hours (see Antidotes in Depth A14: Glucarpidase [Carboxypeptidase G2]).

DOSING The routine dose of leucovorin for “leucovorin rescue” ranges from 10 to 25 mg/m2 IM or IV every 6 hours for 72 hours to 100 mg/m2 every 3 hours in patients with renal compromise. If administration to neonates is necessary, a benzyl-alcohol-free preparation must be used because of the toxicity of benzyl alcohol in neonates (see Chap. 55).34 For methotrexate overdoses, equimolar serum leucovorin concentrations should provide adequate protection, but precise determinations are invariably delayed, and the administration of leucovorin should not be delayed until a serum methotrexate concentration is determined. As a rough guide, a single dose of IV 25 mg leucovorin in an adult produces a peak concentration of the active l-5-CH3-THF metabolite of approximately 258 ng/mL which is 5.5 × 10−7 M.15 A dose of about 150 mg every 4 hours in an adult achieves a steady-state concentration of about 4.85 × 10−6 M.32 And although the dose of leucovorin can be as high as 1000 mg/m2 every 6 hours, this is rarely warranted and cannot adequately compete with serum concentrations of methotrexate above 10−4 M; under these circumstances glucarpidase should be strongly considered. An IV leucovorin dose of 100 mg/m2 every 3 to 6 hours should be effective in all but the most severe overdoses and should be administered IV as soon as possible over 15 to 30 minutes, but not faster than 160 mg/min in adults due to the calcium content. This dose should be continued for at least several days, or until the serum methotrexate concentration falls below 1 × 10−8 mol/L in the absence of bone marrow toxicity. Either folic acid or leucovorin (folinic acid) should be administered parenterally at the first suspicion of methanol poisoning. No complications are reported with the use of 50 to 70 mg of IV folic acid every 4 hours for the first 24 hours in the treatment of methanol-poisoned patients.22 The precise dose necessary is unknown, but 1 to 2 mg/kg every 4 to 6 hours is probably sufficient. The folic acid should be continued until the methanol and formate are eliminated. As the first dose is usually administered prior to hemodialysis, a second dose should be administered at the completion of hemodialysis, because hemodialysis will remove this highly water-soluble vitamin.

AVAILABILITY Leucovorin (folinic acid) powder for injection is available in 50-, 100-, 200-, and 350-mg vials. Each mg of leucovorin contains 0.004 mEq of calcium. Reconstitution with sterile water for injection—5 mL to the

Leucovorin (Folinic Acid) and Folic Acid

785

TABLE A13–1. Rapid Calculations 1 mole = 1 gram molecular weight 1 Molar = 1 mole/L = 1 gram molecular weight/L 1 × 10−3 moles = 1 millimole = 1 mmole 1 × 10−6 moles = 1 micromole = 1 μmole 1 × 10−9 moles = 1 nanomole = 1 nmole 1 mole of methotrexate weighs 455 daltons; 1 mole methotrexate = 455 grams 1 Molar methotrexate = 455 grams/L = 455 mg/mL 1 × 10−8 Molar methotrexate = 455 × 10−8 g/L = 455 × 10−8 mg/mL = 455 × 10−5 μg/mL = 455 × 10−2 ng/mL = 4.55 ng/mL

50-mg vial, 10 mL to the 100-mg vial, or 20 mL to the 200-mg vial— results in a final concentration of 10 mg/mL. Adding 17.5 mL of sterile water for injection to the 350-mg vial results in a final concentration of 20 mg/mL. Leucovorin is also available in a single-use vial as a solution for injection at a concentration of 10 mg/mL in a 50-mL vial. Because of the calcium content, the rate of intravenous administration should not be faster than 160 mg/min in adults.15 Leucovorin is also available orally in a variety of strengths, including 5-, 10-, 15-, and 25-mg tablets. Levoleucovorin (Fusilev) lyophilized powder for injection is available in a single-use 50-mg vial containing the equivalent of 50 mg of levoleucovorin as the calcium pentahydrate salt and 50 mg mannitol. Reconstitution with 5.3 mL of 0.9% sodium chloride injection, USP, yields a concentration of 10 mg/mL. Because of the calcium content, the rate of IV administration should not be faster than 160 mg/min (16 mL of reconstituted solution/min).5 Folic acid is available parenterally in 10-mL multidose vials with 1.5% benzyl alcohol in concentrations of 5 or 10 mg/mL from a variety of manufacturers. Once opened, this vial must be kept refrigerated.

SUMMARY Leucovorin (folinic acid) is the primary antidote for a patient who receives an overdose of methotrexate. Leucovorin is the biologically active, reduced form of folic acid, the synthesis of which is prevented by methotrexate. Only leucovorin (folinic acid) is an acceptable antidote for a patient with methotrexate toxicity, but either folic acid or leucovorin is acceptable for a patient poisoned by methanol. Following a methanol overdose, folic acid enhances the elimination of formate (Table A13-1).

REFERENCES 1. American College of Obstetricians and Gynecologists practice bulletin. Medical management of tubal pregnancy. Number 3, December 1998. Clinical management guidelines for obstetrician-gynecologists. Int J Gynaecol Obstet. 1999;65:97-103. 2. Bleyer WA. New vistas for leucovorin in cancer chemotherapy. Cancer. 1989;63:995-1007. 3. Booser DJ, Walters RS, Holmes FA, Hortobagyi GN. Continuous-infusion high-dose leucovorin with 5-fluorouracil and cisplatin for relapsed metastatic breast cancer: a phase II study. Am J Clin Oncol. 2000;23:40-41. 4. Chabner BA, Young RC. Threshold methotrexate concentration for in vivo inhibition of DNA synthesis in normal and tumorous target tissues. J Clin Invest. 1973;52:1804-1811. 5. Fusilev [package insert]. Irvine, CA: Manufactured by Chesapeake Biological Labs Inc for Spectrum Pharmaceuticals Inc; 2008.

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6. Gibbon BN, Manthey DE. Pediatric case of accidental oral overdose of methotrexate. Ann Emerg Med. 1999;34:98-100. 7. Hillman RS. Hematopoetic agents: growth factors, minerals and vitamins. In: Hardman JG, Limbird CE, eds. Goodman and Gilman’s The Pharmacologic Basis of Therapeutics. 10th ed. New York: McGraw-Hill; 2001:1487-1517. 8. Houben PF, Hommes OR, Knaven PJ. Anticonvulsant drugs and folic acid in young mentally retarded epileptic patients. A study of serum folate, fit frequency and IQ. Epilepsia. 1971;12:235-247. 9. Jacobsen D, McMartin KE. Methanol and ethylene glycol poisonings: mechanism of toxicity, clinical course, diagnosis and treatment. Med Toxicol. 1986;1:309-334. 10. Janinis J, Papakostas P, Samelis G, et al. Second-line chemotherapy with weekly oxaliplatin and high-dose 5-fluorouracil with folinic acid in metastatic colorectal carcinoma: a Hellenic Cooperative Oncology Group (HeCOG) phase II feasibility study. Ann Oncol. 2000;11:163-167. 11. Jardine LF, Ingram LC, Bleyer WA. Intrathecal leucovorin after intrathecal methotrexate overdose. J Pediatr Hematol Oncol. 1996;18:302-304. 12. Johlin F, Fortman C, Nghiem D, Tephly TR. Studies on the role of folic acid and folate dependent enzymes in human methanol poisoning. Mol Pharmacol. 1987;31:557-561. 13. Lampkin BC, Wells R. Intrathecal leucovorin after intrathecal methotrexate. J Pediatr Hematol Oncol. 1996;18:249. 14. Lee ACW, Wong KW, Fong KW, So KT. Intrathecal methotrexate overdose. Acta Pediatr. 1997;86:434-437. 15. Leucovorin Calcium Injection, USP [package insert]. Bedford, OH: Manufactured by Ben Venue Labs Inc for Bedford Labs; 2008. 16. Levitt M, Nixon PF, Pincus JH, Bertino JR. Transport characteristics of folates in cerebrospinal fluid; a study utilizing doubly labeled 5-methyltetrahydrofolate and 5-formyltetrahydrofolate. J Clin Invest. 1971; 50:1301-1308. 17. Lonardi F, Jirillo A, Bonciarelli G, Pavanato G, Balli M. Toxicity of laevoleucovorin and dose lowering. Eur J Cancer. 1992;28A:1007-1008. 18. McGuire BW, Sia LL, Haynes JD, et al. Absorption kinetics of orally administered leucovorin calcium. NCI Monogr. 1987;5:47-56. 19. McMartin KE, Martin-Amat G, Makar AB, Tephly TR. Methanol poisoning. V: role of formate metabolism in the monkey. J Pharmacol Exp Ther. 1977;201:564-572. 20. Metropol NJ, Creaven PJ, Petrelli N, White RM, Arbuck SG. Seizures associated with leucovorin administration in cancer patients. J Natl Cancer Inst. 1995;87:56-58. 21. Noker PE, Eells MS, Tephly TR. Methanol toxicity: treatment with folic acid and 5-formyltetrahydrofolic acid. Alcohol Clin Exp Res. 1980;4:378-383.

22. Osterloh J, Pond S, Grady S, Becker CE. Serum formate concentrations in methanol intoxication as a criterion for hemodialysis. Ann Intern Med. 1986;104:200-203. 23. Patel R, Newman EM, Villacorte DG, et al. Pharmacology and phase I trial of high-dose oral leucovorin plus 5-fluorouracil in children with refractory cancer: A report from the Children’s Cancer Study Group. Cancer Res. 1991;51:4871-4875. 24. Priest DG, Schmitz JC, Bunni MA, Stuart RK. Pharmacokinetics of leucovorin metabolites in human plasma as a function of dose administered orally and intravenously. J Natl Cancer Inst. 1991;83:1806-1812. 25. Reynolds EH. Effects of folic acid on the mental state and fit-frequency of drug-treated epileptic patients. Lancet. 1967;1:1086-1088. 26. Riva L, Conter V, Rizzari C, et al. Successful treatment of intrathecal methotrexate overdose with folinic acid rescue: a case report. Acta Paediatr. 1999;88:780-782. 27. Salmon SE, Sartorelli AC. Cancer chemotherapy. In: Katzung BG, ed. Basic and Clinical Pharmacology. 7th ed. Norwalk, CT: Appleton & Lange; 1998:889-891. 28. Schleyer E, Rudolph KL, Braess J, et al. Impact of the simultaneous administration of the (+)- and (–)-forms of formyl-tetrahydrofolic acid on plasma and intracellular pharmacokinetics of (–)-tetrahydrofolic acid. Cancer Chemother Pharmacol. 2000;45:165-171. 29. Smith DB, Racusen LC. Folate metabolism and the anticonvulsant efficacy of phenobarbital. Arch Neurol. 1973;28:18-22. 30. Smith S, Nelson L. Case files of the New York City Poison Control Center: Antidotal strategies for the management of methotrexate toxicity. J Med Tox. 2008;4:132-140. 31. Stover P, Schirch V. The metabolic role of leucovorin. Trends Biochem Sci. 1993;18:102-106. 32. Straw JA, Newman EM, Doroshow JH. Pharmacokinetics of leucovorin (dl-5 formyltetrahydrofolate) after intravenous injection and constant intravenous infusion. NCI Monogr. 1987;5:41-45. 33. Straw JA, Szapary D, Wynn W. Pharmacokinetics of the diastereoisomers of leucovorin after intravenous and oral administration to normal subjects. Cancer Res. 1984;44:3114-3119. 34. Tenenbein M. Recent advancements in pediatric toxicology. Pediatr Clin North Am. 1999;46:1179-1788. 35. Trinkle R, Wu JK. Intrathecal leucovorin after intrathecal methotrexate overdose. J Pediatr Hematol Oncol. 1997;19:267-268. 36. Weh HJ, Bittner S, Hoffknecht M, Hossfeld DK. Neurotoxicity following weekly therapy with folinic acid and high-dose 5-fluorouracil 24h infusion in patients with gastrointestinal malignancies. Eur J Cancer. 1993;29A:1218-1219.

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A N T I D O T E S I N D E P T H ( A 14 ) GLUCARPIDASE (CARBOXYPEPTIDASE G2) Silas W. Smith Glucarpidase (carboxypeptidase G2, CPDG2) is indicated for the management of methotrexate (MTX) toxicity. When given intravenously or intrathecally it rapidly enzymatically inactivates intravascular or intrathecal MTX, respectively as well as folates and folate analogues. It is not a substitute for and must be used in conjunction with leucovorin (see Antidotes in Depth A13: Leucovorin [Folinic Acid] and Folic Acid). In most cases glucarpidase administration should precede or follow the use of leucovorin by at least 2 to 4 hours, unless a carefully considered benefit-risk analysis suggests the need to more rapidly eliminate MTX and risk leucovorin inactivation.

HISTORY AND DEVELOPMENT Soon after the discovery of the structure and synthesis of folate,7 a Flavobacterium species capable of removing the glutamate moiety of folate was described.34 This was followed by additional reports of Bacillus species with glutamyl peptidase activity.33,68 From 1955 to 1996 a series of experiments demonstrated the inactivation of folate analogues (including chemotherapeutic aminopterin) by bacteria and yeasts.49,74 Other bacteria with similar folate glutamate-cleaving ability were later identified.41,56,72 In 1967 purification of “carboxypeptidase G,” a pseudomonad derived zinc-dependent enzyme responsible for MTX cleavage, was reported.25,35 Carboxypeptidases from other bacterial species which differed in their substrate specificity and kinetics were later isolated and purified in 1971 (Pseudomonas stutzeri carboxypeptidase G1),40 1978 (Flavobacterium carboxypeptidase),6 and 1992 (Pseudomonas sp. M-27 carboxypeptidase G3).82 By 1976 carboxypeptidase G1 was scaled to pilot manufacturing production.17 The carboxypeptidase currently used in clinical practice (carboxypeptidase G2) was cloned from Pseudomonas strain R-16 and sequenced, characterized, and expressed in Escherichia coli in the early 1980s.44-46,63 A preliminary crystal structure was provided in 1991, with a complete characterization (at 2.5 Å), description of the active site, and biochemical mechanism of action was presented in 1997.36,58,70 Carboxypeptidase G1 was initially explored as an anticancer agent because of its ability to deprive growing tumors of folate.9,10,15,30 Human usage of CPDG1 for this purpose was reported in 1974.10 The antidotal potential of carboxypeptidase was suggested in 1972— carboxypeptidase G1 rapidly decreased MTX levels and improved survival in mice injected with lethal MTX doses.16 CPDG1 was subsequently used to selectively eliminate systemic MTX in patients treated with high dosages targeting central nervous system (CNS) malignancy.1,2 CPDG1 was first used for rescue in a patient receiving MTX with renal failure in 1978.28 Unfortunately, the enzyme source

of CPDG1 was then lost.5,84 Following the revival of the recombinant CPDG2 product, it underwent nonhuman primate testing for both intravenous (IV) and intrathecal (IT) rescue for MTX overdose.4,5 Reports of successful use in human IV and IT MTX overdose rapidly emerged.8,14,18,20,26,28,31,32,37,47,50,51,53,59-62,64,66,67,73,76,77,79,80,84 The US FDA designated glucarpidase as an approved Orphan Product in 2003 for treatment of patients at risk of MTX toxicity.71

MECHANISM OF ACTION Glucarpidase is a dimerized protein structure with two domains—a beta-sheet interaction site and a zinc-dependent catalytic domain.58 The catalytic domain hydrolyzes C-terminal glutamate residues of folate and folate analogues such as MTX. MTX and its metabolite 7-hydroxy-MTX are thus split into inactive DAMPA and hydroxyDAMPA plus glutamate.80,81 Glucarpidase similarly inactivates leucovorin (folinic acid) and folate by cleavage of terminal glutamate residues (Fig. A14–1), although to a lesser degree.6 Several clinical studies supported the mechanism of action of glucarpidase as rapid cleavage of MTX.14,26,32,61,77

PHARMACOKINETICS AND PHARMACODYNAMICS In a manufacturer-sponsored study, 50 Units/kg of glucarpidase IV was given to eight volunteer subjects with normal renal function and four volunteers with severely impaired renal function.54 In those with normal renal function the mean maximum serum concentration of glucarpidase was 3.1 μg/mL, with a mean half-life of 9.0 hours. These values were essentially unaffected by compromised renal function. Following glucarpidase administration, a rapid decline of serum MTX concentrations by 71% to 99% occurs within minutes, with the concurrent appearance of DAMPA.14,32,62,64,75-77 However, CPDG2 does not cross the blood-brain barrier, cannot cross the cell membrane to act intracellularly, and does not act on MTX in the gut lumen.1,16,18 Intracellular MTX is polyglutamated, which hinders transmembrane transport and increases its intracellular half-life. This MTX pool, inaccessible to CPDG2 (and hemodialysis), can persist for greater than 24 hours to cause cytotoxicity and a rebound in serum MTX concentrations.24,79

INDICATIONS AND ROLE IN METHOTREXATE TOXICITY Patients receiving high-dose MTX therapy are routinely “rescued” with leucovorin (eg, 10 mg orally every 6 hours).83 Treatment nomograms and institutional algorithms recommend higher leucovorin doses when MTX concentrations are excessive or prolonged.11,75,83 However, at MTX concentrations above 100 μmol/L (and perhaps even lower), data suggest that adequate leucovorin concentrations cannot be achieved for competitive and complete reversal of toxicity.14,32,38,55 Also, high-dose leucovorin therapy leads to the administration of 0.004 mEq calcium per mg of leucovorin and may be associated with hypercalcemia.84

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A

COOH CH3

H2O NH

N

N N H2N

O

N

COOH

glucarpidase

OH COOH

N

N

O

H2N

N

+

N

H2N COOH

NH2

N Methotrexate

NH2

B

DAMPA

COOH OH CH3

OH CH3

NH

N

O

COOH

glucarpidase

N H2N

OH COOH O

N

+

N

N N

Glutamate

N

N

H2O

N

N H2N

CH3 N

COOH

NH2 OH-DAMPA

7-OH-methotrexate

H2N Glutamate

NH2

COOH

C H

NH N

N N

O

N

H2N

O

HN

H

OH

COOH

glucarpidase

HN O

COOH

H

NH O

H2N

OH 5-formylpteroic acid

N N

H2N

+

O

HN

COOH

glucarpidase

Folate

OH

N N

H2N

Glutamate

COOH

N

N

H2O

N

O

N

COOH H

COOH

N

N H2N

Leucovorin

D

N

OH

H N

H2O

HN O Pteroic acid

O +

H2N COOH Glutamate

FIGURE A14–1. MECHANISM OF ACTION: Glucarpidase is a dimerized protein structure with two domains—a beta-sheet interaction site and a zinc-dependent catalytic

domain. The catalytic domain hydrolyzes C-terminal glutamate residues of folate and folate analogues such as MTX. (A+B) MTX and its metabolite 7-hydroxy-MTX are thus split into inactive DAMPA and hydroxy-DAMPA plus glutamate. (C) Glucarpidase similarly inactivates leucovorin (folinic acid) and folate (D) by cleavage of terminal glutamate residues, although to a lesser degree.

Studies support the use of glucarpidase to treat patients who are at risk of toxicity from MTX due to either persistently elevated MTX concentrations or renal dysfunction.14,26,61,76 As glucarpidase has not yet received marketing approval at the time of writing in either the United States or Europe, it lacks definitive administration indications. Table A14-1 summarizes the indications used in selected clinical trials and reviews, which vary by malignancy, degree of renal impairment, initial MTX dose, and serum MTX concentration. Mucositis, gastrointestinal distress, myelosuppression, hepatitis, or neurotoxicity should prompt consideration of glucarpidase in addition to aggressive leucovorin therapy. Patients with

significant, persistent serum MTX concentration (essentially less than or equal to 50% the normal clearance rate), or MTX concentrations requiring high-dose leucovorin rescue or renal impairment (oliguria or creatinine greater than 1.5 times baseline) following high-dose MTX, should be candidates for glucarpidase. Since leucovorin is contraindicated for IT administration,22,29,69 IT glucarpidase provides an effective means to rapidly lower cerebrospinal fluid (CSF) MTX concentrations in cases of overdose or persistence.50,79 Inadvertent or intentional MTX exposure48,65 would also be amenable to glucarpidase, particularly prior to drug distribution. Additionally,

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Glucarpidase (Carboxypeptidase G 2)

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TABLE A14–1. Indications for Glucarpidase Use in Clinical Trials and Reviews Trial/Review

Malignancy

Creatinine/Creatinine Clearance

Methotrexate Concentration

Various Various

Unspecified Cr ≥1.5 times the ULN or CrCL 5 μmol/L beyond 42 h

Osteosarcoma

Cr increase >2 times baseline

Various

Cr >1.5 times the ULN or CrCL 1.5 times the ULN or diuresis of 1.5 times the ULN and/or urine output 1 μmol/L beyond 42 h or >0.4 μmol/L beyond 48 h ≥ 0.1 μmol/L at 72 ± 2 h (for MTX doses 1–3.5 g/m2) or ≥0.3 μmol/L at 72 ± 2 h (for MTX doses >3.5 g/m2) >50 μmol/L at 24 h, >5 μmol/L at 48 h, or >2 standard deviations above the mean MTX elimination curve beyond 12 h >10 μmol/L beyond 42 h or >2 standard deviations above the mean MTX elimination curve beyond 2 h >10 μmol/L at 36 h, >5 μmol/L at 42 h, or >3 μmol/L at 48 h >10 μmol/L beyond 42 h >10 μmol/L beyond 42 h; consider if 1–10 μmol/L beyond 42 h

Where time-specific methotrexate concentrations are given, these indicate time following the initiation of the MTX infusion. Cr, creatinine; CrCL, creatinine clearance; ALL, acute lymphoblastic leukemia; NHL, non-Hodgkin lymphoma; ULN, upper limit of normal.

glucarpidase has been proposed as an antidote for pemetrexed (a folate antimetabolite) toxicity.12 In international patent applications, the manufacturer disclosed experiments that demonstrated glucarpidase cleavage of additional antifolates in clinical and experimental use including AAGI 13-161, edatrexate, lometrexol, pemetrexed, and raltitrexed.42,43

MONITORING False elevations of MTX have been reported clinically with all of the various immunoassay techniques following glucarpidase administration.20,27,32,53,80,84 The DAMPA product of MTX cleavage significantly cross-reacts with both the MTX radioimmunoassay (RIA) and the competitive dihydrofolate reductase binding assays.19 Both MTX metabolites (7-hydroxy-MTX and DAMPA), appreciably interfere with the newer fluorescence polarization immunoassay (FPIA) and enzyme multiplied immunoassay technique (EMIT) assays. For DAMPA, the cross-reactivity rates are 100% (EMIT) and 36% to 44% (FPIA).52 7-OH-MTX cross-reactivity using EMIT is 4% to 31%, and 0.6% to 3% with FPIA.23,52 Clinically, the concentrations of DAMPA detected are comparable to that of MTX following administration of CPDG2.18 Thus, the use of high performance liquid chromatography (HPLC) to determine actual MTX concentrations is mandated when glucarpidase is given.13

ADVERSE EFFECTS AND OTHER SAFETY ISSUES Initial studies reported adverse effects in four of nine patients treated with CPDG1, including development of inactivating antibodies, “sensitization” to CPDG1, and anaphylactoid reactions.1,2,10,28 Studies with the current recombinant enzyme glucarpidase (CPDG2) report a much lower incidence of adverse effects than with the initial CPDG1 enzyme. These typically include warmth, tingling, head pressure, flushing, shaking, and burning of the face and extremities.77 The current manufacturer reports that 8% of patients (25 of 329) reported a total of 50 possibly related adverse events.57 One-third of these were “allergic” reactions (burning sensation, flushing, hot flush, allergic dermatitis, feeling hot, pruritus, and hypersensitivity). Two of the adverse events were considered serious (hypertension and dysrhythmia), but both were considered more likely to be associated with MTX itself. In one recent study with glucarpidase, three of seven patients tested produced antiglucarpidase antibodies.61 In patients administered CPDG2 fused to a murine single-chain Fv antibody, 36% (11 of 30) developed antiCPDG2 antibodies, while no antimurine antibodies were detected.39 Although antiglucarpidase antibodies might decrease clinical efficacy or predispose to allergic reaction upon re-exposure,2,5,21,61 many patients have been successfully treated with more than one dose of glucarpidase for persistently elevated MTX concentrations.14,18,32,51,53,61,66,80,84 Clinical

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trials will explore planned repeated use (eg, NCT00727831). Late glucarpidase administration, more then 96 hours after MTX initiation may not prevent significant MTX toxicity.3 Since “inactive” DAMPA has a urinary solubility eight to ten times less than MTX (depending on pH),27,76 alkalinization and saline diuresis must be continued to prevent DAMPA precipitation and further renal compromise. Because of the inability of glucarpidase to access intracellular MTX, rebound may occur.79 Significant delayed rebound of MTX may occur up to 85 hours after glucarpidase is administered.61 This slow egress of persistent intracellular MTX requires continued leucovorin therapy at 250 mg/m2 IV every 6 hours for 48 hours after the last dose of carboxypeptidase. Then, leucovorin is continued until the MTX concentration is less than 50 nmol/L (0.05 μmol/L).75 Carboxypeptidase has a 10- to 15-fold higher affinity for MTX than for leucovorin, although its affinity for its active metabolite 5-methyltetrahydrofolate and folate are similar.6,21,63 Leucovorin is commonly provided as a racemate, although the active enantiomer is now an approved pharmaceutical. Since glucarpidase cleaves the active levo-(6S)-leucovorin about 50% faster than the inactive dextro(6R)-isomer,27 glucarpidase may compromise leucovorin rescue if both antidotes are administered at similar times. Fifteen minutes post CPDG2, median leucovorin and active 5-methyltetrahydrofolate concentrations dropped by 8% and greater than 97%; the remaining leucovorin was likely the inactive d-isomer.75,78 When provided at 2 or 26 hours after a glucarpidase dose to healthy volunteers, “exposures to” active leucovorin and activated levo-5-methyl-tetrahydrofolate were 50% and 0% (administration after 2 hours) and 80% and 25% (administration after 26 hours) of anticipated, respectively.21 Thus, because leucovorin and 5-methyltetrahydrofolate can act as competitive substrates for glucarpidase, most protocols recommend that leucovorin should not be administered for 2 to 4 hours before, and for up to 2 to 4 hours after glucarpidase is provided. Administration of glucarpidase more proximate to leucovorin would require a thoughtful benefit-risk assessment. The exigency to rapidly eliminate MTX—ascertained by the patient’s clinical status, renal function, and MTX concentration— would be weighed against the risks of inactivating leucovorin and 5-methyltetrahydrofolate, particularly in cases of prolonged exposure to MTX, in which intracellular MTX inaccessible to glucarpidase would be expected. In the setting of oral MTX overdose, gastrointestinal decontamination should be considered, as glucarpidase has no intraluminal activity. The supplied product contains lactose and Tris-HCl with zinc buffer. Lactose intolerant patients can receive glucarpidase. In those who have previously experienced allergic reactions to lactose-containing xenobiotics or the other excipients, or patients with rare hereditary problems of fructose intolerance, galactose intolerance, galactosemia, or glucose-galactose malabsorption, the anticipated clinical benefit of glucarpidase would need to be weighed against the risk of adverse effects.

DOSING Glucarpidase is dosed in units per kilogram in both children and adults. One unit of enzyme activity catalyzes the hydrolysis of 1 μmol of MTX per minute at 37°C.4 After reconstituting each 1000-Units vial with 1 mL of sterile sodium chloride (0.9%), a single dose of 50 U/kg is administered immediately by bolus IV injection over 5 minutes. A second dose can be administered 24 to 48 hours later if there is evidence of persistent MTX. In cases of IT MTX overdose, a fixed dose of glucarpidase (2000 Units) reconstituted in sterile 0.9% sodium chloride is administered intrathecally over 5 minutes.50,79 With excessive MTX dosing, the

glucarpidase could be given IV and IT simultaneously. As compatibility studies have not been performed, glucarpidase should not be mixed with other agents. Glucarpidase should be refrigerated (2°C to 8°C), but not frozen.

AVAILABILITY Glucarpidase is available in single-use glass vials containing glucarpidase (1000 Units) with lactose (10 mg), buffered to pH 6.5 to 8.0 with Tris-HCl and zinc buffer. At the time of writing, glucarpidase has not yet received US FDA or European marketing approval. Glucarpidase for IV administration may be obtained in the United States under an openlabel treatment protocol (ClinicalTrials.gov identifier: NCT00481559). US emergency inquiries, supply details, and procedural details can be directed to AAIPharma: 866-918-1731 (for intravenous emergencies) or BTG: 888-327-1027 (for intrathecal emergencies). Points of contact for other countries, IRB approval, IRB emergency exemption, and intrathecal emergency-use IND procedures are detailed at the manufacturer’s and FDA’s websites (www.btgplc.com/BTGPipeline/273/Voraxaze.html; http://www.btgplc.com/Voraxaze/284/VoraxazeUSSupplies.html; www. fda.gov/cder/cancer/singleIND.htm.).57 Ongoing or anticipated clinical trials (eg, ClinicalTrials.gov identifiers: NCT00481559, NCT00634322, NCT00634504, NCT00727831) or specialty cancer centers that may have access to this antidote might also serve as a resource, particularly after hours or on weekends.

SUMMARY Glucarpidase is a bacterially derived metalloenzyme used in the treatment of MTX toxicity. It cleaves MTX in the serum compartment to rapidly reduce serum MTX concentrations. Ongoing studies are addressing the extent and consequences of concurrent enzymatic destruction of folate and leucovorin and product immunogenicity. Glucarpidase does not substitute for leucovorin, which counteracts persistent intracellular and CNS MTX. In most cases glucarpidase administration should be separated from the leucovorin administration by 2 to 4 hours.

REFERENCES 1. Abelson HT, Ensminger W, Rosowsky A, Uren J. Comparative effects of citrovorum factor and carboxypeptidase G1 on cerebrospinal fluidmethotrexate pharmacokinetics. Cancer Treat Rep. 1978;62:1549-1552. 2. Abelson HT, Kufe DW, Skarin AT, et al. Treatment of central nervous system tumors with methotrexate. Cancer Treat Rep. 1981;65(Suppl 1):137140. 3. Adamson PC, Balis FM, Boron M, et al. Carboxypeptidase-G2 (CPDG2) and leucovorin (LV) rescue with and without addition of thymidine (Thd) for high-dose methotrexate (HDMTX) induced renal dysfunction [abstract]. J Clin Oncol (Meeting Abstracts). 2005;23(16S):2076. 4. Adamson PC, Balis FM, McCully CL, et al. Rescue of experimental intrathecal methotrexate overdose with carboxypeptidase-G2. J Clin Oncol. 1991;9:670-674. 5. Adamson PC, Balis FM, McCully CL, Godwin KS, Poplack DG. Methotrexate pharmacokinetics following administration of recombinant carboxypeptidaseG2 in rhesus monkeys. J Clin Oncol. 1992;10:1359-1364. 6. Albrecht AM, Boldizsar E, Hutchison DJ. Carboxypeptidase displaying differential velocity in hydrolysis of methotrexate, 5-methyltetrahydrofolic acid, and leucovorin. J Bacteriol. 1978;134:506-513. 7. Angier RB, Boothe JH, Hutchings BL, et al. The structure and synthesis of the liver L. casei factor. Science. 1946;103:667-669. 8. Anoop P, Vaidya SJ, Mycroft J. Methotrexate rechallenge following delayed clearance and life-threatening toxicity. Pediatr Hematol Oncol. 2008;25: 119-121.

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9. Bertino JR, O’Brien P, McCullough JL. Inhibition of growth of leukemia cells by enzymic folate depletion. Science. 1971;172:161-162. 10. Bertino JR, Skeel R, Makulu D, Gralla EJ, Bertino JR. Initial clinical studies with carboxypeptidase G1 (CPG1), a folate depleting enzyme. Clin Res. 1974;22:483A. 11. Bleyer WA. Methotrexate: clinical pharmacology, current status and therapeutic guidelines. Cancer Treat Rev. 1977;4:87-101. 12. Brandes JC, Grossman SA, Ahmad H. Alteration of pemetrexed excretion in the presence of acute renal failure and effusions: presentation of a case and review of the literature. Cancer Invest. 2006;24:283-287. 13. Brandsteterova E, Seresova O, Miertus S, Reichelová V. HPLC determination of methotrexate and its metabolite in serum. Neoplasma. 1990;37:395-403. 14. Buchen S, Ngampolo D, Melton RG, et al. Carboxypeptidase G2 rescue in patients with methotrexate intoxication and renal failure. Br J Cancer. 2005;92:480-487. 15. Chabner BA, Chello PL, Bertino JR. Antitumor activity of a folate-cleaving enzyme, carboxypeptidase G1. Cancer Res. 1972;32:2114-2119. 16. Chabner BA, Johns DG, Bertino JR. Enzymatic cleavage of methotrexate provides a method for prevention of drug toxicity. Nature. 1972;239:395-397. 17. Cornell R, Charm SE. Purification of carboxypeptidase G-1 by immunoadsorption. Biotechnol Bioeng. 1976;18:1171-1173. 18. DeAngelis LM, Tong WP, Lin S, Fleisher M, Bertino JR. Carboxypeptidase G2 rescue after high-dose methotrexate. J Clin Oncol. 1996;14:2145-2149. 19. Donehower RC, Hande KR, Drake JC, Chabner BA. Presence of 2,4-diaminoN10-methylpteroic acid after high-dose methotrexate. Clin Pharmacol Ther. 1979;26:63-72. 20. Estève M-, Devictor-Pierre B, Galy G, et al. Severe acute toxicity associated with high-dose methotrexate (MTX) therapy: use of therapeutic drug monitoring and test-dose to guide carboxypeptidase G2 rescue and MTX continuation. Eur J Clin Pharmacol. 2007;63:39-42. 21. European Medicines Agency (EMEA). Pre-authorisation Evaluation of Medicines for Human Use. Withdrawal Assessment Report for Voraxaze. EMEA/CHMP/171907/2008. London, UK: European Medicines Agency (EMEA); 2008. http://www.emea.europa.eu/humandocs/PDFs/EPAR/ voraxaze/H-681-WAR-en.pdf. Accessed September 17, 2008. 22. Finkelstein Y, Zevin S, Raikhlin-Eisenkraft B, et al. Intrathecal methotrexate neurotoxicity: clinical correlates and antidotal treatment. Environ Toxicol Pharmacol. 2005;19:721-725. 23. Fotoohi K, Skarby T, Soderhall S, Peterson C, Albertioni F. Interference of 7-hydroxymethotrexate with the determination of methotrexate in plasma samples from children with acute lymphoblastic leukemia employing routine clinical assays. J Chromatogr B Analyt Technol Biomed Life Sci. 2005;817:139-144. 24. Genestier L, Paillot R, Quemeneur L, Izeradjene K, Revillard JP. Mechanisms of action of methotrexate. Immunopharmacology. 2000;47:247-257. 25. Goldman P, Levy CC. Carboxypeptidase G: purification and properties. PNAS. 1967;58:1299-1306. 26. Green MR, Chamberlain MC. Renal dysfunction during and after highdose methotrexate. Cancer Chemother Pharmacol. 2009;63(4):599-604. 27. Hempel G, Lingg R, Boos J. Interactions of carboxypeptidase G2 with 6S-leucovorin and 6R-leucovorin in vitro: implications for the application in case of methotrexate intoxications. Cancer Chemother Pharmacol. 2005;55:347-353. 28. Howell SB, Blair HE, Uren J, Frei E 3rd. Hemodialysis and enzymatic cleavage of methotrexate in man. Eur J Cancer. 1978;14:787-792. 29. Jardine LF, Ingram LC, Bleyer WA. Intrathecal leucovorin after intrathecal methotrexate overdose. J Pediatr Hematol Oncol. 1996;18:302-304. 30. Kalghatgi KK, Moroson BA, Horvath C, Bertino JR. Enhancement of antitumor activity of 2,4-diamino-5-(3’,4’-dichlorophenyl)-6-methylpyrimidine and Baker’s antifol (Triazinate) with carboxypeptidase G1. Cancer Res. 1979;39:3441-3445. 31. Krackhardt A, Schwartz S, Korfel A, Thiel E. Carboxypeptidase G2 rescue in a 79 year-old patient with cranial lymphoma after high-dose methotrexate induced acute renal failure. Leuk Lymphoma. 1999;35:631-635. 32. Krause AS, Weihrauch MR, Bode U, et al. Carboxypeptidase-G2 rescue in cancer patients with delayed methotrexate elimination after high-dose methotrexate therapy. Leuk Lymphoma. 2002;43:2139-2143. 33. Kream J, Borek BA, DiGrado CJ, Bovarnick M. Enzymatic hydrolysis of γ-glutamyl polypeptide and its derivatives. Arch Biochem Biophys. 1954;53:333-340. 34. Lemon J, Sickels JP, Hutchings BL, et al. Conversion of pteroylglutamic acid to pteroic acid by bacterial degradation. Arch Biochem. 1948;19:311-316.

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35. Levy CC, Goldman P. The enzymatic hydrolysis of methotrexate and folic acid. J Biol Chem. 1967;242:2933-2938. 36. Lloyd LF, Collyer CA, Sherwood RF. Crystallization and preliminary crystallographic analysis of carboxypeptidase G2 from Pseudomonas sp. strain RS-16. J Mol Biol. 1991;220:17-18. 37. Mantadakis E, Rogers ZR, Smith AK, et al. Delayed methotrexate clearance in a patient with sickle cell anemia and osteosarcoma. J Pediatr Hematol Oncol. 1999;21:165-169. 38. Matherly LH, Barlowe CK, Goldman ID. Antifolate polyglutamylation and competitive drug displacement at dihydrofolate reductase as important elements in leucovorin rescue in L1210 cells. Cancer Res. 1986;46:588-593. 39. Mayer A, Francis RJ, Sharma SK, et al. A phase I study of single administration of antibody-directed enzyme prodrug therapy with the recombinant anticarcinoembryonic antigen antibody-enzyme fusion protein MFECP1 and a bis-iodo phenol mustard prodrug. Clin Cancer Res. 2006;12:6509-6516. 40. McCullough JL, Chabner BA, Bertino JR. Purification and properties of carboxypeptidase G 1. J Biol Chem. 1971;246:7207-7213. 41. McNutt S. The enzymic deamination and amide cleavage of folic acid. Arch Biochem Biophys. 1963;101:1-6. 42. Melton R, Atkinson A. Cleavage of antifolate compounds [patent application]. Application number PCT/GB2005/003297. Publication number WO/2007/023243. World Intellectual Property Organization; 2007. http:// www.wipo.int/pctdb/en/wo.jsp?IA=GB2005003297&DISPLAY=STATUS. Accessed September 17, 2008. 43. Melton R, Atkinson A. Use of carboxypeptidase G for combating antifolate toxicity [patent application]. Application number PCT/GB2005/000751. Publication number WO/2005/084695. World Intellectual Property Organization; 2005. http://www.wipo.int/pctdb/en/wo.jsp?IA=GB2005000 751&DISPLAY=STATUS. Accessed September 17, 2008. 44. Minton NP, Atkinson T, Bruton CJ, Sherwood RF. The complete nucleotide sequence of the Pseudomonas gene coding for carboxypeptidase G2. Gene. 1984;31:31-38. 45. Minton NP, Atkinson T, Sherwood RF. Molecular cloning of the Pseudomonas carboxypeptidase G2 gene and its expression in Escherichia coli and Pseudomonas putida. J Bacteriol. 1983;156:1222-1227. 46. Minton NP, Clarke LE. Identification of the promoter of the Pseudomonas gene coding for carboxypeptidase G2. J Mol Appl Genet. 1985;3:26-35. 47. Mohty M, Peyriere H, Guinet C, et al. Carboxypeptidase G2 rescue in delayed methotrexate elimination in renal failure. Leuk Lymphoma. 2000;37:441-443. 48. Moisa A, Fritz P, Benz D, Wehner HD. Iatrogenically related, fatal methotrexate intoxication: a series of four cases. Forensic Sci Int. 2006;156:154-157. 49. Nickerson WJ, Webb M. Effects of folic acid analogues on growth and cell division of nonexacting microorganisms. J Bacteriol. 1956;71:129-139. 50. O’Marcaigh AS, Johnson CM, Smithson WA, et al. Successful treatment of intrathecal methotrexate overdose by using ventriculolumbar perfusion and intrathecal instillation of carboxypeptidase G2. Mayo Clin Proc. 1996;71:161-165. 51. Park ES, Han KH, Choi HS, et al. Carboxypeptidase-G2 rescue in a patient with high dose methotrexate-induced nephrotoxicity. Cancer Res Treat. 2005;37:133-135. 52. Pesce MA, Bodourian SH. Evaluation of a fluorescence polarization immunoassay procedure for quantitation of methotrexate. Ther Drug Monit. 1986;8:115-121. 53. Peyriere H, Cociglio M, Margueritte G, et al. Optimal management of methotrexate intoxication in a child with osteosarcoma. Ann Pharmacother. 2004;38:422-427. 54. Phillips M, Smith W, Balan G, Ward S. Pharmacokinetics of glucarpidase in subjects with normal and impaired renal function. J Clin Pharmacol. 2008;48:279-284. 55. Pinedo HM, Zaharko DS, Bull JM, Chabner BA. The reversal of methotrexate cytotoxicity to mouse bone marrow cells by leucovorin and nucleosides. Cancer Res. 1976;36:4418-4424. 56. Pratt AG, Crawford EJ, Friedkin M. The hydrolysis of mono-, di-, and triglutamate derivatives of folic acid with bacterial enzymes. J Biol Chem. 1968;243:6367-6372. 57. Protherics Inc (a BTG Company). Voraxaze” glucarpidase. Voraxaze” Emergency Enquires. BTG; 2009. http://www.btgplc.com/BTGPipeline/273/ Voraxaze.html. Accessed May 25, 2009. 58. Rowsell S, Pauptit RA, Tucker AD, et al. Crystal structure of carboxypeptidase G2, a bacterial enzyme with applications in cancer therapy. Structure. 1997;5:337-347.

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59. Saland JM, Leavey PJ, Bash RO, et al. Effective removal of methotrexate by high-flux hemodialysis. Pediatr Nephrol. 2002;17:825-829. 60. Schwartz S, Borner K, Korfel A, et al. Effects of carboxypeptidase G2 (CPG2) rescue in 30 lymphoma patients with high-dose methotrexate (HD-MTX) induced renal failure [abstract]. Ann Oncol. 2005;16(Suppl 5):136-137. 61. Schwartz S, Borner K, Müller K, et al. Glucarpidase (carboxypeptidase g2) intervention in adult and elderly cancer patients with renal dysfunction and delayed methotrexate elimination after high-dose methotrexate therapy. Oncologist. 2007;12:1299-1308. 62. Schwartz S, Müller K, Fischer L, et al. Favorable outcome in excessive methotrexate (MTX) intoxication after high-dose (HD) MTX therapy by early use of carboxypeptidase G2 (CPG2) [abstract]. J Clin Oncol (Meeting Abstracts). 2005;23(16S):8255. 63. Sherwood RF, Melton RG, Alwan SM, Hughes P. Purification and properties of carboxypeptidase G2 from Pseudomonas sp. strain RS-16. Use of a novel triazine dye affinity method. Eur J Biochem. 1985;148:447-453. 64. Sieniawski M, Rimpler M, Herrmann R, et al. Successful carboxypeptidase G2 rescue of a high-risk elderly Hodgkin lymphoma patient with methotrexate intoxication and renal failure. Leuk Lymphoma. 2007;48:1641-1643. 65. Sinicina I, Mayr B, Mall G, Keil W. Deaths following methotrexate overdoses by medical staff. J Rheumatol. 2005;32:2009-2011. 66. Smith SW, Nelson LS. Case files of the New York City Poison Control Center: antidotal strategies for the management of methotrexate toxicity. J Med Toxicol. 2008;4:132-140. 67. Snyder RL. Resumption of high-dose methotrexate after methotrexateinduced nephrotoxicity and carboxypeptidase G2 use. Am J Health Syst Pharm. 2007;64:1163-1169. 68. Thorne CB, Gomez CG, Noyes HE, Housewright RD. Production of glutamyl polypeptide by bacillus subtilis. J Bacteriol. 1954;68:307-315. 69. Trinkle R, Wu JK. Intrathecal leukovorin after intrathecal methotrexate overdose. J Pediatr Hematol Oncol. 1997;19:267-269. 70. Tucker AD, Roswell S, Melton RG, Paupitt RA. A new crystal form of carboxypeptidase G2 from Pseudomonas sp. strain RS-16 which is more amenable to structure determination. Acta Crystallogr D Biol Crystallogr. 1996;52:890-892. 71. US FDA. Cumulative List of All Orphan Designated and or Approved Products. FDA; 2008. http://www.fda.gov/orphan/designat/alldes.rtf. Accessed September 17, 2008.

72. Volcani BE, Margalith P. A new species (Flavobacterium polyglutamicum) which hydrolyzes the γ-l-glutamyl bond in polypeptides. J Bacteriol. 1957; 74:646-655. 73. von Poblozki A, Dempke W, Schmoll HJ. Carboxypeptidase-G2-rescue in a woman with methotrexate-induced renal failure. Med Klin (Munich). 2000;95:457-460. 74. Webb M. Inactivation of analogues of folic acid by certain non-exacting bacteria. Biochim Biophys Acta. 1955;17:212-225. 75. Widemann BC, Adamson PC. Understanding and managing methotrexate nephrotoxicity. Oncologist. 2006;11:694-703. 76. Widemann BC, Balis FM, Kempf-Bielack B, et al. High-dose methotrexateinduced nephrotoxicity in patients with osteosarcoma. Cancer. 2004; 100:2222-2232. 77. Widemann BC, Balis FM, Murphy RF, et al. Carboxypeptidase-G2, thymidine, and leucovorin rescue in cancer patients with methotrexate-induced renal dysfunction. J Clin Oncol. 1997;15:2125-2134. 78. Widemann BC, Balis FM, O’Brien M, et al. Rescue with carboxypeptidase-G2 (CPDG2) and leucovorin (LV) for patients with high-dose methotrexate (HDMTX) induced renal failure. Proc Am Soc Clin Oncol. 1998;17:222a. 79. Widemann BC, Balis FM, Shalabi A, et al. Treatment of accidental intrathecal methotrexate overdose with intrathecal carboxypeptidase G2. J Natl Cancer Inst. 2004;96:1557-1559. 80. Widemann BC, Hetherington ML, Murphy RF, Balis FM, Adamson PC. Carboxypeptidase-G2 rescue in a patient with high dose methotrexateinduced nephrotoxicity. Cancer. 1995;76:521-526. 81. Widemann BC, Sung E, Anderson L, et al. Pharmacokinetics and metabolism of the methotrexate metabolite 2, 4-diamino-N(10)-methylpteroic acid. J Pharmacol Exp Ther. 2000;294:894-901. 82. Yasuda N, Kaneko M, Kimura Y. Isolation, purification, and characterization of a new enzyme from Pseudomonas sp. M-27, carboxypeptidase G3. Biosci Biotechnol Biochem. 1992;56:1536-1540. 83. Zelcer S, Kellick M, Wexler LH, Gorlick R, Meyers PA. The Memorial Sloan-Kettering Cancer Center experience with outpatient administration of high dose methotrexate with leucovorin rescue. Pediatr Blood Cancer. 2008;50:1176-1180. 84. Zoubek A, Zaunschirm HA, Lion T, et al. Successful carboxypeptidase G2 rescue in delayed methotrexate elimination due to renal failure. Pediatr Hematol Oncol. 1995;12:471-477.

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S P E C I A L C O N S I D E R AT I O N S ( S C 3 ) EXTRAVASATION OF XENOBIOTICS Richard Y. Wang Extravasational injuries are among the most consequential local toxic events. When an antineoplastic leaks into the perivascular space, significant necrosis of skin, muscles, and tendons can occur with resultant loss of function. The initial manifestations may include swelling, pain, and a burning sensation that can last for hours. Days later, the area may become erythematous and indurated and can either resolve or proceed to ulceration and necrosis.30 These early findings may sometimes be difficult to distinguish from other forms of local drug toxicity, such as irritation and hypersensitivity where either the antineoplastic or its vehicle (ethanol, propylene glycol) can cause local irritation as defined by an inflammatory response. Some of the therapeutics associated with local irritation include fluorouracil, carmustine, cisplatin, and dacarbazine. The local irritation and hypersensitivity manifestations are self-limiting and typified by an immediate onset of a burning sensation, pruritus, erythema, and a flare reaction of the vein being infused. Pretreatment with an antihistamine can prevent some of the hypersensitivity manifestations.38 Drugs reported to cause hypersensitivity reactions include daunorubicin, doxorubicin, idarubicin, and mitoxantrone. When local reactions cannot be differentiated, it is always best to presume extravasation and manage the situation accordingly. The occurrence of these extravasational events appears to be about 50 times more frequent in the hands of the inexperienced clinician.14 Several factors are associated with extravasational injuries from peripheral intravenous lines, including (a) patients with poor vessel integrity and blood flow, such as the elderly, those who undergo numerous venipunctures, and those who have received radiation therapy to the site; (b) limited venous and lymphatic drainage caused by either obstruction or surgical resection; and (c) the use of venous access overlying a joint, which increases the risk of dislodgments because of movement.13,30 Extravasational injuries from implanted ports in central venous vessels can occur from inadequate placement of the needle, needle dislodgment, fibrin sheath formation around the catheter, perforation of the superior vena cava, and fracture of the catheter.32 When extravasation from a port is suspected and radiographic studies are not diagnostic, a CT scan of the chest with contrast is necessary for evaluation.1 The factors associated with a poor outcome from extravasational injuries include (a) areas of the body with little subcutaneous tissue, such as the dorsum of the hand, volar surface of the wrist, and the antecubital fossa, where healing is poor and vital structures are more likely to be involved; (b) increasing concentrations of extravasate; (c) increased volume and duration of contact with tissue; and (d) the type of chemotherapeutic.30,31 Vesicants, such as doxorubicin, daunorubicin, dactinomycin, epirubicin, idarubicin, mechlorethamine, mitomycin, and the vinca alkaloids, result in more significant local tissue destruction. Mitomycin infusions can cause dermal ulcerations at venipuncture

sites remote from the location of administration.28 The anthracycline antibiotics are associated with a higher incidence of significant injuries and delayed healing, which may be a result of their slow release from bound tissue into surrounding viable tissue. Doxorubicin extravasation is associated with local tissue necrosis in approximately 25% of cases. The extravasational injuries from taxanes appear similar to the vesicants, but are milder in response and more delayed in presentation.3,29 Prevention is the best form of therapy for these injuries. Specialized nursing care and the use of indwelling central venous catheters limit the extent of these injuries.

MANAGEMENT The treatment for extravasational injuries is somewhat controversial, varying from conservative care to early surgical debridement and the use of selective antidotes.33 This uncertainty is a result of the limited number of clinical cases available for study and the discordance between animal studies and human experience. However, general management guidelines for an extravasation and their theoretical foundations exist (Table SC3-1).6,9 Once extravasation is suspected, the infusion should be immediately halted. A physician should be notified and the xenobiotic, its concentration, and the approximate amount infused should be noted. The venous access should be maintained so that aspiration of as much of the infusate as possible can be performed and an antidote can be administered, if indicated. Injection of normal saline into the catheter to dilute the extravasate may be beneficial.17,33 The intermittent local application of ice and elevation of the extremity should be done for 48 to 72 hours so as to limit further progression of the xenobiotic and the development of dependent edema. Cooling the area is believed to prevent cell injury by reducing the amount of xenobiotic absorbed by the tissue and lowering the cellular metabolic rate.18,37 With just cold application and strict elevation, only 13 (11%) of 119 patients with mild extravasations required surgical intervention for their injuries.22 In the past, heat was recommended to disperse the agent, but investigations with mice treated with intradermal doxorubicin demonstrated that this practice increased the area of skin ulceration.11,22 However, dry, warm compresses are still recommended for the vinca alkaloids and etoposide to promote systemic uptake.6 This is combined with the immediate and local infiltration with hyaluronidase to enhance absorption (Table SC3–1). The amount of hyaluronidase administered at the site ranges from 150 to 900 Units, and the chosen concentration of the solution depends on the area to be treated. For extravasational injuries involving a small area, the initial solution of 150 Units/mL may be adequate. Otherwise, the solution may be diluted by 10-fold with 0.9% NaCl to increase the amount of volume that would be needed to treat a larger surface area. If the intravenous cannula is still accessible, 1 mL of hyaluronidase can be administered through the catheter. Wounds that are either cancerous or infected should not be treated with hyaluronidase stored in a refrigerator. Patients treated with hyaluronidase need to be monitored for allergic reactions, such as anaphylaxis, although the newer human recombinant form (Hylener) is less allergenic than previous animal derivatives. The wound should be observed closely for the first 7 days, and a surgeon consulted if either pain persists or evidence of ulceration

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The Clinical Basis of Medical Toxicology

TABLE SC3–1. Management of Extravasational Injuries6,16 Therapy General

Purpose/Mechanism Stop infusion and maintain intravenous cannula at the site. Aspirate extravasate from the site by accessing the original intravenous cannula. Irrigation of subcutaneous tissue at the site with 0.9% sodium chloride by accessing the original intravenous cannula. Apply dry cool compresses for 1 hour, every 8 hours for 3 days.

Elevate extremity and administer analgesia.

Specific Anthracyclines

Dexrazoxane 1000 mg/m2, daily (max. 2000 mg per day), on days 1 and 2, and 500 mg/m2 on day 3 (max. 1000 mg). Mechlorethamine IV sodium thiosulfate: Take 4mL of 25% sodium thiosulfate and add to 21mL of sterile water for injection to make an isotonic (4%) concentration. Infiltrate the site of extravasation. Mitomycin Dimethyl sulfoxide (DMSO): 55%–99%. Applied topically and allowed to dry. Vinca alkaloids and Hyaluronidase: Inject, epipodophyllotoxins intradermally or subcutaneously, 150–900 Units into the site. . Dry warm compresses.

secondary infection. The use of intravenous fluorescein or other dye indicators can aid in identifying viable tissue.2 The patient may require surgical reconstruction or skin grafts depending on the extent of the injury.

ANTIDOTES Minimizes amount of antineoplastic localized at the site.

Localizes area of involvement and diminishes cellular uptake of the antineoplastic. Promotes drainage, prevents dependent edema, and provides comfort. Limits free radical formation.

Prevents tissue alkylation

Free radical scavenger. Degrades hyaluronic acid to enhance systemic absorption Promotes systemic absorption.

appears.30 However, in severe extravasations—where there is a high incidence of necrosis because of the type of drug (doxorubicin), the volume or concentration, and any area in which there may be significant long-term morbidity (over joints)—early surgical consultation is warranted. If tissue ulceration occurs, initial management may be restricted to sterile dressings to prevent secondary infections. After the area of necrotic skin has evolved to the point where it can be clearly delineated from surviving tissue, surgical debridement may be beneficial to limit

Antidotal therapy should be considered when the extravasate is known to respond poorly to conservative care. The vesicants are associated with a significantly worse outcome, and when the exposure is large, a more aggressive approach should be initiated. Otherwise, conservative supportive management may be adequate. The specific antidotal treatments can be divided into several categories based upon their mechanism of action, one of which is the reduction of the inflammatory response through the application of steroids. Hydrocortisone has been used in varying concentrations (50–200 mg) as either subcutaneous or intradermal injections for doxorubicin and the vinca alkaloids,4,14,23,36 and as a topical cream.17 Corticosteroids may have only a limited role in doxorubicin-induced lesions because inflammatory cells do not predominate at the wound site.8 Corticosteroids should not be added to doxorubicin infusions, because the drugs are chemically incompatible.35 A prophylactic approach is to inactivate the drug by affecting the pH of the environment. The administration of 5 mL of 8.4% sodium bicarbonate through the same IV line to decrease the DNA binding of doxorubicin was advocated in 1980.5 The use of sodium bicarbonate should not be considered as a routine treatment because its intrinsic hyperosmolarity can cause tissue necrosis.12 Sodium thiosulfate is recommended for mechlorethamine extravasations, and is believed to work by inactivating the xenobiotic by reacting with the active ethylenimmonium ring.13,27 The site should be infiltrated with 2 mL of a sterile sodium thiosulfate 0.17 M solution for each mg of mechlorethamine and then ice compresses are applied intermittently for 48 to 72 hours.6 Finally, there are antidotes, such as dimethyl sulfoxide (DMSO), that scavenge the free radicals that are believed to cause tissue damage from doxorubicin. Dimethyl sulfoxide has been shown to be beneficial for anthracycline extravasations in both animal and human clinical trials.7,10,23,27,34 The concentration of DMSO used ranged from 55–99% and was applied topically with intermittent cool compresses.7,23,26 Some of the other beneficial properties of DMSO are its antiinflammatory, analgesic, and vasodilatory effects, and its ability to promote systemic absorption of the chemotherapeutic at local sites.24 However, the role for DMSO in the treatment of anthracycline extravasations has become secondary because of the efficacy of dexrazoxane for these exposures and the preparations necessary to make DMSO available in the clinical setting.21 Also, DMSO is not recommended with the use of dexrazoxane for the treatment of anthracycline extravasations. The systemic administration of dexrazoxane limits anthracycline-induced skin lesions in a murine model19 and used successfully in patients following doxorubicin20 and epirubicin15,19 extravasations. Dexrazoxane was given to these patients over 3 days intravenously at a starting dose of 1000 mg/m2. In two prospective, open-label, single-arm, multicenter clinical trials, the systemic administration of dexrazoxane within 6 hours of anthracycline extravasation resulted in the need for surgical resection of the wound site in only 1 of 54 (1.8%) patients.25 Dexrazoxane (Totect) is approved by the FDA for use in the treatment of anthracycline extravasation.16 This antidote is administered as an infusion over 15-30 min. at a site distant to that of the extravasation because of its irritating property. Cool compress at the site of the extravastion is discontinued for 15 minutes prior to therapy to promote the antidote’s perfusion at the site. The dose of dexrazoxane (see Table SC3–1) is decreased for patients with diminished renal function (creatinine clearance < 40 mL/min). Patients need to be monitored with CBC and serum AST/ALT because dexrazoxane can cause reversible bone marrow suppression and elevated

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Special considerations

concentrations of these liver enzymes. Additional clinical evidence needs to be gathered to better define the medical management of other antineoplastic extravasations. Although the overall incidence of extravasations with antineoplastics is small, the associated morbidity may be significant. Prevention is the best form of therapy.

ACKNOWLEDGMENT This chapter was written by Richard Y. Wang in his private capacity. No official support or endorsement by the Centers for Disease Control and Prevention is intended or should be inferred.

REFERENCES 1. Anderson CM, Walters RS, Hortobagyi GN. Mediastinitis related to probable central vinblastine extravasation in a woman undergoing adjuvant chemotherapy for early breast cancer. Am J Clin Oncol. 1996;19:566-568. 2. Argenta LC, Manders EK. Mitomycin C extravasation injuries. Cancer. 1983;51:1080-1082. 3. Bailey WL, Crump RM. Taxol extravasation: a case report. Can Oncol Nurs J. 1997;7:96-99. 4. Barlock AL, Howsen DM, Hubbard SM. Nursing management of Adriamycin extravasation. Am J Nurs. 1979;79:94-96. 5. Bartowski-Dodds L, Daniels JR. Use of sodium bicarbonate as a means of ameliorating doxorubicin-induced dermal necrosis in rats. Cancer Chemother Pharmacol. 1980;4:179-181. 6. Bertelli G. Prevention and management of extravasation of cytotoxic drugs. Drug Saf. 1995a;12:245-255. 7. Bertelli G, Gozza A, Forno GB, et al. Topical dimethylsulfoxide for the prevention of soft tissue injury after extravasation of vesicant cytotoxic drugs: a prospective clinical study. J Clin Oncol. 1995b;13:2851-2855. 8. Bhawan J, Petry J, Rybak ME. Histologic changes induced in skin by extravasation of doxorubicin (adriamycin). J Cutan Pathol. 1989;16:158-163. 9. Boyle DM, Engelking C. Vesicant extravasation: myths and realities. Oncol Nurs Forum. 1995;22:57-67. 10. Desai MH, Teres D. Prevention of doxorubicin-induced skin ulcers in the rat and pig with dimethyl sulfoxide (DMSO). Cancer Treat Rep. 1982;66:1371-1374. 11. Dorr RT, Alberts DS, Stone A. Cold protection and heat enhancement of doxorubicin skin toxicity in the mouse. Cancer Treat Rep. 1985;69:431-437. 12. Gaze NR. Tissue necrosis caused by commonly used intravenous infusions. Lancet. 1978;2:417-419. 13. Ignoffo RJ, Friedman MA. Therapy of local toxicities caused by extravasation of cancer chemotherapeutic drugs. Cancer Treat Rev. 1980;7:17-27. 14. Ignoffo RJ. Neoplastic disorders. In: Lloyd Y. Young and Mary Anne Koda-Kimble, eds. Applied Therapeutics: The Clinical Use of Drugs. 4th ed. Vancouver, WA: Applied Therapeutics. 1988;1197-1201. 15. Jensen JN, Lock-Andersen J, Langer SW, Mejer J. Dexrazoxane-a promising antidote in the treatment of accidental extravasation of anthracyclines. Scand J Plast Reconstr Surg Hand Surg. 2003;37:174-175. 16. Kane RC, McGuinn WD Jr, Dagher R, et al. Dexrazoxane (Totect): FDA review and approval for the treatment of accidental extravasation following intravenous anthracycline chemotherapy. Oncologist. 2008;13:445-450.

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17. Khan MS, Holmes JD. Reducing the morbidity from extravasation injuries. Ann Plast Surg. 2002;48:628-632. 18. Kleiter MM, Yu D, Mohammadian LA, et al. A tracer dose of technetium99m-labeled liposomes can estimate the effect of hyperthermia on intratumoral doxil extravasation. Clin Cancer Res. 2006;12:6800-6807. 19. Langer SW, Sehested M, Jensen PB. Dexrazoxane is a potent and specific inhibitor of anthracycline induced subcutaneous lesions in mice. Ann Oncol. 2001;12:405-410. 20. Langer SW, Sehested M, Jensen PB, et al. Dexrazoxane in anthracycline extravasation. J Clin Oncol. 2000;18:3064. 21. Langer SW, Thougaard AV, Sehested M, Jensen PB. Treatment of anthracycline extravasation in mice with dexrazoxane with or without DMSO and hydrocortisone. Cancer Chemother Pharmacol. 2006;57:125-128. 22. Larson DL. Treatment of tissue extravasation by antitumor agents. Cancer. 1982;49:1796-1799. 23. Lawrence HJ, Goodnight SH Jr. Dimethyl sulfoxide and extravasation of anthracycline agents. Ann Intern Med. 1983; 98:1025. 24. Lopez AM, Wallace L, Dorr RT, et al. Topical DMSO treatment for pegylated liposomal doxorubicin-induced palmar-plantar erythrodysesthesia. Cancer Chemother Pharmacol. 1999;44:303-306. 25. Mouridsen HT, Langer SW, Buter J, et al. Treatment of anthracycline extravasation with Savene (dexrazoxane): results from two prospective clinical multicentre studies. Ann Oncol. 2007;18:546-550. 26. Olver IN, Aisner J, Hament A, et al. A prospective study of topical dimethyl sulfoxide for treating anthracycline extravasation. J Clin Oncol. 1988;6:1732-1735. 27. Olver IN, Schwarz MA. Use of dimethyl sulfoxide in limiting tissue damage caused by extravasation of doxorubicin. Cancer Treat Rep. 1983;67:407-408. 28. Patel JS, Krusa M. Distant and delayed mitomycin C extravasation. Pharmacotherapy. 1999;19:1002-1005. 29. Raley J, Geisler JP, Buekers TE, Sorosky JI. Docetaxel extravasation causing significant delayed tissue injury. Gynecol Oncol. 2000;78:259-260. 30. Rudolph R, Larson DL. Etiology and treatment of chemotherapeutic agent extravasation injuries: a review. J Clin Oncol. 1987;5:1116-1126. 31. Rudolph R, Suzuki M, Luce JK. Experimental skin necrosis produced by adriamycin. Cancer Treat Rep. 1979;63:529-537. 32. Schulmeister L, Camp-Sorrell D. Chemotherapy extravasation from implanted ports. Oncol Nurs Forum. 2000;27:531-538. 33. Scuderi N, Onesti MG. Antitumor agents: extravasation, management, and surgical treatment. Ann Plast Surg. 1994;32:39-44. 34. Svingen BA, Powis G, Appel PL, Scott M. Protection against adriamycininduced skin necrosis in the rat by dimethyl sulfoxide and alpha-tocopherol. Cancer Res. 1981;41:3395-3399. 35. Trissel LA. Handbook of Injectable Drugs. Bethesda, MD: American Society of Hospital Pharmacists; 1988. 36. Tsavaris NB, Karagiaouris P, Tzannou I, et al. Conservative approach to the treatment of chemotherapy-induced extravasation. J Dermatol Surg Oncol. 1990;16:519-522. 37. van der Heijden AG, Verhaegh G, Jansen CF, et al. Effect of hyperthermia on the cytotoxicity of 4 chemotherapeutic agents currently used for the treatment of transitional cell carcinoma of the bladder: an in vitro study. J Urol. 2005;173:1375-1380. 38. Vogelzang NJ. “Adriamycin flare”: a skin reaction resembling extravasation. Cancer Treat Rep. 1979;63:2067-2069.

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intracellular calcium.89,96 Doxorubicin and dactinomycin are quinone derivatives and can be reduced to free radicals. These metabolites are extremely cytotoxic through the promotion of lipid peroxidation. Paraquat and bleomycin have similar mechanisms of toxicity. The limited efficacy of free radical scavengers (α-tocopherol, N-acetylcysteine) for anthracycline cardiotoxicity led to an understanding of the importance of iron as a cofactor for these radical-producing reactions.90 The anthracyclines have a high affinity for metal ions. Doxorubicin has an iron (Fe3+) binding constant of 1041, which is comparable to deferoxamine.48 The heart’s increased susceptibility to free radicals is attributed to its lack of sufficient enzyme activity responsible for free radical scavenging.38

CHAPTER 54

MISCELLANEOUS ANTINEOPLASTICS Richard Y. Wang The anthracyclines,31,70,118 nitrogen mustards,1,27,45,64,65,70,95,112,118,129 and platinum-based antineoplastics23,24,41,44,57,68,73,76,80,88,97,108 are discussed in this chapter because of their increased likelihood for overdose based on past reports and current clinical use.

ANTHRACYCLINES O

OH

O C

CH2OH

OH OCH3 O

OH

H3C

O

O Doxorubicin

HO

NH2

Daunorubicin and doxorubicin share many common indications for cancer therapy, but they differ in that doxorubicin is used in solid tumors such as breast carcinoma. The clinical toxicity of the anthracyclines is limited by the use of structural analogs (eg, epirubicin, idarubin) and liposomal encapsulated formulations (pegylated liposomal doxorubicin).

■ PHARMACOLOGY The antineoplastics derived from the bacterium Streptomyces are dactinomycin, daunorubicin, doxorubicin, bleomycin, mitomycin, and plicamycin. Only plicamycin crosses the blood–brain barrier. The terminal elimination half-life for doxorubicin is about 30 hours.50 Doxorubicin and daunorubicin are both eliminated by the liver and patients with hepatic dysfunction should have their dosage decreased. Delayed drug elimination contributes to increased drug area under the drug concentration versus time curve (AUC) and peak concentration, which are associated with myelosuppression and cardiac toxicity, respectively.75 The mechanism of therapeutic action of the anthracyclines is attributed to DNA intercalation101 and inactivation of topoisomerase II.117 These xenobiotics are metabolized to active metabolites, which have lesser degrees of activity than their parent compounds. A typical dose schedule for daunorubicin is 30 to 60 mg/m2 daily for 3 days; for doxorubicin, 45 to 60 mg/m2 every 18 to 21 days.

■ PATHOPHYSIOLOGY The red anthracycline antibiotics—dactinomycin and doxorubicin— can be associated with cardiotoxicity, which limits their therapeutic use. The mechanism responsible for their therapeutic effects is different from that which causes cardiotoxicity.117 The purported mechanism of cardiac toxicity is from the formation of free radicals and impaired

■ CLINICAL MANIFESTATIONS The cardiotoxic manifestations can be divided into acute and lateonset categories. The various findings described with acute toxicity include dysrhythmias, ST and T-wave changes on the electrocardiogram (ECG), diminished ejection fraction that usually resolves over 24 hours, and sudden death.16,114 Abnormal findings on ECG are present in 41% of patients receiving doxorubicin.7,54,74,103,114,125,130,132 They are neither dose related nor associated with the development of cardiomyopathy. Acute pericarditis and myocarditis resulting in conduction defects and congestive heart failure are also reported.15 Animal studies with doxorubicin demonstrate beneficial effects of adrenergic antagonists for toxicity because of elevated concentrations of catecholamines,15 although the use of β-adrenergic antagonists in the potential setting of diminished cardiac output needs to be considered. Significant cardiotoxicity results from elevated peak serum concentrations and accounts for continuous and periodic infusions practiced in therapy. In cumulative doses, the anthracycline antibiotics cause a congestive cardiomyopathy that typically presents at 1 to 4 months after exposure depending on the toxicity of the xenobiotic.62 The condition is irreversible and is associated with a 48% mortality.98 This drug-induced congestive heart failure is associated with pathognomonic changes on electron microscopy that can distinguish it from infectious and ischemic etiologies. These histologic changes include reduced number of myocardial fibrils, and mitochondrial and cellular degeneration.13 The incidence of late-onset cardiotoxicity for doxorubicin is between 1% and 10% when the cumulative dose is less than 450 mg/m2, and becomes greater than 20% when more than 550 mg/m2 (comparable to dactinomycin, 950 mg/m2, and epirubicin, 720 mg/m2) is administered.84,124 Daunorubicin and mitoxantrone are associated with a 2% incidence at the cumulative doses of 600 mg/m2 and 140 mg/m2, respectively. The best way of monitoring cardiac function during therapy is to use radionuclide cineradiography to measure the left ventricular ejection fraction.3 Therapy should be discontinued when the ejection fraction falls below 50%. Two-dimensional echocardiography can demonstrate left ventricular wall thickening and fractional shortening from anthracycline overexposure. Newer approaches used to assess for early or subclinical signs of cardiac dysfunction from these agents include cardiac-specific contractile protein, troponin, cardiac natriuretic peptide, and radionuclide-tagged monoclonal antibody imaging.21,25,37,69 Factors associated with an increased risk for cardiotoxicity include mediastinal irradiation, preexisting cardiac disease in children, age more than 70 years, and the concomitant use of cyclophosphamide, paclitaxel, and other anthracyclines.15 Also, the proximate therapeutic use of the monoclonal antibody to human epidermal growth factor receptor 2 (HER2), trastuzumab, with anthracyclines appears to enhance cardiac toxicity.33 Children are at risk for developing increased left ventricular afterload from doxorubicin toxicity because of the drug’s ability to inhibit myocardial growth, which can lead to a disproportionate ratio of left ventricular wall thickness to left

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ventricular chamber size.77 Fatalities are reported with minimum doses of 150 to 333 mg/m2, and occur within 1 to 16 days after exposure.31 Myelosuppression and mucositis are other effects associated with the use of the anthracycline agents. They typically occur in 1 to 2 weeks, and patients recover.10 The white cells are affected more than either the red cells or platelets. Patients with diminished drug clearance due to hepatic failure are at risk for the development of these findings. Mitoxantrone is recognized to be less toxic than doxorubicin and daunorubicin. Major organs of toxicity remain the heart, bone marrow, and gut. Gastrointestinal effects are less severe and less frequent with mitoxantrone than with doxorubicin.110 Four cases of mitoxantrone overdose are reported in the literature.53,110 Common to these events is a 10-fold error in dosing (100 mg/m2 instead of 10 mg/m2), early onset of nausea with vomiting, and myelosuppression with fever. Acute decreased cardiac contractility was observed by echocardiography in one patient who was asymptomatic.53 Otherwise, no patients developed dysrhythmias, congestive failure, ECG changes, or elevated creatine phosphokinase levels early after exposure. Three patients developed fatal congestive heart failure (CHF) from 1 to 4 months later.110

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■ ENHANCED ELIMINATION The anthracyclines are highly protein bound and have a large volume of distribution, which makes them unlikely candidates for hemodialysis. However, the early institution of hemoperfusion may enhance elimination. In an animal model, serum doxorubicin clearance could be enhanced up to 20-fold with hemoperfusion.128 Factors determining this were duration of therapy, rate of flow, and the use of a 2% acrylic hydrogel-coated cartridge. Three patients with a doxorubicin overdose were treated with hemoperfusion, one with an Amberlite cartridge, and all had a rapid reduction in their serum levels.31 One survived a 10-fold error in dosing. In a patient with a mitoxantrone overdose of 98 mg intravenously (IV), hemoperfusion was begun within hours, but in two trials, only 0.287 and 0.236 mg of drug were removed.53

NITROGEN MUSTARDS

■ MANAGEMENT Dexrazoxane is a specific antidote for doxorubicin; otherwise, management is largely supportive. Monitoring for cardiotoxicity and pancytopenia is necessary. A baseline chest radiograph, electrocardiogram, and echocardiogram to determine left ventricular ejection fraction (at rest and/or with stress) are required. Endomyocardial biopsy and cardiac catheterization can assist in distinguishing other causes of cardiac dysfunction. Left ventricular function is the best predictor for cardiomyopathy.43,104 A 10% absolute decrease in the left ventricular ejection fraction (LVEF) or a drop in LVEF of 50% from baseline is a significant finding for the discontinuation of further anthracycline therapy.104 Although digoxin and furosemide should be used to manage acute CHF, a variable response can be expected.110 Digoxin and lowdose verapamil benefit patients treated with doxorubicin; however, this benefit may be limited by the severity of the disorder.47,126 At higher doses of verapamil, hypotension and heart block were observed, which limited further use.92,116 The role for angiotensin-converting enzyme inhibitor (enalapril) as an effective treatment for congestive cardiomyopathy remains investigatory.61,111 Dexrazoxane is a cardioprotectant that limits the adverse cardiac effects of doxorubicin by chelating intracellular iron, which mediates the formation of free radical cellular damage. In clinical trials, patients receiving dexrazoxane had smaller decreases in LVEF per dose of doxorubicin, had fewer histologic changes on cardiac biopsy, were better able to tolerate doxorubicin doses greater than 600 mg/m2, and had a lower occurrence of serum cardiac troponin T elevations than did patients who were not pretreated with dexrazoxane.77,78,113 The current role of this chelator is to limit cardiotoxicity in patients receiving more than 300 mg/m2 of doxorubicin.106 It is administered 30 minutes before doxorubicin in a 10:1 ratio. Dexrazoxane increased the systemic clearance of epirubicin in a clinical trial, which may be an added benefit to patients with increased exposure.8 Further investigations are required to determine the optimal use of dexrazoxane in children receiving anthracycline therapy and in patients with overdose exposures. Another cardioprotectant under investigation is monohydroxyethylrutoside. Monohydroxyethylrutoside is a semisynthetic flavonoid that can chelate iron and scavenge free radicals, although the contribution of this action to its cardioprotective effects against doxorubicin-induced toxicity remains unclear.9 In experimental models, monohydroxyethylrutoside decreased doxorubicin-induced cardiotoxicity as measured by ST segment elevation on ECG119 and left ventricular function.60 Clinical trials are lacking for this agent.

■ PHARMACOLOGY The nitrogen mustards are cyclophosphamide, ifosfamide, chlorambucil, mechlorethamine, and melphalan. Their indicated uses include immunosuppression (eg, controlling graft-versus-host rejection, collagen vascular diseases) and chemotherapy. The tumoricidal activity of these xenobiotics is the result of the formation of reactive intermediates that bind to nucleophilic moieties on DNA, which inactivates DNA synthesis. Unlike the other xenobiotics, cyclophosphamide and ifosfamide require P450 isoenzymes to achieve their alkylating properties. Mechlorethamine is the original compound from which all of the others were derived. It is highly reactive when it comes in contact with water and undergoes rapid chemical transformation. Local reactions caused by mechlorethamine spillage (eg, extravasation) include tissue injury and thrombophlebitis (see Special Considerations SC 3–Extravasation of Xenobiotics). Nonenzymatic hydrolysis is the major route by which the nitrogen mustards are metabolized, thus accounting for their relatively short elimination half-lives (ie, less than 3 hours).12 Cyclophosphamide, ifosfamide, and chlorambucil have active metabolites, which prolongs their alkylating activity after administration.66

■ CLINICAL MANIFESTATIONS Chlorambucil and ifosfamide can produce altered mental status and seizures from therapeutic use or from an overdose.19,45 Both antineoplastics undergo hepatic N-dechloroethylation to produce chloroacetaldehyde, which is purported to be a nervous system toxin.72 Encephalopathy occurs in 9% of patients receiving 5 g/m2 of ifosfamide, and is more frequent with oral than with IV administration because of the first-pass effect and increased chloroacetaldehyde production.81 Seizures are more commonly associated with chlorambucil. Acute overdoses reported in the literature are all from the oral route, and range in dosing from 1.5 to 6.8 mg/kg (therapeutic is 0.1 to 0.2 mg/kg).5,20 The seizures occur within 6 hours, may appear as generalized tonic– clonic activity or staring spells, and can last for 24 hours. However, in one instance in which therapeutic dosing was increased, seizures occurred 17 hours later. This delay may be attributed to a lower serum

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Part C

The Clinical Basis of Medical Toxicology

concentration or a slower time to peak than in the overdose setting. A similar reasoning would explain why a patient with a chronic overdose of 4.1 mg/kg over 5 days did not sustain central nervous system (CNS) toxicity.40 Patients with increased likelihood for seizures include those with underlying seizure disorders or with nephrotic syndrome, which can alter pharmacokinetics.102 Electroencephalograms (EEGs) demonstrated multiple paroxysms of bilaterally symmetric 2 to 3-Hz spikes and slow high-voltage rhythmic slowing that progressed to slower bursts of rhythmic spike and wave discharge in a child with an acute overdose.20 Myelosuppression occurs in patients with both acute and chronic overdoses, and can present as late as 41 days postexposure. Recovery is expected within 1 week of the nadir, and granulocyte colony-stimulating factor (G-CSF) treatment may be necessary.64 Renal failure from an acute overdose with ifosfamide is reversible following the immediate institution of hemodialysis.45 Cyclophosphamide and its analog ifosfamide induce hemorrhagic cystitis from their irritating metabolite acrolein. This occurs in approximately 5% to 10% of patients who receive therapy.18,30 The incidence of cystitis does not appear to be related to the total dose and administration route, age, or gender. The course is usually self-limiting, although blood transfusions may be required. Water retention is observed in patients receiving more than 50 mg/kg of cyclophosphamide.34 This effect is attributed to the activity of the alkylating metabolite on the renal tubule and is observed at 6 to 8 hours after administration. The patient typically develops decreased urinary output, increased urine osmolality, and decreased serum osmolality, which is self-limiting, lasting for about 12 to 16 hours. In the overdose setting, cyclophosphamide can cause dysrhythmias, myocardial necrosis, hemorrhagic pericarditis, and death. ECG changes are noted at doses of 120 mg/kg and heart failure and myocarditis at doses greater than 150 mg/kg.6,86 Diminished QRS voltage has been noted on the ECG, which is attributed to myocardial swelling from edema or hemorrhage. An ordering error led to the death of one patient and to irreversible cardiac damage in another patient from cyclophosphamide overdose. These two patients received 6520 mg daily for 4 consecutive days, when the amount was to be divided over 4 days.100 The onset of heart failure can be sudden and patients older than 50 years of age, and those with a history of cardiac dysfunction or prior treatment with anthracyclines, are at greatest risk for cardiac toxicity.115

■ MANAGEMENT Recommendations for patients with an acute chlorambucil exposure include routine gastrointestinal decontamination, a 6-hour observation, a determination of a complete blood count (CBC) and hepatic enzymes, and a follow-up CBC weekly for 4 weeks.121 Ifosfamideinduced encephalopathy can be managed with methylene blue (50 mg IV as a 1% solution), although the mechanism by which methylene blue acts is unknown.72,131 Seizures are reported to be more effectively managed with benzodiazepines and barbiturates than with phenytoin.5,129 When gross hematuria from cyclophosphamide or ifosfamide therapy persists, treatments reported to be effective in the literature can be considered. These treatments include electrocauterization, systemic vasopressin,99 intravesical administration of silver nitrate,72 formalin,46,107 prostaglandin F2,109 and hydrostatic pressure.58 Some of the preventive therapies that seem to reduce this occurrence include adequate hydration for dilution effect, frequent bladder emptying, IV administration of 2-mercaptoethane sulfonate sodium (MESNA), and intravesical administration of N-acetylcysteine.18 The thiol group of N-acetylcysteine is believed to directly interact with acrolein to limit its irritating effect on the bladder epithelium. MESNA is believed to work

by inactivating acrolein to an inert thioether.59 The IV dose of MESNA is 20% of the cyclophosphamide or ifosfamide amount (wt/wt) and administered during therapy and again at 4 and 8 hours. MESNA is used during standard-dose therapy for ifosfamide and high-dose therapy for cyclophosphamide. In the overdose setting, MESNA does not protect patients from the renal toxic effects of these agents and hemodialysis is indicated. Hemodialysis effectively enhances the elimination of ifosfamide and its metabolites when instituted soon after exposure, and it is more effective than hemoperfusion (Adsorba 300 C, Gambro 300 g active carbon) in removing ifosfamide.45 Patients with large exposures to cyclophosphamide require baseline ECGs and echocardiograms. Intravenous fluid restriction, digoxin, and furosemide were successfully used to treat a patient with cyclophosphamide-induced congestive cardiomyopathy.123

PLATINOIDS

■ PHARMACOLOGY The cytotoxic effects of the platinum-containing compounds were first recognized in 1965. Since then, many types have been derived. The ones of clinical significance are cisplatin, carboplatin, and oxaliplatin.87 The latter two agents were designed to reduce the incidence of nephrotoxicity and to counter drug resistance to cisplatin. Differences in chemical structure exist among these antineoplastics. Most notably, cisplatin is an inorganic and carboplatin an organic compound. Similarities exist in their mechanism of toxicity, which is the binding of platinum to DNA to form inter- and intrastrand bonds, which lead to DNA dysfunction and strand breakage. These xenobiotics are eliminated from the body primarily in the urine and at varying rates. The amount eliminated at 24 hours is 25% for cisplatin and 90% for carboplatin. Patients with decreased creatinine clearance (< 30 mL/min) will have prolonged elimination half-lives of platinoids.39

■ PATHOPHYSIOLOGY Renal failure from renal tubular necrosis occurs with cisplatin in a dose-dependent manner. Upon entering the cell, cisplatin forms a cationic complex when the chloride ions are nonenzymatically displaced by water molecules. The reactive complex covalently binds to DNA to disrupt replication and transcription, resulting in cell death. The formation of the hydrated platinum complex is favored by a low chloride concentration in the environment; thus, a sodium chloride infusion promotes the native state of cisplatin by preventing hypochloremia. The presence of alanine aminopeptidase and N-acetylD-glucosaminidase in the urine can be early indicators of renal tubular damage.32,36,49 The sensory neuropathy associated with these platinum-containing antineoplastics can be attributed to their accumulation and toxicity at the dorsal root ganglion, which depends on the water solubility and chemical reactivity of these xenobiotics.105 Clinical pathologic evaluation demonstrates increased platinum content at the dorsal root ganglion following cisplatin therapy, which suggests that the increased

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vascularity and fenestration of the endothelium at this tissue site contributes to the uptake of cisplatin.51,63

■ CLINICAL MANIFESTATIONS The more common manifestations of toxicity with cisplatin during therapy are renal dysfunction, auditory impairment, and peripheral sensory neuropathy. The other antineoplastics recognized to cause a peripheral neuropathy are the Vinca alkaloids and the taxoids. Oxaliplatin-induced neuropathy is triggered or enhanced by exposure to cold and can subside over several months.42 Myelosuppression is a dose-limiting factor for carboplatin and iproplatin, which does not occur with cisplatin. At a carboplatin dose of 800 mg/m2, 25% of patients develop marrow toxicity.93 The marrow effects are delayed, with nadir occurring 3 to 5 weeks after the start of therapy. Patients developing an anemia within the first week of cisplatin therapy should be evaluated for hemolytic anemia.26 The sources of error associated with cisplatin are frequency of administration (total dose versus over a period of time), mistaking it for carboplatin, and writing the wrong dose.28,97 Manifestations in the overdose setting involve neurologic, visual, hearing, bone marrow, pancreatic, and renal disorders.108 The most common renal disorder is renal failure, which is dose-related and begins at 50 mg/m2. At this dose, approximately 30% of patients treated with cisplatin develop renal failure and a rise in serum BUN and creatinine typically occurs at 1 to 2 weeks posttreatment. Attributed to the renal toxicity is electrolyte disorders, include hypomagnesemia, hypocalcemia, and hyponatremia.41 Hyponatremia is an uncommon finding with cisplatin exposure and is attributed to either sodium-wasting nephropathy from renal tubular dysfunction or syndrome of inappropriate secretion of antidiuretic hormone (SIADH). At doses greater than 200 mg/m2, the development of seizures, encephalopathy, and irreversible peripheral sensory neuropathy is of concern.11,29,56,92,93,94 At this dose, visual impairment may occur within the first week of exposure.24,80,127 This can include temporary visual loss, with permanent loss of color discrimination. Physical examination of the anterior chamber and fundus of the eye will be normal; however, an electroretinogram will demonstrate a disorder with the postphotoreceptor neural function.68 Some other ocular disorders are papilledema and retrobulbar neuritis. High-frequency (2000 Hz) hearing loss is evident 2 to 3 days after exposure to doses greater than 500 mg/m2.22

■ MANAGEMENT Renal protection and enhanced elimination of platinum are the two primary goals in the management of a cisplatin overdose. Expectant management for myelosuppression and neurotoxicity can follow. Hydration with 0.9% NaCl solution and an osmotic diuretic (eg, mannitol) should be administered to achieve a high urine output (eg, 1 to 3 mL/kg/h) for 6 to 24 hours postexposure. Sodium chloride diuresis both promotes the inactive state of cisplatin and decreases the urine platinum concentration to limit nephrotoxicity during therapy.4,122 In the setting of nonoliguric renal failure, careful hydration is recommended to maintain urinary output, because platinum renal excretion is directly related to urinary flow and independent of creatinine clearance.24 Aside from evaluating BUN and creatinine, assessment of renal function can include glomerular filtration, filtration fraction, and renal plasma flow.52,82,83,91 Amifostine (Ethyol™) and sodium thiosulfate are effective nephroprotectants. Amifostine’s role is more preventative and its use is approved by the US Food and Drug Administration (FDA) to protect against cisplatin-induced nephrotoxicity. However, additional benefits can include the limitation of myelosuppression, mucositis, and neurotoxicity.2 Unlike thiosulfate, amifostine is activated intracellularly by

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alkaline phosphatase to scavenge free radicals, regenerate glutathione, prevent cisplatin-DNA adduct formation, and facilitate DNA repair.71 The patient requires adequate hydration during amifostine infusion because hypotension can occur. Sodium thiosulfate is effective postexposure. Thiosulfate remains in the extracellular space to bind free platinum and limit cellular damage at the renal tubules. Little or no renal toxicity occurred in patients receiving as much as 270 mg/m2 of cisplatin when thiosulfate was given as an IV bolus of 4 g/m2 followed by infusion of 12 g/m2 over 6 hours.55,95 In a 14-year-old patient with renal failure, thiosulfate was continued at 2.7 g/m2 a day until urinary platinum concentration was below 1 μg/mL.41 Thiosulfate may offer the additional benefit of limiting neurotoxicity and should be administered to all patients after an overdose.79,120 The effectiveness of thiosulfate is limited by the time in which it needs to be administered after exposure (ie, 1 to 2 hours). N-acetylcysteine and BNP7787 (2,2ʹdithio-bis-ethanesulfonate) are being investigated as alternative rescue agents for cisplatin toxicity.14,35,85 Also, BNP7787 is under clinical investigation to limit peripheral neuropathy from paclitaxel therapy. Hemodialysis is ineffective in patients with cisplatin overdoses, likely as a result of high protein binding.17 However, in patients with renal failure, hemodialysis may be beneficial when plasmapheresis is not available. Plasmapheresis was performed in four adults and there was a fall in blood serum platinum concentrations with clinical improvement.23,24,57,67 In one incident, a patient received an overdose of 280 mg/m2 and was plasmapheresed on day 12 of exposure.24 After three daily treatments, the serum platinum concentration decreased from 2900 to 200 ng/mL and the patient had noticeable improvement in gastrointestinal and visual symptoms. On day 20, the serum platinum concentration rebounded to 700 ng/mL and the symptoms worsened. Further plasmapheresis lowered the concentration to 290 ng/mL by day 27 and symptoms improved. In another event, a patient received 300 mg/m2 of cisplatin and received four daily treatments of plasmapheresis starting on day 6 postexposure.67 The serum platinum concentration declined from 2979 to 430 ng/mL and the patient became more awake and less nauseous. On day 11, platinum concentrations rebounded to 834 ng/mL and fell to 279 ng/mL on reinstitution of plasmapheresis. The amount of platinum removed by three trials in this patient was approximately 4.6 mg. The author of the paper contends that plasmapheresis prevented the need for hemodialysis in renal failure. Other reports have noted an improvement in patients’ mental status and hearing loss following the decline in the serum cisplatin (platinum) concentration from plasmapheresis.23,57 Thus, plasmapheresis appears to be effective in cisplatin overdose and should be instituted immediately after exposure. Patients who remain symptomatic days later also may benefit.

SUMMARY Anthracyclines, nitrogen mustards, and the platinum-based antineoplastics are some of the antineoplastic agents reported as overdoses in patients undergoing therapy. The primary clinical manifestations of toxicity for these agents include congestive dilated cardiomyopathy (anthracyclines), encephalopathy and seizures (nitrogen mustards), and renal failure (platinum-based agents). The management for these overdoses includes supportive care, enhanced elimination using plasmapheresis for cisplatin, and antidotal therapy, such as dexrazoxane for anthracyclines and amifostine for platinum-based agents. Although rescue agents are available, their effectiveness is markedly diminished in the postexposure period. Specialists in poison information and medical toxicologists need to maintain a current level of understanding of these exposures so they can better assist their patients and interact with other healthcare professionals.

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Part C

The Clinical Basis of Medical Toxicology

ACKNOWLEDGMENT This chapter was written by Richard Y. Wang in his private capacity. No official support or endorsement by the Centers for Disease Control and Prevention is intended or should be inferred. Paul Calabresi contributed to this chapter in a previous edition.

REFERENCES 1. Aguiar Bujanda D, Cabrera Suarez MA, Bohn Sarmiento U, Aguiar Morales J. Successful recovery after accidental overdose of cyclophosphamide. Ann Oncol. 2006;17:1334. 2. Alberts DS, Bleyer WA. Future development of amifostine in cancer treatment. Semin Oncol. 1996;23:90-99. 3. Alexander J, Dainiak N, Berger HJ, et al. Serial assessment of doxorubicin cardiotoxicity with quantitative radionuclide angiocardiography. N Engl J Med. 1979;300:278-283. 4. Al-Sarraf M, Fletcher W, Oishi N, et al. Cisplatin hydration with and without mannitol diuresis in refractory disseminated malignant melanoma: a Southwest Oncology Group study. Cancer Treat Rep. 1982;66:31-35. 5. Ammenti A, Reitter B, Muller-Wiefel DE. Chlorambucil neurotoxicity: report of two cases. Helv Paediatr Acta. 1980;35:281-287. 6. Appelbaum F, Strauchen JA, Graw RG Jr, et al. Acute lethal carditis caused by high-dose combination chemotherapy. A unique clinical and pathological entity. Lancet. 1976;1:58-62. 7. Arena E, D’Allesandro N, Dusonchet L, et al. Influence of pharmacokinetic variations on the pharmacologic properties of Adriamycin. In: Carter SK, ed. International Symposium on Adriamycin. Berlin ed. New York: Springer-Verlag; 1972:96-116. 8. Basser RL, Sobol MM, Duggan G, et al. Comparative study of the pharmacokinetics and toxicity of high-dose epirubicin with or without dexrazoxane in patients with advanced malignancy. J Clin Oncol. 1994;12:7. 9. Bast A, Kaiserova H, den Hartog GJ, Haenen GR, van der Vijgh WJ. Protectors against doxorubicin-induced cardiotoxicity: flavonoids. Cell Biol Toxicol. 2007;23:39-47. 10. Benjamin RS, Wiernik PH, Bachur NR. Adriamycin chemotherapy—efficacy, safety, and pharmacologic basis of an intermittent single high-dosage schedule. Cancer. 1974;33:19-27. 11. Berman IJ, Mann MP. Seizures and transient cortical blindness associated with cis-platinum (II) diamminedichloride (PDD) therapy in a thirty-yearold man. Cancer. 1980;45:764-766. 12. Betcher DL, Burnham N. Melphalan. J Pediatr Oncol Nurs. 1990;7:35-36. 13. Billingham ME, Mason JW, Bristow MR, Daniels JR. Anthracycline cardiomyopathy monitored by morphologic changes. Cancer Treat Rep. 1978;62:865-872. 14. Boven E, Westerman M, van Groeningen CJ, et al. Phase I and pharmacokinetic study of the novel chemoprotector BNP7787 in combination with cisplatin and attempt to eliminate the hydration schedule. Br J Cancer. 2005;92:1636-1643. 15. Bristow MR, Minobe WA, Billingham ME, et al. Anthracycline-associated cardiac and renal damage in rabbits. Evidence for mediation by vasoactive substances. Lab Invest. 1981;45:157-168. 16. Bristow MR. Toxic cardiomyopathy due to doxorubicin. Hosp Pract (Off Ed). 1982;17:101-108, 110-101. 17. Brivet F, Pavlovitch JM, Gouyette A, et al. Inefficiency of early prophylactic hemodialysis in cis-platinum overdose. Cancer Chemother Pharmacol. 1986;18:183-184. 18. Brock N, Pohl J. Prevention of urotoxic side effects by regional detoxification with increased selectivity of oxazaphosphorine cytostatics. IARC Sci Publ. 1986;269-279. 19. Brock N, Stekar J, Pohl J, Niemeyer U, Scheffler G. Acrolein, the causative factor of urotoxic side-effects of cyclophosphamide, ifosfamide, trofosfamide and sufosfamide. Arzneimittelforschung. 1979;29:659-661. 20. Byrne TN, Jr., Moseley TA 3rd, Finer MA. Myoclonic seizures following chlorambucil overdose. Ann Neurol. 1981;9:191-194. 21. Carrio I, Lopez-Pousa A, Estorch M, et al. Detection of doxorubicin cardiotoxicity in patients with sarcomas by indium-111-antimyosin monoclonal antibody studies. J Nucl Med. 1993;34:1503-1507. 22. Chiuten D, Vogl S, Kaplan B, Camacho F. Is there cumulative or delayed toxicity from cis-platinum? Cancer. 1983;52:211-214.

23. Choi JH, Oh JC, Kim KH, et al. Successful treatment of cisplatin overdose with plasma exchange. Yonsei Med J. 2002;43:128-132. 24. Chu G, Mantin R, Shen YM, Baskett G, Sussman H. Massive cisplatin overdose by accidental substitution for carboplatin. Toxicity and management. Cancer. 1993;72:3707-3714. 25. Cil T, Kaplan AM, Altintas A, et al. Use of N-terminal pro-brain natriuretic peptide to assess left ventricular function after adjuvant doxorubicin therapy in early breast cancer patients: a prospective series. Clin Drug Investig. 2009;29:131-137. 26. Cinollo G, Dini G, Franchini E, et al. Positive direct antiglobulin test in a pediatric patient following high-dose cisplatin. Cancer Chemother Pharmacol. 1988;21:85-86. 27. Coates TD. Survival from melphalan overdose. Lancet. 1984;2:1048. 28. Cohen MR. Medication errors. Cisplatin death. Nursing. 1998;28:18. 29. Cohen RJ, Cuneo RA, Cruciger MP, Jackman AE. Transient left homonymous hemianopsia and encephalopathy following treatment of testicular carcinoma with cisplatinum, vinblastine, and bleomycin. J Clin Oncol. 1983;1:392-393. 30. Cox PJ. Cyclophosphamide cystitis—identification of acrolein as the causative agent. Biochem Pharmacol. 1979;28:2045-2049. 31. Curran CF. Acute doxorubicin overdoses. Ann Intern Med. 1991;115: 913-914. 32. Daugaard G, Abildgaard U, Holstein-Rathlou NH, et al. Renal tubular function in patients treated with high-dose cisplatin. Clin Pharmacol Ther. 1988;44:164-172. 33. de Korte MA, de Vries EG, Lub-de Hooge MN, et al. 111Indium-trastuzumab visualises myocardial human epidermal growth factor receptor 2 expression shortly after anthracycline treatment but not during heart failure: a clue to uncover the mechanisms of trastuzumab-related cardiotoxicity. Eur J Cancer. 2007;43:2046-2051. 34. DeFronzo RA, Braine H, Colvin M, Davis PJ. Water intoxication in man after cyclophosphamide therapy. Time course and relation to drug activation. Ann Intern Med. 1973;78:861-869. 35. Dickey DT, Muldoon LL, Doolittle ND, et al. Effect of N-acetylcysteine route of administration on chemoprotection against cisplatin-induced toxicity in rat models. Cancer Chemother Pharmacol. 2008;62:235-241. 36. Diener U, Knoll E, Langer B, et al. Urinary excretion of N-acetyl-beta-Dglucosaminidase and alanine aminopeptidase in patients receiving amikacin or cis-platinum. Clin Chim Acta. 1981;112:149-157. 37. Dodos F, Halbsguth T, Erdmann E, Hoppe UC. Usefulness of myocardial performance index and biochemical markers for early detection of anthracycline-induced cardiotoxicity in adults. Clin Res Cardiol. 2008;97:318-326. 38. Doroshow JH, Locker GY, Myers CE. Enzymatic defenses of the mouse heart against reactive oxygen metabolites: alterations produced by doxorubicin. J Clin Invest. 1980;65:128-135. 39. Egorin MJ, Van Echo DA, Tipping SJ, et al. Pharmacokinetics and dosage reduction of cis-diammine(1,1-cyclobutanedicarboxylato)platinum in patients with impaired renal function. Cancer Res. 1984;44:5432-5438. 40. Enck RE, Bennett JM. Inadvertent chlorambucil overdose in adult. N Y State J Med. 1977;77:1480-1485. 41. Erdlenbruch B, Pekrun A, Schiffmann H, Witt O, Lakomek M. Topical topic: accidental cisplatin overdose in a child: reversal of acute renal failure with sodium thiosulfate. Med Pediatr Oncol. 2002;38:349-352. 42. Extra JM, Marty M, Brienza S, Misset JL. Pharmacokinetics and safety profile of oxaliplatin. Semin Oncol. 1998;25:13-22. 43. Fantine EO, Garnier-Suillerot A. Interaction of 5-iminodaunorubicin with Fe(III) and with cardiolipin-containing vesicles. Biochim Biophys Acta. 1986;856:130-136. 44. Fassoulaki A, Pavlou H. Overdosage intoxication with cisplatin—a cause of acute respiratory failure. J R Soc Med. 1989;82:689. 45. Fiedler R, Baumann F, Deschler B, Osten B. Haemoperfusion combined with haemodialysis in ifosfamide intoxication. Nephrol Dial Transplant. 2001;16:1088-1089. 46. Firlit CF. Intractable hemorrhagic cystitis secondary to extensive carcinomatosis: management with formalin solution. J Urol. 1973;110:57-58. 47. Garbrecht M, Mullerleile U. Verapamil in the prevention of adriamycininduced cardiomyopathy. Klin Wochenschr. 1986;64(Suppl 7):132-134. 48. Garnier-Suillerot A. Metal anthracycline and anthracenedione complexes as a new class of anticancer agents. In: Lown JW, ed. Anthracycline and Anthracenedione-Based Anticancer Agents. Amserdam ed. Amsterdam: Elsevier; 1988:129-157.

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49. Goren MP, Wright RK, Horowitz ME. Cumulative renal tubular damage associated with cisplatin nephrotoxicity. Cancer Chemother Pharmacol. 1986;18:69-73. 50. Greene RF, Collins JM, Jenkins JF, Speyer JL, Myers CE. Plasma pharmacokinetics of adriamycin and adriamycinol: implications for the design of in vitro experiments and treatment protocols. Cancer Res. 1983;43:3417-3421. 51. Gregg RW, Molepo JM, Monpetit VJ, et al. Cisplatin neurotoxicity: the relationship between dosage, time, and platinum concentration in neurologic tissues, and morphologic evidence of toxicity. J Clin Oncol. 1992;10:795-803. 52. Groth S, Nielsen H, Sorensen JB, et al. Acute and long-term nephrotoxicity of cis-platinum in man. Cancer Chemother Pharmacol. 1986;17:191-196. 53. Hachimi-Idrissi S, Schots R, DeWolf D, Van Belle SJ, Otten J. Reversible cardiopathy after accidental overdose of mitoxantrone. Pediatr Hematol Oncol. 1993;10:35-40. 54. Herman E, Mhatre R, Lee IP, Vick J, Waravdekar VS. A comparison of the cardiovascular actions of daunomycin, adriamycin and N-acetyldaunomycin in hamsters and monkeys. Pharmacology. 1971;6:230-241. 55. Hirosawa A, Niitani H, Hayashibara K, Tsuboi E. Effects of sodium thiosulfate in combination therapy of cis-dichlorodiammineplatinum and vindesine. Cancer Chemother Pharmacol. 1989;23:255-258. 56. Hitchins RN, Thomson DB. Encephalopathy following cisplatin, bleomycin and vinblastine therapy for non-seminomatous germ cell tumour of testis. Aust N Z J Med. 1988;18:67-68. 57. Hofmann G, Bauernhofer T, Krippl P, et al. Plasmapheresis reverses all side-effects of a cisplatin overdose—a case report and treatment recommendation. BMC Cancer. 2006;6:1. 58. Holstein P, Jacobsen K, Pedersen JF, Sorensen JS. Intravesical hydrostatic pressure treatment: new method for control of bleeding from the bladder mucosa. J Urol. 1973;109:234-236. 59. Hows JM, Mehta A, Ward L, et al. Comparison of mesna with forced diuresis to prevent cyclophosphamide induced haemorrhagic cystitis in marrow transplantation: a prospective randomised study. Br J Cancer. 1984;50:753-756. 60. Husken BC, de Jong J, Beekman B, et al. Modulation of the in vitro cardiotoxicity of doxorubicin by flavonoids. Cancer Chemother Pharmacol. 1995; 37:55-62. 61. Jensen BV, Nielsen SL, Skovsgaard T. Treatment with angiotensinconverting-enzyme inhibitor for epirubicin-induced dilated cardiomyopathy. Lancet. 1996;347:297-299. 62. Jensen BV, Skovsgaard T, Nielsen SL. Functional monitoring of anthracycline cardiotoxicity: a prospective, blinded, long-term observational study of outcome in 120 patients. Ann Oncol. 2002;13:699-709. 63. Jimenez-Andrade JM, Herrera MB, Ghilardi JR, et al. Vascularization of the dorsal root ganglia and peripheral nerve of the mouse: implications for chemical-induced peripheral sensory neuropathies. Mol Pain. 2008;4:10. 64. Jirillo A, Gioga G, Bonciarelli G, Dalla Valle G. Accidental overdose of melphalan per os in a 69-year-old woman treated for advanced endometrial carcinoma. Tumori. 1998;84:611. 65. Jost LM. [Overdose with melphalan (Alkeran): symptoms and treatment. A review]. Onkologie. 1990;13:96-101. 66. Juma FD, Rogers HJ, Trounce JR. The pharmacokinetics of cyclophosphamide, phosphoramide mustard and nor-nitrogen mustard studied by gas chromatography in patients receiving cyclophosphamide therapy. Br J Clin Pharmacol. 1980;10:327-335. 67. Jung HK, Lee J, Lee SN. A case of massive cisplatin overdose managed by plasmapheresis. Korean J Intern Med. 1995;10:150-154. 68. Katz BJ, Ward JH, Digre KB, Creel DJ, Mamalis N. Persistent severe visual and electroretinographic abnormalities after intravenous Cisplatin therapy. J Neuroophthalmol. 2003;23:132-135. 69. Kilickap S, Barista I, Akgul E, et al. cTnT can be a useful marker for early detection of anthracycline cardiotoxicity. Ann Oncol. 2005;16:798-804. 70. Kim IS, Gratwohl A, Stebler C, et al. Accidental overdose of multiple chemotherapeutic agents. Korean J Intern Med. 1989;4:171-173. 71. Korst AE, van der Sterre ML, Eeltink CM, et al. Pharmacokinetics of carboplatin with and without amifostine in patients with solid tumors. Clin Cancer Res. 1997;3:697-703. 72. Kupfer A, Aeschlimann C, Wermuth B, Cerny T. Prophylaxis and reversal of ifosfamide encephalopathy with methylene-blue. Lancet. 1994;343:763-764. 73. Lagrange JL, Cassuto-Viguier E, Barbe V, et al. Cytotoxic effects of longterm circulating ultrafiltrable platinum species and limited efficacy of haemodialysis in clearing them. Eur J Cancer. 1994;30A:2057-2060.

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74. Lefrak EA, Pitha J, Rosenheim S, Gottlieb JA. A clinicopathologic analysis of adriamycin cardiotoxicity. Cancer. 1973;32:302-314. 75. Legha SS, Benjamin RS, Mackay B, et al. Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion. Ann Intern Med. 1982;96:133-139. 76. Liem RI, Higman MA, Chen AR, Arceci RJ. Misinterpretation of a Calvertderived formula leading to carboplatin overdose in two children. J Pediatr Hematol Oncol. 2003;25:818-821. 77. Lipshultz SE, Colan SD, Gelber RD, et al. Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. N Engl J Med. 1991;324:808-815. 78. Lipshultz SE, Rifai N, Dalton VM, et al. The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia. N Engl J Med. 2004;351:145-153. 79. Markman M, Cleary S, Pfeifle CE, Howell SB. High-dose intracavitary cisplatin with intravenous thiosulfate. Low incidence of serious neurotoxicity. Cancer. 1985;56:2364-2368. 80. Marmor MF. Negative-type electroretinogram from cisplatin toxicity. Doc Ophthalmol. 1993;84:237-246. 81. Meanwell CA, Blake AE, Kelly KA, Honigsberger L, Blackledge G. Prediction of ifosfamide/mesna associated encephalopathy. Eur J Cancer Clin Oncol. 1986;22:815-819. 82. Meijer S, Mulder NH, Sleijfer DT, et al. Influence of combination chemotherapy with cis-diamminedichloroplatinum on renal function: long-term effects. Oncology. 1983;40:170-173. 83. Meijer S, Sleijfer DT, Mulder NH, et al. Some effects of combination chemotherapy with cis-platinum on renal function in patients with nonseminomatous testicular carcinoma. Cancer. 1983;51:2035-2040. 84. Michelotti A, Venturini M, Tibaldi C, et al. Single agent epirubicin as first line chemotherapy for metastatic breast cancer patients. Breast Cancer Res Treat. 2000;59:133-139. 85. Miller AA, Wang XF, Gu L, et al. Phase II randomized study of dose-dense docetaxel and cisplatin every 2 weeks with pegfilgrastim and darbepoetin alfa with and without the chemoprotector BNP7787 in patients with advanced nonsmall cell lung cancer (CALGB 30303). J Thorac Oncol. 2008;3:1159-1165. 86. Mills BA, Roberts RW. Cyclophosphamide-induced cardiomyopathy: a report of two cases and review of the English literature. Cancer. 1979;43:2223-2226. 87. Misset JL. Oxaliplatin in practice. Br J Cancer. 1998;77(Suppl 4):4-7. 88. Munoz A, Barcelo R, Viteri A, et al. Oxaliplatin overdosage successfully recovered with mild toxicities. Acta Oncol. 2006;45:621-622. 89. Myers C. Organ directed toxicities of anticancer drugs: proceedings of the First International Symposium on the Organ Directed Toxicities of Anticancer Drugs, Burlington, Vermont, USA, June 4-6, 1987. In: Developments in Oncology 53. Edition Boston, MA: Kluwer Academic Publishers; 1988;17-30. 90. Myers C, Bonow R, Palmeri S, et al. A randomized controlled trial assessing the prevention of doxorubicin cardiomyopathy by N-acetylcysteine. Semin Oncol. 1983;10:53-55. 91. Offerman JJ, Meijer S, Sleijfer DT, et al. Acute effects of cis-diamminedichloroplatinum (CDDP) on renal function. Cancer Chemother Pharmacol. 1984;12:36-38. 92. Ozols RF, Cunnion RE, Klecker RW Jr, et al. Verapamil and adriamycin in the treatment of drug-resistant ovarian cancer patients. J Clin Oncol. 1987;5:641-647. 93. Ozols RF, Ostchega Y, Curt G, Young RC. High-dose carboplatin in refractory ovarian cancer patients. J Clin Oncol. 1987;5:197-201. 94. Panici PB, Greggi S, Scambia G, et al. High-dose (200 mg/m2) cisplatinnduced neurotoxicity in primary advanced ovarian cancer patients. Cancer Treat Rep. 1987;71:669-670. 95. Pecherstorfer M, Zimmer-Roth I, Weidinger S, et al. High-dose intravenous melphalan in a patient with multiple myeloma and oliguric renal failure. Clin Investig. 1994;72:522-525. 96. Pessah IN, Durie EL, Schiedt MJ, Zimanyi I. Anthraquinone-sensitized Ca2+ release channel from rat cardiac sarcoplasmic reticulum: possible receptor-mediated mechanism of doxorubicin cardiomyopathy. Mol Pharmacol. 1990;37:503-514. 97. Pike IM, Arbus MH. Cisplatin overdosage. J Clin Oncol. 1992;10:1503-1504. 98. Pratt CB, Ransom JL, Evans WE. Age-related adriamycin cardiotoxicity in children. Cancer Treat Rep. 1978;62:1381-1385. 99. Pyeritz RE, Droller MJ, Bender WL, Saral R. An approach to the control of massive hemorrhage in cyclophosphamide-induced cystitis by intravenous vasopressin: a case report. J Urol. 1978;120:253-254.

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100. Roush W. Dana-Farber death sends a warning to research hospitals. Science. 1995;269:295-296. 101. Rusconi A, Calendi E. Action of daunomycin on nucleic acid metabolism in HeLa cells. Biochim Biophys Acta. 1966;119:413-415. 102. Salloum E, Khan KK, Cooper DL. Chlorambucil-induced seizures. Cancer. 1997;79:1009-1013. 103. Schwartz CL, Hobbie WL, Truesdell S, Constine LC, Clark EB. Corrected QT interval prolongation in anthracycline-treated survivors of childhood cancer. J Clin Oncol. 1993;11:1906-1910. 104. Schwartz RG, McKenzie WB, Alexander J, et al. Congestive heart failure and left ventricular dysfunction complicating doxorubicin therapy. Sevenyear experience using serial radionuclide angiocardiography. Am J Med. 1987;82:1109-1118. 105. Screnci D, McKeage MJ, Galettis P, et al. Relationships between hydrophobicity, reactivity, accumulation and peripheral nerve toxicity of a series of platinum drugs. Br J Cancer. 2000;82:966-972. 106. Seymour L, Bramwell V, Moran LA. Use of dexrazoxane as a cardioprotectant in patients receiving doxorubicin or epirubicin chemotherapy for the treatment of cancer. The Provincial Systemic Treatment Disease Site Group. Cancer Prev Control. 1999;3:145-159. 107. Shah BC, Albert DJ. Intravesical instillation of formalin for the management of intractable hematuria. J Urol. 1973;110:519-520. 108. Sheikh-Hamad D, Timmins K, Jalali Z. Cisplatin-induced renal toxicity: possible reversal by N-acetylcysteine treatment. J Am Soc Nephrol. 1997;8:1640-1644. 109. Shurafa M, Shumaker E, Cronin S. Prostaglandin F2-alpha bladder irrigation for control of intractable cyclophosphamide-induced hemorrhagic cystitis. J Urol. 1987;137:1230-1231. 110. Siegert W, Hiddemann W, Koppensteiner R, et al. Accidental overdose of mitoxantrone in three patients. Med Oncol Tumor Pharmacother. 1989;6:275-278. 111. Silber JH, Cnaan A, Clark BJ, et al. Enalapril to prevent cardiac function decline in long-term survivors of pediatric cancer exposed to anthracyclines. J Clin Oncol. 2004;22:820-828. 112. Slimowitz R. Thoughts on a medical disaster. Am J Health Syst Pharm. 1995;52:1464-1465. 113. Speyer JL, Green MD, Kramer E, et al. Protective effect of the bispiperazinedione ICRF-187 against doxorubicin-induced cardiac toxicity in women with advanced breast cancer. N Engl J Med. 1988;319:745-752. 114. Steinberg JS, Cohen AJ, Wasserman AG, Cohen P, Ross AM. Acute arrhythmogenicity of doxorubicin administration. Cancer. 1987;60: 1213-1218. 115. Steinherz LJ, Steinherz PG, Mangiacasale D, et al. Cardiac changes with cyclophosphamide. Med Pediatr Oncol. 1981;9:417-422.

116. Stephens LC, Wang YM, Schultheiss TE, Jardine JH. Enhanced cardiotoxicity in rabbits treated with verapamil and adriamycin. Oncology. 1987;44:302-306. 117. Tewey KM, Chen GL, Nelson EM, Liu LF. Intercalative antitumor drugs interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II. J Biol Chem. 1984;259:9182-9187. 118. Uner A, Ozet A, Arpaci F, Unsal D. Long-term clinical outcome after accidental overdose of multiple chemotherapeutic agents. Pharmacotherapy. 2005;25:1011-1016. 119. van Acker FA, van Acker SA, Kramer K, et al. 7-monohydroxyethylrutoside protects against chronic doxorubicin-induced cardiotoxicity when administered only once per week. Clin Cancer Res. 2000;6:1337-1341. 120. van Rijswijk RE, Hoekman K, Burger CW, Verheijen RH, Vermorken JB. Experience with intraperitoneal cisplatin and etoposide and i.v. sodium thiosulphate protection in ovarian cancer patients with either pathologically complete response or minimal residual disease. Ann Oncol. 1997;8:1235-1241. 121. Vandenberg SA, Kulig K, Spoerke DG, et al. Chlorambucil overdose: accidental ingestion of an antineoplastic drug. J Emerg Med. 1988;6:495-498. 122. Vogl SE, Zaravinos T, Kaplan BH. Toxicity of cis-diamminedichloroplatinum II given in a two-hour outpatient regimen of diuresis and hydration. Cancer. 1980;45:11-15. 123. von Bernuth G, Adam D, Hofstetter R, et al. Cyclophosphamide cardiotoxicity. Eur J Pediatr. 1980;134:87-90. 124. Von Hoff DD, Layard MW, Basa P, et al. Risk factors for doxorubicininduced congestive heart failure. Ann Intern Med. 1979;91:710-717. 125. Von Hoff DD, Rozencweig M, Piccart M. The cardiotoxicity of anticancer agents. Semin Oncol. 1982;9:23-33. 126. Whittaker JA, Al-Ismail SA. Effect of digoxin and vitamin E in preventing cardiac damage caused by doxorubicin in acute myeloid leukaemia. Br Med J (Clin Res Ed). 1984;288:283-284. 127. Wilding G, Caruso R, Lawrence TS, et al. Retinal toxicity after high-dose cisplatin therapy. J Clin Oncol. 1985;3:1683-1689. 128. Winchester JF, Rahman A, Tilstone WJ, et al. Will hemoperfusion be useful for cancer chemotherapeutic drug removal? Clin Toxicol. 1980;17:557-569. 129. Wolfson S, Olney MB. Accidental ingestion of a toxic dose of chlorambucil;report of a case in a child. J Am Med Assoc. 1957;165:239-240. 130. Zbinden G, Brandle E. Toxicologic screening of daunorubicin (NSC82151), adriamycin (NSC-123127), and their derivatives in rats. Cancer Chemother Rep. 1975;59:707-715. 131. Zulian GB, Tullen E, Maton B. Methylene blue for ifosfamide-associated encephalopathy. N Engl J Med. 1995;332:1239-1240. 132. Zweier JL. Iron-mediated formation of an oxidized adriamycin free radical. Biochim Biophys Acta. 1985;839:209-213.

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CHAPTER 55

PHARMACEUTICAL ADDITIVES Sean P. Nordt and Lisa E. Vivero This chapter summarizes the available literature on commonly used additives associated with direct toxicities. Data on pharmacokinetics and mechanism of toxicity are presented where data are available. Although many additives are associated with hypersensitivity reactions, including anaphylaxis, these are not discussed because of their nonpharmacologic basis. However, excipients should always be considered as possible causative agents in patients developing hypersensitivity reactions (Table 55–1).

HISTORY AND EPIDEMIOLOGY During the last century there were several US outbreaks of toxicity associated with pharmaceutical additives (Chap. 1). The 1937 Massengill sulfanilamide disaster is the most notorious of these epidemics. Diethylene glycol, an excellent solvent that is a nephrotoxin, was substituted for the additives propylene glycol and glycerin in the liquid formulation of a new sulfanilamide antibiotic because of lower cost.24,58,65 As a result, more than 100 people died from acute renal failure.24 More recently, outbreaks of acute renal failure occurred when diethylene glycol was used to solubilize acetaminophen in South Africa, Bangladesh, Nigeria, and Haiti; cough syrup in Panama; and teething powder in Nigera.19,27,29,67,76,115,126 In December 1983, E-Ferol, a new parenteral vitamin E formulation, was introduced. It contained 25 Units/mL of α-tocopherol acetate, 9% polysorbate 80, 1% polysorbate 20, and water for injection. At the time, no premarketing testing was required for new formulations of an already approved xenobiotic. Several months after its release, a fatal syndrome in low-birth-weight infants, characterized by thrombocytopenia, renal dysfunction, cholestasis, hepatomegaly, and ascites, was described.1,102 Thirty-eight deaths and 43 cases of severe symptoms were attributed to E-Ferol. Vitamin E was thought to be the cause and E-Ferol was recalled from the market 4 months after its release. It is now believed that the polysorbate emulsifiers were responsible.1 There has been concern over potential mercury toxicity from the preservative thimerosal, a mercury derivative that has been used in parenteral vaccines for 70 years. Although there are a few reports of toxicity from both large oral and injectable thimerosal dosages, no evidence has yet shown toxicity to result from routine vaccination. Potential concerns of toxicity, particularly autism, have spurred ongoing efforts to eliminate thimerosal from vaccines wherever possible. Although these additive-related occurrences are rare, relative to the frequency of pharmaceutical additive use, they illustrate the potential of pharmaceutical additive toxicity. Pharmaceuticals are labeled specifically to focus attention on the active ingredient(s) of a product, thus giving the misimpression that additive ingredients are inert and unimportant. Additives, or excipients as they are more properly termed, are necessary to act as vehicles, add color, improve

taste, provide consistency, enhance stability and solubility, and impart antimicrobial properties to medicinal formulations. Although it is true that most cases of excipient toxicity involve exposure to large quantities, or to prolonged or improper use, these adverse events are nonetheless related to the toxicologic properties of the excipient. Prior to selecting the specific additives and quantity necessary for a drug formulation, the drug manufacturer must consider several factors, including the active ingredient’s physical form, its solubility and stability, the desired final dosage form and route of administration, and compatibility with the dispensing container materials. The same active ingredient may require different excipients to impart appropriate pharmacokinetic characteristics to different dosage forms, such as in long-acting and immediate-release formulations. Similarly, multipledose injection vials containing the same active ingredients as singledose vials specifically require the addition of a bacteriostatic agent not necessary for single-dose vials. Unlike requirements for active ingredients, there is no specific US Food and Drug Administration (FDA) approval system for pharmaceutical excipients. As such, the FDA determines the amount and type of data necessary to support the use of a specific excipient on a case-bycase basis. Under current practice, only excipients that were previously permitted for use in foods or pharmaceuticals are defined as generally recognized as safe (GRAS), or “GRAS listed.” All components of a pharmaceutical product, including excipients, must be produced in accordance with current good manufacturing practice standards to ensure purity. The Safety Committee of the International Pharmaceutical Excipients Council developed guidelines for the toxicologic testing of new excipients.150 Because of patent protection laws, it was not until very recently that manufacturers were required to provide a list of inactive ingredients contained in all pharmaceutical products. Although it is becoming easier to identify pharmaceutical additives in products, information on their effects and the mechanisms by which they cause adverse responses are often unknown or difficult to obtain.

BENZALKONIUM CHLORIDE CH3 CH2

N+ R

Cl–

CH3

Benzalkonium chloride (BAC), or alkyldimethyl (phenylmethyl) ammonium chloride, is a quaternary ammonium cationic surfactant composed of a mixture of alkyl benzyl dimethyl ammonium chlorides. Although it is the most widely used ophthalmic preservative in the United States, it is also considered the most cytotoxic (Table 55–2).82,88 Benzalkonium chloride is also used in otic and nasal formulations, and in some small-volume parenterals. The antimicrobial activity of BAC includes gram-positive and gram-negative bacteria, and some viruses, fungi, and protozoa. Because of its rapid onset of action, good tissue penetration, and long duration of action, BAC is preferred over other preservatives. The concentration of BAC in ophthalmic medications usually ranges from 0.004% to 0.01%.88 Strong BAC solutions (greater than 0.1%) can be caustic (Chap. 104).

■ OPHTHALMIC TOXICITY Corneal epithelial cells harvested from human cadavers within 12 hours of death were exposed to a medium containing 0.01% BAC.148 The surfactant properties of BAC resulted in intracellular matrix

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TABLE 55–1. Potential Systemic Toxicity of Various Pharmaceutical Excipients Cardiovascular Chlorobutanol Propylene glycol Fluid and electrolyte Polyethylene glycol Propylene glycol Sorbitol Gastrointestinal Sorbitol Neurologic Benzyl alcohol Chlorobutanol Polyethylene glycol Propylene glycol Thimerosal

Ophthalmic Benzalkonium chloride Chlorobutanol Renal Polyethylene glycol Propylene glycol

dissolution and loss of epithelial superficial layers. Following exposure to the medium, mitotic activity ceased and degenerative changes to corneal epithelium were noted. During a 24-hour observation period, epithelial cell cytokinetic or mitotic activity did not occur. Patients with a compromised corneal epithelium may be at increased risk for the adverse corneal effects of BAC.148

TABLE 55–2. Benzalkonium Chloride Concentrations of Common Ophthalmic Medications Medication

Percent (%)

Artificial tears (various) Acular (ketorolac) Betagan (levobunolol) Betoptic (betaxolol) Ciloxan (ciprofloxacin) Cyclogyl (cyclopentolate) Decadron (dexamethasone) Garamycin (gentamicin) Glaucon (epinephrine) Isopto Carpine (pilocarpine) Murocoll-2 (scopolamine/phenylephrine) Mydriacyl (tropicamide) Phenylephrine (various) Ocuflox (ofloxacin) Ocupress (carteolol) Polytrim (polymyxin B sulfate/trimethoprim) Timoptic (timolol) Tobrex (tobramycin) Visine (tetrahydrozoline)

0.005-0.01 0.01 0.004 0.01 0.006 0.01 0.02 0.01 0.01 0.01 0.01 0.01 0.005-0.01 0.005 0.005 0.004 0.01 0.01 0.01

Two case reports demonstrate the potential toxicity of BAC and the difficulty in recognizing it. A 36-year-old woman complained of decreased vision when she inadvertently switched from Lensrins, a contact lens cleaning solution, to Dacriose, an isotonic boric acid solution preserved with BAC. After 3 days, she had inflammation, pain, and decreased visual acuity. Examination of the cornea revealed many superficial punctate erosions of the epithelium. An in vitro experiment identified significant binding of BAC to soft contact lenses.53 In the second case, a 56-year-old man diagnosed with keratoconjunctivitis sicca was treated with topical antibiotics and artificial tears containing BAC. Following 1 year of continual use, the patient developed intractable pain, photophobia, and extensive breakdown of the corneal epithelium. Not suspecting the BAC-containing products, the patient continued to use the artificial tears solution for another 9 years despite continued pain and decreasing visual acuity. Replacement with a preservative-free saline solution resulted in resolution of pain, photophobia, and corneal changes.88 There was a case series of the inadvertent intraocular use of balanced salt solution (BSS) preserved with BAC instead of preservative-free BSS in 12 patients undergoing phacoemulsification, a surgical technique to remove cataract lenses. The BSS was instilled in the anterior chamber. The operating room had run out of preservative-free BSS and, unbeknownst to the surgeon, it was replaced with the BAC-containing BSS, which contained 0.013% BAC. This is in excess of recommended concentration for intraocular use and is associated with corneal endothelial injury and edema. At 6-months follow-up, only one patient had slight improvement in visual acuity with the other 11 limited to only being able to count fingers from a distance of 2 feet.89

■ NASOPHARYNGEAL AND OROPHARYNGEAL TOXICITY Human adenoidal tissue was exposed to oxymetazoline nasal spray preserved with BAC at concentrations ranging from 0.005 to 0.15 mg/mL for 1 to 30 minutes.14 Irregular and broken epithelial cells occurred with all concentrations; however, it developed earlier and more frequently with the higher concentrations. The number of beating ciliary bodies also decreased as the duration and the concentrations increased. Benzalkonium chloride may decrease the viscosity of the normal protective mucous lining of the naso- and oropharynx, resulting in cytotoxicity. Administration of one of three nasal steroid sprays preserved with either 0.031% or 0.022% BAC in the right nostril of rats twice daily for 21 days caused squamous cell metaplasia and a decrease in the number of goblet cells, cilia, and mucus.15 No histologic changes occurred in rats receiving the preservative-free steroid or in tissue exposed to 0.9% sodium chloride solution administered into the left nostril as the control. Similarly, in another study, epithelial desquamation, inflammation, and edema occurred when 0.05% and 0.10% BAC was applied hourly to the nasal cavities of rats for 8 hours.85 No lesions developed in the nasal cavities of rats receiving 0.01% BAC. In an in vitro study, cultured human nasal epithelial cells were exposed to varying concentrations of BAC compared with another preservative, potassium sorbate (PS), with phosphate-buffered saline (PBS) as a control. Cell viability was greatly reduced at the higher concentrations of BAC compared with no decrease in cell viability in the PS or PBS groups. Additionally, at concentrations used clinically loss of microvilli, destruction of cell membranes, and poor cytoskeletal alignment demonstrated by electron microscope occurred.74 An in vitro study of human nasal mucosa exposed mucosa to either fluticasone or mometasone preserved with either BAC or PS at various concentrations measuring ciliary beat frequency. While PS did not affect ciliary beat frequency at any concentration, BAC adversely affected ciliary beat frequency. At lower concentrations, BAC slowed ciliary beat frequency and brought it to standstill at higher concentrations.75

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BENZYL ALCOHOL

H H

H H

C

C

O OH

Benzyl alcohol

O

O

C

Oxidation

OH

805

Pharmaceutical Additives

OH

C

NH

CH2

C

OH

Conjugation

Benzoic acid

Hippuric acid

FIGURE 55–1. The oxidative metabolism of benzyl alcohol.

Benzyl alcohol (benzene methanol) is a colorless, oily liquid with a faint aromatic odor that is most commonly added to pharmaceuticals as a bacteriostatic agent (Table 55-3). In 1982, a “gasping” syndrome, which included hypotension, bradycardia, gasping respirations, hypotonia, progressive metabolic acidosis, seizures, cardiovascular collapse, and death, was first described in low-birth-weight neonates in intensive care units.20,60,94 All the infants had received either bacteriostatic water or sodium chloride solution containing 0.9% benzyl alcohol to flush intravenous catheters or in parenteral medications reconstituted with bacteriostatic water or saline.20,60 The syndrome occurred in infants who had received greater than 99 mg/kg of benzyl alcohol (range, 99 to 234 mg/kg).60 The World Health Organization (WHO) currently estimates the acceptable daily intake of benzyl alcohol to be not more than 5 mg/kg body weight.22

■ PHARMACOKINETICS In adults, benzyl alcohol is oxidized to benzoic acid, conjugated in the liver with glycine, and excreted in the urine as hippuric acid. The immature metabolic capacities of infants diminish their ability to metabolize and excrete benzyl alcohol.60 Preterm babies have a greater ability to metabolize benzyl alcohol to benzoic acid than do term babies, but

TABLE 55–3. Benzyl Alcohol Concentration of Common Medications

a

Medication

Percent (%)

mL/Average Dosea

Ativan (lorazepam) Bacteriostatic water for injection Bacteriostatic saline for injection Bactrim, Septra (trimethoprimsulfamethoxazole) Bumex (bumetanide) Compazine (prochlorperazine) Cordarone (amiodarone) Lasix (furosemide) Librium (chlordiazepoxide) Methotrexate Norcuron (vecuronium) Tracrium (atracurium) Valium (diazepam) Vasotec (enalapril) VePesid (etoposide) Versed (midazolam) Vistaril (hydroxyzine)

2.0 1.5 1.5 1.0

0.02 — — 0.61b

1.0 0.75 2.0 0.9 1.5 0.9 0.9 0.9 1.5 0.9 3.0 1.0 0.9

0.03 0.01 0.42b 0.04 0.03 0.01 0.01 0.03 0.03 0.01 0.14 0.01 0.01

Based on dosage for a 70-kg person.

b

Based on 24-hour dosage.

are unable to convert benzoic acid to hippuric acid, possibly because of glycine deficiency. This results in the accumulation of benzoic acid (Fig. 55-1).60 A fatal case of metabolic acidosis was reported in a 5-yearold girl who had received 2.4 mg/kg/h diazepam preserved with benzyl alcohol for 36 hours to control status epilepticus. Elevated benzoic acid concentrations were identified in serum and urine samples. The estimated daily dosage of benzyl alcohol was 180 mg/kg.60,90

■ NEUROLOGIC TOXICITY Benzyl alcohol is believed to have a role in the increased frequency of cerebral intraventricular hemorrhages and mortality reported in very-low-birth-weight (VLBW) infants (weight less than 1000 g) who received flush solutions preserved with benzyl alcohol.73 An increased incidence of developmental delay and cerebral palsy was also noted in the same VLBW patients, suggesting a secondary damaging effect of benzyl alcohol.12 There are several case reports of transient paraplegia following the intrathecal or epidural administration of antineoplastics or analgesics containing benzyl alcohol as a preservative.8,37,66,132 The local anesthetic effects are most likely responsible for the immediate paraparesis and limited duration of effects, rather than actual demyelination of nerve roots. In a study in rats, lumbosacral dorsal root action potential amplitudes were measured after exposure to 0.9% or 1.5% benzyl alcohol solutions in either 0.9% sodium chloride solution or distilled water.66 Rats exposed to all benzyl alcohol solutions for less than 1 minute had inhibited dorsal root action potentials. This was attributed to the local anesthetic effects of benzyl alcohol. Nerve function was 50% to 90% restored after rinsing the nerves with 0.9% sodium chloride solution. Chronic intrathecal exposure to benzyl alcohol 0.9% over 7 days resulted in scattered areas of demyelinization and early remyelinization. The 1.5% benzyl alcohol solution–exposed dorsal nerve roots showed greater changes with widespread areas of demyelinization and fatty degeneration of nerve fibers.

CHLOROBUTANOL Cl CH3 Cl

C

C

CH3

Cl OH Chlorobutanol, or chlorbutol (1,1,1-trichloro-2-methyl-2-propanol) is available as volatile, white crystals with an odor of camphor. Chlorobutanol has antibacterial and antifungal properties and is widely used as a preservative in injectable, ophthalmic, otic, and cosmetic preparations at concentrations up to 0.5% (Table 55-4). Chlorobutanol also has mild sedative and local anesthetic properties and was formerly used therapeutically as a sedative-hypnotic.18 Because chlorobutanol is a halogenated hydrocarbon, theoretically it can sensitize the myocardium

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TABLE 55–4. Chlorobutanol Concentrations of Common Medications Medication

Percent (%)

mg/Dose

Adrenaline chloride (epinephrine) injection Aquasol A (vitamin A) Chloroptic (chloramphenicol) ophthalmic solution Dolophine (methadone) injection Epinephrine ophthalmic solution Novocaine (procaine) injection Phospholine iodide (echothiophate iodide) ophthalmic solution Pyridoxine HCl Rhinall (phenylephrine) nasal spray Tobrex (tobramycin) ophthalmic ointment Vasopressin 20 Units/mL injectable

0.5 0.5 0.5

5 5 —

0.5 0.5 0.25 0.55

10 — 87 —

0.5 0.14 0.5 0.5

5 — — 5

to catecholamines, although no cases of ventricular dysrhythmias are described in the literature to date. The lethal human chlorobutanol dose is estimated to be 50 to 500 mg/kg.110

■ CENTRAL NERVOUS SYSTEM TOXICITY Chlorobutanol has a chemical structure similar to trichloroethanol (Fig. 74–1), the active metabolite of chloral hydrate, and is believed to exhibit similar pharmacologic properties. Central nervous system depression was reported in a 40-year-old alcoholic man who chronically abused Seducaps, formerly available in Australia and several other countries, a nonprescription hypnotic containing chlorobutanol as the active ingredient.18 On admission to the emergency department (ED) he had drowsiness, dysarthria, slurred speech, and occasional episodes of myoclonic movements. His peak serum chlorobutanol concentration was 100 μg/mL, decreasing to 48 μg/mL over 2 weeks, with a half-life of 13 days. His speech abnormality resolved over 4 weeks. Only chlorobutanol was detected in the patient’s urine or serum. In a second case, a possible central nervous system depressant effect from chlorobutanol was suggested in a 19-year-old woman treated with high doses of intravenous morphine preserved with chlorobutanol.42 She received approximately 90 mg/h of chlorobutanol for several days. Her peak serum chlorobutanol concentration was 83 μg/mL, a concentration similar to that in the previous case report18; however, the coadministration of morphine precludes the effects being attributed to chlorobutanol alone. Ketamine is neurotoxic when administered intrathecally to animals.99,100 The potential neurotoxic effects of chlorobutanol as a preservative in ketamine compared with preservative-free ketamine was studied in rabbits.100 Forty rabbits were given 0.3 mL intrathecally of 1% preservative-free ketamine, 1% ketamine, 0.05% chlorobutanol, or 1% lidocaine as control. The rabbits were observed and hemodynamically monitored for 8 days then euthanized. Histological evaluation of the spinal cord as well as for blood–brain barrier (BBB) lesions was performed. Seven of 10 rabbits given intrathecal chlorobutanol showed both white and grey matter histologic changes as well as diffuse BBB injury. No histologic changes were seen in either ketamine groups or the lidocaine group, and only one rabbit in each ketamine group had BBB

injury. These results suggest chlorobutanol should not be administered intrathecally.100 A case series of five patients were given intraarterial papaverine preserved with 0.5% chlorobutanol, which is used to prevent cerebral vasospasm in patients with subarachnoid hemorrhage. Immediately after administration of papaverine in either left, right, or bilateral anterior cerebral arteries, patients had an acute decrease in neurologic status. Subsequent brain magnetic resonance images (MRIs) identified selective grey matter toxicity in the territories treated with papaverine. Postmortem brain histology analysis in one patient identified grey matter changes as well. These authors state the absence of white matter changes is not consistent with ischemic infarction but suggest direct toxic effect of either the papaverine or chlorobutanol. The manufacturer of the papaverine stated that no other reports had been made and the papaverine used came from two different lots; therefore, it is unclear if an unidentified independent variable caused these effects, but authors caution using intraarterial papaverine in patients with subarachnoid hemorrhage.137

■ OPHTHALMIC TOXICITY Chlorobutanol is a commonly used preservative in ophthalmic preparations and is less toxic to the eye than benzalkonium chloride.114 Chlorobutanol increases the permeability of cells by impairing cell membrane structure.148 An in vitro experiment using corneal epithelial cells harvested from human cadavers demonstrated arrested mitotic activity following chlorobutanol exposure.148

LIPIDS In general, there are three types of commercial intravenous lipid drug-delivery systems available: lipid emulsion, liposomal, and lipid complex (Table 55-5). Lipid emulsions are immiscible lipid droplets dispersed in an aqueous phase stabilized by an emulsifier (eg, egg or soy lecithin). Liposomes differ from emulsion lipid droplets in that they are vesicles comprised of one or more concentric phospholipid bilayers surrounding an aqueous core. Lipophilic drugs can be formulated for intravenous administration by partitioning them into the lipid phase of either an emulsion or liposome. Liposomes are capable of encapsulating hydrophilic therapeutic agents within their aqueous core to exploit lipid pharmacokinetic properties.144 Attaching a therapeutic drug to a lipid to form a lipid complex is another way to take advantage of lipid pharmacokinetics.

TABLE 55–5. Lipid Carrier Formulations of Common Medications Medication

Lipid Carrier

Propofol (Diprivan) Cytarabine (DepoCyt) Daunorubicin (DaunoXome) Doxorubicin (Doxil) Amphotericin B (AmBisome) Amphotericin B (Abelcet) Amphotericin B (Amphotec)

Emulsion Liposome Liposome Liposome (stealth) Liposome Lipid complex Cholesteryl complex

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Lipid carriers are biocompatible because of their similarity to endogenous cell membranes. They can be used to stabilize labile drugs against hydrolysis or oxidation, to decrease toxicity, and to enhance therapeutic efficacy by altering drug pharmacokinetic and pharmacodynamic parameters. The biodistribution, and the rate of release and metabolism of a drug incorporated in a lipid formulation can be regulated by the type and concentration of oil and emulsifier used, pH, drug concentration dispersed in the medium, the size of the lipid particle, and the manufacturing process.116,144 Intravenous formulations are usually isotonic and have a pH of 7 to 8.144 The rate of clearance of a lipid carrier from the blood depends on its physiochemical properties and the molecular weight of the emulsifier. Electrically charged lipid carriers are removed faster than neutral particles.23,116 Smaller lipid particle size and high-molecularweight emulsifiers decrease clearance. Stealth liposome formulations incorporate a polyethylene glycol coating that prevents rapid detection and clearance of liposomes by the reticuloendothelial system prolonging circulation time.116 Active drug targeting can be achieved by conjugating antibodies or vectors to side chains on the emulsifier.23,116 For a therapeutic drug available in more than one lipid-carrier formulation (eg, amphotericin B) it is important to note that any change in the lipid formulation can alter the drug’s pharmacokinetic, pharmacodynamic, and safety parameters; consequently, they are not equivalent dosage formulations (see Chap. 56). The physiochemical properties of lipid emulsions not only affect the therapeutic drugs carried by them, but the lipids themselves may also have direct pharmacologic effects on the central nervous159 and immune systems.87 Lipid fatty acid mediators can affect the membrane receptor channels of N-methyl-D-aspartate (NMDA) receptors, potentiating synaptic transmission. This is supported by one animal103 and several in vitro104,119,147 studies. Dogs given a medium-chain triglyceride emulsion intravenous infusion developed dose-related central nervous system metabolic and neurologic effects, accompanied by electroencephalographic changes consistent with encephalopathy observed when serum octanoate concentration reached 0.5 to 0.9 mM.103 In an in vitro model, three of nine lipid emulsions tested (Abbolipid, 20% soya and safflower oil; Intralipid, 20% soya oil; and Structolipid, 20% structured triglycerides) demonstrated a doserelated activation of cortical neuronal NMDA receptor channels.159 The lipid source for all but one (Omegaven, 10% fish oil) of the emulsions tested was made up solely or partially by soya oil. The authors could not explain why the other six lipid emulsions did not induce membrane currents. Adequate control for the nonlipid constituent contribution of these emulsions is lacking. In another in vitro study, the same authors found that NMDA-induced neuronal currents are reduced by an unknown factor in the aqueous portion of Abbolipid.160 This suggests that lipid emulsions may pharmacologically enhance the anesthetic effect of hypnotics such as propofol. The clinical relevance of these studies remains to be assessed. Triglycerides in parenteral nutrition emulsions are implicated in altering the immune system, leading to an increased susceptibility to infection,52,157 and altering lung function and hemodynamics in patients with acute respiratory distress syndrome (ARDS).87 Phospholipid activation of phospholipase A2 may be an initiating cause.52,87,157 However, it is not clear if these immunologic effects are a consequence of factors other than the lipid in the emulsion. More recently, lipid emulsions have been employed in the treatment of poisonings in both animal models and human case reports (see Antidotes in Depth A 21:Intravenous Fat Emulsion).10,118,136 Although no toxicity has been reported in these cases, all of the patients were seriously ill and any adverse effects may have been attributed to their primary exposures.

807

Pharmaceutical Additives

PARABENS O C

O

CH3

OH Methylparaben The parabens, or parahydroxybenzoic acids, are a group of compounds widely employed as preservatives in cosmetics, food, and pharmaceuticals because of their bacteriostatic, fungistatic, and antioxidant properties (Table 55-6).133 A survey conducted by the FDA identified the parabens as the second most common ingredients in cosmetic formulations, with water being the most common.91 Parabens are often used in combination, because the presence of two or more parabens are synergistic.91 Methylparabens and propylparabens are most commonly used.133 Pharmaceutical parabens concentrations usually range from 0.1% to 0.3%.127 Widespread usage of parabens since the 1920s has shown that they have a relatively low order of toxicity.91 However, because of their allergenic potential they are currently considered less suitable for injectable and ophthalmic preparations.127 Based on long-term animal studies, the WHO has set the total acceptable daily intake of ethyl-, methyl-, and propylparabens to be 10 mg/kg body weight.127 In addition to allergic reactions, parabens have the potential to cause other adverse effects. Bilirubin displacement from albumin binding sites occurred with administration of methyl- and propylparabens preserved gentamicin when serum parabens concentrations were 3 to 15 μg/mL.39

TABLE 55–6. Paraben Concentrations of Common Medications

a

Medication

Percent (%)

mg/Dose

Aldomet (methyldopa) injection Brofed (pseudoephedrine/ brompheniramine) elixir Bupivicaine HCl 0.25% injectiona Haldol (haloperidol) injection Inapsine (droperidol) injection Isopto Cetamide (sulfacetamide) ophthalmic solution Narcan (naloxone) injection Oncovin (vincristine) injection Prolixin HCl (fluphenazine) injection Prostigmin (neostigmine) injection Romazicon (flumazenil) injection Talwin (pentazocine) injection Trandate (labetalol) injection Xylocaine (lidocaine) injection Zofran (ondansetron) injection

0.17 0.2

8 20

0.1 0.2 0.2 0.06

— 2 2 —

0.2 0.15 0.11 0.2 0.2 0.1 0.09 0.1 0.14

2 4 1 2 4 1 4 — 3

Amount varies depending on volume used (contains 1mg/mL paraben)

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Gentamicin alone has no effect on bilirubin displacement.92 Spermicidal activity was demonstrated in an in vitro study of human semen specimens exposed to local parabens concentrations of 1 to 8 mg/mL.141 Possible interference with conception and potential adverse effects on fertility were not investigated. More recently concern has arisen regarding the potential estrogenic and antiandrogenic effects of the parabens and their common metabolite, p-hydroxybenzoic acid. Substances with these effects are commonly referred to as endocrine disrupting substances. However, the clinical significance of these effects has not been elucidated.31,40,124,125,153

PHENOL OH

a similar case, multifocal premature ventricular contractions (PVCs) were observed in a 10-year-old boy after application of a chemical peeling solution of 40% phenol, 0.8% croton oil in hexachlorophene soap, and water for the treatment of a giant hairy nevus.158 The PVCs were refractory to intravenous lidocaine but resolved with intravenous bretylium. No phenol concentrations were obtained to confirm systemic absorption. Drowsiness, respiratory depression, and blue-colored urine were noted in a 6-month-old infant 12 hours after topical application of magenta paint over most of the body for seborrheic eczema.129 Magenta paint (also known as Castellani paint) was widely used for seborrheic eczema and contained 4% phenol, magenta, boric acid, resorcinol, acetone, and methylated spirit. Further investigation found that phenol was detected in urine samples of four of 16 other infants with seborrheic eczema who had approximately 11% to 15% of their body surface area painted with magenta paint for 2 days.

POLYETHYLENE GLYCOL Phenol (carbolic acid, hydroxybenzene, phenylic acid, phenylic alcohol) is a commonly used preservative in injectable medications (Table 55-7). Phenol is a colorless to light pink, caustic liquid with a characteristic odor. When exposed to air and light, phenol turns a red or brown color.36 Phenol exerts antimicrobial activity against a wide variety of microorganisms, such as gram-negative and grampositive bacteria, mycobacteria, and some fungi and viruses.36 Phenol is well absorbed from the gastrointestinal tract, skin, and mucous membranes, and is excreted in the urine as phenyl glucuronide and phenyl sulfate metabolites.36 Although there are numerous reports of phenol toxicity following intentional ingestions or unintentional dermal exposures (Chap. 104), adverse reactions to its use as a pharmaceutical excipient are uncommon, most likely because of the small quantities used.36

■ CUTANEOUS ABSORPTION Systemic toxicity from cutaneous absorption of phenol is reported. Ventricular tachycardia was observed in an 11-year-old boy following application of a chemical peel solution containing 88% phenol in water and liquid soap. The solution was applied to 15% of his body surface area for the treatment of xeroderma pigmentosum. Immediately following the onset of the ventricular tachycardia, the phenol-treated areas were irrigated, an infusion of 0.9% sodium chloride solution was begun, and two intravenous lidocaine boluses were given followed by a lidocaine infusion. The dysrhythmia persisted for 3 hours. The urinary phenol concentration the following day was 58.9 mg/dL.151 In

Polyethylene glycols (PEGs, Carbowax, Macrogol) include several compounds with varying molecular weights (MWs) (200 to 40,000 D).123 They are typically available as mixtures designated by a number denoting their average molecular weight. Polyethylene glycols are stable, hydrophilic substances, making them useful excipients for cosmetics, and pharmaceuticals of all routes of administration (Table 55-8). Pegylation, a process that modifies the pharmacokinetics of therapeutic liposomes and proteins (eg, peginterferon-α), is the most recent application of PEG. At room temperature, PEGs with molecular weights less than 600 are clear, viscous liquids with a slight characteristic odor and bitter taste. PEGs with molecular weights greater than 1000 are soluble solids and range in consistency from pastes and waxy flakes to powders.123 Commercially available products used for bowel cleansing preparations and whole bowel irrigation are solutions of PEG 3350 that are sometimes combined with electrolytes and known as polyethylene glycol electrolyte lavage solutions (PEG-ELS) (see Antidotes in Depth A3: Whole Bowel Irrigation and Other Intestinal Evacuants). The solid, high-molecular-weight PEGs are essentially nontoxic. Conversely, low-molecular-weight PEG exposures have caused adverse effects similar to the chemically related toxic alcohols ethylene and diethylene glycol27 (see Special Considerations SC5: Diethylene Glycol).

TABLE 55–8. Common Medications Containing Polyethylene Glycol (PEG)

TABLE 55–7. Phenol Concentration of Common Medications Medication

Percent (%)

mg/Dose

Antivenom (Crotaline) Antivenom (Micrurus fulvius) Dryvax (smallpox) vaccine Pneumovax 23 (pneumococcal) vaccine Prostigmin (neostigmine) injection Quinidine gluconate injection

0.25 0.25 0.25 0.25

25 (per vial) 25 (per vial) 2.5 1.25

0.45 0.25

4.5 18.75

Medication Chloroptic (chloramphenicol) ointment Furacin (nitrofurazone) ointment VePesid (etoposide) injection Ativan (lorazepam) injection Decadron (dexamethasone) ophthalmic ointment Depo-Provera (medroxyprogesterone) Polyethylene glycol electrolyte solution Peginterferon alfa-2a (PEGASYS)

PEG Molecular Weight (Daltons) 300 300 300 400 400 3350 3350 40,000

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■ PHARMACOKINETICS High-molecular-weight PEGs (greater than 1000) are not significantly absorbed from the gastrointestinal tract, but low-molecular-weight PEGs may be absorbed when taken orally.44,138,139 Topical absorption can occur when PEGs are applied to damaged skin.21,145 The pharmacokinetics of intravenously administered PEG 3350 has not been studied; however, it did not appear to have any systemic effects when unintentionally given by this route.128 Once in the systemic circulation, PEGs are mainly excreted unchanged in the urine44; however, low-molecular-weight PEGs are metabolized by alcohol dehydrogenase to hydroxyacid and diacid metabolites. PEG may also be partially broken down to ethylene glycol, although the clinical consequence of this is unknown.21,146

■ NEPHROTOXICITY In rats fed various PEGs (200, 300, and 400) in their drinking water for 90 days, a solution of 8% PEG 200 produced renal tubular necrosis in all of the animals, followed by death within 15 days; however, a 4% PEG 200 solution resulted in only two of nine rats dying within 80 days. A 16% PEG 400 solution killed all animals within 13 days; however, both 8% and 4% PEG 400 solutions had no observable effect except for a decrease in kidney weight when compared to control animals.140 Acute tubular necrosis with oliguria, azotemia, and high anion gap metabolic acidosis has been reported after oral and topical exposures to low-molecular-weight PEGs (200 and 300). Acute renal failure occurred in a 65-year-old man with a history of alcohol abuse and seizure disorder after ingestion of the contents of a lava lamp containing 13% PEG 200.45 Forty-eight hours after admission (approximately 50 to 72 hours postingestion), the patient became oliguric with an anion gap metabolic acidosis and acute renal failure. Blood sample analysis confirmed traces of the lava lamp fluid; no traces were detected in the urine. After clinical complications from ethanol withdrawal and aspiration pneumonitis, the patient was discharged 3 months later with residual kidney dysfunction attributed to the PEG component of the lamp contents. Acute tubular necrosis was noted on autopsy of six burn patients treated with a topical antibiotic cream in a PEG 300 base.21,145 Mass spectrometry detected hydroxyacid and diacid metabolites in serum and urine samples. Oxalate crystals were seen in two cases. These effects were reproduced with the topical application of PEG for 7 days to rabbits with full-thickness skin defects.145

theorized that PEG increases osmolality by sequestering water through hydrogen binding, reducing the availability of water to interact with solutes, thus increasing the chemical and osmotic activity of the solute. Hyperosmolality following the administration of a PEG-containing substance may suggest systemic PEG absorption. Two cases of metabolic acidosis were reported following administration of therapeutic dosages of an intravenous nitrofurantoin solution containing PEG 300.146 Similarly, an otherwise unexplained increased anion gap was reported in three patients being treated with a topical PEG-based burn cream.21 Metabolism of PEG by alcohol dehydrogenase to hydroxyacid and diacid metabolites can explain the metabolic acidosis.70

PROPYLENE GLYCOL OH

OH

CH2 CH CH3 Propylene glycol (PG), or 1,2-propanediol, is a clear, colorless, odorless, sweet, viscous liquid employed in numerous pharmaceuticals (Table 55-9), foods, and cosmetics. Propylene glycol is used as a solvent and preservative with antiseptic properties similar to ethanol. The WHO has set the daily allowable intake of PG at a maximum of 25 mg/kg,161 or 17.5 g/d for a 70-kg person.

■ PHARMACOKINETICS Propylene glycol is rapidly absorbed from the gastrointestinal (GI) tract following oral administration and has a volume of distribution of approximately 0.6 L/kg.101,142 When applied to intact epidermis, the absorption of PG is minimal. Percutaneous absorption may occur following application to damaged skin (eg, extensive burn surface areas). Approximately 12% to 45% of PG is excreted unchanged in

TABLE 55–9. Propylene Glycol Concentration of Common Medications

■ NEUROTOXICITY There are reports of neurologic complications, such as paraplegia and transient bladder paralysis, following intrathecal steroidal injections containing 3% PEG as a vehicle.13,17 In an in vitro experiment, rabbit vagus nerves were exposed to concentrations of PEG 3350 ranging from 3% to 40% for 1 hour.13 Three percent and 10% PEG had no effect on nerve action potential amplitude or conduction velocity. Twenty percent and 30% PEG significantly slowed nerve conduction and had varying effects on the amplitudes of action potentials. Forty percent PEG completely abolished action potentials. These changes were reversible and thought to be related to PEG-induced osmotic effects.

■ FLUID, ELECTROLYTE, AND ACID–BASE DISTURBANCES Hyperosmolality was reported in three patients with burn surface areas ranging from 20% to 56% following repeated applications of Furacin, a topical antibiotic dressing containing 63% PEG 300, 32% PEG 4000, and 5% PEG 1000.21 Polyethylene glycol produces an osmotic effect that is greater than expected for its molecular weight.134 It is

809

Pharmaceutical Additives

a

Medication

Percent (%)

Grams (g)/ Average Dosea

Agenerase (amprenavir) oral solution Amidate (etomidate) Ativan (lorazepam) injection Bactrim, Septra (trimethoprimsulfamethoxazole) injection Brevibloc (esmolol) injection Dilantin (phenytoin) injection Lanoxin (digoxin) injection Librium (chlordiazepoxide) injection Luminal (phenobarbital sodium) injection MVI-12 (multivitamins) injection Nembutal (pentobarbital) Tridil (nitroglycerin) injection Valium (diazepam) injection

55

57.75

35 80 40

3.6 0.64 10.0b

25 40 40 20 67.8 30 40 30 40

2.5 4.8 0.4 0.08 0.7 0.45 1.2 0.3 0.4

Based on dosage for 70-kg person.

b

Based on 24-hour dosage.

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the urine43; the remainder is hepatically metabolized sequentially by alcohol dehydrogenase to lactaldehyde, which is metabolized further by aldehyde dehydrogenase to lactic acid. Lactic acid is also formed by another metabolite, methylglyoxal.113 Lactic acid may be additionally oxidized to pyruvic acid and then to carbon dioxide and water.113 The terminal half-life of propylene glycol is reported to be between 1.4 and 5.6 hours in adults, and as long as 16.9 hours in neonates.43,144

■ CARDIOVASCULAR TOXICITY Intravenous preparations of phenytoin contain 40% PG to facilitate the solubility of phenytoin. Nine years after intravenous phenytoin became available, several deaths were attributed to the rapid administration of phenytoin used for the treatment of cardiac dysrhythmias.59,149,171 Cardiovascular effects reported in these cases included hypotension, bradycardia, widening of the QRS interval, increased amplitude of T waves with occasional inversions, and transient ST elevations. Studies in cats93 and calves63 confirmed PG as the cardiotoxin. Bradycardia and depression of atrial conduction were not observed in cats pretreated with atropine, or in those with vagotomy following rapid intravenous infusion of PG, suggesting that these effects are vagally mediated.93 Amplification of the QRS complex was noted in these same pretreated cats, also suggesting a direct cardiotoxic effect of PG. Similar results were reported in calves pretreated with atropine that received oxytetracycline in a PG vehicle.63

■ NEUROTOXICITY Smaller infants appear to have a decreased ability to clear PG when compared with older children and adults.94 An increased frequency of seizures was reported in low-birth-weight infants who received PG 3 g daily in a parenteral multivitamin preparation.94 Seizures developed in an 11-year-old boy receiving long-term oral therapy with vitamin D dissolved in PG.6 Serum calcium, magnesium, electrolytes, and blood glucose were normal. Seizures abated after the product was discontinued. Propylene glycol possesses inebriating properties similar to ethanol. Central nervous system depression was reported following an intentional oral ingestion of a PG-containing product.101 A black-box warning was added to the product information for amprenavir (Agenerase), an oral protease inhibitor solution, because of concerns over its high PG (550 mg/mL) vehicle content.131 The recommended daily dosage of amprenavir supplies 1650 mg/kg/d of PG. A 61-year-old man experienced visual hallucinations, disorientation, tinnitus, and vertigo after receiving a 750-mg dose (474 mg/kg PG) of amprenavir solution.80

■ OTOTOXICITY Otic preparations can contain up to 94% PG in solutions and 10% in suspensions as part of their vehicles.48 In animal studies, application of high concentrations of PG (greater than 10%) to the middle ear can produce hearing impairment106,107,155 and morphologic changes, including tympanic membrane perforation, middle ear adhesions, and cholesteatoma.106,154,166 Although the effects of PG in the human middle ear have not been studied, all medications applied to the external ear canal are contraindicated in patients with perforated tympanic membranes.

■ FLUID, ELECTROLYTE, AND ACID–BASE DISTURBANCES Patients receiving continuous or large intermittent quantities of medications containing PG can develop high PG concentrations, particularly those with renal or hepatic insufficiency.26,43 Propylene glycol electrolyte and metabolic disturbances are evidenced by hyperosmolarity, and

an elevated osmolar gap attributed to the osmotically active properties of PG. In most cases, an elevated anion gap, with an otherwise unexplained elevated lactate concentration, is also present. Metabolic acidosis and hyperlactatemia produced from PG metabolism.25 These adverse effects have been reported with intravenous preparations such as lorazepam,5,168 diazepam,162 etomidate,152 nitroglycerin,43 pediatric multivitamins,61 and topical silver sulfadiazine.11,49,84 Systemic absorption of PG from topical application of silver sulfadiazine cream49 resulted in hyperosmolality in patients with burn surface areas greater than 35% of their body.11,49,84 In one study, nine of 15 burn patients had osmolar gaps (greater than 12) after application of the cream.84 Hyperosmolarity occurred in five infants receiving a parenteral multivitamin that provided a daily PG dose of 3 g.61 After 12 days, one premature infant had a PG concentration of 930 mg/dL and an osmolar gap of 136. Anion gap and lactic acid concentrations were normal. In a study of 11 intubated pediatric patients, aged 1 to 15 months, who were receiving continuous lorazepam infusions over 3 to 14 days, accumulated serum PG concentrations of 17 to 226 mg/dL did not result in significant increases in osmolar gap or serum lactate concentrations from baseline.32 This was attributed to normal renal function and the low cumulative PG doses received (mean 60 g). Several small studies have found a strong correlation between elevated PG concentrations and increased osmolar gap measurements in critically ill patients receiving intravenous lorazepam and/ or diazepam.5,163,167,168 An osmolar gap greater than 10 has been suggested as a marker for potential PG toxicity and also indicates when to consider obtaining a serum PG concentration.167 An osmolar gap of 20 corresponds to a serum PG concentration of approximately 48 mg/ dL.5 This equation should be used cautiously, as larger, more comprehensive studies are needed to validate it. There are rare cases where PG accumulation did not result in an osmolar gap.62,168 In addition, elevated anion gap measurements and lactate concentrations are seen. As PG toxicity can mimic sepsis in these critically ill patients, sepsis should always be considered as the potential etiology of increased lactate, hypotension, and worsening renal function when considering PG toxicity. Both hemodialysis and fomepizole have been used to treat PG toxicity.117,170

■ NEPHROTOXICITY Human proximal tubular cells exposed in vitro to PG concentrations of 500 to 2000 mg/dL exhibited significant cellular injury and membrane damage within 15 minutes of exposure.109 Repeated exposure for up to 6 days produced dose-dependent toxic effects at lower concentrations (76, 190, and 380 mg/dL).108 The chronic administration of PG may contribute to proximal tubular cell damage and subsequent decreased renal function. In a retrospective study of eight patients who developed elevations in serum creatinine concentration while receiving continuous lorazepam infusions, serum creatinine rose within 3 to 60 days (median, 9 days).168 The magnitude of serum creatinine rise was found to correlate with the serum PG concentration and duration of infusion. Serum creatinine decreased within 3 days of discontinuing the infusion. Patients with renal dysfunction are at greater risk for accumulating PG because 45% of PG is eliminated unchanged by the kidneys43; the remainder is metabolized by the liver. Caution should be used when prolonged administration of a PG-containing medication is necessary in the presence of renal or hepatic dysfunction.109 Propylene glycol-induced renal tubular necrosis has been reported in several cases. Daily PG-vehicle dosages of 11 to 90 g/d over 14 days was associated with rising serum creatinine concentrations (from 0.7 mg/dL to 2.1 mg/dL), elevated serum lactate concentrations,

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Chapter 55

osmolar and anion gaps, and a serum PG concentration of 21 mg/dL.169 Urine sediment analysis revealed numerous granular, muddy-browncolored casts and no eosinophils, suggesting an acute renal tubular necrosis. A renal biopsy and electron microscopy showed extensive dilation of the proximal renal tubules, with swollen epithelial cells and mitochondria. Numerous vacuoles containing debris were also noted. A renal biopsy of another case with a serum PG concentration of 30 mg/dL showed disrupted brush borders of the proximal renal tubules after a sudden rise in serum creatinine concentration (3.1 mg/dL), nonoliguric renal failure, and metabolic acidosis. This was attributed to an average daily PG dose of 70 g for 17 days.68

SORBITOL CH2OH HC HO

OH

CH HC

OH

HC

OH

CH2OH Sorbitol (D-glucitol) is widely used in the pharmaceutical industry as a sweetening agent, moistening agent, and a diluent (Table 55-10). Sorbitol occurs naturally in the ripe berries of many fruits, trees, and plants, and was first isolated in 1872 from the berries of the European mountain ash (Sorbus aucuparia).111 It is particularly useful in chewable tablets because of its pleasant taste. In addition, it is widely used by the food industry in chewing gums, dietetic candies, foods, and enteral nutrition formulations. Sorbitol is approximately 50% to 60% as sweet as sucrose.111

TABLE 55–10. Common Medications Containing Sorbitol Medication

Percent (%)

Grams (g)/Dose

Aluminum hydroxide/ magnesium hydroxide Brofed elixir (brompheniramine and pseudoephedrine) Calcium carbonate suspension Chloral hydrate syrup Fer-In-Sol drops (ferrous sulfate) Guaifenisin/dextromethorphan syrup Lanoxin (digoxin) elixir Lasix (furosemide) solution Methadone HCl solution Potassium chloride solution Sudafed (pseudoephedrine) syrup Symmetrel syrup (amantadine HCI) Tagamet (cimetidine) syrup Tegretol (carbamazepine) syrup Triaminic syrup (chlorpheniramine and pseudoephedrine)

10

3

20

2

28 40 31 64 21 35 14 17.5 35 64 46 17 7

1.4 2 0.2 6.4 0.1 1.75 5.6 1.35 1.75 6.4 2.3 0.85 0.7

Pharmaceutical Additives

811

■ PHARMACOKINETICS Unlike sucrose, sorbitol is not readily fermented by oral microorganisms and is poorly absorbed from the gastrointestinal tract. Any absorbed sorbitol is metabolized in the liver to fructose and glucose.111 Sorbitol has a caloric value of 4 kcal/g and is better tolerated by diabetics than sucrose; however, because some of it is metabolized to glucose, it is not unconditionally safe for diabetics.111 There is a concern of potentially fatal toxicity for individuals with hereditary fructose intolerance (HFI) receiving sorbitol-containing xenobiotics.50 HFI is an autosomal recessive disorder caused by a deficiency of fructose-1,6-bisphosphonate aldolase in the liver, kidney, cortex, and small intestine.81 This results in the accumulation of fructose-1-phosphate, which prevents glycogen breakdown and glucose synthesis causing hypoglycemia. The prevalence of HFI is most commonly reported to be one in 20,000 persons, but can range between one in 11,000 and one in 100,000.2,79,81 In individuals with HFI, the prolonged administration of sorbitol, fructose, or sucrose can result in death from liver or renal failure.35,135 Dietary exclusion of fructose, sucrose, and sorbitol prevents the adverse effects. This condition should not be confused with the more common disorder of dietary fructose intolerance (DFI), which is caused by a defect in the glucose-transport protein 5 (GLUT5) system. This leads to the breakdown of fructose to carbon dioxide, hydrogen, and shortchain fatty acids by colonic bacteria, resulting in abdominal pain and bloating.86 Dietary fructose intolerance symptoms are minimized by limiting sorbitol, fructose, and sucrose in the diet.

■ GASTROINTESTINAL TOXICITY In large dosages, sorbitol can cause abdominal cramping, bloating, flatulence, vomiting, and diarrhea. Sorbitol exerts its cathartic effects by its osmotic properties, resulting in fluid shifts within the gastrointestinal tract. Iatrogenic osmotic diarrhea is reported following administration of many different liquid medication formulations containing sorbitol.72,95 In a human volunteer study, 42 healthy adults ingested 10 g of a sorbitol solution. Sorbitol intolerance was detected in up to 55% of subjects.78 One theoretical explanation for why all subjects did not experience the gastrointestinal adverse effects is unrecognized DFI. Diarrhea resulting from sorbitol-containing medications is common and often overlooked as a possible etiology.30,69 Ingestion of large quantities of sorbitol (more than 20 g/d in adults) is not recommended (see Antidotes in Depth A3: Whole-Bowel Irrigation and Other Intestinal Evacuants).111

THIMEROSAL COO– Na+ S

Hg

CH2

CH3

Thimerosal (Merthiolate, Mercurothiolate), or sodium ethylmercurithiosalicylate, is an organic mercury compound that is approximately 49% elemental mercury (Hg) by weight.130,156 It is metabolized to ethylmercury and thiosalicylate. Thimerosal has a wide spectrum of antibacterial activity at concentrations ranging from 0.01% to 0.1%; however, higher concentrations are sometimes also used.83,105 Thimerosal has been widely used as a preservative since the 1930s in contact lens solutions, biologics, and vaccines, particularly those in multidose containers (Table 55-11). The use of thimerosal, which is necessary for the production process of some vaccines (eg, pertussis, influenza), may leave

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TABLE 55–11. Thimerosal Concentration of Common Medications Medication Injectable Antivenom (Crotaline polyvalent immune) Fab Antivenom (Lactrodectus mactans) Antivenom (Micrurus fulvius) Diphtheria and tetanus toxoidsa DTaP (all products) Fluzonea (influenza virus vaccine) HibTITER (Haemophilus B conjugate vaccine)a Menomune-A/C/Y/W-135a (meningococcal vaccine) Tetanus toxoid (adsorbed) Topical Mersol (thimerosal tincture) Neosporin (triple antibiotic) ophthalmic solution Ocufen (flurbiprofen) ophthalmic solution Sulf-10 (sulfacetamide) ophthalmic solution

Percent (%)

Milligrams (mg)/Dose

0.001

0.11 (per vial)

0.01

0.25 (per vial)

0.005 0.01 0.01 0.01

0.5 (per vial) 0.05 0.05 0.025

0.01

0.05

0.01

0.05

0.01

0.05

0.1 0.001

— —

0.005

—

0.01

—

a

Multidose.

trace amounts in the final product.9 High-dose thimerosal exposure has resulted in neurotoxicity and nephrotoxicity. Although concerns exist regarding infant exposure to low-dose thimerosal through vaccinations and its effects on neurodevelopment, including possible links to causes of autism,16 these concerns have never been substantiated (see Chap. 96).41 Because specific guidelines for ethylmercury exposure have not been developed, regulatory guidelines for dietary methylmercury exposure were applied to monitor ethylmercury exposure from injected thimerosal-containing vaccines. Methylmercury is a similar, but more toxic, organic mercury compound (Chap. 96). Maximum daily recommended methylmercury exposures range from 0.1 μg Hg/kg (US Environmental Protection Agency [EPA]) to 0.47 μg Hg/kg (WHO).3,29,34 An FDA review of thimerosal-containing vaccines revealed that some infants, depending on the immunization schedule, vaccine formulations, and infant’s weight, might be exceeding the EPA exposure limit of 0.1 μg Hg/kg/d for methylmercury. Over the first 6 months of life, a total cumulative dose of up to 187.5 μg Hg total from thimerosalcontaining vaccines was possible. The US Public Health Service (USPHS) and the American Academy of Pediatrics (AAP) responded jointly by recommending the preemptive reduction or removal of thimerosal from vaccines wherever possible.3,28 The WHO and European regulatory bodies have made similar recommendations.51 To date, thimerosal has been removed from most US-licensed immunoglobulin products. All vaccines routinely recommended for children younger than 7 years of age are either thimerosal-free or contain only trace amounts (less than 0.5 μg Hg per dose), with the exception of some inactivated

influenza vaccines. Multidose vials requiring thimerosal preservative remain important for immunization programs in developing countries. Although efforts continue to eliminate all sources of mercury exposure, complete elimination of thimerosal from all vaccines is unlikely in the near future.9 When a thimerosal-containing vaccine is the only alternative, the benefits of vaccination far exceed any theoretical risk of mercury toxicity.112 Prior to thimerosal use in pharmaceuticals, evidence for its safety and effectiveness was provided in several animal species and in 22 humans.122 Only limited data exist on infant mercury exposure from thimerosal-containing vaccines. Clinical studies that assess the effects of thimerosal exposure on neurodevelopment and renal and immunologic function are lacking. Based on a comprehensive review of epidemiologic data from the United States,33,54-57,156 Denmark,77,96 Sweden,143 and the United Kingdom,4,71 the Institute of Medicine’s (IOM’s) Immunization Safety Review Committee,112 the Global Advisory Committee on Vaccine Safety (GACVS),165 and the European Agency for the Evaluation of Medicinal Products (EMEA)46 have all concluded that there is no causal relationship between thimerosal-containing vaccines and autism. Continued surveillance of autistic spectrum disorders as thimerosal use declines will be conducted to evaluate any associated trends.

PHARMACOKINETICS Limited pharmacokinetic data exist for thimerosal and ethylmercury. Once absorbed, thimerosal breaks down to form ethylmercury and thiosalicylate. Some ethylmercury further decomposes into inorganic mercury in the blood, and the remainder distributes into kidney and, to a lesser extent, brain tissue.97,98 Because of its longer organic chain, ethylmercury is less stable and decomposes more rapidly than methylmercury, leaving less ethylmercury available to enter kidney and brain tissue.97 Ethylmercury crosses the blood–brain barrier by passive diffusion.98 Intracellular ethylmercury decomposes to inorganic mercury, which accumulates in kidney and brain tissues.98 The half-life of thimerosal is estimated to be about 18 days.99 Thimerosal is eliminated in the feces as inorganic mercury (see Chap. 96).121

MERCURIAL TOXICITY Oral Administration A case report described a 44-year-old man who ingested 5 g (83 mg/kg) of thimerosal in a suicide attempt; within 15 minutes he began vomiting spontaneously. Gastric lavage was performed and chelation therapy begun with dimercaptopropane sulfonate (DMPS). Gastroscopy revealed a hemorrhagic gastritis. Polyuric acute renal failure was noted on the day of admission and persisted for 40 days. Four days after admission the patient developed a fever and a maculopapular exanthem attributed to thimerosal. The patient also developed an autonomic and ascending peripheral polyneuropathy that persisted for 13 days. Chelation therapy was continued for a total of 50 days with DMPS followed by succimer. Elevated blood and urine mercury concentration persisted for more than 140 days. The patient was discharged 148 days following the ingestion with only sensory defects in his toes. No other neurologic sequelae were noted.120 Oral absorption of thimerosal resulted in the fatal poisoning of an 18-month-old girl from the intra-otic instillation of a solution containing 0.1% thimerosal and 0.14% sodium borate. Tympanostomy tubes placed 1 year earlier allowed the irrigation solution to flow through the auditory tube into the nasopharynx, and subsequently to be swallowed and absorbed through the oral mucosa and gastrointestinal tract. A total of 1.2 L of solution (500 mg Hg) was instilled over

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a 4-week period, resulting in severe mercury poisoning. Four days after admission, the serum mercury concentration was 163 μg/dL. The patient also received 1.7 g of boric acid. It is unclear what contribution, if any, the boric acid made to the serum mercury concentration. Chelation therapy with N-acetyl-d-penicillamine was initiated on day 51. Despite increased urinary mercury concentrations following administration of the N-acetyl-d-penicillamine, her neurologic function and blood mercury concentrations remained unchanged. The child died 3 months after admission. An autopsy was not performed.130 Intramuscular Administration Urine mercury concentrations of 26 patients with hypogammaglobulinemia, who received weekly intramuscular IgG replacement therapy preserved with 0.01% thimerosal were studied. The dosages of IgG ranged from 25 to 50 mg/kg, containing 0.6 to 1.2 mg of mercury per dose.64 The total estimated dose of mercury administered ranged from 4 to 734 mg over a period of 6 months to 17 years. Urine mercury concentrations were elevated in 19 patients, ranging from 31 to 75 μg/L; however, no patients had clinical evidence of chronic mercury toxicity.64 Six cases of severe mercury poisoning resulting in four deaths were reported following the intramuscular administration of chloramphenicol preserved with thimerosal. A manufacturing error produced vials containing 510 mg of thimerosal (250 mg Hg) instead of 0.51 mg per vial. Two adults received 4 g and 5.5 g of mercury each and four children received 0.2 to 1.8 g each. All six patients had extensive tissue necrosis at the site of injection. Fever, altered mental status, slurred speech, and ataxia were noted. Autopsy identified widespread degeneration and necrosis of the renal tubules; however, creatine kinase concentrations were not reported, so pigment-induced nephrotoxicity cannot be excluded. Elevated mercury concentrations were found in the injection site tissues, and in the kidneys, livers, and brains.7 Topical Administration Thirteen infants were exposed to 9 to 48 topical applications of a 0.1% thimerosal tincture for the treatment of exomphalos. Analysis for elevated mercury concentrations was performed in 10 of 13 infants who unexpectedly died. Mercury concentrations were determined in various tissues from six of the infants. Mean tissue concentrations in fresh samples of liver, kidney, spleen, and heart ranged from 5152 to 11,330 ppb, suggesting percutaneous absorption from these repeated topical applications.47 Ophthalmic Administration Nine patients undergoing keratoplasty were exposed to a contact lens stored in a solution containing 0.002% thimerosal.164 After 4 hours, the lens was removed and mercury concentrations of the aqueous humor and excised corneal tissues were determined. Mercury concentrations were elevated in both aqueous humor (range, 20 to 46 ng/mL higher) and corneal tissues (range, 0.6 to 14 ng higher) as compared with eyes that had not been fitted with contact lenses. Only residual amounts of mercury remained on the contact lenses after 4 hours of wear. The authors noted that although the aqueous humor concentrations were in the same range as those measured in 10 patients with vision loss from systemic mercury poisoning (11 to 104 ng/mL), adverse effects did not occur. A possible drug interaction between orally administered tetracyclines and thimerosal was reported to result in acute, varying degrees of eye irritation in contact lens wearers using thimerosal-containing contact lens solutions who started treatment with tetracycline.38

SUMMARY The benefits of pharmaceutical excipients include improved drug solubility, stability and palatability, antimicrobial activity, the availability of various dosage forms, the provision of products with long-term storage, and the availability of multiple-dose packaging. Excipients are

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813

often termed “inert,” implying that they possess no pharmacologic or toxicologic properties of their own. While excipients are essential and efficacious, they may also be responsible for severe, and sometimes fatal, adverse effects. The toxicity of pharmaceutical excipients should be considered for patients requiring high doses or prolonged administration of any medication containing excipients, particularly those additives known to have toxicities. Individuals with decreased renal or hepatic function or patients at the extremes of age may be at an increased risk of accumulating excipients. Under circumstances in which there is no option but to continue treating a patient with a particular xenobiotic, switching to a preservative-free product, or to another brand without the offending excipient, may obviate the need for discontinuation of an effective agent. In addition to inherent toxicities, many excipients may also be responsible for allergic reactions. Their prevalence in numerous pharmaceuticals, cosmetics, and foods may allow for sensitization. However, in the majority of cases, pharmaceutical excipients are safe and effective, and their benefits far exceed their potential for adverse effects when administered properly.

REFERENCES 1. Alade SL, Brown RE, Paquet A. Polysorbate 80 and E-Ferol toxicity. Pediatrics. 1986;77:593-597. 2. Ali M, Rellos P, Cox TM. Hereditary fructose intolerance. J Med Genet. 1998;35:353-365. 3. American Academy of Pediatrics. Committee on Infectious Diseases and Committee on Environmental Health. Thimerosal in vaccines—an interim report to clinicians (RE9935). Pediatrics. 1999;104:570-574. 4. Andrews N, Miller E, Grant A, et al. Thimerosal exposure in infants and developmental disorders. A retrospective cohort study in the United Kingdom does not support a causal association. Pediatrics. 2004;114:584-591. 5. Arroliga AC, Shehab N, McCarthy K, Gonzales JP. Relationship of continuous infusion lorazepam to serum propylene glycol concentration in critically ill adults. Crit Care Med. 2004;32:1709-1714. 6. Arulanantham K, Genel M. Central nervous system toxicity associated with ingestion of propylene glycol. J Pediatr. 1978;93:515-516. 7. Axton JH. Six cases of poisoning after parenteral organic mercurial compound (Merthiolate). Postgrad Med J. 1972;48:417-421. 8. Bagshawe KD, Magrath IT, Golding PR. Intrathecal methotrexate. Lancet. 1969;2:1258. 9. Ball LK, Ball R, Pratt RD. An assessment of thimerosal use in childhood vaccines. Pediatrics. 2001;107:1147-1154. 10. Bania TC, Chu J, Perez E, Su M, Hahn IH. Hemodynamic effects of intravenous fat emulsion in an animal model of severe verapamil toxicity resuscitated with atropine, calcium, and saline. Acad Emerg Med. 2007;4: 105-111. 11. Bekeris L, Baker C, Fenton J, Kimball D, Bermes E. Propylene glycol as a cause of an elevated serum osmolality. Am J Clin Pathol. 1979;72: 633-636. 12. Benda GI, Hiller JL, Reynolds JW. Benzyl alcohol toxicity. Impact on neurologic handicaps among surviving very-low-birth-weight infants. Pediatrics. 1986;77:507-512. 13. Benzon HT, Gissen AJ, Strichartz GR, Avram MJ, Covino BG. The effect of polyethylene glycol on mammalian nerve impulses. Anesth Analg. 1987;66:553-559. 14. Berg ØH, Henriksen RN, Steisvåg SK. The effect of a benzalkonium chloride-containing nasal spray on human respiratory mucosa in vitro as a function of concentration and time of action. Pharmacol Toxicol. 1995;76:245-249. 15. Berg ØH, Lie K, Steisvåg SK. The effects of topical nasal steroids on rat respiratory mucosa in vivo, with special reference to benzalkonium chloride. Allergy. 1997;52:627-632. 16. Bernard S, Enayati A, Redwood L, et al. Autism. A novel form of mercury poisoning. Med Hypotheses. 2001;56:462-471. 17. Bernat JL. Intraspinal steroid therapy. Neurology. 1981;31:168-171. 18. Borody T, Chinwah PM, Graham GG, Wade DN, Williams KM. Chlorobutanol toxicity and dependence. Med J Aust. 1979;1:288.

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19. Bowie MD, McKenzie D. Diethylene glycol poisoning in children. S Afr Med J. 1972;46:931-934. 20. Brown WJ, Buist WJ, Cory Gipson HT, et al. Fatal benzyl alcohol poisoning in an neonatal intensive care unit. Lancet. 1982;1:1250. 21. Bruns DE, Herold DA, Rodheaver GT, Edlich RF. Polyethylene glycol intoxication in burn patients. Burns. 1982;9:49-52. 22. Brunson EL. Benzyl alcohol. In: Rowe RC, Sheskey PJ, Weller PJ, eds. Handbook of Pharmaceutical Excipients, 4th ed. Washington, DC: American Pharmaceutical Association; 2003:53-55. 23. Buszello K, Muller BW. Emulsions as drug delivery systems. In: Nielloud F, Marti-Mestres G, eds. Drugs and the Pharmaceutical Sciences. Pharmaceutical Emulsions and Suspensions. New York: Marcel Dekker; 2000:191-224. 24. Calvery HO, Klumpp TG. The toxicity for human beings of diethylene glycol with sulfanilamide. South Med J. 1939;32:1105-1109. 25. Cate JC, Hedrick R. Propylene glycol intoxication and lactic acidosis. N Engl J Med. 1980;303:1237. 26. Cawley MJ. Short-term lorazepam infusion and concern for propylene glycol toxicity. Case report and review. Pharmacotherapy. 2001;21:1140-1144. 27. Centers for Disease Control and Prevention. Fatalities associated with ingestion of diethylene glycol-contaminated glycerin used to manufacture acetaminophen syrup—Haiti, November 1995-June 1996. MMWR Morb Mortal Wkly Rep. 1996;45:649-650. 28. Centers for Disease Control and Prevention. Recommendations regarding the use of vaccines that contain thimerosal as preservative. MMWR Morb Mortal Wkly Rep. 1999;48:996-998. 29. Centers for Disease Control and Prevention. Thimerosal in vaccines. A joint statement of the American Academy of Pediatrics. and the Public Health Service. MMWR Morb Mortal Wkly Rep. 1999;48:563-565. 30. Chassany O, Michaux A, Bergmann JF. Drug-induced diarrhoea. Drug Saf. 2000;22:53-72. 31. Chen J, Ahn KC, Gee NA, et al. Antiandrogenic properties of parabens and other phenolic containing small molecules in personal care products. Toxicol Appl Pharmacol. 2007;221:278-284. 32. Chicella M, Jansen P, Parthiban A, et al. Propylene glycol accumulation associated with continuous infusion of lorazepam in pediatric intensive care patients. Crit Care Med. 2002;30:2752-2756. 33 The evidence for the safety of thiomersal in newborn and infant vaccines. Vaccine. 2004;22:1854-1861. 34. Clements CJ, Ball LK, Ball R, Pratt D. Thiomersal in vaccines. Lancet. 2000;355:1279-1280. 35. Collins J. Time for fructose solutions to go. Lancet. 1993;341:600. 36. Conway V, Mulski M. Phenol. In: Rowe RC, Sheskey PJ, Weller PJ, eds. Handbook of Pharmaceutical Excipients. 4th ed. Washington, DC: American Pharmaceutical Association; 2003:426-428. 37. Craig DB, Habib GG. Flaccid paraparesis following obstetrical epidural anesthesia. Possible role of benzyl alcohol. Anesth Analg. 1977;56: 219-221. 38. Crook TG, Freeman JJ. Reactions induced by the concurrent use of thimerosal and tetracycline. Am J Optom Physiol Optics. 1983;60:759-761. 39. Cukier JO, Seungdamrong S, Odell JL, et al. The displacement of albumin bound bilirubin by gentamicin. Pediatr Res. 1974;8:399. 40. Darbre PD, Harvey PW. Paraben esters: review of recent studies of endocrine toxicity, absorption, esterase and human exposure, and discussion of potential human health risks. J Appl Toxicol. 2008;28:561-578. 41 Davidson PW, Myers GJ, Weiss B. Mercury exposure and child development outcomes. Pediatrics. 2004;113:1023-1029. 42. DeChristoforro R, Corden BJ, Hood JC, Narang PK, Magrath IT. Highdose morphine complicated by chlorobutanol-somnolence. Ann Intern Med. 1983;98:335-336. 43. Demey HE, Daelemans RA, Verpooten GA, et al. Propylene glycol induced side effects during intravenous nitroglycerin therapy. Intensive Care Med. 1988;14:221-226. 44. DiPiro JT, Michael KA, Clark BA, et al. Absorption of polyethylene glycol after administration of a PEG-electrolyte lavage solution. Clin Parm. 1986;5: 153-155. 45. Erickson TB, Aks SE, Zabaneh R, Reid R. Acute renal toxicity after ingestion of lava light liquid. Ann Emerg Med. 1996;27:781-784. 46. European Agency for the Evaluation of Medicinal Products. EMEA public statement on thiomersal in vaccines for human use-recent evidence supports safety of thimerosal-containing vaccines. Doc Ref. EMEA/CMP/ VEG/1194/04/Adopted. London, England, 2004. http://www.eu.int/pdfs/ human/press/pus/119404en.pdf. Accessed December 4, 2004.

47. Fagan DG, Pritchard JS, Clarkson TW, Greenwood MR. Organ mercury levels in infant with omphaloceles treated with organic mercurial antiseptic. Arch Dis Child. 1977;52:962-964. 48. FDA Center for Drug Evaluation and Research. Inactive Ingredient Guide (Redacted) January 1996. Rockville, MD; 2001. http://www.fda.gov/cder/ drug/iig/default.htm. Accessed February 24, 2005. 49. Fligner CL, Jack R, Twiggs GA, Raisys VA. Hyperosmolality induced by propylene glycol, a complication of silver sulfadiazine therapy. JAMA. 1985;253:1606-1609. 50. Florence AT, Salole EG, eds. Formulation Factors in Adverse Reactions. London: Wright; 1990:11. 51. Freed GL, Andreae MC, Cowan AE, Katz SL. Vaccine safety policy analysis in three European countries. The case of thimerosal. Health Policy. 2002; 62:291-307. 52. Garnacho-Montero J, Ortiz-Leyba C, Garnacho-Montero MC, et al. Effects of three intravenous lipid emulsions on the survival and mononuclear phagocytes function of septic rats. Nutrition. 2002;18:751-754. 53. Gassett AR. Benzalkonium chloride toxicity to the human cornea. Am J Ophthamol. 1977;84:169-171. 54. Geier DA, Geier MR. A comparative evaluation of the effects of MMR immunization and mercury doses from thimerosal-containing childhood vaccines on the population prevalence of autism. Med Sci Monit. 2004;10:PI33-PI39. 55. Geier DA, Geier MR. An assessment of the impact of thimerosal on childhood neurodevelopmental disorders. Pediatr Rehabil. 2003;6:97-102. 56. Geier DA, Geier MR. Thimerosal in childhood vaccines, neurodevelopmental disorders, and heart disease in the United States. J Am Phys Surg. 2003;8:6-11. 57. Geier MR, Geier DA. Neurodevelopmental disorders after thimerosal containing vaccines. A brief communication. Exp Biol Med. 2003;228:660-664. 58. Geiling EM, Cannon PR. Pathologic effects of elixir of sulfanilamide (diethylene glycol) poisoning. JAMA. 1938;111:919-926. 59. Gellerman GL, Martinez C. Fatal ventricular fibrillation following intravenous sodium diphenylhydantoin therapy. JAMA. 1967;200:337-338. 60. Gershanik J, Boecler B, Ensley H, McCloskey S, George W. The gasping syndrome and benzyl alcohol poisoning. N Engl J Med. 1982:1384-1388. 61. Glasgow AM, Boeckx RL, Miller MK, et al. Hyperosmolality in small infants due to propylene glycol. Pediatrics. 1983;72:353-355. 62. Glover ML, Reed MD. Propylene glycol. The safe diluent that continues to cause harm. Pharmacotherapy. 1996;16:690-693. 63. Gross DR, Kitzman JV, Adams HR. Cardiovascular effects of intravenous administration of propylene glycol and oxytetracycline in propylene glycol in calves. Am J Vet Res. 1979;40:783-791. 64. Haeney MR, Carter GF, Yeoman WB, Thompson RA. Long-term parenteral exposure to mercury in patients with hypogammaglobulinaemia. Br Med J. 1979;2:12-14. 65. Hagebusch OE. Necropsies of four patients following administration of elixir sulfanilamide—Massengill. JAMA. 1937;109:1537-1539. 66. Hahn AF, Feasby TE, Gilbert JJ. Paraparesis following intrathecal chemotherapy. Neurology. 1983;33:1032-1038. 67. Hanif M, Mobarak MR, Ronan A. Fatal renal failure by diethylene glycol in paracetamol elixir. The Bangladesh epidemic. BMJ. 1995;311:88-91. 68. Hayman M, Seidl EC, Ali M, Malik K. Acute tubular necrosis associated with propylene glycol from concomitant administration of intravenous lorazepam and trimethoprim-sulfamethoxazole. Pharmacotherapy. 2003;23:1190-1194. 69. Henley E. Sorbitol-based elixirs, diarrhea and enteral tube feeding. Am Fam Physician. 1997;55:2084-2086. 70. Herold DA, Keil K, Bruns DE. Oxidation of polyethylene glycols by alcohol dehydrogenase. Biochem Pharmacol. 1989;38:73-76. 71. Heron J, Golding J, ALSPAC Study Team. Thimerosal exposure in infants and developmental disorders. A prospective cohort study in the United kingdom does not support a causal association. Pediatrics. 2004;114: 577-583. 72. Hill DB, Henderson LM, McClain CJ. Osmotic diarrhea by sugar-free theophylline solution in critically ill patients. J Parenter Enteral Nutr. 1991;15:332-336. 73. Hiller JL, Benda GI, Rahatzad M, et al. Benzyl alcohol toxicity. Impact on mortality and intraventricular hemorrhage among very-low birth-weight infants. Pediatrics. 1986;77:500-506. 74. Ho CY, Wu MC, Lan MY, Tan CT, Yang AH. In vitro effects of preservatives in nasal sprays on human nasal epithelial cells. Am J Rhinol. 2008;22:125-129.

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75. Hofmann T, Gugatschga M, Koidl B, Wolf G. Influence of preservatives and topical steroids on ciliary beat frequency in vitro. Arch Otolaryngol Head Neck Surg. 2004;130:440-445. 76. http://www.ajc.com/services/content.shared-gen/ap/Africa/AF_Nigeria_ Fatal_Formula.html?cxntlid=inform_sr. Nigeria:84 children dead from teething formula. Associated Press Article. 77. Hviid A, Stellfeld M, Wohlfahrt J, Melbye M. Association between thimerosal containing vaccine and autism. JAMA. 2003;290:1763-1766. 78. Jain NK, Patel VP, Pitchumoni CS. Sorbitol intolerance in adults. Am J Gastroenterol. 1985;80:678-681. 79. James CL, Rellos P, Alli M, et al. Neonatal screening for HFI. Frequency of the most common mutant aldolase B allele (A149P) in the British population. J Med Genet. 1996;33:837-841. 80. James CW, McNelis KC, Matalia MD, Cohen DM, Szabo S. Central nervous system toxicity and amprenavir oral solution. Ann Pharmacother. 2001;35:174. 81. Jorde LB, Carey JC, Bamshad MJ, White RL. Biochemical genetics. Disorders of metabolism. In: Jorde LB, Carey JC, Bamshad MJ, White RL, eds. Medical Genetics. 2nd ed. St. Louis: Mosby; 2000:136-155. 82. Kibbe AH. Benzalkonium chloride. In: Rowe RC, Sheskey PJ, Weller PJ, eds. Handbook of Pharmaceutical Excipients. 4th ed. Washington, DC: American Pharmaceutical Association; 2003:45-47. 83. Kibbe AH, Weller PJ. Thimerosal. In: Rowe RC, Sheskey PJ, Weller PJ, eds. Handbook of Pharmaceutical Excipients. 4th ed. Washington, DC: American Pharmaceutical Association; 2003:648-650. 84. Kulick MI, Lewis NS, Bansal V, Warpeha R. Hyperosmolality in the burn patient. Analysis of an osmolal discrepancy. J Trauma. 1980;20:223-228. 85. Kuoyama Y, Suzuki K, Hara T. Nasal lesion induced by intranasal administration of benzalkonium chloride in rats. J Toxicol Sci. 1997;22:153-160. 86. Ledochowski M, Widner B, Bair H, Probst T, Fuchs D. Fructose and sorbitol-reduced diet improves mood and gastrointestinal disturbances in fructose malabsorbers. Scand J Gastroenterol. 2000;35:1048-1052. 87. Lekka ME, Liokatis S, Nathanail C, Galani V, Nakos G. The impact of intravenous fat emulsion administration in acute lung injury. Am J Respir Crit Care Med. 2004;169:638-644. 88. Lemp MA, Zimmerman LE. Toxic endothelial degeneration in ocular surface disease treated with topical medications containing benzalkonium chloride. Am J Ophthamol. 1988;105:670-673. 89. Liu H, Routley I, Teichmann KD. Toxic endothelial cell destruction from intraocular benzalkonium chloride. J Cataract Refract Surg. 2001;27:1746-1750. 90. Lopez-Herce J, Bonet C, Meana A, Albajara L. Benzyl alcohol poisoning following diazepam intravenous infusion. Ann Pharmacother. 1995;29:632. 91. Lorenzetti OJ, Wernet TC. Topical parabens. Benefits and risks. Dermatologica. 1977;154:244-250. 92. Loria CJ, Echeverria P, Smith AL. Effect of antibiotic formulations in serum protein. Bilirubin interaction of newborn infants. J Pediatr. 1976;89:479-482. 93. Louis S, Kutt H, McDowell F. The cardiovascular changes caused by intravenous Dilantin and its solvent. Am Heart J. 1967;74:523-529. 94. MacDonald MG, Getson PR, Glasgow AM, et al. Propylene glycol. Increased incidence of seizures in low-birth-weight infants. Pediatrics. 1987;79:622-625. 95. Madigan SM, Courtney DE, Macauley D. The solution was the problem. Clin Nutr. 2002;21:531-532. 96. Madsen KM, Lauritsen MB, Pedersen CB, et al. Thimerosal and the occurrence of autism. Negative ecological evidence from Danish populationbased data. Pediatrics. 2003;112:604-606. 97. Magos L. Neurotoxic character of thimerosal and the allometric extrapolation of adult clearance half-time to infants. J Appl Toxicol. 2003;23:263-269. 98. Magos L, Brown AW, Sparrow S, et al. The comparative toxicology of ethyl and methylmercury. Arch Toxicol. 1985;57:260-297. 99. Malinovsky JM, Cozian A, Lepage JY, Pinaud M. Ketamine and midazolam neurotoxicity in the rabbit. Anesthesiology. 1991;75:91-97. 100. Malinovsky JM, Lepage JY, Cozian A, et al. Is ketamine or its preservative responsible for neurotoxicity in the rabbit? Anesthesiology. 1993;78: 109-115. 101. Martin G, Finberg L. Propylene glycol. A potentially toxic vehicle in liquid dosage form. J Pediatr. 1970;77:877-878. 102. Martone WJ, Williams WW, Mortensen ML, et al. Illness with fatalities in premature infants. Association with intravenous vitamin E preparation, E-Ferol. Pediatrics. 1986;78:591-600. 103. Miles JM, Cattalini M, Sharbrough FW, et al. Metabolic and neurologic effects of an intravenous medium-chain triglyceride emulsion. JPEN J Parenter Enteral Nutr. 1991;15:37-41.

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104. Miller B, Traynelis SF, Attwell D. Potentiation of NMDA receptor currents by arachidonic acid. Nature. 1992;355:722-725. 105. Möller H. Merthiolate allergy. A nationwide iatrogenic sensitization. Acta Derm Venereol. 1977;57:509-517. 106. Morizono T. Toxicity of ototopical drugs. Animal modeling. Ann Otol Rhinol Laryngol Suppl. 1990;148:42-45. 107. Morizono T, Paparella MM, Juhn SK. Ototoxicity of propylene glycol in experimental animals. Am J Otolaryngol. 1980;1:393-399. 108. Morshed KM, Jain SK, McMartin KE. Propylene glycol-mediated injury in a primary cell culture of human proximal tubule cells. Toxicol Sci. 1998;46:410-417. 109. Morshed KM, Jain SK, McMartin KE. Acute toxicity of propylene glycol. An assessment using cultured proximal tubule cells of human origin. Fundam Appl Toxicol. 1994;23:38-43. 110. Nash RA. Chlorbutanol. In: Rowe RC, Sheskey PJ, Weller PJ, eds. Handbook of Pharmaceutical Excipients. 4th ed. Washington, DC: American Pharmaceutical Association; 2003:141-143. 111. Nash RA. Sorbitol. In: Rowe RC, Sheskey PJ, Weller PJ, eds. Handbook of Pharmaceutical Excipients. 4th ed. Washington, DC: American Pharmaceutical Association; 2003:596-599. 112. National Academy of Sciences. Immunization Safety Review Committee. Immunization Safety Review. Vaccines and Autism (Free Executive Summary). ISBN: 0-309-53275-2. Washington, DC: Author; 2004. See http://www.nap.edu/catalog/10997.html for ordering information; accessed December 5, 2004.) 113. Neale BW, Mesler EL, Young M, Rebuck JA, Weise WJ. Propylene glycolinduced lactic acidosis in a patient with normal renal function: a proposed mechanism and monitoring recommendations. Ann Pharmacother. 2005;39:1732-1736. 114. Neville R, Dennis, P, Sens D, Crouch R. Preservative cytotoxicity to cultured corneal epithelial cells. Curr Eye Res. 1986;5:367-372. 115. Okuonghae HO, Ighogboja IS, Lawson JO, Nwana EJ. Diethylene glycol poisoning in Nigerian children. Ann Trop Paediatr. 1992;12:235-238. 116. Papahadjopoulos D. Steric stabilization an overview. In: Janoff SA, ed. Liposomes Rational Design. New York: Marcel Dekker; 1999:1-12. 117. Parker MG, Fraser GL, Watson DM, Riker RR. Removal of propylene glycol and correction of increased osmolar gap by hemodialysis in a patient on high dose lorazepam infusion therapy. Intens Care Med. 2002;28:81-81. 118. Perez E, Bania TC, Medlej K, Chu J. Determining the optimal dose of intravenous fat emulsion for the treatment of severe verapamil toxicity in a rodent model. Acad Emerg Med. 2008;15:1284-1289. 119. Petrou S, Ordway RW, Hamilton JA, Walsh JV Jr, Singer JJ. Structural requirements for charged lipid molecules to directly increase or suppresses K+ channel activity in smooth muscle cells. J Gen Physiol. 1994;103: 471-486. 120. Pfab R, Mückter H, Roider G, Zilker T. Clinical course of severe poisoning with thimerosal. J Toxicol Clin Toxicol. 1996;34:453-460. 121. Pichichero ME, Cernichiari E, Lopreiato J, Treanor J. Mercury concentrations and metabolism in infants receiving vaccines containing thimerosal. A descriptive study. Lancet. 2002;360:1737-1741. 122. Powell HM, Jamieson WA. Merthiolate as a germicide. Am J Hygiene. 1931;13:296-310. 123. Price JC. Polyethylene glycol. In: Rowe RC, Sheskey PJ, Weller PJ, eds. Handbook of Pharmaceutical Excipients. 4th ed. Washington, DC: American Pharmaceutical Association; 2003:454-459. 124. Prusakiewicz JJ, Harville HM, Zhang Y, Ackermann C, Voorman RL. Parabens inhibit human skin estrogen sulfotransferase activity: possible link to paraben estrogenic effects. Toxicology. 2007;232:248-256. 125. Pugazhendhi D, Pope GS, Darbre PD. Oestrogenic activity of p-hydroxybenzoic acid (common metabolite of paraben esters) and methylparaben in human breast cancer cell lines. J Appl Toxicol. 2005;25:301-309. 126. Rentz ED, Lewis L, Mujica OJ, et al. Outbreak of acute renal failure in Panama in 2006: a case-control study. Bull World Health Organ. 2008; 86:749-756. 127. Rieger MM. Methylparaben. In: Rowe RC, Sheskey PJ, Weller PJ, eds. Handbook of Pharmaceutical Excipients. 4th ed. Washington, DC: American Pharmaceutical Association; 2003:390-394. 128. Rivera W, Velez LI, Guzman DD, Shepherd G. Unintentional intravenous infusion of GoLYTELY in a 4-year-old girl. Ann Pharmacother. 2004;38: 1183-1185. 129. Rogers SC, Burrows D, Neill D. Percutaneous absorption of phenol and methyl alcohol in magenta paint BPC. Br J Dermatol. 1978;98:559-560.

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130. Rohyans J, Walson PD, Wood GA, MacDonald WA. Mercury toxicity following Merthiolate ear irrigations. J Pediatr. 1984;104:311-313. 131. Rubin M. Dear Health Care Professional Letter. Agenerase. Research Triangle Park, NC: Glaxo Wellcome; May 2000. 132. Saiki JH, Thompson S, Smith F, Atkinson R. Paraplegia following intrathecal chemotherapy. Cancer. 1972;29:370-374. 133. Schamberg IL. Allergic contact dermatitis to methyl and propyl paraben. Arch Dermatol. 1967;95:626-328. 134. Schiller LR, Emmett M, Santa CA, et al. Osmotic effects of polyethylene glycol. Gastroenterology. 1988;94:933-941. 135. Schulte MJ, Lenz W. Fatal sorbitol infusion in patient with fructose sorbitol intolerance. Lancet. 1977;2:188. 136. Sirianni AJ, Osterhoudt KC, Calello DP, et al. Use of lipid emulsion in the resuscitation of a patient with prolonged cardiovascular collapse after overdose of bupropion and lamotrigine. Ann Emerg Med. 2008;51:412-415. 137. Smith WS, Dowd CF, Johnston SC, et al. Neurotoxicity of intra-arterial papaverine preserved with chlorobutanol used for the treatment of cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Stroke. 2004;35:2518-2522. 138. Smyth HF, Carpenter CP, Shaffer CB. The toxicity of high-molecularweight polyethylene glycols: chronic oral and parenteral administration. J Am Pharm Assoc (Wash). 1947;36:157-160. 139. Smyth HF, Carpenter CP, Weil CS. The chronic oral toxicity of the polyethylene glycols. J Am Pharm Assoc (Wash). 1955;44;27-30. 140. Smyth HF, Carpenter CP, Weil CS. The toxicology of the polyethylene glycols. J Am Pharm Assoc (Wash). 1950;39:349-354. 141. Song BL, Li HY, Peng DR. In vitro spermicidal activity of parabens against human spermatozoa. Contraception. 1989;39:331-335. 142. Speth PA, Vree TB, Neilen NF, et al. Propylene glycol pharmacokinetics and effect after intravenous infusion in humans. Ther Drug Monit. 1987;9:255-258. 143. Stehr-Green P, Tull P, Stellfeld M, Mortenson PB, Simpson D. Autism and the thimerosal containing vaccines. Lack of consistent evidence for an association. Am J Prev Med. 2003;25:101-106. 144. Strickley RG. Solubilizing excipients in oral and injectable formulations. Pharm Res. 2004;21:201-230. 145. Sturgill BC, Herold DA, Bruns DE. Renal tubular necrosis in burn patients treated with topical polyethylene glycol. Lab Invest. 1982;46:81A. 146. Sweet AY. Fatality from intravenous nitrofurantoin. Pediatrics. 1958;22:1204. 147. Tabuchi S, Kume K, Aihara M, et al. Lipid mediators modulate NMDA receptor currents in a Xenopus oocyte expression system. Neurosci Lett. 1997;237:13-16. 148. Tripathi BJ, Tripathi RC. Cytotoxic effects of benzalkonium chloride and chlorobutanol on human corneal epithelial cells in vitro. Lens Eye Toxic Res. 1989;6:395-403. 149. Unger AH, Sklaroff HJ. Fatalities following intravenous use of sodium diphenylhydantoin for cardiac arrhythmias. JAMA. 1967;200:35-36. 150. United States Pharmacopeia 24/National Formulary 19. Rockville, MD: United States Pharmacopeial Convention; 2000. 151. Unlu RE, Alagoz MS, Uysai AC, et al. Phenol intoxication in a child. J Craniofac Surg. 2004;15:1010-1013. 152. Van de Wiele B, Rubinstein E, Peacock W, Martin N. Propylene glycol toxicity caused by prolonged infusion of etomidate. J Neurosurg Anesthesiol. 1995;7:259-262.

153. van Meeuwen JA, van Son O, Piersma AH, de Jong PC, van den Berg M. Aromatase inhibiting and combined estrogenic effects of parabens and estrogenic effects of other additives in cosmetics. Toxicol Appl Pharmacol. 2008;230:372-382. 154. Vassalli L, Harris DM, Gradini R, Applebaum EL. Propylene glycolinduced cholesteatoma in chinchilla middle ears. Am J Otolaryngol. 1988;9:180-188. 155. Vernon J, Brummett R, Walsh T. The ototoxic potential of propylene glycol in guinea pigs. Arch Otolaryngol. 1978;104:726-729. 156. Verstraeten T, Davis RL, DeStefano F, et al. Safety of thimerosal-containing vaccines. A two-phased study of computerized health maintenance organization databases. Pediatrics. 2003;112:1039-1048. 157. Wanten GJ, Netea MG, Naber TH, et al. Parenteral administration of medium-but not long-chain lipid emulsions may increase the risk for infections by candida albicans. Infect Immun. 2002;70:6471-6474. 158. Warner MA, Harper JV. Cardiac dysrhythmias associated with chemical peeling with phenol. Anesthesiology. 1985;62:366-367. 159. Weigt HU, Georgieff M, Beyer C, Föhr KJ. Activation of neuronal N-methyl-daspartate receptor channels by lipid emulsions. Anesth Analg. 2002;94:331-337. 160. Weigt HU, Georgieff M, Beyer C, et al. Lipid emulsions reduce NMDAevoked currents. Neuropharmacology. 2004;47:373-380. 161. Weller PJ. Propylene glycol. In: Rowe RC, Sheskey PJ, Weller PJ, eds. Handbook of Pharmaceutical Excipients. 4th ed. Washington, DC: American Pharmaceutical Association; 2003:521-523. 162. Wilson KC, Reardon C, Farber HW. Propylene glycol toxicity in a patient receiving intravenous diazepam. N Engl J Med. 2000;343:815. 163. Wilson KC, Reardon C, Theodore AC, Farber HW. Propylene glycol toxicity: a severe iatrogenic illness in ICU patients receiving IV benzodiazepines. a case series and prospective, observational pilot study. Chest. 2005; 128:1674-1681. 164. Winder AF, Astbury NJ, Sheraidah GA, Ruben M. Penetration of mercury from ophthalmologic preservatives into the human eye. Lancet. 1980;2:237-239. 165. World Health Organization Global Advisory Committee on Vaccine Safety. Statement on Thiomersal. Geneva, Switzerland; August 2003. http://www.who.int/vaccine_safety/topics/thiomersal/statement200308/ en/print.html. Accessed December 4, 2004. 166. Wright CG, Bird LL, Meyerhoff WL. Tympanic membrane microstructure in experimental cholesteatoma. Acta Otolaryngol. 1991;111: 101-111. 167. Yahwak JA, Riker RR, Fraser GL, Subak-Sharpe S. Determination of a lorazepam dose threshold for using the osmol gap to monitor for propylene glycol toxicity. Pharmacotherapy. 2008;28:984-991. 168. Yaucher NE, Fish JF, Smith HW, et al. Propylene glycol-associated renal toxicity from lorazepam infusion. Pharmacotherapy. 2003;23: 1094-1099. 169. Yorgin PD, Theodorou AA, Al-Uzri A, et al. Propylene glycolinduced proximal tubule cell injury. Am J Kidney Dis. 1997;30:134-139. 170. Zar T, Yusufzai I, Sullivan A, Graeber C. Acute kidney injury, hyperosmolality and metabolic acidosis associated with lorazepam. Nat Clin Pract Nephrol. 2007;3:515-520. 171. Zoneraich S, Zoneraich O, Siegel, J. Sudden death following intravenous sodium diphenylhydantoin. Am Heart J. 1976;91:375-377.

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D. ANTIMICROBIALS

CHAPTER 56

PHARMACOLOGY AND TOXICOLOGY

ANTIBACTERIALS, ANTIFUNGALS, AND ANTIVIRALS

Antimicrobial pharmacology is aimed at the destruction of microorganisms through the inhibition of cell-cycle reproduction or the altering of a critical function within a microorganism. Table 56–1 lists antimicrobials and their associated mechanisms of activity. Often the mechanisms for toxicologic effects following acute overdose differ from the therapeutic mechanisms. Table 56–1 also lists the toxicologic effects and related mechanisms. Table 56–2 lists the pharmacokinetics of each class of drugs.

Christine M. Stork Antimicrobials in the forms of antibacterials, antifungals, and antivirals have added significantly to the clinical care of infected patients since the introduction of penicillin in the 1940s. The development of drugresistant strains of these pathogens has greatly expanded the number of antimicrobials necessary, and this has increased the overall potential for toxicity after use. Fortunately, toxicity due to acute overdose and even chronic therapeutic doses does not preclude their appropriate use in the majority of patients.

ANTIBACTERIALS ■ AMINOGLYCOSIDES R1

H N

R2

C O H2N

H2N O

HISTORY AND EPIDEMIOLOGY

HO

NH2

O The majority of the adverse effects related to antimicrobials occur as a result of iatrogenic complications rather than intentional overdose. The diverse origins of these complications include dosing, route and decision errors, allergic reactions, adverse drug effects, and drug-drug interactions. Prevention in the form of process improvements and information regarding populations at risk for adverse drug effects is required to minimize these untoward events. Dosing errors are common in neonates and infants, necessitating careful and constant diligence on the part of all healthcare providers. Antimicrobials are more commonly associated with anaphylactic reactions than are other xenobiotics. The reason for this is unclear, but it may be a result of their high frequency of use, repeated interrupted exposures caused by intermittent prescriptive use, or environmental contamination. A complete and clear allergy history is essential to minimize these adverse events in patients being considered for antimicrobial therapy. Many adverse effects attributed to antimicrobials are difficult to predict even when given patient- and population-specific parameters. In some cases, a diluent or an excipient is responsible for the adverse effect, as recognized with the use of procaine penicillin G in patients with procaine allergy. Antimicrobials are involved in many of the common and severe drug interactions, primarily through the inhibition of metabolic enzymes. Patients being considered for antimicrobial therapy should be carefully assessed for the use of concomitant drug therapy that may be pharmacokinetically or pharmacodynamically affected by the chosen antimicrobial.

HO

CH3

NH H3C Gentamicin C1: R1 = R2 = CH3 Gentamicin C2: R1 = CH3, R2 = H Gentamicin C1a: R1 = R2 = H

OH

Aminoglycoside antimicrobials that are in current use in the United States include amikacin, gentamicin, kanamycin, neomycin, netilmicin, streptomycin, and tobramycin. Since aminoglycosides are only available in parenteral, topical, and ophthalmic forms, overdoses are almost exclusively the result of dosing errors. Fortunately, overdoses are rarely life threatening, and most patients can be safely managed with minimal intervention.28,136 The adverse effects of aminoglycosides are generally class based, although subtle differences may exist in the potency with which the adverse effects occur (Table 56–3). Large intravenous doses of aminoglycosides are both sufficiently effective and safe for use in single daily doses.4 Rarely, acute aminoglycoside overdose results in nephrotoxicity, ototoxicity, or vestibular toxicity.131,157 In one reported case, postmortem analysis confirmed complete loss of hair cells in the inner and outer cochlear (Chap. 20).

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Part C

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TABLE 56–1. Antimicrobial Pharmacology and Adverse Effects Antimicrobial

Antimicrobial Mechanism of Action

Antibacterials Aminoglycosides

Inhibits 30s ribosomal subunit

Penicillins, cephalosporins, and other β-lactams Chloramphenicol

Inhibits cell wall mucopeptide synthesis

Acute Overdose

Chronic Administration

Neuromuscular blockade—inhibits the release of acetylcholine from presynaptic nerve terminals and acts as an antagonist at acetylcholine receptors Seizures—agonist at picrotoxin binding site causing GABA antagonism

Nephrotoxicity/ototoxicity—forms an iron complex that inhibits mitochondrial respiration and causes lipid peroxidation Hypersensitivity—immune Other—see text

Inhibits 50s ribosomal subunit and inhibits protein synthesis in rapidly dividing cells Inhibits DNA topoisomerase and DNA gyrase Inhibits bacterial protein synthesis through inhibition of N-formylmethionyl-t RNA Inhibit 50s ribosomal subunit in multiplying cells

Cardiovascular collapse

“Gray baby syndrome” Same as mechanism of action

Same as mechanism of action; binds to cations (Mg2+), seizures None clinically relevant

Not entirely known; binds to cations (Mg2+), tendon rupture, hyper- and hypoglycemia MAOI activity: vasopressor response to tyramine; serotonin syndrome with SSRI and possibly meperidine Not entirely known; cytotoxic effect; exacerbation of myasthenia gravis

Bacterial enzymatic inhibitor

Gastritis

Sulfonamides

Inhibit para-aminobenzoic acid and/or para-amino glutamic acid in the synthesis of folic acid

None clinically relevant

Tetracycline

Inhibits 30s and 50s ribosomal subunits; binds to aminoacyl transfer RNA Inhibits glycopeptidase polymerase in cell wall synthesis

None clinically relevant

Dermatologic, hematologic, pancreatitis, partotitis, hepatitis, crystaluria, pulmonary fibrosis Hypersensitivity—metabolite acts as hapten leading to hemolysis/methemoglobinemia— exposure to UVB causes free radical formation Unknown

“Red-man syndrome”—anaphylactoid

Unknown

Binds with ergosterol on cytoplasmic membrane to cause pores to facilitate organelle leak Increases permeability of cell membranes

Same as mechanism of action

Nephrotoxicity—vehicle deoxycholate may be involved; nephrocalcinosis

None clinically relevant

None clinically relevant ?CYP inhibition

Fluoroquinolones Linezolid

Macrolides, lincosamides, and ketolides Nitrofurantoin

Vancomycin Antifungal Amphotericin B

Triazoles and imidazoles

Prolong QT; block delayed rectifier potassium channel

γ-aminobutyric acid; MAOI, monoamine oxidase inhibitor; SSRI, selective serotonin reuptake inhibitor; UVB, ultraviolet B.

Aminoglycosides may exacerbate neuromuscular blockade, particularly at times corresponding to high-peak serum aminoglycoside concentrations (Chap. 68).187 Aminoglycosides inhibit the release of acetylcholine from presynaptic nerve terminals by antagonism of the aminoglycoside of the presynaptic calcium channel. Risk factors for enhanced neuromuscular blockade include patients with abnormal neuromuscular junction function, such as those with myasthenia gravis and botulism. Adverse Effects Associated With Therapeutic Use Adverse effects, including nephrotoxicity and ototoxicity, correlate more closely with elevated trough serum concentrations than with elevated peak concentrations.120,166

Less common adverse effects associated with chronic use include electrolyte abnormalities, allergic reactions, hepatotoxicity, anemia, granulocytopenia, thrombocytopenia, eosinophilia, retinal toxicity, reproductive dysfunction, tetany, and psychosis.62,125,142,229,244 When aminoglycosides are administered at high doses or during once-daily dosing, sepsis-like reactions, including chills and malaise, can occur.51 This is likely a result of excipients that are delivered to the patient during the infusion. Nephrotoxicity The mechanism of nephrotoxicity and ototoxicity is incompletely understood, but appears to include the formation of reactive oxygen species in the presence of iron. Mitochondrial respiration is inhibited, lipid peroxidation occurs, and stimulation of

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TABLE 56–2. Antimicrobial Pharmacokinetics Xenobiotic Antibacterial Aminoglycosides Penicillins, cephalosporins, and other β-lactams Chloramphenicol Fluoroquinolones Ketolides Macrolides Sulfonamides Tetracyclines Vancomycin Antifungal Triazoles and imidazoles Amphotericin B Antiviral Acyclovir

Absorption

Volume of Distribution (L/kg)

Elimination Route

t1/2 (h)

Parenteral Oral, parenteral

0.25 Variable

Renal Renal (predominant)

2–3 Variable

Oral, parenteral, otic Oral, parenteral Oral

0.5–1.0 Variable 2.9 L/kg

1.6–3.3 3–5 10–13

Oral, parenteral Oral, parenteral Oral Parenteral

Variable Variable Variable 0.2–1.25

90% hepatic, 10% renal Renal 63% renal, 37% hepatic (50% of which is CYP3A4) Hepatic Hepatic Hepatic Renal

Variable Variable 6–26 4–6

Oral Parenteral

Variable 4.0

Hepatic Hepatic

Variable 360

Parenteral, oral, topical

0.8

Renal

2.2–20

glutamate activated N-methyl-D-aspartate (NMDA) receptors may play a role.108,253 The incidence of nephrotoxicity with aminoglycoside therapy is estimated at 5% to 10%.9 Although the aminoglycosides are almost completely excreted prior to biotransformation in the kidney, a small fraction of filtered aminoglycoside is transported by absorptive endocytosis across the apical membrane of proximal tubular cells where it becomes sequestered within lysosomes. The aminoglycoside then binds to and destroys phospholipids contained on brush border membranes in the proximal renal tubule.9 When this happens, acute tubular necrosis occurs after 7 to 10 days of standard-dose therapy. Laboratory abnormalities include granular casts, proteinuria, elevated urinary sodium, and increased fractional excretion of sodium. Usually renal dysfunction is reversible; however, irreversible toxicity is reported. Functional renal injury occurs days prior to elevations in serum creatinine concentration, and for this reason a delay in diagnosis is common.217 Risk factors for the development of nephrotoxicity include increasing age, renal dysfunction, female sex,

TABLE 56–3. Predominant Aminoglycoside Toxicity Cochlear Kanamycin Neomycin

Cochlear and Vestibular Amikacin Gentamicin Tobramycin

Vestibular

Renal

Streptomycin

Amikacin Gentamicin Kanamycin Neomycin Streptomycin Tobramycin

previous aminoglycoside therapy, liver dysfunction, large total dose, long duration of therapy, frequent doses, high trough concentrations, presence of other nephrotoxic drugs, and shock.9,170 Because the uptake of aminoglycosides into organs is saturable, appropriate once-daily high-dose regimens are less problematic than several lesser doses given in a single day. Ototoxicity Ototoxicity can occur after acute or prolonged exposure to aminoglycosides.105 Both cochlear and vestibular dysfunction are correlated with high trough aminoglycoside concentrations. Because aminoglycosides bioaccumulate in the endolymph and perilymph spaces, they have prolonged contact time with sensory hair cells. Vestibular toxicity, caused by destruction of sensory receptor portions of the inner ear or destruction of hair cells in the utricle and saccule, occurs in 0.4% to 10% of patients. Symptoms include vertigo or tinnitus. Table 56–3 details the relative characteristic toxicity of various aminoglycosides. Full-tone audiometric testing may first show high-frequency hearing loss, which may subsequently progress. Given the inability of cochlear hair cells to regenerate, all hearing loss that develops is permanent. Electronystagmography is the diagnostic tool of choice for vestibular dysfunction, and up to 63% of patients with early findings of vestibular dysfunction may improve after discontinuation of the drug.124 Simultaneous administration of other ototoxic xenobiotics enhances the ototoxicity of aminoglycosides (Chap. 20). Withdrawal of the offending xenobiotic is indicated in patients with either nephrotoxicity or ototoxicity caused by an aminoglycoside antibiotic. Supportive care is the mainstay of therapy. Experimental treatments in animal models include the use of deferoxamine, glutathione, and NMDA receptor antagonists in an attempt to chelate and/or detoxify a reactive intermediate.181,231 The antibiotic ticarcillin forms a renally eliminated complex with aminoglycosides in the blood to provide protection against tobramycin-induced renal toxicity. In humans, ticarcillin removes 50% more tobramycin in 48 hours than two hemodialysis sessions.79 However, ticarcillin therapy is generally of limited value because in most instances

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the serum concentration of the aminoglycoside has decreased before any therapeutic measures can be used. The use of ticarcillin should be considered only early after large overdose in patients with either demonstrated toxicity or renal failure where the risks of toxicity are significant.

■ PENICILLINS O

CH3

S

R C NH

CH3

N O

COOH

TABLE 56–4. Classification of Anaphylactic Reactions Grade

Description

I II III IV

Large local contiguous reaction (>15 cm) Pruritus (urticaria) generalized Asthma, angioedema, nausea, vomiting Airway (asthma, lingual swelling, dysphagia, respiratory distress, laryngeal edema) Cardiovascular (hypotension, cardiovascular collapse)

Penicillin nucleus Penicillin is derived from the fungus Penicillium and many semisynthetic derivatives have clinical utility. Penicillins, as a class, contain a 6-aminopenicillanic acid nucleus, composed of a β-lactam ring fused to a five-member thiazolidine ring. Classic available penicillins include penicillin G, penicillin V, and the antistaphylococcal penicillins (nafcillin, oxacillin, cloxacillin, and dicloxacillin). Penicillins developed to enhance the spectrum of antibiotic efficacy, particularly against gram-negative bacilli, include the second-generation penicillins (ampicillin, amoxicillin, bacampicillin, and mezlocillin), third-generation penicillins (carbenicillin and ticarcillin), and fourth-generation penicillins (piperacillin). Table 56–1 lists the pharmacologic mechanism of penicillins and Table 56–2 lists their pharmacokinetic properties. Acute oral overdoses of penicillin-containing drugs are usually not life threatening.237 The most frequent complaints following acute overdose are nausea, vomiting, and diarrhea. Seizures occur in persons given large intravenous or intraventricular doses of penicillins.40,127,139,164 More than 50 million units intravenously in less than 8 hours are generally required to produce seizures in adults.222 Penicillin-induced seizures appear to be mediated through an interaction of the drug with the picrotoxin-binding site on the neuronal chloride channel near the γ-aminobutyric acid (GABA) binding site (Chap. 13). Binding of the penicillin produces an allosteric change in the receptor that prevents GABA from binding, resulting in a relative lack of inhibitory tone.66 Penicillin analogs (such as imipenem) also cause seizures, presumably through a similar mechanism. Treatment of patients who develop penicillin-induced seizures include GABA agonists such as the benzodiazepines and barbiturates, if needed. Patients who receive an intraventricular overdose may require cerebrospinal fluid exchange or perfusion to attenuate seizure activity (see Special Considerations SC 2: Intrathecal Administration of Xenobiotics).139 There are rare reports of hyperkalemia resulting in electrocardiographic abnormalities after the rapid intravenous infusion of potassium penicillin G to patients with renal failure and amoxicillin overdose resulting in frank hematuria and renal failure.37,94 There is also a single case report of penicillin-associated hearing loss.33 Adverse Effects Associated With Therapeutic Use Penicillins are associated with a myriad of adverse effects after therapeutic use, the most common of which are allergic reactions. Penicillins are commonly implicated in immune-related reactions such as bone marrow suppression, cholestasis, hemolysis, interstitial nephritis, and vasculitis.6,92,114,230 Rare effects include pemphigus after penicillin use and corneal damage after the use of methicillin.23,263 Acute Allergy Penicillins are the pharmaceuticals most commonly implicated in the development of acute anaphylactic reactions. Anaphylactic reactions are severe life-threatening immune-mediated (IgE) reactions involving multiple organ systems that occur most often immediately after exposure to a trigger. Table 56–4 lists the classifications of anaphylactic reactions. Anaphylaxis to penicillin typically

occurs after IgE antibody formation, which requires prior exposure. Life-threatening clinical manifestations include angioedema, tongue and airway swelling, bronchospasm, bronchorrhea, dysrhythmias, cardiovascular collapse, and cardiac arrest.80 The pathophysiology of systemic anaphylaxis is complex and involves multiple pathways. IgE antibodies are cross-linked on the surface of mast cells and basophils, resulting in local and systemic release of preformed mediators of anaphylactic response, including leukotrienes C4 and D4, histamine, eosinophilic chemotactic factor, and other vasoactive substances, such as bradykinin, kallikrein, prostaglandin D2, and platelet-activating factor. The incidence of penicillin hypersensitivity is 5% overall, with 1% of penicillin reactions resulting in anaphylaxis. The risk for a fatal hypersensitivity reaction after penicillin administration is two per 100,000 (0.002%) patient exposures.251 All routes of penicillin administration can result in anaphylaxis; however, it occurs most commonly after intravenous administration. Treatment is supportive with careful attention to airway, breathing, and circulation. If the penicillin was ingested, the patient may theoretically benefit from oral activated charcoal 1 g/kg. This is unlikely to prevent anaphylaxis, as only a few molecules need be absorbed to trigger the immunologic response. Initial drug therapy for anaphylaxis includes epinephrine 0.01 mg/Kg (up to 0.5 mL) of 1:1000 dilution subcutaneously (SC) every 10 to 20 minutes. Through β-receptor stimulation, epinephrine bronchodilates and increases cardiac output. In addition, β-receptor stimulation results in decreased peripheral vascular tone. Oxygen and inhaled β2-adrenergic agonists are warranted in severe cases, as are corticosteroids. H1-receptor antagonists may be sufficient in patients with mild allergic reactions who do not have pulmonary manifestations or airway concerns. H2-receptor antagonism as a treatment for anaphylaxis is controversial. H2-receptors, when stimulated in the peripheral vasculature, cause vasodilation; in the heart, they cause positive inotropy, positive chronotropy, and coronary vasodilation; and in the lung, they cause increased mucus production.212 Theoretically, H2-receptor antagonists can lead to a decrease in myocardial activity at a time when H1-receptor stimulation is causing hypotension, coronary vasoconstriction, and bronchospasm. However, in vitro and animal models demonstrate decreases in coronary circulation and decreases in the overall anaphylactic response following administration of H1 blockers.16,27 Cimetidine and ranitidine are useful for the treatment of pruritus and flushing after acute allergic reactions involving the skin.154,168 Cimetidine use following anaphylaxis may result in clinical improvement, particularly hypotension and tachycardia.72,264 There is one case, however, of chronic ranitidine administration, which was postulated to result in heart block after an anaphylactic response to latex.189 Available data indicate that treatment using H2-receptor antagonists should only be

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considered when other therapies have failed and the patient is adequately H1-receptor blocked. Aminophylline, although mentioned in some references for the treatment of anaphylaxis, is inadequately studied and should not be routinely used. Finally, glucagon may be of some benefit, particularly in patients who are maintained on β-adrenergic antagonists (Chap. 61 and A-19). Amoxicillin-Clavulanic Acid and Hepatitis Cholestatic hepatitis occurs 1 to 6 weeks after initiation of therapy with amoxicillin-clavulanate.7 The incidence of hepatotoxicity typically is estimated at 1.1 to 2.7 per 100,000 prescriptions.91 The mechanism of hepatotoxicity is not clear, but may be related to clavulanate, a β-lactamase inhibitor used to prevent the bacterial destruction of β-lactam antimicrobials, or one of its metabolites. Treatment is supportive and clinical findings typically resolve after the discontinuation of therapy. However, prolonged hepatitis, ductopenia (vanishing bile duct syndrome), and pancreatitis rarely occur.53,199 Behavorial disturbance with disorientation, agitation, and visual hallucinations is also reported temporally related to use.19 Hoigne Syndrome and Jarisch-Herxheimer Reaction The most common adverse effects occurring after administration of large intramuscular or intravenous doses of procaine penicillin G are the Hoigne syndrome and the Jarisch-Herxheimer reaction.12,90,102,122,163 Hoigne syndrome is characterized by extreme apprehension and fear, illusions, or hallucinations; changes in auditory and visual perception; tachycardia; systolic hypertension; and, occasionally, seizures that begin within minutes of injection.250 These effects occur in the absence of signs or symptoms of anaphylaxis. The cause of this syndrome is unknown. Procaine is implicated as the causative agent because of this syndrome’s similarity to events that occur after the administration of other pharmacologically similar local anesthetics.214,223,246 Hoigne syndrome is six times more common in men than women.226 The reason for this increased prevalence is unclear, but autosomal dominance and influences of prostaglandin and thromboxane A2 activity in this population may be responsible.12 The Jarisch-Herxheimer reaction is a self-limited reaction that develops within a few hours of antibiotic therapy for the treatment of early syphilis or Lyme disease. Clinical findings include myalgias, chills, headache, rash, and fever, which spontaneously resolve within 18 to 24 hours, even with continued antibiotic therapy.169 The pathogenesis of this reaction is likely an acute antigen release by lysed bacteria.178

■ CEPHALOSPORINS O R1

C

S

NH N O

R2

COOH Cephem nucleus Cephalosporins are semisynthetic derivatives of cephalosporin C produced by the fungus Acremonium, previously called Cephalosporium. Cephalosporins have a ring structure similar to that of penicillins. Cephalosporins are generally divided into first, second, third, and fourth generations based on their antimicrobial spectrum. Firstgeneration cephalosporins include cefadroxil, cefazolin, cephalexin, cephapirin, and cephradine. Second-generation cephalosporins include cefaclor, cefamandole, cefonicid, cefotetan, cefoxitin, cefprozil, and cefuroxime. Third-generation cephalosporins include cefdinir, ceftazidime, cefixime, ceftibuten, cefoperazone, ceftizoxime, cefotaxime,

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ceftriaxone, and cefpodoxime. Finally, of the fourth-generation cephalosporins, cefepime was the first to be marketed. Effects occurring after acute overdose of cephalosporins resemble those occurring after penicillin exposure. Some cephalosporins also have epileptogenic potential similar to penicillin.255 Case reports demonstrate seizures after inadvertent intraventricular administration.39,146,265 Management of cephalosporin overdose is similar to that of penicillin overdose. Table 56–1 lists the pharmacologic mechanism of cephalosporins and Table 56–2 lists their pharmacokinetic properties. Adverse Effects Associated With Therapeutic Use Cephalosporins rarely cause an immune-mediated acute hemolytic crisis.78 Cefaclor is the cephalosporin most commonly reported to cause serum sickness, although this can occur with other cephalosporins.132,156 Also like penicillins, first-generation cephalosporins are associated with chronic toxicity, including interstitial nephritis and hepatitis.262 Cefepime is reported in a single case to cause reversible coma and electroencephalogram (EEG) confirmed nonconvulsive seizures.2 Cross-Hypersensitivity The cephalosporins contain a six-member dihydrithiazine ring instead of the five-member thiazolidine penicillin ring. The extent of cross-reactivity between penicillins and cephalosporins in an individual patient is largely determined by the type of penicillin allergic response experienced by the patient. The incidence of anaphylaxis to cephalosporins is between 0.0001% and 0.1%, with a threefold increase in patients with previous penicillin allergy.133 Ten percent of patients with prior penicillin-related anaphylactic reactions will have positive skin test for cephalosporin hypersensitivity.205 A negative skin test predicts a negative allergic response on oral cephalosporin challenge in penicillin-allergic patients. Finally, the incidence of delayed hypersensitivity reactions after cephalosporin use is 1% to 2.8% in the general population and 8.1% in those with prior penicillin delayed hypersensitivity. Cross-reactivity may be greater with the first- and second-generation cephalosporins that are more structurally similar to penicillin or that are contaminated by penicillin.8 Antibody binding after cephalosporin exposure occurs at the determinants located on the side-chain groups of the cephalosporin.14 In fact, IgE directed against a methylene substituent linking the side chain to the penicillin molecule is identified.107 These determinants are quite distinct among cephalosporins, which cause the pattern of cross-hypersensitivity among cephalosporins to be much less well defined than among the penicillins. Caution should be used when considering cephalosporins in penicillin- or cephalosporin-allergic patients; however, if a risk-to-benefit analysis demonstrates a clear benefit to the patient without equivalent alternatives, the cephalosporin should be given. N-methylthiotetrazole Side-Chain Effects Cephalosporins containing an N-methylthiotetrazole (nMTT) side chain (moxalactam, cefazolin, cefoperazone, cefmetazole, cefamandole, cefotetan) have toxic effects unique to their group structure. As these cephalosporins undergo metabolism, they release free nMTT, which is responsible for their effects (Fig. 56–1).165 Free nMTT inhibits the enzyme aldehyde dehydrogenase and, in conjunction with ethanol, can cause a disulfiram-like reaction (Chap. 79).43 The nMTT side chain is also associated with hypoprothrombinemia, although a causal relationship is controversial.101 It is thought that nMTT depletes vitamin K-dependent clotting factors by inhibition of vitamin K epoxide reductase.183 In a study of children 1 month to 1 year of age who were maintained on a prolonged antibiotic regimen, a significant degree of vitamin K depletion was found.25 Treatment of patients suspected of hypoprothrombinemia caused by these cephalosporins consists of fresh-frozen plasma, if bleeding is evident, and vitamin K1 in doses required to resynthesize vitamin K cofactors (Chap. 59).

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S

N N

Cross-Hypersensitivity Aztreonam is a monobactam that does not contain the antigenic components required for cross-allergy with penicillins, and generalized cross-allergenicity is not expected.215 However, aztreonam cross-reacts in vitro with ceftriaxone, thought to be the result of the similarity in their side-chain structure.192 Cross-allergenicity has also been noted between imipenem and penicillin, although the incidence has yet to be determined.

N N

H 3C nMTT side chain O S

CH2

C

NH

CH C N

S

O

OH

O

CH

C

NH

CH C N

O

■ TRIMETHOPRIM-SULFAMETHOXAZOLE

O

C

CH3

CH2 COOH

S

N

CH2 O COOH Cephalothin (without side chain) S

N

Cefamandole (with side chain)

N N

Trimethoprim and sulfamethoxazole work as antibacterials in tandem effectively preventing tetrahydrofolic acid synthesis in bacterial cells. Significant toxicity after acute overdose is not expected; however, a myrid of effects occur after chronic therapeutic use. Trimethoprim/ sulfamethoxazole combinations are commonly reported to result in cutaneous allergic reactions, hematologic disorders, methemoglobinemia, hypoglycemia, rhabdomyolysis, and psychosis.134,135,234,254,260

■ CHLORAMPHENICOL OH

H3C FIGURE 56-1. Characteristic structures of cephalosporins emphasizing the nMTT side chain.

O2N

CH

Cl CH

NH

H2C

C O

CH Cl

OH

■ OTHER β-LACTAM ANTIMICROBIALS H HO

C H

H S

N

H3C

NH

N O

COOH Imipenem S

H2N

O N

H

CH3

N N

N O

O HOOC

SO3H

CH3 CH3

Aztreonam Included in this group are monobactams such as aztreonam and carbapenems such as imipenem and meropenem. Table 56–1 lists the pharmacologic mechanism of these drugs, and Table 56–2 lists their pharmacokinetic properties. Effects occurring after acute overdose of other β-lactam antimicrobials resemble those occurring after penicillin exposure. Imipenem has epileptogenic potential in both overdose and therapeutic dosing (see section Adverse Effects Associated With Therapeutic Use).48,148 Management guidelines for other β-lactam overdoses are similar to those for penicillin overdoses. Adverse Effects Associated With Therapeutic Use The risk factors for imipenem-related seizures include central nervous system disease, prior seizure disorders, and abnormal renal function.190 The mechanism for seizures appears to be GABA antagonism (similar to the penicillins) in conjunction with enhanced activity of excitatory amino acids.67,235

Chloramphenicol was originally derived from Streptomyces venezuelae and is now produced synthetically. Antimicrobial activity exists against many gram-positive and gram-negative aerobes and anaerobes. Table 56–1 lists the pharmacologic mechanism of chloramphenicol, and Table 56–2 lists its pharmacokinetic properties. Acute overdose of chloramphenicol commonly causes nausea and vomiting. Effects are caused by its ability to inhibit protein synthesis in rapidly proliferating cells. Metabolic acidosis occurs as a result of the inhibition of mitochondrial enzymes, oxidative phosphorylation, and mitochondrial biogenesis.88 Infrequently, sudden cardiovascular collapse can occur 5 to 12 hours after acute overdoses. In case series, cardiovascular compromise was more frequent in patients with serum concentrations greater than 50 μg/mL.88,172,242 Because concentrations are not readily available, all poisoned patients should be closely observed for at least 12 hours after exposure. Orogastric lavage may be useful for recent ingestions when the patient has not vomited, and activated charcoal 1 g/kg should be given orally. Extracorporeal means of eliminating chloramphenicol are not usually required because of its rapid metabolism (see Table 56–2). However, both hemodialysis and charcoal hemoperfusion decrease elevated serum chloramphenicol concentrations and may be of benefit in patients with large overdoses, or in patients with severe hepatic or renal dysfunction.87,167,227 Exchange transfusion also lowers chloramphenicol serum concentrations in neonates.233 Surviving patients should be closely monitored for signs of bone marrow suppression. Adverse Effects Associated With Therapeutic Use Chronic toxicity of chloramphenicol is similar to that which occurs following acute poisoning. The classic description of chronic chloramphenicol toxicity is the “gray baby syndrome.”87,88,167,233 Children with this syndrome exhibit vomiting, anorexia, respiratory distress, abdominal distension, green stools, lethargy, cyanosis, ashen color, metabolic acidosis, hypotension, and cardiovascular collapse. The majority (90%) of a dose of chloramphenicol is metabolized via glucuronyl transferase, forming a glucuronide conjugate. The remainder is excreted renally unchanged. Infants, in particular, are predisposed to the gray baby syndrome because they have a limited capacity to form a glucuronide conjugate of chloramphenicol and, concomitantly, a limited ability to excrete unconjugated chloramphenicol in the urine.97,261

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There are two types of bone marrow suppression that occur after use of chloramphenicol. The most common type is dose dependent and occurs with high serum concentrations of chloramphenicol.118,119,221 Clinical manifestations usually occur within several weeks of therapy and include anemia, thrombocytopenia, leukopenia, and very rarely, aplastic anemia. Bone marrow suppression is generally reversible on discontinuation of therapy. A second type of bone marrow suppression caused by chloramphenicaol occurs through this inhibition of protein synthesis in the mitochondria of marrow cell lines.175 This type causes the development of aplastic anemia, which is not dose related and generally occurs in susceptible patients within 5 months of treatment and has an approximately 50% mortality rate (Chap. 24).77,268 The dehydro and nitroso bacterial metabolites of chloramphenicol injure human bone marrow cells through inhibition of myeloid colony growth, inhibition of DNA synthesis, and inhibition of mitochondrial protein synthesis.129 Other adverse effects associated with chloramphenicol include peripheral neuropathy195; neurologic abnormalities, such as confusion and delirium150; optic neuritis59; nonlymphocytic leukemia225; and contact dermatitis.140

■ FLUOROQUINOLONES HN N

N

F

COOH O Ciprofloxacin

The fluoroquinolones are a structurally similar, synthetically derived group of antimicrobials that have diverse antimicrobial activities. They include balofloxacin, ciprofloxacin, clinafloxacin, enoxacin, fleroxacin, gatifloxacin, gemifloxacin, grepafloxacin, levofloxacin, lomefloxacin, moxifloxacin, nadifloxacin, nalidixic acid, norfloxacin, ofloxacin, pefloxacin, rufloxacin, sparfloxacin, temafloxacin, tosufloxacin, and trovafloxacin. Like other antimicrobials, the fluoroquinolones rarely produce life-threatening effects following acute overdose, and most patients can be safely managed with minimal intervention.11 Table 56–1 lists the pharmacologic mechanism of fluoroquinolones, and Table 56–2 lists their pharmacokinetic properties. Rarely, acute overdose of a fluoroquinolone results in renal failure or seizures.143 The mechanism of renal failure after fluoroquinolone exposure is controversial. In animals, ciprofloxacin and norfloxacin cause nephrotoxicity, especially in the setting of neutral or alkaline urine.61,218 In humans, renal failure is reported after both acute and chronic exposure to fluoroquinolones. A hypersensitivity reaction is postulated to explain pathologic changes consistent with interstitial nephritis.116,202 Treatment includes discontinuation of the fluoroquinolone and supportive care. Improvement in renal function is usually noticed within several days. Seizures are reported with ciprofloxacin and may be a result of the inhibition of GABA.228,245 Others postulate that seizures result from the ability of fluoroquinolones to bind efficiently to cations, particularly magnesium. This hypothesis is related to the inhibitory role of magnesium at the excitatory NMDA-gated ion channel (Chap. 13).68,219 Treatment is supportive, using benzodiazepines and, if necessary, barbiturates to increase inhibitory tone.

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can result in drug interactions, which are especially important with drugs that have a narrow therapeutic index. Serious adverse effects related to fluoroquinolone use consist of central nervous system toxicity, as discussed, cardiovascular toxicity,126 hepatotoxicity, and notable musculoskeletal toxicity. Fluoroquinolones cause prolongation of the QT interval and may cause torsades de pointes.40,126,213 Although the mechanism is unclear, sequestering of magnesium, resulting in clinical hypomagnesemia, is postulated.219 Treatment of patients presenting with QT prolongation is supportive, with careful attention to magnesium supplementation if necessary. The fluoroquinolones rarely result in potentially fatal hepatotoxicity.54,89,99,144,158,206 This adverse effect is most notable with trovafloxacin. In vitro models show trovafloxacin to be uniquely capable of altering gene expression that regulates oxidative stress and RNA processing leading to mitochondrial damage.152 Consequently, trovafloxacin (Trovan) is now reserved only for the treatment of patients with life-threatening infections in whom the benefits are thought to outweigh the risks. In addition, the manufacturer has initiated a limited distribution system that allows drug shipment only to pharmacies within inpatient healthcare facilities. Fluoroquinolones should be used with caution in children and pregnant women because of their potential adverse effects on developing cartilage and bone. Damage to articular cartilage is demonstrated in young dogs and rats, although the extent varies among different fluoroquinolones.45,238 There are very limited data regarding damage to articular cartilage as a result of using fluoroquinolones in humans; however, children given ciprofloxacin on a compassionate basis developed complaints of swollen, painful, and stiff joints after 3 weeks of therapy.128 All signs and symptoms abated within 2 weeks of discontinuation of therapy. However, 29 additional children treated with ofloxacin or ciprofloxacin showed no differences with respect to cartilage thickness, cartilage structure, edema, cartilage-bone borderline, or synovial fluid.65 Women who received quinolones during pregnancy had larger babies and more caesarean deliveries because of fetal distress than did controls.22 However, there were no congenital malformations, delay to developmental milestones, or musculoskeletal abnormalities found. Fluoroquinolones are also implicated as a cause of tendon rupture, which is reported to occur up to 120 days after the start of treatment and even after the discontinuation of therapy.191 The fluoroquinolone should be discontinued in patients, particularly athletes who complain of symptoms consistent with painful and swollen tendons. Other adverse effects include acute psychosis, dysglycemia (hyperand hypoglycemia), rash, tinnitus, eosinophilia, serum sickness, and photosensitivity.44,103,173,188,232

■ MACROLIDES AND KETOLIDES

Adverse Effects Associated With Therapeutic Use Several fluoroquinolones are substrates and/or inhibitors of cytochrome CYP isozymes. This

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The macrolide antimicrobials include various forms of erythromycin (base, estolate, ethylsuccinate, gluceptate, lactobionate, stearate), azithromycin, clarithromycin, troleandomycin, and dirithromycin. Ketolides are similar in pharmacology to macrolides; telithromycin is the only available agent at this time. Table 56–1 lists the pharmacologic mechanism of macrolides and ketolides, and Table 56–2 lists their pharmacokinetic properties. Acute oral overdoses of macrolide antimicrobials are usually not life threatening and symptoms, which are generally confined to the gastrointestinal tract, include nausea, vomiting, and diarrhea. A single case of pancreatitis is reported.241 Erythromycin lactobionate causes QT prolongation and torsades de pointes after intravenous use.184 Oral erythromycin is also implicated in causing prolongation of the QT and torsades de pointes, especially in patients concurrently taking cytochrome P450 (CYP) 3A4 inhibitors.196 In vitro models demonstrate erythromycin’s ability to slow repolarization in a concentrationdependent manner.177 The cause of prolonged QT interval was once thought to be from hypokalemia-induced promotion of intracellular efflux of potassium.197 Data, however, demonstrate that the QT interval prolongation results from blockade of delayed rectifier potassium currents (Chaps. 22 and 23).208 QT prolongation and torsades de pointes are common after intravenous erythromycin lactobionate.184 More pronounced prolongation occurs in patients with underlying heart disease and correlates with the infusion rate.106 Epidemiologic studies note an increased incidence of ventricular dysrhythmias in women treated with erythromycin.75 Although there are no acute overdose data regarding ketolide antimicrobials, effects are expected to be similar to macrolide antimicrobials. Therapeutic use of telithromycin is reported to result in QT prolongation, hepatotoxicity, toxic epidermal necrolysis and anaphylaxis.1,17,27,29,74,185 Adverse Events Associated With Therapeutic Use Drug Interactions. Erythromycin is the prototypical macrolide and, as such, has received the most attention with respect to potential and documented drug interactions. 115 Clarithromycin, erythromycin, and troleandomycin are all potent inhibitors of the CYP3A4 enzyme system; azithromycin does not inhibit this enzyme.64 Erythromycin inhibits cytochrome P450 after metabolism to a nitroso intermediate, which then forms an inactive complex with the iron (II) of cytochrome P450. Chapter 12 (Appendix) lists substrates for the CYP3A4 system. Clinically significant interactions occur with erythromycin and warfarin, carbamazepine, terfenadine or cyclosporine.46,111,115,194 Inhibition of cisapride metabolism results in increased concentrations of the parent drug, which is capable of causing prolongation of the QT interval and causing torsades de pointes.35 Cases of carbamazepine toxicity are documented when combined with the use of erythromycin.111 Erythromycin also inhibits CYP1A2, producing clinically significant interactions with clozapine, theophylline, and warfarin.204 Macrolides may also interact with the absorption and renal excretion of drugs that are amenable to intestinal P-glycoprotein excretion, or interfere with normal gut flora responsible for metabolism. This may be part of the underlying mechanism of cases of macrolide-induced digoxin toxicity (Chap. 64).182 End-Organ Effects The most common toxic effect of macrolides after

chronic use is hepatitis, which may be immune mediated.49 Erythromycin estolate is the agent most frequently implicated in causing cholestatic hepatitis.96,123 Large doses (more than 4 g/d) of macrolide antimicrobials are also associated with reversible high-frequency sensorineural hearing loss.41 Renal impairment may be a risk factor.211,236 There are rare case reports in which ototoxicity did not resolve following discontinuation of therapy.149 There are insufficient data concerning the ototoxic

potential of the other macrolide antimicrobials. Other, rare toxic effects associated with macrolides include cataracts after clarithromycin use in animals and acute pancreatitis in humans.82,249 Allergy is rare and reported at a rate of 0.4% to 3%.70 Telithromycin contains a carbamate side chain that may interfere with the normal function of neuronal cholinesterase. It should be used cautiously in patients with myasthenia gravis, particularly patients receiving pyridostigmine because of the risk of cholinergic crisis.240 Clindamycin is a lincosamide with similar structure and clinical effects to macrolides. Clindamycin phosphate is commonly used topically while clindamycin hydrochloride is available for intravenous use. Data regarding acute overdose is limited and the majority of the chronic toxicity is seen after use of systemic doses of clindamycin phosphate. The most consequental toxicity is gastrointestinal resulting in esophageal ulcers, diarrhea, and colitis.203

■ SULFONAMIDES O

N

O S

NH

O CH3

H2N Sulfamethoxazole Sulfonamides antagonize para-aminobenzoic acid or para-aminobenzyl glutamic acid, which are required for the biosynthesis of folic acid. Table 56–1 lists the pharmacologic mechanism of sulfonamides, and Table 56–2 lists their pharmacokinetic properties. Acute oral overdoses of sulfonamides are usually not life threatening, and symptoms are generally confined to nausea, although allergy and methemoglobinemia occur rarely.86 Treatment is similar to acute oral penicillin overdoses. Adverse Effects Associated With Therapeutic Use The most common adverse effects associated with sulfonamide therapy are nausea and cutaneous hypersensitivity reactions. Hypersensitivity reactions are thought to be caused by the formation of hapten sulfamethoxazole metabolites, N-hydroxy-sulfamethoxazole and nitroso-sulfamethoxazole. The degree of hapten binding is mitigated in vitro by cysteine and glutathione.176 The incidence of adverse reactions to sulfonamides, including allergy, is increased in HIV-positive patients and is positively correlated to the number of previous opportunistic infections experienced by the patient.147 This may be caused by a decrease in the mechanisms available for detoxification of free radical formation, as cysteine and glutathione levels are low in these patients.257 Whether supplementation with a glutathione precursor such as N-acetylcysteine will reduce the incidence of these reactions is unknown.3 Methemoglobinemia and hemolysis also rarely occur.76,155 The mechanism for adverse reactions is not entirely clear. However, when sulfamethoxazole is exposed to ultraviolet B (UVB) radiation in vitro, free radicals are formed that can participate in the development of tissue peroxidation and hemolysis.268 This finding may be of particular importance in treating patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency associated with decreased in reducing capabilities.5 The sulfonamides are associated with many chronic adverse effects. Bone marrow suppression is rare, but the incidence is increased in patients with folic acid or vitamin B12 deficiency, and in children, pregnant women, alcoholics, dialysis patients, and immunocompromised patients, as well as in patients who are receiving other folate antagonists. Other adverse effects include hypersensitivity pneumonitis, stomatitis, aseptic meningitis, hepatotoxicity, renal toxicity, and central nervous system toxicity.30

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■ TETRACYCLINES OH

O

OH

OH

O

O NH2

OH CH3

N H3C

CH3

Tetracycline Tetracyclines are derivatives of Streptomyces cultures. Currently available tetracyclines include demeclocycline, doxycycline, methacycline, minocycline, oxytetracycline, and tetracycline. Table 56–1 lists the pharmacologic mechanism of tetracyclines, and Table 56–2 lists their pharmacokinetic properties. Significant toxicity after acute overdose of tetracyclines is unlikely. Gastrointestinal effects consisting of nausea, vomiting, and epigastric pain have been reported.42 Adverse Effects Associated With Therapeutic Use Tetracycline should not be used in children during the first 6 to 8 years of life or by pregnant women after the 12th week of pregnancy because of the risk of development of secondary tooth discoloration in children or developing children in utero. Other effects associated with tetracyclines include nephrotoxicity, hepatotoxicity, skin hyperpigmentation in sun-exposed areas, and hypersensitivity reactions.49,100,121,239 More severe hypersensitivity reactions, drug-induced lupus, and pneumonitis are reported after minocycline use, as are cases of necrotizing vasculitis of the skin and uterine cervix, and lymphadenopathy with eosinophilia.160,220,224 Demeclocycline rarely causes nephrogenic diabetes insipidus (Chap. 16).50 Of historical interest, outdated older formulations of tetracycline were reported to cause hypouricemia, hypokalemia, and a proximal and distal renal tubular acidosis.57

■ VANCOMYCIN NH2 H3C

O

CH3

OH

OH

O HO

825

activated charcoal and potentially high-flux hemodialysis can be considered for patients with large overdoses when the patient is expected to have prolonged clearance.141,248

C

HO

Antimicrobials, Antifungals, and Antivirals

CH2OH

Adverse Effects Associated With Therapeutic Use Patients who receive intravenous vancomycin may develop the “red man syndrome” through an anaphylactoid reaction.93 Symptoms include chest pain, dyspnea, pruritus, urticaria, flushing, and angioedema.207 Signs and symptoms spontaneously resolve, typically within 15 minutes. Other symptoms attributable to red man syndrome include hypotension, cardiovascular collapse, and seizures.13,179 The incidence of red man syndrome appears to be related to the rate of infusion and is approximately 14% when 1 g is given over 10 minutes, whereas it is 3.4% when given over 1 hour.179,186 A trial in 11 healthy persons studied the relationship between intradermal skin hypersensitivity and the development of red man syndrome. Each of the 11 subjects underwent skin testing that was followed 1 week later by an intravenous dose of vancomycin 15 mg/kg over 60 minutes. Following intravenous vancomycin, all subjects developed dermal flare responses and erythema, and 10 of 11 subjects developed pruritus within 20 to 45 minutes. After the infusion was terminated, symptoms resolved within 60 minutes.193 The signs and symptoms of red man syndrome are related to the rise and fall of histamine concentrations.110,151 Tachyphylaxis occurs in patients given multiple doses of vancomycin.109,256 Animal models demonstrated a direct myocardial depressant and vasodilatory effect of vancomycin.60 More serious reactions result when vancomycin is given via intravenous bolus, further supporting a rate-related anaphylactoid mechanism.24 Patients most often experience red man syndrome after vancomycin is administered intravenously. In rare cases, oral administration of vancomycin can also result in the syndrome.21 Treatment includes increasing the dilution of vancomycin and slowing intravenous administration. Antihistamines may be useful as pretreatment, especially prior to the first dose.198 A placebo-controlled trial in adult patients studied the incidence of these symptoms in patients given 1 g of vancomycin over 1 hour, as well as the effect of diphenhydramine in the prevention of the syndrome.256 There was a 47% incidence of reaction without diphenhydramine and a 0% incidence with diphenhydramine. Chronic use of vancomycin may cause reversible nephrotoxicity, particularly in patients with prolonged excessive steady-state se rum levels.10,201 Concomitant administration of aminoglycoside antimicrobials may increase the risk of nephrotoxicity.209 Vancomycin also causes, though rarely, thrombocytopenia and neutropenia.56,58,73

O Cl

O O HO

H

H O

O N

ANTIFUNGALS

O

H

H

Cl

H

N

N

N O

H

HOOC

O

O N H NH2

OH O NHCH3

N

O

H H3C

Numerous antifungals are available. Toxicity related to the use of antifungals is variable and is based generally on their mechanism of action.

■ AMPHOTERICIN B CH3

OH HO

OH

Vancomycin

Vancomycin is obtained from cultures of Nocardia orientalis and is a tricyclic glycopeptide. Vancomycin is biologically active against numerous gram-positive organisms. Table 56–1 lists the pharmacologic mechanism of vancomycin, and Table 56–2 lists its pharmacokinetic properties. Acute oral overdoses of vancomycin rarely cause significant toxicity and most cases can be treated with supportive care alone. Multiple-dose

Amphotericin B is a potent antifungal derived from Streptomyces nodosus. Amphotericin B is generally fungistatic against fungi that contain sterols in their cell membrane. Table 56–1 lists the pharmacologic mechanism of amphotericin B, and Table 56–2 lists its pharmacokinetic

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The Clinical Basis of Medical Toxicology

properties. Development of lipid and colloidal formulations of amphotericin B attenuate the adverse effects associated with amphotericin B.104 In these preparations, the amphotericin B is complexed with either a lipid or cholesteryl sulfate. On contact with a fungus, lipases are released to free the complexed amphotericin B, resulting in focused cell death.113 There are several case reports of amphotericin B overdose in infants and children. Significant clinical findings include hypokalemia, increased aspartate aminotransferase concentrations, and cardiac complications. Dysrhythmias and cardiac arrest have occurred following doses of 5 to 15 mg/kg of amphotericin B.36,58,137 Care should be used in the doses of amphotericin B administered according to dosage form, as these are not interchangeable. For example, intravenous therapy for fungal infections includes a usual dose of 0.25 to 1 mg/kg/d of amphotericin B or 3 to 4 mg/kg/d of amphotericin B cholesteryl. The potential for significant dosage errors and their sequelae is readily apparent in this comparison. Adverse Effects Associated With Therapeutic Use Infusion of amphotericin B results in fever, rigors, headache, nausea, vomiting, hypotension, tachycardia, and dyspnea.161 Pretreatment with acetaminophen, diphenhydramine, ibuprofen, and hydrocortisone is helpful in alleviating the febrile symptoms, as are slower rates of infusion and lower total daily doses.95,247 Doses greater than 1 mg/kg/d and rapid administration of drug in less than 1 hour are not recommended. Infusion concentrations of amphotericin B greater than 0.1 mg/mL can result in localized phlebitis. Slower infusion rates, hot packs, and frequent line flushing with dextrose in water may help to alleviate symptoms. Eighty percent of patients exposed to amphotericin B will sustain some degree of renal insufficiency (Chap. 27).47 Initial distal renal tubule damage causes renal artery vasoconstriction ultimately resulting in azotemia.83 Studies in animals show depressed renal blood flow and glomerular filtration rate, and increased renal vascular resistance. It is unclear why this occurs, but at this time, renal nerves, angiotensin II, nitric oxide, and tubuloglomerular feedback are excluded.210,216 The toxic effects associated with amphotericin B may also be caused by the deoxycholate vehicle.267 After large total doses of amphotericin B, residual decreases in glomerular filtration rate may occur even after discontinuation of therapy. This is hypothesized to be the result of nephrocalcinosis. Potassium and magnesium wasting, proteinuria, decreased renal concentrating ability, renal tubular acidosis, and hematuria also occur (Chap. 16).15,161 Strategies to reduce renal toxicity after amphotericin B include intravenous saline or magnesium and potassium supplementation.34,84,112 Liposomal formulations of amphotericin B resulted in fewer patients with breakthrough fungal infections, infusion-related fever, rigors, or nephrotoxicity.258 However, chest pain is uniquely reported after use of the liposomal agent.130 Other adverse effects reported after treatment with amphotericin B include normochromic, normocytic anemia secondary to decreased erythropoietin release;159 respiratory insufficiency with infiltrates; and, rarely, dysrhythmias, tinnitus, thrombocytopenia, peripheral neuropathy, and leukopenia.153,159,161 Exchange transfusion may be useful in neonates and infants and should be considered after large intravenous exposures. In adults, extracorporeal elimination is not expected to be useful because of the low water solubility and high blood-protein binding of the drug.

■ AZOLE ANTIFUNGALS: TRIAZOLE AND IMIDAZOLES OH

N N

C

C

N

N C

N F

N

Common triazole antifungals include fluconazole, itraconazole, and voriconazole. Common imidazoles include clotrimazole, econazole, ketoconazole, and miconazole. Triazole antifungals are active to treat an array of fungal pathogens, whereas imidazoles are used almost exclusively in the treatment of superficial mycoses and vaginal candidiasis. Severe toxicity is not expected in the overdose setting. Hepatotoxicity, thrombocytopenia, and neutropenia are uncommon.31 Rare case reports implicate voriconazole in the development of toxic epidermal necrolysis.117 The majority of toxic effects noted after the use of these drugs result from their drug interactions. Fluconazole, itraconazole, ketoconazole, and miconazole competitively inhibit CYP3A4, the enzyme system responsible for the metabolism of many drugs. Table 56–5 lists other organ system manifestations associated with antifungal agents and other antimicrobials.

ANTIPARASITICS Antiparasitics such as thiabendazole, mebendazole, albendazole, diethylcarbazine, ivermectin, metrifonate, niclosamide, oxamniquine, piperazine, priziquantel, and pyrantel pamoate generally have a low level of toxicity in the overdose setting. Common symptoms after therapeutic use are gastrointestinal in nature and include abdominal pain, nausea, vomiting, and diarrhea. A single case of ivermectin-associated hepatic failure is reported 1 month after a single dose.252

ANTIVIRAL Acyclovir is well tolerated in therapeutic doses and overdoses, although data are limited. In 105 dogs ingesting 40 to 2195 mg/kg, gastrointestinal symptoms were most common with one dog developing mild creatinine increases.200 Depressed mental status and nephrotoxicity are also reported after therapeutic use in humans.32

ANTIMICROBIALS SPECIFIC TO THE TREATMENT OF HUMAN IMMUNODEFICIENCY VIRUS AND RELATED INFECTIONS The evaluation and management of patients infected with the human immunodeficiency virus (HIV) and associated acquired immune deficiency syndrome (AIDS) is ever evolving at a rapid and progressive pace. Medications used to manage this disorder have dramatically increased life expectancy as new, more powerful antiviral agents and drug combinations become available. Drug therapy for HIV commonly consists of a combination of drugs from different classes (nucleoside reverse transcriptase inhibitor [NRTI], nonnucleoside reverse transcriptase inhibitor [NNRTI], and protease inhibitor) in order to take advantage of the unique mechanism that each drug offers in inhibiting viral replication and minimizing drug resistance. Resistance patterns to the typical drugs used in attenuating viral replication and proliferation are a substantial issue and will continue to be addressed with yet more evolution in management in the foreseeable future. This section focuses on overdoses and major toxic effects from HIV-directed antiviral therapy, as well as from drugs that are specifically used in the management of opportunistic infections.20 Table 56–6 lists the common antibiotic agents used to treat HIV-related opportunistic infections, and Table 56–7 lists common adverse drug effects and overdose effects, if known, for antimicrobials that are specific in their use for HIV-related infections.

■ SPECIFIC ANTIRETROVIRAL CLASSES

Fluconazole F

Nucleoside Analog Reverse Transcriptase Inhibitors The nucleoside analog reverse transcriptase inhibitors inhibit the reverse transcription

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Antimicrobials, Antifungals, and Antivirals

TABLE 56–5. Consequential Organ System Manifestations Associated With Antimicrobials

TABLE 56–6. Antimicrobials Used to Treat Common Opportunistic Infections20

Antimicrobial

Antimicrobial

Opportunistic Infection

Albendazole Amphotericin B

Microsporidiosis Aspergillosis Coccidioidomycosis Cryptococcosis Histoplasmosis Leishmaniasis Paracoccidioidomycosis Penicilliosis Leishmaniasis Pneumocystis jiroveci Mycobacterium avium complex Mycobacterium avium complex Aspergillosis Pneumocystis jiroveci Toxoplasma gondii Pneumocystis jiroveci Mycobacterium avium complex Coccidioidomycosis Histoplasmosis Cryptococcosis Cytomegalovirus Microsporidiosis Cytomegalovirus Histoplasmosis Pneumocystis jiroveci Toxoplasma gondii Cryptosporidiosis Microsporidiosis Cryptosporidiosis Pneumocystis jiroveci Pneumocystis jiroveci Toxoplasma gondii Mycobacterium avium complex Toxoplasma gondii Pneumocystis jiroveci Toxoplasma gondii Isosporiasis Pneumocystis jiroveci Cytomegalovirus Aspergillosis

Antibacterials Bacitracin Clindamycin

Colistimethate (colistin sulfate)

System

Signs, Symptoms, Laboratory

Immune Immune Gastrointestinal Nervous Renal

Hypersensitivity reactions Hypersensitivity reactions Nausea, vomiting, diarrhea Dizziness, headache, vertigo Decreased function, acute tubular necrosis Peripheral paresthesias, confusion, coma, seizures, neuromuscular blockade Nausea, vomiting, diarrhea Hypersensitivity reactions Peripheral neuropathy, seizures Nausea, vomiting Disulfiram reactions Hypersensitivity reactions Ointment contains polyethylene glycols (renal dysfunction) Nausea, vomiting, diarrhea Jaundice Rash, acute and chronic pulmonary hypersensitivity Peripheral neuropathy Rash Nausea, vomiting, diarrhea Pancytopenia, hemolytic anemia Muscle weakness, seizures Azotemia, proteinuria Contact dermatitis, alopecia (rare) Contact dermatitis Anemia, aplastic anemia Rash (rare)

Nervous

Lincomycin Metronidazole

Nitrofurazone

Nitrofurantoin

Novobiocin

Polymyxin B sulfate Selenium sulfide Silver sulfadiazine Spectinomycin Antifungals Benzoic acid Carbol-fuchsin solution (phenol/ resorcinol/ fuchsin) Gentian violet

Gastrointestinal Immune Neurologic Gastrointestinal Other Immune Other Gastrointestinal Hepatic Immune Neurologic Immune Gastrointestinal Hematologic Neurologic Renal Cutaneous Cutaneous Hematologic Immune

Gastrointestinal Nausea, vomiting, diarrhea Gastrointestinal Nausea, vomiting, diarrhea

Gastrointestinal Immune Renal Hepatic Gastrointestinal Immune Other

Nausea, vomiting, diarrhea Rash (rare) Griseofulvin Proteinuria, nephrosis Increased enzymes Nausea, vomiting, diarrhea Granulocytopenia Disulfiram reactions, increased porphyrins Nystatin Gastrointestinal Nausea, vomiting, diarrhea Salicylic acid Gastrointestinal Higher concentrations are caustic and dermal Undecylenic acid and Gastrointestinal Nausea, vomiting, diarrhea undecylenate salt

Antimony (pentavalent) Atovaquone Azithromycin Clarithromycin Caspofungin Clindamycin Dapsone Ethambutol Fluconazole Flucytosine Foscarnet Fumagillin Ganciclovir Itraconazole Leucovorin Nitazoxanide Paromomycin Pentamidine Primaquine Pyrimethamine Rifabutin Sulfadiazine Trimethoprinsulfamethoxazole Trimetrexate Valganciclovir Voriconazole

827

of viral RNA into proviral DNA. Currently available drugs include abacavir (ABC), emtricitabine (FTC), didanosine (ddI), lamivudine (3TC), stavudine (d4T), tenofovir (TDF), zidovudine (AZT, ZDV), and zalcitabine (ddC). Acute Overdose Effects. Many intentional overdoses of reverse tran-

scriptase inhibitors occur without major toxicologic effect. The most serious adverse effect anticipated after acute overdose of an NRTI is

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TABLE 56–7. Antimicrobials Used in the Treatment of HIV-Related Infections20 Antimicrobial

Overdose Effects

Common Adverse Drug Effects

Albendazole

No reported cases

Antimony (pentavalent) Atovaquone

Acute tubular necrosis No clinical relevant effects in reported cases55 No reported cases No reported cases No reported cases

Increased AST/ALT, nausea, vomiting, and diarrhea. Hematologic, rare—encephalopathy, renal failure, rash Acute tubular necrosis. Multiorgan system failure Rashes, anemia, leukopenia, increased AST/ALT

Caspofungin Flucytosine Foscarnet

Fumagillin Ganciclovir

No reported cases No clinical relevant effects in reported cases138

Nitazoxzanide

No reported cases

Pentamidine

40 times dosing error in a 17-month-old child resulted in cardiac arrest259

Primaquine

No reported cases

Pyrimethamine Rifabutin

No reported cases High doses (>1 g daily): arthralgia/ arthritis Acute renal failure and hypoglycemia63

Sulfadiazine

Trimetrexate Valganciclovir

No reported cases; treat similar to methotrexate (Chap. 53) No reported cases; expect to be similar to ganciclovir

Phlebitis, headache, hypokalemia, increased AST/ALT, fever Bone marrow suppression, hepatotoxicity, nausea, vomiting, diarrhea, and rash Azotemia, hypocalcemia and renal failure (common); anemia, leukopenia, thrombocytopenia, fever, headache, seizures, genital and oral ulcers, fixed-drug eruptions, nausea, vomiting, diarrhea, headaches, seizures, coma, diabetes insipidus, hypophosphatemia, hypokalemia, and hypomagnesemia Neutropenia and thrombocytopenia Leukopenia, worsening of renal function; can also cause nausea, vomiting, diarrhea, increased AST/ALT, anemia, thrombocytopenia, headache, dizziness, confusion, seizures Hypotension, headache, abdominal pain, nausea, vomiting; may cause green-yellow urine discoloration Hypoglycemia (early) followed by hyperglycemia, azotemia; can cause hypotension, torsades de pointes, phlebitis, rash, Stevens-Johnson syndrome, hypocalcemia, hypokalemia, anorexia, nausea, vomiting, metallic taste, leukopenia, and thrombocytopenia Granulocytopenia, hemolytic anemia, methemoglobinemia, leukocytosis; hypertension Agranulocytosis, aplastic anemia, thrombocytopenia, and leukopenia Nausea, vomiting, diarrhea; can cause hepatotoxicity, neutropenia, thrombocytopenia, and hypersensitivity reactions Rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme; headaches, depression, hallucinations, ataxia, tremor, crystalluria, hematuria, proteinuria, and nephrolithiasis Myelosuppression, nausea, vomiting, histaminergic reactions Anemia, neutropenia, thrombocytopenia; nausea, vomiting, headache, peripheral neuropathy

AST/ALT, serum alanine aminotransferase or serum aspartate aminotransferase.

the development of a lactic acidemia, which appears to be more common in women.52,81,162 Following incorporation of the nucleoside analog into mitochondrial DNA by RNA polymerase, DNA polymerase γ is inhibited. This results in decreased production of mitochondrial DNA electron transport proteins, which ultimately inhibits oxidative phosphorylation (Chap. 12). Organ system toxicity follows in addition to the development of acidemia. The reported mortality in patients with NRTI-associated metabolic acidosis associated with elevated lactate is 33% to 57%.81 Resolution of symptoms in survivors is 1 to 24 weeks. Patients with NRTI-associated acidemia may recover more quickly after the use of cofactors such as thiamine, riboflavin, l-carnitine, vitamin C, and antioxidants.38,71 The indications for the use of these drugs are unclear at this time; however, because of the relative lack of toxicity, they may be considered.

Chronic Effects. Development of acidemia is more commonly associ-

ated with therapeutic use of reverse transcriptase inhibitors than with acute overdose. The mechanism is likely identical to that described above. Other common adverse effects are somewhat agent specific and include hematologic toxicity after zidovidine,71,98 pancreatitis with didanosine,145 hypersensitivity after abacavir,70 and sensory peripheral neuropathy after zalcitabine, stavudine, and didanosine.171 Nonnucleoside Reverse Transcriptase Inhibitors NNRTI bind directly to reverse transcriptase enzymes enabling allosteric inhibition of enzymatic function.243 Delavirdine (Rescriptor), etravirine (Intelence), efavirenz (Sustiva), and nevirapine (Viramune) comprise the currently available agents. There are no substantial acute overdose data on these drugs, although they generally appear to be safe in overdose. Treatment should include

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supportive care until more information is available. The NNRTIs are also limited in toxicity after chronic use. Nevirapine and delavirdine use commonly results in hypersensitivity reactions such as rash.69 Efavirenz is reported to result in dizziness and dysphoria. Otherwise, toxicity can result from the ability of these drugs to either inhibit or enhance CYP isozymes in the metabolism of other drugs. Protease Inhibitors Protease inhibitors inhibit the vital enzyme (proteinase), which is required for viral replication.85 Currently available drugs include ataznavir (Reyatax), darunavir (Prezista), fosamprenavor (Lexiva), indinavir (Crixivan), lopinavir (Kaletra), nelfinavir (Viracept), ritonavir (Norvir), saquinavir mesylate (Invirase), and tipranavir (Aptivus). Data after protease inhibitor overdose are limited. A review of data submitted to the manufacturer of indinavir found that of 79 reports, the complaints were nausea, vomiting, abdominal pain, and nephrolithiasis. Protease inhibitors as a class commonly result in gastrointestinal symptoms and rash.85 A unique finding is an altered fat distribution pattern that, over time, results in lymphodystrophy central obesity, “buffalo hump,” breast enlargement, cushingoid appearance, and peripheral wasting.85 Entry/Fusion Inhibitors This class of drugs interferes with the binding or entry of the HIV viron into the cell.26 No acute overdose data are available for this class, but after chronic use, hypersensitivity, hepatotoxicity, and infusion reactions seem to be of greatest concern.18,174,180 The currently available agents include enfuvirtide (Fuzeon) and maraviroc (Selzentry). Integrace Inhibitor This class of drugs prevents the activity of the enzyme in HIV to function normally. This enzyme is responsible for the incorporation of the virus into DNA. The currently available agent is raltegravir (Isentress). No information is currently available regarding its toxicity.

SUMMARY Adverse effects attributable to antimicrobials are largely related to chronic administration, although rarely acute toxicity does occur. Acute toxic effects of antimicrobials are more common following intravenous administration, drug interactions, or iatrogenic overdose. Vigilance on the part of the healthcare provider will prevent the majority of acute toxic manifestations following antimicrobial use.

REFERENCES 1. [No authors listed.] Telithromycin. QT prolongation. Prescrire Int. 2007; 16:71. 2. Abanades S, Nolla J, Rodriguez-Campello A, et al. Reversible coma secondary to cefepime neurotoxicity. Ann Pharmacother. 2004;38:606-608. 3. Akerlund B, Tynell E, Bratt G, Bielenstein M, Lidman C. N-Acetylcysteine treatment and the rise of toxic reactions to trimethoprim-sulfamethoxazole in primary Pneumocystis carinii prophylaxis in HIV-infected patients. J Infect. 1997;35:143-147. 4. Ali MZ, Goetz MB. A meta-analysis of the relative efficacy and toxicity of single daily dosing versus multiple daily dosing of aminoglycosides. Clin Infect Dis. 1997;24:796-809. 5. Ali NA, Al-Naama LM, Khalid LO. Haemolytic potential of three chemotherapeutic agents and aspirin in glucose-6-phosphate dehydrogenase deficiency. East Mediterr Health J. 1999;5:457-464. 6. Andrade RJ, Guilarte J, Salmeron FJ, Lucean MI, Bellot V. Benzylpenicillininduced prolonged cholestasis. Ann Pharmacother. 2001;35:783-784. 7. Andrade RJ, Lucena MI, Fernandez MC, Vega JL, Camargo R. Hepatotoxicity in patients with cirrhosis, an often unrecognized problem. Lessons from a fatal case related to amoxicillin/clavulanic acid. Dig Dis Sci. 2001;46: 1416-1419.

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39. Brossner G, Engelhardt K, Beer R, et al. Accidental intrathecal infusion of cefotiam. Clinical presentation and management. Eur J Clin Pharmacol. 2004; 60:373-375. 40. Brozanski BS, Scher MS, Albright AL. Intraventricular nafcillin-induced seizures in a neonate. Pediatr Neurol. 1988;4:188-190. 41. Brummett RE. Ototoxic liability of erythromycin and analogues. Otolaryngol Clin North Am. 1993;26:811-819. 42. Bryant SG, Fisher S, Kluge RM. Increased frequency of doxycycline side effects. Pharmacotherapy. 1987;7:125-129. 43. Buening MK, Wold JS, Israel KS, Kammer RB. Disulfiram-like reaction to beta-lactams. JAMA. 1980;245:2027-2028. 44. Burdge DR, Nakielna EM, Rabin HR. Photosensitivity associated with ciprofloxacin use in adult patients with cystic fibrosis. Antimicrob Agents Chemother. 1995;39:793. 45. Burkhardt JE, Hill MA, Lamar CH, Smith GN Jr, Carlton WW. Effects of difloxacin on the metabolism of glycosaminoglycans and collagen in organ cultures of articular cartilage. Fundam Appl Toxicol. 1993;20:257-263. 46. Bussey HI, Knodel LC, Boyle DA. Warfarin-erythromycin interaction. Arch Intern Med. 1985;145:1736-1737. 47. Butler WT, Bennett JE, Hill GJ 2nd. Electrocardiographic and electrolyte abnormalities caused by amphotericin B in dog and man. Proc Soc Exp Biol Med. 1964;116:857-863. 48. Calandra GB, Wang C, Aziz M, Brown KR. The safety profile of imipenem/ cilastatin. Worldwide experience base on 3,470 patients. J Antimicrob Chemother. 1986;18(Suppl E):193-202. 49. Carson JL, Strom BL, Duff A, et al. Acute liver disease associated with erythromycins, sulfonamides, and tetracyclines. Ann Intern Med. 1993;119:576-583. 50. Castell DO, Sparks HA. Nephrogenic diabetes insipidus due to demethylchlortetracycline hydrochloride. JAMA. 1965;193:237. 51. Centers for Disease Control. Endotoxin-like reactions associated with intravenous gentamicin—California, 1998. MMWR Morb Mortal Wkly Rep. 1998;47:877-880. 52. Chattha G, Arieff AI, Cummings C, Tierney LM. Lactic acidosis complicating the acquired-immunodeficiency syndrome. Ann Intern Med. 1993;118:37-39. 53. Chawla A, Kahn E, Yunis EJ, Daum F. Rapidly progressive cholestasis. An unusual reaction to amoxicillin/clavulanic acid therapy in a child. J Pediatr. 2000;136:121-123. 54. Chen HJ, Bloch KL, Maclean JA. Acute eosinophilic hepatitis from trovafloxacin. N Engl J Med. 2000;342:359-360. 55. Cheung TW. Overdose of atovaquone in a patient with AIDS. AIDS. 1999;13:1984. 56 Christie DJ, Van Buren N, Lennon SS, Putnam JL. Vancomycin-dependent antibodies associated with thrombocytopenia and refractoriness to platelet transfusion in patients with leukemia. Blood. 1990;75:518-525. 57. Chusil S, Tungsanga K, Wathanavaha A, Pansin P. Hypouricemia, hypokalemia, proximal and distal tubular acidification defect following administration of outdated tetracycline. A case report. J Med Assoc Thai. 1994;77:98-102. 58. Cleary JD, Hayman J, Sherwood J, Lasala GP, Piazza-Hepp T. Amphotericin B overdose in pediatric patients with associated cardiac arrest. Ann Pharmacother. 1993;27:715-719. 59. Cocke JG, Brown RE, Geppert LJ. Optic neuritis with prolonged use of chloramphenicol. J Pediatr. 1966;68:27-31. 60. Cohen LS, Wechsler AS, Mitchell JH, Glick G. Depression of cardiac function by streptomycin and other antimicrobial agents. Am J Cardiol. 1970;26:505-511. 61. Connor JP, Curry JM, Selby TL, Perlmutter AD. Acute renal failure secondary to ciprofloxacin use. J Urol. 1994;154:975-976. 62. Covinsky JO. Aminoglycoside-induced electrolyte imbalance. Hosp Ther. 1986;5:17-29. 63. Craft AW, Brocklebank JT, Jackson RH. Acute renal failure and hypoglycaemia due to sulphadiazine poisoning. Postgrad Med J. 1977;53:103-104. 64. Danan G, Descatoire V, Pessayre D. Self-induction of erythromycin by its own transformation into a metabolite forming an inactive complex with reduced cytochrome P-450. J Pharmacol Exp Ther. 1989;250:746-751. 65 Danisovicova A, Brezina M, Belan S, et al. Magnetic resonance imaging in children receiving quinolones. No evidence of quinolone-induced arthropathy. A multicenter survey. Chemotherapy. 1994;40:209-214. 66. De Boer T, Stoof JC, Van Duyn H. Effect of penicillin on neurotransmitter release from rat cortical tissue. Brain Res. 1980;192:296-300.

67. De Sarro A, Ammendola D, De Sarro G. Effects of some quinolones on imipenem-induced seizures in DBA/2 mice. Gen Pharmacol. 1994;25:369-379. 68. De Sarro G, Nava F, Calapai G, De Sarro A. Effects of some excitatory amino acid antagonists and drugs enhancing gamma-amino butyric acid neurotransmission on pefloxacin-induced seizures in DBA/2 mice. Antimicrob Agents Chemother. 1997;41:427-434. 69. Deeks SG, Volberding PA. Antiretroviral therapy. In: Sande MA, Volberding PA, eds. The Medical Management of AIDS, 6th ed. Philadelphia: WB Saunders; 1999:97-115. 70. Demoly P, Benahmed S, Valembois M, et al. Allergy to macrolide antibiotics. Review of the literature [French]. Presse Med. 2000;29:321-326. 71 DeRay G, Diquet B, Martinez F, et al. Pharmacokinetics of zidovudine in a patient on maintenance hemodialysis. N Engl J Med. 1988;319:1606-1607. 72. DeSoto H. Cimetidine in anaphylactic shock refractory to standard therapy. Anesth Analg. 1989;69:260-269. 73. Domen RE, Horowitz S. Vancomycin-induced neutropenia associated with anti-granulocyte antibodies. Immunohematology. 1990;6:41-43. 74. Dore DD, DiBello JR, Lapane KL. Telithromycin use and spontaneous reports of hepatotoxicity. Drug Saf. 2007;30:697-703. 75. Drici MD, Knollmann BC, Wang WX, Woosley RL. Cardiac actions of erythromycin. Influence of female sex. JAMA. 1998;280:1774-1776. 76. Dunn RJ. Massive sulfasalazine and paracetamol ingestion causing acidosis, hyperglycemia, coagulopathy and methemoglobinemia. J Toxicol Clin Toxicol. 1998;36:239-242. 77. Durosinmi MA, Ajayi AA. A prospective study of chloramphenicolinduced aplastic anaemia in Nigerians. Trop Geogr Med. 1993;45:159-161. 78. Ehmann WC. Cephalosporin-induced hemolysis. A case report and review of the literature. Am J Hematol. 1992;40:121-125. 79. English J, Gilbert DN, Kohlhepp S, et al. Attenuation of experimental tobramycin nephrotoxicity by ticarcillin. Antimicrob Agents Chemother. 1985;27:897-902. 80. Engrav MB, Zimmerman M. Electrocardiographic changes associated with anaphylaxis in a patient with anaphylaxis in a patient with normal coronary arteries. West J Med. 1994;161:602. 81. Falco V, Rodriguez D, Ribera E, et al. Severe nucleoside-associated lactic acidosiss in human immunodeficiency virus-infected patients. Report of 12 cases and review of the literature Clin Infect Dis. 2002;34:838-846. 82. Fang CC, Wang HP, Lin JT. Erythromycin-induced acute pancreatitis. J Toxicol Clin Toxicol. 1996;34:93-95. 83. Fanos V, Cataldi L. Amphotericin-B induced nephrotoxicity. A review. J Chemother. 2000;12:463-470. 84. Fisher MA, Talbot GH, Maislin G, et al. Risk factors for amphotericin B associated nephrotoxicity. Am J Med. 1989;87:547-552. 85. Flexner C. HIV-protease inhibitors. N Engl J Med. 1998;338:1281-1292. 86. Fraser DG. Suicide attempt with Azo Gantanol resulting in methemoglobinemia. Mil Med. 1969;134:679-681. 87. Freundlich M, Cynamon H, Tames A, et al. Management of chloramphenicol intoxication in infancy by charcoal hemoperfusion. J Pediatr. 1983;103:485-487. 88. Fripp RR, Carter MC, Werner JC. Cardiac function and acute chloramphenicol toxicity. J Pediatr. 1983;103:487-490. 89. Fuchs S, Simon Z, Brezis M. Fatal hepatic failure associated with ciprofloxacin. Lancet. 1994;343:738-739. 90. Galpin JE, Chow AW, Yoshikawa TT, Guze LB. Pseudoanaphylactic reactions for inadvertent infusion of procaine penicillin G. Ann Intern Med. 1974;81:358-359. 91. Garica RLA, Stricker BH, Zimmerman HJ. Risk of acute liver injury associated with the combination of amoxicillin and clavulanic acid. Arch Intern Med. 1996;156:1327-1332. 92. Garratty G. Immune cytopenia associated with antibiotics. Transfus Med Rev. 1993;7:255-267. 93. Garrelts JC, Peterie JD. Vancomycin and the “red man’s syndrome.” N Engl J Med. 1985;312:245. 94 Geller RJ, Chevalier RL, Spyker DA. Acute amoxicillin nephrotoxicity following an overdose. J Toxicol Clin Toxicol. 1986;24:175-182. 95. Gigliotti F, Shenep JL, Lott L, Thornton D. Induction of prostaglandin synthesis as the mechanism responsible for the chills and fever produced by infusing amphotericin B. J Infect Dis. 1987;156:784-789. 96. Gilbert FI Jr. Cholestatic hepatitis caused by esters of erythromycin and oleandomycin 1962 (classical article). Hawaii Med J. 1995;54:603-605. 97. Glazko AJ. Identification of chloramphenicol metabolites and some factors affecting metabolic disposition. Antimicrob Agents Chemother. 1966;6:655-665.

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155. Lopez A, Bernado B, Lopez-Herce J, Cristina AI, Carrillo A. Methaemoglobinaemia secondary to treatment with trimethoprim and sulfamethoxazole associated with inhaled nitric oxide. Acta Paediatr. 1999;88:915-916. 156. Lowery N, Kearns GL, Young RA, Wheeler JG. Serum sickness-like reactions associated with cefprozil therapy. J Pediatr. 1994;125:325-328. 157. Lu CMC, James SH, Lien YHH. Acute massive gentamicin intoxication in a patient with end-stage renal disease. Am J Kidney Dis. 1996;28:767-771. 158. Lucena MI, Andrake RJ, Rodrigo L, et al. Trovafloxacin-induced acute hepatitis. Clin Infect Dis. 2000;30:400-401. 159 MacGregor RR, Bennett JE, Erslev AJ. Erythropoietin concentration in amphotericin B induced anemia. Antimicrob Agents Chemother. 1978;14:270-273. 160. MacNeil M, Haase DA, Tremaine R, Marrie TJ. Fever, lymph-adenopathy, eosinophilia, lymphocytosis, hepatitis and dermatitis. A severe adverse reaction to minocycline. J Am Acad Dermatol. 1997;36:347-350. 161. Maddux MS, Barriere SL. A review of complications of amphotericin therapy. Recommendations for prevention and management. DICP. 1980;14:177-180. 162. Maignen F, Meglio S, Bidault I, Castot A. Acute toxicity of zidovu-dine. Analysis of the literature and number of cases at the Paris poison control center [French]. Therapie. 1993;48:129-131. 163. Malone JD, Lebar RD, Hilder R. Procaine-induced seizures after intramuscular procaine penicillin G. Mil Med. 1988;153:191-192. 164. Marks C, Cummins BH. Rescue after 2 megaunits of intrathecal penicillin. Lancet. 1981;1:658-659. 165. Matsubara T, Otsubo S, Ogawa A, et al. Effects of beta-lactam antibiotics and N-methyltetrazolethiol on the alcohol-metabolizing system in rats. Jpn J Pharmacol. 1987;45:303-315. 166. Mattle H, Craig WA, Pechere PC. Determinants of efficacy and toxicity of aminoglycosides. J Antimicrob Chemother. 1989;24:281-293. 167. Mauer SM, Chavers BM, Kjellstrand CM. Treatment of an infant with severe chloramphenicol intoxication using charcoal-column hemoperfusion. J Pediatr. 1980;96:136-139. 168. Mayumi H, Kimura S, Asano M, et al. Intravenous cimetidine as an effective treatment for systemic anaphylaxis and acute allergic skin reactions. Ann Allergy. 1987;58:447-450. 169. Meislin HW, Bremer JC. Jarisch-Herxheimer reaction case report. JACEP. 1976;5:779-781. 170. Moore RD, Smith CR, Lipsky JJ, Mellits ED, Lietman PS. Risk factors for nephrotoxicity in patients treated with aminoglycosides. Ann Intern Med. 1984;100:352-357. 171. Moyle GJ, Sadler M. Peripheral neuropathy with nucleoside antiretrovirals. Risk factors, incidence and management. Drug Saf. 1998;19:34-40. 172. Mulhall A, deLouvois J, Hurley R. Chloramphenicol toxicity in neonates. Its incidence and prevention. Br Med J. 1983;287:1424-1427. 173. Mulhall JP, Bergmann LS. Ciprofloxacin-induced acute psychosis. Urology. 1995;46:102-103. 174. Myers SA, Selim AA, McDaniel MA, et al. A prospective clinical and pathological examination of injection site reactions with the HIV-1 fusion inhibitor enfuvirtide. Antivir Ther (Lond). 2006;11:935-939. 175. Nahtha MC. Serum concentrations and adverse effects of chloramphenicol in pediatric patients. Chemotherapy. 1987;33:322-327. 176. Naisbitt DJ, Hough SJ, Gill HJ, et al. Cellular deposition of sulphamethoxazole and its metabolites. Implications for hypersensitivity. Br J Pharmacol. 1999;126:1393-1407. 177. Nattel S, Ranger S, Talajic M, Lemery R, Rogy D. Erythromycin-induced prolonged QT syndrome. Concordance with quinidine and underlying cellular electrophysiologic mechanism. Am J Med. 1990;89:235-238. 178. Negussie Y, Remick DG, De Forge LE, et al. Detection of plasma tumour necrosis factor, interleukins 6 and 8 during Jarisch-Herxheimer reaction of relapsing fever. J Exp Med. 1992;175:1207-1212. 179. Newfield P, Roizen MF. Hazards of rapid administration of vancomycin. Ann Intern Med. 1979;91:58. 180. Nichols WG, Steel HM, Bonny T, et al. Hepatotoxicity observed in clinical trials of aplaviroc (GW873140). Antimicrob Agents Chemother. 2008;52:858-865. 181. Nishidi I, Takumida M. Attenuation of aminoglycoside ototoxicity by glutathione. ORL J Otorhinolaryngol Relat Spec. 1996;58:68-73. 182. Nordt SP, Williams SR, Manoguerra AS, Clark RF. Clarithromycin induced digoxin toxicity. J Accid Emerg Med. 1998;15:194-195. 183. Obata H, Iizuka B, Uchida K. Pathogenesis of hypoprothrombinemia induced by antibiotics. J Nutr Sci Vitaminol (Tokyo). 1992;S13-S15:421-424.

184. Oberg KC, Bauman JL. QT prolongation and torsades de pointes due to erythromycin lactobionate. Pharmacotherapy. 1995;15:687-692. 185. Onur O, Guneysel O, Denizbasi A, Celikel C. Acute hepatitis attack after exposure to telithromycin. Clin Ther. 2007;29:1725-1729. 186. O’Sullivan TL, Ruffing MJ, Lamp KC, Warbasse LH, Rybak MJ. Prospective evaluation of red man syndrome in patients receiving vancomycin. J Infect Dis. 1993;168:773-776. 187. Paradelis AG. Aminoglycoside antibiotics and neuromuscular blockade. J Antimicrob Chemother. 1979;5:737-738. 188. Park-Wyllie LY, Juurlink DN, Kopp A, et al. Outpatient gatifloxacin therapy and dysglycemia in older adults. N Engl J Med. 2006;354:1352-1361. 189. Patterson LJ, Milne B. Latex anaphylaxis causing heart block. Role of ranitidine. Can J Anesth. 1999;46:776-778. 190. Pestotnik SL, Classen DC, Evans RS, Stevens LE, Burke JP. Prospective surveillance of imipenem/cilastatin use and associated seizures using a hospital information system. Ann Pharmacother. 1993;27:497-501. 191. Pierfitte C, Gillet P, Royer RJ. More on fluoroquinolone antibiotics and tendon rupture. N Engl J Med. 1995;332:193. 192. Pimiento PA, Martinez GM, Mena MA, et al. Aztreonam and ceftazidime. Evidence of in vivo cross allergenicity. Allergy. 1998;53:624-625. 193. Polk RE, Israel D, Wang J, et al. Vancomycin skin tests and prediction of “red man syndrome” in healthy volunteers. Antimicrob Agents Chemother. 1993;37:2139-2143. 194. Ptachainski RJ, Carpenter BJ, Burckart GJ, Venkataramanan R, Rosenthal JT. Effect of erythromycin on cyclosporine levels. N Engl J Med. 1985;313:1416-1417. 195. Ramilo O, Kinane BT, McCracken GH. Chloramphenicol neurotoxicity. Pediatr Infect Dis J. 1988;7:358-359. 196. Ray WA, Murray KT, Meredity S, et al. Oral erythromycin and the risk of sudden death from cardiac causes. N Engl J Med. 2004;351:1089-1096. 197. Regan TJ, Khan MI, Olde IHA, Passannant AJ. Antibiotic effect on myocardial K transport and the production of ventricular tachycardia [abstract]. J Clin Invest. 1969;48:66A. 198. Renz CL, Thurn JD, Finn HA, Lynch JP, Moss, J. Antihistamine prophylaxis permits rapid vancomycin infusion. Crit Care Med. 1999;27:1732-1737. 199. Richardet JP, Mallat A, Zafrani ES, et al. Prolonged cholestasis with ductopenia after administration of amoxicillin/clavulanic acid. Dig Dis Sci. 1999;44: 1997-2000. 200. Richardson JA. Accidental ingestion of acyclovir in dogs. 105 reports. Vet Hum Toxicol. 2000;42:370-371. 201. Riley HD Jr. Vancomycin and novobiocin. Med Clin North Am. 1970;54: 1277-1289. 202. Rippelmeyer DJ, Synhavsky A. Ciprofloxacin and allergic interstitial nephritis. Ann Intern Med. 1988;109:170. 203. Rivera Vaquerizo PA, Santisteban Lopez Y, Blasco Colmenarejo M, et al. Clindamycin-induced esophageal ulcer. Revista Espanola de Enfermedades Digestivas. 2004;96:143-145. 204. Rockwood RP, Embardo LS. Theophylline, ciprofloxacin, erythromycin. A potentially harmful regimen. Ann Pharmacother. 1993;27:651-652. 205. Romano A, Gueant-Rodriguez RM, Viola M, Pettinato R, Gueant JL. Cross-reactivity and tolerability of cephalosporins in patients with immediate hypersensitivity to penicillins. Ann Intern Med. 2004;141:16-22. 206. Romero-Gomez M, Suarez GE, Fernandez MC. Norfloxacin-induced acute cholestatic hepatitis in a patient with alcoholic liver cirrhosis. Am J Gastroenterol. 1999;94:2324-2325. 207. Rothenberg HJ. Anaphylactoid reaction to vancomycin. JAMA. 1959;171: 1101-1102. 208. Rubart M, Pressler ML, Pride HP, Zipes DP. Electrophysiological mechanisms in a canine model of erythromycin-associated long QT syndrome. Circulation. 1993;88(Pt 1):1832-1844. 209. Rybak MJ, Boike SC. Additive toxicity in patients receiving vancomycin and aminoglycosides. Clin Pharm. 1983;2:508. 210. Sabra R, Takahashi K, Branch RA, Badr KF. Mechanisms of amphotericin B-induced reduction of glomerular filtration rate. A micro-puncture study. J Pharmacol Exp Ther. 1990;253:34-37. 211. Sacristan JA, Soto JA, deCos MA. Erythromycin-induced hypoacusis. 11 new cases and literature review. Ann Pharmacother. 1993;27:950-955. 212. Sage DJ. Management of acute anaphylactoid reactions. Int Anesthesiol Clin. 1985;23:175-186. 213. Samaha FF. QTC interval prolongation and polymorphic ventricular tachycardia in association with levofloxacin. Am J Med. 1999;107:528-529. 214. Saraway SM, Marke J, Steinberg M, et al. Doom anxiety and delirium in lidocaine toxicity. Am J Psychiatry. 1987;144:159-163.

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215. Saxon A, Swabb EA, Adkinson NF Jr. Investigation into the immunologic cross-reactivity of aztreonam with other beta lactam antibiotics. Am J Med. 1985;78(Suppl A):19-26. 216. Sayawa BP, Weihprecht H, Cambell WR, et al. Direct vasoconstriction as a possible cause for amphotericin B-induced nephrotoxicity in rats. J Clin Invest. 1991;87:2079-2107. 217. Schentag JJ, Plaut ME. Patterns of beta-2-microglobulin excretion in patients treated with aminoglycosides. Kidney Int. 1980;16:654-661. 218. Schluter G. Ciprofloxacin. Review of potential toxicologic effects. Am J Med. 1987;82(Suppl 4A):91-93. 219. Schmuck G, Schurmann A, Schluter G. Determination of the excitatory potencies of fluoroquinolones in the central nervous system by an in vitro model. Antimicrob Agents Chemother. 1998;42:1831-1836. 220. Schrodt BJ, Kulp-Shorten CL, Callen JP. Necrotizing vasculitis of the skin and uterine cervix associated with minocycline therapy for acne vulgaris. South Med J. 1999;92:502-504. 221. Scott JL, Finegold SM, Belkins GA, Lawrence JS. A controlled doubleblind study of the hematologic toxicity of chloramphenicol. N Engl J Med. 1965;272:1137. 222. Seamans KB, Gloor P, Dobell RAR, Wyant JD. Penicillin-induced seizures during cardiopulmonary bypass. A clinical and electroencephalographic study. N Engl J Med. 1968;278:861-868. 223. Seldon R, Sasahara AA. Central nervous system toxicity induced by lidocaine. JAMA. 1967;202:908-909. 224. Shapiro LE, Knowles SR, Shear N. Comparative safety of tetracycline, minocycline and doxycycline. Arch Dermatol. 1997;133:1224-1230. 225. Shu XO, Gao YT, Linet MS, et al. Chloramphenicol use and childhood leukaemia in Shanghai. Lancet. 1987;2:934-937. 226. Silber T, D’Angelio L. Doom, anxiety, and Hoigne’s syndrome. Am J Psychiatry. 1987;144:1365. 227. Slaughter RL, Cerra FB, Koup JR. Effect of hemodialysis on total body clearance of chloramphenicol. Am J Hosp Pharm. 1980;37:1083-1086. 228. Slavich IL, Gleffe RF, Haas EJ. Grand mal epileptic seizures during ciprofloxacin therapy. JAMA. 1989;261:558-559. 229. Slayton W, Anstine D, Lakhdir F, Sleasman J, Neiberger R. Tetany in a child with AIDS receiving intravenous tobramycin. South Med J. 1996; 89:1108-1110. 230. Somer T, Finegold SM. Vasculitis associated with infections, immunization, and antimicrobial drugs. Clin Infect Dis. 1995;20:1010-1036. 231. Song BB, Sha SH, Schacht J. Iron chelators protect from aminoglycoside-induced cochleo- and vestibulo-toxicity. Free Radic Biol Med. 1998;25:189-195. 232. Stahlmann R, Lode H. Toxicity of quinolones. Drugs. 1999;58(Suppl 2):37-42. 233. Stevens DC, Kleiman MB, Lietman PS, Schreiner RL. Exchange transfusion in acute chloramphenicol toxicity. J Pediatr. 1981;99:651-653. 234. Strevel EL, Kuper A, Gold WL. Severe and protracted hypoglycaemia associated with co-trimoxazole use. Lancet Infect Dis. 2006;6:178-182. 235. Sunagawa M, Matsumura H, Sumita Y, Nouda H. Structural features resulting in convulsive activity of carbapenem compounds. Effect of C-2 side chain. J Antibiot (Tokyo). 1995;48:408-416. 236. Swanson DJ, Sung RJ, Fine MJ, et al. Erythromycin ototoxicity. Prospective assessment with serum concentrations and audiograms in a study of patients with pneumonia. Am J Med. 1992;92:61-68. 237. Swanson-Biearman B, Dean BS, Lopez G, Krenzelok EP. The effects of penicillin and cephalosporin ingestions in children less than six years of age. Vet Hum Toxicol. 1988;30:66-67. 238. Takada S, Kato M, Takayama S. Comparison of lesions induced by intra-articular injections of quinolones and compounds damaging cartilage components in rat femoral condyles. J Toxicol Environ Health. 1994;42:73-88. 239. Teitelbaum JE, Perez-Atayde AR, Cohen M, Bousvaros A, Jonas MM. Minocycline-related autoimmune hepatitis. Case series and literature review. Arch Pediatr Adolesc Med. 1998;152:1132-1136. 240. Telithromycin Product Information. Kansas City, MO: Aventis Pharmaceuticals; 2004. 241. Tenenbein MS, Tenenbein M. Acute pancreatitis due to erythromycin overdose. Pediatr Emerg Care. 2005;21:675-676.

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242. Thompson WL, Anderson SE Jr, Lipsky JJ, et al. Overdose of chloramphenicol. JAMA. 1975;234:149-150. 243. Threlkeld SC, Hirsch MS. Antiviral therapy. The epidemiology of HIV and AIDS. Current trends. In: Gold JWM, Telzak EE, White DA, eds. The Diagnosis and Management of the HIV-Infected Patient, Part 1. Med Clin North Am. 1996;80:1263-1283. 244. Timmermans L. Influence of antibiotics on spermatogenesis. J Urol. 1974; 112:348-349. 245. Tsuji A, Sato H, Kume Y, et al. Inhibitory effects of quinolone antibacterial agents on gamma-aminobutyric acid binding to receptor sites in rat brain membranes. Antimicrob Agents Chemother. 1988;32:190-194. 246. Turner WM. Lidocaine and psychotic reactions. Ann Intern Med. 1982;97:149-150. 247. Tynes BS, Utz JP, Bennett JE, Alling DW. Reducing amphotericin B reactions. Am Rev Respir Dis. 1963;87:264-268. 248. Ulinski T, Deschenes G, Bensman A. Large-pore haemodialysis membranes. an efficient tool for rapid removal of vancomycin after accidental overdose. Nephrol Dial Transplant. 2005;20:1517-1518. 249. Unal M, Peyman GA, Liang C, et al. Ocular toxicity of intravitreal clarithromycin. Retina. 1999;19:442-446. 250. Utley PM, Lucas JB, Billings TE. Acute psychotic reactions to aqueous procaine penicillin. South Med J. 1966;59:1271-1274. 251. Van Arsdel PP Jr. The risk of penicillin reactions. Ann Intern Med. 1968;69:1071-1073. 252. Veit O, Beck B, Steuerwald M, Hatz C. First case of ivermectin-induced severe hepatitis. Trans R Soc Trop Med Hyg. 2006;100:795-797. 253. Walker PD, Barri Y, Shah SV. Oxidant mechanisms in gentamicin nephrotoxicity. Ren Fail. 1999;21:433-442. 254. Walker S, Norwood J, Thornton C, Schaberg D. Trimethoprimsulfamethoxazole associated rhabdomyolysis in a patient with AIDS: case report and review of the literature. Am J Med Sci. 2006;331:339-341. 255. Wallace KL. Antibiotic-induced convulsions. Med Toxicol. 1997;13:741-762. 256. Wallace MR, Mascola JR, Oldfield EC 3rd. Red man syndrome. Incidence, etiology and prophylaxis. J Infect Dis. 1991;164:1180-1185. 257. Walmsley SL, Winn LM, Harrison ML, Uetrecht JP, Wells PG. Oxidative stress and thiol depletion in plasma and peripheral blood lymphocytes from HIV-infected patients. Toxicological and pathological implications. AIDS. 1997;11:1689-1697. 258. Walsh TJ, Finberg RW, Arndt C, et al. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. N Engl J Med. 1999;340:764-771. 259. Watts RG, Conte JE, Zurlinden E, Waldo FB. Effect of charcoal hemoperfusion on clearance of pentamidine isethionate after accidental overdose. J Toxicol Clin Toxicol. 1997;35:89-92. 260. Weis S, Karagulle D, Kornhuber J, Bayerlein K. Cotrimoxazole-induced psychosis. a case report and review of literature. Pharmacopsychiatry. 2006;39:236-237. 261. Weisberger AS, Wessler S, Avioli LV. Mechanisms of action of chloramphenicol. JAMA. 1969;209:97-103. 262. Westphal JF, Vetter D, Brogard JM. Hepatic side-effects of antibiotics. J Antimicrob Chemother. 1994;33:387-401. 263. Wolf R, Brenner DS. An active amide group in the molecule of drugs that induce pemphigus. A casual or causal relationship? Dermatology. 1994;189:1-4. 264. Yarbrough JA, Moffitt JE, Brown DA, Stafford C. Cimetidine in the treatment of refractory anaphylaxis. Ann Allergy. 1989;63:235-238. 265. Yoshioka H, Nambu H, Fujia M, Uehara H. Convulsion following intrathecal cephaloridine. Infection. 1975;2:123-124. 266. Yunis AA. Chloramphenicol-induced bone marrow suppression. Semin Hematol. 1973;10:255-234. 267. Zager RA, Bredl CR, Schimpf BA. Direct amphotericin B-mediated tubular toxicity. Assessments of selected cytoprotective agents. Kidney Int. 1992; 42:1588-1594. 268. Zhou W, Moore DE. Photosensitizing activity of the anti-bacterial drugs sulfamethoxazole and trimethoprim. J Photochem Photobiol. 1997; 39:63-72.

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ANTITUBERCULOUS MEDICATIONS Christina H. Hernon and Edward W. Boyer Tuberculosis and antituberculous therapy have ever increasing global implications. More and more people are exposed to more combinations of antituberculous and antiretroviral drugs throughout the world. Vigilance for depression and suicide risk are particularly important to evaluate as complications of the diseases under treatment and as complications of the therapy. Isoniazid remains the most commonly used and the most consequential in overdose.

HISTORY AND EPIDEMIOLOGY The global burden of tuberculosis is enormous. Approximately two billion people, one-third of the total population of the world, are infected with Mycobacterium tuberculosis. An estimated 8.8 million new cases of disease are diagnosed and 1.6 million persons die from tuberculosis annually.3 In 2007, the incidence of tuberculosis (TB) in the United States was the lowest recorded (13,000 cases) since the inception of national reporting in 1953.22 The introduction of isoniazid (INH) into clinical practice in 1952 produced a steady decline in the number of TB cases in the United States over the subsequent 30 years. However, between 1985 and 1991, there was a resurgence in TB cases in the United States resulting primarily from the effects of human immunodeficiency virus (HIV), homelessness, deterioration in the healthcare infrastructure, and an increased presence of foreign-born persons. With the initiation and implementation of containment strategies, the spread of the infection has been slowed by aggressive case identification and patient-centered management, including directly observed therapy, social support, housing, and substance abuse treatment. These methods have decreased the incidence rate in the United States as well as worldwide. In 2005, the tuberculosis incidence was stable or declining worldwide, although the total number of new TB cases continues to increase slowly. Also in that year, extensively-drug-resistant tuberculosis (XDR-TB) was recognized, with between 4% and 19% of multidrug resistant tuberculosis (MDR-TB) strains being resistant to both INH and rifampin, all fluoroquinolones, and at least one of three injectable drugs (capreomycin, kanamycin, and amikacin).7,21,94 At present, populations that remain at risk for tuberculosis include HIV-positive patients, the homeless, injection drug users, healthcare workers, prisoners, prison workers, and Native Americans. In addition, the tuberculosis rate in foreign-born persons is nearly 10 times higher than in US-born persons. In the US population, countries of birth generating the highest number of tuberculosis cases are Mexico, the Philippines, India, and Vietnam.7,21 The use of second-line (reserve) drugs and multidrug antituberculous regimens for MDR-TB and XDR-TB resulted in an increased incidence of adverse drug effects, increasing to 40-70% and sometimes requiring discontinuation of the treatment. Hepatotoxicity, peripheral neuropathy, and ocular neuropathy are often irreversible and potentially fatal. Psychosocial conditions, chronic illness, and adverse drug effects involving anxiety,

depression, and psychosis all contribute to an escalated risk of suicidality, intentional overdose, and noncompliance with therapy.128

ISONIAZID ■ PHARMACOLOGY Isoniazid (INH, or isonicotinic hydrazide) is structurally related to nicotinic acid (niacin, or vitamin B3), nicotinamide-adenosine dinucleotide (NAD), and pyridoxine (vitamin B6) (Fig. 57–1). The pyridine ring is essential for antituberculous activity. Isoniazid itself does not have direct antibacterial activity. It is a prodrug that undergoes metabolic activation by KatG, a catalase-peroxidase in M. tuberculosis that produces a highly reactive intermediate,95,130 which in turn interacts with InhA, a mycobacterial enzyme that functions as an enoyl-acyl carrier protein (enoyl-ACP) reductase.92,93 This activated form of INH is either an anion or radical that is stabilized by the pyridine ring. Enoyl-ACP reductase catalyzes the NADH-dependent reduction of the double bonds in the growing fatty acid chain linked to acyl carrier proteins. InhA is required for the synthesis of very-long-chain lipids, mycolic acids (containing between 40 and 60 carbons) that are important components of mycobacterial cell walls. This INH metabolite enters the binding site of InhA where it reacts with the reduced form of nicotinamide adenine dinucleotide (NADH).95 The covalently linked INH-NADH complex remains bound to the active site of InhA, irreversibly inhibiting the enzyme.76,92

■ PHARMACOKINETICS AND TOXICOKINETICS When therapeutic doses of 300 mg are administered orally, INH is rapidly absorbed, reaching peak serum concentrations typically within 2 hours.60,87,88 Isoniazid diffuses into all body fluids with a volume of distribution of approximately 0.6 L/kg and has negligible binding to serum proteins. After the drug penetrates infected tissue, it persists in concentrations well above those generally required for bacteriocidal activity.88 Isoniazid is metabolized via a cytochrome P450—mediated process, with approximately 75% to 95% of INH renally eliminated in the form of its hepatic metabolites within 24 hours of administration.89 The primary metabolic pathway for INH is via N-acetylation performed by hepatocytes and mucosal cells in the small intestine. Polymorphic N-acetyltransferase-2 (NAT2), the enzyme responsible for this conversion, exhibits Michaelis-Menten kinetics, although the activity of an individual’s enzymes is determined by an autosomal dominant inheritance pattern, with homozygous fast acetylators (FF), heterozygous fast acetylators (FS), and homozygous slow acetylators (SS). Patients are distinguishable phenotypically as slow and fast acetylators. The fast acetylation isoform is found in 40% to 50% of American whites and African Americans, whereas the fast acetylator isoenzymes are found in 80% to 90% of Asians and Inuits.35,39 These isoforms are distinguishable by the following characteristics: (1) slow acetylators have less presystemic clearance, or first-pass effect, than do fast acetylators; (2) fast acetylators metabolize INH five to six times faster than slow acetylators; and (3) serum INH concentrations are 30% to 50% lower in fast acetylators than in slow acetylators. The elimination halflife of INH is approximately 70 minutes in fast acetylators, and 180 minutes in slow acetylators. Twenty-seven percent of INH is excreted unchanged in urine by slow acetylators, as compared with 11% excretion in fast acetylators. The clearance of INH averages 46 mL/min.10,122 Isoniazid is acetylated into acetylisoniazid and then hydrolyzed into isonicotinic acid and acetylhydrazine. Subsequent acetylation of acetylhydrazine into diacetylhydrazine or hydrolysis into hydrazine occurs.

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O

NH

NH2

N Nicotinic acid (Niacin, Vitamin B3)

HO H 3C

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Acute toxicity: seizures Pyridoxine (GABA depletion) depletion Chronic toxicity: peripheral neuropathy

OH

O NH2

N Isonicontinic acid hydrazide (Isoniazid, INH)

Antituberculous Medications

OH N Pyridoxine (Vitamin B6)

Isoniazid N-acetyltransferase

FIGURE 57–1. INH and related compounds.

P450 oxidation Hydrazine + Isonicotinic acid (nontoxic)

Acetylisoniazid Additionally, a small portion of isoniazid is directly hydrolyzed into isonicotinic acid and hydrazine, and this pathway is of greater quantitative significance in slow acetylators than in rapid acetylators. Hepatic microsomal oxidation of the acetylhydrazine intermediate into reactive intermediates has been proposed as the cause of hepatotoxicity, but continuing research suggests that hydrazine plays perhaps an even greater role in hepatic injury.46,80,119 Figure 57–2 illustrates the metabolism of INH.

■ PATHOPHYSIOLOGY Mechanism of Toxicity Toxic effects of INH are caused by two additive mechanisms. First, INH alters the metabolism of pyridoxine (vitamin B6), the coenzyme needed for transamination, transketolization, and decarboxylation biotransformation reactions. Isoniazid creates a functional deficiency of pyridoxine by at least two mechanisms (Fig. 57–3). Hydrazone INH metabolites inhibit pyridoxine phosphokinase, the enzyme that converts pyridoxine to its active form, pyridoxal-5’-phosphate.25,59,78 In addition, INH reacts with pyridoxal phosphate to produce an inactive hydrazone complex that is renally excreted.78,122 Urinary excretion of pyridoxine and its metabolites increases with increasing INH dosage, reflecting the effect of INH on pyridoxine metabolism. The consequences of pyridoxine depletion include impaired activity of pyridoxine-dependent enzyme systems, as well as a decrease in catecholamine synthesis. In addition, INH either replaces nicotinic acid in the synthesis of NAD or reacts with NAD to form inactive hydrazones. Isoniazid disrupts cellular reduction/ oxidation capabilities through both of these mechanisms. Second, isoniazid interferes with the synthesis and metabolism of γ-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the central nervous system (CNS). Two pyridoxine-dependent enzymes control GABA metabolism: glutamic acid decarboxylase

Hydrolysis P450

Acetylhydrazine + Isonicotinic acid (nontoxic)

Hepatotoxic metabolite

oxidation

Acetylation

Diacetylhydrazine (nontoxic)

FIGURE 57–2. Metabolism of INH. Acetylator status is determined by polymorphism in N-acetyltransferase.

(GAD) and GABA aminotransferase. The former catalyzes GABA synthesis from glutamate, while the latter degrades the neurotransmitter. The inhibitory effects are greater on GAD, which leads to both decreased GABA and elevated glutamate concentrations.124 Depletion of GABA is thought to be the etiology of INH-induced seizures.5 Structurally similar chemicals exert similar acute toxic effects. Monomethylhydrazine, a metabolite produced from gyromitrin isolated from the Gyromitra species (“false morel”) mushroom, and the hydrazines used in liquid rocket fuel have a similar mechanism of action (see Chap. 117). The use of isoniazid in pregnancy is of concern since it is a class C drug, crosses the placenta, and produces umbilical cord serum concentrations comparable to maternal serum concentrations.13,14,61 Mammalian teratogen studies suggest that isoniazid is not a human teratology, although fetal deformities following acute overdose of INH have been reported.70,122 Administration of INH to pregnant women was not associated with cancer in their offspring. Although isoniazid

Glutamic acid decarboxylase Isoniazid hydrazines and hydrazides

Inactivation

Inhibit Isoniazid

Isoniazid hydrazines and hydrazides

Isoniazid hydrazones

Glutamic acid

GABA Pyridoxal 5´ phosphate

Pyridoxine phosphokinase

Complexation and urinary elimination Pyridoxine

FIGURE 57–3. The effect of isoniazid on γ-aminobutyric acid (GABA) synthesis.

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Part C

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readily enters breast milk, breast-feeding during therapy is considered acceptable.100,122

■ INTERACTIONS WITH OTHER DRUGS AND FOODS Drug—drug interactions associated with isoniazid are mediated through alteration of hepatic metabolism of several cytochrome P450 (CYP) isoenzymes. The majority of these interactions are inhibitory, with decreased (CYP)-mediated transformations—particularly demethylation, oxidation, and hydroxylation (see Chap. 12 Appendix). Clinically relevant adverse effects with elevated concentrations of theophylline (CYP1A2), phenytoin (CYP2C9/CYP2C19), warfarin (CYP2C9/CYP2C19), valproic acid, and carbamazepine (CYP3A4) are due to decreased hepatic metabolism of these drugs.33,106,126 The CYP2E1 cytochrome subtype, however, exhibits a complex response to isoniazid; a therapeutic dose of INH induces expression of CYP2E1, but simultaneously binds, stabilizes, and inhibits its metabolic activity. Eventual dissociation of isoniazid from the isoenzyme active site creates an increased intracellular concentration of CYP2E1 available to metabolize potential substrates. The formation of the acetaminophen metabolite responsible for toxicity, NAPQI (N-acetyl-p-benzoquinoneimine), is catalyzed by CYP2E1. Isoniazid-mediated effects in acetaminophen-induced hepatotoxicity are uncertain because of differences in acetylator status (fast, slow) and variations in CYP2E1 activity.24,106 Isoniazid interacts with numerous foods. Isoniazid is a weak monoamine oxidase inhibitor, and tyramine reactions to foods (aged cheeses, wines) and serotonin syndrome from meperidine are reported in patients taking INH. Clinical effects include flushing, tachycardia, and hypertension.32,45,69,112 Furthermore, INH inhibits the enzyme histaminase, leading to exacerbated reactions following the ingestion of histamine in scombrotoxic fish.56,77,106 Table 57–1 summarizes additional INH drug and food interactions.

■ CLINICAL MANIFESTATIONS OF INH TOXICITY Acute Toxicity Isoniazid produces the triad of seizures refractory to conventional therapy, severe metabolic acidosis, and coma. These clinical manifestations may appear as soon as 30 minutes following ingestion.54,58,117 The case fatality rate of a single acute ingestion may be as high as 20%.15,18 Although vomiting, slurred speech, dizziness, and tachycardia may represent early manifestations of toxicity, seizures may be the initial sign of acute overdose.72 Seizures may occur following the ingestion of greater than 20 mg/kg of INH, and invariably occur with ingestions greater than 35 to 40 mg/kg. Patients with underlying seizure disorders may develop seizures at lower doses.15 Hyperreflexia or areflexia may herald INH-induced seizures. Consciousness may return between seizures or status epilepticus can occur.30,83 Because GABA, the primary inhibitory neurotransmitter, is depleted in acute INH toxicity, seizure activity may persist until GABA concentrations are restored, even with anticonvulsant therapy. Acute INH toxicity is often associated with seizures and an anion gap metabolic acidosis associated with a high serum lactate concentration. Typically, arterial pH ranges between 6.80 and 7.30, although survival in the setting of an arterial pH of 6.49 was reported.54 Paralyzed animals poisoned with INH do not develop elevated lactate concentrations, a finding that suggests the lactate arises from intense muscular activity.25,84 Protracted coma typically occurs with acute severe INH toxicity. Coma may last as long as 24 to 36 hours and persist beyond the termination of seizure activity as well as the resolution of acidemia. The etiology of coma is unknown.11,54 Additional sequelae from acute INH toxicity include rhabdomyolysis, renal failure, hyperglycemia, glycosuria, and ketonuria, along with hypotension and hyperpyrexia.4,8,19,85,122,123

Chronic Toxicity. Chronic therapeutic INH use is associated with a variety of adverse effects. Overall incidence of adverse reactions to isoniazid is estimated to be 5.4%.89 The most disconcerting is hepatocellular necrosis.41 Although asymptomatic elevation of aminotransferases is common in the first several months of treatment, laboratory testing may reveal the onset of hepatitis up to 1 year after starting INH therapy. In 1978, following several deaths among patients receiving INH therapy, the US Public Health Service reported the incidence of clinically evident hepatitis as 1% of those taking INH; of that subgroup, 10% died, for an overall mortality of 0.1%.17,66 Research performed since the resurgence of TB, however, identified a considerably lower rate of hepatotoxicity. Clinically relevant hepatitis occurred in only 11 patients in a population of 11,141 persons receiving INH and close monitoring, an incidence of 0.1%.82 Additional studies suggest that the death rate from INH hepatotoxicity is only 0.001% (two of 202,497 treated patients).98 Hepatotoxicity is associated with chronic overdosage, increasing age, comorbid conditions such as malnutrition, and combinations of antituberculous drugs that may serve as cytochrome inducers. Overt hepatic failure often occurs if INH therapy is continued after onset of hepatocellular injury in both adults and children.37,38,51,74,109,125 The incidence of hepatitis is two to four times higher in pregnant women than in nonpregnant women.43 Isoniazid-induced hepatitis can arise via two pathways.37,127 The first involves an immunologic mechanism resulting in hepatic injury that is thought to be idiopathic.103,122 The association of hepatitis with lupus erythematosus, hemolytic anemia, thrombocytopenia, arthritis, vasculitis, and polyserositis supports an immunologic process.102,122 However, symptoms commonly found in autoimmune disorders such as fever, rash, and eosinophilia are usually absent with drug-induced lupus erythematosus, and rechallenge with isoniazid often fails to provoke recurrence of hepatocellular injury.37,102,127 The second, more common mechanism involves direct hepatic injury by INH or its metabolites. The metabolites believed responsible for hepatic injury are acetylhydrazine and hydrazine (see Figure 57–2).46,80,118 Peripheral neuropathy and optic neuritis are known adverse drug effects of chronic INH use. Neurotoxicity is probably caused by pyridoxine deficiency aggravated by the formation of pyridoxine-INH hydrazones.39 Peripheral neuropathy, the most common complication of INH therapy, presents in a stocking-glove distribution that progresses proximally. Although primarily sensory in nature, myalgias and weakness may occur.110 Peripheral neuropathy is generally observed in severely malnourished, alcoholic, uremic, or diabetic patients; it is also associated with slow acetylator status, an effect that leads to increased INH concentrations and, consequently, increased pyridoxine depletion.48 Optic neuritis may occur with isoniazid therapy, usually concurrent with other medications such as ethambutol or etarencept, and presents as decreased visual acuity, eye pain, and dyschromatopsia; visual field testing may reveal central scotomata and bitemporal hemianopsia.49,58,64 Isoniazid is also associated with such findings of CNS toxicity as ataxia, psychosis, hallucinations, and coma.1,9,47,97

■ DIAGNOSTIC TESTING Acute INH toxicity is a clinical diagnosis that may be inferred by history and confirmed by measuring serum INH concentrations.105 Acute toxicity from INH has been defined as a serum INH concentration greater than 10 mg/L 1 hour after ingestion, greater than 3.2 mg/L 2 hours after ingestion, or greater than 0.2 mg/L 6 hours after the ingestion.83 Because serum INH concentration measurements are not widely available, clinicians cannot rely on serum concentrations to confirm the diagnosis or initiate therapy. Because of the risk of hepatitis associated with chronic INH use,

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TABLE 57–1. Adverse Reactions and Drug Interactions of Antituberculous Drugs Drug

Major Adverse Reactions

Drug Interactions Clinical Effect

Isoniazid (INH)

Acute: seizures, acidosis, coma, hyperthermia, oliguria, anuria Chronic: elevation of liver enzyme concentrations autoimmune hepatitis, arthritis, anemia, hemolysis, eosinophilia, peripheral neuropathy, optic neuritis, vitamin B6 deficiency (pellagra)

Rifampin

Acute: diarrhea, periorbital edema Chronic: hepatitis, reddish discoloration of body fluids

Ethambutol

Chronic: optic neuritis, loss of red-green discrimination, loss of peripheral vision Chronic: hepatitis, decreased urate excretion

Rifampin, PZA, ethanol: hepatic necrosis Liver enzymes, Acetaminophen: hepatic necrosis ANA, CBC Warfarin: increased INR Theophylline: tachycardia, vomiting, seizures, acidosis Phenytoin: increased phenytoin concentrations Carbamazepine: altered mental status Meperidine: hypertension Lactose: decreased INH absorption Antacids: decreased INH absorption Red wine/soft cheese: tyramine reaction Fish (scombroid): flushing, pruritus Protease inhibitors: decreased serum If administered with HIV concentration of protease inhibitor antiretrovirals, Delavirdine: increased HIV resistance viral titers should be Cyclosporine: graft rejection followed. Liver enzymes; Warfarin: decreased INR monitor serum Oral contraceptives: ineffective contraception concentrations of drugs Methadone: opioid withdrawal (i.e., phenytoin, Phenytoin: higher frequency of seizures cyclosporine) or clinical Theophylline: decreased theophylline markers of efficacy concentrations (i.e., coagulation times) Verapamil: decreased cardiovascular effect Visual acuity, color discrimination

Pyrazinamide (PZA) Cycloserine

INH: increased rates of hepatotoxicity (when extended courses or high dose pyrazinamide used) INH: increased frequency of seizures

Chronic: depression, paranoia, seizures, megaloblastic anemia Ethionamide Chronic: orthostatic hypotension, Cycloserine: may increase CNS effects depression paraChronic: malaise, GI upset, Aminosalicylic elevated liver enzymes, acid hypersensitivity reactions, thrombocytopenia Capreomycin Chronic: hearing loss, tinnitus, proteinuria, sterile abscess at IM injection sites

Monitoring

Liver enzymes

Comments HIV enteropathy may decrease absorption; INH should not be given with lactose-containing drug formulations because lactose can form hydrazones and lower INH concentrations

Interactions of rifampin with several HIV medications are very poorly described; changes in dosing or dosing interval for both rifampin and antiretroviral drugs may be required; teratogenic Contraindicated in children too young for formal ophthalmologic examination Courses of therapy of 2 months or less recommended

CBC, psychiatric monitoring Blood pressure, pulse, orthostasis Liver enzymes, CBC

Audiometry, renal function tests

ANA, antinuclear antibodies; HIV, human immunodeficiency virus.

hepatic aminotransferases should be regularly monitored once therapy is started. In critically ill patients, serum should be assessed for acidosis, renal function, creatine phosphokinase (CPK), and urine myoglobin indicating rhabdomyolysis and possible renal failure.

■ MANAGEMENT Acute Toxicity The initial management requires termination of seizure activity with pyridoxine, benzodiazepines, fluid resuscitation, stabilization

and correction of vital signs and maintenance of a patent airway. Gastrointestinal (GI) decontamination should be performed by administering activated charcoal to patients who are awake and able to comply with therapy.108 Orogastric lavage is relatively contraindicated because of the risk of seizures, unless the patient is intubated. Delayed absorption of INH has not been observed, suggesting that late GI decontamination with activated charcoal will probably be ineffective in preventing toxicity.104 The antidote for INH-induced neurologic dysfunction is pyridoxine. Pyridoxine rapidly terminates seizures, corrects metabolic acidosis, and

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reverses coma. The efficacy of pyridoxine is correlated with the administered dose; one study identified recurrent seizures in 60% of patients who received no pyridoxine and in 47% of those who received 10% of the ideal pyridoxine dose, and no seizures in patients who received the full dose of pyridoxine.121 To treat acute toxicity, the pyridoxine dose in grams should equal the amount of INH ingested in grams, with a first dose of up to 5 g intravenously in adults. Unknown quantities of ingested INH warrant initial empiric treatment with a pyridoxine dose of no more than 5 g (pediatric dose: 70 mg/kg to a maximum of 5 g). Pyridoxine should be administered at a rate of 1 g every 2 to 3 minutes. Seizures that persist beyond administration of the initial dose should receive an additional similar dose of pyridoxine (see Antidotes in Depth A15—Pyridoxine).6 Hospital pharmacies may stock insufficient quantities of intravenous pyridoxine to treat even a single patient with a large INH ingestion.101 In the event that intravenous formulations are unavailable in sufficient quantities, pyridoxine tablets may be crushed and administered with fluids via nasogastric tube.101 Conventional anticonvulsants, although generally used as firstline agents, demonstrate variable effectiveness in terminating INHinduced seizures. Benzodiazepines may be used to potentiate the antidotal efficacy of pyridoxine, particularly if optimal doses of the antidote are unavailable. The benzodiazepines act synergistically with pyridoxine, as well as possess inherent GABA-agonist activity, but as single agents they may be ineffective in the treatment of acute INH poisoning because of their reliance on GABA to exert their activity.26,27,58,121 Phenytoin has no intrinsic GABAergic effect and is not recommended as therapy for patients with INH-induced seizures.58,83,96 Barbiturates, which have potent GABA-agonist activity, are expected to be as effective as the benzodiazepines, although the risk of respiratory depression is greater with this class of anticonvulsant. The efficacy of propofol in terminating INH-induced seizures has not been evaluated in humans. Although hemodialysis has been used to enhance elimination of INH in acute overdose, with clearance rates reported as high as 120 mL/min, hemodialysis is rarely indicated for initial management. It is usually reserved for patients who develop INH-overdose-induced renal failure.19,122 Asymptomatic patients who present to the emergency department (ED) within 2 hours of ingestion of toxic amounts of INH should receive prophylactic administration of 5 g of oral or intravenous pyridoxine. This recommendation is based on the observation that INH reaches its peak serum concentration within 2 hours of ingestion of therapeutic doses. Asymptomatic patients may be observed for a 6-hour period for signs of toxicity. Acute toxicity is unlikely to manifest more than 6 hours beyond ingestion. Chronic Toxicity Hepatitis (defined as aminotransferase concentrations two to three times baseline concentrations) resulting from therapeutic INH administration mandates termination of therapy; malnourished patients may require nutritional support. After resolution of liver injury, INH may be restarted, provided aminotransferase concentrations are closely monitored.37,109 Pyridoxine does not reverse hepatic injury; consequently, surveillance for and recognition of hepatocellular injury remains essential. Cases of hepatitis refractory to medical therapy may require liver transplantation.40,55,125 Neurologic toxicity, including peripheral neuropathies, cerebellar findings, and psychosis, is commonly treated with as much as 50 mg/d of oral pyridoxine, although doses as low as 6 mg/d appear to be effective.1,9,97,113 Because of its effectiveness in preventing neurologic toxicity, pyridoxine is often used concurrently with INH therapy.

RIFAMYCINS

■ PHARMACOLOGY Rifamycins are a class of macrocyclic antibiotics derived from Amycolatopsis mediterranei. Xenobiotics in this class include rifampin (a semisynthetic derivative), rifabutin, and rifapentine, of which the first two are most commonly used.89 Rifampin inhibits the initial steps in RNA chain polymerization through the formation of a stable drugenzyme complex with RNA polymerase. Disruption of RNA synthesis interrupts protein synthesis, leading to cell death. Whereas mycobacterial RNA polymerase is susceptible to rifampin, eukaryotic RNA polymerase is not. High concentrations of rifamycin antibiotics, however, can affect mammalian mitochondrial RNA synthesis, as well as reverse transcriptases and viral DNA-dependent RNA polymerases.89

■ PHARMACOKINETICS AND TOXICOKINETICS When administered orally, rifampin reaches peak serum concentrations in 0.25 to 4 hours; foods, but not antacids, interfere with absorption.88 Rifampin is secreted into the bile and undergoes enterohepatic recirculation. Although the recirculating antibiotic is deacetylated, the metabolite retains antimicrobial activity. The half-life of rifampin, which is normally between 1.5 and 5 hours, increases in the setting of hepatic dysfunction. After therapy is started, however, rifampin induces its own metabolism to shorten its half-life by approximately 40%. Rifampin is distributed widely into body compartments, and imparts a reddish color to all body fluids, including the cerebrospinal fluid (CSF),89 and in this setting has been erroneously identified as xanthochromia suggesting subarachnoid hemorrhage to the clinician.58 Because mycobacteria rapidly develop resistance to rifampin, it should not be used as single-agent therapy against tuberculosis.89 Rifampin therapy carries greater teratogenic risk than other antituberculous therapies, with 4.4% incidence of malformation. Anencephaly, hydrocephalus, and congenital limb abnormality and dislocations have been reported.14,115 Rifampin is associated with hemorrhagic disease of the newborn14 but is nevertheless compatible with breast-feeding, as only minute amounts of rifampin are secreted into breast milk.14,114

■ DRUG—DRUG INTERACTIONS Rifamycins are potent inducers of CYP isoenzymes, which result in numerous drug interactions (Chap. 12 (Appendix)). Of the rifamycins, rifampin has greater activity in inducing CYP3A4 than rifapentine; rifabutin has the least inductive activity of the class.71 Rifampin also induces CYP1A2, CYP2C9, and CYP2C19.126 Additionally, the ability of rifampin to induce CYP3A4 is strongly correlated with p-glycoprotein concentrations. P-glycoprotein is a transmembrane protein that functions as a

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cellular efflux pump of endogenous and exogenous xenobiotics; variations in expression of p-glycoprotein significantly affects the bioavailability of many drugs and subsequent drug—drug interactions (see Chap. 12 Appendix).42 Concurrent administration of rifampin thus affects the metabolism of an array of drugs such as warfarin, cyclosporine, phenytoin, opioids, and oral contraceptives.42,107,126 Enzyme and p-glycoprotein induction by rifampin therefore may be responsible for a variety of pathophysiologic processes, including insufficient anticoagulation in patients receiving oral anticoagulants, acute graft rejection in transplant patients, graft-versus-host disease, difficulty controlling phenytoin concentrations, methadone withdrawal, and unplanned pregnancy. Effects arising from CYP3A4 induction begin within 5 to 6 days after rifampin is started, and persist for up to 7 days after therapy is stopped.89

■ RIFAMYCINS AND HIV There is an increased risk of tuberculosis in patients with HIV, and concurrent highly active antiretroviral therapy (HAART) and antituberculous therapy decreases mortality. However, there are many factors that influence the efficacy and feasibility of treating these illnesses. There is decreased absorption of nearly all antituberculous drugs in patients with advanced HIV due to chronic diarrhea, intestinal pathogens, and general malabsorption. Also, there are many drug—drug interactions between antituberculous and HIV medications due to alterations in absorption, cytochrome isoenzymes, p-glycoprotein transporters, and noncytochrome metabolism.42,52,119 Rifampin accelerates the clearance of protease inhibitors (such as saquinavir, lopinavir) thereby decreasing the serum concentration, resulting in lower trough concentrations, which correlate with antiviral effect, increased frequency of drug-resistant mutations in the protease gene, and promotion of outgrowth of drug-resistant HIV strains.16,116,119 The reduction of serum concentrations of protease inhibitors is of such magnitude that coadministration of rifampin with protease inhibitors could lead to loss of HIV suppression and to the emergence of resistant HIV strains.16 Increasing the dose of protease inhibitor is associated with significant adverse drug effects and therapeutic intolerance, and cannot overcome the significant clearance of protease inhibitors, even when combined with the standard “boosting strategy” of adding ritonavir, a potent CYP3A4 inhibitor that can increase the concentration of other protease inhibitors 20-fold to attain a therapeutic effect.20,90,119 It may be possible that “super boosted protease inhibitors” with highdose ritonavir may be tolerable and effective. Research is ongoing. Rifampin also induces the metabolism and clearance of nucleoside reverse transcriptase inhibitors (NRTIs, such as stavudine, lamivudine, zidovudine) without influencing cytochrome P450 mechanisms. Resulting decreased serum concentrations of NRTIs, however, do not significantly interfere with drug efficacy. The efficacy of NRTIs is not related to the serum concentration of drug, but is instead related to the intracellular concentration of the active metabolite, a triphosphate derivative. Even though rifampin decreases serum zidovudine concentrations by 47%, active metabolite is present within cells in sufficient levels for activity. Rifampin, therefore, has minimal effect on the efficacy of nucleoside reverse transcriptase inhibitors.16 Table 57-1 lists the drug interactions of rifampin. Combining rifampin with nonnucleoside reverse transcriptase inhibitors (NNRTIs, such as efavirenz, nevirapine) should be considered on a case-by-case basis, as NNRTIs vary widely in their role as substrates, inducers, or inhibitors of cytochome P450 systems, particularly CYP3A4. As a result, it is often difficult to anticipate the degree and effect of drug—drug interactions with rifamycins. It is clear, however, that rifamycins have a role in the treatment of HIV-associated tuberculosis, and that drug interactions are often modest and surmountable with dose adjustment or drug substitution.90

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Rifampin suppresses the transformation of antigen-stimulated lymphocytes, as well as normal T-cell function, leading to decreased sensitivity to tuberculin, in turn resulting in false-negative purified protein derivative (PPD) test results.

■ CLINICAL MANIFESTATIONS Acute Toxicity The most common side effects of acute rifampin overdose are GI symptoms consisting of epigastric pain, nausea, vomiting, and diarrhea.37,89 The presence of diarrhea distinguishes rifampin ingestion from overdose of other antimycobacterial agents. Three reported deaths have been described from rifampin or rifampicin ingestion; an autopsy performed on one of these patients demonstrated the presence of pulmonary edema, although no causation was implied.12,62,91 Other effects include flushing, angioedema, and obtundation. Children who receive an overdose of rifampin can develop facial or periorbital edema. Anterior uveitis is occasionally observed, as are neurologic effects consisting of generalized numbness, extremity pain, ataxia, and muscular weakness.50 Isolated rifamycin overdose infrequently produces serious acute effects.

■ CHRONIC TOXICITY When rifampin was originally introduced as an antituberculous drug, hepatitis was more frequently observed in patients taking combination therapy of rifampin and INH than in those taking INH alone. These findings potentially arise from the ability of rifampin to induce cytochromes responsible for INH hepatotoxicity and not from direct hepatic injury by rifampin itself. Liver injury, when attributable to rifampin alone, is predominantly cholestatic, suggesting that clinical surveillance for hepatic injury is important as is regular biochemical monitoring.37,86 Rifampin alters the metabolism of other xenobiotics, such as INH, pyrazinamide, and acetaminophen, to increase their potential for hepatotoxicity.37,81 Although some reports highlight increased compliance and typically mild and transient hepatotoxicity with combined rifampin and pyrazinamide treatment for latent tuberculosis infection, other recent studies suggest a significant risk of fatal hepatotoxicity, and the Centers for Disease Control and Prevention (CDC) recommends generally avoiding this combination of drugs.75 A condition similar to a viral syndrome may result from a hypersensitivity reaction that is associated with rifampin therapy. The syndrome, which occurs in 20% of patients receiving high doses or intermittent (less than twice weekly) dosing, includes fever, chills, and myalgias. Eosinophilia, hemolytic anemia, thrombocytopenia, and interstitial nephritis can develop in severe cases, and acute renal injury is likely related to hypersensitivity. Renal failure is rarely oliguric and is usually self-limited; patients usually recover with supportive care, although rechallenge with rifampin should be undertaken only with caution.86 The concomitant administration of rifampin and protease inhibitors results in increased rates of arthralgias, uveitis, leukopenia, and skin discoloration. Identical side effects occurred during the simultaneous administration of rifampin and CYP3A4 inhibitors such as clarithromycin, suggesting that toxic effects arise from elevated serum rifampin concentrations.16 Current recommendations are that rifampin not be given with protease inhibitors, except for ritonavir in rare circumstances. In patients already on protease inhibitors, rifabutin may be used in place of rifampin.90

■ THERAPEUTIC TESTING AND MANAGEMENT Management of patients with acute rifampin overdose is primarily supportive. Stabilization of vital signs and administration of activated charcoal are usually adequate, although clinicians should remain vigilant for coingestants. For chronic toxicity, recognition of interactions between

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rifampin and other drugs is critical. Hepatic function should be monitored because of the ability of rifampin to augment the hepatotoxicity of other xenobiotics. Treatment for hepatic injury involves withholding rifampin therapy and reassessing the appropriateness of other xenobiotics administered to the patient. Supportive care for hepatotoxicity may be required. Influenza-like symptoms and renal failure secondary to rifampin may respond to decreasing the interval between administration of the drug.86 Although rifampin interacts with protease inhibitors, the utility of therapeutic drug monitoring is uncertain because the correlation of clinical events with serum concentrations of rifampin and antiretroviral drugs is unknown.16

ETHAMBUTOL

■ PHARMACOLOGY Ethambutol is effective against Mycobacterium tuberculosis and Mycobacterium kansasii as well as some strains of Mycobacterium avium complex; however, it has no effect on other bacteria. Ethambutol inhibits arabinosyl transferases, interfering with biosynthesis of arabinogalactan and liparabinomannan, which are required for polymerization of arabinan within mycobacterial cell walls.63,89

■ PHARMACOKINETICS AND TOXICOKINETICS Only the D(+) isomer is used therapeutically, but both enantiomers are bacteriocidal.58 The drug is taken up rapidly by growing cells, where bacteriostatic effects appear approximately 24 hours after ethambutol is incorporated by mycobacteria.89 About 80% of an oral dose is absorbed gastrointestinally, but both foods and antacids decrease absorption.16,89 Maximum serum concentrations are reached within 4 hours of oral administration and are proportional to the dose. Ethambutol is approximately 20% to 30% protein bound and has a half-life of between 4 and 6 hours.68,89 Three-fourths of a standard dose is excreted unchanged into the urine by a combination of glomerular filtration and tubular secretion. Consequently, ethambutol accumulates in patients with renal compromise, making adjustments in dosing necessary.89 Increasingly, mutations in the Mycobacterium embB gene confer resistance to ethambutol, as high as 14.2%, with acquired resistance reaching nearly 40%.63 Ethambutol is considered safe for use during pregnancy as a firstline drug. Although a 2.2% incidence of congenital abnormalities was identified in women undergoing ethambutol therapy, no consistent pattern of abnormalities occurred in their offspring.14 Ethambutol is excreted into breast milk in approximately a 1:1 ratio with serum, but is considered to be compatible with breast-feeding.14

Although peripheral neuropathy and cutaneous reactions occur with chronic therapy, the most significant effect of the therapeutic use of ethambutol is unilateral or bilateral ocular toxicity presenting as painless blurring of vision, decreased perception of color, and loss of peripheral vision. These effects are largely dose and duration related, and are typically reversible with drug discontinuation.23,29 Optic neuritis develops in approximately 15% of patients receiving 50 mg/kg/d, 5% of patients receiving 25 mg/kg/d, and fewer than 1% of those receiving 15 mg/kg/d.86 Patients may develop subclinical ocular disease within 30 days of starting ethambutol.129 The loss of peripheral vision and color discrimination that accompanies the optic neuropathy caused by ethambutol distinguishes this condition from the optic neuropathy secondary to INH.58,86 Management of chronic toxicity from ethambutol involves cessation of therapy, although improvement may be hastened by treatment with hydroxocobalamin.58,89 Recovery is less likely in older patients and is related to the degree of visual impairment.120 Ethambutol is a strong metal-chelator and inactivation of zinc and copper may be related to its induction of retinal cell vacuoles and enlarged lysosomes, which interfere with membrane permeabilization, possibly causing abnormal cell function and cell death.29,65 The visual abnormalities induced by ethambutol are similar to those caused by a hereditary condition known as Leber optic neuropathy. Both ethambutol and Leber hereditary optic neuropathy can affect oxidative phosphorylation through impairment of mitochondrial function.28,65 Ethambutol is suspected of mimicking this condition by binding intracellular copper, altering mitochondrial function, and producing neuronal injury.57,65 Alternatively, optic neuritis may be related to zinc metabolism. Ethambutol chelates intracellular zinc to induce reversible vacuolar degeneration in retinal cultures. Progressive degeneration leads to irreversible neuronal destruction.29 The effect of this injury is a shift in the threshold for wavelength discrimination without changing the absolute sensitivity of the cone system, which leads to a loss of redgreen discrimination.111

■ DIAGNOSTIC TESTING All patients should receive neuro-ophthalmic testing prior to ethambutol therapy. The use of visual-evoked potentials is especially useful in identifying subclinical optic nerve disease. Furthermore, patients should receive regular visual acuity examinations, and clinicians should encourage patients to report any visual subjective symptoms. The use of ethambutol may be relatively contraindicated in children who are unable to comply with an ophthalmic examination.58,86

PYRAZINAMIDE

■ CLINICAL MANIFESTATIONS AND MANAGEMENT

■ PHARMACOLOGY AND PHARMACOKINETICS

Acute overdose of ethambutol is generally well tolerated, although a death has been reported.62 More commonly, nausea, abdominal pain, confusion, visual hallucinations, and optic neuropathy occur following acute ingestions of greater than 10 g.36 Although stabilization of vital signs and GI decontamination with activated charcoal remain the hallmarks of therapy, clinicians must remain vigilant for coingestants, particularly INH. Hemodialysis is rarely used as treatment for multidrug ingestions including ethambutol.36

Pyrazinamide (PZA) is a structural analog of nicotinamide with a mechanism of action similar to that of isoniazid (INH). Like INH, PZA is a prodrug. Pyrazinamide requires deamidation to anionic pyrazinoic acid by pyrazinamidase, an endogenous cytoplasmic bacterial enzyme. In this form, PZA has no antibacterial activity, but once exposed to acidic conditions, it becomes protonated to the uncharged, active form of the drug, 5-hydroxypyrazinoic acid, which enters the cell, accumulates, and kills the bacteria by disruption of mycolic acid biosynthesis.

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Pyrazinamide is effective against both active and dormant bacteria and its use in antituberculous regimens shortens the course of therapy; however, resistance rapidly develops if used as single-agent therapy, and it should therefore only be used with other antituberculous medications.89 Pyrazinamide is synergistic with rifampin, and has greatest efficacy if administered during the first 2 months of treatment with both INH and rifampin; this regimen effectively shortens the treatment course to only 6 months.131 After oral administration, PZA is rapidly absorbed, with maximum concentrations occurring within 1 to 2 hours of administration, and a half-life of approximately 9 hours. Hepatic metabolism to pyrazinoic acid and 5-hydroxypyrazinoic acid occurs with the metabolites subsequently renally excreted.89 When introduced in the 1950s, PZA was administered in doses of 40 to 50 mg/kg for extended periods of time. The dosages produced hepatitis, with clinical manifestations of highly elevated aminotransferase and bilirubin concentrations. Of patients taking high-dose PZA, elevations in aminotransferases were identified in 20%, and symptomatic hepatitis was identified in 10%, with a small number of those who developed hepatitis dying from a fulminant course. As a result of these findings, PZA was believed to be highly hepatotoxic and its use was discouraged. The resurgence of multidrug-resistant mycobacteria, however, has forced clinicians to reassess the role of PZA. Modern dosing regimens of 30 mg/kg for brief courses of 2 months infrequently produce hepatic injury, with some studies suggesting that addition of PZA to multidrug TB regimens confers no additional risk for hepatotoxicity.37 Pyrazinamide is rarely used in pregnancy because the risk of birth defects is poorly defined. Animal studies suggest that PZA has no teratogenic potential at therapeutic doses.2 Pyrazinamide is minimally excreted into breast milk and is presumed safe for breast-feeding.14 It is considered a category C drug in pregnancy.

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somnolence, headache, tremor, dysarthria, vertigo, confusion, irritability, and seizures.53 Psychiatric manifestations include paranoid reactions, depression, and suicidal ideation. Reversible hypersomnolence and asterixis have been reported with cycloserine, corroborated by magnetic resonance imaging (MRI) suggestive of reversible thalamic neurotoxicty.67 Cycloserine is contraindicated in patients with a history of either seizures or depression. If used, cycloserine should be introduced slowly to avoid CNS toxicity.31,58,86 Toxicity is potentiated by alcohol, usually appears within the first 2 weeks of therapy, and ceases upon termination of the drug. Because cycloserine is renally excreted, patients with renal failure may be predisposed to toxicity; it is removed by hemodialysis.31 Although no teratogenic effects were noted in three women exposed to cycloserine during the first trimester, cycloserine is not recommended for use during pregnancy. Cord blood concentrations are approximately 70% of serum concentrations, and no adverse effects occurred in breast-fed infants. Consequently, cycloserine is considered to be safe in women who are breast-feeding.14 Reports of overdose are lacking in the English medical literature.

OTHER ANTIMYCOBACTERIALS

■ CLINICAL MANIFESTATIONS AND MANAGEMENT Proper dosing of PZA and short courses of therapy are the two most important factors in preventing toxicity. Treatment for hepatotoxicity involves cessation of PZA therapy in conjunction with supportive care.37 Pyrazinamide inhibits the renal excretion of uric acid, and hyperuricemia is observed. More than 90% of children treated with short courses developed elevated uric acid concentrations.99 Most patients, regardless of age, remain asymptomatic and do not develop symptoms of gout, but polyarthralgias responsive to probenecid may be observed. Toxic effects from acute overdose of pyrazinamide have not been reported.

CYCLOSERINE Cycloserine, previously avoided because of its adverse effects, is being used increasingly as secondary-line treatment with other tuberculostatic agents when treatment with primary agents (INH, rifampin, ethambutol, and streptomycin) fails or as initial therapy when drug susceptibility testing indicates either MDR-TB or XDR-TB. Cycloserine is a structural analog of alanine, and demonstrates inhibition of D-alanine racemase and D-alanine ligase, which are involved in peptidoglycan cell wall synthesis.53 After oral doses, 70% to 90% of the drug is absorbed and peak concentrations are reached in 3 to 8 hours. Cycloserine is distributed throughout all tissues and body fluids and easily crosses the blood—brain barrier. Less than 35% of the antibiotic is metabolized, and remaining drug is excreted unchanged in the urine.31,89 Toxicity is dose dependent and occurs in as many as 50% of patients taking cycloserine. Cycloserine is a partial agonist at the NMDA/ glycine receptor, which may contribute to neurologic effects such as

■ ETHIONAMIDE Ethionamide, a congener of INH, is a prodrug with a mycotoxic intermediary metabolite thought to have a similar mechanism of action as INH, causing cell death from disruption of mycolic acid biosynthesis. Ethionamide is rapidly absorbed, widely distributed, and crosses the blood—brain barrier. Oral doses yield peak serum concentrations within approximately 3 hours of administration. The half-life of the drug is approximately 2 hours. The most common adverse symptoms associated with ethionamide are GI irritation and anorexia. Toxic effects such as orthostatic hypotension, depression, and drowsiness are common. Rash, purpura, and gynecomastia are observed, as are tremor, paresthesias, and olfactory disturbances. Approximately 5% of patients receiving ethionamide develop hepatitis; patients on this medication should be screened intermittently for hepatic injury. Treatment for toxicity involves withholding ethionamide therapy.89 Birth defects were observed in seven of 23 newborns exposed to ethionamide, in utero, although a consistent pattern of anomalies was lacking. Data regarding the presence and safety of breastfeeding on ethionamide also are lacking.14 Ethionamide is too toxic to be used as first-line therapy, but when needed should only be administered with another antimycobacterial medication, as resistance develops rapidly when ethionamide is used alone.89 Reports of mortality from ethionamide overdose are absent from the English literature.34

■ PARA-AMINOSALICYLIC ACID para-Aminosalicylic acid (PAS) is a structural analog of para-aminobenzoic acid and is thought to inhibit enzymes responsible for folate

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biosynthesis in mycobacteria but not in other organisms.89 Despite common adverse effects, PAS is being used to a greater extent in the multidrug treatment plans for treating extensively drug-resistant tuberculosis.79 PAS is readily absorbed from the gut and is rapidly distributed into all tissues, especially the pleural fluid and caseous material. para-Aminosalicylic acid has a half-life of approximately 1 hour and is renally excreted. Adverse effects of PAS are seen in 10% to 30% of patients and include anorexia, nausea, vomiting, diarrhea, sore throat, and malaise. Between 5% and 10% of patients receiving PAS develop hypersensitivity reactions characterized by high fever, rash, and arthralgias. Hematologic abnormalities of agranulocytosis, leukopenia, eosinophilia, thrombocytopenia, and acute hemolytic anemia have been observed.89 para-Aminosalicylic acid may be removed by hemodialysis in patients with renal failure.73 Adverse effects associated with chronic therapy may be treated by its withdrawal. Data regarding the safety of PAS in pregnancy and breast-feeding are lacking.14

■ CAPREOMYCIN Capreomycin is a cyclic polypeptide being used more frequently now because of its antibacterial activity against multidrug-resistant and intracellular tuberculosis bacilli. Tuberculosis strains resistant to more than one aminoglycoside may be susceptible to this polypeptide. Capreomycin interferes with ribosomes and inhibits protein translation, but may also act by other mechanisms such as alterations in topoisomerase or the glyoxylate shunt pathway.44 Due to poor absorption after oral dosing, capreomycin must be administered intramuscularly. Toxicity associated with capreomycin use includes hearing loss, tinnitus, proteinuria, and electrolyte disturbances, although severe renal failure is rare. Eosinophilia, leukocytosis, and rashes have been described. Pain and sterile abscesses at the site of capreomycin injection are reported.89 Data are lacking regarding the safety of capreomycin in pregnancy and breast-feeding.14 Many other antibiotics and immunomodulators that have been primarily overlooked or rejected for the management of tuberculosis are increasingly being used as part of multidrug regimens against resistant strains. Discussed more extensively in other chapters, these include fluoroquinolones such as ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin, sparfloxicin, macrolides such as clarithromycin, aminoglycosides such as amikacin, streptomycin, kanamycin, capreomycin, interferon, amoxicillin-clavulanate, linezolid, and clofazimine (see Chap. 56).79

SUMMARY In overdose many certain antituberculous drugs become significant toxicologic threats. Patients acutely poisoned with INH require immediate and appropriate action to reverse seizures, acidosis, and coma beginning with the specific antidote pyridoxine. Pyridoxine is effective therapy, alone or if necessary augmented by benzodiazepines. Although less common than previously believed, hepatocellular injury resulting from therapeutic dosing of INH requires regularly scheduled, frequent evaluations to prevent fulminant hepatic failure. With the increasing prevalence of multidrug-resistant and extensivelydrug-resistant tuberculosis strains, antituberculous medications previously avoided or ignored are now being used typically in combination with two or more other antituberculous medications. Despite reduced dosages compared with those previously used, in some cases significant adverse effects remain a concern. In particular, rifampin causes numerous drug—drug interactions, some involving several anti-HIV therapies. Because antituberculous therapies are commonly needed in the HIV-infected population, potential interactions between rifampin and antiretroviral agents should remind clinicians to remain vigilant for

unanticipated adverse effects. Patients receiving ethambutol, pyrazinamide, and other antituberculous medications benefit from careful surveillance for specific adverse effects such as decreased visual acuity, hepatic injury, and psychiatric manifestations. Despite the toxicity of this class of drugs, poisonings are often responsive to intervention when recognized early and treated appropriately.

REFERENCES 1. Alao A, Yolles J. Isoniazid-induced psychosis. Ann Pharmacother. 1998;32: 889-890. 2. Al-Haggag M, Al Haider A, Islam M. Evaluation of the teratogenic potential of pyrazinamide in Wistar rats. Upsala J Med Sci. 1999;104:259-270. 3. Anonymous. Global Tuberculosis Control 2007, World Health Organization, 2007. http://www.who.int/tb/en/. Accessed January 20, 2008. 4. Bear E, Hoffman P, Siegel S, Randal R. Suicidal ingestion of isoniazid: an uncommon cause of metabolic acidosis and seizures. South Med J. 1976;69:31-32. 5. Biggs CS, Pearce BR, Fowler LJ, Whitton PS. Effect of isonicotinic acid hydrazide on extracellular amino acids and convulsions in the rat: reversal of neurochemical and behavioural deficits by sodium valproate. J Neurochem. 1994;63:2197-2201. 6. Blanchard PD, Yao JDC, McAlpine DE, et al. Isoniazid overdose in the Cambodian population of Olmstead Country, Minnesota. JAMA. 1986;256:3131-3133. 7. Bloom B, Murray C. Tuberculosis: commentary on a re-emergent killer. Science. 1992;257:1055-1064. 8. Blowey D, Johnson D, Verjee Z. Isoniazid-associated rhabdomyolysis. Am J Emerg Med. 1995;13:543-544. 9. Blumberg E, Gil R. Cerebellar syndrome caused by isoniazid. Ann Pharmacother. 1990;24:829-831. 10. Boxenbaum HC, Riegelman S. Pharmacokinetics of isoniazid and some metabolites in man. J Pharmacokinet Biopharm. 1976;287:325. 11. Brent J, Vo N, Kulig K, Rumack BH. Reversal of prolonged isoniazidinduced coma by pyridoxine. Arch Intern Med. 1990;150:1751-1753. 12. Broadwell R, Broadwell S, Comer P. Suicide by rifampin overdose. JAMA. 1978;240:2283. 13. Bromberg Y, Salzberger M, Bruderman I. Placental transfer of isonicotinic acid hydrazide. Gynecologie. 1955;140:141-145. 14. Brost B, Newman R. The maternal and fetal effects of tuberculosis therapy. Obstet Gynecol Clin North Am. 1997;24:659-673. 15. Brown C. Acute isoniazid poisoning. Am Rev Respir Dis. 1972;105:206-216. 16. Burman W, Gallicano K, Peloquin C. Therapeutic implications of drug interactions in the treatment of human immunodeficiency virus-related tuberculosis. Clin Infect Dis. 1999;28:419-430. 17. Byrd R, Nelson R, Elliott R. Isoniazid toxicity: a prospective study in secondary complications. JAMA. 1972;220:1471-1473. 18. Cameron W. Isoniazid overdose. Can Med Assoc J. 1978;118:1413-1415. 19. Cash J, Zawada E. Isoniazid overdose: successful treatment with pyridoxine and hemodialysis. West J Med. 1991;155:644-646. 20. Centers for Disease Control and Prevention. Managing drug interactions in the treatment of HIV-related tuberculosis [online]. 2007. http://www. dcd.gov/tb/TB_HIV_Drugs/default.htm. Accessed January 23, 2009. 21. Centers for Disease Control and Prevention. Treatment of tuberculosis. MMWR (Morbidity & Mortality Weekly Report). 20 June 2003;55(RR11):1-77. 22. Centers for Disease Control and Prevention. Trends in tuberculosis 2007. MMWR (Morbidity & Mortality Weekly Report). 21 March 2008;57:281-285. 23. Chan RY, Kwok AK. Ocular toxicity of ethambutol. Hong Kong Med J. 2006;12:56-60. 24. Chien J, Peter R, Nolan C, et al. Influence of polymorphic N-acetyltransferase phenotype on the inhibition and induction of acetaminophen bioactivation with long term isoniazid. Clin Pharmacol Ther. 1997;61:24-34. 25. Chin L, Sievers ML, Herrier HE, Picchioni AL. Convulsions as the etiology of lactic acidosis in acute isoniazid toxicity in dogs. Toxicol Appl Pharmacol. 1979;49:377-384. 26. Chin L, Sievers ML, Laird HE, Herrier RN, Picchioni AL. Potentiation of pyridoxine by depressants and anticonvulsants in the treatment of acute isoniazid intoxication in dogs. Toxicol Appl Pharmacol. 1981;58:504-509. 27. Chin L, Sievers ML, Laird HE, Herrier RN, Picchioni AL. Evaluation of diazepam and pyridoxine as antidotes to isoniazid intoxication in rats and dogs. Toxicol Appl Pharmacol. 1978;45:713-722.

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28. Chowdhury B, Nagpaul AK, Chowdhury D. Leber’s hereditary optic neuropathy masquerading as ethambutol-induced optic neuropathy in a young male. Indian J Ophthalmol. 2006;54:218-219. 29. Chung H, Yoon Y, Hwang J, et al. Ethambutol-induced toxicity is mediated by zinc and lysosomal membrane permeabilization in cultured retinal cells. Toxicol Applied Pharmacol. 2009;235:163-170. 30. Coyer J, Nicholson D. Isoniazid-induced seizures. Part I—clinical. Part II—cxperimental. South Med J. 1972;69:294-297. 31. Cycloserine [package insert]. Indianapolis, IN: Eli Lilly and Company; 2005. 32. DiMartini A. Isoniazid, tricyclics and the “cheese reaction.” Int Clin Psychopharmacol. 1995;10:197-198. 33. Dockweiler U. Isoniazid-induced valproate toxicity, or vice versa. Lancet. 1987;18(2):152. 34. Dolgikh-Litt N. Attempted of suicide with ethionamide. Klin Med (Mosk). 1967;45:148-150. 35. Donald P, Parkin D, Seifart H, et al. The influence of dose and N-acetyltransferase-2 (NAT2) genotype and phenotype on the pharmacokinetics and pharmacodynamics of isoniazid. Eur J Clin Pharmacol. 2007;63:633-639. 36. Ducobu J, Dupont P, Laurent M. Acute isoniazid/ethambutol/rifampin overdosage. Lancet. 1982;1:632. 37. Durand F, Jebrak G, Pessayre D, Fournier M, Bernau J. Hepatotoxicity of antitubercular treatments: Rationale for monitoring liver status. Drug Saf. 1996;15:394-405. 38. Durand F, Pessayre D, Fournier M, et al. Antituberculous therapy and acute liver failure. Lancet. 1995;345:1170. 39. Ellard G. The potential clinical significance of the isoniazid acetylator phenotype in the treatment of pulmonary tuberculosis. Tubercle. 1984;65:211-227. 40. Farrell FJ, Keeffe EB, Man KM, Imperial JC, Esquivel CO. Treatment of hepatic failure secondary to isoniazid hepatitis with liver transplantation. Dig Dis Sci. 1994;39:2255-2259. 41. Farrell G. Drug-Induced Acute Hepatitis. Drug-Induced Liver Disease. Edinburgh: Churchill Livingstone; 1994:247-299. 42. Finch C, Chrisman C, Baciewicz A, Self TH. Rifampin and rifabutin drug interactions: an update. Arch Intern Med. 2002;162:985-989. 43. Franks A, Binkin N, Snider D. Isoniazid hepatitis in pregnant an postpartum Hispanic patients. Public Health Rep. 1989;104:151-155. 44. Fu LM, Shinnick TM. Genome-wide exploration of the drug action of capreomycin in Mycobacterium tuberculosis using Affymetrix oligonucleotide gene chips. J Infection. 2007;54:277-284. 45. Gannon R, Pearsall W, Rowley R. Isoniazid, meperidine, and hypotension. Ann Intern Med. 1983;99:415. 46. Gent W, Seifart H, Parkin D, Donald PR, Lamprecht JH. Factors in hydrazine formation from isoniazid by paediatric and adult tuberculosis patients. Eur J Clin Pharmacol. 1992;43:131-136. 47. Gnam W, Flint A, Goldbloom D. Isoniazid-induced hallucinosis: response to pyridoxine. Psychosomatics. 1993;34:537-539. 48. Goel U, Baja S, Gupta O, Dwiedi N. Isoniazid-induced neuropathy in slow versus rapid acetylators. J Assoc Physicians India. 1992;40:671-672. 49. Gonzalez-Gay MA, Sanchez-Andrade A, Aguero JJ, et al. Optic neuritis following treatment with isoniazid in a hemodialyzed patient. Nephron. 1993;63:360. 50. Griffith D, Brown B, Girard W, Wallace R. Adverse events associated with high-dose rifabutin in macrolide-containing regimens for treatment of Mycobacterium avium complex lung disease. Clin Infect Dis. 1995;21:594-598. 51. Gurumurthy P, Krishnamurthy M, Nazareth O. Lack of relationship between hepatic toxicity and acetylator phenotype and in South Indian patients during treatment with isoniazid for tuberculosis. Am Rev Respir Dis. 1984;129:58-61. 52. Gurumurthy P, Ramachandran G, Kumar AK, et al. Decreased bioavailability of rifampin and other antituberculosis drugs in patients with advanced human immunodeficiency virus disease. Antimicrob Agents Chemother. 2004;48:4473-4475. 53. Halouska S, Chacon O, Fenton R, et al. Use of NMR metabolomics to analyze the targets of D-cycloserine in Mycobacteria: role of D-alanine racemase. J Proteome Res. 2007;6:4608-4614. 54. Hankinns DG, Saxena K, Faville RJ, Warren BJ. Profound acidosis caused by isoniazid ingestion. Am J Emerg Med. 1987;5:165-166. 55. Hasagawa T, Reyes J, Nour B, et al. Successful liver transplantation for isoniazid-induced hepatic failure—a case report. Transplantation. 1994;57:1274-1277.

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56. Hauser M, Baier H. Interactions of isoniazid with foods. Clin Pharmacokinet. 1982;16:617-618. 57. Heng J, Vorwerk C, Lessell E, et al. Ethambutol is toxic to retinal ganglion cells via an excitotoxic pathway. Invest Ophthalmol Vis Sci. 1999;40: 190-196. 58. Holdiness MR. Neurological manifestations and toxicities of the antituberculosis drugs—a review. Med Toxicol. 1987;2:33-51. 59. Holtz P, Palm D. Pharmacological aspects of vitamin B6. Pharmacol Rev. 1964;16:113-178. 60. Hurwitz A, Schlozman DL. Effects of antacids on gastrointestinal absorption of isoniazid in rat and man. Am Rev Respir Dis. 1974;109:41-47. 61. Isoniazid [package insert]. Princeton, NJ: Sandoz Inc; 2006. 62. Jack D, Knepil J, McLay W, Fergie R. Fatal rifampicin-ethambutol overdose. Lancet. 1978;2:1107-1108. 63. Jain A, Mondal R, Srivastava S, et al. Novel mutations in embB gene of ethambutol-resistant isolates of Mycoplasma tuberculosis: A preliminary report. Indian J Med Res. 2008;128:134-139. 64. Kocabay G, Erelel M, Tutkun I, Ecder T. Optic neuritis and bitemporal hemianopsia associated with isoniazid-treatment in end-stage renal failure. Int J Tuberc Lung Dis. 2006;10:1418-1419. 65. Kozak S, Inderlied C, Hsu H, Heller KB, Sadun AA. The role of copper on ethambutol’s antimicrobial action and implications for ethambutolinduced optic neuropathy. Diagn Microbiol Infect Dis. 1998;30:83-87. 66. Kozanoff D, Snider D, Caras G. Isoniazid hepatitis: a US Public Health Service cooperative surveillance study. Am Rev Respir Dis. 1978;117:991-1001. 67. Kwon HM, Kim HK, Cho J, Hong YH, Nam H. Cycloserine-induced encephalopathy: evidence on brain MRI. Eur J Neurology. 2008;15:e60-e61. 68. Lee C, Gambertoglio J, Brater D, Benet L. Kinetics of oral ethambutol in the normal subject. Clin Pharmacol Ther. 1977;22:615-621. 69. Lejonc J, Schaeffer A, Brochard P, Portos JL. Paroxystic hypertension after ingestion of gruyere cheese during isoniazid treatment: a report of two cases. Ann Med Interne (Paris). 1980;131:346-348. 70. Lenke R, Turkel S, Monsen R. Severe fetal deformities associated with ingestion of excessive isoniazid in early pregnancy. Acta Obstet Gynecol Scand. 1985;64:281-282. 71. Li A, Reith M, Rasmussen A, et al. Primary human hepatocytes as a tool for the evaluation of structure-activity relationship in cytochrome P450 induction potential of xenobiotics: evaluation of rifampin, rifapentine, and rifabutin. Chem Biol Interact. 1997;107:17-30. 72. Lopez-Samblas A, Tsiligiannis T. Isoniazid intoxication in three adolescent patients. Hosp Pharm. 1991;26:119-121. 73. Malone R, Fish D, Spiegel D, Childs JM, Peloquin CA. The effect of hemodialysis on cycloserine, ethionamide, para-aminosalicylic acid, and clofazimine. Chest. 1999;116:984-990. 74. Martinez-Roig A, Cami J, Llorens-Terol J. Acetylation phenotype and hepatotoxicity in the treatment of tuberculosis in children. Pediatrics. 1986;77:912-915. 75. McElroy PD, Ijaz K, Lambert LA, et al. National survey to measure rates of liver injury, hospitalization, and death associated with rifampin and pyrazinamide for latent tuberculosis infection. Clin Infect Dis. 2005;41:1125-1133. 76. Mdluli K, Slayden R, Zhu Y, et al. Inhibition of a Mycobacterium tuberculosis beta-ketoacyl ACP synthetase by isoniazid. Science. 1998;280:1607-1610. 77. Miki M, Ishikawa T, Okayama H. An outbreak of histamine poisoning after ingestion of the ground saury paste in eight patients taking isoniazid in tuberculosis ward. Int Med. 2005;44:1133-1136. 78. Miller J, Robinson A, Percy AL. Acute isoniazid poisoning in childhood. Am J Dis Child. 1980;134:290-292. 79. Mitnick CD, Shin SS, Seung KW, et al. Comprehensive treatment of extensively drug-resistant tuberculosis. N Engl J Med. 2008;359:563-574. 80. Nelson S, Mitchell J, Timbrell J, Snodgrass W. Isoniazid activation of metabolites to toxic intermediates in man and rat. Science. 1975;193:901-903. 81. Nicod L, Villon C, Regnier A, et al. Rifampicin and isoniazid increase acetaminophen and isoniazid cytotoxicity in human HapG2 hepatoma cells. Hum Exp Toxicol. 1997;16:28-34. 82. Nolan C, Goldberg S, Buskin S. Hepatotoxicity associated with isoniazid preventive therapy: a 7-year survey from a public health tuberculosis clinic. JAMA. 1999;281:1014-1081. 83. Orlowski JP, Paganini EP, Pippenger CE. Treatment of a potentially lethal dose isoniazid ingestion. Ann Emerg Med. 1988;17:73-76. 84. Pahl MV, Vaziri ND, Ness R, Nathan R, Maksy M. Association of betahydroxybutyric acidosis with isoniazid intoxication. J Toxicol Clin Toxicol. 1984;22:167-176.

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85. Panganiban L, Makalinao I, Cortes-Maramba N. Rhabdomyolysis in isoniazid poisoning. Clin Tox. 2001;39:143-151. 86. Patel A, McKeon J. Avoidance and management of adverse reactions to antituberculosis drugs. Drug Saf. 1995;12:1-25. 87. Paulsen O, Hoglund P, Nilsson LG, Gredeby H. No interaction between H2 blockers and isoniazid. Eur J Respir Dis. 1986;68:286-290. 88. Peloquin C, Namdar R, Dodge A, Nix DE. Pharmacokinetics of isoniazid under fasting conditions, with food, and with antacids. Int J Tuberc Lung Dis. 1999;3(8):703-710. 89. Petri WA. Antimicrobial agents: chemotherapy of tuberculosis, Mycobacterium avium complex disease and leprosy. In: Brunton LL, Lazo JS, Parker KL, eds. Goodman and Gilman’s the Pharmcological Basis of Therapeutics, 11th ed. New York: McGraw-Hill; 2006: 1203-1223. 90. Piscitelli SC, Gallicano KD. Interactions among drugs for HIV and opportunistic infections. N Engl J Med. 2001;344:984-996. 91. Plomp T, Battista H, Unterdorfer H. A case of fatal poisoning by rifampicin. Arch Toxicol. 1981;48:245-248. 92. Quemard A, Dessen A, Sugantino M, et al. Binding of catalaseperoxidase activated isoniazid to wild-type and mutant Mycobacterium tuberculosis enoyl-ACP reductases. J Am Chem Soc. 1996;118:1561-1562. 93. Quemard A, Sacchettini J, Dessen A, et al. Enzymatic characterization of the target for isoniazid in Mycobacterium tuberculosis. Biochemistry. 1995;34:8235-8241. 94. Raviglione M, Smith I. XDR-Tuberculosis—implications for global public health. New Engl J Med. 2007;356:656-659. 95. Rawat R, Whitty A, Tonge P. The isoniazid-NAD adduct is a slow, tight-binding inhibitor of InhA, the Mycobacterium tuberculosis enoyl reductase: adduct affinity and drug resistance. Proc Natl Acad Sci U S A. 2003;100:13881-13886. 96. Saad S, el Masry A, Scott P. Influence of certain anticonvulsants on the concentration of GABA in the cerebral hemispheres of mice. J Am Chem Soc. 1954;76:300-304. 97. Salkind A, Hewitt C. Coma from long-term overingestion of isoniazid. Arch Intern Med. 1997;157:2518-2520. 98. Salpeter SR. Fatal isoniazid-induced hepatitis—its risk during chemoprophylaxis. West J Med. 1993;159:560-564. 99. Sanchez-Albisua I, Vidal L, Joya-Verde F, et al. Tolerance of pyrazinamide in short course chemotherapy for pulmonary tuberculosis in children. Pediatr Infect Dis J. 1997;16:760-763. 100. Sanders B, Draper G. Childhood cancer and drugs in pregnancy. Br Med J. 1979;1:717-718. 101. Santucci K, Shah B, Linakis J. Acute isoniazid exposures and antidote availability. Pediatr Emerg Care. 1999;15:99-101. 102. Sarzi-Puttini P, Atzeni F, Capsoni F, Lubrano E, Doria A. Drug-induced lupus erythematosus. Autoimmunity. 2005;38:507-518. 103. Schreiber J, Zissel G, Greinert U, Schlaak M, Müller-Quernhim J. Lymphocyte transformation test for the evaluation of adverse effects of antituberculous drugs. Eur J Med Res. 1999;4:67-71. 104. Scolding N, Ward M, Hutchings A, Routledge P. Charcoal and isoniazid pharmacokinetics. Hum Toxicol. 1986;5:285-286. 105. Scott E, Wright R. Fluorometric determination of INH in serum. J Lab Clin Med. 1967;70:355-360. 106. Self T, Chrisman C, Baciewicz A, Bronze M. Isoniazid drug and food interactions. Am J Med Sci. 1999;317:304-311. 107. Shenfield G. Oral contraceptives. Are drug interactions of clinical significance? Drug Saf. 1993;9:211-237.

108. Siefkin A, Albertson T, Corbett M. Isoniazid overdose: pharmacokinetics and effects of oral charcoal in treatment. Hum Toxicol. 1987;6:497-501. 109. Singh J, Garg P, Tandon R. Hepatotoxicity due to antituberculosis therapy: clinical profile and reintroduction of therapy. J Clin Gastroenterol. 1996;22:211-214. 110. Siskind MS, Thienemann D, Kirlin L. Isoniazid-induced neurotoxicity in chronic dialysis patients: report of three cases and a review of the literature. Nephron. 1993;64:303-306. 111. Sjoerdsma T, Kamermans M, Spekreijse H. Modulating wavelength discrimination in goldfish with ethambutol and stimulus intensity. Vision Res. 1996;36:3519-3525. 112. Smith C, Durack D. Isoniazid and reaction to cheese. Ann Intern Med. 1979;88:520-521. 113. Snider D. Pyridoxine supplementation during isoniazid therapy. Tubercle. 1980;61:191-196. 114. Snider D, Pwell K. Should women taking antituberculosis drugs breastfeed? Arch Intern Med. 1984;144:589-590. 115. Steen J, Stainton-Ellis D. Rifampicin in pregnancy. Lancet. 1977; 2:604605. 116. Stein D, Fish D, Bilello J, et al. A 24-week open-label phase I/II evaluation of the HIV protease inhibitor MK-639 (indinavir). AIDS. 1996;10:485492. 117. Terman DS, Teitelbaum DT. Isoniazid self-poisoning. Neurology. 1970;20:299-304. 118. Timbrell J, Mitchell J, Snodgrass W. Isoniazid hepatotoxicity: the relationship between covalent binding and metabolism in vivo. J Pharmacol Exp Ther. 1980;213:364-369. 119. Tobairo J, Losso M. Pharmacokinetics interaction studies between rifampin and protease inhibitors: methodological problems. AIDS. 2008;22: 2046-2047. 120. Tsai RK, Lee Y. Reversibility of ethambutol optic neuropathy. J Ocul Pharmacol Ther. 1997;13:473-477. 121. Wason S, Lacouture PG, Lovejoy F. Single high-dose pyridoxine treatment for isoniazid overdose. JAMA. 1981;246:1102-1104. 122. Weber WW, Hein DW. Clinical pharmacokinetics of isoniazid. Clin Pharmacol. 1979;4:401-422. 123. Whitefield C, Klein R. Isoniazid overdose: report of 40 patients with a critical analysis of treatment and suggestions for prevention. Am Rev Respir Dis. 1971;103:887-893. 124. Wood JD, Paesker SJ. The effect on GABA metabolism in brain of isonicotinic acid hydrazide and pyridoxine as a function of time after administration. J Neurochem. 1972;19:1527-1537. 125. Wu S, Chao C, Vargas J, et al. Isoniazid-related hepatic failure in children: a survey of liver transplantation centers. Transplantation. 2007;84:173-179. 126. Yew W. Clinically significant interactions with drugs used in the treatment of tuberculosis. Drug Saf. 2002;25:111-133. 127. Yew W, Leung C. Antituberculous drugs and hepatotoxicity. Respirology. 2006;11:699-707. 128. Yew W, Leung C. Management of multidrug-resistant tuberculosis: update 2007. Respirology. 2008;13:21-46. 129. Yiannidas C, Walsh J, McLeod J. Visual evoked potentials in the detection of subclinical optic toxic effects secondary to ethambutol. Arch Neurol. 1983;40:645-648. 130. Zabinski R, Blanchard J. Activation of INH by KatG. J Am Chem Soc. 1997;1999:2331-2332. 131. Zhang Y, Mitchison D. The curious characteristics of pyrazinamide: a review. Int J Tuberc Lung Dis. 2003;7:6-21.

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A N T I D O T E S I N D E P T H ( A 15 ) PYRIDOXINE

deficiency in animals produces seizures associated with reduced brain concentrations of PLP, glutamic acid decarboxylase, and γ-aminobutyric acid (GABA).16

Mary Ann Howland

PHARMACOKINETICS

Pyridoxine (vitamin B6), a water-soluble vitamin, is administered as an antidote for overdoses of isonicotinic acid hydrazide (isoniazid, INH), Gyromitra esculenta mushrooms, hydrazine, methylated hydrazines, and ethylene glycol. With the exception of ethylene glycol, all of these xenobiotics produce seizures by the competitive inhibition of pyridoxal-5′-phosphate (PLP). Pyridoxine overcomes this inhibition and may also enhance the less-toxic pathway of ethylene glycol metabolism to form benzoic and hippuric acid, instead of oxalic acid.6 Hydrazine and methylated hydrazines (1,1-dimethylhydrazine [UDMH], monomethylhydrazine [MMH]) are used as rocket fuels, and MMH is also found in Gyromitra esculenta mushrooms.3

HISTORY Pyridoxine deficiency characterized by seborrheic dermatitis, cheilosis, stomatitis, and glossitis was first identified in 1926 but was mistakenly attributed to the absence of vitamin B2 (see Chap. 41).31 Ten years later, the deficiency was fully characterized and correctly recognized as a deficiency to vitamin B6.31 A rare genetic abnormality that produced pyridoxine-responsive seizures in newborns was first described in 1954.5

CHEMISTRY The active form of pyridoxine is PLP.31 The alcohol pyridoxine, the aldehyde pyridoxal, and the aminomethyl pyridoxamine are all naturally occurring, related compounds that are metabolized by the body to PLP.31 Pyridoxine was chosen by the Council on Pharmacy and Chemistry to represent vitamin B6.31 Pyridoxine hydrochloride was chosen as the commercial preparation because of its stability.53

PHARMACOLOGY Pyridoxal-5′-phosphate is an important cofactor in more than 100 enzymatic reactions, including decarboxylation and transamination of amino acids, and the metabolism of tryptophan to 5-hydroxytryptamine [serotonin] and methionine to cysteine.23,31 Iatrogenic pyridoxine

Pyridoxine is not protein bound, has a volume of distribution of 0.6 L/kg, and easily crosses cell membranes; in contrast, PLP is nearly entirely plasma protein bound and essential for the synthesis and metabolism of GABA.53 At extrahepatic sites pyridoxine is rapidly metabolized to pyridoxal, PLP, and 4-pyridoxic acid, with only 7% excreted unchanged in the urine.53 After intravenous infusion of 100 mg of pyridoxine over 6 hours, PLP concentration increases rapidly in serum and in erythrocytes.53 Pyridoxal-5’-phosphate rises from 37 nmol/L to 2183 nmol/L in serum and from undetectable to 5593 nmol/L in erythrocytes, with peak concentrations achieved at the end of the infusion.53 Oral pyridoxine, in doses of 600 mg, is 50% absorbed within 20 minutes of ingestion by a first-order process with rapid achievement of peak serum concentrations of pyridoxine, PLP, and pyridoxal.52 The concentration of PLP appears to be tightly controlled in the serum and related to alkaline phosphatase activity.24,52 Oral doses of pyridoxine from 10 to 800 mg result in PLP concentrations of 518 to 732 nmol/L 4 hours after ingestion.52 Chronic alcoholic patients have lower baseline serum PLP concentrations, as acetaldehyde enhances the degradation of PLP in erythrocytes, through stimulation of an erythrocyte membrane-bound phosphatase that hydrolyzes phosphate-containing B6 compounds.30

MECHANISM OF HYDRAZIDE- AND HYDRAZINE-INDUCED SEIZURES The role of pyridoxine as an antidote to poisoning from INH and methylated hydrazines like MMH is based on overcoming the interference of these xenobiotics with the normal function of pyridoxine as a coenzyme. INH produces a syndrome resembling cerebral vitamin B6 deficiency, which results in seizures.43 Specifically, INH and other hydrazides and hydrazines inhibit the enzyme pyridoxine phosphokinase that converts pyridoxine to PLP (see Fig. 57–3).23 In addition, hydrazides directly combine with PLP, causing inactivation through the production of hydrazones that are rapidly excreted by the kidney.23,49 PLP is a coenzyme for L-glutamic acid decarboxylase, which facilitates the synthesis of GABA from L-glutamic acid. Animal studies suggest that interference with PLP disrupts the formation of GABA.23,49,50 The decreased GABA formation and increased glutamic acid reduces cerebral inhibition, which may contribute in part to the seizures resulting from exposure to INH and methylated hydrazines.41,51

ANIMAL STUDIES In a dog model of INH-induced toxicity, pyridoxine reduced the severity of seizures, increased the duration of seizure-free periods, and prevented the mortality of a previously lethal dose of INH in a dose-dependent fashion.13,14 Lower molar ratios prevented deaths and higher molar ratios prevented both deaths and seizures.14 When used

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as single treatments for INH-induced seizures phenobarbital, pentobarbital, phenytoin, ethanol, and diazepam were ineffective in controlling seizures and mortality, but when combined with pyridoxine, each protected the animals from seizures and death.13 Other small-animal experiments have documented the effectiveness of pyridoxine against MMH-induced seizures when used alone23,34,46 and when used in combination with diazepam.20 Anticonvulsant efficacy is also demonstrated in cat42 and monkey44 models. Rat studies with intraperitoneal UDMH also demonstrate the protective effects of pyridoxine given intraperitoneally 90 minutes after exposure.15 Pyridoxine prevented seizures and death in a model that produced 94% mortality and 100% seizures without pyridoxine.15 When intraperitoneal UDMH was followed in 20 minutes by pyridoxine intravenously (IV) in rats, 17% died at 24 hours, compared with a 100% mortality without pyridoxine.15 Other studies in dogs and monkeys also demonstrate the effectiveness of pyridoxine in preventing seizures and mortality, and in treating seizures.4 Pyridoxine intramuscularly (IM) protected the monkeys from death and stopped the seizures caused by IV UDMH.

HUMAN DATA Clinical experience with the use of pyridoxine for INH overdose in humans demonstrates favorable results.2,11 Rapid seizure control with no morbidity or mortality was achieved when the ratio in grams of pyridoxine administered to INH ingested ranged from 0.14 to 1.3, although in practice, most patients receive approximately gramfor-gram amounts. In five patients, the use of gram-for-gram amounts of pyridoxine resulted in the complete control of seizures and a resolution of the metabolic acidosis.48 In eight patients with intentional INH overdoses, basic poison management, intensive supportive care, and a mean dose of 5 g of pyridoxine IV resulted in no fatalities.8 Seizures were controlled in a 22-month-old boy given 100 mg of IV pyridoxine, after an estimated INH ingestion of 5 g.43 Variable results are reported when relatively small doses of pyridoxine are used.32 Seizures were reported in two patients following the ingestion of INH-pyridoxine combination tablets, although the actual amount of pyridoxine ingested was not noted.45 In addition to controlling seizures, the administration of pyridoxine also appears to restore consciousness. Two patients, who remained obtunded for as long as 72 hours after the apparent resolution of the seizures, were reported to awaken immediately after 3 to 10 g of IV pyridoxine was administered.10 A third patient who was lethargic awakened with IV pyridoxine. This suggests that mental status abnormalities associated with INH overdose, and possibly hydrazine overdoses, may be responsive to pyridoxine and also may require repetitive dosing.11,48 Patients treated with large doses of pyridoxine awaken more rapidly even after experiencing sustained seizure activity or status epilepticus. Monomethylhydrazine poisoning can be encountered in a variety of clinical situations. In the aerospace industry, where MMH is used as a rocket propellant, percutaneous or inhalational poisoning may occur. Ingestion of the false morel mushroom, G. esculenta, can also produce toxicity when its major toxic compound, gyromitrin, is metabolized to MMH 3,18 (Chap. 117). The neurologic effects of MMH poisoning are similar to those of INH toxicity and include seizures and respiratory failure.16 Severe liver damage similar to INH-induced hepatotoxicity is also described.9 As in the case of INH hepatotoxicity, there is no evidence that MMH-induced hepatotoxicity can be treated by administration of pyridoxine.9 A patient who was exposed to hydrazine became comatose 14 hours later and remained comatose for 60 hours until 25 mg/kg of pyridoxine aroused him.25 Another case report describes improvement in the mental status of a confused, lethargic, and restless man who had ingested a

mouthful of hydrazine and was treated with a 10-g dose of pyridoxine.22 This improvement developed over 24 hours and may have been unrelated to pyridoxine therapy. A severe sensory peripheral neuropathy lasting for 6 months developed 1 week following the overdose and was most likely a result of the hydrazine ingestion and not the pyridoxine. Six patients exposed to an Aerozine-50 (hydrazine and UDMH) spill were effectively treated with pyridoxine after developing twitching, clonic movements, hyperactivity, or gastrointestinal (GI) symptoms.19 A patient exposed to UDMH during an explosion developed extensive burns, diverse neurologic manifestations and electroencephalogram (EEG) findings that resolved rapidly with the delayed administration of IV pyridoxine.17

ETHYLENE GLYCOL PLP is a cofactor in the conversion of glycolic acid to nonoxalate compounds (Chap. 107). Patients poisoned with ethylene glycol should receive 100 mg/d of pyridoxine IV in an attempt to shunt metabolism preferentially away from the production of oxalic acid. This approach is supported by an animal model6 and by the study of primary hyperoxaluria,21 but has not been studied adequately in humans with ethylene glycol poisoning.36

SAFETY ISSUES Pyridoxal-5′-phosphate is clearly neurotoxic to animals and humans when administered chronically in supraphysiologic doses.25,27,37 Delayed peripheral neurotoxicity occurred in patients taking daily doses of 200 mg to 6 g of pyridoxine for 1 month.35,40,41 Healthy volunteers given 1 or 3 g/d developed a small- and large-fiber distal axonopathy, with sensory findings and quantitative sensory threshold abnormalities occurring after 1.5 months in the high-dose and 4.5 months in the low-dose regimens. Once symptoms occurred, the pyridoxine was immediately stopped, but symptoms progressed for 2 to 3 weeks, leading to speculation that it took time for the reversal of neuronal metabolic manifestations (see chapter 18).7 Pyridoxine may also induce a sensory neuropathy when massive doses are administered, either as a single dose or over several days.1,26,47 Ataxia occurred in dogs receiving 1 g/kg of pyridoxine.47 Larger doses of pyridoxine produce incoordination, ataxia, seizures, and death.47 Death after pyridoxine administration was sometimes delayed for 2 to 3 days.47 Two patients treated with 2 g/kg of IV pyridoxine (132 and 183 g, respectively) over 3 days developed severe and crippling sensory neuropathies.1 One year later, both patients were unable to walk. Inadequate information is available to determine the maximal single acute nontoxic dose in humans; however, there appears to be a wide margin of safety. Doses of pyridoxine ranging from 70 to 375 mg/kg or doses equivalent to the milligram-per-kilogram historical dose of ingested INH have been administered without adverse effects.28,48 The 0.5% chlorobutanol preservative in IV pyridoxine, which equates to doses of 250 to 500 mg of chlorobutanol when 5 and 10 g doses of pyridoxine are administered, might produce CNS depression.12 However, a dose of 5 g IV pyridoxine administered over 5 min to five healthy volunteers produced only a transient minor increase in base deficit, without any CNS depression noted.29

DOSING Considering all of the available data, a safe and effective pyridoxine regimen for INH overdoses in adults is 1 g of pyridoxine for each gram of INH ingested, to a maximum of 5 g or 70 mg/kg in a child.48

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These doses are sufficient in the majority of patients, but the dose can be repeated if necessary. The best way to administer pyridoxine in a patient after an INH overdose has not been established. For a patient who is actively seizing, pyridoxine may be given by slow IV infusion at approximately 0.5 g/min until the seizures stop or the maximum dose has been reached. When the seizures stop, the remainder of the dose should be infused over 4 to 6 hours to maintain pyridoxine availability while the INH is being eliminated. The dose should be repeated if seizures persist or recur, or if the patient exhibits mental status depression. If IV pyridoxine is unavailable, oral pyridoxine should be administered.39 For hydrazine and methylated hydrazines (ie, MMH, UDMH) poisoning, there is no established dose.51 Using the same dosage regimen as for INH is theoretically reasonable, but has never been tested in humans.

AVAILABILITY Pyridoxine HCl is available parenterally at a concentration of 100 mg/ mL with 1 mL in a 2 mL vial with 0.5% chlorobutanol as the preservative and 1.4 μg/1 mL aluminum from APP Pharmaceuticals.38 Thus, a 5 g IV dose of pyridoxine requires fifty 100 mg/mL vials. This is an exception to the rule that appropriate doses of medications rarely require multiple dosages of this magnitude and also emphasizes the necessity of keeping an adequate supply available in the emergency department, as well as in the pharmacy.33 Oral pyridoxine is available in many tablet strengths from 10 to 500 mg depending on the manufacturer.

SUMMARY Pyridoxine should not be the sole therapy used for INH or MMH poisoning. A benzodiazepine should be used with pyridoxine in an attempt to achieve synergistic control of seizures. If the seizures do not respond to both of these measures, they can be repeated, followed by IV agents such as propofol, pentobarbital, or phenobarbital, and, if necessary, neuromuscular blockade and general anesthesia. When neuromuscular blockade is achieved without extinguishing the seizure activity, irreversible neuronal damage may result. Although metabolic acidosis is probably a result of the seizures and should therefore resolve once the underlying condition is controlled, severe or refractory metabolic acidosis may require titration of blood pH using IV sodium bicarbonate.

REFERENCES 1. Albin R, Albers J, Greenberg H, et al. Acute sensory neuropathy-neuronopathy from pyridoxine overdose. Neurology. 1987;37:1729-1732. 2. Alvarez EG, Guntupalli KK. Isoniazid overdose: four case reports and review of the literature. Intensive Care Med. 1995;21:641-644. 3. Andary C, Bourrier MJ. Variations in the monomethylhydrazine content in Gyromitra esculenta. Mycologia. 1985;77:259-264. 4. Back KC, Pinkerton MK, Thomas AA. Therapy of acute UDMH intoxication. Aerosp Med. 1963;34:1001-1004. 5. Baxter P. Pyridoxine-dependent seizures: a clinical and biochemical conundrum. Biochim Biophys Acta. 2003;1647:36-41. 6. Beasley UR, Buck WB. Acute ethylene glycol toxicosis: a review. Vet Hum Toxicol. 1980;22:255-263. 7. Berger AR, Schaumberg HH, Schroeder C, et al. Dose response, coasting, and differential fiber vulnerability in human toxic neuropathy: a prospective study of pyridoxine neurotoxicity. Neurology. 1992;42:1367-1370. 8. Blanchard P, Yao J, McAlpine D, et al. Isoniazid overdose in the Cambodian population of Olmsted County, Minnesota. JAMA. 1986;256:3131-3133. 9. Braun R, Greeff U, Netter KJ. Liver injury by the false morel poison gyromitrin. Toxicology. 1979;12:155-163.

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10. Brent J, Vo N, Kulig K, Rumack BH. Reversal of prolonged isoniazidinduced coma by pyridoxine. Arch Intern Med. 1990;150:1751-1753. 11. Brown CV. Acute isoniazid poisoning. Am Rev Respir Dis. 1972;105:206-216. 12. Burda A, Sigg T, Wahl M. Possible adverse reactions in preservatives in high-dose pyridoxine hydrochloride IV injection. Am J Health Syst Pharm. 2002;59:1886-1887. 13. Chin L, Sievers ML, Herrier RN, Picchioni AL. Potentiation of pyridoxine by depressants and anticonvulsants in the treatment of acute isoniazid intoxication in dogs. Toxicol Appl Pharmacol. 1981;58:504-509. 14. Chin L, Sievers ML, Laird HE, Herrier RN, Picchioni AL. Evaluation of diazepam and pyridoxine as antidotes to isoniazid intoxication in rats and dogs. Toxicol Appl Pharmacol. 1978;45:713-722. 15. Cornish HH. The role of B6 in toxicity of hydrazines. Ann N Y Acad Sci. 1969;166:136-145. 16. Dakshinamurti K, Paulose CS, Viswanathan M, et al. Neurobiology of pyridoxine. Ann N Y Acad Sci. 1990;585:128-144. 17. Dhennin C, Vesin L, Feauveaux J. Burns and the toxic effects of a derivative of hydrazine. Burns Incl Therm Inj. 1988;14:130-134. 18. Franke S, Freimuth U, List PH. Uber die Giftigkeit der fruhjahrslorchel Gyromitra (Helvella) esculenta. Fr Arch Toxicol. 1967;22:293-332. 19. Frierson WB. Use of pyridoxine HCl in acute hydrazine and UDMH intoxication. Ind Med Surg. 1965;34:650-651. 20. George ME, Pinkerton MK, Bach KC. Therapeutics of monomethylhydrazine intoxication. Toxicol Appl Pharmacol. 1982;63:201-208. 21. Gibbs DA, Watts RWE. The action of pyridoxine in primary hyperoxaluria. Clin Sci. 1970;38:277-286. 22. Harati Y, Niakan E. Hydrazine toxicity, pyridoxine therapy and peripheral neuropathy. Ann Intern Med. 1986;104:728-729. 23. Holtz P, Palm D. Pharmacological aspects of vitamin B6. Pharmacol Rev. 1964;16:113-178. 24. Jang YM, Kim DW, Kang TC, et al. Human pyridoxal phosphatase. Molecular cloning, functional expression, and tissue distribution. J Biol Chem. 2003;278:50040-50046. 25. Kirlin JK. Treatment of hydrazine induced coma with pyridoxine. N Engl J Med. 1976;294:938-939. 26. Krinke G, Naylor DC, Skorpil V. Pyridoxine megavitaminosis: an analysis of the early changes induced with massive doses of vitamin B6 in rat primary sensory neurons. J Neuropathol Exp Neurol. 1985;44:117-129. 27. Krinke G, Schaumburg HH, Spencer PS, et al. Pyridoxine megavitaminosis produces degeneration of peripheral sensory neurons (sensory neuropathy) in the dog. Neurotoxicology. 1980;2:13-24. 28. Lheureux P, Penaloza A, Gris M. Pyridoxine in clinical toxicology: a review. Eur J Emerg Med. 2005;12:78-85. 29. Lo Vecchio F, Curry S, Graeme K, et al. Intravenous pyridoxine-induced metabolic acidosis. Ann Emerg Med. 2001;38:62-64. 30. Lumeng L, Li T. Vitamin B6 metabolism in chronic alcohol abuse. J Clin Invest. 1974;53:693-704. 31. Marcus R, Coulston AM. Water-soluble vitamins. In: Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, eds. Goodman and Gilman’s the Pharmacological Basis of Therapeutics, 10th ed. New York: McGraw-Hill; 2001:1760-1761. 32. Miller J, Robinson A, Percy AK. Acute isoniazid poisoning in childhood. Am J Dis Child. 1980;134:290-292. 33. Morrow LE, Wear RE, Schuller D, Malesker M. Acute isoniazid toxicity and the need for adequate pyridoxine supplies. Pharmacotherapy. 2006;26:1529-1532. 34. O’Brien RD, Kirkpatrick M, Miller PS. Poisoning of the rat by hydrazine and alkylhydrazines. Toxicol Appl Pharmacol. 1964;84:371-377. 35. Parry G, Bredesen D. Sensory neuropathy with low dose pyridoxine. Neurology. 1985;35:1466-1468. 36. Parry MF, Wallach R. Ethylene glycol poisoning. Am J Med. 1974;57:143-150. 37. Perry TA, Weerasuriya A, Mouton PR, Holloway HW, Greig NH. Pyridoxine-induced toxicity in rats: A stereological quantification of the sensory neuropathy. Exp Neurol. 2004;190:133-144. 38. Pyridoxine Hydrochloride Injection, USP [package insert]. Schaumburg, IL: APP Pharmaceuticals, LLC; 2008. 39. Scharman EJ, Rosencrance JG. Isoniazid toxicity: a survey of pyridoxine availability. Am J Emerg Med. 1994;12:386-388. 40. Schaumburg H. Sensory neuropathy from pyridoxine abuse. N Engl J Med. 1984;310:198. 41. Schaumburg H, Kaplan J, Windebank A, et al. Sensory neuropathy from pyridoxine abuse: a new megavitamin syndrome. N Engl J Med. 1983;309:445-448.

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42. Shouse MN. Acute effects of pyridoxine hydrochloride on monomethylhydrazine seizure latency and amygdaloid kindled seizure thresholds in cats. Exp Neurol. 1982;75:79-88. 43. Starke H, Williams S. Acute poisoning from overdose of isoniazid: a case report. Lancet. 1963;83:406-408. 44. Sterman MB, Kovalesky RA. Anticonvulsant effects of restraint and pyridoxine on hydrazine seizures in the monkey. Exp Neurol. 1979;65: 78-86. 45. Terman DS, Teitelbaum DT. Isoniazid self-poisoning. Neurology. 1970;20:299-304. 46. Toth B, Erickson J. Reversal of the toxicity of hydrazine an analogues by pyridoxine hydrochloride. Toxicology. 1977;7:31-36. 47. Unna IC. Studies of the toxicity and pharmacology of vitamin B6 (2-methyl, 3-hydroxy-4,5-bis-pyridine). Pharmacol Exp Ther. 1940;70:400-407.

48. Wason S, Lacouture PG, Lovejoy FH. Single high-dose pyridoxine treatment for isoniazid overdose. JAMA. 1981;246:1102-1104. 49. Wood JD, Peesker SJ. A correlation between changes in GABA metabolism and isonicotinic acid. Hydrazide-induced seizures. Brain Res. 1972;45:489-498. 50. Wood JD, Peesker SJ. The effect on GABA metabolism of isonicotinic acid hydrazide and pyridoxine as a function of time after administration. J Neurochem. 1972;19:1527-1537. 51. Zelnick SD, Mattie DR, Stepaniak PC. Occupational exposure to hydrazines: Treatment of acute central nervous system toxicity. Aviat Space Environ Med. 2003;74:1285-1291. 52. Zempleni J. Pharmacokinetics of vitamin B6 supplements in humans. J Am Coll Nutr. 1995;14:579-586. 53. Zempleni J, Kubler W. The utilization of intravenously infused pyridoxine in humans. Clin Chim Acta. 1994;229:27-36.

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ANTIMALARIALS J. Dave Barry The malaria parasite has caused untold grief throughout human history. The name originated from Italian mal aria (bad air), since the ancient Romans believed the disease was caused by the decay in marshes and swamps, and was carried by the malodorous “foul” air emanating from these areas.5 In the 1880s both the Plasmodium protozoa as well as its mosquito vector were identified.5 Today, 40% of world’s population lives in areas where malaria is endemic. More than 500 million people suffer acute malaria infection, and one to three million die from the infection each year.5,41,129 Included among those at risk of becoming infected are 50 million travelers from industrialized countries who visit the developing countries each year. Despite using prophylactic medications (Table 58–1), 30,000 of these travelers will acquire malaria.97

HISTORY AND EPIDEMIOLOGY The bark of the cinchona tree, the first effective remedy for malaria, was introduced to Europeans more than 350 years ago.114 The toxicity of its active ingredient, quinine, was noted from the inception of its use. Pharmaceutical advances occurred, funded largely by the military during World War II (chloroquine, proguanil, amodiaquine, pyrimethamine) and later during the Vietnam conflict (mefloquine, halofantrine).109,114 Chloroquine, hydroxychloroquine, primaquine, amodiaquine, mefloquine, and halofantrine are all related to quinine, but have different patterns of toxicity. Other drugs used to treat malaria include the folate inhibitors proguanil and pyrimethamine (frequently used in combination with atovaquone), the sulfonamide sulfadoxine, or the sulfone dapsone, as well as tetracyclines and the macrolides (Chap. 56). With the introduction of each new drug, resistance developed, particularly in Oceania, Southeast Asia, and Africa.109,114 In some places, quinine is once again the first-line therapy for some types of malaria.58 In the last two decades, the search for active xenobiotics has returned to a natural product, the Chinese herb qinghaosu.86,110 The active ingredient, artemisinin, in the form of an artemisinin-based combination therapy (ACT), is recommended by the World Health Organization (WHO) as the preferred treatment of malaria in drug-resistant areas.5,129 With increased leisure travel, a greater number of North Americans are taking prophylactic medications with potential toxicity.

QUINOLINE DERIVATIVES ■ QUININE H2C

C

H

N HO

H

H3CO N

The therapeutic benefits of the bark of the cinchona tree have been known for centuries. As early as 1633, cinchona bark was used for its antipyretic and analgesic effects,73 and in the 1800s it was used for the treatment of “rebellious palpitations.”114 Quinine, the primary alkaloid in cinchona bark, was the first effective treatment for malaria. Due to a reported curare-like action, quinine has been used as a treatment for muscle cramps. Due to its extremely bitter taste similar to that of heroin, quinine is used as an adulterant in drugs of abuse. Small quantities of quinine can be also found in some tonic waters. High doses of quinine and other cinchona alkaloids are oxytocic, potentially leading to abortion or premature labor in pregnant women. Because of this, quinine has been used as an abortifacient (Chap. 28).74 Chloroquine continues to be used for this purpose in some parts of the developing world.7,90 Neither is safe for this purpose because of their narrow toxic-to-therapeutic ratio. Pharmacokinetics and Toxicokinetics See Table 58–2 for the pharmacokinetic properties of quinine. Quinine and quinidine are optical isomers and share similar pharmacologic effects as class IA antidysrhythmics and antimalarials. Both are extensively metabolized in the liver, kidneys, and muscles to a variety of hydroxylated metabolites. Quinine undergoes transplacental distribution and is secreted in breast milk. Pathophysiology Quinine overdose affects multiple organ systems through a number of different pathophysiologic mechanisms. Studies evaluating mechanisms of toxicity have focused on those organ systems primarily affected. Outcomes appear to be most closely related to the degree of cardiovascular dysfunction.38 Quinine and quinidine share anti- and prodysrhythmic effects primarily from an inhibiting effect on the cardiac sodium channels and potassium channels (Chaps. 23 and 63).39 Blockade of the sodium channel in the inactivated state decreases inotropy, slows the rate of depolarization, slows conduction, and increases action potential duration. Inhibition of this rapid inward sodium current is increased at higher heart rates (called use-dependent blockade), leading to a rate-dependent widening of the QRS complex.114,123 Inhibition of the potassium channels suppresses the repolarizing delayed rectifier potassium current, particularly the rapidly activating component,123 leading to prolongation of the QT interval. The resultant increase in the effective refractory period is also rate dependent, causing greater repolarization delay at slower heart rates and predisposing to torsades de pointes. As a result, syncope and sudden dysrhythmogenic death may occur. An additional α-adrenergic blocking effect contributes to the syncope and hypotension occuring in quinine toxicity. Inhibition of the adenosine triphosphate (ATP)-sensitive potassium channels of the pancreatic β cells results in the release of insulin, similar to the action of sulfonylureas (Chap. 48).30 Patients at increased risk of quinine-induced hyperinsulinemia include those patients receiving high-dose intravenous (IV) quinine, intentional overdose, and patients with other metabolic stresses, such as concurrent malaria, pregnancy, malnutrition, and alcohol consumption.18,59,81,84,85,94 The mechanism of quinine-induced inhibition of hearing appears to be multifactorial.109 Microstructural lengthening of the outer hair cells of the cochlea and organ of Corti occurs.43 Additionally, vasoconstriction and local prostaglandin inhibition within the organ of Corti may contribute to decreased hearing.109 Inhibition of the potassium channel may impair hearing and produce vertigo, as it is known that the homozygous absence of gene products that form part of some potassium channels (Jervell and Lange-Nielson syndrome) causes deafness and prolonged QT intervals (Chap. 20 and 22).108 Although older theories suggested that quinine caused retinal ischemia, the preponderance of evidence points to a direct toxic effect on the retina.40,44 Electroretinographic studies demonstrate a rapid and direct effect on the retina (decreased potentials) within minutes after doses of

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TABLE 58–1. Common Adult Doses of Antimalarials Used Worldwide Drug

Prophylactic Dose

Upper Dose Range, Treatmenta

Amodiaquine Artemether/lumefantrine Artesunate/amodiaquine Artesunate/mefloquine

Not used Not used Not used Not used

Artesunate/pyrimethamine/sulfadozine

Not used

Chloroquine phosphate (Aralen) Doxycycline (Vibramycin) Halofantrine Hydroxychloroquine sulfate (Plaquenil) Mefloquine (Lariam) Primaquine phosphate Proguanil/atovaquone (Malarone)

500 mg/wk as single dose 100 mg/day Not used 400 mg/wk as single dose 250 mg/wk as single dose 30 mg of base/d × 14 daysc 100 mg proguanil + 250 mg atovaquone once per day 200 mg proguanil + 100 mg chloroquine once per day Not used Not used

10 mg of base/kg/d × 3 days 80 mg artomether + 480 mg lumefantrine bid × 3 days 200 mg arteunate + 612 mg amodiaquine × 3 days 200 mg artesunate × 3 days, 1000 mg mefloquine on day 2, 500 mg mefloquine on day 3 200 mg artesunate × 3 days, 75 mg pyrimethamine + 1500 mg sulfadoxine as single dose 1000 mg STAT then 500 mg at 6 h, 24 h, and 48 h 100 mg bidd 500 mg q6h × 3 doses, repeat in 7 days Rarely used 750 mg STAT, then 500 mg 8 h later 30 mg of base/d × 14 days 400 mg proguanil 1000 mg atovaquone per day × 3 days

Proguanil/chloroquine Pyrimethamine/sulfadoxine (Fansidar) Quinine sulfate (Qualaquin) a

Not used 75 mg pyrimethamine + 1500 mg sulfadoxine as single dose 650 mg tid × 7 daysb

Choice, duration, and dosage may vary with malarial species and frequency of drug resistance in the geographic area.

b

Usually with doxycycline, tetracycline, or clindamycin for chloroquine-resistant cases.

c

After leaving Plasmodium vivax or Plasmodium ovale area.

d

With quinine sulfate for chloroquine-resistant cases.

quinine.40 These early retinographic changes, as well as histologic lesions in photoreceptor and ganglion cell layers, provide evidence of direct damage.40 Changes in the electrooculogram suggest changes in the retinal pigment epithelium, and parallel changes in visual acuity. In contrast, no electrophysiologic, angiographic, or morphologic experimental evidence for retinal ischemia has been found.40,44 Quinine may also antagonize cholinergic neurotransmission in the inner synaptic layer. Quinine has direct irritant effects on the gastrointestinal (GI) tract and stimulates the center in the brainstem responsible for nausea and emesis.114 Clinical Manifestations Quinine overdose typically leads to GI complaints, tinnitus, and visual symptoms within hours, but the time course varies with the formulation ingested, coingestants, patient characteristics, and other case-specific details. Significant overdose is heralded by cardiovascular and central nervous system toxicity. Death can occur within hours to days, usually from a combination of shock, ventricular dysrhythmias, respiratory arrest, or renal failure. Patients receiving even therapeutic doses often experience a syndrome known as “cinchonism,” which typically includes GI complaints, headache, vasodilation, tinnitus, and decreased hearing acuity.73,114 Vertigo, syncope, dystonia, tachycardia, diarrhea, and abdominal pain are also described.47,63,81,114 Quinine toxicity is closely correlated with total serum concentrations, but only the non-protein-bound portion is likely responsible for toxic effects. However, since free and total quinine concentrations vary widely from person to person,35 a single quinine concentration may not always correlate with clinical toxicity. In general, serum concentrations of greater than 5 μg/mL may cause cinchonism, greater than 10 μg/mL

visual impairment, greater than 15 μg/mL cardiac dysrhythmias, and greater than 22 μg/mL death.2 Similar concentrations in individuals who are severely ill with malaria do not necessarily result in as severe toxicity because of the increase α1-acid glycoprotein and consequent reduction in free fraction of quinine present.98,103 The margin between therapeutic and toxic dosing of quinine is very small. It is not surprising that patients taking therapeutic doses frequently develop toxicity since the recommended range of serum quinine concentrations for treatment of falciparum malaria is 5 to 15 μg/mL, well above the concentration reported to cause cinchonism. The average oral lethal dose of quinine is 8 g, although a dose as small as 1.5 g has been reported to cause death.36,47 Delirium, coma, and seizures are less common, usually occurring only after severe overdoses.14 Cardiovascular manifestations of quinine use are related to myocardial drug concentrations.11 They manifest on the electrocardiogram (ECG) as prolongation of the PR interval; prolongation of the QRS complex, QT interval, and ST depression with or without T-wave inversion also occurs.11 Patients may develop complete heart block or dysrhythmias.11 Patients on high doses of quinine must be monitored for torsades de pointes, ventricular tachycardia, and ventricular fibrillation. Quinine toxicity can also result in significant hypotension. Although mild hyperinsulinemia may occur, hypoglycemia is not commonly described in cases of oral quinine overdose.14,18,38,59,102,122,12 6 Hypoglycemia with elevated serum insulin concentrations following therapeutic dosing was seen in case reports complicated by severe congestive heart failure and significant ethanol consumption. Hypoglycemia was also noted in a healthy patient following overdose.59,121

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TABLE 58–2. Pharmacokinetic Properties of Antimalarials Antimalarial

Bioavailability (%)

Time to Peak Hours (oral)

Protein Bound (%)

Volume of Distribution (L/kg)

Half-Life

Urinary Excretion (%)

Artemisinin

Limited

—

Large

—

2–5 h

—

Chloroquine Dapsone Halofantrine Mefloquine

80 90 Low, varies >85

2–5 3–6 4–7 8–24

50-65 70–80 — 98

>100 0.5–1 >100 15–40

40–55 d 21–30 h 1–6 d 15–27 d

55 20 — 95 76

2–6 1–3

87 93

3 1.8–4.6

3–4 d 9–15 h

16-32 20

Comments Metabolism largely through cytochrome p450 system. — — Active metabolite. Hepatic metabolism. Inactive metabolite. Metabolites primarily responsible for therapeutic and toxic effects. — Protein binding increased in alkaline environments. Urinary excretion increased with acidic urine.

—, poorly studied or unknown.

Eighth-nerve dysfunction results in tinnitus and deafness. The decreased acuity is not usually clinically apparent, although the patient recognizes tinnitus.95 These findings usually resolve within 48 to 72 hours, and permanent hearing impairment is unlikely. Ophthalmic presentations include blurred vision, visual field constriction, tunnel vision, diplopia, altered color perception, mydriasis, photophobia, scotomata, and sometimes complete blindness.14,32,40 Onset of blindness is invariably delayed and usually follows the onset of other manifestations by at least 6 hours. The pupillary dilation that occurs is usually nonreactive and correlates with the severity of visual loss. Funduscopic examination may be normal, but usually demonstrates extreme arteriolar constriction associated with optic disc and retinal edema. Normal arteriolar caliber may be initially present, but funduscopic manifestations such as vessel attenuation and disc pallor may develop as clinical improvement occurs. Improvement in vision can occur rapidly, but is usually slow, occurring over a period of months after a severe exposure. Initially, improvement occurs centrally and is followed later by improvement in peripheral vision. The pupils may remain dilated even after return to normal vision.36 Patients with the greatest exposure may develop optic atrophy. Hypokalemia is often described in the setting of quinine poisoning,102 although the mechanism is unclear. An intracellular shift of potassium rather than a true potassium deficit is the predominant theory behind the hypokalemia associated with chloroquine,68,70 and the mechanism may be similar with quinine. A number of hypersensitivity reactions are described. These are the result of antiquinine or antiquinine-hapten antibodies cross-reacting with a variety of membrane glycoproteins.15,51 Asthma, and dermatologic manifestations including urticaria, photosensitivity dermatitis, cutaneous vasculitis, lichen planus, and angioedema also occur.94 Hematologic manifestations of hypersensitivity are rare, but include thrombocytopenia (Chap. 24), agranulocytosis, microangiopathic hemolytic anemia, and disseminated intravascular coagulation (DIC), which can lead to jaundice, hemoglobinuria, and renal failure.47,51 Hemolysis may also occur in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Immunogenic drug-platelet complex

interactions can occur even after low doses of quinine, such as those in tonic drinks. This self-limited interaction has previously been termed “cocktail purpura.”73,114 A hepatitis hypersensitivity reaction,34 acute respiratory distress syndrome (ARDS), and a sepsis-like syndrome are also reported.55 Diagnostic Testing Urine thin-layer chromatography is sensitive enough to confirm the presence of quinine, even following the ingestion of tonic water.126 Quinine immunoassay techniques are also available. Quantitative serum testing is not rapidly or widely available. Management Patients may frequently vomit spontaneously. Emetics should not be used in the absence of vomiting since seizures, dysrhythmias, and hypotension can occur rapidly. Orogastric lavage should only be considered for patients with recent, substantial (potentially life-threatening) ingestions with no spontaneous emesis. Activated charcoal effectively adsorbs quinine and may additionally decrease serum concentrations by altering enteroenteric circulation.3,62 Supportive care should be initiated including oxygen, cardiac and hemodynamic monitoring, IV fluid resuscitation, and frequent ECG and blood glucose measurements. Cardiac. Prolonged QRS should be treated with sodium bicarbonate alkalinization to achieve a serum pH of 7.45 to 7.50, as would be done in patients with cardiotoxicity associated with cyclic antidepressant overdoses (see Antidotes in Depth A5: Sodium Bicarbonate). The cardiotoxic manifestations of quinine and increased protein binding in the setting of alkalosis make the choice of serum alkalinization a logical therapeutic intervention. Sodium bicarbonate therapy has been successful in case reports,11,38,73 but has not been specifically studied. Hypertonic sodium bicarbonate may result in or worsen existing hypokalemia, potentially exacerbating the effect of potassium channel blockade. Potassium supplementation for quinine-induced hypokalemia is controversial since experimental data from the 1960s suggest that hypokalemia is protective against cardiotoxicity and prolongs survival.17,68,102 Since hypokalemia can also lead to lethal dysrhythmias, supplementation for hypokalemia is presently recommended. The QT interval should be carefully monitored for prolongation. If necessary, interventions for torsades de pointes, including magnesium

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administration, potassium supplementation, and overdrive pacing, should be initiated (Chap. 22). Class IA, IC, or III antidysrhythmics and other xenobiotics with sodium-channel- and/or potassium-channel-blocking activity should not be used to treat a quinine overdosed patient because they may exacerbate quinine-induced conduction disturbances or dysrhythmias. Type IB antidysrhythmics, such as lidocaine, have been used with reported success, but no clinical trials have been performed (Chap. 63). Hypotension refractory to IV crystalloid boluses should be treated with vasopressors. Although not directly studied, direct-acting vasopressors such as epinephrine, norepinephrine, or phenylephrine are recommended. An intraaortic balloon pump was successfully used for the treatment of refractory hypotension in one case report.102 Ophthalmic. Funduscopic examination, visual field examination, and color testing may be appropriate bedside diagnostic studies. Electroretinography, electrooculogram, visual-evoked potentials, and dark adaptation may be helpful in assessing the injury, but are not practical because they require equipment that is not portable or readily available in most clinical settings. There is no specific, effective treatment for quinine retinal toxicity,40,42 although hyperbaric oxygen (HBO) was used in three patients who recovered vision, but the role of HBO in that recovery was not established.40,127 Hypoglycemia. A low serum glucose concentration should be supported with an adequate infusion of dextrose. Serum potassium concentration and the QT interval should be monitored during correction and maintenance. Octreotide has been successfully used to correct quinine-induced hyperinsulinemia in adult malaria victims.84,85 In volunteers, quinineinduced hyperinsulinemia was suppressed within 15 minutes following a 100 μg intramuscular dose of octreotide (see Antidotes in Depth A11: Octreotide).85 Octreotide should be used for cases of refractory hypoglycemia in a fashion similar to that recommended in sulfonylurea toxicity which is 50 μg subcutaneously (SC) every 6 hours (Chap. 48). Enhanced Elimination The effect of multiple-dose activated charcoal (MDAC) on quinine elimination was studied in an experimental human model as well as in symptomatic patients.88 In these patients, MDAC decreased the half-life of quinine from approximately 8 hours to about 4.5 hours, and increased clearance by 56%.88 Although numerous studies show that activated charcoal decreases quinine half-life,9,62,88 evidence of clinical benefit is lacking. Nevertheless, because ophthalmic, central nervous system (CNS), and cardiovascular toxicity are related to serum concentration, it is prudent to reduce concentrations as quickly as practicable; thus, activated charcoal (0.5 g/kg) should be administered every 2 to 4 hours, unless otherwise contraindicated, for about four doses. There is conflicting evidence about a benefit of urinary acidification in enhancing clearance.9,98 But because of the increased potential for cardiotoxicity associated with acidification, this technique is never recommended. Because quinine has a relatively large volume of distribution and is highly protein bound, hemoperfusion, hemodialysis, and exchange transfusion have only a limited effect on drug removal.9,14,67,98,114,119 Although the blood compartment can be cleared with these techniques, total body clearance is only marginally altered. After rapid tissue distribution occurs, there is little impact on the total body burden because of the large volume of distribution and extensive protein binding. Extracorporeal membrane oxygenation (ECMO) was used in one case of severe quinidine poisoning with bradydysrhythmias and refractory hypotension to stabilize the cardiovascular system while a quinidine-activated charcoal bezoar was removed, and the patient metabolized the remaining quinidine.112 A similar approach should be considered for intractable quinine toxicity.

■ CHLOROQUINE, HYDROXYCHLOROQUINE, AND AMODIAQUINE Cl

N Chloroquine C2H5 HN

CH CH2

CH2

CH2 N C2H5

CH3 Cl

N Amodiaquine

HN N OH Cl

CH3 CH3

N

HN

CH3

Hydroxychloroquine OH N H3C

The structurally related compounds chloroquine and amodiaquine were once used extensively for malaria prophylaxis. However, with the development of resistance, they are used in fewer geographic regions. Amodiaquine is associated with a higher incidence of hepatic toxicity and agranulocytosis. In general, these xenobiotics have low toxicity when used in therapeutic doses. Because of its low toxicity, chloroquine remains the first-line drug for malaria prophylaxis and treatment in areas where Plasmodium remains sensitive. Hydroxychloroquine is similar to chloroquine in therapeutic, pharmacokinetic, and toxicologic properties.67 The side-effect profiles of the two are slightly different, favoring chloroquine use for malarial prophylaxis and hydroxychloroquine use as an antiinflammatory agent.63,114 Hydroxychloroquine is used in the treatment of rheumatic diseases such as rheumatoid arthritis and lupus erythematosus. In animal studies, chloroquine is two to three times more toxic than hydroxychloroquine.49 Piperaquine is structurally similar to chloroquine but is primarily used in conjunction with artemisinin compounds as a component of an artemisinin-based combination therapy (ACT). Piperaquine is discussed in more detail in the Artemisinin and Derivatives section. Pharmacokinetics and Toxicodynamics See Table 58–2 for the pharmacokinetic properties of chloroquine. Oral chloroquine is rapidly and completely absorbed and is ultimately sequestered in many different organs, particularly the kidney, liver, and lung, as well as erythrocytes.13,43 Chloroquine is slowly distributed from the blood compartment to the larger central compartment, leading to transiently high whole blood concentrations shortly after ingestion.90,104 It is the initial high blood concentrations that are thought to be responsible for the rapid development of profound cardiorespiratory collapse, which is typical of chloroquine toxicity. These whole-blood chloroquine concentrations correlate with mortality.26 Pathophysiology With structural similiarity to quinine, the pathophysiologic mechanisms of chloroquine and hydroxychloroquine are also

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similar. Most notably, sodium and potassium channel blockade are the proposed primary mechanisms of cardiovascular toxicity.123 Although less common in quinine toxicity, hypokalemia is extremely common in chloroquine overdose. The mechanism appears to be a shift of potassium from the extracellular to the intracellular space and not a true potassium deficit.68,90,102 Clinical Manifestations Like quinine, chloroquine has a small toxic-totherapeutic margin. Severe chloroquine poisoning is usually associated with ingestions of 5 g or more in adults, systolic blood pressure less than 80 mm Hg, QRS duration of more than 120 milliseconds, ventricular fibrillation, hypokalemia, and serum chloroquinine concentrations exceeding 25 μmol/L (8 μg/mL).24,92 Symptoms usually occur within 1 to 3 hours of ingestion.92 The range of symptoms associated with chloroquine toxicity are similar to quinine, but the frequencies of various manifestations differ and other features such as cinchonism, are uncommon. Nausea, vomiting, diarrhea, and abdominal pain occur less commonly than with quinine.47,63 In contrast, respiratory depression is common and apnea, hypotension, and cardiovascular compromise can be precipitous.47 The cardiovascular effects of chloroquine and hydroxychloroquine are similar to those of quinine, including QRS prolongation, atrioventricular (AV) block, ST- and T-wave depression, increased U waves, and QT interval prolongation. Hypotension is more prominent in chloroquine toxicity than with quinine.47 Significant hypokalemia in chloroquine toxicity is invariably associated with cardiac manifestations.25,47 In fact, the extent of hypokalemia is a good indicator of the severity of chloroquine overdose.24 Neurologic manifestations include CNS depression, dizziness, headache, and convulsions.47 Rarely, dystonic reactions occur.82 Transient parkinsonism has been reported following excessive dosing.82 Ophthalmic manifestations are infrequent in acute chloroquine toxicity and transient in nature.47,63 More severe and irreversible vision and hearing changes are described in association with the chronic use of chloroquine and hydroxychloroquine as antiinflammatory agents.63,75 Myopathy, neuropathy, and cardiomyopathy also occur in this context.5,120 Dermatologic findings and hypersensitivity reactions are similar to those associated with quinine.31 Likewise, red blood cell (RBC) oxidant stress from chloroquine may result in hemolysis in patients with G6PD deficiency (Chap. 24). Acute hydroxychloroquine toxicity is similar to chloroquine toxicity.49 Side effects from therapeutic doses include nausea and abdominal pain, hemolysis in G6PD-deficient patients and, rarely, retinal damage, sensorineural deafness, and hypoglycemia.10,48,101 Hypersensitivity reactions, including myocarditis and hepatitis, are described.37,66 One report of amodiaquine toxicity suggests that involuntary movements, muscle stiffness, dysarthria, syncope, and seizures may occur.47 Amodiaquine is associated with hypersensitivity hepatitis and neutropenia in prophylactic use, but not therapeutic use.18 There is no overdose experience reported. Management Aggressive supportive care should be initiated including oxygen, cardiac and hemodynamic monitoring, and large-bore IV access, and serial blood glucose concentrations should be obtained. Orogastric lavage could be considered for life-threatening ingestions presenting early, but there is little evidence of efficacy. Activated charcoal adsorbs chloroquine well, binding 95% to 99% when administered within 5 minutes of ingestion.54 The frequent development of precipitous cardiovascular and CNS toxicity should be considered before initiating any type of GI decontamination. Early aggressive management of severe chloroquine toxicity decreases mortality.92 This includes early endotracheal intubation and mechanical ventilation. There is evidence to suggest barbiturates may not be the best agent for induction in chloroquine overdose. When thiopental

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was used to facilitate intubation, its use immediately preceded sudden cardiac arrest in seven of 25 patients after chloroquine overdose.26 An adequate FiO2, tidal volume and ventilatory rate should be ensured. Although theoretically any direct-acting pressor would be beneficial in the setting of hypotension not responsive to fluid resuscitation, epinephrine is the pressor that has been studied the most and is considered the vasopressor of choice. High doses of epinephrine were used in the original studies describing the benefits of early mechanical ventilation and the administration of diazepam and epinephrine in chloroquine poisoning.92,93 The epinephrine doses used in these studies are still recommended today.92,93 The recommended dose is 0.25 μg/kg/min, increasing by 0.25 μg/kg/min until an adequate systolic blood pressure (greater than 90 mm Hg) is achieved.28,70,92,93 Clinicians should be mindful that high doses of epinephrine could exacerbate preexisting hypokalemia. The use of diazepam to augment the treatment of dysrhythmias and hypotension is a unique use of this drug. Initial observations with regard to patients with mixed overdoses of chloroquine and diazepam suggested less cardiovascular toxicity and a potential benefit of high-dose diazepam.24,68 Animal and human studies that followed also showed a potential benefit.28,92,93 When early mechanical ventilation was combined with the administration of high-dose diazepam and epinephrine in patients severely poisoned by chloroquine, a dramatic improvement in survival compared with historical controls (91% versus 9% survival) occurred.92 Studies in moderately poisoned patients failed to show similar benefit,24 and a rat model failed to show an inotropic effect. Although the definitive study has yet to be done, high-dose diazepam therapy (2 mg/kg IV over 30 minutes, followed by 1 to 2 mg/kg/d for 2 to 4 days) seems warranted for serious toxicity. Diazepam or an equivalent benzodiazepine should also be used to treat seizures and for sedation. The mechanism for a potential benefit of diazepam is unclear, but multiple theories have been postulated: (1) a central antagonistic effect, (2) anticonvulsant effect, (3) antidysrhythmic effect by an electrophysiologic action inverse to chloroquine, (4) pharmacokinetic interaction between diazepam and chloroquine, and (5) decrease in chloroquine-induced vasodilation.68,90,92,93 (see Antidotes in Depth A24: Benzodiazepines). The use of sodium bicarbonate for correction of QRS prolongation is also controversial. Although alkalinization would be expected to counteract the effects of sodium channel blockade, it could also exacerbate preexisting hypokalemia. Although case reports describe the successful use of sodium bicarbonate in conjunction with other agents for massive hydroxychloroquine overdose, no clinical trials have been performed.60,130 Before using sodium bicarbonate in the setting of chloroquine toxicity clinicians should consider the overall clinical status of the patient, including the suspected degree of cardiac toxicity and severity of hypokalemia. Hypokalemia in the setting of chloroquine toxicity correlates with the severity of the intoxication.24,68 This hypokalemia is thought to be due to intracellular shift, not total-body potassium depletion.25,47,49 Potassium replacement in this setting is, again, controversial since it has not been shown that potassium supplementation will improve cardiac toxicity. In fact, several reports suggest a possible protective effect of hypokalemia in acute chloroquine toxicity.24,68,90 This should be balanced against the fact that severe hypokalemia can itself result in lethal dysrhythmias and data suggesting severe hypokalemia (less than 1.9 mEq/L) is associated with severe, life-threatening ingestion.22,47,68,104 Hypokalemia could not be directly attributed as the cause of death in most cases, however.24 Based on the available evidence, potassium replacement for significant hypokalemia seems warranted, but it is essential to anticipate rebound hyperkalemia as chloroquine toxicity resolves and redistribution of intracellular potassium occurs. Cases of hyperkalemia-related complications after aggressive potassium supplementation have been reported.49,60,68 Because chloroquine and hydroxychloroquine have high volumes of distribution and significant protein binding, enhanced elimination procedures are not beneficial.13,47

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■ PRIMAQUINE

■ MEFLOQUINE H3C

F

NH2 F

NH

F

F

F

N

N

F H3C O Pharmacokinetics and Toxicodynamics See Table 58–2 for the pharmacokinetic properties of primaquine. Pathophysiology Primaquine blocks sodium channels both in vitro and animal models.47,123 Significant cardiovascular toxicity has not been reported, although experience with primaquine overdose is limited primarily to case reports. The predominant clinical toxicity of primaquine relates to its ability to cause RBC oxidant stress and resultant hemolysis or methemoglobinemia (metHb). Methemoglobinemia and hemolysis can even occur in normal individuals given high doses as well as those with the autosomal recessive disorder nicotinamide adenine dinucleotide (NADH) methemoglobin reductase deficiency.63,111 The major complication of primaquine in therapeutic use has been hemolysis in G6PD-deficient individuals.29 Primaquine is contraindicated in pregnant women because of the risk of metHb or hemolysis in the fetus. Reversible bone marrow suppression can occur. Clinical Manifestations Gastrointestinal irritation is also common and dose related. The extent of hemolysis in G6PD-deficient individuals is dependent on the extent of enzyme activity, those with higher levels of enzyme activity having less severe hemolysis than those with less enzyme activity (see Chap. 24). Other variables include the dose of primaquine and comorbid conditions, such as infection, liver disease, and administration of other drugs with hemolytic activity. Overdose with primaquine is rarely reported and unintentional overdoses have led to metHb requiring IV methylene blue.111 Acute liver failure has occurred following unintentional overdose and fatal hepatotoxicity is described in animal models.61 Management Therapy should be directed at minimizing absorption with appropriate decontamination, and diagnosing then treating significant metHb or hemolysis. Because of structural similarities with other quinolone antimalarials and animal model evidence of sodium channel blockade, cardiovascular toxicity should be anticipated with continuous monitoring and resuscitative interventions initiated as needed. Activated charcoal would be expected to bind primaquine well if given early (see Antidotes in Depth A2: Activated Charcoal). Methylene blue (Chap. 127 and Antidotes in Depth A41: Methylene Blue) should be administered for patients who are symptomatic with methemoglobinemia. Treatment of hemolysis necessitates avoiding further exposure to primaquine and possibly exchange transfusion in severe cases. Adequate hydration should be ensured to protect against hemoglobin-induced renal injury. Urinary alkalinization with sodium bicarbonate is controversial in this setting but may have some benefit (see Antidotes in Depth A5—Sodium Bicarbonate). Although no clinical studies have been performed, primaquine’s large volume of distribution makes it an unlikely candidate for benefit from extracorporeal removal.

H HO HN Pharmacokinetics and Toxicodynamics See Table 58–2 for the pharmacokinetic properties of mefloquine. Clinical Manifestations Common effects with prophylactic and therapeutic dosing include nausea, vomiting, and diarrhea.78 These effects are noted particularly in the extremes of age and with high therapeutic dosing. Similar symptoms should be expected in acute overdose.94,124 Mefloquine has a mild cardiodepressant effect—less than that of quinine or quinidine—which is not clinically significant in prophylactic dosing or with therapeutic administration. Bradycardia is commonly reported.22,63,78 With prophylactic use, neither the PR interval nor the QRS complex is prolonged, but QT prolongation has been reported.31,63 Reports of torsades de pointes are rare, but the increase in QT and risk of torsades de pointes are increased when mefloquine is used concurrently with quinine, chloroquine or, most particularly, with halofantrine.63,78,79,123 The long half-life of mefloquine means that particular care must be taken with therapeutic use of other antimalarials when breakthrough malaria occurs during mefloquine prophylaxis or within 28 days of mefloquine therapy to avoid potential drug—drug interactions. This risk may increase with acute overdose, although there is little clinical experience. Mefloquine commonly has neuropsychiatric side effects. During prophylactic use, 10% to 40% of patients experience insomnia and bizarre or vivid dreams, and complain of dizziness, headache, fatigue, mood alteration, and vertigo.99,117 Only 2% to 10% of these complications necessitate the traveler to seek medical advice or change normal activities.22,46,100 Predisposing factors include a past history of neuropsychiatric disorders, recent prior exposure to mefloquine (within 2 months), previous mefloquine-related neuropsychiatric adverse effects, and previous treatment with psychotropic drugs.111 Women appear to be more likely than men to experience neuropsychiatric adverse effects.111,117 The risk of serious neuropsychiatric adverse effects during prophylaxis is estimated to be 1:10,600, but is reported to be as high as 1:200 with therapeutic dosing.29,94,111 Seizures occur rarely with prophylaxis and therapeutic use.87,96 In many of these cases, there is a history of previous seizures, seizures in a first-degree relative, or other seizure risk factors. Other neuropsychiatric symptoms include dysphoria, “clouded” consciousness, encephalopathy, anxiety, depression, giddiness, and an agitated delirium with psychosis. Although there is a suggestion that the severity of neuropsychiatric events is dose dependant, there does not seem to be a correlation with serum or tissue concentrations.51 In one case report, the severe neuropsychiatric manifestations of mefloquine were reversed with physostigmine, leading the authors to suggest a possible central anticholinergic etiology.107 A self-resolving postmalaria neurologic syndrome including confusion, seizures, and/or tremor is associated with therapeutic use of mefloquine for severe malaria.65,96

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The effect of mefloquine on the pancreatic potassium channel is much less than that of quinine, resulting in only a mild increase in insulin secretion.30,31 Symptomatic hypoglycemia has not been reported as an effect of mefloquine alone in healthy individuals, but has occurred with concomitant use of ethanol and in a severely malnourished patient with acquired immune deficiency syndrome (AIDS).6,31,63 In overdose, particularly when accompanied by alcohol use or starvation, hypoglycemia could be severe. Rare events such as hypersensitivity reactions reported with prophylaxis include urticaria, alopecia, erythema multiforme, toxic epidermal necrolysis, myalgias, mouth ulcers, neutropenia, and thrombocytopenia.69,78,99,105 It is unclear which, if any, would be significant following overdose. ARDS was linked to therapeutic dosing in one case.115 In therapeutic use, mefloquine is associated with an increased incidence of stillbirth compared with quinine and a group of other antimalarial medications.80 Mefloquine was not, however, linked to an increased incidence of abortion, low birth weight, mental retardation, or congenital malformations. The implications of overdose in the absence of malaria are unknown, but fetal monitoring should be instituted. The consequences of excessive dosing and overdose are not only severe, but also prolonged and potentially permanent. Mefloquine overdose led to acute hearing loss and gradual resolution of acute symptoms over one year in one case and persistent symptoms even after one year in another.61 After ingesting 5.25 g of mefloquine over 6 days, a man suffered prolonged prothrombin time and weakness persisting for two months after resolution of the acute symptoms.16 A fourth case involved coingestion of 2.5 times the usual therapeutic dose of mefloquine, chloroquine, and sulfadoxine-pyrimethamine over 3 days. The man suffered encephalopathy that had not resolved 8 months later.20 Management In overdose, treatment is primarily supportive with monitoring for potential adverse effects. Decontamination with activated charcoal is indicated if the patient presents soon after the ingestion. Specific monitoring for ECG abnormalities, hypoglycemia, and liver injury should be provided. Patients should also be followed for CNS and cranial nerve complications. In two patients with renal failure who received mefloquine, prophylactic hemodialysis did not remove mefloquine.27 Given the large volume of distribution and high degree of protein binding of mefloquine, extracorporeal elimination techniques are unlikely to be effective.

PHENANTHRENE METHANOLS ■ HALOFANTRINE Cl

Cl F F

CH3 F HO

N

CH3 Because of erratic absorption, potential for lethal cardiotoxicity, and concern for cross-resistance with mefloquine, halofantrine is not presently recommended for malaria prophylaxis by the WHO.111

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Lumefantrine is structurally similar to halofantrine. Since lumefantrine is primarily used as a partner drug in an ACT, it is discussed in more detail in the Artemisinin and Derivatives section. Pharmacokinetics and Toxicodynamics See Table 58–2 for the pharmacokinetic properties of halofantrine.19 Clinical Manifestations The primary toxicity from therapeutic and supratherapeutic doses is prolongation of the QT interval and the risk of torsades de pointes and ventricular fibrillation.79,113 Palpitations, hypotension, and syncope may occur. First-degree heart block is common, but bradycardia is rare.79 Dysrhythmias are also likely in the context of combined overdose, or combined or serial therapeutic use with other xenobiotics that cause QT interval prolongation, particularly mefloquine.52 Because the QT interval duration is directly related to serum halofantrine concentration, dysrhythmias should be expected in overdose.22,79,111 Fifty percent of children receiving a therapeutic course of halofantrine will have a QT interval greater than 440 milliseconds.106 Other side effects, including nausea, vomiting, diarrhea, abdominal cramps, headache, and light-headedness, which frequently occur in therapeutic use, are also expected in overdose.63 Less frequently described side effects include pruritus, myalgias, and rigors. Seizures, minimal liver enzyme abnormalities, and hemolysis are described.63,72,116 Whether these manifestations are related to halofantrine or to the underlying malaria is not clear. Management Management of halofantrine overdose should focus on decontamination, supportive care, monitoring for QT interval prolongation, and treatment of any associated dysrhythmias.

■ ARTEMISININ AND DERIVATIVES CH3 O O

H3C O

O CH3 Artemisinin

O

The medicinal value of natural artemisinin, the active ingredient of Artemisia annua (sweet wormwood or quinghao), has been known for thousands of years. Its antimalarial properties were first recognized by Chinese herbalists in 340 ad, but the primary active component of qinghaosu, now known as artemisinin, was not isolated until 1974.5,114 Artemisinin and its semisynthetic derivatives, artesunate, artemether, arteether, and dihydroartemisinin, are the most potent and rapidly acting of all antimalarial drugs. They were introduced in the 1980s in China for the treatment of malaria, and since then millions of doses have been used in Asia and Africa. Because of their extremely short half-lives, artemisinins are now used in combination with longer halflife drugs to delay or prevent the emergence of resistance. Artemisininbased combination therapies (ACTs) are currently recommended by the WHO for the treatment of uncomplicated malaria,5,128 but have not been licensed for use in the United States. Only four ACTs are currently recommended by the WHO. These include artesunate plus mefloquine, artesunate plus pyrimethamine/sulfadoxine, artesunate plus amodiaquine, and artemether plus lumefantrine. Pharmacokinetics and Toxicodynamics See Table 58–2 for the pharmacokinetic properties of artemisinin. The efficacy and toxicity of artemisinin is thought to be a result of the ability of the trioxane molecular core to form intracellular free radicals, particularly in the presence of heme. In animals, damage to brainstem nuclei is

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consistently produced following prolonged, high-dose, and parenteral administration.111 Sustained CNS exposure from slowly absorbed or eliminated artemisinins is considered markedly more neurotoxic than intermittent brief exposure seen after oral dosing.94 Embryonic loss has also been observed in animals.94 Clinical Manifestations In contrast to the experience with animals, the experience of more than 8000 human study participants shows that these drugs have a very low incidence of side effects.94 Uncommon side effects include nausea, vomiting, abdominal pain, diarrhea, and dizziness. Prospective studies have failed to identify adverse neurologic outcomes.53,94 Rare reports of adverse CNS effects during therapeutic use suggest the possibility of CNS depression, seizures, or cerebellar symptoms following intentional self-poisoning. In children with cerebral malaria, a higher incidence of seizures and a delay to recovery from coma were noted in a comparison with quinine.12 No neurologic difference was noted in long-term follow-up. In an artemether— quinine comparative trial of adults with severe malaria, recovery from coma was also prolonged in the artemether group.45 Rare patients receiving an artemisinin derivative in two other studies experienced transient dizziness or cerebellar signs.71,89 Most recovered within days. One patient in each study suffered prolonged symptoms, 1 month and 4 months, respectively, but both ultimately recovered.71,89 When serial ECGs were obtained, a small but statistically significant fall in heart rate was noted, coincident with peak drug concentrations.71 In one therapeutic trial, 7% of adult patients receiving artemether had an asymptomatic QT interval prolongation of at least 25%.45 Changes in the QRS are not reported. Although uncommon, neutropenia, reticulocytopenia, anemia, eosinophilia, and elevated concentrations of aminotransferases are reported.94 Two of the ACT partner drugs frequently being used today have not been previously discussed: lumefantrine, in the ACT artemether-lumefantrine (AL), and piperaquine, in the ACT dihydroartemisinin-piperaquine (DP). Lumefantirine Lumefantrine is pharmacologically related to mefloquine and halofantrine. Little toxicity of lumefantrine alone or in combination is reported.125 Studies do not show an increase in QT or evidence of cardiac toxicity related to lumefantrine.33,118 Cough and angioedema were described in one case.56 As with all antimalarials there is difficulty in differentiating drug-related adverse events from those of malaria, comorbid diseases, or other ingested drugs, which confounds the study of potential complications.

a rediscovery as a viable combination with atremisinin derivatives in ACT DP therapy. Animal studies show piperaquine to be substantially less toxic than chloroquine, with cumulative doses of piperaquine associated with cardiovascular toxicity about fivefold higher than that for chloroquine. Hepatotoxicity occurs following chronic exposure in animals. In a human study, no significant ECG, changes in serum glucose concentration, or postural hypotension was seen following therapeutic doses of DP. Cl

Cl N N

N piperaquine

N

N

Management Patients with overdose should be managed with supportive measures and expectant observation including cardiovascular and CNS monitoring.

OTHER ANTIMALARIALS ■ ATOVAQUONE/PROGUANIL, PYRIMETHAMINE/ SULFADOXINE, AND DAPSONE

Atovaquone

N

O

O

N

S NH

Cl

lumefantrine

N

O

CH3

O CH3

Cl Sulfadoxine H2N Cl

NH

HO

NH

NH NH

CH3 CH3

Cl

N

Proguanil H2N

CH3

NH

CH3

Piperaquine Piperaquine, a bisquinolone with a structure similar to chloroquine, was used extensively in China and Indonesia as an antimalarial until the development of piperaquine-resistant strains led to the use of better alternatives. Piperaquine has since undergone

N CH3 N NH2

Cl

Pyrimethamine

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Pharmacokinetics and Toxicodynamics Proguanil, pyrimethamine, sulfadoxine, and dapsone all interfere with malarial folate metabolism at concentrations far lower than that required to produce comparable inhibition of mammalian enzymes.114 Slow onset of action and concerns for the development of resistance have led to the use of these agents in synergistic combinations. Proguanil (chloroguanide) may be used alone, but is most often used with dapsone (Lapdap), chloroquine, or the antiparasitic atovaquone (Malarone) for prophylaxis. Atovaquone inhibits the de novo pyrimidine synthesis that is necessary for protozoal survival and replication, but is unnecessary in mammalian cells. Based on its beneficial side-effect profile, many North American physicians are switching from mefloquine to atovaquone/proguanil for routine antimalarial prophylaxis for travelers. Atovaquone and proguanil may now be the most common antimalarials used in North America. The price of this combination limits its use mainly to treatment and prevention in travelers from affluent countries.22 Pyrimethamine is used synergistically in combination with sulfonamides such as sulfadoxine (Fansidar) or dapsone (Maloprim), but growing malarial resistance and unfavorable toxicity profiles have limited the usefulness of these drug combinations (see Table 58–2 for pharmacokinetic profile). Neither combination is recommended for antimalarial use by the US Centers for Disease Control and Prevention (CDC). Genetic polymorphism is described in the metabolism of proguanil and dapsone.50,91 This may be the cause of the significant hypersensitivity reactions noted with dapsone.91 Clinical Manifestations The side effects of proguanil during prophylaxis include nausea, diarrhea, and mouth ulcers.63 Because of the interference with folate metabolism, megaloblastic anemia is a rare complication. Megaloblastic bone marrow toxicity has been reported in renal failure patients.111 Folate supplementation may be required in pregnancy and renal failure to avoid this complication.29 Rarely, neutropenia, thrombocytopenia, rash, and alopecia are also noted.29 In a single case report, hypersensitivity hepatitis was described.29 When used to treat malaria, atovaquone/proguanil causes vomiting, sometimes severe, in a significant portion of patients (15% to 45%).94 This combination is also associated with aminotransferase elevations.94 Unintentional or deliberate overdose has caused little serious toxicity.111 Atovaquone alone, primarily used to treat Pneumocystis jiroveci in AIDS patients, is relatively well tolerated.83 Side effects include maculopapular rash, erythema multiforme (rarely), GI complaints, and mild aminotransferase elevations. Three cases of three- to 42-fold overdose or excess dosing have been reported.23 No symptoms occurred in one case (at three times therapeutic serum concentration). Rash occurred in another, and in the third case metHb was attributed to a simultaneous overdose of dapsone. Overdose of pyrimethamine alone is rare. In children, it results in nausea, vomiting, the rapid onset of seizures, fever, and tachycardia.1,47 Blindness, deafness, and mental retardation have followed.1,47 Seizures were attributed to sulfadoxine-pyrimethamine in an overdose of 12 tablets over 2 days (usual dose is three tablets taken once).77 It is unclear whether the chronic neurologic deficits described in case reports are due to direct toxicity of pyrimethamine on the central nervous system or to complications of toxicity such as status epilepticus.1,47 Chronic high-dose use may be associated with a megaloblastic anemia, requiring folate replacement.1 The sulfonamides, including the sulfone dapsone, have a long history of causing idiosyncratic reactions, including neutropenia, thrombocytopenia, eosinophilic pneumonia, aplastic anemia, neuropathy, and hepatitis.63,94 The rare occurrence of life-threatening erythema multiforme major and toxic epidermal necrolysis, associated with pyrimethamine-sulfadoxine prophylaxis, has limited the use of this combination for prophylaxis. Acute ingestion of dapsone may result in nausea, vomiting, and abdominal pain.47 Following overdose, dapsone produces RBC oxidant

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stress leading to metHb and, to a much lesser extent, sulfhemoglobinemia through formation of an active metabolite (Chap. 127).21,64 The onset of hemolysis may be either immediate or delayed. Dapsone, in particular, is known for its tendency to cause prolonged metHb. Other symptoms, particularly tachycardia, dyspnea, dizziness, visual hallucinations, seizure, syncope, and coma resulting from end-organ hypoxia, can occur.21,47 Additional effects described in overdose include hepatitis and peripheral neuropathy.47 Management Folate supplementation should be considered after overdose of proguanil or pyrimethamine (Antidotes in Depth A13: Leucovorin [Folinic Acid] and Folic Acid ). Other efforts should include supportive care. Following dapsone ingestion, clinically significant metHb should be treated with methylene blue and possibly cimetidine (Chap. 127 and Antidotes in Depth A41: Methylene Blue). There is no antidote for sulfhemoglobinemia, but it constitutes an insignificant portion of total hemoglobin. Both hemodialysis and multidose activated charcoal enhance elimination of dapsone during therapy.76 Multidose activated charcoal is routinely recommended in the treatment of dapsone overdose.64 Required support may include RBC transfusion and urinary alkalinization if hemolysis is extensive (Antidotes in Depth A5: Sodium Bicarbonate).

SUMMARY A variety of xenobiotics are used in the prevention and treatment of malaria. The optimal choices and, consequently, the most widely available xenobiotics, change rapidly with shifting patterns of parasite resistance. Most antimalarials have significant toxicity in acute overdose. Although many toxic effects are related to quinine, even within the quinine group, the pattern of predominant symptoms is xenobiotic dependent. Effects at the low doses associated with prophylaxis and therapy include nausea, vomiting, headache, and confusion. Autoimmune-mediated idiosyncratic reactions are described with most of the antimalarials. In overdose, cardiovascular, neurologic, and hematologic symptoms predominate. Dysrhythmias are the effects that are the most life threatening, particularly with quinine derivatives and especially with chloroquine. These result from sodium channel blockade effect, potassium channel blockade, and myocardial depression. Other significant effects are coma, seizures, and neurologic injury, particularly to the special senses. Primaquine and dapsone produce significant oxidant stress resulting in metHb and often hemolysis. Little is known of the acute toxicity of the newest agent, artemisinin. Decontamination, including the administration of activated charcoal, should be considered. Multidose activated charcoal is particularly important for quinine and dapsone ingestions. When xenobioticspecific symptoms are anticipated and specific management strategies followed, improved outcome has resulted, particularly for chloroquine poisoning.

ACKNOWLEDGMENT G. Randall Bond, MD contributed to this chapter in previous editions.

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3. American Academy of Clinical Toxicology, European Association of Poisons Centres and Clinical Toxicologists. Position statement and practice guidelines on the use of multi-dose activated charcoal in the treatment of acute poisoning. J Toxicol Clin Toxicol. 1999;37:731-751. 4. Assan R, Perronne C, Chotard L, Larger E, Vilder JL. Mefloquine-associated hypoglycemia in a cachectic AIDS patient. Diabete Metab. 1995;21:54-57. 5. Aweeka FT, German PI. Clinical pharmacology of artemisinin-based combination therapies. Clin Pharmacokinet. 2008;47(2):91-102. 6. Baguet JP, Tremel F, Fabre M. Chloroquine cardiomyopathy with conduction disorders. Heart. 1999;81:221-223. 7. Ball De, Tagwireyi D, Nhachi CFB. Chloroquine poisoning in Zimbabwe: a toxicoepidemiological study. J Appl Toxicol. 2002;22:311-315. 8. Baselt RC. Quinine. In Disposition of Toxic Drugs and Chemicals in Man, 7th ed. Foster City, CA: Biomedical Publications; 2004:981-983. 9. Bateman DN, Blain PG, Woodhouse KW, et al. Pharmacokinetics and clinical toxicity of quinine overdose: lack of efficacy of techniques intended to enhance elimination. Q J Med. 1985;54:125-131. 10. Block JA. Hydroxychloroquine and retinal safety. Lancet. 1998;351:1388. 11. Bodenhamer JE, Smilkstein MJ. Delayed cardiotoxicity following quinine overdose: a case report. J Emerg Med. 1993;11:279-285. 12. Boele van Hensbroek M, Onyiorah E, Jaffar E, et al. A trial of artemether or quinine in children with cerebral malaria. N Engl J Med. 1996;335:65-75. 13. Boereboom F, Ververs FF, Meulenbelt J, van Dijk A. Hemoperfusion is ineffectual in severe chloroquine poisoning. Crit Care Med. 2000;28: 3346-3350. 14. Boland ME, Roper SMB, Henry JA. Complications of quinine poisoning. Lancet. 1985;1(8425):384-385. 15. Bougie DW, Wilker PR, Aster RH. Patients with quinine-induced immune thrombocytopenia have both “drug-dependent” and “drug-specific” antibodies. Blood. 2006;108(3):922-927. 16. Bourgeade A, Tonin V, Keudjian F, Levy PY, Faugere B. Intoxication accidentale a la mefloquine. Presse Med. 1990;19:1903. 17. Brandfonbrener M, Kronholm J, Jones HR. The effect of serum potassium concentration on quinidine toxicity. J Pharmacol Exp Ther. 1966;154(2): 250-254. 18. Breckenridge AM, Winstanley PA. Clinical pharmacology and malaria. Ann Trop Med Parasitol. 1997;91:727-733. 19. Bryson HM, Goa KL. Halofantrine: a review of its antimalarial activity, pharmacokinetic properties and therapeutic potential. Drugs. 1992;43: 236-258. 20. Burgmann H, Winkler S, Uhl F, et al. Mefloquine and sulfadoxine/ pyrimethamine overdose in malaria tropica. Wien Klin Wochenschr. 1993;105:61-63. 21. Carrazza MA, Carrazza FR, Oga S. Clinical and laboratory parameters in dapsone acute intoxication. Rev Saude Publica. 2000;4:396-401. 22. Chattopadhyay R, Mahajan B, Kumar S. Assessment of safety of the major antimalarial drugs. Expert Opin Drug Saf. 2007;6(5):505-521. 23. Cheung TW. Overdose of atovaquone in a patient with AIDS. AIDS. 1999;13:1984-1985. 24. Clemessy JL, Angel G, Borron SW, et al. Therapeutic trial of diazepam versus placebo in acute chloroquine intoxications of moderate gravity. Intensive Care Med. 1996;22(12):1400-1405. 25. Clemessy JL, Favier C, Borron SW, et al. Hypokalemia related to acute chloroquine ingestion. Lancet. 1995;346:877-880. 26. Clemessy JL, Taboulet P, Hoffman JR, et al. Treatment of acute chloroquine poisoning: a 5-year experience. Crit Care Med. 1996;24: 1189-1195. 27. Crevoisier C, Joseph I, Fischer M, Graf H. Influence of hemodialysis on plasma concentration-time profiles of mefloquine in two patients with end stage renal disease: a prophylactic drug monitoring study. Antimicrob Agents Chemother. 1995;39:1892-1895. 28. Crouzette J, Vicaut E, Palombo J, et al. Experimental assessment of the protective activity of diazepam on the acute toxicity of chloroquine. J Toxicol Clin Toxicol. 1983;20(3):271-279. 29. Davis TME. Adverse effects of antimalarial prophylactic drugs: an important consideration in the risk-benefit equation. Ann Pharmacother. 1998;22:1104-1106. 30. Davis TME. Antimalarial drugs and glucose metabolism. Br J Clin Pharmacol. 1997;44:1-7. 31. Davis TME, Dembo LG, Kaye-Eddie SA, et al. Neurological, cardiovascular, and metabolic effects of mefloquine in healthy volunteers: a doubleblind placebo-controlled trial. Br J Clin Pharmacol. 1996;42:415-421.

32. Dyson EH, Proudfoot AT, Bateman DN. Quinine amblyopia: is current management appropriate? J Toxicol Clin Toxicol. 1985;23:571-578. 33. Ezzet F, van Vugt M, Nosten F, Looareesuwan S, White NJ. Pharmacokinetics and pharmacodynamics of lumefantrine (benflumetol) in acute falciparum malaria. Antimicrob Agents Chemother. 2000;44:697-704. 34. Farver DK, Lavin MN. Quinine-induced hepatotoxicity. Ann Pharmacother. 1999;33:32-34. 35. Flanagan KL, Budkley-Sharp M, Doherty T, Whitty CJ. Quinine levels revisited: the value of routine drug level monitoring for those on parenteral therapy. Acta Trop. 2006;97(2):233-237. 36. Gangitano JL, Keltner JL. Abnormalities of the pupil and visual-evoked potential in quinine amblyopia. Am J Ophthalmol. 1980;89:425-430. 37. Getz MA, Subramian R, Logeman R, Bellantyne F. Acute necrotizing eosinophilic myocarditis as a manifestation of severe hypersensitivity myocarditis. Ann Intern Med. 1991;115:201-202. 38. Goldenberg AM, Wexler LF. Quinine overdose: review of toxicity and treatment. Clin Cardiol. 1988;11(10):716-718. 39. Grace AA, Camm AJ. Quinidine. N Engl J Med. 1998;338:35-45. 40. Grant WM, Schuman JS. Quinine sulfate. In Toxicology of the Eye, Vol. II: Effects on the Eyes and Visual System from Chemicals, Drugs, Metals and Minerals, Plants, Toxins and Venoms, 4th ed. Springfield, IL: Charles C. Thomas; 1993:1225-1233. 41. Guinovart C, Navia MM, Tanner M, Alonso PL. Malaria: burden of disease. Curr Mol Med. 2006;6(2):137-140. 42. Guly U, Driscoll P. The management of quinine induced blindness. Arch Emerg Med. 1992;9:317-322. 43. Gustafsson LI, Walker O, Alvan G, et al. Disposition of chloroquine in man after single intravenous and oral doses. Br J Clin Pharmacol. 1983;15:471-479. 44. Hall A, Williams S, Rajkumar K, Galloway R. Quinine-induced blindness. Br J Ophthalmol. 1997;81:1-4. 45. Hein TT, Day NPJ, Phu NH, et al. A controlled trial of artemether or quinine in Vietnamese adults with severe falciparum malaria. N Engl J Med. 1996;335:76-83. 46. Ingram RJH, Ellis-Pegler RB. Malaria, mefloquine and the mind. N Z Med J. 1997;110:137-138. 47. Jaeger A, Sauder P, Kopferschmitt J, Flesch F. Clinical features and management of poisoning due to antimalarial drugs. Med Toxicol. 1987;2: 242-273. 48. Johansen PB, Gran JT. Ototoxicity due to hydroxychloroquine: report of two cases. Exp Rheumatol. 1998;16:472-474. 49. Jordan P, Brookes JG, Nickolic G, LeCouteur DG. Hydroxychloroquine overdose, toxicokinetics and management. J Toxicol Clin Toxicol. 1999;37:861-864. 50. Kaneko A, Bergqvist Y, Taleo G, et al. Proguanil disposition and toxicity in malaria patients from Vanuatu with high frequencies of CYP2C19 mutations. Pharmacogenetics. 1999;9:317-326. 51. Karbwang J, White NJ. Clinical pharmacokinetics of mefloquine. Clin Pharmacokinet. 1990;19:264-279. 52. Karbwang J, Na Bangchang K, Bunnag D, Harinasuta T, Laothavorn P. Cardiac effect of halofantrine. Lancet. 1993;342:501. 53. Kissinger E, Hien TT, Hung NT, et al. Clinical and neurophysiological study of the effects of multiple doses of artemisinin on brain-stem function in Vietnamese patients. Am J Trop Med Hyg. 2000;63:48-55. 54. Kivisto KT, Neuvonen PJ. Activated charcoal for chloroquine poisoning. BMJ. 1993;307(6911):1068. 55. Krantz MJ, Dart RC, Mehler PS. Transient pulmonary infiltrates possibly induced by quinine sulfate. Pharmacotherapy. 2002;22:775-778. 56. Krippner R, Staples J. Suspected allergy to artemether-lumefantrine treatment of malaria. J Travel Med. 2003;10:303-305. 57. Krishna S, White NJ. Pharmacokinetics of quinine, chloroquine and amodiaquine: clinical implications. Clin Pharmacokinet. 1996;30:263-299. 58. Lalloo, DG, Shineadia D, Pasvol G, et al. UK malaria treatment guidelines. J Infect. 2007;54(2):111-121. 59. Limburg PJ. Katz H, Grant CS, Service FJ. Quinine-induced hypoglycemia. Ann Intern Med. 1993;119:218-219. 60. Ling Ngan Wong A, Tsz Fung Cheung I, Graham CA. Hydroxychloroquine overdose: case report and recommendations for management. Eur J Emerg Med. 2008;15(1):16-18. 61. Lobel Ho, Coyne PE, Rosenthal PJ. Drug overdoses with antimalarial agents: prescribing and dispensing errors. JAMA. 1998;280:1483. 62. Lockey D, Bateman DN. Effect of oral activated charcoal on quinine elimination. Br J Clin Pharmacol. 1989;27:92-94.

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63. Luzzi GA, Peto TWA. Adverse effects of antimalarials. Drug Saf. 1993;8: 295-311. 64. MacDonald RD, McGuigan MA. Acute dapsone intoxication: a pediatric case report. Pediatr Emerg Care. 1997;13:127-129. 65. Mai N, Day N, Van Chuong L, et al. Post-malaria neurological syndrome. Lancet. 1996;348:917-921. 66. Makin AJ, Wendon J, Fitt S, Portmann BC, Williams R. Fulminant hepatic failure secondary to hydroxychloroquine. Gut. 1994;35:569-571. 67. Markham TN, Dodson VN, Eckberg DL. Peritoneal dialysis in quinine sulfate intoxication. JAMA. 1967;202:1102-1103. 68. Marquardt K, Albertson TE. Treatment of hydroxychloroquine overdose. Am J Emerg Med. 2001;19(5):420-424. 69. McBride SR, Lawrence CM, Pape SA, Reid CA. Fatal toxic epidermal necrolysis associated with mefloquine antimalarial prophylaxis. Lancet. 1997;349:101. 70. Meeran K, Jacobs MG, Scott J, et al. Chloroquine poisoning. Rapidly fatal without treatment. BMJ. 1993;307:49-50. 71. Miller LG, Panosian CB. Ataxia and slurred speech after artesunate treatment for falciparum malaria. N Engl J Med. 1997;336:1328. 72. Monlun E, Le Metayer P, Szwandt S, et al. Cardiac complications of halofantrine: a prospective study of 20 patients. Trans R Soc Trop Med Hyg. 1995;89:430-433. 73. Morrison LD, Velez LI, Shepherd G, et al. Death by quinine. Vet Hum Toxicol. 2003;45(6):303-306. 74. Netland K, Martinez J. Abortifacients: toxidromes, ancient to modern—a case series and review of the literature. Acad Emerg Med. 2000;7: 824-829. 75. Neubauer AS, Stiefelmeyer S, Berninger T, Arden GB, Rudolph G. The multifocal pattern electroretinogram in chloroquine retinopathy. Ophthalmic Res. 2004;36:106-113. 76. Neuvonen PJ, Elonen E, Haapenen EJ. Acute dapsone poisoning: clinical findings and effect of oral activated charcoal and haemodialysis on dapsone elimination. Acta Med Scand. 1983;214:215-220. 77. Nicolas X, Granier H, Laborde JP, Martin J, Talarmin F. Danger of malaria self-treatment. Acute neurologic toxicity of mefloquine and its combination with pyrimethamine-sulfadoxine. Presse Med. 2001;30:1349-1350. 78. Nosten F, Price RN. New antimalarials: a risk-benefit analysis. Drug Saf. 1995:12:264-272. 79. Nosten F, Ter Kuile FO, Luxemburger C, et al. Cardiac effects of antimalarial treatment with halofantrine. Lancet. 1993;341:1054-1056. 80. Nosten F, Vincenti M, Simpson J, et al. The effects of mefloquine treatment in pregnancy. Clin Infect Dis. 1999;28:808-815. 81. Okitolonda W, Delacollette C, Malengreau M, Henquin JC. High incidence of hypoglycemia in African patients treated with intravenous quinine for severe malaria. Br Med J. 1987;295:716-718. 82. Parmar RC, Valvi CV, Kamat JR, Vaswani RK. Chloroquine induced parkinsonism. J Postgrad Med. 2000;46:29-30. 83. Peters BS, Carlin E, Weston RJ, et al. Adverse effects of drugs used in the management of opportunistic infections associated with HIV infection. Drug Saf. 1994;10:439-454. 84. Phillips RE, Looareesuwan S, Bloom SR, et al. Effectiveness of SMS 201-995, a synthetic long-acting somatostatin analogue, in treatment of quinine-induced hyperinsulinemia. Lancet. 1986;i:713-716. 85. Phillips RE, Looareesuwan S, Molyneux ME, Hatz C, Warrell DA. Hypoglycemia and counterregulatory hormone responses in severe falciparum malaria: treatment with Sandostatin. Q J Med. 1993;86:233-240. 86. Ploypradith P. Development of artemisinin and its structurally simplified trioxane derivatives as antimalarial drugs. Acta Trop. 2003;89:329-342. 87. Pous E, Gascon J, Obach J, Corachan M. Mefloquine-induced grand mal seizure during malaria chemoprophylaxis in a non-epileptic subject. Trans R Soc Trop Med Hyg. 1995;89:434. 88. Prescott LF, Hamilton AR, Heyworth R. Treatment of quinine overdose with repeated oral charcoal. Br J Clin Pharmacol. 1989;27:95-97. 89. Price R, van Vugt M, Phaipun L, et al. Adverse effects in patients with acute falciparum malaria treated with artemisinin derivatives. Am J Trop Med Hyg. 1999;60:547-555. 90. Reddy VG, Sinna S. Chloroquine poisoning: report of two cases. Acta Anaesthesiol Scand. 2000;44:1017-1020. 91. Reilly TP, Woster PM, Swensson CK. Methemoglobin formation by hydroxylamine metabolites of sulfamethoxazole and dapsone: implications for differences in adverse drug reactions. J Pharmacol Exp Ther. 1999;288:951-959.

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92. Riou B, Barriot P, Rimailho A, Baud FJ. Treatment of severe chloroquine poisoning. N Engl J Med. 1988;318:1-7. 93. Riou B, Rimailho A, Galliot M, Bourdon R, Huet Y. Protective cardiovascular effects of diazepam in experimental acute chloroquine poisoning. Intensive Care Med. 1988;14:610-616. 94. Robert W, Taylor J, White NJ. Antimalarial drug toxicity: a review. Drug Saf. 2004;27:25-61. 95. Roche RJ, Silamut K, Pukrittayakamee S, et al. Quinine induces reversible high tone hearing loss. Br J Clin Pharmacol. 1990;29:780-782. 96. Rouviex B, Bricaire F, Michon C, et al. Mefloquine and an acute brain syndrome. Ann Intern Med. 1989;110:577-578. 97. Ryan ET, Kain KC. Health advice and immunizations for travelers. N Engl J Med. 2000;342:1716-1725. 98. Sabto J, Pierce RM, West RH, Gurr FW. Haemodialysis, peritoneal dialysis, plasmapheresis and forced diuresis for the treatment of quinine overdose. Clin Nephrol. 1981;16:264-268. 99. Schlagenhauf P. Mefloquine for malaria prophylaxis: a review. J Travel Med. 1999;6:122-133. 100. Schlagenhauf P, Tschopp A, Johnson R, et al. Tolerability of malaria chemoprophylaxis in non-immune travelers to sub-Saharan Africa: multicentre, randomized, double blind, four arm study. BMJ. 2003;327: 1078-1082. 101. Shojania K, Koehler BE, Elliot T. Hypoglycemia induced by hydroxychloroquine in a type II diabetic treated for polyarthritis. J Rheumatol. 1999;26:195-196. 102. Shub C, Gau GT, Sidell PM, Brennan LA Jr. The management of acute quinidine intoxication. Chest. 1978;73(2):173-178. 103. Sialmut K, Molunto P, Ho M, Davis JM, White NJ. Alpha 1-acid glycoprotein (orosomucoid) and plasma protein binding of quinine in falciparum malaria. Br J Clin Pharmacol. 1991;32:311-315. 104. Smith ER, Klein-Schwartz W. Are 1-2 dangerous? Chloroquine and hydroxychloroquine exposure in toddlers. J Emerg Med. 2005;28(4):437-443. 105. Smith HR, Croft AM, Black MM. Dermatological adverse effects with the antimalarial drug mefloquine: a review of 74 published case reports. Clin Exp Dermatol. 1999;24:249-254. 106. Sowunmi A, Fehintola FA, Ogundahansi AT, et al. Comparative cardiac effects of halofantrine and chloroquine plus chlorpheniramine in children with acute uncomplicated falciparum malaria. Trans R Soc Trop Med Hyg. 1999;93:78-83. 107. Speich R, Haller A. Central anticholinergic syndrome with the anti-malarial drug mefloquine. N Engl J Med. 1994;331:57-58. 108. Splawski I, Timothy KW, Vincent GM, Atkinson DL, Keating MT. Molecular basis of the long-QT syndrome associated with deafness. N Engl J Med. 1997;336:1562-1567. 109. Tange RA. Ototoxicity. Adverse Drug React Toxicol Rev. 1998;17:75-89. 110. Taylor S, Berridge V. Medicinal plants and malaria: an historical case study of research at the London School of Hygiene and Tropical Medicine in the twentieth century. Trans R Soc Trop Med Hyg. 2006;100(8):707-714. 111. Taylor WR, White NJ. Antimalarial drug toxicity: a review. Drug Saf. 2004;27(1):25-61. 112. Tecklenburg FW, Thomas NJ, Webb SA, Case C, Habib DM. Pediatric ECMO for severe quinidine cardiotoxicity. Pediatr Emerg Care. 1997;13:111-113. 113. Touze JE, Keundjian BA, Viguier PIA, et al. Electrocardiographic changes and halofantrine plasma level during acute falciparum malaria. Am J Trop Med Hyg. 1996;54:225-228. 114. Tracy JW, Webster LT. Drugs used in the chemotherapy of protozoal infection: malaria. In Hardman JG, Limbird LE, Molinoff PB, et al., eds. Goodman and Gilman’s the Pharmacological Basis of Therapeutics, 10th ed. New York: McGraw-Hill; 2001:1059-1095. 115. Udry E, Bailly F, Dusmet M, et al. Pulmonary toxicity with mefloquine. Eur Respir J. 2000;18:890-892. 116. Vachon F, Fajac I, Gachot B, Coulaud JP, Charmot G. Halofantrine and acute intravascular haemolysis. Lancet. 1992;340:909-910. 117. Van Riemsdijk MM, Sturkenboom MC, Ditters JM, et al. Atovaquone plus chloroguanide versus mefloquine for malaria prophylaxis: a focus on neuropsychiatric adverse events. Clin Pharmacol Ther. 2002;72:294-301. 118. Van Vugt M, Ezzet F, Nosten F, et al. No evidence of cardiotoxicity during antimalarial treatment with artemether-lumefantrine. Am J Trop Med Hygiene. 1999;61:964-967. 119. Wanwimolruk S, Denton JR. Plasma protein binding of quinine: binding to human serum albumin, α1-acid glycoprotein and plasma from patients with malaria. J Pharm Pharmacol. 1992;44:806-811.

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120. Wasay M, Wolfe GI, Herrold JM, Burns DK, Barohn RJ. Chloroquine myopathy and neuropathy with elevated CSF protein. Neurology. 1998;51:1226-1227. 121. Wenstone R, Bell M, Mostafa SM. Fatal adult respiratory distress syndrome after quinine overdose. Lancet. 1989;1:1143-1144. 122. Winek CL, Davis ER, Collom WD, Shanor SP. Quinine fatality—case report. Clin Toxicol. 1974;7(2):129-132. 123. White NJ. Cardiotoxicity of antimalarial drugs. Lancet Infect Dis. 2007;7(8):549-558. 124. White NJ. The treatment of malaria. N Engl J Med. 1996;335:800-806. 125. White NJ, van Vugt M, Ezzet F. Clinical pharmacokinetics and pharmacodynamics of artemether-lumefantrine. Clin Pharmacokinet. 1999;37:105-125.

126. Wolf LR, Otten EJ, Spadafora MP. Cinchonism: two case reports and review of acute quinine toxicity and treatment. J Emerg Med. 1992;10:295-301. 127. Wolff RS, Wirtschafter D, Adkinson C. Ocular quinine toxicity treated with hyperbaric oxygen. Undersea Hyperb Med. 1997;24:131-134. 128. World Health Organization. Facts on ACTs (Atreminisinin-based combination therapies). http://www.searo.who.int/LinkFiles/Drug_Policy_ RBMInfosheet_9.pdf. Published January 2006 [cited]. 129. World Health Organization. Malaria fact sheet. http://www.who.int/ mediacentre/factsheets/fs094/en/. Published May 2007 [cited]. 130. Yanturali S. Diazepam for treatment of massive chloroquine intoxication. Resuscitation. 2004;63(3):347-348.

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CHAPTER 59

ANTICOAGULANTS Mark Su Anticoagulants have numerous clinical applications, including in the treatment of coronary artery disease, cerebrovascular events, deep venous thrombosis, and pulmonary embolism. The anticoagulants are a diverse group of xenobiotics that are widely studied and constantly in the process of therapeutic evolution. Bleeding is a major complication of these xenobiotics. Knowledge of anticoagulants will be of everincreasing utility for clinicians as their use increases.

HISTORY AND EPIDEMIOLOGY The origins and discovery of anticoagulants are extraordinary.2,16,73,131 The discovery of modern-day oral anticoagulants originated following investigations of a hemorrhagic disorder in Wisconsin cattle in the early 20th century that resulted from the ingestion of spoiled sweet clover silage. The hemorrhagic agent, eventually identified as bishydroxycoumarin, would be the precursor to its synthetic congener warfarin (named after the Wisconsin Alumni Research Foundation). This knowledge also led to the use of warfarin as a rodenticide. “Superwarfarins” were subsequently developed as selective pressure caused rats to develop genetic resistance to warfarin. These potent anticoagulants permitted either small, repetitive ingestions or single, larger ingestions to successfully function as rodenticides. As in the case of warfarin, the origins of the anticoagulant heparin are equally fascinating. A medical student initially attempting to study ether-soluble procoagulants derived from porcine intestines serendipitously found that, over time, these apparent “procoagulants” actually prevented normal blood coagulation. The phospholipid anticoagulant responsible for this effect would later be identified as an early form of heparin. Shortly thereafter, the water-soluble mucopolysaccharide termed heparin (because of its abundance in the liver) was then discovered. Unfractionated heparin is a mixture of polysaccharide chains with varying molecular weights. Following the identification of the active pentasaccharide segment of heparin in the 1970s, multiple lowmolecular-weight heparins were isolated and synthetic forms created. In the late 19th century, human urine was noted to have proteolytic activity with a specificity for fibrin. A substance found to be an activator of endogenous plasminogen leading to the consumption of fibrin, fibrinogen, and other coagulation proteins was isolated and purified and given the name urokinase. Streptokinase, a protein produced by β-hemolytic streptococci, tissue plasminogen activator (t-PA), and other synthetic thrombolytics were later discovered. Although known

to exist for many years, ancrod (a purified derivative of snake venom) and hirudin (a product of leeches) only recently gained attention as naturally occurring antithrombotic therapeutic agents. The diversity of these anticoagulants and fibrinolytics has led to ever-increasing use in many fields of medicine. Warfarin is the most common oral anticoagulant in use today because of its utility in patients with cerebrovascular disease, cardiac dysrhythmias, and thromboembolic disease. During the period of 2005 to 2007, the total number of cases of reported warfarin exposures to the American Association of Poison Control Centers was 10,508 with eight deaths (Chap. 135). Throughout this time, there was a general trend toward an increasing number of reports. Additionally, because the common problem of excessive warfarin effects leading to hemorrhage is poorly quantitated as an adverse drug reaction, it frequently goes unrecorded. Thus, as long as warfarin continues to be routinely prescribed, it is likely that the incidence of adverse drug events will continue. Physicians must be cognizant of the complications of warfarin and other anticoagulants, as well as their various therapeutic modalities, while balancing the potential for their risk and benefits.

PHYSIOLOGY ■ BALANCE BETWEEN COAGULATION AND ANTICOAGULATION An understanding of the normal function of the coagulation pathways is essential to appreciate the etiology of a coagulopathy. This section summarizes the critical steps of the coagulation cascade. For additional details, the reader is referred to Chap. 24 and several reviews.63,129,155 Coagulation consists of a series of events that prevent blood loss and assist in the restoration of blood vessel integrity. Although the traditional understanding of the events that occur in the coagulation cascade,48,114 as discussed below, adequately describe in vitro events, the current understanding emphasizes some distinct differences that occur in vivo.63,129,155 Despite these differences, an understanding of the traditional model is most useful for interpreting the results of diagnostic tests of coagulation. Within the cascade, coagulation factors exist as inert precursors and are transformed into enzymes when activated. Activation of the cascade occurs through one of two distinct pathways, the intrinsic and extrinsic systems (Fig. 59–1).48,114 Once activated, these enzymes catalyze a series of reactions that ultimately converge and lead to the generation of thrombin and the formation of a fibrin clot. The intrinsic pathway is activated by the complexation of factor XII (Hageman factor) with high-molecular-weight kininogen (HMWK) and prekallikrein, or vascular subendothelial collagen. This results in sequential activation of factor XII, active kallikrein, active factors IX to XI, and prothrombin (factor II) (Fig. 59–2). Prothrombin is converted to thrombin in the presence of factor V, calcium, and phospholipid. The integrity of this system is usually evaluated by determining the partial thromboplastin time (PTT).

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In the extrinsic or tissue-factor-dependent pathway, a complex is formed between factor VII, calcium, and tissue factor, which is released following injury. A calcium and lipid-dependent complex is then created between factors VII and X. The factor VII–X complex subsequently converts prothrombin to thrombin, which promotes the formation of fibrin from fibrinogen (see Fig. 59–1). The integrity of this pathway is usually assessed by determining the prothrombin time (PT or international normalized ratio [INR]). Activation of factor X provides the important link between the intrinsic and extrinsic coagulation pathways. Additional evidence that tissue factors can activate both factors IX and X suggests that there are more interrelations between the two pathways.143 Furthermore, cell surfaces facilitate the process of clotting. Platelets are also known to interact with proteins of the coagulation cascade through surface receptors for factors V, VIII, IX, and X.66,118,169 As a final step, factor XIII assists in the cross-linking of fibrin to form a stable thrombus. Antithrombin III (now known simply as AT), protein C, protein S, and protein Z serve as inhibitors, maintaining the homeostasis that is required to prevent spontaneous clotting and keep blood fluid. Protein C, when aided by protein S, inactivates two plasma factors, V and VIII.27,40,63 Protein Z is a glycoprotein molecule that forms a complex with the protein Z-dependent protease inhibitor (ZPI) which, in turn, inhibits the activated factor X (Xa)184 AT complexes with all the serine protease coagulation factors (factor Xa, factor IXa, and contact factors, including XIIa, kallikrein, and HMWK), except factor VII.27,63,155 Thrombolytics such as streptokinase, urokinase, anistreplase, and recombinant tissue plasminogen activator (rt-PA) enhance the normal processes that lead to clot degradation.129 Thrombosis is initiated when exposed endothelium or released tissue factors leads to platelet adherence and aggregation, the formation of thrombin, and cross-linking of fibrinogen to form fibrin strands.63,129,155 This results in a hemostatic plug or thrombus formation. Thrombus formation, in turn, leads to generation of plasmin from plasminogen, which causes fibrinolysis and eventual dissolution of the hemostatic plug.42,43 Thus the fibrinolytic system may be thought of as a natural balance against unregulated coagulation. Thrombolytic therapy increases fibrinolytic activity by accelerating the conversion of plasminogen to plasmin, which actively degrades fibrin.42,43 Following the administration of thrombolytics, a drug-induced coagulopathy ensues, and fibrin degradation products are elevated secondary to the rapid turnover of clot.

DEVELOPMENT OF COAGULOPATHY Impaired coagulation results from decreased production or enhanced consumption of coagulation factors, the presence of inhibitors of coagulation, activation of the fibrinolytic system, or abnormalities in platelet number or function. Platelets are involved in the initial phases of clotting following blood vessel injury by assisting in the formation of the fibrin plug. For the purposes of this chapter, a discussion of platelet-related abnormalities is excluded. Some of this information can be found in Chap. 24. Decreased production of coagulation factors results from congenital and acquired etiologies. Although congenital disorders of factor VIII (hemophilia), factor IX (Christmas factor), factor XI, and factor XII (Hageman factor) are all reported, their overall incidence is still quite low. Clinical conditions that result in acquired factor deficiencies are much more common and result from either a decrease in synthesis or activation. Factors II, V, VII, and X are entirely synthesized in the liver,63,129,155 making hepatic dysfunction a common cause of acquired coagulopathy. In addition, factors II, VII, IX, and X require postsynthetic

activation by an enzyme that uses vitamin K as a cofactor,174,179,180 such that vitamin K deficiency (from malnutrition, changes in gut flora secondary to xenobiotics, or malabsorption), or inhibition of vitamin K cycling (from warfarin, as will be described) is capable of impairing coagulation. Excessive consumption of coagulation factors usually results from massive activation of the coagulation cascade. Massive activation occurs during severe hemorrhage or disseminated intravascular coagulation. The latter results from infection, such as sepsis, and from conditions that introduce tissue factor into the blood, such as neoplasms, snake envenomations, stagnant blood flow, diffuse endothelial injury secondary to hyperthermia, ruptured aortic aneurysm, or aortic dissection. The hallmark of a consumptive coagulopathy is a depressed concentration of fibrinogen with an elevation of fibrin-degradation products. This combination suggests the rapid turnover of fibrin in the coagulation process. In the other coagulopathic conditions, the failure to activate the coagulation cascade is associated with normal or high fibrin concentrations and low fibrin-degradation products because of limited clot formation. Inhibitors of the coagulation cascade (circulating anticoagulants) are of two types: immunoglobulin and nonimmunoglobulin. Immunoglobulins, which are often antibodies to existing coagulation factors, may occur without obvious cause. They may be part of a systemic autoimmune disorder or as a result of repeated transfusions with exogenous factors (as occurs in hemophilia).77,106,165 The clinical syndromes associated with antibody inhibitors are similar to those associated with deficiencies of the particular coagulation factors involved. Antibodies to factors V, VII to XI, and XIII are described.20,165 Alternatively, nonimmunoglobulin neutralizers of coagulation occur in conditions associated with rapid white blood cell turnover.20 These lysosomal cationic proteins are neutralizers that compete with coagulation factors for negatively charged phospholipid membrane surfaces. Although they prolong in vitro coagulation times, they are rarely responsible for clinical coagulopathy because of the excess of phospholipid surface area available in vivo.77,106

ORAL ANTICOAGULANTS ■ WARFARIN AND “WARFARINLIKE” ANTICOAGULANTS Oral anticoagulants can be divided into two groups: (1) hydroxycoumarins, including warfarin (commonly called by its trade name Coumadin), difenacoum, panwarfarin, warficide, coumachlor, coumafuryl, fumasol, prolin, ethyl biscoumacetate (Tromexan), phenprocoumon, dicumarol bishydroxycoumarin, and acenocoumarin (Sintrom); and (2) indanediones, including chlorophacinone, pindone, pivalyn, diphacinone, diphenadione, phenindione, and anisindione. Regardless of the classification, their mechanism of action involves inhibition of the vitamin K cycle. Vitamin K is a cofactor in the postribosomal synthesis of clotting factors II, VII, IX, and X (Fig. 59–2). The vitamin K–sensitive enzymatic step that occurs in the liver involves the γ-carboxylation of 10 or more glutamic acid residues at the amino terminal end of the precursor proteins, to form a unique amino acid γ-carboxyglutamate.53,174,179,180 These amino acids chelate calcium in vivo, which allows the binding of the four vitamin K–dependent clotting factors to phospholipid membranes during activation of the coagulation cascade.195 Vitamin K is inactive until it is reduced from its quinone form to a quinol (or hydroquinone) form in hepatic microsomes. This reduction of vitamin K must precede the carboxylation of the precursor factors. The carboxylation activity is coupled to an epoxidase activity for

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Extrinsic pathway

Intrinsic pathway

Activation inhibited by warfarin like anticoagulants VII + TF IIa

Inhibited by heparin* Selected venom proteins

XIIa

Inhibitory signals XI

XIa

HMWK

Ca2+

VIIa-TF

IX

Vessel injury Phospholipase

IXa

Prothrombin activators

VIIIa

VIII

VIIa-TF AT

X

Platelets/Ca2+ V

Xa

Plasminogen activator XIII

Va Platelets/Ca2+

II

tPA

PAI-1

IIa Plasmin

Plasminogen

XIIIa

Protein S active

Fibrinogen

Fibrin

XL fibrin

Chapter 59

Protein S

XLFDP

Plasmin Protein C active FGDP

Thrombin-like enzyme

FIGURE 59–1. A schematic overview of the coagulation and fibrinolytic pathways indicating where phospholipids on the platelet surface interact with the coagulation pathway intermediates. Arrows are not shown from platelets to phospholipids involved in the tissue factor VIIa and the factor IXa to VIIIa interactions to avoid confusion. Interactions of selected venom proteins are indicated in the purple boxes. The diagram is not complete with reference to the multiple sites of interaction of the SERPINS (serine protease inhibitors) to avoid overcrowding.115; XL cross-linked. FDP, fibrin degredation products FGDP, fibrinogen degredation products. HMWK = high molecular-weight kininogen. Dashed lines indicate inhibitory effects.

Anticoagulants

Protein C

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Active factors II, VII, IX, X proteins S and C

Inactive factors II, VII, IX, X proteins S and C

TABLE 59–1. Common Xenobiotic Interactions With Warfarin Anticoagulation Potentiation

OH

OH

CH3 O R

CH3 R OH Vitamin K quinol

O Vitamin K 2,3 epoxide

X-(SH)2

X-(SH)2

X-S2

X-S2

Vitamin K quinone reductase

OH CH3

Vitamin K 2,3-epoxide reductase (VKORC1)

R O Vitamin K quinone CH3

R= CH3

CH3

CH3

CH3

Acetaminophen Allopurinol Amiodarone Anabolic steroids Aspirin Carbenicillin Clarithromycin Cephalosporins Chloral hydrate Cimetidine Clofibrate Cyclic antidepressants Disulfiram Erythromycin Ethanol Fluconazole fluoroquinolone antibiotics HMG-CoA reductase Inhibitors

Antagonism

Isoniazid Ketoconazole Metronidazole Nonsteroidal antiinflammatory drugs Omeprazole Phenytoin Propafenone Propoxyphene Quinidine Quinolones Sulfonylureas Tamoxifen Tetracycline Thyroxine TrimethoprimSulfamethoxazole Vitamin E

Antacids Barbiturates Carbamazepine Cholestyramine Colestipol Corticosteroids Griseofulvin Oral contraceptives Phenytoin Rifampin Vitamin K

FIGURE 59–2. The vitamin K cycle. Dotted lines represent pathways that can be blocked with warfarin and warfarinlike anticoagulants. The aliphatic side chain (R) of vitamin K is shown below the metabolic pathway. VKORC1=Vitamin K reductase complex 1.

vitamin K, whereby vitamin K is oxidized simultaneously to vitamin K 2,3-epoxide (see Fig. 59–2).179,195 This inactive form of the vitamin is converted back to the active form by two successive reductions.53,116,146 In the first step, an epoxide reductase (known as vitamin K 2,3-epoxide reductase) uses reduced nicotinamide adenine dinucleotide (NADH) as a cofactor to convert vitamin K 2,3-epoxide to a quinone form.139,179 Subsequently, the quinone is reduced to the active vitamin K quinol form (see Antidotes in Depth A16–Vitamin K1). Warfarin is a racemic mixture of R warfarin and S warfarin enantiomers. In rodents, S warfarin is three to six times more potent than R warfarin at producing hypoprothrombinemia.29 In humans, S warfarin may only be about 1.5 times as potent as R warfarin.30 Warfarin and all warfarinlike compounds inhibit the activity of vitamin K 2,3-epoxide reductase, as can be demonstrated by the observation of elevated concentrations of vitamin K 2,3-epoxide in orally anticoagulated subjects.39,198 Additional evidence suggests that another enzyme, vitamin K quinone reductase, is also inhibited by warfarin and its related compounds (Fig. 59–2).53,57 This reduction in the cyclic activation of vitamin K subsequently inhibits the formation of activated clotting factors. Pharmacology of Warfarin Orally ingested warfarin is virtually completely absorbed, and peak serum concentrations occur approximately 3 hours after administration.178 Because only the free warfarin is therapeutically active, concurrent administration of xenobiotics that alter the concentration of free warfarin, either by competing for binding to albumin or by inhibiting warfarin metabolism, may markedly influence the anticoagulant effect.12,61,178 The pharmacologic response to warfarin is a polygenic trait with approximately 30 genes contributing to its

therapeutic effects.101 Table 59–1 lists the xenobiotics that interfere with or potentiate warfarin’s effects. Although vitamin K regeneration is altered almost immediately, the anticoagulant effect of warfarin, as well as other oral anticoagulants, is delayed until the existing stores of vitamin K are depleted and the active coagulation factors are removed from circulation. Because vitamin K turnover is rapid, this effect is largely dependent on factor half-life (t1/2), with factor VII (t1/2 ~5 hours) depleted most rapidly.61 For a prolongation of the INR to occur, factor concentrations must fall to approximately 25% of normal values. Assuming complete inhibition of the vitamin K cycle, this suggests that in most patients who are not originally anticoagulated, at least 15 hours (three factor VII half-lives) are required before warfarin’s effect is evident.59 In fact, complete inhibition does not occur, and hence the onset of coagulation is even further delayed. Because the half-life of warfarin in humans is 35 hours, its duration of action may be as long as 5 days.29,178 On average, it takes approximately 6 days of warfarin administration to reach a steady-state anticoagulant effect. R warfarin is metabolized by isozymes CYP1A2 and CYP3A4, and S warfarin is metabolized by CYP2C9 of the hepatic microsomal P450 enzyme system. R warfarin is metabolized by side-chain reduction to secondary alcohols that are subsequently excreted by the kidney, whereas S warfarin is metabolized by hydroxylation to 7-hydroxy warfarin, which is excreted into the bile.178 The elimination of S warfarin is more rapid than that of R warfarin.30 The therapeutic dose of warfarin is established for both adults and children. Typical adult recommendations are to give a starting dose of 5 mg/d with subsequent doses based on nomograms, computer programs, and/or clinical experience.64 Previous recommendations of

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initiating with a “loading” dose appear to be unnecessary.5 Wide variability of maintenance dosing also exists, depending on, for example, individual responsiveness, comorbid health conditions, and age. For children, the suggested starting dose of warfarin is 0.2 mg/kg, followed by continued loading over 3 days, followed by a daily maintenance dose to maintain the INR between 2 and 3.127,152 For patients with mechanical heart valves, depending on the type of valve, an increased intensity of anticoagulation (INR 3.0 to 4.0) may be recommended.54 Dosing of warfarin and other vitamin K antagonists is potentially problematic in certain individuals. In one study, genetic polymorphisms of the vitamin K epoxide reductase complex 1 (VKORC1) and CYP2C9 genes appear to be the strongest predictors of interindividual variability in the anticoagulant effect of warfarin.101 Furthermore, pharmacogenomic research with complex xenobiotics, such as warfarin, may improve the treatment of patients and predict or prevent interactions with other xenobiotics. In fact, the US Food and Drug Administration (FDA) has recently approved a commercially available test to identify variants within these genes.97

■ PHARMACOLOGY OF LONG-ACTING ANTICOAGULANTS Within the coumarin group are two 4-hydroxycoumarin derivatives— difenacoum and brodifacoum differ from warfarin by their longer, higher-molecular-weight polycyclic hydrocarbon side chains ( Fig. 59–3 ). Together with chlorophacinone, an indandione derivative, they are known as “superwarfarins,” or long-acting anticoagulants. Long-acting anticoagulants were designed to be effective rodenticides in warfarin-resistant rodents.113 Their mechanism of action is identical to that of the traditional warfarinlike anticoagulants, as demonstrated by the measurement of increased concentrations of vitamin K 2,3-epoxide after long-acting anticoagulant administration.28,31,32,107,145 The ability of these xenobiotics to perform as superior rodenticides is attributed to their high lipid solubility and concentration in the liver.107,113,145 They also may saturate hepatic enzymes at very low concentrations, as demonstrated by zero-order elimination following overdose.32 These factors make them about 100 times more potent than warfarin on a molar basis.107,113,145 In addition, they have a longer duration of action than the traditional warfarins.107,113,145 For example, to obtain 100% lethality in a mouse, more than 21 days of feeding with a warfarin-containing rodenticide (0.025% anticoagulant by weight of bait) is required.113 Similar efficacy can be achieved with a single ingestion of brodifacoum (0.005% anticoagulant by weight of bait).113

OH

O

O Brodifacoum

OH

Br

O

CH3 O

O

Warfarin FIGURE 59–3. Structural comparison of prototypical short-acting (warfarin) and longacting (brodifacoum) anticoagulants.

Anticoagulants

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Many animals have been poisoned with long-acting anticoagulants, either secondary to the unintentional ingestion of rodenticides or intentionally for scientific investigation. In rats, the half-life of brodifacoum is reported to be 156 hours.9 The half-life in dogs is reported to be between 6 and 120 days.200 Horses intentionally poisoned with brodifacoum had a half-life of 1.22 days.23 The veterinary literature is replete with reports of fatalities and of animals that remained anticoagulated in excess of 1 month.130,176 Likewise, many cases of intentional overdose of long-acting anticoagulants in humans are also described in the literature. These patients’ clinical courses are characterized by a severe coagulopathy that may last weeks to months, often accompanied by consequential blood loss. The most common sites of bleeding are the gastrointestinal and genitourinary tracts. Although initial parenteral vitamin K1 doses as high as 400 mg have been required for reversal,33 daily oral vitamin K1 requirements may be in the range of 50 to 100 mg. Recent experience in both animals and humans suggests that parenteral vitamin K1 therapy might not be required (see Antidotes in Depth A16: Vitamin K1).32,200 It should also be noted that although ingestions of these xenobiotics are the most common route of exposure and subsequent cause of toxicity, dermal absorption can occur also resulting in coagulopathy.172 Patients with unintentional ingestions must be distinguished from those with intentional ingestions, because the former individuals demonstrate a low likelihood of producing coagulation abnormalities and have only rare morbidity or mortality. Prolongation of the INR is unlikely with a single small ingestion of a superwarfarin rodenticide. Clinically significant anticoagulation is even rarer. In a combined pediatric case series, prolongation of the INR occurred in only eight of 142 children (5.6%) reported with single small ingestions of longacting anticoagulants.15,94,95,171 Only one child in this group was reported to have “abnormal prolonged bleeding,” but this required no medical attention.171 In a single case report, a 36-month-old child developed a coagulopathy manifested by epistaxis and hematuria, with anticoagulation persisting for more than 100 days after a presumed, but unwitnessed, single unintentional ingestion of brodifacoum.182 Clinically significant coagulopathy can result, however, following small repeated ingestions. Two children reportedly became poisoned by repeated ingestions of a long-acting anticoagulant. One child presented with a neck hematoma that compromised his airway, and the other with a hemarthrosis.69 Similarly, a 7-year-old girl required multiple hospitalizations over a 20-month period following repeated nonsuicidal ingestions of brodifacoum.192 Finally, a 24-month-old child who presented with unexplained bruising and a PT greater than 125 seconds was the victim of brodifacoum poisoning because of a Munchausen syndrome by proxy.8 Most patients (usually children) are entirely asymptomatic and have a normal coagulation profile following an acute unintentional exposure. Knowing that the risk of coagulopathy is low and that it takes days to develop, most authors recommend supportive care only.93,171 Despite the fact that significant toxicity from superwarfarins is rare, it should be recognized that the reported benign courses of pediatric exposures may be misleading. Multiple retrospective studies suggest that children with unintentional acute exposures do not require any follow-up coagulation studies.128,132,147,166 However, this conclusion and approach to management may be an unjustified attempt to decrease the cost of “unnecessary” coagulation studies. There are clearly insufficient data to justify this conclusion, as many of these “exposed” children were never documented to have ingested long-acting anticoagulants (see Chap. 135). We recommend that clinicians continue to manage these children as possible significant exposures, and that all children be followed up with at least a single INR at least 48 hours after the exposure.

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A baseline INR is usually unnecessary but may be performed if there is a suspicion of chronic ingestion.

■ CLINICAL MANIFESTATIONS Typical warfarin rodenticides contain only small concentrations of anticoagulant, 0.025% (or 25 mg of warfarin per 100 g of product). Using the data previously listed, a 10-kg child would require an initial dose of 2.5 mg of warfarin (or 10 g of rodenticide). These quantities are far greater than those that occur in typical “tastes.” Thus, single small unintentional ingestions of warfarin-containing rodenticides pose a minimal threat to normal patients.93 In contrast, intentional and large unintentional ingestions of pharmaceutical-grade anticoagulants have the potential to produce a coagulopathy and bleeding. In one study describing 12 patients with surreptitious ingestion of oral anticoagulants, nine were healthcare professionals.140 These patients presented with bruising, hematuria, hematochezia, and menorrhagia, the typical manifestations of impaired coagulation. Hemorrhage into the neck with resultant airway compromise is a rare but life-threatening complication that has occurred.24 Although intentional ingestions of warfarin-containing products are uncommon, adverse drug events resulting in excessive anticoagulation and bleeding frequently occur. The risk of hemorrhage during oral anticoagulant therapy depends on a myriad of factors, including the intensity of anticoagulation, patient characteristics, and comorbid conditions such as hypertension, renal insufficiency, hepatic dysfunction, malignancy, length of anticoagulant therapy, and indications for anticoagulation—cerebrovascular disease, prosthetic heart valves, atrial fibrillation, ischemic heart disease, and venous and arterial thromboembolism. Although the significance of each of these clinical conditions varies among different reports, most studies demonstrate that there is a greater incidence of bleeding complications with increasing INR,41 increasing intensity (or variation) of coagulation, advanced age, a history of previous bleeding episodes while on therapeutic warfarin, drug interactions, impaired liver function, and dietary changes.59,61,71,76,150,197 Clearly, the most serious complication of excessive anticoagulation is intracranial hemorrhage, which is reported to occur in as many as 2% of patients on long-term therapy.61 This complication is associated with a fatality rate as high as 77%.121 A recent study of patients with intracranial hemorrhage found that decreased level of consciousness and increased size of hemorrhage were predictors of poor prognosis.203 Somewhat surprisingly, the degree of INR elevation was not associated with worse outcome.203 An Outpatient Bleeding Risk Index was created and shown to be more accurate than physician judgment in classifying patients according to the risk of major bleeding.18 The index was based on independent risk factors: age 65 years or older; history of cerebrovascular accident; history of gastrointestinal bleeding; and history of recent myocardial infarction, hematocrit less than 30%, serum creatinine greater than 1.5 mg/dL, or diabetes mellitus. The sum of the number of risk factors successfully predicted major bleeding at 48 months to be 3% in low-risk (zero risk factors), 12% in intermediate risk (one to two risk factors), and 53% in high-risk (three to four risk factors) patients. Because physicians are often unable to accurately estimate the probability of bleeding, use of the Outpatient Bleeding Risk Index seems appropriate to improve awareness and treatment of these highrisk patients and was validated in at least one subsequent study.193 In a study of 32 patients who developed life-threatening hemorrhage while on warfarin therapy, most patients had multiple risk factors including excessive anticoagulation.197 The gastrointestinal tract was identified as the source of bleeding in 67% of the patients.197 Sixty-six percent of patients were given vitamin K1, 50% were given fresh-frozen plasma (FFP), and 7% were given both therapies.197

■ LABORATORY ASSESSMENT Established screening tests are helpful for diagnosis. Four studies—PT (INR), PTT, thrombin time, and fibrinogen concentration—are usually adequate. Prothrombin time is calculated by adding standardized thromboplastin reagent (phospholipid and tissue factor) to a sample of the patient’s citrated plasma (the citrate removes calcium to prevent clotting). Calcium is then introduced and the time to clotting measured. With the exception of factor X, the PT is unaffected by the presence or absence of factors VIII to XIII, platelets, prekallikrein, and HMWK. An individual’s PT was formerly expressed as a ratio (PT observed to PT control). Because this ratio is directly affected by both laboratory methodology and the source of the thromboplastin reagent used, the generated results suffered from significant variability. Thus, a standard, the INR, was developed in an attempt to limit interlaboratory variability.78,136 The INR is derived by raising the PT ratio to a power value known as the International Sensitivity Index (ISI): (PT ratio)ISI. The ISI is a measure of responsiveness of the particular thromboplastin to warfarin. Although the use of the INR does not completely eliminate variability,80,135 it does improve the potential for standardized interpretation and limits interinstitutional variations. It should be noted that in patients taking oral anticoagulants, specifically warfarin, the INR is extremely effective at monitoring the extent of anticoagulation. However, use of the INR measurement in the setting of fulminant hepatic failure, as in the recently developed Model for End-Stage Liver Disease (MELD) score, a tool to predict the need for liver transplantation, is unwarranted.35 In these patients the INR is extremely variable and inaccurate as a consequence of the variability in thromboplastins.154 This problem may be mitigated in the United States because of the use of recombinant human preparations of thromboplastin, which results in greater consistency.36 The partial thromboplastin time is measured by adding kaolin or celite to citrated plasma in order to activate the “contact” components of the intrinsic system. This mixture is then recalcified and the time to clotting observed. Some tests use phospholipids in the reagent to activate the remaining coagulation factors, thereby giving rise to the term activated partial thromboplastin time (aPTT). Because the PTT and aPTT are essentially interchangeable, the term PTT is used hereafter to represent the concept. The PTT is not affected by alterations in factors VII, XIII, or platelets. The thrombin time, determined by adding exogenous thrombin to citrated plasma, evaluates the ability to convert fibrinogen to fibrin, and is thus unaffected by abnormalities of factors II, V, VII to XIII, platelets, prekallikrein, or HMWK. Finally, either a fibrinogen concentration or a determination of fibrin degradation products will help distinguish between problems with clot formation and consumptive coagulopathy (disseminated intravascular coagulation). An evaluation of the combination of normal and abnormal results of these tests usually determines a patient’s clotting abnormality (Table 59–2). Inhibitors can be diagnosed by “mixing studies,” because only a small percentage of the coagulation factors present in normal plasma are necessary to have normal clotting studies. If the patient with an abnormal PT or PTT suffers from even a severe factor deficiency, restoration of that factor activity to 50% of normal will completely normalize the PT or PTT. Thus the presence of an abnormal PT or PTT that will not correct by incubation of the patient’s plasma with an equal volume of normal plasma is diagnostic of an inhibitor of coagulation. Heparin-induced anticoagulation results in an elevated PTT that corrects when mixing studies are performed. More sophisticated studies can be used to identify specific coagulation-factor deficiencies. The reader is referred to one of several standard references for a more detailed discussion of the approach to patients with abnormal coagulation studies.156

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TABLE 59–2. Evaluation of Abnormal Coagulation Times PT normal, PTT prolonged, bleeding Deficiencies of factors VIII, IX, XI von Willebrand disease PT normal, PTT prolonged, no bleeding Deficiencies of factor XII, prekallikrein, high-molecular-weight kininogen inhibitor syndrome PT prolonged, PTT normal Deficiency of factor VII Warfarin therapy (early) Vitamin K deficiency (mild) Liver disease (mild) PT and PTT prolonged, thrombin time normal, fibrinogen normal Deficiencies of factors II, V, IX; vitamin K deficiency (severe) Warfarin therapy (late) PT and PTT prolonged, thrombin time abnormal, fibrinogen normal Heparin effect Dysfibrinogenemia PT and PTT prolonged, thrombin time abnormal, fibrinogen abnormal Liver disease Disseminated intravascular coagulation Fibrinolytic therapy Crotaline envenomation PT, prothrombin time; PTT, partial thromboplastin time.

Although warfarin concentrations may be useful to confirm the diagnosis in unknown cases and to study drug kinetics,72,138 the routine use of simple and inexpensive measures such as INR determination seems more appropriate.

■ LABORATORY EVALUATION OF LONG-ACTING ANTICOAGULANTS For patients who have ingested long-acting anticoagulants and who are considered likely to develop a coagulopathy, baseline coagulation studies are not usually helpful, but they may provide information about chronic exposures. If the history is reliable and the patient is healthy, baseline studies can be avoided. A single INR at 48 hours should identify all patients at risk of coagulopathy.171 Depending on the social situation, these studies can be obtained while the patient remains in the home setting. In contrast, all patients with intentional ingestion of long-acting anticoagulants should be presumed to be at risk for a severe coagulopathy. In fact, most patients do not seek medical care until bruising or bleeding is evident.11,32,33,38,56,82,95,100,133,181 These events often occur many days after ingestion, which obviates the need for gastric decontamination unless there is a suggestion of repetitive ingestion. These patients should be managed as described below. For patients who have suspected long-acting anticoagulant overdose, daily or twice-daily INR evaluations for 2 days should be adequate to identify most patients at risk for coagulopathy. Early detection through coagulation factor analysis may be preferred,72,82 however, and concentrations of long-acting anticoagulants can now be measured.102,138

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GENERAL MANAGEMENT AND ANTIDOTAL TREATMENT Gastrointestinal decontamination should be performed on patients who are believed to have potentially significant life-threatening ingestions unless they already present with significant bleeding. For patients who present after a few hours of ingestion, gastric emptying is not indicated (see Chap. 7). Although convincing data on the efficacy of either single- or multiple-dose activated charcoal (AC; possible enterohepatic circulation) are lacking, at least a single dose of AC should be administered unless it is contraindicated. Oral cholestyramine can also be used to enhance warfarin elimination,151 but no studies are available that compare these two therapies or evaluate the role of combined activated charcoal and cholestyramine therapy. Although in animal models phenobarbital also enhances elimination, it is relatively contraindicated in humans because of the decreased ability to reliably monitor the mental status of a patient who has the possibility of spontaneous intracranial hemorrhage and subsequent increased risk of falling. In addition to general supportive measures, the patient should be placed in a supervised medical and psychiatric environment that offers protection against external or self-induced trauma, and permits observation for the onset of coagulopathy. Blood transfusion is required for any patient with a history of blood loss or active bleeding who is hemodynamically unstable, has impaired oxygen transport, or is expected to become unstable. Although a transfusion of packed red blood cells is ideal for replacing lost blood, it cannot correct a coagulopathy, and thus patients will continue to bleed. Whole blood contains both the cellular elements the patient is losing and the necessary coagulation factors to reverse the coagulopathy. Transfusion of whole blood may be considered in severe cases because whole blood contains many components, including platelets, white blood cells, and non–vitamin-K-dependent factors. However, because whole blood contains only relatively small amounts of vitamin K–dependent factors, selective use of specific blood products is generally preferred. These products include packed red blood cells, FFP, cryoprecipitate, or other factor concentrates, such as factor IX complex (Konyne 80), recombinant factor VIIa (rFVIIa), and prothrombin complex concentrate. Life-threatening hemorrhage secondary to oral anticoagulant toxicity should be immediately reversed with FFP, followed by vitamin K1. FFP is rich in active vitamin K–dependent coagulation factors and will reverse oral anticoagulant-induced coagulopathy in most patients. In general, approximately 15 mL/kg of FFP should be adequate to reverse any coagulopathy.47 However, the specific factor quantities and volume of each unit may be varied, leading to an unpredictable response.117 A study comparing the efficacy of FFP and various clotting factor concentrates (prothrombin complex concentrate, factor VII concentrate, and Prothromplex T [factors II, VII, IX, and X]) in rapid reversal of anticoagulation, showed that despite significant reduction in the INR, FFP had an extremely varied effect on factor IX repletion. These clotting factor concentrates not only significantly decreased the INR, but completely corrected it, and factor IX replacement was much more consistent.117 Additionally, multiple FFP transfusions may also be required because of the rapid degradation of coagulation factors in the absence of vitamin K. Administration of FFP to patients with intracerebral hemorrhage may also result in volume overload.1 Prothrombin complex concentrates (PCCs) are likely to produce complete INR reversal faster than FFP and appear to be associated with fewer adverse effects.50 One group in the United Kingdom reports success with its use for the reversal of oral anticoagulation.92 Consequently, prothrombin complex concentrates may be preferable to FFP if readily available.

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Preliminary data using rVIIa demonstrates it to be a useful pharmacologic therapy for bleeding secondary to warfarin-induced excessive anticoagulation.51,126 There is also a single case report demonstrating efficacy at reversing severe bleeding caused by enoxaparin,86 and a recent case series showing beneficial effects in four patients with superwarfarin toxicity.204 Since a possible complication of its use may be thrombosis, further experience with rVIIa is necessary to determine its safety and efficacy in anticoagulant-induced hemorrhage. It should also be noted that if rVIIa is used, assays based on PT may be inaccurate and should be avoided when administering rVIIa.96 Several issues influence the decision to administer vitamin K1 to a patient with a suspected overdose of a warfarinlike anticoagulant. Answers to the following questions should always be considered. Does the ingestion involve a warfarin-containing rodenticide or a pharmaceutical preparation? Is the ingestion unintentional or intentional? Does the patient require maintenance of therapeutic anticoagulation? Moreover, although vitamin K1 administration is required to reverse the blockade of coagulation factor activation, it cannot be relied on for the patient with acute and consequential hemorrhage (see Antidotes in Depth A16: Vitamin K1). Treatment with vitamin K1 takes several hours to activate enough factors to reverse the patient’s coagulopathy,117,146 and this delay may be potentially fatal. Repetitive, large doses of vitamin K1 (on the order of 60 mg/d) may be required in some patients.72,140 If complete reversal of INR prolongation occurs or is desirable (as in most cases of life-threatening bleeding), and the patient’s underlying medical condition still requires some degree of anticoagulation, they can then receive anticoagulation with heparin once the bleeding is controlled and they are otherwise stable. Heparin anticoagulation was used without apparent bleeding complications in 25% of patients in one cross-sectional study.197 Vitamin K1 is preferable over the other forms of vitamin K; the other forms are ineffective90,133,139,183 and are potentially toxic.10 (Vitamins K3 [menadione] and K4 [menadiol sodium diphosphate] can cause oxidative stress on neonatal erythrocytes and produce hemolysis, hyperbilirubinemia, and kernicterus.) Parenteral administration of vitamin K1 (phytonadione) is traditionally preferred as initial therapy by many authors, but success can also be achieved with early oral therapy, especially when the coagulopathy is not severe.32 In most cases, the patient can be switched to oral vitamin K1 for long-term care. Vitamin K1 can be administered intramuscularly, subcutaneously, intradermally, or intravenously. Although intravenous therapy has the most rapid onset of action of all routes of delivery, its use as the sole therapeutic agent is still associated with a delay of several hours116,146 and carries the added risk of anaphylactoid reactions.153 The use of low doses and slow rate of administration reduces this risk168 (see Antidotes in Depth A16–Vitamin K1). In cases where oral administration is undesirable, for example, with significant gastrointestinal hemorrhage, the subcutaneous route may be used, realizing that absorption may be erratic. Furthermore, if a patient is anticoagulated or overanticoagulated, administration of vitamin K1 by the intramuscular route may result in a large hematoma. Caution should be exercised if this route of administration is chosen. For patients with non–life-threatening hemorrhage, the clinician must consider whether anticoagulation is required for long-term care. In patients not requiring chronic anticoagulation, even small elevations of the INR may be treated with vitamin K1 alone to prevent deterioration in coagulation status and reduce the risk of bleeding. Because in most cases of warfarin ingestion coagulopathy persists only for several days, there may be a rationale for prophylactic vitamin K1 administration in known warfarinlike anticoagulant ingestions in patients not requiring anticoagulation. In contrast to ingestions of warfarin, prophylactic vitamin K1 should never be given to asymptomatic patients

with unintentional ingestions of long-acting anticoagulants because (1) if the patient develops a coagulopathy, it will last for weeks, and the one or two doses of vitamin K1 given will not prevent complications; (2) a gradual decline in coagulation factors occurs over the first day of anticoagulation, so no one would be expected to develop a life-threatening coagulopathy in 1 or 2 days; and (3) after vitamin K1 is administered, the onset of an INR abnormality will be delayed, which could impair the clinician’s ability to diagnose any coagulation abnormality, possibly requiring the patient to undergo an unnecessarily prolonged observation period. For patients requiring chronic anticoagulation, the American College of Chest Physicians has issued guidelines for the management of patients with elevated INRs (Table 59–3). Moreover, the use of a regression formula may assist in calculating the amount of oral vitamin K1 necessary to partially correct the INR, without completely discontinuing the oral anticoagulant. Although it remains unvalidated, it would be extremely useful prior to minor surgery or dental procedures in patients requiring chronic anticoagulation, while theoretically decreasing the likelihood of thromboembolism.194 It should also be noted that low-dose vitamin K may be safely administered to patients with mildly elevated INRs (4 to 10) to decrease the INR more

TABLE 59–3. Recommendations for Management of Elevated INRs or Bleeding in Patients Receiving Vitamin K Antagonists5 INR

Recommendationsa

5.0 but 9.0; no significant bleeding

Serious bleeding at any INR concentration or lifethreatening bleeding

Administration of vitamin K

FFP, fresh-frozen plasma; INR, international normalized ratio; PCC, prothrombin complex concentrate; rVIIa, recombinant factor VIIa. a If continued warfarin therapy is indicated after high doses of vitamin K1, then anticoagulation with heparin or low-molecular-weight heparin can be concomitantly given. INR values greater than 4.5 are also less reliable than values at or near the therapeutic range. b

rVIIa may cause thrombosis and we do not advocate its routine use at this time.

c

Although parenteral infusion of vitamin K1 is recommended, we urge caution with this route of administration because there may not be an appreciable difference in onset of therapeutic effect and, although rare, it may cause severe anaphylactoid reactions.

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rapidly; however, one study did not demonstrate decreased bleeding in the treatment group.46 Furthermore, simply omitting warfarin doses may be adequate for the patient without active hemorrhage who has an INR between 4 and 9.46 It is often unclear why patients with consistent therapeutic dosing have seemingly random elevations in their INR. A recent case-control study identified the following risk factors associated with overcoagulation from vitamin K antagonists: previous medical history of increased INR levels, antibiotic therapy, fever and concomitant use of amiodarone and proton pump inhibitors.34 Clinicians should pay particular attention to patients with these conditions and close monitoring of coagulation profiles should be performed.34

■ TREATMENT OF LONG-ACTING ANTICOAGULANT OVERDOSES Treatment of a patient with a long-acting anticoagulant overdose is essentially the same as the treatment of oral anticoagulant toxicity with certain exceptions. Long-acting anticoagulants are metabolized by the hepatic mixedfunction oxidase system (cytochrome P450 [CYP]).9,139 In a rat model, the duration of coagulopathy was shortened by administering phenobarbital, a CYP3A4 inducer.9 Although a phenobarbital effect has never been systematically studied in humans, this approach was used by several authors in isolated human cases of long-acting anticoagulant toxicity.33,90,110,182,192 Although these anecdotal reports suggest some improvement with phenobarbital therapy, the risks of producing sedation in a patient who might be prone to bleeding complications appear consequential. Patients with long-acting anticoagulant overdose should be followed until their coagulation studies remain normal while off therapy for several days. This usually requires daily or even twice-daily INR measurements until the INR is at the lower limit of the therapeutic range. Monitoring of serial INR measurements should allow for a gradual decrease in vitamin K1 requirement over time. Periodic coagulation factor analysis, however, may provide an early clue to the resolution of toxicity.82 The patient may require weeks to months of close observation for both psychiatric and medical management. Emphasis has been placed on determining a critical superwarfarin concentration below which anticoagulation does not occur.33 In one case report, brodifacoum was observed to follow zero-order elimination kinetics.32 If this type of toxicokinetics is consistent in the analysis of other longacting anticoagulants, these laboratory measurements may prove more reliable than the current empiric end points of therapy.

■ OTHER ORAL ANTICOAGULANTS Because of the potential therapeutic limitations of warfarin (eg, dosing, risk of hemorrhage, narrow therapeutic window, etc) novel oral anticoagulants have been developed with directed activity against specific clotting factors. Ximelagatran was one of the first direct thrombin inhibitors that appeared to be as effective as warfarin in the treatment of stroke prevention, nonvalvular atrial fibrillation, and deep venous thrombosis, and was shown to be more effective than aspirin alone for patients who have had a recent myocardial infarction.81 Ximelagatran had many advantages over warfarin, including rapidity of onset, fixed dosing, stable absorption, decreased risk of drug interactions, and lack of necessity for therapeutic monitoring.81 However, because of its major side effect of heptatotoxicity, it has been removed from the world market by its manufacturer. Since then, new anticoagulants including factor Xa inhibitors (eg, rivaroxaban, apixaban) and direct thrombin inhibitors (eg, argatroban, dabigatran) are gaining in popularity for their therapeutic effects.173 Argatroban binds noncovalently

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to the active site of thrombin to function as a competitive inhibitor.79 It is metabolized by CYP3A4/5 in the liver and is particularly useful in patients with renal impairment.79 These medications show tremendous promise and may revolutionize the treatment of thromboembolic disease. Limited data are currently available regarding toxicity of these agents; however, overdose of argatroban was successfully treated with FFP in one recent case report.201

PARENTERAL ANTICOAGULANTS ■ HEPARIN Conventional or unfractionated heparin is a heterogeneous group of molecules within the class of glycosaminoglycans.89 The heparin precursor molecule is composed of long chains of mucopolysaccharides, a polypeptide, and carbohydrates. The main carbohydrate components of heparin molecules include uronic acids and amino sugars in polysaccharide chains. Heparin for pharmaceutical use is extracted from bovine lung tissue and porcine intestines.163 Heparin inhibits thrombosis by accelerating the binding of AT to thrombin (factor II) and other serine proteases involved in coagulation.115,157 Thus, factors IX to XII, kallikrein, and thrombin are inhibited. Heparin also affects plasminogen activator inhibitor, protein C inhibitor, and other components of coagulation. Heparin’s therapeutic effect is usually measured through the activated PTT. The activated blood coagulation time (ACT) may be more useful for monitoring large therapeutic doses or in the overdose situation.103 Low-molecular-weight heparins (LMWHs) are 4000- to 6000-dalton fractions obtained from conventional (unfractionated) heparin.62 As such, they share many of the pharmacologic and toxicologic properties of conventional heparin.26 The various LMWHs (eg, fraxiparine, enoxaparin, dalteparin) are prepared by different methods of depolymerization of heparin; consequently, they each differ to a certain extent regarding their pharmacokinetic properties and anticoagulant profiles. The major differences between LMWHs and conventional heparin are greater bioavailability, longer half-life, more predictable anticoagulation with fixed dosing, targeted activity against activated factor X, and less targeted activity against activated factor II.26,62 As a result of this targeted factor X activity, LMWHs have minimal effect on the activated PTT, thereby eliminating either the need for, or the usefulness of, monitoring. They are therefore administered on a fixed-dose schedule. However, in certain instances (eg, patients with impaired renal function, pregnancy, etc), monitoring of anti–factor Xa activity may be performed to assess adequacy of anticoagulation and prevent risk of bleeding.75 Controversy exists as to whether such testing is clinically necessary.25 LMWHs have been investigated for prevention of thromboembolic disease after hip surgery and trauma, in patients with stroke or deep venous thrombosis, in pregnancy, and in other conditions where anticoagulation with heparin would otherwise be indicated (eg, at the onset of oral anticoagulation therapy). Although these xenobiotics are presumed to have a minimal risk in pregnancy124 because they do not cross the placenta,60,177 they are not yet approved for treatment or prophylaxis of thromboembolic disease in pregnancy. Most studies demonstrate a lower incidence of embolization; however, there is still a trend toward increased bleeding.17,70,109

■ PHARMACOLOGY Because of the large size of heparin and negative charge it is unable to cross cellular membranes. These factors prevent oral administration, and

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heparin must be administered by either subcutaneous injection or continuous intravenous infusion. Following parenteral administration, heparin remains in the intravascular compartment, in part bound to globulins, fibrinogen, and low-density lipoproteins, resulting in a volume of distribution of 0.06 L/kg in humans.55,141 Because of its rapid metabolism in the liver by a heparinase, heparin has a short duration of effect.115 Although the half-life of elimination is dose dependent and ranges from 1 to 2.5 hours,115,122,141 the duration of anticoagulant effect is usually reported as 1 to 3 hours.115 Dosing errors or drug interactions with thrombolytic agents, antiplatelet drugs, or nonsteroidal antiinflammatory drugs may increase the risk of hemorrhage.76 LMWHs are nearly 90% bioavailable following subcutaneous administration and have an elimination half-life of 3 to 6 hours.79 Anti–factor Xa activity peaks between 3 and 5 hours after dosing.79 LMWHs are renally eliminated and patients with severe renal insufficiency (creatinine clearance less than 30 mL/min) or endstage renal disease are at increased risk of toxicity.187

■ CLINICAL MANIFESTATIONS Intentional overdoses with heparin are rare.120 Most reported cases involve unintentional poisoning in hospitalized patients.65,67,120,144,162 These cases have involved the administration of large amounts of heparin as a consequence of misidentification of heparin vials, during the process of flushing intravenous lines, and secondary to intravenous pump malfunction. Significant bleeding complications occurred in several cases, including one fatality.65 Similar adverse effects to unfractionated heparins are also reported with LMWHs and include epidural/spinal hematoma, intrahepatic hemorrhage,84 abdominal wall hematomas,6 psoas hematoma after lumbar plexus block,98 and intracranial hemorrhage in patients with malignancy in the brain.52 These complications were all reported in patients who received the LMWH enoxaparin.

■ EVALUATION AND TREATMENT After stabilization of the airway and breathing, and circulation are assured, the physician should be prepared to replace blood loss and reverse the coagulopathy, if indicated. Because of the relatively short duration of action of heparin, observation alone might be indicated if significant bleeding has not occurred. For the patient requiring anticoagulation, serial PTT determinations will indicate when it is safe to resume therapy. If significant bleeding occurs, either removal of the heparin or reversal of its anticoagulant effect is indicated. Because heparin has a very small volume of distribution, it can be effectively removed by exchange transfusion.162 Although this technique has been used successfully in neonates, it is not generally applicable to older children and adults. When severe bleeding occurs, heparin may be effectively neutralized by protamine sulfate.3 Protamine is a low-molecular-weight protein found in the sperm and testes of salmon, which forms ionic bonds with heparin and renders it devoid of anticoagulant activity. 115 One milligram of protamine sulfate injected intravenously neutralizes 100 Units of heparin.115 The dose of protamine should be calculated from the dose of heparin administered if known and assuming heparin’s approximate half-life to be 60 to 90 minutes; the amount of protamine should not exceed the amount of heparin expected to be found intravascularly at the time of infusion. As with other foreign proteins, protamine administration is associated with numerous adverse effects such as hypotension, bradycardia, and allergic reactions. Because approximately 0.2% of patients receiving protamine experience anaphylaxis, a complication that carries a 30% mortality rate, most authors commonly recommend that protamine be reserved for patients with life-threatening hemorrhage (see Antidotes in Depth

A17–Protamine).83 It should also be noted that excess protamine administration may result in paradoxical anticoagulation. Because of the severe adverse effects associated with protamine, research has focused on safer methods to reverse heparin anticoagulation. These agents include heparinase,125 synthetic protamine variants,188,189 and platelet factor 4, but these therapies are not widely available. If life-threatening bleeding occurs following LMWH administration, patients should be treated with protamine. In a case report of a 10-fold dosing error of enoxaparin, protamine effectively reversed the anticoagulant effects.199 Current recommendations are to administer 1 mg protamine per 100 anti–factor Xa units where 1 mg enoxaparin equals 100 anti–factor Xa units if within 8 hours of the LMWH.79 A second dose of 0.5 mg protamine should be administered per 100 anti–factor Xa units if bleeding continues.79 If more than 8 hours has elapsed, then a smaller dose of protamine can be administered. The appropriate dosages for protamine are described in detail in the Antidotes in Depth A17: Protamine. The newer experimental protamine variants appear to be effective against LMWHs but are not yet available.188,189 Interestingly, there is one case report of recombinant activated factor VII reversing the effects of LMWH in the setting of postoperative renal failure.134

NONBLEEDING COMPLICATIONS OF ANTICOAGULANTS Warfarin therapy is associated with three nonhemorrhagic lesions of the skin: urticaria,161 purple toe syndrome,58 and warfarin skin necrosis.44,99,104,123,186 Although warfarin skin necrosis was once thought to be a rare and idiosyncratic reaction,99,104 more recent evidence suggests a link between this disorder and protein C deficiency.104,186 Protein C activation is also dependent on vitamin K.40 Patients who are homozygotes for protein C deficiency have an increased incidence of thrombosis and embolic events, such that they often require longterm anticoagulant therapy.40 Because the half-life of protein C is shorter than that of many of the vitamin K–dependent coagulation factors, protein C concentrations fall rapidly during the first hours of warfarin therapy. In the protein C–deficient patient, protein C concentrations fall dramatically prior to a reduction in coagulation factors. This results in an imbalance that actually favors coagulation, and skin necrosis results due to microvascular thrombosis in dermal vessels.123,186 Although warfarin skin necrosis is more common in patients with protein C deficiency, this disorder is also described in patients with protein S and AT deficiencies.44 Unfortunately, these deficiencies are neither necessary nor sufficient to account for the incidence of warfarin necrosis.44 If necrosis occurs, warfarin should be discontinued and heparin should be initiated to decrease thrombosis of postcapillary venules. Some patients may also require surgical débridement.158 The purple toe syndrome, in contrast to warfarininduced skin necrosis, is presumed to result from small atheroemboli that are no longer adherent to their plaques by clot (see Fig. 29–7). An additional major nonhemorrhagic complication of warfarin therapy relates to its use in pregnant women. Most warfarin-induced fetal abnormalities occur during weeks 6 to 12 of gestation, but central nervous system (CNS) and ocular abnormalities can develop at any time during gestation (see Chap. 30 for further details).74,175 Heparin therapy is associated with a transient and mild thrombocytopenia called heparin-induced thrombocytopenia (HIT) that occurs in approximately 25% of patients during the first few days of therapy.191 Although this syndrome results from heparin-induced platelet aggregation, a more severe form of thrombocytopenia, heparin-induced thrombocytopenia and thrombosis syndrome (HITT; formerly known

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as HIT-2 or the white clot syndrome), occurs in 1% to 5% of patients between days 7 and 14 of therapy.116 In patients who were previously treated with heparin, these events can occur earlier than 7 days. Heparin stimulates platelets to release platelet factor 4, which subsequently complexes with heparin to provoke an IgG response. These antibodies against the heparin–platelet factor 4 complex activate platelets, which may lead to platelet–fibrin thrombotic events.7,202 Patients may present with either hemorrhagic or thromboembolic complications. LMWH may also be associated with thrombocytopenia (isolated HIT), and less frequently with HITT.190 Consequently, once HITT occurs, LMWH is contraindicated.190 Treatment of HIT includes discontinuation of heparin or LMWH and immediate use of alternative anticoagulant such as danaparoid, lepirudine, or argatroban.37 (Danaparoid is currently unavailable in the United States.79) In addition to HIT and HITT, necrotizing skin lesions149 and hyperkalemia from aldosterone suppression142 also rarely occur in patients receiving heparin therapy. These patients should not receive heparin or LMWH again, not even in low doses to keep veins open. Some additional complications of heparin use include osteoporosis, which mostly occurs in patients on long-term therapy with unfractionated heparin.85 A small percentage of these patients may develop bone fractures if treated continuously for more than 3 months. Data for LMWHs are limited and the incidence of osteoporosis may be less compared with unfractionated heparin.85 In 2008, an outbreak of adverse events was linked to heparin contaminated with oversulfated chondroitin sulfate.111 The contaminated heparin, which was found in at least 10 countries, originated in China.22 Many patients developed anaphylactoid-type reactions with at least 100 reported deaths.111

■ HIRUDIN Hirudin, a 65-amino-acid polypeptide produced by the salivary glands of the medicinal leech (Hirudo medicinalis), irreversibly blocks thrombin without the need for AT.164 Unlike heparin, the small size of hirudin allows it to enter clots and inhibit clot-bound thrombin, offering the distinct advantage of restricting further thrombus formation. Hirudin demonstrates enhanced bioavailability and a longer half-life than unfractionated heparin. In addition, there are no known natural inhibitors of hirudin, such as platelet factor 4. Desirudin is a recombinant hirudin that is used in acute coronary syndrome, in the prevention of thromboembolic disease, and in patients with heparin-induced thrombocytopenia.21,160,164 Both of these xenobiotics appear to be at least as effective as unfractionated heparin, and without increased bleeding or thrombocytopenia. However, in the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb study of patients with unstable angina/non–Q wave myocardial infarction, there was an increase in the number of blood transfusions in patients who received desirudin as compared with those who received heparin.4

FIBRINOLYTICS ■ THROMBOLYTICS The fibrinolytic system is designed to remove unwanted clots, while leaving those clots protecting sites of vascular injury intact. Plasminogen exists as a proenzyme and is converted to the active form, plasmin, by various plasminogen activators.42,43 t-PA is released from the endothelium and is under the inhibitory control of two inactivators known as tissue plasminogen activator inhibitors 1 and 2 (t-PAI-1 and t-PAI-2).42,43,116,129 Plasmin’s actions are nonspecific in that it degrades not only fibrin clots but also some plasma proteins and coagulation factors.116 Inhibition of plasmin occurs through α2-antiplasmin.

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With their diverse indications in acute myocardial infarction, unstable angina, arterial and venous thrombosis and embolism, and cerebrovascular disease, the thrombolytic agents (streptokinase, urokinase, alteplase, and anistreplase) are commonly used.14 The reader is referred to a number of reviews for specific indications and dosing regimens.45,105,116,148,170,196 Although all xenobiotics enhance fibrinolysis, they differ in their specific sites of action and durations of effect. t-PA is specific for clot (it does not increase fibrinolysis in the absence of a thrombus), whereas streptokinase, urokinase, and anistreplase are not clot specific. t-PA has the shortest half-life and duration of effect (5 minutes and 2 hours, respectively), and anistreplase the longest (90 minutes and 18 hours, respectively).148,170 Streptokinase has the additional risk of severe allergic reaction on rechallenge, limiting its use to once in a lifetime. Newer thrombolytic drugs such a reteplase, and some non–commercially available agents, including monteplase, lanoteplase, pamiteplase, and desmoteplase, are being evaluated for therapeutic use.112 These fibrinolytics have a longer half-life and may be administered via single or repeated bolus injections. They also have increased fibrin selectivity, but no improvement in mortality is demonstrated when compared to t-PA.91 Although the incidence of bleeding requiring transfusion may be as high as 7.7% following high-dose (150 mg) t-PA and 4.4% following low-dose t-PA,45 the incidence of intracranial hemorrhage with t-PA appears to be similar to the newer agents (monteplase, tenecteplase, reteplase, and lanoteplase).185 The addition of heparin to the thrombolytic regimen increases the risk of bleeding. Reviews of multiple trials suggest that life-threatening events such as intracranial hemorrhage occur in 0.30% to 0.58% of patients receiving anistreplase, 0.42% to 0.73% of patients receiving alteplase, and 0.08% to 0.30% of patients receiving streptokinase.196 Regardless of the thrombolytic agent used the frequency of bleeding events is similar even with the newer agents, with the exception that lanoteplase may have a decreased incidence of significant bleeding.49 Supportive care is indicated for patients with minor bleeding complications; however, for patients with significant bleeding, fibrinogen and coagulation factor replacement with cryoprecipitate and FFP should be administered.159

■ SNAKE VENOMS A detailed discussion of snake envenomations is found in Chap. 121; only a few specific issues are discussed here. Snake venoms may be composed of a vast number of complex proteins and peptides that interact with components of the human hemostatic system. In general, their functions may be thought of as being procoagulant, anticoagulant, fibrinolytic, vessel wall interactive, platelet active, or as protein inactivators. Additionally, they may more specifically also be classified based on their specific biologic activity; some of the various mechanisms include individual factor activation, inhibition of protein C and thrombin, fibrinogen degradation, platelet aggregation, and inhibition of serine protease inhibitors (SERPINS). Currently, there are more than 100 different snake venoms that affect the hemostatic system87,88; Fig. 59–2 is an overview of their multiple interactions with the coagulation and fibrinolytic systems.119 Some of these venom proteins are being used as therapeutic agents for human diseases. Ancrod, a purified derivative of the Malayan pit viper, Calloselasma rhodostoma (formerly known as Agkistrodon rhodostoma), is therapeutically used because of its defibrinogenating property.13 The mechanism of action of ancrod and other similar agents is to link fibrinogen end to end and subsequently prevent cross-linking. It has been investigated in the treatment of deep vein thrombosis, myocardial infarction, pulmonary embolus, acute cerebrovascular thrombosis, HIT, and warfarin-related vascular complications. In a multicenter study of 500 patients with acute or

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progressing ischemic neurologic events, ancrod showed a favorable benefit-to-risk ratio compared with placebo.167 As expected, an increased risk of hemorrhage is observed; however, the risk appears to be less than that with thrombolytic agents.167 Monitoring of fibrinogen levels is essential to avoid potential complications, as no specific antidote exists. For envenomation of other snake venoms (such as from the Crotalinae family) that induce hemorrhage, antivenin treatment may be required.

■ PENTASACCHARIDES Pentasaccharides are recently developed synthetic anticoagulants that possess activity exclusively against factor Xa and are used for the prevention and treatment of venous thromboembolic disorders. Although other agents are currently being studied, fondaparinux is the only pentasaccharide currently available for clinical use.108 The pentasaccharides have long half-lives and have no reliable antidote if bleeding occurs; they do not bind to protamine.79 They are also contraindicated in patients with renal failure (CrCl less than 30 mL/min).79 No controlled trials are available yet, but rVIIa may be effective, as demonstrated in one study of healthy volunteers.19

■ ANTICOAGULANT APTAMERS Aptamer anticoagulants are small nucleic acid molecules that are currently under development to target specific blood coagulation proteins.137 They are direct protein inhibitors and function similarly to monoclonal antibodies.137 Specific aptamers that are currently being studied include the anti–factor IX aptamer, the anti–activated protein C aptamer, and the anti–factor VIIa aptamer.68 These xenobiotics may have clinical utility in the future as their anticoagulant effects appear to be easier to control, and consequently safer, compared with the anticoagulants currently most used.

SUMMARY The ever-increasing frequency of anticoagulant therapeutic use is associated with complications and adverse outcomes. A complete understanding of the normal mechanisms of coagulation, anticoagulation, and thrombolysis, combined with an understanding of the pharmacology of the agent and the patient’s clinical needs, will allow the clinician to better choose among the complex therapies currently available. Supportive care is often adequate for certain complications associated with these therapies; however, occasionally, more aggressive interventions and specific antidotes are necessary depending on the particular agent and medical condition of the patient.

ACKNOWLEDGMENTS Teresa Kierenia, MD (deceased), and Robert S. Hoffman contributed to this chapter in a previous edition.

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179. Suttie JW. Warfarin and vitamin K. Clin Cardiol. 1990;13:VI16-18. 180. Suttie JW, Jackson CM. Prothrombin structure, activation, and biosynthesis. Physiol Rev. 1977;57:1-70. 181. Swigar ME, Clemow LP, Saidi P, et al. “Superwarfarin” ingestion. A new problem in covert anticoagulant overdose. Gen Hosp Psychiatry. 1990;12: 309-312. 182. Travis SF, Warfield W, Greenbaum BH, et al. Spontaneous hemorrhage associated with accidental brodifacoum poisoning in a child. J Pediatr. 1993;122:982-984. 183. Udall JA. Don’t use the wrong vitamin K. Calif Med. 1970;112:65-67. 184. Vasse M. Protein Z, a protein seeking a pathology. Thromb Haemost. 2008;100:548-556. 185. Verstraete M. Third-generation thrombolytic drugs. Am J Med. 2000;109: 52-58. 186. Vigano S, Mannucci PM, Solinas S, et al. Decrease in protein C antigen and formation of an abnormal protein soon after starting oral anticoagulant therapy. Br J Haematol. 1984;57:213-220. 187. Von Visger J, Magee C. Low molecular weight heparins in renal failure. J Nephrol. 2003;16:914-916. 188. Wakefield TW, Andrews PC, Wrobleski SK, et al. Effective and less toxic reversal of low-molecular weight heparin anticoagulation by a designer variant of protamine. J Vasc Surg. 1995;21:839-849; discussion 849-850. 189. Wakefield TW, Andrews PC, Wrobleski SK, et al. A [+18RGD] protamine variant for nontoxic and effective reversal of conventional heparin and lowmolecular-weight heparin anticoagulation. J Surg Res. 1996;63:280-286. 190. Warkentin TE, Greinacher A, Koster A, et al. Treatment and prevention of heparin-induced thrombocytopenia. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:340S-380S. 191. Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med. 1995;332:1330-1335. 192. Watts RG, Castleberry RP, Sadowski JA. Accidental poisoning with a superwarfarin compound (brodifacoum) in a child. Pediatrics. 1990;86:883-887. 193. Wells PS, Forgie MA, Simms M, et al. The outpatient bleeding risk index: validation of a tool for predicting bleeding rates in patients treated for deep venous thrombosis and pulmonary embolism. Arch Intern Med. 2003;163:917-920. 194. Wentzien TH, O’Reilly RA, Kearns PJ. Prospective evaluation of anticoagulant reversal with oral vitamin K1 while continuing warfarin therapy unchanged. Chest. 1998;114:1546-1550. 195. Wessler S, Gitel SN. Warfarin. From bedside to bench. N Engl J Med. 1984;311:645-652. 196. White HD. Comparative safety of thrombolytic agents. Am J Cardiol. 1991;68:30E-37E. 197. White RH, McKittrick T, Takakuwa J, et al. Management and prognosis of life-threatening bleeding during warfarin therapy. National Consortium of Anticoagulation Clinics. Arch Intern Med. 1996;156:1197-1201. 198. Whitlon DS, Sadowski JA, Suttie JW. Mechanism of coumarin action: significance of vitamin K epoxide reductase inhibition. Biochemistry. 1978;17:1371-1377. 199. Wiernikowski JT, Chan A, Lo G. Reversal of anti-thrombin activity using protamine sulfate. Experience in a neonate with a 10-fold overdose of enoxaparin. Thromb Res. 2007;120:303-305. 200. Woody BJ, Murphy MJ, Ray AC, et al. Coagulopathic effects and therapy of brodifacoum toxicosis in dogs. J Vet Intern Med. 1992;6:23-28. 201. Yee AJ, Kuter DJ. Successful recovery after an overdose of argatroban. Ann Pharmacother. 2006;40:336-339. 202. Young MA, Ehrenpreis ED, Ehrenpreis M, et al. Heparin-associated thrombocytopenia and thrombosis syndrome in a rehabilitation patient. Arch Phys Med Rehabil. 1989;70:468-470. 203. Zubkov AY, Mandrekar JN, Claassen DO, et al. Predictors of outcome in warfarin-related intracerebral hemorrhage. Arch Neurol. 2008;65:1320-1325. 204. Zupancic-Salek S, Kovacevic-Metelko J, Radman I. Successful reversal of anticoagulant effect of superwarfarin poisoning with recombinant activated factor VII. Blood Coagul Fibrinolysis. 2005;16:239-244.

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876

A N T I D O T E S I N D E P T H ( A 16 ) VITAMIN K1 Mary Ann Howland

DAILY REQUIREMENT The human daily requirement for vitamin K is small; the Food and Nutrition Board set the recommended daily allowance at 1 μg/kg/d of phylloquinone for adults, although 10 times that amount is required for infants to maintain normal hemostasis.29 Extrahepatic enzymatic reactions that are vitamin K dependent relate to carboxylation of proteins in the bone, kidney, placenta, lung, pancreas, and spleen, and include the synthesis of osteocalcin, matrix Gla protein, plaque Gla protein, and one or more renal Gla proteins.29,30,34 Variations in an individual’s dietary vitamin K intake while receiving therapeutic oral anticoagulation can significantly result in either over- or under-anticoagulation.1,13

PHARMACOKINETICS OF DIETARY VITAMIN K Vitamin K1 (phytonadione) is the commercial preparation of the natural form of vitamin K (phylloquinone) that is indicated for the reversal of elevated prothrombin times (PTs) and international normalized ratios (INRs) in patients with xenobiotic-induced vitamin K deficiency. Acquired vitamin K deficiency is typically induced following the therapeutic administration of warfarin, or following the overdose of warfarin or the long-acting anticoagulant rodenticides (LAARs), such as brodifacoum. The optimal dosage regimen of vitamin K1 to treat patients who develop an elevated INR while receiving warfarin has been reviewed and a revised guideline regarding the dose and route of administration published.1,7 Oral administration of vitamin K1 is used safely and successfully. Because intravenous administration of vitamin K1 may be associated with anaphylactoid reactions, it should be avoided unless serious or life-threatening bleeding is present. Subcutaneous administration should only be considered when a patient is unable to tolerate oral vitamin K therapy yet is not clinically compromised enough to necessitate intravenous vitamin K1.7

HISTORY It was noted in 1929 that chickens fed a poor diet developed spontaneous bleeding. In 1935, Dam and coworkers discovered that incorporating a fat-soluble substance defined as a “koagulation factor,” into the diet could correct the bleeding. Hence the name vitamin K was developed.20,30,35

Dietary vitamin K in the forms of phylloquinone and menaquinones is solubilized in the presence of the bile salts, free fatty acids, and monoglycerides, which enhance absorption. Vitamin K is incorporated into chylomicrons, entering the circulation through the lymphatic system in transit to the liver.30 In the plasma, vitamin K is primarily in the phylloquinone form, whereas liver stores are 90% menaquinones and 10% phylloquinone.30 Within 3 days of a low vitamin K diet, a group of surgical patients showed a fourfold decrease of liver vitamin K concentrations.33 Rats given a vitamin K—deficient diet develop severe bleeding within 2 to 3 weeks.

PHARMACOLOGY Activation of coagulation factors II, VII, IX, and X, and proteins S and C and Z require γ-carboxylation of the glutamate residues in a vitamin K—dependent process. Only the reduced (K1H2, hydroquinone) form of vitamin K manifests biologic activity. During the carboxylation step, the active reduced vitamin K1 is converted to an epoxide. This 2,3-epoxide is reduced and recycled to the active K1H2 in a process that is inhibited by warfarin (Fig. 59-3). For further details, the reader is referred to an in-depth model of the chemical basis of this reaction.9,39 The phytonadione form of vitamin K can be activated to the reduced, vitamin K1H2 form directly by nicotinamide adenine dinucleotide (phosphate) (NAD(P)H)-dehydrogenase (DT-diaphorase)—dependent pathway that is relatively insensitive to warfarin, while the vitamin K 2,3-epoxide form cannot be activated through this pathway.30,34,35,36

CHEMISTRY

VITAMIN K DEFICIENCY AND MONITORING

Vitamin K is an essential fat-soluble vitamin encompassing at least two distinct natural forms. Vitamin K1 (phytonadione, phylloquinone) is the only form synthesized by plants and algae. Vitamin K2 (menaquinones) is actually a series of compounds with the same 2-methyl-1, 4-naphthoquinone ring structure as phylloquinone, but with a variable number (1-13) of repeating 5-carbon units on the side chain. Bacteria synthesize vitamin K2 (menaquinones). Most of the vitamin K ingested in the diet is phylloquinone (vitamin K1).

Vitamin K deficiency can result from inadequate intake, malabsorption, or interference with the vitamin K cycle. Malnourishment and any condition in which bile salts or fatty acids are inadequate, such as extrahepatic cholestasis or severe pancreatic insufficiency, can lead to vitamin K deficiency. Additionally, multifactorial etiologies place newborns at risk for hemorrhage. Phylloquinone does not readily cross the placenta, and breast milk contains less phylloquinone than vitamin K—fortified formula. Fetal hepatic stores of phylloquinone

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are low and therapy such as maternal anticonvulsant therapy may lead to increased vitamin K metabolism.30,34 Although menaquinones are produced in the colon by bacteria, it is unlikely that enteric production contributes significantly to vitamin K stores or that eradication of the bacteria with antibiotics, without a coexistent dietary deficiency of vitamin K, results in deficiency.30 Determination of vitamin K deficiency is usually established on the basis of a prolonged PT or INR, which are surrogate markers of specific coagulation factors. Measurement of the vitamin K—dependent factors, II, VII, IX, and X, appears to be an effective way to determine the adequacy of vitamin K1 dosing.16 Serial measurements of factor VII, the factor with the shortest halflife, allows for the early detection of inadequate vitamin K in the diet or a therapeutic regimen.6 Direct measurement of serum vitamin K concentrations is done by high-performance liquid chromatography (HPLC) analysis. The human serum vitamin K concentration required for adequate production of activated clotting factors in the presence of LAARs is still unclear. A single study in a patient who overdosed on brodifacoum suggested that a serum vitamin K concentration of 0.2 to 0.4 μg/mL was sufficient, to achieve a normal coagulation profile. Prior studies suggested 1.0 μg/mL was necessary in rabbits.6,25

MECHANISM OF ACTION FOR XENOBIOTIC-INDUCED VITAMIN K DEFICIENCY Oral anticoagulants are vitamin K antagonists that interfere with the vitamin K cycle, causing the accumulation of vitamin K 2,3-epoxide, an inactive metabolite. Warfarin is a strong irreversible inhibitor of the vitamin K 2,3 epoxide reductase, which regenerates vitamin K into its active (K1H2, hydroquinone) form.3 The superwarfarins are even more potent vitamin K reductase inhibitors. Without exogenous interference, vitamin K is recycled and only 1 μg/kg/d is required in adults to maintain adequate coagulation. NAD(P)H-dehydrogenases (DT-diaphorases) are warfarin-insensitive enzymes capable of reducing vitamin K1 to its active hydroquinone form, but it is incapable of regenerating vitamin K from vitamin K 2,3-epoxide following carboxylation of the coagulation factor (Fig. 59-3).3 Thus, in the presence of warfarin or superwarfarin, additional vitamin K1 must be administered to supply this active cofactor for each and every carboxylation step, as it can no longer be recycled.6 The minimum vitamin K1 requirement in the presence of a LAAR is unknown. Other compounds have varying degrees of vitamin K antagonistic activity and include the N-methylthiotetrazole side-chain-containing antibiotics such as moxalactam and cefamandole (Chap. 56), as well as salicylates (Chap. 35).30

AVAILABILITY OF DIFFERENT FORMS OF VITAMIN K Vitamin K1 (phytonadione) is the only vitamin K preparation that should be used to reverse anticoagulant-induced vitamin K deficiency or to treat infants or pregnant women. In addition, patients with glucose-6phosphate dehydrogenase (G6PD) deficiency have an increased risk of hemolysis with other vitamin K preparations. Vitamin K1 is superior to the other previously commercially available vitamin K preparations because it is more active, thus requiring comparatively smaller doses, because it works more rapidly (6 vs. 12 hours), and because it has fewer associated risks.14,32 Vitamins K3 (menadione) and K4 (menadiol sodium diphosphate) (no longer FDA approved in the US) can produce hemolysis, hyperbilirubinemia, and kernicterus in neonates, and hemolysis in

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877

G6PD-deficient patients. The only advantage that menadione and menadiol sodium diphosphate have is that these preparations are absorbed directly from the intestine by a passive process that does not require the presence of bile salts. Theoretically, they are advantageous for patients with cholestasis or severe pancreatic insufficiency. However, they are neither interchangeable with vitamin K1, nor a substitute for vitamin K1, when anticoagulants such as warfarin or LAAR are responsible for coagulation deficits. Therefore, for a patient deficient in bile salts who requires vitamin K1, exogenous bile salts, such as ox bile extract 300 mg or dehydrocholic acid 500 mg, should be given with each dose of oral vitamin K1.26

PHARMACOKINETICS AND PHARMACODYNAMICS OF ADMINISTERED VITAMIN K1 There are only a limited number of pharmacokinetic studies of vitamin K1.6,15,25,40 One study evaluated the pharmacokinetics of vitamin K1 in healthy volunteers, brodifacoum-anticoagulated rabbits, and a patient poisoned with brodifacoum.25 In the volunteers and the poisoned patient, a 10-mg intravenous (IV) dose of vitamin K1 had a half-life of 1.7 hours. After oral administration of doses of 10 and 50 mg of vitamin K1, peak concentrations of 100 to 400 ng/mL and 200 to 2000 ng/mL, respectively, occurred at 3 to 5 hours. Bioavailability varied significantly between patients (10% to 65%) for both doses, and in individual patients with the 50-mg dose. Oral vitamin K1 is absorbed in an energy-dependent saturable process in the proximal small intestine, and this likely contributes to the variability.25 In maximally brodifacoum-anticoagulated rabbits, IV vitamin K1 (10 mg/kg) increased prothrombin complex activity (PCA) from 14% to 50% by 4 hours, and to 100% by 9 hours, after which it declined with a half-life of 6 hours.25 High doses of oral vitamin K1 were effectively used to treat a patient anticoagulated with brodifacoum.6 The pharmacokinetics of oral and intramuscular (IM) vitamin K1 were compared in eight healthy female volunteers. Baseline serum vitamin K concentrations were 0.23 ng/mL. Following the oral administration of 5 mg of vitamin K, peak serum concentrations of 90 ng/mL were achieved between 4 and 6 hours. These concentrations dropped to a steady state of 3.8 ng/mL, and exhibited a half-life of about 4 hours. The pharmacokinetics were distinctly different and quite variable after IM administration. IM administration of 5 mg of vitamin K resulted in peak serum concentrations of only 50 ng/mL with delays from 2 to 30 hours following administration and with the maintenance of a plateau for about 30 hours.15 Consequently, IM administration is not recommended; either oral or IV is more appropriate and the route will be defined by the severity of bleeding. Only in the case of acute gastrointestinal disease in a patient without life-threatening overanticoagulation is the subcutaneous route an appropriate alternative to the oral route (see Table 59-3).

ROUTES OF ADMINISTRATION AND ADVERSE EFFECTS Although vitamin K1 can be administered orally, subcutaneously, intramuscularly, or intravenously, the oral route is preferred for maintenance therapy. When administered orally, vitamin K1 is virtually free of adverse effects, except for overcorrection of the INR for a patient who requires maintenance anticoagulation. The preparations available for IV administration are rarely associated with anaphylactoid reactions. Because of the lipid solubility of vitamin K these preparations are not available in solution, but rather as an aqueous colloidal

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Part C

The Clinical Basis of Medical Toxicology

suspension of a polyoxyethylated fatty acid derivative, dextrose, and benzyl alcohol. IV administration has resulted in death secondary to anaphylactoid reactions, probably as a result of the colloidal formulation of the preparation.4,8,21 Numerous anaphylactoid reactions are reported, even when the preparation is properly diluted and administered slowly.12,24,38 Rarely non-IV routes of administration may also result in an anaphylactoid reaction.12 New liposomal preparations are under development, which may become safer alternatives.

ONSET OF EFFECT The time necessary for the INR to return to a safe or normal range is variable and dependent on the rate of absorption of vitamin K1, the serum concentration achieved, and the time necessary for the synthesis of activated clotting factors. A decrease in the INR can often occur within several hours, although it may take 8 to 24 hours to reach target values.5,11,22,27 Maintenance of a normal INR depends on the half-life of the vitamin K1, maintenance of an effective serum concentration, and the half-life of the anticoagulant involved. The IV route is unpredictably faster than the oral route in restoring the INR to a safe range.15,19 A comparison of oral versus IV vitamin K1 therapy for excessive anticoagulation, without major bleeding, demonstrated that individuals with INRs of 6 to 10 had similarly improved INRs at 24 hours and that the IV group was more often overcorrected to an INR of less than two.19

DOSING AND ADMINISTRATION The optimal dosage regimen for vitamin K1 remains unclear. Variables include the vitamin K1 pharmacokinetics and the amount and type of anticoagulant ingested.28 Reported cases of LAAR poisoning have required as much as 50 to 250 mg of vitamin K1 daily for weeks to months.2,6,10,17,18,31,37 A reasonable starting approach for a patient who has overdosed on LAAR is 25 to 50 mg of vitamin K1 orally three to four times a day for 1 to 2 days. The INR should be monitored and the vitamin K1 dose adjusted accordingly. Once the INR is less than 2, a downward titration in the dose of vitamin K1 can be made on the basis of factor VII analysis. For an ingestion of brodifacoum, serial serum concentrations of brodifacoum may be helpful in determining the ultimate duration of treatment.6,23 The management of patients with elevated INRs secondary to excessive warfarin is described in Table 59-3. IV administration of vitamin K1 should be reserved for life-threatening bleeding and serious bleeding at any elevation of INR.1 Under these circumstances, patients may be supplemented with prothrombin complex concentrate, fresh-frozen plasma (FFP), or recombinant factor VIIa based on a risk to benefit analysis. A starting dose of 10 mg of vitamin K1 is recommended. To minimize the risk of an anaphylactoid reaction, the preparation should be diluted with preservative-free 5% dextrose, 0.9% sodium chloride, or 5% dextrose in 0.9% sodium chloride, and administered slowly, at a rate not to exceed 1 mg/min in adults. Precautions should be anticipated in the event of an anaphylactoid reaction. Because the duration of action of vitamin K1 is short-lived, the dose must be repeated two to four times daily. The onset of the effect of vitamin K1 is not immediate, regardless of the route of administration.

AVAILABILITY Vitmain K1 is available for IV and subcutaneous administration as AquaMEPHYTON and phytonadione injection emulsion in 2 mg/mL and 10 mg/mL concentrations. The preparation should be diluted with preservative-free 5% dextrose, 0.9% sodium chloride, or 5% dextrose in

0.9% sodium chloride, and administered slowly, at a rate not to exceed 1 mg/min in adults to minimize the risk of an anaphylactoid reaction. These preparations contain benzyl alcohol (0.9%) as a preservative. Oral vitamin K1 is available as Mephyton in 5 mg tablets.

SUMMARY Vitamin K1 (phytonadione) is indicated for the reversal of elevated prothrombin times (PTs) and international normalized ratios (INRs) in patients with xenobiotic-induced vitamin K deficiency. IV administration is reserved for patients with serious or life-threatening bleeding. Vitamin K1 is administered with other therapies such as prothrombin complex, recombinant factor VIIa, and FFP that have rapid onsets of action. The onset of action of vitamin K1 is delayed for several hours regardless of the route of administration. The parenteral route of administration is rarely associated with consequential adverse events.

REFERENCES 1. Ansell J, Hirsh J, Hylek E, et al. The pharmacology and management of the vitamin K antagonists. The eighth ACCP conference on antithrombotic and thrombolytic therapy. Chest. 2008;133:160S-198S. 2. Babcock J, Hartman K, Pedersen A, Murphy M, Alving B. Rodenticide induced coagulopathy in a young child. Am J Pediatr Hematol Oncol. 1993;15: 126-130. 3. Baglin T. Management of warfarin (Coumadin) overdose. Blood Rev. 1998;12: 91-98. 4. Barash P, Kitahata LM, Mandel S. Acute cardiovascular collapse after intravenous phytonadione. Anesth Analg. 1976;55:304-306. 5. Brophy M, Fiore L, Deykin D. Low-dose vitamin K therapy in excessively anticoagulated patients: a dose finding study. J Thromb Thrombolysis. 1997;4: 289-292. 6. Bruno GR, Howland MA, McMeeking A, Hoffman RS. Long-acting anticoagulant overdose: brodifacoum kinetics and optimal vitamin K1 dosing. Ann Emerg Med. 2000;36:262-267. 7. Crowther MA, Douketis JD, Schnurr T, et al. Oral vitamin K reversed warfarin-associated coagulopathy faster than subcutaneous vitamin K. Ann Intern Med. 2002;137:251-254. 8. De la Rubia J, Grau E, Montserrat I, Zuazu I, Payá A. Anaphylactic shock and vitamin K1. Ann Intern Med. 1989;110:943. 9. Dowd P, Ham SW, Naganathan S, Hershline R. The mechanism of action of Vitamin K. Annu Rev Nutr. 1995;15:419-440. 10. Exner DV, Brien WF, Murphy MJ. Superwarfarin ingestion. CMAJ. 1992;146: 34-35. 11. Fetrow CW, Overlock T, Leff L. Antagonism of warfarin induced hypoprothrombinemia with use of low-dose subcutaneous vitamin K1. J Clin Pharmacol. 1997;37:751-757. 12. Fiore L, Scola M, Cantillon C. Anaphylactoid reactions to Vitamin K. J Thromb Thrombolysis. 2001;11:175-183. 13. Franco V, Polanczyk CA, Clausell N, Rohde LE. Role of dietary vitamin K intake in chronic oral anticoagulation: prospective evidence from observational and randomized protocols. Am J Med. 2004;116:651-656. 14. Gamble JR, Dennis EW, Coon WW, et al. Clinical comparison of vitamin K1 and water-soluble vitamin K. Arch Intern Med. 1955;5:52-58. 15. Hagstrom JN, Bovill EG, Soll R, Davidson KW, Sadowksi JA. The pharmacokinetics and lipoprotein fraction distribution of intramuscular versus oral vitamin K1 supplementation in women of childbearing age: effects on hemostasis. Thromb Haemost. 1995;74:1486-1490. 16. Hoffman R, Smilkstein M, Goldfrank L. Evaluation of coagulation factor abnormalities in long-acting anticoagulant overdose. J Toxicol Clin Toxicol. 1998;26:233-248. 17. Hollinger B, Pastoor T. Case management and plasma half-life in a case of brodifacoum poisoning. Arch Intern Med. 1993;153:1925-1928. 18. La Rosa F, Clarke S, Lefkowitz J. Brodifacoum intoxication with marijuana smoking. Arch Pathol Lab Med. 1997;121:67-69. 19. Lubetsky A, Yonath H, Olchovsky D, et al. Comparison of oral vs intravenous phytonadione (vitamin K1) in patients with excessive anticoagulation: a prospective randomized controlled study. Arch Intern Med. 2003;163:2469-2473.

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20. Majerus P, Tollefsen D. Blood coagulation and anticoagulant, thrombolytic, and antiplatelet drugs. In: Brunton L, Lazo J, Parker K eds. Goodman and Gilman’s the Pharmacological Basis of Therapeutics, 11th ed. New York: McGraw-Hill; 2006:1467-1488. 21. Mattea E, Quinn K. Adverse reactions after intravenous phytonadione administration. Hosp Pharm. 1981;16:230-235. 22. Nee R, Doppenschmidt, Donovan D, Andrews T. Intravenous versus subcutaneous vitamin K1 in reversing excessive oral anticoagulation. Am J Cardiol. 1999;83:286-288. 23. Olmos V, Lopez C. Brodifacoum poisoning with toxicokinetic data. Clin Tox. 2007;45:487-489. 24. O’Reilly R, Kearns P. Intravenous vitamin K1 injections: dangerous prophylaxis. Arch Intern Med. 1995;155:2127-2128. 25. Park BK, Scott AK, Wilson AC, et al. Plasma disposition of vitamin K1 in relation to anticoagulant poisoning. Br J Clin Pharmacol. 1984;18: 655-662. 26. Phytonadione. In: GK McEvoy, ed. AHFS Drug Information. Bethesda, MD: American Society of Health System Pharmacists; 2004:3525-3527. 27. Raj G, Kumar R, Mckinney P. Time course of reversal of anticoagulant effect of warfarin by intravenous and subcutaneous phytonadione. Arch Intern Med. 1999;159:2721-2724. 28. Routh CR, Triplett DA, Murphy MJ, et al. Superwarfarin ingestion and detection. Am J Hematol. 1991;36:50-54.

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29. Shearer MJ. Vitamin K. Lancet. 1995;345:229-233. 30. Shearer MJ. Vitamin K metabolism and nutrition. Blood Rev. 1992;6:92-104. 31. Sheen S, Spiller H. Symptomatic brodifacoum ingestion requiring highdose phytonadione therapy. Vet Hum Toxicol. 1994;36:216-217. 32. Udall JA. Don’t use the wrong vitamin K. West J Med. 1970;112:65-67. 33. Usuri Y, Taminura M, Nishimura N, et al. Vitamin K concentrations in the plasma and liver of surgical patients. Am J Clin Nutr. 1990;51:846-852. 34. Vermeer C, Hamulyak K. Pathophysiology of vitamin K deficiency and oral anticoagulants. Thromb Haemost. 1991;66:153-159. 35. Vermeer C, Schurgers L. A comprehensive review of vitamin K and vitamin K antagonists. Hem Onc Clin N Am. 2000;15:339-353. 36. Wallin R, Hutson S. Warfarin and the vitamin K dependent γ -carboxylation system. Trends Molec Med. 2004;10:299-302. 37. Weitzel J, Sadowski J, Furie BC, et al. Surreptitious ingestion of a longacting vitamin K antagonist/rodenticide, brodifacoum: clinical and metabolic studies of three cases. Blood. 1990;76:2555-2559. 38. Wjasow C, McNamara R. Anaphylaxis after low dose intravenous vitamin K. J Emerg Med. 2003;24:169-172. 39. Wilson CR, Sauer J, Carlson GP, et al. Species comparison of vitamin K1 2,3-epoxide reductase activity in vitro: kinetics and warfarin inhibition. Toxicology. 2003;189:191-198. 40. Winn MJ, Cholerton S, Park BK. An investigation of the pharmacological response to vitamin K1 in the rabbit. Br J Pharmacol. 1988;94:1077-1084.

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A N T I D O T E S I N D E P T H ( A 17 ) PROTAMINE Mary Ann Howland Protamine is a rapidly acting antidote that is used primarily to reverse the anticoagulant effects of unfractionated heparin (UFH). It also can partially reverse the effects of low-molecular-weight heparin (LMWH).

HISTORY The antidotal property of protamine was recognized in the late 1930s, leading to its approval as an antidote for heparin overdose in 1968.57 However, the largest body of literature pertaining to protamine originates from its use in neutralizing heparin following cardiopulmonary bypass and dialysis procedures.

PHARMACOLOGY The protamines are a group of simple basic cationic proteins found in fish sperm that bind to heparin to form a stable neutral salt, rapidly inactivating heparin and reversing its anticoagulant effect.62 Commercially available protamine sulfate is derived from the sperm of mature testes of salmon and related species. On hydrolysis, it yields basic amino acids, particularly arginine, proline, serine, and valine, but not tyrosine and tryptophan. The effects of protamine sulfate and protamine chloride appear to be comparable.43 The molecular weight of heparins ranges from 3000 to 30,000 daltons and is composed of approximately 45 monosaccharide chains. One milligram of protamine will neutralize approximately 100 U (1 mg) of standard UFH (mean molecular weight [MW]~12,000 daltons). In contrast to the case of heparin there is no proven method for neutralizing LMWH. Protamine neutralizes the anti-IIa activity of LMWH and a variable portion of the anti-Xa activity of LMWH.28 Because the interaction of protamine and heparin is dependent on the MW of heparin, LMWH (mean MW 4500 daltons) has reduced protamine binding. The protamine-resistant fraction in LMWH is an ultralow-molecularweight fraction with low sulfide charge.15 It is suggested that 1 mg of enoxaparin equals approximately 100 antifactor-Xa units. To reverse the antithrombotic effects of LMWH within the first 8 hours following administration, the recommendation is to administer 1 mg protamine per 100 antifactor-Xa units of LMWH followed by administration of a second dose of 0.5 mg protamine per 100 anti factor-Xa units if bleeding continues.28 No human studies offer convincing evidence either demonstrating or disputing a beneficial effect of protamine as treatment for hemorrhage following LMWH use.28 Case studies demonstrating both failure and success exist.10,50,52,80 In animal studies, synthetic protamine variants were effective in reversing the anticoagulant effects of LMWH and are reported to be less toxic than protamine. These xenobiotics are not available for clinical use.5,28,33,71,72

■ MECHANISM OF ACTION Heparins are large electronegative xenobiotics that are rapidly complexed by the electropositive protamine, forming an inactive salt. Heparin is an indirect anticoagulant, requiring a cofactor. This cofactor, AT, was formerly called antithrombin III.28 Heparin alters the stereochemistry of AT, thereby catalyzing the subsequent inactivation of thrombin and other clotting factors.24 Only about one-third of an administered dose of unfractionated heparin binds to AT, and this fraction is responsible for most of its anticoagulant effect.3,45 LMWH has a reduced ability to inactivate thrombin as a result of lesser AT binding, but the smaller fragments of LMWH inactivate factor Xa almost as well as the larger molecules of UFH, allowing for equal efficacy.28 Immunoelectrophoretic studies demonstrate that because of the net positive charge of protamine it has a greater affinity for heparin than AT, producing a dissociation of the heparin–AT complex in favor of a protamine–heparin complex.59

ADVERSE EFFECTS, RISK FACTORS, AND SAFETY ISSUES Protamine is routinely used in the neutralization of heparin at the completion of cardiopulmonary bypass surgery. Millions of patients are exposed to protamine each year and approximately 100 deaths are reported in total with the use of protamine under these circumstances. It is largely in this setting that the adverse effects of protamine are also documented and studied.30,31,49,58 It is often difficult to separate the adverse effects caused by protamine from those of the protamine– heparin complex or those actually related to heparin. Adverse effects associated with protamine include both rate- and non–rate-related hypotension,12,18-21,23,35,38,65,68 anaphylaxsis34,48 and anaphylactoid reactions,37,53,55 bradycardia,1 thrombocytopenia,76 thrombogenicity,14 leukopenia, decreased oxygen consumption,73,75 acute lung injury,4,70 pulmonary hypertension and pulmonary vasoconstriction,7,27 cardiovascular collapse,46,63 and anticoagulant effects.2 The mechanisms for these adverse effects are multifactorial. The significant electropositivity of protamine may be responsible for some of the adverse effects and probably directly injures a variety of organelles, including platelets.9,77 The protamine–heparin complex activates the arachidonic acid pathway and the production of thromboxane is at least partly responsible for some of the hemodynamic changes, including pulmonary hypertension.7,13,29,54,77 Pretreatment with indomethacin limits these effects.13,29,54,77 Free protamine or protamine complexed with heparin can convert L-arginine to nitric oxide (formerly called endothelium-derived relaxing factor), which in turn causes vasodilation and inhibits platelet aggregation and adhesion.60 Protamine administered in the absence of heparin, or in an amount exceeding that necessary for heparin neutralization, can act as an anticoagulant and may inhibit platelet function, resulting in weaker clot formation.36,73 This anticoagulant effect may result from effects on factor VII and/ or AT. Protamine in excess of heparin can enter the myocardium and decrease cyclic adenosine monophosphate (cAMP), causing myocardial depression.7,67 Protamine and protamine–heparin complexes can activate the complement pathway and contribute to vasoactive

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events.7,61 Protamine stimulates mast cells in the human heart and skin to release histamine.7 Risk factors for protamine-induced adverse reactions include prior exposure to protamine in insulin or during previous surgery with protamine reversal or a previous vasectomy, as well as an allergy to fish or a rapid rate of protamine infusion.46,61 A prospective study reported a 0.06% incidence of anaphylactic reactions to protamine in all patients undergoing coronary artery bypass, but a 2% incidence in diabetics using neutral protamine Hagedorn (NPH) insulin.6 A recent systematic review of the literature revealed an incidence of 1% but expressed caution in interpreting the results because of the heterogeneity of the studies.58 The resultant elevation of histamine concentrations, the activation of complement, and elevated IgE, IgA, and IgG concentrations are also suggested as possible mechanisms for the adverse effects.44,69,78,79 Diabetic patients receiving daily subcutaneous injections of a protamine-containing insulin (NPH) have a 40% to 50% increased risk of immune-mediated adverse reactions.22,25,34,42,68 Occasionally, patients manifesting a protamine allergy are incorrectly presumed to have insulin allergy.41 In diabetic patients receiving protamine insulin injections, the presence of serum antiprotamine IgE antibody is a significant risk factor for acute protamine reactions. Only patients with previous exposure to protamine insulin injections had serum antiprotamine IgE antibodies. However, in the group without previous protamine insulin exposure, antiprotamine IgG antibody was noted as a risk factor for protamine reactions.79 Either naturally occurring cross-reacting antibodies, or perhaps previously unrecognized protamine exposure, was responsible for the generation of these IgG antibodies.

ALTERNATIVES TO PROTAMINE FOR PATIENTS AT HIGH RISK FOR AN ADVERSE DRUG REACTION There are limited options to replace protamine for the reversal of heparin in patients who have previously experienced anaphylaxis following protamine therapy, or in patients who are suspected of being at high risk. Clotting factors may be replaced, or exchange transfusion instituted in neonates, and protamine avoided, or protamine may be used while being prepared to treat anaphylaxis expectantly. Several alternatives under investigation include the placement of heparin removal devices in the coronary artery bypass extracorporeal circuit, as well as the use of hexadimethrine, methylene blue, platelet factor 4, and heparinase as antidotes.6,40 Pretreatment with antihistamines and corticosteroids may be sufficient for immune-mediated mechanisms, but will probably not be beneficial for pulmonary vasoconstriction and non–immune-mediated anaphylactoid reactions.32

DOSING IN CARDIOPULMONARY BYPASS Protamine is most frequently used at the conclusion of cardiopulmonary bypass operations to reverse the effects of heparin. There are many regimens used for protamine dosing, including (1) administration of an arbitrary amount of protamine (eg, greater than 2 mg/kg); (2) administration of protamine in a ratio of 0.6 to 1.5:1 times the initial heparin dose that results in an activated coagulation time (ACT) of about 480 seconds; and (3) giving protamine in a ratio of 0.75 to 2:1 times the total operative heparin dose.81 Two additional methods of calculating the protamine dose to improve accuracy and avoid excess protamine have been proposed.36,81 One advocates an initial protamine dose based on ACT, with subsequent doses based on the ratio of the change in thrombin time to the heparin-neutralized thrombin time. If this ratio is greater than 12 seconds, then 10-mg incremental

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protamine doses should be administered.36 The other uses a nomogram based on heparin activity in milligrams per kilograms versus ACT.81 Both methods demonstrate efficacy with 2 mg/kg doses of protamine, about one-half of the dose previously used. With these approaches, the ACT responded to protamine within 5 minutes, decreasing in value from between 550 and 700 seconds to a control of 150 seconds. Other investigators suggest a variety of monitoring methods and dosing schemas in this setting.16,26,47,66

HEPARIN REBOUND AND REDOSING OF PROTAMINE A heparin anticoagulant rebound effect is noted after cardiopulmonary bypass and is attributed to the presence of detectable circulating heparin several hours after apparently adequate heparin neutralization with protamine. The incidence of heparin rebound and the need for additional protamine range from 4% to 42% depending on the neutralization protocol.24,51,64 It is likely that larger heparin doses may prolong the clearance of heparin, contributing to higher than expected heparin concentrations.64 When 300 Units/kg of body weight doses of heparin were reversed with 3 mg/kg of protamine at the conclusion of cardiopulmonary bypass a 14% incidence of small but detectable concentrations of circulating heparin was noted at 2 hours, which lasted less than 1 hour in all but one case.51 A prolonged prothrombin time and thrombocytopenia occurred without increase in hemorrhage.

DOSING CONSIDERATIONS Approximately 1 mg of protamine will neutralize about 100 Units (1 mg) of heparin (UFH). A limited number of studies suggest incomplete neutralization by protamine of the LMWHs enoxaparin, dalteparin, and tinzaparin. Current recommendations are to administer 1 mg protamine per 100 anti–factor Xa units, where 1 mg enoxaparin equals 100 anti–factor Xa units if administered within 8 hours of the LMWH.28 A second dose of 0.5 mg protamine should be administered per 100 anti–factor Xa units if bleeding continues.17,28 If more than 8 hours have elapsed, then a smaller dose of protamine can be administered. A number of tests directly measure heparin concentrations or indirectly measure the effect of heparin on the clotting cascade.8,11,16 These tests may be helpful in determining the appropriate dose of protamine. Because excessive protamine can act as an anticoagulant, the dose chosen should always be an underestimation of that which is needed. In the case of unintentional overdose, the half-life of heparin should be considered, because half of the administered dose of heparin is eliminated within 60 to 90 minutes. In the case of an unintentional overdose without hemorrhage, the short half-life of heparin and the potential risks of protamine administration limit the need for and benefit from protamine reversal of anticoagulation. If protamine use is necessary to treat active hemorrhage, the dose must be administered very slowly intravenously either undiluted or diluted in D5W or 0.9% NaCl over 10 to 15 minutes to limit rate-related hypotension.39,62,74

DOSING IN THE OVERDOSE SETTING When a patient is believed to have received an overdose of an unknown quantity of heparin, the decision to use protamine should be determined by the presence of a prolonged activated partial thromboplastin time (aPTT) and the presence of persistent hemorrhage. The risks of protamine use, especially in those who have had a prior life-threatening reaction to protamine as well as in a diabetic receiving protamine-containing insulin,

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Part C

The Clinical Basis of Medical Toxicology

and the risks of continued heparin anticoagulation must be evaluated. A baseline ACT, thrombin time, heparin-neutralized thrombin time, heparin activity, platelets, prothrombin time, partial thromboplastin time, hemoglobin, and hematocrit should be obtained. Because of the routine nature of heparin reversal following cardiopulmonary bypass, consultation with members of the bypass team may be helpful. An empiric dose of protamine may be suggested by the baseline ACT: (1) an ACT of 150 seconds necessitates no protamine; (2) an ACT of 200 to 300 seconds necessitates 0.6 mg/kg; and (3) an ACT of 300 to 400 seconds necessitates 1.2 mg/kg. These doses have not been tested outside the operating room. The ACT should be repeated 5 to 15 minutes following the protamine dose and in 2 to 8 hours to evaluate the potential for heparin rebound. Further dosing should be based on these values. When the ACT is not available, 25 to 50 mg of protamine can be administered to an adult and adjusted accordingly. The initial dose should not be more than 50 mg in an adult.62 Repeat dosing in several hours may be necessary if heparin rebound occurs. The dose should be administered slowly intravenously over 15 minutes with resuscitative equipment immediately available. Neonates should not receive protamine that has been diluted with bacteriostatic water containing benzyl alcohol. Future interventions for bleeding following heparin may include activated factor VII. Activated factor VII therapy was recently shown to be successful in treating postoperative bleeding in a patient with renal failure who was given LMWH and aspirin.56 Adenosine triphosphate, an experimental nucleotide, completely reversed clinical bleeding related to LMWH in a rat model.17 Other substances or devices include hexadimethrine, heparinase, PF4, synthetic protamine variants, and extracorporeal heparin-removal devices.24 These xenobiotics have not been approved by the Food and Drug Administration (FDA) for clinical use in this setting.17,28

AVAILABILITY Protamine is available as a parenteral solution ready for injection in a concentration of 10 mg/mL in either a 5-mL or 25-mL vial containing totals of 50 mg and 250 mg, respectively.62

SUMMARY Protamine is an effective, rapidly acting antidote used to reverse the anticoagulant effect of unfractionated heparin, while its ability to reverse the effects of LMWH is less clear. This antidote should only be used for a prolonged aPTT in the presence of persistent hemorrhage, since potential risks of its use include hypotension, anaphylaxis, dysrhythmias, leukopenia, thrombocytopenia, and acute lung injury.

REFERENCES 1. Alvarez J, Alvarez L, Escudero C, Olivares JLC. Sinus node function and protamine sulfate. J Cardiothorac Anesth. 1989;3:44-51. 2. Andersen MN, Mendelow M, Alfano GA. Experimental studies of heparinprotamine activity with special reference to protamine inhibition of clotting. Surgery. 1959;46:1060-1068. 3. Andersson LO, Barrowcliffe TW, Holmer E, et al. Anticoagulant properties of heparin fractionated by affinity chromatography on matrix-bound antithrombin III and by gel filtration. Thromb Res. 1976;6:575-583. 4. Brooks JC. Noncardiogenic pulmonary edema immediately following rapid protamine administration. Ann Pharmacother. 1999;33:927-930. 5 Byun Y, Singh VK, Yang VC. Low molecular weight protamine: a potential nontoxic heparin antagonist. Thromb Res. 1999;94:53-61. 6. Carr JA, Silverman N. The heparin-protamine interaction. A review. J Cardiovasc Surg (Torino). 1999;40:659-666.

7. Carr ME, Carr, SL. At high heparin concentrations, protamine concentrations which reverse heparin anticoagulant effects are insufficient to reverse heparin antiplatelet effects. Thromb Res. 1994;75:617-630. 8. Castellani WJ, Hodges ED, Bode AP. Effect of protamine sulfate on the ACA heparin assay. Clin Chem. 1991;37:1119-1120. 9. Chang SW, Westcott JY, Henson JE, Voelkel NF. Pulmonary vascular injury by polycations in perfused rat lungs. J Appl Physiol. 1987;62:1932-1943. 10. Chawla L, Moore G, Seneff M. Incomplete reversal of enoxaparin toxicity by protamine: implications of renal insufficiency, obesity and low molecular weight heparin sulfate content. Obesity Surgery. 2004;14:695-698. 11. Chen W, Yang V. Versatile non-clotting based heparin assay requiring no instrumentation. Clin Chem. 1991;37:832-837. 12 Chilukuri K, Henrikson C, Dalal D, et al. Incidence and outcomes of protamine reactions in patients undergoing catheter ablation of atrial fibrillation. J Interv Card Electrophysiol. 2009;25:175-181. 13. Conzen PF, Habazettl H, Gutmann R, et al. Thromboxane mediation of pulmonary hemodynamic responses after neutralization of heparin by protamine in pigs. Anesth Analg. 1989;68:25-31. 14. Cosgrove J, Qasim A, Latib A, et al. Protamine usage following implantation of drug-eluting stents: a word of caution. Cath Cardiovas Interv. 2008; 71:913-914. 15. Crowther MA, Berry LR, Monagle PT, Chan AKC. Mechanisms reponsible for the failure of protamine to inactivate low-molecular-weight heparin. Br J Haematol. 2002;116:178-186. 16. Despotis GJ, Gravlee G, Filos K, Levy J. Anticoagulation monitoring during cardiac surgery: a review of current and emerging techniques. Anesthesiology. 1999;91:1122-1151. 17. Dietrich CP, Shinjo SK, Moraes FA, et al. Structural features and bleeding activity of commercial low-molecular-weight heparins: neutralization by ATP and protamine. Semin Thromb Hemost. 1999;3:43-50. 18. Fadali MA, Ledbetter M, Papacostas CA, et al. Mechanism responsible for the cardiovascular depressant effect of protamine sulfate. Ann Surg. 1974;180:232-235. 19. Fadali MA, Papacostas CA, Duke JJ, et al. Cardiovascular depressant effect of protamine sulfate. Thorax. 1976;31:320-323. 20. Frater RMW, Oka Y, Hong Y, et al. Protamine-induced circulatory changes. J Thorac Cardiovasc Surg. 1984;87:687-692. 21. Goldman BS, Joison J, Austen WG. Cardiovascular effects of protamine sulfate. Ann Thorac Cardiovasc Surg. 1969;7:459-471. 22. Gottschlich GM, Gravlee GP, Georgitis JW. Adverse reactions to protamine sulfate during cardiac surgery in diabetic and nondiabetic patients. Ann Allergy. 1988;61:277-281. 23. Gourin A, Streisand RL, Greineder JK, Stuckey JH. Protamine sulfate administration and the cardiovascular system. J Thorac Cardiovasc Surg. 1971;62:193-204. 24. Gundry SR, Drongowski RA, Klein MD, et al. Postoperative bleeding in cardiovascular surgery: does heparin rebound really exist? Am Surg. 1989;55:162-165. 25. Gupta SK, Veith FJ, Wengerter KR, et al. Anaphylactoid reactions to protamine: an often lethal complication in insulin-dependent diabetic patients undergoing vascular surgery. J Vasc Surg. 1989;9:342-350. 26. Hall RI. Protamine dosing—the quandary continues. Can J Anaesth. 1998; 45:1-5. 27. Hiong Y, Tang Y, Chui W, et al. A case of catastrophic pulmonary vasoconstriction after protamine administration in cardiac surgery: role of intraoperative transesophageal echocardiography. J Cardiothoracic and Vascular Anesth. 2008;22:727-731. 28. Hirsh J, Bauer K, Donati M, et al. Parenteral anticoagulants. The Eighth ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2008;133:141S-198S. 29. Hobbhahn J, Conzen PF, Zenker B, et al. Beneficial effect of cyclooxygenase inhibition on adverse hemodynamic responses after protamine. Anesth Analg. 1988;67:253-260. 30. Holland CL, Singh AK, McMaster PRB, Fang W. Adverse reactions to protamine sulfate following cardiac surgery. Clin Cardiol. 1984;7:157-162. 31. Horrow JC. Protamine: a review of its toxicity. Anesth Analg. 1985;64:348-361. 32. Hughes C, Haddock M. Protamine reaction in a patient undergoing coronary artery bypass grafting. CRNA. 1995;6:172-176. 33. Hulin MS, Wakefield TW, Andrews PC, et al. Comparison of the hemodynamic and hematologic toxicity of a protamine variant after reversal of lowmolecular-weight heparin anticoagulation in a canine model. Lab Anim Sci. 1997;47:153-160.

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34. Jackson DR. Sustained hypotension secondary to protamine sulfate. Angiology. 1970;21:295-298. 35. Jastrebski MK, Sykes MK, Woods DG. Cardiorespiratory effects of protamine after cardiopulmonary bypass in man. Thorax. 1974;20:534-538. 36. Jobes DR, Aitken GL, Shaffer GW. Increased accuracy and precision of heparin and protamine dosing reduces blood loss and transfusion in patients undergoing primary cardiac operations. J Thorac Cardiovasc Surg. 1995;110:36-45. 37. Kambam JR, Merrill WH, Smith BE. Histamine2 receptor blocker in the treatment of protamine-related anaphylactoid reactions: two case reports. Can J Anaesth. 1989;36:463-465. 38. Katz NM, Kim YD, Siegelman R, et al. Hemodynamics of protamine administration. J Thorac Cardiovasc Surg. 1987;94:881-886. 39. Kien ND, Quam DD, Reitan JA, White DA. Mechanism of hypotension following rapid infusion of protamine sulfate in anesthetized dogs. J Cardiothorac Vasc Anesth. 1992;6:143-147. 40. Kikura M, Lee MK, Levy JH. Heparin neutralization with methylene blue, hexadimethrine, or vancomycin after cardiopulmonary bypass. Anesth Analg. 1996;83:223-227. 41. Kim R. Anaphylaxis to protamine masquerading as an insulin allergy. Del Med J. 1993;65:17-23. 42. Kimmel SE, Sekers MA, Berlin JA, et al. Risk factors for clinically important adverse events after protamine administration following cardiopulmonary bypass. J Am Coll Cardiol. 1998;32:1916-1922. 43. Kuitunen AH, Salmenpera MT, Heinonen J, et al. Heparin rebound: a comparative study of protamine chloride and protamine sulfate in patients undergoing coronary artery bypass surgery. J Cardiothorac Vasc Anesth. 1991;5:221-226. 44. Lakin JD, Blocker TJ, Strong DM, Yocum MW. Anaphylaxis to protamine sulfate mediated by a complement dependent IgG antibody. J Allergy Clin Immunol. 1978;61:102-107. 45. Lam LH, Silbert JE, Rosenberg RD. The separation of active and inactive forms of heparin. Biochem Biophys Res Commun. 1976;69:570-577. 46. Levy J, Adkinson N. Anaphylaxis during cardiac surgery: implications for clinicians. Anesth Anal. 2008;106:392-403. 47. Levy J, Tanaka K. Anticoagulation and reversal paradigms: is too much of a good thing bad? Anesth Anal. 2009;108:692-694. 48. Lieberman P, Kemp S, Oppenheimer J, et al. The diagnosis and amanagement of anaphylaxis: an updated practice parameter. J Allergy Clin Immunol. 2005;115:S483-S523. 49. Lindblad B. Protamine sulphate: a review of its effects—hypersensitivity and toxicity. Eur J Vasc Surg. 1989;3:195-201. 50. Makris M, Hough RE, Kitchen S. Poor reversal of low molecular weight heparin by protamine. Br J Hematol. 2000;108:884-885. 51. Martin P, Horkay F, Gupta NK, et al. Heparin rebound phenomenon: much ado about nothing. Blood Coagul Fibrinolysis. 1992;3:187-191. 52. Massonnet-Castel S, Pelissier E, Bara L, et al. Partial reversal of low molecular weight heparin (PK 10169) anti-Xa activity by protamine sulfate: in vitro and in vivo study during cardiac surgery with extracorporeal circulation. Hemostais. 1986;16:139-146. 53. Moorthy SS, Pond W, Rowland RG. Severe circulatory shock following protamine (an anaphylactoid reaction). Anesth Analg. 1980;59:77-78. 54. Morel DR, Zapol WM, Thomas SJ, et al. C5a and thromboxane generation associated with pulmonary vaso- and broncho-constriction during protamine reversal of heparin. Anesthesiology. 1987;66:597-604. 55. Neidhart PP, Meier B, Polla BS, et al. Fatal anaphylactoid response to protamine after percutaneous transluminal coronary angioplasty. Eur Heart J. 1992;13:856-858. 56. Ng HJ, Koh LR, Lee LH. Successful control of postsurgical bleeding by recombinant factor VIIa in a renal failure patient given low molecular weight heparin and aspirin. Ann Hematol. 2003;82:257-258. 57. New Drug Application. Washington, DC: Food and Drug Administration; 1968, 6460, log 775. 58. Nybo M, Madsen S. Serious anaphylaxis reactions to protamine sulfate: a systematic literature review. Basic Clin Pharmacol Toxicol. 2008;103:192-196.

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59. Okajirna Y, Kanayama S, Maeda Y, et al. Studies on the neutralizing mechanism of antithrombin activity of heparin by protamine. Thromb Res. 1981;24:21-29. 60. Pearson PJ, Evora PRB, Ayrancioglu K, Schaff HV. Protamine releases endothelium-derived relaxing factor from systemic arteries. Anesth Prog. 1991; 38:99-100. 61. Porsche R, Brenner ZR. Allergy to protamine sulfate. Heart Lung. 1999;28: 418-428. 62. Protamine sulfate injection, USP [package insert]. Schaumberg, IL: APP Pharmaceuticals, LLP; 2008. 63. Pugsley M, Kalra V, Froebel-Wilson S. Protamine is a low molecular weight polycationic amine that produces actions on cardiac muscle. Life Sci. 2002; 72:293-305. 64. Raul TK, Crow MJ, Rajah SM, et al. Heparin administration during extracorporeal circulation: heparin rebound and postoperative bleeding. J Thorac Cardiovasc Surg. 1979;78:95-102. 65. Shapira N, Schaff HV, Piehler JM, et al. Cardiovascular effects of protamine sulfate in man. J Thorac Cardiovasc Surg. 1982;84:505-514. 66. Shore-Lesserson L, Reich DL, DePerio M. Heparin and protamine titration do not improve haemostasis in cardiac surgical patients. Can J Anaesth. 1998;45:10-18. 67 Stefaniszyn HJ, Novick RJ, Salerno TA. Toward a better understanding of the hemodynamic effects of protamine and heparin interaction. J Thorac Cardiovasc Surg. 1984;87:678-686. 68. Stewart WJ, McSweeney SM, Kellett MA, et al. Increased risk of severe protamine reactions in NPH insulin-dependent diabetics undergoing cardiac catheterization. Circulation. 1984;70:788-792. 69. Stoelting RK, Henry DD, Verburg KM. Hemodynamic changes and circulating histamine concentrations following protamine administration to patients and dogs. Can Anaesth Soc J. 1984;31:534-540. 70. Urdaneta F, Lobato EB, Kirby RR, Horrow JC. Noncardiogenic pulmonary edema associated with protamine administration during coronary artery bypass graft surgery. J Clin Anesth. 1999;11:675-681. 71. Wakefield TW, Andrews PC, Wrobleski SK. A [18RGD] protamine variant for nontoxic and effective reversal of conventional heparin and lowmolecular-weight heparin anticoagulation. J Surg Res. 1996;63:280-296. 72. Wakefield TW, Andrews PC, Wrobleski SK, et al. Effective and less toxic reversal of low-molecular weight heparin anticoagulation by a designer variant of protamine. J Vasc Surg. 1995;21:839-849. 73. Wakefield TW, Bies LE, Wrobleski SK, et al. Impaired myocardial function and oxygen utilization due to protamine sulfate in an isolated rabbit heart preparation. Ann Surg. 1990;212:387-393. 74. Wakefield TW, Mantler CB, Wrobleski SK, et al. Effects of differing rates of protamine reversal of heparin anticoagulation. Surgery. 1996;119:123-128. 75. Wakefield TW, Ucros I, Kresowik TF, et al. Decreased oxygen consumption as a toxic manifestation of protamine sulfate reversal of heparin anticoagulation. J Vasc Surg. 1989;9:772-777. 76. Wakefield TW, Wrobleski SK, Nichol BJ, et al. Heparin-mediated reduction of the toxic effects of protamine sulfate on rabbit myocardium. J Vasc Surg. 1992;16:47-53. 77. Wakefield TW, Wrobleski BS, Wirthlin DJ, et al. Increased prostacyclin and adverse hemodynamic responses to protamine sulfate in an experimental canine model. J Surg Res. 1991;50:449-456. 78. Weiss ME, Chatham F, Kagey Sobotka A, Adkinson NF. Serial immunological investigations in a patient who had a life-threatening reaction to intravenous protamine. Clin Exp Allergy. 1990;20:713-720. 79. Weiss ME, Nyhan D, Zhikang P, et al. Association of protamine IgE and IgG antibodies with life-threatening reactions to intravenous protamine. N Engl J Med. 1989;320:886-892. 80. Wiernikowski J, Chan A, Lo G. Reversal of anti-thrombin activity using protamine sulfate. Experience in a neonate with a 10-fold overdose of enoxaparin. Thromb Res. 2007;120:303-305. 81. Wright SJ, Murray WB, Hampton WA, et al. Calculating the protamineheparin reversal ratio: a pilot study investigating a new method. J Cardiothorac Vasc Anesth. 1993;7:416-421.

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CHAPTER 60

CALCIUM CHANNEL BLOCKERS Francis Jerome DeRoos

These receptor-binding differences among the CCB classes determine their potential therapeutic role. Verapamil and diltiazem are used in the management of hypertension, to reduce myocardial oxygen demand, to achieve rate control in atrial flutter and atrial fibrillation, and to abolish supraventricular reentrant tachycardias.1 Dihydropyridines are typically used to treat diseases with increased peripheral vascular tone such as hypertension, Raynaud phenomenon, Prinzmetal angina, esophageal spasm, vascular headaches, and post-subarachnoid hemorrhage vasospasm, but not for rhythm disturbances.

PHARMACOKINETICS AND TOXICOKINETICS Since calcium channel blockers (CCBs) were first introduced experimentally in the 1960s, their use has steadily risen to make them among the most frequently prescribed cardiovascular medications. Mirroring this widespread use, poisonings involving CCBs have also risen. The combination of sustained-release formulations to improve compliance and the potent hemodynamic effects complicates the management of patients poisoned with CCBs. The hallmarks of CCB toxicity include hypotension and bradydysrhythmias. Unfortunately, in severely poisoned patients, no therapeutic intervention is demonstrated to be consistently effective. Management decisions must be made on an individual patient basis with careful assessment of the physiologic response to each treatment.

HISTORY AND EPIDEMIOLOGY CCBs were first introduced commercially in the United States in the late 1970s. Currently, there are 10 individual CCBs available in either immediate or sustained-release formulations (Table 60–1), plus several combination products. They are used for a variety of medical conditions, including hypertension, stable angina, dysrhythmias, migraine headache, Raynaud phenomenon, and subarachnoid hemorrhage. In 1986, more than 1200 exposures and seven deaths related to CCBs were reported to the American Association of Poison Control Centers. In 2007, those figures increased to 10,084 exposures with 435 of moderate to major toxicity, including 17 deaths (Chap. 135). This reported rise in fatalities is most likely the result of the increased use and access to these drugs, along with the introduction of sustained-release preparations in 1988.

PHARMACOLOGY There are many types of calcium channels, including L, N, P, T, Q, and R types, that can be found either intracellularly on the sarcoplasmic reticulum or on cell plasma membranes, particularly in neuronal and secretory tissue.91 All CCBs commercially available in the United States exert their physiologic effects by antagonizing L-type voltage-sensitive calcium channels and are classified into three structural groups (see Table 60–1).50,107 Each group binds a slightly different region of the alpha1c subunit of the calcium channel and thus has different affinities for the various L-type calcium channels, both in the myocardium and the vascular smooth muscle.1,28 Verapamil and diltiazem have profound inhibitory effects on the sinoatrial (SA) and atrioventricular (AV) nodal tissue, whereas the dihydropyridines as a class have little, if any, direct myocardial effects at therapeutic doses.51,107 A fourth class of CCBs, sometimes referred to as “nonselective,” includes mibefradil and bepridil, which are no longer available in the United States because of adverse drug events.

All CCBs are well-absorbed orally and undergo hepatic oxidative metabolism predominantly via the CYP3A4 subgroup of the cytochrome P450 (CYP) isoenzyme system.68 Norverapamil, formed by N-demethylation of verapamil, is the only active metabolite and retains 20% of the activity of the parent compound.46 Diltiazem is predominantly deacetylated into minimally active deacetyldiltiazem, which is then eliminated via the biliary tract.39 After repeated doses, as well as overdose, these hepatic enzymes become saturated, reducing the potential of the first-pass effect and increasing the quantity of active drug absorbed systemically.116 Saturation metabolism contributes to the prolongation of the apparent half-lives reported following overdose of various CCBs.84 All CCBs are highly protein bound.68 Volumes of distribution are large for verapamil (5.5 L/kg) and diltiazem (5.3 L/kg), and somewhat smaller for nifedipine (0.8 L/kg). Although not well studied, the substantial protein binding and the large volumes of distribution make it unlikely that extracorporeal drug removal with hemodialysis or hemoperfusion would be of any value in overdose. Several case reports offer clinical support for this conclusion.89,104 One interesting aspect of the pharmacology of CCBs is their potential for drug–drug interactions. CYP3A4, which metabolizes most CCBs, is also responsible for the initial oxidation of numerous other xenobiotics. Verapamil and diltiazem specifically compete for this isoenzyme and can decrease the clearance of many drugs including carbamazepine, cisapride, quinidine, various β-hydroxy-β-methylglutarylcoenzyme A (HMG-CoA) reductase inhibitors, cyclosporine, tacrolimus, most HIV-protease inhibitors, and theophylline (see Chap. 12 Appendix).33,78 In June 1998, mibefradil, a structurally unique CCB, was voluntarily withdrawn following several reports of serious adverse drug interactions caused in part by its potent inhibition of CYP3A4.58 Other inhibitors of CYP3A4, such as cimetidine, fluoxetine, some antifungals, macrolide antibiotics, and even the flavinoids in grapefruit juice, raise serum concentrations of several CCBs and may result in toxicity.32,93 In addition to affecting CYP3A4, verapamil and diltiazem also inhibit P-glycoprotein–mediated drug transport into peripheral tissue—an inhibition that results in elevated serum concentrations of xenobiotics such as cyclosporine and digoxin that use this transport system (Chap. 12 Appendix). Unlike diltiazem and verapamil, nifedipine and the other dihydropyridines do not appear to affect the clearance of other xenobiotics via CYP3A4 or P-glycoprotein–mediated transport.1

PHYSIOLOGY AND PATHOPHYSIOLOGY Calcium initiates excitation-contraction coupling and myocardial conduction (Fig. 60–1; see Chap. 22 and 23). Ca2+ enters the cardiac myocyte through L-type calcium channels and follows electrochemical gradients.66 The alpha1c subunit is the pore-forming portion of this channel and is where all CCBs bind to prevent Ca2+ transport.12,83 In myocardial cells, this Ca2+ influx is slower relative to the initial sodium influx that initiates cellular depolarization, and prolongs this

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Chapter 60

TABLE 60–1. Classification of Calcium Channel Blockers Available in the United States Phenylalkylamine Verapamil (Calan, Isoptin, Verelan) Benzothiazepine Diltiazem (Cardizem, Dilacor, Tiazac) Dihydropyridines Nifedipine (Adalat, Procardia) Amlodipine (Norvasc) Clevidipine (Cleviprex) Felodipine (Plendil) Isradipine (DynaCirc) Nicardipine (Cardene) Nimodipine (Nimotop) Nisoldipine (Sular)

depolarization, creating the plateau phase (phase 2) of the action potential. The Ca2+ subsequently stimulates a receptor-operated calcium channel on the sarcoplasmic reticulum, known as the ryanodine receptor (RyR2), releasing Ca2+ from the vast stores of the sarcoplasmic reticulum into the cytosol.74 This is often termed calcium-dependent calcium release. Calcium then binds troponin C, which causes a

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conformational change that displaces troponin and tropomyosin from actin, allowing actin and myosin to bind, resulting in a contraction (see Fig. 23–2).16,24 In addition to its role in myocardial contractility, Ca2+ influx is also important in myocardial conduction. Calcium influx plays an important role in the spontaneous depolarization (phase 4) of the action potential in the SA node. This Ca2+ influx also allows normal propagation of electrical impulses via the specialized myocardial conduction tissues, particularly the AV node.85 After opening, the rate of recovery of these slow calcium channels, in both the SA and AV nodal tissue, determines rate of conduction.107 In smooth muscle, calcium influx stimulates myosin light-chain kinase activity through calmodulin.66 The myosin light-chain kinase phosphorylates, and thus activates, myosin, which subsequently binds actin, causing a contraction to occur.66 The life-threatening toxicities of CCBs are manifested largely within the cardiovascular system and are an extension of their therapeutic effects. Inhibition of L-type-voltage–sensitive calcium channels is particularly significant in the myocardium and smooth muscle, which are dependant on this influx for normal function. In the myocardium, this impaired Ca2+ flow results in a decreased force of contraction. In addition, the delay in recovery of the slow calcium channels in the SA and AV nodal tissue results in decreased heart rate and conduction. In the vascular smooth muscle, the cytosolic Ca2+ concentration maintains basal tone and any decrease of Ca2+ influx results in relaxation and arterial vasodilation.45 The pharmacological differences among CCBs on the myocardium and the vascular smooth muscle is the result of their different affinities for the various L-type calcium channels.1,28 In the myocardium, verapamil has the most marked effects, while diltiazem has less and dihydropyridines have little, if any, effect at therapeutic doses.51 In fact, in several experimental models, nifedipine does not alter the recovery of myocardial calcium channels.57 In addition, not only do verapamil and, to a lesser extent, diltiazem impede Ca2+ influx and channel recovery in the myocardium, but their blockade is potentiated as the frequency of channel opening increases.34,75 Therefore, in a frequently contracting tissue, such as the myocardium, the blockade of verapamil and diltiazem would be augmented. In the peripheral vascular tissue, dihydropyridines have the most potent vasodilatory effects; verapamil is the next most potent, followed by diltiazem. Dihydropyridines bind the calcium channel best at less-negative membrane potentials. Because the resting potential for myocardial muscle (–90 mV) is lower than that of vascular smooth muscle (–70 mV), dihydropyridines bind preferentially in the peripheral vascular tissue.75 Consequently, verapamil is the most effective at decreasing heart rate, cardiac output, and blood pressure, whereas the dihydropyridines produce the greatest decrease in systemic vascular resistance. Because dihydropyridines have limited myocardial effect at therapeutic concentrations, the baroreceptor reflex remains intact and a slight increase in heart rate and cardiac output may occur. Isradipine is the only dihydropyridine whose inhibitory effect on the SA node is significant enough to blunt any reflex tachycardia.

CLINICAL MANIFESTATIONS FIGURE 60–1. Normal contraction of myocardial cells. The L-type voltage sensitive calcium channels (Cav-L) open to allow calcium ion influx during myocyte depolarization. This causes the concentration-dependent release of more calcium ions from the ryanodyne receptor (RyR) of the sarcoplasmic reticulum (SR) that ultimately produce cardiac contraction.

Myocardial depression and peripheral vasodilation occur, producing bradycardia and hypotension.90 Myocardial conduction may be impaired, producing AV conduction abnormalities, idioventricular rhythms, and complete heart block.8,29,41,44,63,77 Junctional escape rhythms frequently occur in patients with significant poisonings.20,27 The negative inotropic effects may be so profound, particularly with verapamil,

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that ventricular contraction may be completely inhibited.11,27,36 Patients may initially be asymptomatic but deteriorate rapidly and develop cardiogenic shock.95,109 Hypotension is the most common abnormal vital sign finding following a CCB overdose.81 The associated clinical findings represent the degree of cardiovascular compromise and hypoperfusion of the central nervous system (CNS). Early or mild symptoms include dizziness, fatigue, and lightheadedness, whereas more severely poisoned patients may manifest lethargy, syncope, altered mental status, coma, and death.41,76 Seizures,38,41 cerebral ischemic events,87,92 ischemic bowel,98,110 and renal failure,77 occurring in the presence of CCB-induced cardiogenic shock, also are reported. Severe CNS depression is distinctly uncommon, and if respiratory depression or coma is present without severe hypotension, coingestants or other causes of altered mental status must be considered. Gastrointestinal (GI) symptoms, such as nausea and vomiting, are also uncommon.42 Although receptor selectivity is lost in overdose, and all CCBs can produce severe bradycardia, hypotension, and death, there are some subtle variations in presentation, depending on the xenobiotic. The CCBs with the most significant myocardial effects, verapamil and, to a lesser extent, diltiazem, are associated with more negative inotropic and chronotropic effects.72 In a prospective, poison center– based study, AV nodal block occurred much more frequently in the setting of verapamil poisoning.80 In contrast, nifedipine, and likely the other dihydropyridines because of their limited myocardial binding, may produce tachycardia or a “normal” heart rate initially, with bradycardia developing only in patients with more substantial ingestions.19,112 While deaths are much more commonly associated with verapamil and diltiazem, they nevertheless occur with the dihydropyridines. Numerous reports document hyperglycemia in patients with severe CCB poisoning.38,41,61 Insulin release from the β-islet cells in the pancreas is dependent on calcium influx via an L-type calcium channel. In CCB overdose, this channel is blocked, reducing insulin release.23 This may be due to dysregulation of the insulin-dependent phosphatidylinositol 3-kinase pathway.9 The hyperglycemic effect may be exacerbated in a diabetic patient, or if glucagon is used as inotropic therapy (Chap. 48).105 Acute pulmonary injury is also associated with CCB poisoning.43,49,60 Although the mechanism is unknown, precapillary vasodilation may cause an increase in transcapillary hydrostatic pressure.43 The elevated pressure gradient results in increased pulmonary capillary transudates and, ultimately, interstitial edema. Several factors, including the CCB involved, the dose ingested, the product formulation, and the patient’s underlying cardiovascular health, may play a role in the ultimate degree of toxicity. Coingestion with other cardioactive xenobiotics, such as β-adrenergic antagonists and digoxin, may potentiate conduction abnormalities.15,47,118 The product formulation (immediate or regular versus sustained release) affects the onset of symptoms and duration of toxicity. With regular-release formulations, toxicity is often present within 2 to 3 hours of ingestion.10,81 With sustained-release products, however, initial signs or symptoms may be delayed for 6 to 8 hours, and delays of up to 15 hours are reported.10,81,97 In addition, with ingestion of sustainedrelease products, the apparent half-life is prolonged and toxicity may last longer than 48 hours.3,8,27 Comorbidity and age are two factors that negatively impact both morbidity and mortality in patients with CCB poisoning. Elderly patients, and those with underlying cardiovascular disease such as congestive heart failure, are much more sensitive to the myocardial depressant effects of CCBs.67 Even at therapeutic doses, these individuals more frequently develop symptoms of mild hypoperfusion, such as dizziness and fatigue.37,70 One or two tablets of any of the CCBs may produce significant poisoning in toddlers.10,82

DIAGNOSTIC TESTING All patients with suspected CCB ingestions should have continuous cardiac monitoring and a 12-lead electrocardiogram (ECG) performed to assess heart rate and rhythm, as well as any conduction abnormalities. Careful assessment of the degree of hypoperfusion, if any, may include pulse oximetry and serum chemistry analysis for metabolic acidosis. Assays for various CCB serum concentrations are not routinely available and are not used to manage patients after overdose. If a patient presents with bradydysrhythmias of unclear origin, assessment of electrolytes, particularly potassium and magnesium, renal function, and a digoxin concentration, may be helpful, although careful history taking often provides the most valuable clues. If hyperkalemia is present, cardioactive steroid poisoning should be considered, particularly in the absence of renal failure. Acute lung injury can be initially assessed by auscultation, pulse oximetry, and chest radiography. Because calcium channel blocker poisoning can impair insulin secretion from the pancreas, hyperglycemia may be detected. A recent retrospective study suggests that serum glucose concentrations correlate with the severity of the poisoning. The initial mean serum glucose concentration in patients who required vasopressors or a pacemaker, or who died, was 188 mg/dL versus 122 mg/dL in those not requiring intervention. Peak serum glucose concentrations were also significantly different.61 This finding may become a useful early sign of severity and an indicator for when to initiate hyperinsulinemia-euglycemia therapy.

MANAGEMENT Any patient with a suspected CCB ingestion should be immediately evaluated, even if there are no abnormal clinical findings and the initial vital signs are normal. Intravenous access should be initiated. A 12-lead ECG should be repeated at least every 1 to 2 hours for the first several hours. If the patient’s condition remains normal (or normalizes), ECGs can be repeated subsequently at longer intervals. Initial treatment should begin with adequate oxygenation and airway protection (as clinically indicated), and aggressive GI decontamination. For a patient who is hypotensive with no evidence of congestive heart failure or acute lung injury, an initial fluid bolus of 10 to 20 mL/kg of crystalloid should be given, and repeated as needed. Attempts to prevent absorption of drug from the GI tract may prevent or mitigate toxicity and is often a critical intervention. The importance of early initiation of GI decontamination even for wellappearing patients with a history of sustained-release CCB ingestion, particularly children, cannot be overemphasized. It is imperative to minimize any absorption and prevent delayed cardiovascular toxicity, which can be profound and difficult to reverse. Several reports describe patients who presented with mild signs of poisoning, in whom GI decontamination was not performed aggressively and who subsequently displayed severe toxicity. The most important measures to eliminate CCBs after an ingestion are multiple-dose activated charcoal (MDAC) and, for sustained-release CCBs, whole-bowel irrigation (WBI). Induced emesis is contraindicated because CCB-poisoned patients can rapidly deteriorate. Orogastric lavage should be considered for all patients who present early (1 to 2 hours postingestion) after large ingestions, and for patients who are critically ill. Although the effects of orogastric lavage following overdose of a sustained-release CCB have not been specifically studied, and although most of these formulations tend to be large and poorly soluble, because of their significant danger in overdose, orogastric lavage should still be strongly considered. When performing orogastric lavage in a CCB-poisoned patient, it is important to remember that lavage may increase vagal tone and

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potentially exacerbate any bradydysrhythmias.106 Pretreatment with a therapeutic dose of atropine may prevent this. All patients with CCB ingestions should receive 1 g/kg of activated charcoal orally. Multiple doses (0.5 g/kg) of activated charcoal (MDAC) without a cathartic should be administered to nearly all patients with either sustained-release pill ingestions or signs of continuing absorption. Although data are limited, there is no evidence that MDAC increases CCB clearance from the serum.84 Rather, its efficacy may be a result of the continuous presence of activated charcoal throughout the GI tract, which adsorbs any active xenobiotic from its slow-release formulation. MDAC should not be administered to a patient with inadequate GI function (eg, hypotensive, no bowel sounds; see Antidotes in Depth A2–Activated Charcoal). WBI with polyethylene glycol solution (1 to 2 L/h orally or via nasogastric tube in adults, up to 500 mL/h in children) should be initiated for patients who ingest sustained-release products.14 Administration should be continued until the rectal effluent is clear (see Antidotes in Depth A3–Whole-Bowel Irrigation and Other Intestinal Evacuants). There are no data to clearly support extracorporeal removal, and its use is generally limited by the hemodynamic effects of the CCBs.86 Pharmacotherapy should focus on maintenance or improvement of both cardiac output and peripheral vascular tone. Although atropine, calcium, insulin, glucagon, isoproterenol, dopamine, epinephrine, norepinephrine, and phosphodiesterase inhibitors, have been used with reported success in CCB-poisoned patients, no single intervention has consistently demonstrated total efficacy. Little prospective or basic research specifically evaluates effective treatment modalities. Therapy should begin with crystalloids and atropine, but more critically poisoned patients will not respond to these initial efforts, and inotropes and vasopressors will be needed. Although it would be ideal to initiate each therapy individually and monitor the patient’s hemodynamic response, in the most critically ill patients, multiple therapies should be administered simultaneously. A reasonable treatment sequence includes calcium followed by a catecholamine such as epinephrine or norepinephrine, hyperinsulinemia-euglycemia therapy, glucagon, and perhaps a phosphodiesterase inhibitor. In addition, in the event of a cardiac arrest, a 20% intravenous fat emulsion may be administered.

■ ATROPINE Atropine is considered by many to be the drug of choice for patients with symptomatic bradycardia. In an early dog model of verapamil poisoning, atropine improved heart rate and cardiac output.31 In one prospective study, two of eight bradycardic CCB-poisoned patients also had an improvement in heart rate with atropine therapy.80 Clinical experience, however, demonstrates atropine to be largely ineffective in improving heart rate in severe CCB-poisoned patients.76,95 Initial treatment with calcium might improve the efficacy of atropine.42 Given its availability, familiarity, efficacy in mild poisonings, and safety profile, atropine should still be considered as initial therapy in patients with symptomatic bradycardia. Dosing should begin with 0.5 to 1.0 mg (0.02 mg/kg in children) minimum 0.1mg) intravenously (IV) every 2 or 3 minutes up to a maximum dose of 3 mg in all patients with symptomatic bradycardia. However, because of its limited efficacy in severely poisoned patients, treatment failures should be anticipated. In patients in whom WBI or MDAC will be used, the use of atropine must be carefully considered, weighing the potential benefits of improved heart rate, and thus cardiac output, against the anticholinergic effects, potentially decreasing GI motility.

■ CALCIUM Pharmacologically, Ca2+ appears to be a logical choice to treat patients with CCB toxicity. Pretreatment with intravenous Ca2+, prior to

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verapamil use for supraventricular tachydysrhythmias, prevents hypotension without diminishing the antidysrhythmic efficacy.25,94 This is also observed in the overdose setting where Ca2+ tends to improve blood pressure more than it does the heart rate. Although the exact mechanism is unclear, boluses of Ca2+ increase the extracellular Ca2+ concentration and increase the transmembrane concentration gradient. Calcium salts are beneficial in experimental models of CCB poisoning.31,36 In verapamil-poisoned dogs, improvement in inotropy and blood pressure was demonstrated after increasing the serum Ca2+ concentration by 2 mEq/L with an intravenous infusion of 10% calcium chloride (CaCl2) at 3 mg/kg/min.36 Calcium ion reverses the negative inotropy, impaired conduction, and hypotension in humans poisoned by CCBs.14,59,62,70 Unfortunately, this effect is often short lived and more severely poisoned patients may not improve significantly with Ca2+ administration.18,21,84,89 Although some authors believe that these failures might represent inadequate dosing,14,42,59 optimal effective dosing of Ca2+ is unclear. Moreover, if there is any suspicion that a cardioactive steroid such as digoxin is involved in an overdose, Ca2+ should be avoided until after digoxin-specific Fab is administered because of concerns that it may worsen digoxin toxicity (Chap. 64 and A 20).13 Reasonable recommendations for poisoned adults include an initial intravenous infusion of approximately 13 to 25 mEq of Ca2+ (10 to 20 mL of 10% calcium chloride or 30 to 60 mL of 10% calcium gluconate) followed by either repeat boluses every 15 to 20 minutes up to three to four doses or a continuous infusion of 0.5 mEq/kg/h of Ca2+ (0.2 to 0.4 mL/kg/h of 10% calcium chloride or 0.6 to 1.2 mL of 10% calcium gluconate; see Antidotes in Depth A19–Glucagon).72 Careful selection and attention to the type of calcium salt used is critical for dosing. Although there is no difference in efficacy of calcium chloride or calcium gluconate, 1 g of calcium chloride contains 13.4 mEq of Ca2+, which is more than three times the 4.3 mEq found in 1 g of calcium gluconate. Consequently, to administer equal doses of Ca2+, three times the volume of calcium gluconate compared with that of calcium chloride is required. The main limitation of using calcium chloride, however, is that it has significant potential for causing tissue injury if extravasated, so administration should ideally be via central venous access. If repeat dosing or continuous infusions are necessary serum Ca2+ and PO4–3 concentrations should be closely monitored to detect developing hypercalcemia or hypophosphatemia. These concerns are not unfounded, and may in fact significantly limit Ca2+ therapy. Other adverse effects of intravenous Ca2+ include nausea, vomiting, flushing, constipation, confusion, and angina.

■ INOTROPES AND VASOPRESSORS Catecholamines are the next line of therapy in the treatment of CCB poisoning. Numerous case reports describe the success or failure of a wide variety of vasopressors, including epinephrine (success,18 failure38,63), norepinephrine (success,41 failure63), dopamine (success,3 failure18,38,63), isoproterenol (success,77 failure38), dobutamine (success,77 failure21,63), and vasopressin.31,48,101 Experimentally, no single therapy is consistently effective. This is not surprising, given the significant variability in both the CCBs and the patients involved. Mechanistically, however, stimulation of either β1-adrenergic receptors on the myocardium or α1-adrenergic receptors on the peripheral vascular smooth muscle is the most logical target, but which one depends upon the etiology of the hypotension. β-Adrenergic agonists activate adenylate cyclase via Gs protein, resulting in formation of cyclic adenosine monophosphate (cAMP), which stimulates protein kinase A to phosphorylate the α1 subunit of various calcium channels (Fig. 60–2).96 It is unclear whether this phosphorylation allows calcium channels to remain open longer,19 or if

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FIGURE 60–2. Myocardial toxicity of calcium channel blockers and use of antidotal therapies. Calcium channel blockers reduce calcium ion influx through the L-type calcium channel (Cav-L) and thus reduce contractility. Mechanisms to increase intracellular calcium include recruitment of new or dormant calcium channels by increasing cyclic adenosine monophosphate (cAMP) either by stimulating its formation by adenyl cyclase (AC) with catecholamines or glucagon (see text), or by inhibiting its degradation to 5′-monophosphate with phosphodiesterase inhibitors (PDEI) such as amrinone. Increasing the calcium concentration gradient across the cellular membrane to further its influx may improve contractility. The mechanism by which insulin therapy enhances inotropy is not fully known. PKA, protein kinase A; RyR = ryanodyne receptor.

it opens dormant channels within the plasma membrane. In addition, protein kinase A also phosphorylates phospholamban, which improves calcium release from troponin after contraction.100 In the myocardium, this multifactorial increase in intracellular calcium results in improved chronotropy, dromotropy, and inotropy. In the peripheral vascular smooth muscle, α1-adrenergic receptor agonists activate receptor-operated calcium channels. This opening of nonpoisoned calcium channels allows calcium influx (Fig. 60–3), which makes α1-adrenergic agonists such as norepinephrine and phenylephrine logical choices if the hypotension is primarily the result of peripheral vasodilation, as would occur most typically with the dihydropyridine CCBs. Based on these pharmacologic mechanisms, and on experimental data epinephrine, or perhaps norepinephrine, appears to be the most an appropriate initial catecholamine to use in hypotensive CCB-poisoned patients. The significant β1-adrenergic activity of both catecholamines combat the myocardial depressant effects, while the α1-adrenergic agonist effects of norepinephrine (more so than epinephrine) increase peripheral vascular resistance if desired. There is some theoretical concern about using pure β-adrenergic receptor agonists, such as isoproterenol and, to a lesser extent, dobutamine, because β2-adrenergic receptor agonist–induced peripheral vasodilation may worsen hypotension, particularly at high doses. Dopamine is predominantly an indirect acting pressor that acts by stimulating the release of norepinephrine from the distal nerve terminal, and not by direct α- and β-adrenergic receptor stimulation. This may limit its effectiveness in severely stressed patients who may have catecholamine depletion.109 Published clinical experience of patients with severe CCB poisonings support these concerns.20,38,63,109

FIGURE 60–3. Vascular toxicity of calcium channel blockers and antidotal therapies. Calcium’s entry via voltage-sensitive channels (Cav-L) initiates a cascade of events that result in actin-myosin coupling and contraction; this is inhibited by calcium channel blockers. Mechanisms to increase intracellular calcium include activation of receptoroperated calcium channels with α1-adrenergic agonists or increasing the calcium ion gradient across the cellular membrane to further its influx; RyR = ryanodyne receptor.

Improvement in blood pressure may be noted with dopamine at high dosing, when it has additional direct α- and β-adrenergic effects. The choice of a catecholamine is based on numerous factors, including the individual pharmacologic profile, the patient’s underlying physiologic condition, and the physician’s familiarity and comfort with the medication. If one catecholamine is unsuccessful, determining the cardiac output and systemic vascular resistance may be helpful in assessing whether the myocardial depressant or peripheral vasodilatory effects are responsible for the hypotension.76 This knowledge will help guide the subsequent choice of pharmacologic agents.

■ GLUCAGON Glucagon is an endogenous polypeptide hormone secreted by the pancreatic α cells in response to hypoglycemia and catecholamines. In addition, it has significant inotropic and chronotropic effects (see Antidotes in Depth A19–Glucagon).17,99 Glucagon is a therapy of choice for β-adrenergic antagonist poisoning (Chap. 61) because of its ability to bypass the β-adrenergic receptor and activate adenylate cyclase via a Gs protein in the myocardium.115 Thus, glucagon is unique in that it is functionally a “pure” β1 agonist, with no peripheral vasodilatory effects. However, in CCB poisoning, because the cellular lesion is “downstream” from adenylate cyclase, glucagon offers no pharmacologic advantage over more traditional β-adrenergic agents (see Fig. 60–2).4 There are reports of both successes26 and failures20,38 of glucagon in CCB-poisoned patients who failed to respond to fluids, Ca2+, or dopamine and dobutamine. Dosing for glucagon is not well established.4 An initial dose of 3 to 5 mg IV, slowly over 1 to 2 minutes, is reasonable in adults, and if there is no hemodynamic improvement within 5 minutes, retreatment with a dose of 4 to 10 mg may be effective. The initial pediatric dose is 50 μg/kg.

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Because of the short half-life of glucagon repeat doses may be useful. A maintenance infusion should be initiated once a desired effect is achieved (see Antidotes in Depth A19–Glucagon). Adverse effects include vomiting and hyperglycemia, particularly in diabetics or during continuous infusion.105

■ INSULIN AND GLUCOSE Hyperinsulinemia euglycemia (HIE) therapy has become the treatment of choice for patients who are severely poisoned by CCBs.61,69 Healthy myocardial tissue relies predominantly on free fatty acids for their metabolic needs and CCB poisoning forces them to become more carbohydrate dependent.52,55,56 At the same time, CCBs inhibit calciummediated insulin secretion from the β-islet cells in the pancreas,23,71 resulting in glucose uptake in myocardial cells becoming dependent upon concentration gradients rather than insulin-mediated active transport.53 In addition, there is evidence that the CCB-poisoned myocardium also becomes insulin resistant possibly by dysregulation of the phosphatidylinositol 3 kinase pathway.9,54 This may not allow normal recruitment of insulin-responsive glucose transporter proteins.9 The combination of inhibition of insulin secretion and impaired glucose utilization may explain why severe CCB toxicity often produces significant hyperglycemia and may be a marker for the severity of poisoning (see Antidotes in Depth A18–Insulin-Euglycemia Therapy).61 There are now several reported cases of CCB-poisoned patients in whom adjuvant HIEG therapy successfully improved hemodynamic function mainly by improving contractility, with little effect on heart rate.65,108,117 There are reports of the failure of this treatment,22 but this may represent initiation of therapy in terminally ill patients with multiple organ failure. Although the dose of insulin is not definitively established, therapy typically begins with a bolus of 1 Unit/kg of regular human insulin along with 0.5 g/kg of dextrose. If blood glucose is greater than 400 mg/dL (22.2 mmol/L), the dextrose bolus is not necessary. An infusion of regular insulin should follow the bolus starting at 0.5 Units/kg/h titrated up to 2 Units/kg/h if no improvement after 30 minutes. A continuous dextrose infusion, beginning at 0.5 g/kg/h should also be started. Glucose should be monitored every half hour for the first 4 hours and titrated to maintain euglycemia. The response to insulin is typically delayed for 15 to 60 minutes so it will usually be necessary to start a catecholamine infusion before the full effects of insulin are apparent.35,69

■ PHOSPHODIESTERASE INHIBITORS Another class of therapeutics that has some demonstrated usefulness in treating CCB poisoning is the cardiac and vascular phosphodiesterase 3 inhibitors: inamrinone, milrinone, and enoximone. These agents inhibit the breakdown of cAMP by phosphodiesterase, thereby increasing intracellular cAMP concentrations. These noncatecholamine inotropic agents do not disproportionately increase myocardial oxygen demand and have been traditionally used for congestive heart failure (see Fig. 60–2).5 This inhibition results in increased cAMP, increased intracellular calcium, and improved inotropy. Inamrinone improved myocardial contractility in two canine models of verapamil poisoning.2,64 In addition, phosphodiesterase inhibitors have been reported to be clinically successful in patients with CCB poisoning when used in combination with another inotrope, such as isoproterenol or glucagon.88,113,114 This “two-pronged” approach of increasing myocardial cAMP concentrations, by stimulating its formation and inhibiting its breakdown, is pharmacologically rational. However, because of the nonselective inhibition of phosphodiesterase 3 by these inhibitors, cAMP is also increased in the vascular smooth muscle. This causes smooth muscle relaxation, peripheral vasodilation and, unfortunately often, hypotension, which may severely limit its usefulness in

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many CCB-poisoned patients. Phosphodiesterase inhibitors should be used only as second-line agents, in combination with another inotrope and preferably in patients with hemodynamic monitoring. Dosing in the treatment of CCB-poisoned patients is not well defined, but should be based on traditional dosing for congestive heart failure. For inamrinone, the experimental data and the case reports suggest that an initial bolus of 1 mg/kg over 2 minutes followed by a continuous infusion of 5 to 20 μg/kg/min is appropriate.2,113

■ EXPERIMENTAL ANTIDOTES In animal models intravenous fat emulsions (IFE) decreases the toxicity of a few lipid-soluble drugs, most notably bupivacaine. Other models suggest that IFE is an effective therapy for CCB-poisoned patients.7,73,102,111 This mechanism is most likely pharmacokinetic in nature, in that IFE incorporates these highly cardiotoxic drugs and thus lower the free or effective serum drug concentrations.7,111 Until more data are available, IFE should be considered adjuvant therapy for critically ill, preterminal CCB-poisoned patients (see Antidotes in Depth A21–Intravenous Fat Emulsion). Digoxin has been experimentally evaluated in CCB poisoning since inhibiting the sodium/potassium adenosine triphosphatase (ATPase), the cardioactive steroids raise the intracellular Ca2+ concentration.6 In a canine model of verapamil poisoning, digoxin, in conjunction with atropine or calcium, improved both systolic blood pressure and myocardial inotropy.6,79 However, because digoxin requires a significant amount of time to distribute into tissue, and because limited efficacy data and no safety data have yet been collected, more work is needed before digoxin is administered to patients with CCB poisoning.

■ ADJUNCTIVE HEMODYNAMIC SUPPORT The most severely CCB-poisoned patients may not respond to any pharmacologic intervention.27,38 Transthoracic or intravenous cardiac pacing may be required to improve heart rate, as several case reports demonstrate.95,109 However, in a prospective cohort of CCB poisonings, two of four patients with significant bradycardia requiring electrical pacing had no electrical capture.80 In addition, even if electrical pacing is effective in increasing the heart rate, blood pressure often remains unchanged.40,41 Intraaortic balloon counterpulsation is another invasive supportive option to be considered in CCB poisoning refractory to pharmacologic therapy. Intraaortic balloon counterpulsation was used successfully to improve cardiac output and blood pressure in a patient with a mixed verapamil and atenolol overdose.30 The synchronized inflation and deflation is dependent on regular cardiac electrical activity, so cardiac pacing is often required in addition to the intraaortic balloon. It is important to remember that CCB-poisoned patients typically have a much better prognosis than patients with severe left ventricular failure from ischemic heart disease, in whom this technology is traditionally used. Between 24 and 48 hours of assisted cardiac output allows metabolism and elimination of the CCBs and a return of baseline myocardial function. Severely CCB-poisoned patients have also been supported for days and subsequently recovered fully with much more invasive and technologically demanding extracorporeal membrane oxygenation (ECMO) and emergent open and percutaneous cardiopulmonary bypass.27,38,40 The major limitation of all these technologies, however, is that they are available only at tertiary care facilities.

DISPOSITION Every patient who manifests any signs or symptoms of toxicity should be admitted to an intensive care setting. Because of the potential for delayed toxicity, despite some recommendations to the contrary,10 any

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patient ingesting sustained-release products should be admitted for 24 hours to a monitored setting, even if asymptomatic. This is particularly important for toddlers and small children in whom just one or a few tablets may produce significant toxicity.10,38,82 All admitted patients should be treated with activated charcoal, and those with a history of sustained-release product ingestion should be treated with WBI. Only patients with a reliable history of an “immediate-release” preparation ingestion who have received adequate gastrointestinal decontamination, have serial ECGs over 6 to 8 hours that have remained unchanged, and are asymptomatic can be “medically cleared” for disposition. Patients with unintentional overdose may be discharged at this point, and those whose poisoning is intentional typically receive psychiatric evaluation.

SUMMARY Calcium channel blockers are commonly used to treat hypertension, stable and vasospastic angina, dysrhythmias, migraine headaches, Raynaud phenomenon, and subarachnoid hemorrhage. Hallmarks of toxicity include bradydysrhythmias and hypotension, which are an extension of the pharmacologic effects of these agents. Although most patients develop symptoms of hypoperfusion, such as lightheadedness, nausea, or fatigue, within hours of a significant ingestion, sustainedrelease formulations may significantly delay any and all hemodynamic consequences and certainly may prolong toxicity. Because of the significant lethality of large ingestions of sustainedrelease CCBs, it is imperative to make GI decontamination with WBI a high priority. Aggressive decontamination of patients with exposures to sustained-release products should begin as soon as possible and should not be delayed by waiting for signs of toxicity.103 Once hemodynamic toxicity develops, in addition to supportive care, pharmacologic treatment with HIE and calcium salt boluses should be initiated. Traditional catecholamines are also typically needed, but their use alone may not be sufficient for the most critically poisoned patients. Other therapeutic options include the use of glucagon, phosphodiesterase inhibitors, and possibly IFE. Patients who fail to respond to all pharmaceutical interventions should be considered for extracorporeal mechanical support whenever available.

REFERENCES 1. Abernethy DR, Schwartz JB. Calcium-antagonist drugs. N Engl J Med. 1999; 341:1447-1457. 2. Alousi AA, Canter JM, Fort DJ. The beneficial effect of amrinone on acute drug-induced heart failure in the anaesthetised dog. Cardiovasc Res. 1985;19:483-494. 3. Ashraf M, Chaudhary K, Nelson J, Thompson W. Massive overdose of sustained-release verapamil: a case report and review of literature. Am J Med Sci. 1995;310:258-263. 4. Bailey B. Glucagon in β-blocker and calcium channel blocker overdoses: a systematic review. J Toxicol Clin Toxicol 2003;41:595-602. 5. Baim DS. Effect of phosphodiesterase inhibition on myocardial oxygen consumption and coronary blood flow. Am J Cardiol. 1989;63:23A-26A. 6. Bania TC, Chu J, Almond G, Perez E. Dose-dependent hemodynamic effect of digoxin therapy in severe verapamil toxicity. Acad Emerg Med. 2004;11:221-227. 7. Bania TC, Chu J, Perez, E, Su M, Hahn IH. Hemodynamic effects of intravenous fat emulsion in an animal model of severe verapamil toxicity resuscitated with atropine, calcium, and saline. Acad Emerg Med. 2007;14: 105-111. 8. Barrow PM, Houston PL, Wong DT. Overdose of sustained-release verapamil. Br J Anaesth. 1994;72:361-365. 9. Bechtel LK, Haverstick DM, Holstege CP. Verapamil toxicity dysregulates the phophotidylinosotil 3-kinase pathway. Acad Emerg Med. 2008;15:368-374.

10. Belson MG, Gorman SE, Sullivan K, Geller RJ. Calcium channel blocker ingestions in children. Am J Emerg Med 2000;18:581-586. 11. Beniam ME. Asystole after verapamil. Br Med J. 1972;2:169-170. 12. Bodi I, Mikala G, Koch SE, Akhter SA, Schwartz A. The L-type calcium channel in the heart. the beat goes on. J Clin Invest. 2005;115:3306-3317. 13. Bower JO, Mengle HAK. The additive effects of calcium and digitalis: a warning with a report of two deaths. JAMA. 1936;106:1151-1153. 14. Buckley N, Dawson AH, Howarth D, Whyte IM. Slow-release verapamil poisoning. Use of polyethylene glycol whole-bowel lavage and high-dose calcium. Med J Aust. 1993;158:202-204. 15. Carruthers SG, Freeman DJ, Gailey DG. Synergistic adverse hemo-dynamic interaction between oral verapamil and propranolol. Clin Pharmacol Ther. 1989;46:469-477. 16. Chakraborti S, Das S, Kar P, et al. Calcium signaling phenomena in heart diseases: a perspective. Mol Cell Biochem. 2007;298:1-40. 17. Chernow B, Zagola GP, Malcolm D, et al. Glucagon’s chronotropic action is calcium dependent. J Pharmacol Exp Ther. 1987;241:833-837. 18. Chimienti M, Previtali M, Medici A, Piccinini M. Acute verapamil poisoning: successful treatment with epinephrine. Clin Cardiol. 1982;5: 219-222. 19. Clifton DG, Booth DC, Hobbs S, et al. Negative inotropic effect of intravenous nifedipine in coronary artery disease. Relation to plasma levels. Am Heart J. 1990;119:283-290. 20. Connolly DL, Nettleton MA, Bastow MD. Massive diltiazem overdose. Am J Cardiol. 1993;72:742-743. 21. Crump BJ, Holt DW, Vale JA. Lack of response to intravenous calcium in severe verapamil poisoning. Lancet. 1982;2:939-940. 22. Cumpston K, Mycyk M, Pallasch E, et al. Failure of hyperinsulinemia/ euglycemia therapy in severe overdose [abstract]. J Toxicol Clin Toxicol. 2002;40:618. 23. Devis G, Somers G, Van Obberghen E, Malaisse WJ. Calcium antagonists and islet function. I: inhibition of insulin release by verapamil. Diabetes. 1975;24:547-551. 24. Dibb KM, Graham HK, Venetucci LA, Eisner DA, Trafford AW. Analysis of cellular calcium fluxes in cardiac muscle to understand calcium homeostasis in the heart. Cell Calcium. 2007;42(4-5):503-512. 25. Dolan DL. Intravenous calcium before verapamil to prevent hypotension. Ann Emerg Med. 1991;20:588-589. 26. Doyon S, Roberts JR. The use of glucagon in a case of calcium channel blocker overdose. Ann Emerg Med. 1993;22:1229-1233. 27. Durward A, Guerguerian AM, Lefebvre M, Shemien SD. Massive diltiazem overdose treated with extracorporeal membrane oxygenation. Pediatr Crit Care Med. 2003;4:372-376. 28. Eisenberg MJ, Brox A, Bestawros AN. Calcium channel blockers: an update. Am J Med. 2004;116:35-43. 29. Fauville JP, Hantson P, Honore P, et al. Severe diltiazem poisoning with intestinal pseudo-obstruction: case report and toxicological data. J Toxicol Clin Toxicol. 1995;33:273-277. 30. Frierson J, Bailly D, Shultz T, et al. Refractory cardiogenic shock and complete heart block after unsuspected verapamil-SR and atenolol overdose. Clin Cardiol. 1991;14:933-935. 31. Gay R, Angeo S, Lee R, et al. Treatment of verapamil toxicity in intact dogs. J Clin Invest. 1986;77:1805-1811. 32. Geronimo-Pardo M, Cuartero-del-Pozo AB, Jimenez-Vizuete JM, et al. Clarithromycin-nifedipine interaction as possible cause of vasodilatory shock. Ann Pharmacother. 2005;39:538-542. 33. Gladding P, Pilmore H, Edwards C. Potentially fatal interaction between diltiazem and statins. Ann Intern Med. 2004;140:W31. 34. Grace AA, Camm AJ. Voltage-gated calcium-channels and antiar-rhythmic drug action. Cardiovasc Res. 2000;45:43-51. 35. Greene SL, Gawarammana I, Wood DM, et al. Relative safety of hyperinsulinaemia/euglycaemia therapy in the management of calcium channel blocker overdose: a prospective observational study. Intensive Care Med. 2007;33:2019-2024. 36. Hariman RJ, Mangiardi LM, McAllister RG, et al. Reversal of the cardiovascular effects of verapamil by calcium and sodium: differences between electrophysiologic and hemodynamic responses. Circulation. 1979;59:797-804. 37. Hattori VT, Mandel WJ, Peter T. Calcium for myocardial depression from verapamil. N Engl J Med. 1982;306:238. 38. Hendren WC, Schreiber RS, Garretson LK. Extracorporeal bypass for the treatment of verapamil poisoning. Ann Emerg Med. 1989;18:984-987.

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39. Hermann PH, Rodger SD, Remones G, et al. Pharmacokinetics of diltiazem after intravenous and oral administration. Eur J Clin Pharmacol. 1983;24:349-352. 40. Holzer M, Sterz F, Schoerkhuber W, et al. Successful resuscitation of a verapamil-intoxicated patient with percutaneous cardiopulmonary bypass. Crit Care Med. 1999;27:2818-2823. 41. Horowitz BZ, Rhee KJ. Massive verapamil ingestion: a report of two cases and a review of the literature. Am J Emerg Med. 1989;7:624-631. 42. Howarth DM, Dawson AH, Smith AJ, Buckley N, Whyte IM. Calcium channel blocking drug overdose: an Australian series. Hum Exp Toxicol. 1994;13:161-166. 43. Humbert VH, Munn NJ, Hawkins RF. Noncardiogenic pulmonary edema complicating massive diltiazem overdose. Chest. 1991;99:258-260. 44. Ishikawa T, Imamura T, Koiwaya Y, Tanaka K. Atrioventricular dissociation and sinus arrest induced by oral diltiazem. N Engl J Med. 1983;309: 1124-1125. 45. Johns A, Leijten P, Yamamoto H, et al. Calcium regulation in vascular smooth muscle contractility. Am J Cardiol. 1987;59:18A-23A. 46. Johnson KE, Balderston SM, Pieper JA, Mann E, Reiter MJ. Electrophysiologic effects of verapamil metabolites in the isolated heart. J Cardiovasc Pharmacol. 1991;17:830-837. 47. Jolly SR, Kipnis JN, Lucchesi BR. Cardiovascular depression by verapamil: reversal by glucagon and interactions with propranolol. Pharmacology. 1987;35:249-255. 48. Kanagarajan K, Marraffa JM, Bouchard NC, et al. The use of vasopressin in the setting of recalcitrant hypotension due to calcium channel blocker overdose. Clin Toxicol. 2007;45:56-59. 49. Karti S, Ulusoy H, Yandi M, et al. Non-cardiogenic pulmonary oedema in the course of verapamil intoxication. Emerg Med J. 2002;19:458-459. 50. Katz AM. Calcium channel diversity in the cardiovascular system. J Am Coll Cardiol. 1996;28:522-529. 51. Kawai C, Konishi T, Matsuyama E, Okazaki H. Comparative effects of three calcium antagonist, diltiazem, verapamil, and nifedipine, on the sinoatrial and atrioventricular nodes. Circulation. 1981;63:1035-1042. 52. Kline JA, Leonova E, Raymond RM. Beneficial myocardial metabolic effects of insulin during verapamil toxicity in the anesthetized canine. Crit Care Med. 1995;23:1251-1263. 53. Kline JA, Leonova E, Williams TC, et al. Myocardial metabolism during graded intraportal verapamil infusion in awake dogs. J Cardiovasc Pharmacol. 1996;27:719-726. 54. Kline JA, Raymond RM, Leonova E, et al. Insulin improves heart function and metabolism during non-ischemic cardiogenic shock in awake canines. Cardiovasc Res. 1997;34:289-298. 55. Kline JA, Raymond RM, Schroeder JD, Watts JA. The diabetogenic effects of acute verapamil poisoning. Toxicol Appl Pharmacol. 1997;145:357-362. 56. Kline JA, Tomaszewski CA, Schroeder JD, Raymond RM. Insulin is a superior antidote for cardiovascular toxicity induced by verapamil in the anesthetized canine. J Pharm Exp Ther. 1993;267:744-750. 57. Kochegarov AA. Pharmacological modulators of voltage-gated calcium channels and their therapeutical application. Cell Calcium. 2003;33:145-162. 58. Krayenbuhl JC, Vozeh S, Kondo-Oestreicher M, Dayer P. Drug-drug interactions of new active substances: Mibefradil example. Eur J Clin Pharmacol. 1999;55:559-565. 59. Lam YM, Tse HF, Lau CP. Continuous calcium chloride infusion for massive nifedipine overdose. Chest. 2001;119:1280-1282. 60. Leesar MA, Martyn R, Talley JD, Frumin H. Noncardiogenic pulmonary edema complicating massive verapamil overdose. Chest. 1994;105:606-607. 61. Levine M, Boyer EW, Pozner CN, et al. Assessment of hyperglycemia after calcium channel blocker overdoses involving diltiazem or verapamil. Crit Care Med. 2007;35:2071-2075. 62. Luscher TF, Noll G, Sturmer T, et al. Calcium gluconate in severe verapamil intoxication. N Engl J Med. 1994;330:718-720. 63. MacDonald D, Alguire PC. Case report: fatal overdose with sustainedrelease verapamil. Am J Med Sci. 1992;303:115-117. 64. Makela HMV, Kapur PA. Amrinone and verapamil-propranolol induced cardiac depression during isoflurane anesthesia in dogs. Anesthesiology. 1987;66:792-797. 65. Marques I, Gomes E, de Oliveira J. Treatment of calcium channel blocker intoxication with insulin infusion: case report and literature review. Resuscitation. 2003;57:211-213. 66. Marston S, El-Mezgueldi M. Role of tropomyosin in the regulation of contraction in smooth muscle. Adv Exp Med Biol. 2008;644:110-123.

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67. Materne P, Legrand V, Vandormael M, et al. Hemodynamic effects of intravenous diltiazem with impaired left ventricular function. Am J Cardiol. 1984;54:733-737. 68. McAllister RG, Hamann SR, Blouin RA. Pharmacokinetics of calciumentry blockers. Am J Cardiol. 1985;55:30B-40B. 69. Megarbane, B, Karyo S, Baud FJ. The role of insulin and glucose (hyperinsulinemia/euglycaemia) therapy in acute calcium channel antagonist and β-blocker poisoning. Toxicol Rev. 2004;23:215-222. 70. Morris DL, Goldschlager N. Calcium infusion for reversal of adverse effects of intravenous verapamil. JAMA. 1981;249:3212-3213. 71. Ohta M, Nelson D, Nelson J, et al. Effect of Ca channel blockers on energy level and stimulated insulin secretions in isolated rat islets of Langerhans. J Pharmacol Exp Ther. 1993;264:35-40. 72. Pearigen PD, Benowitz NL. Poisoning due to calcium antagonists. Drug Saf. 1991;6:408-430. 73. Perez E, Bania TC, Medlej K, Chu J. Determining the optimal dose of intravenous fat emulsion for the treatment of severe verapamil toxicity in a rodent model. Acad Emerg Med. 2008;15:1-6. 74. Petrovic MM, Vales K, Putnikovic B, Djulejic V, Mitrovic DM. Ryanodine receptors, voltage-gated calcium channels and their relationship with protein kinase A in the myocardium. Physiol Res. 2008;57:141-149. 75. Pitt B. Diversity of calcium antagonists. Clin Ther. 1997;19(Suppl A):3-17. 76. Proano L, Chiang WK, Wang RY. Calcium channel blocker overdose. Am J Emerg Med. 1995;13:444-450. 77. Quezado Z, Lippmann M, Wertheimer J. Severe cardiac, respiratory, and metabolic complications of massive verapamil overdose. Crit Care Med. 1991;19:436-438. 78. Quinn DI, Day RO. Drug interactions of clinical importance. Drug Saf. 1995;12:393-452. 79. Ramo MP, Grupp I, Pesola MK, et al. Cardiac glycosides in the treatment of experimental overdose with calcium-blocking agents. Res Exp Med. 1992;192:335-343. 80. Ramoska EA, Spiller HA, Myers A. Calcium channel blocker toxicity. Ann Emerg Med. 1990;19:649-653. 81. Ramoska EA, Spiller HA, Winter M, Borys D. A one-year evaluation of calcium channel blocker overdoses: toxicity and treatment. Ann Emerg Med. 1993;22:196-200. 82. Ranniger C, Roche C. Are one of two dangerous? Calcium channel blocker exposure in toddlers. J Emerg Med. 2007;33:145-154. 83. Ravens U, Wettwer E, Hála O. Pharmacological modulation of ion channels and transporters. Cell Calcium. 2004;35:575-582. 84. Roberts D, Honcharik N, Sitar DS, Tenenbein M. Diltiazem overdose: pharmacokinetics of diltiazem and its metabolites and effect of multiple dose charcoal therapy. J Toxicol Clin Toxicol. 1991;29:45-52. 85. Roden DM, George AL. The cardiac ion channels: relevance to management of arrhythmias. Annu Rev Med. 1996;47:135-148. 86. Rosansky SJ. Verapamil toxicity—treatment with hemoperfusion. Ann Intern Med. 1991;114:340-341. 87. Samniah N, Schlaeffer F. Cerebral infarction associated with oral verapamil overdose. J Toxicol Clin Toxicol. 1988;26:365-369. 88. Sandroni C, Cavallaro F, Addario C, et al. Successful treatment with enoximone for severe poisoning with atenolol and verapamil: a case report. Acta Anaesthesiol Scand. 2004;48:790-792. 89. Schiffl H, Ziupa J, Schollmeyer P. Clinical features and management of nifedipine overdosage in a patient with renal insufficiency. J Toxicol Clin Toxicol. 1984;22:387-395. 90. Schoffstall JM, Spivey WH, Gambone LM, et al. Effects of calcium channel blocker overdose-induced toxicity in the conscious dog. Ann Emerg Med. 1991;20:1104-1108. 91. Schwartz A. Molecular and cellular aspects of calcium channel antagonism. Am J Cardiol. 1992;70:6F-8F. 92. Shah AR, Passalacqua BR. Case report: sustained-released verapamil overdose causing stroke: an unusual complication. Am J Med Sci. 1992;304:257-359. 93. Sica DA. Interaction of grapefruit juice and calcium channel blockers. AJH. 2006;19:768-773. 94. Singh NA. Intravenous calcium and verapamil—when the combination may be indicated. Int J Cardiol. 1983;4:281-284. 95. Snover SW, Bocchino V. Massive diltiazem overdose. Ann Emerg Med. 1986;15:1221-1224. 96. Sperelakis N. Cyclic AMP and phosphorylation in regulation of calcium influx into myocardial cells and blockade by calcium antagonist drugs. Am Heart J. 1984;107:347-357.

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97. Spiller HA, Meyers A, Ziemba T, Riley M. Delayed onset of cardiac arrhythmias from sustained-release verapamil. Ann Emerg Med. 1991;20:201-203. 98. Sporer KA, Manning JJ. Massive ingestion of sustained-release verapamil with a concretion and bowel infarction. Ann Emerg Med. 1993;22:603-605. 99. Stone CK, May WA, Carroll R. Treatment of verapamil overdose with glucagon in dogs. Ann Emerg Med. 1995;25:369-374. 100. Sulakhe MV, Vox T. Regulation of phospholamban and troponin 1 phosphorylation in the intact rat cardiomyocytes by adrenergic and cholinergic stimuli: roles of cyclic nucleotides, calcium, protein kinases, and phosphatases and depolarization. Mol Cell Biochem. 1995;149-150:103-126. 101. Sztajnkrycer MD, Bond GR, Johnson SB, Weaver AM. Use of vasopressin in a canine model of severe verapamil poisoning: a preliminary descriptive study. Acad Emerg Med. 2004;11:1253-1261. 102. Tebbutt S, Harvey M, Nicholson T, Cave G. Intralipid prolongs survival in a rat model of verapamil toxicity. Acad Emerg Med. 2006;13:134-139. 103. Tenenbein M, Cohen S, Sitar DS. Whole bowel irrigation as a decontamination procedure after acute drug overdose. Arch Intern Med. 1987;147: 905-907. 104. Ter Wee PM, Kremer Hovinga TK, Uges DRA, van der Geest S. 4-aminopyridine and haemodialysis in the treatment of verapamil intoxication. Hum Toxicol. 1985;4:327-329. 105. Thomas SH, Stone K, May WA. Exacerbation of verapamil-induced hyperglycemia with glucagon. Am J Emerg Med. 1995;13:27-29. 106. Thompson AM, Robbins, JP, Prescott JL. Changes in cardiorespiratory function during gastric lavage for drug overdose. Hum Toxicol. 1987;6:215-218. 107. Triggle DJ. L-type calcium channels. Curr Pharm Des. 2006;12:443-457. 108. Verbrugge LB, va Wezel HB. Pathopysiology of verapamil overdose: new insights in the role of insulin. J Cardiothoracic Vasc Anesth. 2007;21:406-409.

109. Watling SM, Crain JL, Edwards TD, Stiller RA. Verapamil overdose: case report and review of the literature. Ann Pharmacother. 1992;26: 1373-1377. 110. Wax P. Intestinal infarction due to nifedipine overdose. J Toxicol Clin Toxicol. 1995;33:725-728. 111. Weinberg GL, Ripper R, Feinstein DL, Hoffman W. Lipid emulsion infusion rescues dogs from bupivacaine-induced cardiac toxicity. Reg Anesth Pain Med. 2003;28:198-202. 112. Whitebloom D, Fitzharris J. Nifedipine overdose. Clin Cardiol. 1988;11: 505-506. 113. Wolf LR, Spadafora MP, Otten EJ. Use of amrinone and glucagon in a case of calcium channel blocker overdose. Ann Emerg Med. 1993;22: 1225-1228. 114. Wood DM, Wright KD, Jones AL, Dargan PI. Metaraminol (Aramine) in the management of a significant amlodipine overdose. Human Exp Toxicol. 2005;24:377-381. 115. Yagami T. Differential coupling of glucagon and beta-adrenergic receptors with the small and large forms of the stimulatory G protein. Mol Pharmacol. 1995;48:849-854. 116. Yeung PKF, Alcos A, Tang J, Tsui B. Pharmacokinetics and metabolism of diltiazem in rats: comparing single vs repeated subcutaneous injections. Biopharm Drug Dispos. 2007;28:403-407. 117. Yuan TH, Kerns WP, Tomaszewski CA, et al. Insulin-glucose as adjunctive therapy for severe calcium channel antagonist poisoning. J Toxicol Clin Toxicol. 1999;37:463-474. 118. Yust I, Hoffman M, Aronson RJ. Life-threatening bradycardic reactions due to beta blocker-diltiazem interactions. Isr J Med Sci. 1992;28: 292-294.

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A N T I D O T E S I N D E P T H ( A 18 ) INSULIN-EUGLYCEMIA THERAPY William Kerns In the last decade, insulin has gained increased attention and importance in the management of a spectrum of critical illnesses including sepsis, heart failure, and cardiac drug toxicity. The benefits of insulin go well beyond simple control of hyperglycemia. In xenobiotic-induced myocardial depression the use of high-dose insulin along with sufficient glucose to maintain euglycemia can restore normal hemodynamics.

BACKGROUND To understand the role of insulin specifically for resuscitating cardiac drug toxicity, it is useful to briefly review the altered myocardial physiology that occurs during drug-induced shock. The hallmark of severe beta-adrenergic antagonist (BAA) and calcium channel blocker (CCB) toxicity is cardiogenic shock with bradycardia, vasodilation, and decreased contractility.7 This is due to direct β-adrenergic receptor antagonism and calcium channel blockade. In addition to direct receptor or ion channel effects, metabolic derangements may occur that closely resemble diabetes with acidemia, hyperglycemia, and insulin deficiency. In the nonstressed state, the heart primarily catabolizes free fatty acids for its energy needs. On the other hand, the stressed myocardium switches preference for energy substrates to carbohydrates, as demonstrated in models of both BAA and CCB toxicity.19,35 The greater the degree of shock, the greater the demand for carbohydrates.20 The liver responds to stress by making more glucose available via glycogenolysis. As a result, blood glucose concentrations are elevated. Hyperglycemia is noted both in animal models and in human cases of cardiac drug overdose.4,9,22,36 Hyperglycemia is especially evident with CCB toxicity. This is because CCBs interfere with carbohydrate use by inhibiting pancreatic insulin release that is necessary to transport glucose across cell membranes. Insulin release from the islet cell requires functioning L-type or voltage-gated calcium channels similar to those found in myocardial and vascular tissue. Calcium channel blocking drugs directly inhibit pancreatic calcium channels.6 In models of verapamil toxicity, circulating glucose increases without an associated increase in insulin.20 There is additional evidence that CCBs interfere with phosphotidyl inositol 3-kinase–mediated glucose transport into cells.1 As a result of diminished circulating insulin and inhibited enzymatic glucose uptake, glucose movement into cells becomes concentration dependent and may not sufficiently support the myocardial demand. Calcium channel blockers further contribute to metabolic abnormalities by inhibiting lactate oxidation.19,23 This likely occurs through inhibition of pyruvate dehydrogenase, the enzyme responsible for conversion of pyruvate to

acetylcoenzyme A (acetyl-CoA). As a result, pyruvate is preferentially converted to lactate, rather than the acetyl-CoA that would ordinarily enter the Krebs cycle; lactate then accumulates. Lactate accumulation and acidemia are consistent manifestations of CCB toxicity.7,23

PROPOSED MECHANISM Initially, insulin’s ability to improve cardiac function was attributed to increased catecholamine release. However, there is evidence that this is not the mechanism. For example, β-receptor antagonism does not inhibit improved myocardial performance that followed insulin administration.24,35 In a CCB toxic model that measured circulating hormone concentrations, insulin therapy improved function and survival without increasing catecholamines.22 In contrast, evidence demonstrates that insulin works via altered calcium, potassium, and sodium ion homeostasis.8,24 However, the preponderant evidence demonstrates that insulin’s positive inotropic effects occur because of metabolic support of the heart during hypodynamic shock. Insulin facilitates myocardial utilization of carbohydrate that is favored during stress. A number of studies demonstrate a direct correlation between carbohydrate metabolism and the improved indices of cardiac function that occur with insulin therapy. Despite β-adrenergic antagonism by propranolol, insulin increased myocardial glucose uptake with subsequent increased contractility.35 In a model of verapamil toxicity, insulin increased glucose uptake with resultant improved contractility.19 Insulin therapy also increased lactate uptake, most likely by restoring pyruvate dehydrogenase activity.21 In this way, lactate serves as an energy source following conversion to pyruvate and then acetyl-CoA that can then enter the Krebs cycle. Insulin-mediated improved contractility appears to be a critical factor to survival from hypodynamic shock. In models of BAA and CCB toxicity, survival is directly due to improved contractility, as insulin neither affected druginduced hypotension nor bradycardia.19,23 In studies comparing insulin to more traditional therapies for druginduced cardiogenic shock such as epinephrine and glucagon, insulin improved cardiac function and work efficiency.21 Epinephrine and glucagon did not perform as well because they promoted free fatty acid utilization. As such, epinephrine and glucagon afforded limited increases in contractility at the expense of less efficient work due to increased oxygen demand.

CLINICAL EXPERIENCE Insulin-euglycemia therapy for drug-induced shock was first reported in 1999.39 This case series included four patients who overdosed on verapamil and one with combined amlodipine-atenolol overdose. All failed traditional antidote therapy, but responded to rescue insulin therapy. Since the initial case series, the author’s institution has treated six additional patients with rescue insulin therapy following inadequate response to standard antidotes, five of the six with good outcome. Sixty-seven cases appear in the literature that were treated at other institutions.2,3,5,10-13,16,25-29,31,33,34,36-38 Thus, there is an aggregate of 78 cases in which insulin was used. Of these cases, 72 primarily

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involved CCBs, five combined CCBs-BAAs, and one BAA. Various regimens of standard antidotes were used prior to insulin therapy and no case received insulin alone. Although no direct outcome comparisons can be made between insulin and standard therapies in these 78 cases, overall survival was 88% when insulin was included in resuscitation. Further review of these cases yields important clinical information that can be used to guide insulin therapy. Experimental models suggest that large doses of insulin (2.5 to 10 units of regular insulin/kg/h) may be necessary to provide inotropic support.1,18,21,23 However, humans appear to respond to less insulin. The most common doses given were 0.5 (n = 31) and 1.0 Units/kg/h (n = 19) of regular insulin in 62 patients where dose was reported. A few patients were treated with higher rates of infusion, up to 2.6 Units/kg/h in one case.36 Sixteen patients received an insulin bolus (10 to 100 Units) prior to continuous infusion. The theoretical advantage to giving an initial insulin bolus is to rapidly saturate insulin receptors to enhance the physiological response. Interestingly, one report noted that patients receiving an insulin bolus prior to the infusion showed a better blood pressure response than patients who received only a continuous infusion.10 Three patients received bolus insulin without continuous infusion, including a patient who inadvertently received 1000 units.34 In this case, hemodynamics improved and there was no adverse event related to the extreme insulin dose. The mean duration of insulin infusion in 24 patients was 33 hours with a range of 0.75 to 96 hours. The need for prolonged infusion likely reflects the prolonged effects and kinetics of cardiovascular drugs typically observed following overdose. The predominant clinical effect of insulin was increased contractility with subsequent blood pressure improvement. Contractility typically increased within 15 to 60 minutes after initiating insulin and often allowed a decrease in concurrent vasopressor requirements. The timing of increased contractility is consistent with the observed response times in animal models.18,23 Other salutary effects were observed during insulin therapy. In two cases, blood pressure increased directly because of increased vascular resistance rather than increased cardiac function.28,37 Two patients converted from third-degree heart block to normal sinus rhythm with increased pulse in temporal relationship to insulin.40 Except for these two patients, insulin therapy did not significantly affect heart rate in other reports. In four cases, authors reported a lack of response to insulin. Reasons for no response in three of these reports may include inadequate dose and excessive delay to insulin therapy.5

ADVERSE EVENTS The major anticipated adverse event associated with the use of large amounts of insulin, especially in insulin-naïve patients, is hypoglycemia, defined here as blood glucose less than 60 mg/dL (3.3 mmol/L) regardless of the presence or absence of symptoms. Because of potential hypoglycemia, all experimental animals received sufficient dextrose during insulin infusion to maintain euglycemia. In the aggregate human cases, patients typically received empiric supplemental dextrose as well as frequent glucose monitoring. The mean dextrose dose was 23 g/h, but requirements varied widely from 0.5 to 75 g/h (actual data only available in 14 cases). The duration of exogenous dextrose averaged 43 hours, but like the dextrose dose, also varied significantly from patient to patient (9-100 hours). Dextrose supplementation was sometimes necessary beyond cessation of insulin. In seven of 10 cases with evaluable data, dextrose was continued an average of 10 hours after stopping insulin. Despite empiric dextrose and blood glucose monitoring (albeit not standardized), hypoglycemia occurred in some

patients. In 58 cases where authors specifically document the presence or absence of complications related to insulin therapy, there were 10 patients with hypoglycemia. In five cases, insulin therapy was stopped because of hypoglycemia.27 These five patients were characterized as mildly hypotensive. If mildly toxic, they may have been more sensitive to insulin. In the remaining cases, euglycemia was restored and insulin treatment continued. Another anticipated consequence of insulin treatment is lowered serum potassium concentration. Although serum concentrations may at times fall below normal laboratory ranges, this change simply reflects shifting of potassium from the extracellular to intracellular space that occurs as a result of the action of insulin. In other words, patients maintain normal total body potassium stores and do not experience true deficiency unless they have other reasons for potassium loss. In the initial case series, three patients had a nadir of potassium ranging from 2.2 to 2.8 mEq/L without sequelae.39 There is a theoretical risk of excessive potassium replacement in the instance of lowered serum potassium, but normal total body stores, as hyperkalemia may worsen verapamil-induced myocardial depression.15,30 Other observed ion changes during insulin therapy include hypomagnesemia and hypophosphatemia. Similar to action on potassium, insulin causes an intracellular shift of both phosphorus and magnesium.17,32 Insulin (0.6 Units/kg/hr) for diabetic ketoacidosis is likewise associated with a marked decline of serum magnesium and phosphorus.14 In the initial series of drug-induced shock treated with insulin, four patients had lowered magnesium (0.4 to 0.6 mmol/L; normal 0.8 to 1.2 mmol/L) and phosphorus (0.2 to 0.5 mmol/L; normal 1 to 1.4 mmol/L) concentrations. No symptoms were attributed to lowered serum concentrations, but three patients received supplementation of both electrolytes. No other insulin-treated CCB cases address these two electrolytes.

INSULIN-EUGLYCEMIA TREATMENT GUIDELINES Based on the experimental studies and aggregate human cases, insulin-euglycemia is most likely going to benefit patients with cardiac drug-induced myocardial depression. Insulin-euglycemia may also be considered for those patients with hypotension due to poor vascular resistance without myocardial depression that does not respond to standard vasopressor treatment. Lastly, it is reasonable to initiate empiric insulin-euglycemia if a delay to cardiac diagnostic studies is expected. The experimental evidence and human case experience is strongest for CCB toxicity. Animal studies and limited human experience also support its use for BAA intoxication. Myocardial function can be estimated at the bedside via emergency department ultrasonography or more formally via echocardiography or placement of a pulmonary artery catheter. When decreased myocardial function is present, insulin therapy can be used by first administering a 1 Unit/kg bolus of regular human insulin along with 0.5 g/kg of dextrose. If blood glucose is greater than 400 mg/dL (22.2 mmol/L), the dextrose bolus is not necessary. An infusion of regular insulin should follow the bolus starting at 0.5 to 1 Unit/kg/h. A continuous dextrose infusion, beginning at 0.5 g/kg/h should also be started. Dextrose is best delivered as D25W or D50W via central venous access to lessen large fluid volumes that would otherwise be necessary with administration of more dilute dextrose solutions. Patients with markedly elevated blood glucose may not require dextrose support at the start of insulin therapy. If possible, cardiac function should be reassessed every 20 to 30 minutes after starting insulin-euglycemia therapy. If cardiac function

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remains depressed or there is persistent hypotension, the insulin dose can be increased. Doses up to 2.5 Units/kg/h have been used, although the maximum dose is not established in humans. The blood glucose should be monitored every 30 minutes until stable and then every 1 to 2 hours. The dextrose infusion should be titrated to keep blood glucose between 100 and 250 mg/dL (5.5 to 14 mmol/L). The serum potassium concentration should be measured during insulin-euglycemia therapy. If it is low, especially when potassium loss is suspected, then supplementation to maintain the concentration in the “mildly hypokalemic” range (2.8 to 3.2 mEq/L) can be given. Magnesium and phosphorus can also be measured and supplemented as medically indicated. However, unless there is reason for loss of these three electrolytes, lowered serum concentrations likely reflect compartmental shifts, not depletion. The ultimate goal of insulin-euglycemia is improvement in organ perfusion as demonstrated by increased blood pressure, improved mental status, and adequate urine output. Other markers of effective insulin-euglycemia therapy are reversal of acidemia and decreasing lactate concentrations. An increase in dextrose infusion to maintain euglycemia often accompanies hemodynamic and metabolic improvements. This is due to drug metabolism and loss of the drug-induced diabetogenic influences, and can be regarded as a favorable prognostic indicator.

REFERENCES 1. Bechtel LK, Haverstick DM, Holstege CP. Verapamil toxicity dysregulates the phosphatidylinositol 3-kinase pathway. Acad Emerg Med. 2008;15: 368-374. 2. Boyer EW, Duic PA, Evans A. Hyperinsulinemia/euglycemia therapy for calcium channel blocker poisoning. Pediatr Emerg Care. 2002;18:36-37. 3. Boyer EW, Shannon M. Treatment of calcium-channel-blocker intoxication with insulin infusion. N Engl J Med. 2001;344:1721-1722. 4. Buiumsohn A, Eisenberg ES, Jacob H, Rosen N, Bock J, Frishman WH. Seizures and intraventricular conduction defect in propranolol poisoning. A report of two cases. Ann Intern Med. 1979;91:860-862. 5. Cumpston K, Mycyk M, Pallasch E, et al. Failure of hyperinsulinemia/ euglycemia therapy in severe diltiazem overdose. J Toxicol Clin Toxicol. 2002; 40:618 (abstract). 6. Devis G, Somers G, Obberghen E, Malaisse WJ. Calcium antagonists and islet function. I. Inhibition of insulin release by verapamil. Diabetes. 1975;24: 247-251. 7. DeWitt CR, Waksman JC. Pharmacology, pathophysiology, and management of calcium channel blocker and beta-blocker toxicity. Toxicol Rev. 2004;23: 223-238. 8. Draznin B. Intracellular calcium, insulin secretion, and action. Am J Med. 1988; 85:44-58. 9. Enyeart JJ, Price WA, Hoffman DA, Woods L. Profound hyperglycemia and metabolic acidosis after verapamil overdose. J Am Coll Cardiol. 1983;2: 1228-1231. 10. Greene SL, Gawarammana IB, Wood DM, Jones AE, Dargan PI. Relative safety of hyperinsulinaemia/euglycaemia in the management of calcium channel blocker overdose: a prospective observational study. Intensive Care Med. 2007;33:2019-2024. 11. Harris NS. Case records of the Massachusetts General Hospital. Case 24-2006. A 40-year-old woman with hypotension after an overdose of amlodipine. N Engl J Med. 2006;355:602-611. 12. Hasin T, Lebowitz D, Antopolsky M. The use of low-dose insulin in cardiogenic shock due to combined overdose of verapamil, enalapril and metoprolol. Cardiology. 2006;106:233-236. 13. Herbert JX, O’Malley C, Tracey JA, Dwyer R, Power M. Verapamil overdosage unresponsive to dextrose/insulin therapy. J Toxicol Clin Toxicol. 2001;39: 293-294 (abstract). 14. Ionescu-Tirgoviste C, Bruckner I, Mihalache N, Ionescu C. Plasma phosphorus and magnesium values during treatment of severe diabetic ketoacidosis. Med Intern. 1981;19:66-68.

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15. Jolly SR, Keaton N, Movahed A, Rose GC, Reeves WC. Effect of hyperkalemia on experimental myocardial depression by verapamil. Am Heart J. 1991;121: 517-523. 16. Kanagarajan K, Marraffa JM, Bouchard NC, Krishnan P, Hoffman RS, Stork CM. The use of vasopressin in the setting of recalcitrant hypotension due to calcium channel blocker overdose. Clin Toxicol. 2007;45:56-59. 17. Kebler R, McDonald FD, Cadnapaphornchai P. Dynamic changes in serum phosphorus levels in diabetic ketoacidosis. Am J Med. 1985;79:571-576. 18. Kerns W, Schroeder JD, Williams C, Tomaszewski CA, Raymond RM. Insulin improves survival in a canine model of acute beta-blocker toxicity. Ann Emerg Med. 1997;29:748-757. 19. Kline J, Leonova E, Raymond RM. Beneficial myocardial metabolic effects of insulin during verapamil toxicity in the anesthetized canine. Crit Care Med. 1995;23:1251-1263. 20. Kline JA, Leonova E, Williams TC, Schroeder JD, Watts JA. Myocardial metabolism during graded intraportal verapamil infusion in awake dogs. J Cardiovasc Pharmacol. 1996;27:719-726. 21. Kline JA, Raymond RM, Leonova E, Winter M, Watts JA. Insulin improves heart function and metabolism during non-ischemic cardiogenic shock in awake canines. Cardiovasc Res. 1997;34:289-298. 22. Kline JA, Raymond RM, Schroeder JD, Watts JA. The diabetogenic effects of acute verapamil poisoning. Toxicol Appl Pharmacol. 1997;145:357-362. 23. Kline JA, Tomaszewski CA, Schroeder JD, Raymond RM. Insulin is a superior antidote for cardiovascular toxicity induced by verapamil in the anesthetized canine. J Pharmacol Exp Ther. 1993;267:744-750. 24. Lucchesi BR, Medina M, Kniffen FJ. The positive inotropic actions of insulin in the canine heart. Eur J Pharmacol. 1972;18:107-115. 25. Marques M, Gomes E, de Oliviera J. Treatment of calcium channel blocker intoxication with insulin infusion: case report and literature review. Resuscitation. 2003;57:211-213. 26. Masters TN, Glaviano VV. Effects of d,l-propranolol on myocardial free fatty acid and carbohydrate metabolism. J Pharmacol Exp Ther. 1969;167:187-193. 27. Meyer M, Stremski E, Scanlon M. Verapamil-induced hypotension reversed with dextrose-insulin. J Toxicol Clin Toxicol. 2001;39:500 (abstract). 28. Miller AD, Maloney GE, Kanter MZ, DesLauriers CM, Clifton JC. Hypoglycemia in patients treated with high-dose insulin for calcium channel blocker poisoning. J Toxicol Clin Toxicol. 2006;44:782-783 (abstract). 29. Min L, DeshPande K. Diltiazem overdose haemodynamic response to hyperinsulinaemia-euglycemia therapy: a case report. Crit Care Resusc. 2004;6:28-30. 30. Morris-Kukoski CL, Biswas AK, Parra M, Smith C. Insulin “euglycemia” therapy for accidental nifedipine overdose. J Toxicol Clin Toxicol. 2000;38:577 (abstract). 31. Nugent M, Tinker JH, Moyer TP. Verapamil worsens rate of development and hemodynamic effects of acute hyperkalemia in halothane-anesthetized dogs: effects of calcium therapy. Anesthesiology. 1984;60:435-439. 32. Ortiz-Munoz L, Rodriguez-Ospina LF, Figeroa-Gonzalez M. Hyperinsulinemiaeuglycemia therpay for intoxication with calcium channel blockers. Boletin Associacion Medica de Puerto Rico. 2005;97:182-189. 33. Paolisso G, Sgambato S, Passariello N, et al. Insulin induces opposite changes in plasma and erythrocyte magnesium concentrations in man. Diabetologia. 1986;29:644-647. 34. Place R, Carlson A, Leiken J, Hanashiro P. Hyperinsulin therapy in the treatment of verapamil overdose. J Toxicol Clin Toxicol. 2000;38:576-577 (abstract). 35. Rasmussen L, Husted SE, Johnsen SP. Severe intoxication after an intentional overdose of amlodipine. Acta Anaesthesiol Scand. 2003;47:1038-1040. 36. Reikeras O, Gunnes P, Sorlie D, Ekroth R, Jorde R, Mjos OD. Metabolic effects of high doses of insulin during acute left ventricular failure in dogs. Eur Heart J. 1985;6:451-457. 37. Smith SW, Ferguson KL, Hoffman RS, Nelson LS, Greller HA. Prolonged severe hypotension following combined amlodipine and valsartan ingestion. Clin Toxicol. 2008;46:470-474. 38. Verbrugge LB, van Wezel HB. Pathophysiology of verapamil overdose: new insights in the role of insulin. J Cardiothorac Vasc Anesth. 2007;21:406-409. 39. Vogt S, Mehlig A, Hunziker P, et al. Survival of severe amlodipine intoxication due to medical intensive care. Forensic Sci Int. 2006;161:216-220. 40. Yuan TH, Kerns WP, Tomaszewski CA, Ford MD, Kline JA. Insulinglucose as adjunctive therapy for severe calcium channel antagonist poisoning. J Toxicol Clin Toxicol. 1999;37:463-467.

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CHAPTER 61

a-ADRENERGIC ANTAGONISTS Jeffrey R. Brubacher

generically named α and β receptors. At that time, the contemporary “antiepinephrines,” such as phenoxybenzamine, reversed the hypertension but not the tachycardia associated with epinephrine. According to Alquist’s theory, these drugs acted at the α-adrenergic receptors. The β-adrenergic receptors, in his schema, mediated catecholamine-induced tachycardia. The British pharmacist Sir James Black was influenced by Alquist’s work and recognized the potential clinical benefit of a β-adrenergic antagonist. In 1958, Black synthesized the first β-adrenergic antagonist, pronethalol. This drug was briefly marketed as Alderlin, named after Alderly Park, the research headquarters of ICI Pharmaceuticals. Pronethalol was discontinued because it produced thymic tumors in mice. Propranolol was soon developed and marketed as Inderal (an incomplete anagram of Alderlin) in the United Kingdom in 196417,146 and in the United States in 1973. Before the introduction of β-adrenergic antagonists, the management of angina was limited to medications such as nitrates that reduced preload through dilatation of the venous capacitance vessels and increased myocardial oxygen delivery by vasodilation of the coronary arteries. Propranolol gave clinicians the ability to decrease myocardial oxygen utilization. This new approach proved to decrease morbidity and mortality in patients with ischemic heart disease.74 New drugs soon followed, and by 1979 there were ten β-adrenergic antagonists available in the United States.37 Unfortunately it soon became apparent that these medications were dangerous when taken in overdose, and by 1979 cases of severe toxicity and death from β-adrenergic overdose were reported.37 Today 19 β-adrenergic antagonists are approved by the Food and Drug Administration (FDA), and other β-adrenergic antagonists are available worldwide (Table 61–1).

EPIDEMIOLOGY

The pharmacology, toxicology, and poison management issues discussed in this chapter are applicable to all of the β-adrenergic antagonists. They are commonly used in the treatment of patients with cardiovascular disease, including hypertension, coronary artery disease, and tachydysrhythmias. Additional indications for β-adrenergic antagonists include congestive heart failure, migraine headaches, benign essential tremor, panic attack, stage fright, and hyperthyroidism. Ophthalmic preparations containing β-adrenergic antagonists are used in the treatment of glaucoma.56 The diverse indications have led to complex toxicologic emergencies from intentional and unintentional overdoses as well as adverse drug reactions and drug–drug interactions. The management of patients with β-adrenergic antagonist overdoses is complicated by the lack of a routine strategy or a simple antidote. It is for these reasons that this class of xenobiotics remains intensely under study.

HISTORY In 1948, Raymond Alquist postulated that epinephrine’s cardiovascular actions of hypertension and tachycardia were best explained by the existence of two distinct sets of receptors that he

Intentional β-adrenergic antagonist overdose, although relatively uncommon, continues to account for a number of deaths annually. From 1985 to 1995, there were 52,156 β-adrenergic antagonist exposures reported to the American Association of Poison Control Centers (see Chap. 135). These exposures accounted for 164 deaths of which β-adrenergic antagonists were implicated as the primary cause of death in 38. The other fatalities could not be clearly ascribed to β-adrenergic antagonists because of cardioactive co-ingestants such as calcium channel blockers or other factors. Children younger than age 6 years accounted for 19,388 exposures, but no fatalities were reported in this age group. The youngest fatality reported in this series was 7 years old. It is interesting to note that more than 50% of the patients who died developed cardiac arrest after reaching healthcare personnel.91 The number of exposures to β-adrenergic antagonists reported to the National Poison Data System (NPDS) has increased annually from 9500 in 1999 to nearly 20,000 in 2007. Each year in this period, β-adrenergic antagonist exposures resulted in 200 to 400 cases with a “major toxic effect” and 20 to more than 40 deaths. This changed in 2006, when deaths and major morbidity were only tabulated for singlesubstance exposures. In 2007, β-adrenergic antagonists were the sole ingestant in 61 exposures, with major morbidity and three deaths (see Chap. 135). Compared with the other β-adrenergic antagonists, propranolol accounts for a disproportionate number of cases of self-poisoning25,117 and deaths.72,91 This may be explained by the fact that propranolol is frequently prescribed to patients with diagnoses such as anxiety, stress, and migraine who may be more prone to suicide attempts.117 Propranolol is also more lethal because of its lipophilic and membrane stabilizing properties.51,117

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β-Adrenergic Antagonists

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TABLE 61–1. Pharmacologic Properties of the β-adrenergic Antagonists38,51,109,154,101,165 Adrenergic Partial Membrane Antagonist Agonist Stabilizing Vasodilating Activity Activity (ISA) Activity Property

Protein Lipid Binding Solubility (%)

Oral Bioavailability (%)

Half-Life (h)

Metabolism

Volume of Distribution (L/kg)

β1 β1 β1

Yes No No

Yes No Yes

Low Low Low

40 40–50 80–90

2–4 5–9 14–22

Hepatic or renal Renal Hepatic or renal

1.2 1 NA

β1 β1, β2

No No

No

Low 30 Moderate

8 30

9–12 8 ± 4.5

Hepatic or renal Hepatic

NA NA

Carteolol β1, β2 (ophthalmic)

Yes

No

Low

85

5–6

Renal

NA

Yes

Moderate ∼98

25–35

6–10

Hepatic

115

Low

30–70

5

Hepatic

NA

Low 50 Moderate 50

NA 20–33

∼8 min 4–8

RBC esterases Hepatic

2 9

NA

NA

NA

6

NA

NA

NA

NA

3–4

NA

NA

Acebutolol∗ Atenolol Betaxolol (tablets and ophthalmic) Bisoprolol Bucindolola

a

Carvedilol

β1, β2, α1

No

Celiprolola

α2, β1

No

Esmolol Labetalol

β1 α1, β1, β2

No β2

No Low

Levobunolol (ophthalmic) Metipranolol (ophthalmic) Metoprolol (long-acting form available) Nadolol Nebivolola

β1, β2

No

No

No No Yes (Calcium channel blockade) No Yes (β2-agonism and α1 blockade) Yes (β2-agonism and nitric oxide mediated) Yes (α1 blockade; calcium channel blockade) Yes (β2-agonism, nitric oxide mediated) No Yes (α1 blockade, β2 agonism) No

25 90 μg/mL and any symptom 2. Serum theophylline or caffeine concentration >40 μg/mL and A. Seizures B. Hypotension unresponsive to intravenous fluid or C. Ventricular dysrhythmias

studies and clinical experience are the basis for the following suggested indications for extracorporeal elimination by charcoal hemoperfusion, hemodialysis, combined charcoal hemoperfusion and hemodialysis, or combined hemodialysis and MDAC. Many recommendations regarding hemoperfusion and hemodialysis for theophylline toxicity use serum theophylline concentration as a guideline. Serum levels may not be available in instances of caffeine poisoning and do not exist for theobromine poisoning. Thus, the clinical aspects of theophylline management guidelines can be generalized to all methylxanthine toxicities. When indicated, hemodialysis preferably should be initiated while the patient is still hemodynamically stable. Hemodialysis therapy should be used for patients with consequential chronic theophylline poisoning associated with a serum theophylline concentration above 40 to 60 μg/mL or with a deteriorating clinical status. Hemodialysis should be strongly considered any time a methylxanthine exposure results in a serum theophylline or caffeine concentration of greater than 90 μg/mL and symptoms, regardless of clinical stability (Table 65–2). Any patient with a symptomatic methylxanthine poisoning that is associated with ventricular dysrhythmias, seizures, hypotension unresponsive to fluids, or emesis unresponsive to antiemetics should also be treated with charcoal hemoperfusion, hemodialysis, or both. The fact that a patient experiences seizure or dysrhythmias or becomes extremely ill is not a contraindication for extracorporeal drug removal. To the contrary, these events make administration of such therapy more critical to ensure survival of the patient.

■ TREATMENT OF CHRONIC METHYLXANTHINE TOXICITY Treatment of chronic methylxanthine toxicity is determined by the patient’s clinical status and by the efficacy of MDAC. The precise serum theophylline or caffeine concentration at which patients with chronic theophylline or caffeine toxicity should receive hemodialysis is controversial. For a hemodynamically stable patient without signs of life-threatening methylxanthine toxicity such as ventricular dysrhythmias or seizure, therapy with MDAC may be sufficient. If the serum theophylline or caffeine concentration does not decline after the administration of AC or if the patient’s clinical status deteriorates, hemodialysis is indicated.

■ TREATMENT OF ACUTE-ON-CHRONIC METHYLXANTHINE TOXICITY Patients chronically receiving theophylline or caffeine who acutely overdose should be initially managed in the same manner as patients with acute overdose, although action concentrations for dialysis are the same for chronic toxicity. Total body stores of the methylxanthines are

higher in patients who are chronically exposed, and the threshold for toxicity may be reached at lower serum concentrations.

SUMMARY Selective β2AAs were widely used for the treatment of bronchospasm. Selective β2AA toxicity typically results from excessive therapeutic use of these agents, but illicit use of clenbuterol or admixture of clenbuterol with drugs of abuse has become prominent. Methylxanthine toxicity results from both the use of medicinal and therapeutic agents as well as from consumption of methylxanthine-containing foods and beverages. There are significant differences in the clinical presentation and management of patients with acute and chronic methylxanthine poisoning. Supportive care and treatment of GI, cardiovascular, CNS, metabolic, and musculoskeletal toxicities are the mainstay of therapy. The unique properties of methylxanthines necessitate specific therapies for the GI, cardiovascular, and CNS toxicities of methylxanthines. With some unique exceptions, selective β2AA toxicity is usually well tolerated and only requires supportive care. Clenbuterol is such an exception, and toxicity from this substance is typically more severe than that from other β2AA. For this reason, clenbuterol toxicity should be managed with greater caution and cognizance for the potential for severe morbidity and possible mortality from this substance. Methods of enhanced elimination, particularly extracorporeal elimination by charcoal hemoperfusion, hemodialysis, or charcoal hemoperfusion and hemodialysis in series, as well as gut dialysis with MDAC, are effective treatments for patients with methylxanthine toxicity. Supportive care is typically the management strategy for β2AAs.

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Methylxanthines and Selective β 2 Adrenergic Agonists

15. Astrup A. Thermogenic drugs as a strategy for treatment of obesity. Endocrine. 2000;13:207-212. 16. Bania TC, Hoffman RS, Howland MA, et al. Plasmapheresis for theophylline intoxication. Vet Hum Toxicol. 1992;34:330. 17. Banner W Jr, Czajka PA. Acute caffeine overdose in the neonate. Am J Dis Child. 1980;134:495-498. 18. Barbosa J, Cruz C, Martins J, et al. Food poisoning by clenbuterol in Portugal. Food Additives & Contaminants. 2005;22:563-566. 19. Bell DG, Jacobs I, Zamecnik J. Effects of caffeine, ephedrine and their combination on time to exhaustion during high-intensity exercise. Eur J Appl Physiol Occup Physiol. 1998;77:427-433. 20. Bender BG, Ikle DN, DuHamel T, Tinkelman D. Neuropsychological and behavioral changes in asthmatic children treated with beclomethasone dipropionate versus theophylline. Pediatrics. 1998;101:355-360. 21. Bender PR, Brent J, Kulig K. Cardiac arrhythmias during theophylline toxicity. Chest. 1991;100:884-886. 22. Benowitz NL, Osterloh J, Goldschlager N, et al. Massive catecholamine release from caffeine poisoning. JAMA. 1982;248:1097-1098. 23. Berlinger WG, Spector R, Goldberg MJ, et al. Enhancement of theophylline clearance by oral activated charcoal. Clin Pharmacol Ther. 1983;33:351-354. 24. Bernard S. Severe lactic acidosis following theophylline overdose. Ann Emerg Med. 1991;20:1135-1137. 25. Bernstein GA, Carroll ME, Crosby RD, et al. Caffeine effects on learning, performance, and anxiety in normal school-age children. J Am Acad Child Adolesc Psychiatry. 1994;33:407-415. 26. Biberstein MP, Ziegler MG, Ward DM. Use of beta-blockade and hemoperfusion for acute theophylline poisoning. West J Med. 1984;141:485-490. 27. Blake KV, Massey KL, Hendeles L, et al. Relative efficacy of phenytoin and phenobarbital for the prevention of theophylline-induced seizures in mice. Ann Emerg Med. 1988;17:1024-1028. 28. Bloss JD, Hankins GD, Gilstrap LC 3rd, Hauth JC. Pulmonary edema as a delayed complication of ritodrine therapy. A case report. J Reprod Med. 1987;32:469-471. 29. Bodenhamer J, Bergstrom R, Brown D, et al. Frequently nebulized betaagonists for asthma: effects on serum electrolytes. Ann Emerg Med. 1992;21:1337-1342. 30. Bonati M, Latini R, Sadurska B, et al. Kinetics and metabolism of theobromine in male rats. Toxicology. 984;30:327-341. 31. Bory C, Baltassat P, Porthault M, et al. Metabolism of theophylline to caffeine in premature newborn infants. J Pediatr. 1979;94:988-993. 32. Brouard C, Moriette G, Murat I, et al. Comparative efficacy of theophylline and caffeine in the treatment of idiopathic apnea in premature infants. Am J Dis Child. 1985;139:698-700. 33. Brown CR, Jacob P 3rd, Wilson M, Benowitz NL. Changes in rate and pattern of caffeine metabolism after cigarette abstinence. Clin Pharmacol Ther. 1988;43:488-491. 34. Bruce CR, Anderson ME, Fraser SF, et al. Enhancement of 2000-m rowing performance after caffeine ingestion. Med Sci Sports Exerc. 2000;32: 1958-1963. 35. Bryant CA, Farmer A, Tiplady B, et al. Psychomotor performance: investigating the dose-response relationship for caffeine and theophylline in elderly volunteers. Eur J Clin Pharmacol. 1998;54:309-313. 36. Burgess E, Sargious P. Charcoal hemoperfusion for theophylline overdose: case report and proposal for predicting treatment time. Pharmacotherapy. 1995;15:621-624. 37. Burkhart KK, Wuerz RC, Donovan JW. Whole-bowel irrigation as adjunctive treatment for sustained-release theophylline overdose. Ann Emerg Med. 1992;21:1316-1320. 38. Centers for Disease Control and Prevention. Atypical reactions associated with heroin use—five states, January–April 2005. MMWR Morbid Mortal Wkly Rep. 2005;54:793-796. 39. Cereda JM, Scott J, Quigley EM. Endoscopic removal of pharmacobezoar of slow release theophylline. Br Med J (Clin Res Ed). 1986;293:1143. 40. Chang TM, Espinosa-Melendez E, Francoeur TE, Eade NR. Albumincollodion activated charcoal hemoperfusion in the treatment of severe theophylline intoxication in a 3-year-old patient. Pediatrics. 1980;65:811-814. 41. Chazan R, Karwat K, Tyminska K, et al. Cardiac arrhythmias as a result of intravenous infusions of theophylline in patients with airway obstruction. Int J Clin Pharmacol Ther 1995;33:170-175. 42. Chelben J, Piccone-Sapir A, Ianco J, et al. Effects of amino acid energy drinks leading to hospitalization in individuals with mental illness. Gen Hosp Psychiatry. 2008;30:187-189.

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43. Chiang VW, Burns JP, Rifai N, et al. Cardiac toxicity of intravenous terbutaline for the treatment of severe asthma in children: a prospective assessment. J Pediatr. 2000;137:73-77. 44. Cohen BS, Nelson AG, Prevost MC, et al. Effects of caffeine ingestion on endurance racing in heat and humidity. Eur J Appl Physiol Occup Physiol. 1996;73:358-363. 45. Cohen S, Booth GH, Jr. Gastric acid secretion and lower-esophagealsphincter pressure in response to coffee and caffeine. N Engl J Med. 1975; 293:897-899. 46. Conolly ME, Tashkin DP, Hui KK, et al. Selective subsensitization of betaadrenergic receptors in central airways of asthmatics and normal subjects during long-term therapy with inhaled salbutamol. J Allergy Clin Immunol. 1982;70:423-431. 47. Craig TJ, Smits W, Soontornniyomkiu V. Elevation of creatine kinase from skeletal muscle associated with inhaled albuterol. Ann Allergy Asthma Immunol. 1996;77:488-490. 48. Craig VL, Bigos D, Brilli RJ. Efficacy and safety of continuous albuterol nebulization in children with severe status asthmaticus. Pediatr Emerg Care. 1996;12:1-5. 49. Czuczwar SJ, Janusz W, Wamil A, Kleinrok Z. Inhibition of aminophylline-induced convulsions in mice by antiepileptic drugs and other agents. Eur J Pharmacol. 1987;144:309-315. 50. Dalvi RR. Acute and chronic toxicity of caffeine: a review. Vet Hum Toxicol. 1986;28:144-150. 51. Daly D, Taylor JN. Ondansetron in theophylline overdose. Anaesth Intensive Care. 1993;21:474-475. 52. Datto C, Rai AK, Ilivicky HJ, Caroff SN. Augmentation of seizure induction in electroconvulsive therapy: a clinical reappraisal. J ECT. 2002;18: 118-125. 53. Daubert GP, Mabasa VH, Leung VW, Aaron C. Acute clenbuterol overdose resulting in supraventricular tachycardia and atrial fibrillation. J Med Toxicol. 2007;3:56-60. 54. Denaro CP, Wilson M, Jacob P,3rd, Benowitz NL. The effect of liver disease on urine caffeine metabolite ratios. Clin Pharmacol Ther. 1996;59: 624-635. 55. Derlet RW, Tseng JC, Albertson TE. Potentiation of cocaine and d-amphetamine toxicity with caffeine. Am J Emerg Med. 1992;10:211-216. 56. Dettloff RW, Touchette MA, Zarowitz BJ. Vasopressor-resistant hypotension following a massive ingestion of theophylline. Ann Pharmacother. 1993;27:781-784. 57. Drolet R, Arendt TD, Stowe CM. Cacao bean shell poisoning in a dog. J Am Vet Med Assoc. 1984;185:902. 58. Drouillard DD, Vesell ES, Dvorchik BH. Studies on theobromine disposition in normal subjects: alterations induced by dietary abstention from or exposure to methylxanthines. Clin Pharmacol Ther. 1978;23:296-302. 59. Eldridge FL, Paydarfar D, Scott SC, Dowell RT. Role of endogenous adenosine in recurrent generalized seizures. Exp Neurol. 1989;103:179-185. 60. Falk B, Burstein R, Ashkenazi I, et al. The effect of caffeine ingestion on physical performance after prolonged exercise. Eur J Appl Physiol Occup Physiol. 1989;59:168-173. 61. Fisher AA, Davis MW, McGill DA. Acute myocardial infarction associated with albuterol. Ann Pharmacother. 2004;38:2045-2049. 62. Fligner CL, Opheim KE. Caffeine and its dimethylxanthine metabolites in two cases of caffeine overdose: a cause of falsely elevated theophylline concentrations in serum. J Anal Toxicol. 1988;12:339-343. 63. Folsom AR, McKenzie DR, Bisgard KM, et al. No association between caffeine intake and postmenopausal breast cancer incidence in the Iowa Women’s Health Study. Am J Epidemiol. 1993;138:380-383. 64. Forman J, Aizer A, Young CR. Myocardial infarction resulting from caffeine overdose in an anorectic woman. Ann Emerg Med. 1997;29:178-180. 65. Fredholm BB. Theophylline actions on adenosine receptors. Eur J Respir Dis Suppl. 1980;109:29-36. 66. Fried RE, Levine DM, Kwiterovich PO, et al. The effect of filtered-coffee consumption on plasma lipid levels. results of a randomized clinical trial. JAMA. 1992;267:811-815. 67. Friedman L, Weinberger MA, Farber TM, et al. Testicular atrophy and impaired spermatogenesis in rats fed high levels of the methylxanthines caffeine, theobromine, or theophylline. J Environ Pathol Toxicol. 1979;2:687-706. 68. Gaar GG, Banner W Jr, Laddu AR. The effects of esmolol on the hemodynamics of acute theophylline toxicity. Ann Emerg Med. 1987;16: 1334-1339.

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69. Gal P, Miller A, McCue JD. Oral activated charcoal to enhance theophylline elimination in an acute overdose. JAMA. 1984;251:3130-3131. 70. Gartrell BD, Reid C. Death by chocolate: a fatal problem for an inquisitive wild parrot. N Z Vet J. 2007;55:149-151. 71. Giacoia G, Jusko WJ, Menke J, Koup JR. Theophylline pharmacokinetics in premature infants with apnea. J Pediatr. 1976;89:829-832. 72. Gilbert SG, Rice DC. Somatic development of the infant monkey following in utero exposure to caffeine. Fundam Appl Toxicol. 1991;17:454-465. 73. Goldberg MJ, Spector R, Miller G. Phenobarbital improves survival in theophylline-intoxicated rabbits. J Toxicol Clin Toxicol. 1986;24:203-211. 74. Graham TE, Rush JW, van Soeren MH. Caffeine and exercise: metabolism and performance. Can J Appl Physiol. 1994;19:111-138. 75. Graham TE, Spriet LL. Metabolic, catecholamine, and exercise performance responses to various doses of caffeine. J Appl Physiol. 1995;78: 867-874. 76. Greenway FL. The safety and efficacy of pharmaceutical and herbal caffeine and ephedrine use as a weight loss agent. Obes Rev. 2001;2:199-211. 77. Griffiths RR, Woodson PP. Caffeine physical dependence: a review of human and laboratory animal studies. Psychopharmacology (Berl). 1988;94:437-451. 78. Grobbee DE, Rimm EB, Giovannucci E, et al. Coffee, caffeine, and cardiovascular disease in men. N Engl J Med. 1990;323:1026-1032. 79. Grygiel JJ, Birkett DJ. Cigarette smoking and theophylline clearance and metabolism. Clin Pharmacol Ther. 1981;30:491-496. 80. Hadeed A, Siegel S. Newborn cardiac arrhythmias associated with maternal caffeine use during pregnancy. Clin Pediatr (Phila). 1993;32:45-47. 81. Hagley MT, Traeger SM, Schuckman H. Pronounced metabolic response to modest theophylline overdose. Ann Pharmacother. 1994;28:195-196. 82. Hall KW, Dobson KE, Dalton JG, et al. Metabolic abnormalities associated with intentional theophylline overdose. Ann Intern Med. 1984;101: 457-462. 83. Haller CA, Benowitz NL. Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids. N Engl J Med. 2000;343:1833-1838. 84. Hanington E, Bell H. Suspected chocolate poisoning of calves. Vet Rec. 1972;90:408-409. 85. Hantson P, Gautier P, Vekemans MC, et al. Acute myocardial infarction in a young woman: possible relationship with sustained-release theophylline acute overdose? Intensive Care Med. 1992;18:496. 86. Hayes AH. New drug status of OTC combination products containing caffeine, phenylpropanolamine, and ephedrine. Fed Reg. 1982;47:3534435346. 87. Hoffman A, Pinto E, Gilhar D. Effect of pretreatment with anticonvulsants on theophylline-induced seizures in the rat. J Crit Care. 1993;8:198-202. 88. Hoffman RS, Chiang WK, Howland MA, et al. Theophylline desorption from activated charcoal caused by whole bowel irrigation solution. J Toxicol Clin Toxicol. 1991;29:191-201. 89. Hootkins RS, Lerman MJ, Thompson JR. Sequential and simultaneous “in series” hemodialysis and hemoperfusion in the management of theophylline intoxication. J Am Soc Nephrol. 1990;1:923-926. 90. Huang JD. Kinetics of theophylline clearance in gastrointestinal dialysis with charcoal. J Pharm Sci. 1987;76:525-527. 91. Infante-Rivard C, Fernandez A, Gauthier R, et al. Fetal loss associated with caffeine intake before and during pregnancy. JAMA. 1993;270:2940-2943. 92. Jackson SH, Johnston A, Woollard R, Turner P. The relationship between theophylline clearance and age in adult life. Eur J Clin Pharmacol. 1989;36: 29-34. 93. Jacobs MH, Senior RM. Theophylline toxicity due to impaired theophylline degradation. Am Rev Respir Dis. 1974;110:342-345. 94. Jacobson BH, Thurman-Lacey SR. Effect of caffeine on motor performance by caffeine-naive and familiar subjects. Percept Mot Skills. 1992;74: 151-157. 95. James JE. Critical review of dietary caffeine and blood pressure: a relationship that should be taken more seriously. Psychosom Med. 2004;66:63-71. 96. January B, Seibold A, Whaley B, et al. Beta2-adrenergic receptor desensitization, internalization, and phosphorylation in response to full and partial agonists. J Biol Chem. 1997;272:23871-23879. 97. Jenny RW, Jackson KY. Two types of error found with the seralyzer ARIS assay of theophylline. Clin Chem. 1986;32:2122-2123. 98. Jensen TK, Henriksen TB, Hjollund NH, et al. Caffeine intake and fecundability: a follow-up study among 430 Danish couples planning their first pregnancy. Reprod Toxicol. 1998;12:289-295.

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Methylxanthines and Selective β 2 Adrenergic Agonists

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188. Victor BS, Lubetsky M, Greden JF. Somatic manifestations of caffeinism. J Clin Psychiatry. 1981;42:185-188. 189. Vozeh S, Powell JR, Riegelman S, et al. Changes in theophylline clearance during acute illness. JAMA. 1978;240:1882-1884. 190. Wang-Cheng R, Davidson BJ. Ritodrine-induced neutropenia. Am J Obstet Gynecol. 1986;154:924-925. 191. Wasserman D, Amitai Y. Hypoglycemia following albuterol overdose in a child. Am J Emerg Med. 1992;10:556-557. 192. Weinberger M, Bronsky E, Bensch GW, et al. Interaction of ephedrine and theophylline. Clin Pharmacol Ther. 1975;17:585-592. 193. Whitehurst VE, Joseph X, Vick JA, et al. Reversal of acute theophylline toxicity by calcium channel blockers in dogs and rats. Toxicology. 1996;110:113-121. 194. Wiley JF 2nd, Spiller HA, Krenzelok EP, Borys DJ. Unintentional albuterol ingestion in children. Pediatr Emerg Care. 1994;10:193-196.

195. Willett WC, Stampfer MJ, Manson JE, et al. Coffee consumption and coronary heart disease in women. A ten-year follow-up. JAMA. 1996;275: 458-462. 196. Woo OF, Pond SM, Benowitz NL, Olson KR. Benefit of hemoperfusion in acute theophylline intoxication. J Toxicol Clin Toxicol. 1984;22:411424. 197. Wrenn KD, Oschner I. Rhabdomyolysis induced by a caffeine overdose. Ann Emerg Med. 1989;18:94-97. 198. Yeh TF, Pildes RS. Transplacental aminophylline toxicity in a neonate. Lancet. 1977;1:910. 199. Young D, Dragunow M. Status epilepticus may be caused by loss of adenosine anticonvulsant mechanisms. Neuroscience. 1994;58:245-261. 200. Yurchak AM, Jusko WJ. Theophylline secretion into breast milk. Pediatrics. 1976;57:518-520.

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F. ANESTHETICS AND RELATED MEDICATIONS

CHAPTER 66

LOCAL ANESTHETICS David R. Schwartz and Brian Kaufman Local anesthetics are xenobiotics that block excitation of, and transmission along, a nerve axon in a predictable and reversible manner. The anesthesia produced is selective to the chosen body part in contrast to the nonselective effects of a general anesthetic. Local anesthetics do not require the circulation as an intermediate carrier, and they usually are not transported to distant organs. Therefore, the actions of local anesthetics are largely confined to the structures with which they come into direct contact. Local anesthetics may provide analgesia in various parts of the body by topical application, injection in the vicinity of peripheral nerve endings and major nerve trunks, or via instillation within the epidural or subarachnoid spaces. The various local anesthetics differ with regard to their potency, duration of action, and degree of effects on sensory and motor fibers. Toxicity may be local or systemic. With systemic toxicity, the central nervous system (CNS) and cardiovascular systems typically are affected.

HISTORY Until the 1880s, the only xenobiotics available for pain relief were centrally acting depressants such as alcohol and opioids, which blunted the perception of pain rather than attacking the root cause. The coca shrub (Erythroxylon coca) was brought back to Europe from Peru by Karl Von Scherzer, an Austrian explorer, in the mid-1800s. Some of the coca leaves were analyzed by the chemist Albert Niemann, who in 1860 successfully extracted and named the active principle, the alkaloid cocaine (see Chap. 76). Sigmund Freud studied the use of cocaine to cure morphine addiction. Koller at the Ophthalmological Clinic at the University of Vienna dissolved coca powder in distilled water; instilled the solution in the conjunctival sacs of a frog, a rabbit, a dog, and himself; and noted that their corneas as well as his own could be touched without any evidence of a reflex blink. In 1884, Koller performed an operation for glaucoma with topical cocaine anesthesia, and the news spread rapidly, leading to diversification of use.42 Although the clinical benefits of cocaine anesthesia were significant, so were its toxic and addictive potential. At least 13 deaths were reported in the first 7 years after the introduction of cocaine in Europe, and within 10 years after the introduction of cocaine as a regional anesthetic, reviews of “cocaine poisoning” appeared in the literature.66,84 The toxicity of cocaine, coupled with the tremendous advantages it provided for surgery, led to a search for less toxic substitutes. After the elucidation of the chemical structure of cocaine (the benzoic acid methyl ester of the alkaloid ecgonine) in 1895, other amino esters

were examined. Synthetic compounds with local anesthetic activity were introduced, but they were either highly toxic or irritating or had an impractically brief clinical effectiveness. In 1904, Einhorn synthesized procaine, but its short duration of action limited its clinical utility. Research then focused on synthesis of xenobiotics with more prolonged durations of action. The potent, long-acting local anesthetics dibucaine and tetracaine were synthesized in 1925 and 1928, respectively, and were introduced into clinical practice. However, these anesthetics were not safe for regional anesthetic techniques because of systemic toxicity secondary to the large volumes of drug that were required to ensure distribution throughout the entire neuronal sheath. On the other hand, these drugs were very useful for spinal anesthesia, which required much smaller volumes. Lofgren synthesized the prototypical local anesthetic lidocaine from a series of aniline derivatives in 1943. This amino amide combined high tissue penetrance and a moderate duration of action with acceptably low systemic toxicity. Additionally, the metabolites of lidocaine did not include para-aminobenzoic acid (PABA), which was the reported cause of allergic reactions to the amino ester anesthetics. Subsequent to the release of lidocaine in 1944, several other amino amide compounds were synthesized and introduced into clinical practice. These include mepivacaine in 1956, prilocaine in 1959, bupivacaine in 1963, etidocaine in 1971, and ropivacaine in 1996.

EPIDEMIOLOGY Considering how frequently local anesthetics are administered, both within and outside healthcare facilities, clinically significant toxic reactions are few, and most are iatrogenic. In reports of fatalities resulting from toxic exposures reported to U.S. poison centers, local anesthetics are rare, representing less than 0.5% of cases (see Chap. 135). Most poisonings result from inadvertent injection of a therapeutic dose into a blood vessel, repeated use of a therapeutic dose, or unintentional administration of a toxic dose. The amide local anesthetics have largely replaced the esters in clinical use because of their increased stability and relative absence of hypersensitivity reactions (see Pharmacology below). Poisoning from topical benzocaine is relatively common because of the large number of nonprescription products available for treatment of teething and hemorrhoids and because of the widespread use of benzocaine, mostly as a spray, for topical mucosal anesthesia before intubation, upper endoscopy, and transesophageal echocardiography. With nonprescription use, toxic effects after exposure are typically mild, and death rarely occurs. Toxicity usually occurs as a therapeutic misadventure, but child abuse or neglect should be considered if the patient is younger than 2 years, and suicide should be considered in older children and adults. Benzocaine spray may be the most important cause of severe acquired methemoglobinemia in the hospital setting3 (see Chap. 127). Between November 1997 and March 2002, the U.S. Food and Drug

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Administration (FDA) received 198 reported adverse events secondary to benzocaine products. A total of 132 cases (66.7%) involved definite or probable methemoglobinemia; most were serious adverse events, and two deaths occurred.75 In these cases, a single spray of unspecified duration of 20% benzocaine was the dose most commonly reported. Because of the difficulty in limiting the dose to the manufacturer’s recommendation given the current formulations available, these authors recommend a metered-dosing preparation and prominent package warnings.

PHARMACOLOGY ■ CHEMICAL STRUCTURE Local anesthetics fall into one of two chemically distinct groups: amino esters and amino amides (Fig. 66–1). The basic structure of all local

Intermediate chain

Lipophilic group

Amine substituents H3C N

COOCH3 Esters

O

Cocaine

C

O

O Benzocaine H2N

C

O

CH2

CH3

O

CH2

CH2

O Procaine

H2N

C

C2H5 N C2H5

O Tetracaine

HN

C

CH3 O

CH2

CH2

N

■ MODE OF ACTION All local anesthetics function by reversibly binding to specific receptor proteins within the membrane-bound sodium channels of conducting tissues. These receptors can be reached only via the cytoplasmic side of the cell membrane, that is, by intracellular drug. Blockade of ion conductance through the sodium channel eventually leads to failure to form and propagate action potentials (Fig. 66–2). The analgesic effect results from inhibiting axonal transmission of the nerve impulse in small-diameter myelinated and unmyelinated nerve fibers carrying pain and temperature sensation. Conduction block of these fibers occurs at lower concentrations than in the larger fibers responsible for touch, motor function, and proprioception.22 This likely occurs in myelinated nerves because smaller fibers have closer spacing of the nodes of Ranvier. Given that a fixed number of nodes must be blocked for conduction failure to occur, the shorter critical length of nerve is reached sooner by the locally placed anesthetic in small fibers.36 For unmyelinated fibers, the smaller diameter limits the distance that such fibers can passively propagate the electrical impulse. In addition, differential nerve block may relate to voltage and time dependence of the affinity of local anesthetics to the sodium channels. The sodium channel may exist in three states (see Chap. 23). At resting membrane potential or in the hyperpolarized membrane, the channel is closed to sodium conductance. With an appropriate activating stimulus, the channel opens, allowing rapid sodium influx and membrane depolarization. Milliseconds later, the channel is inactivated, terminating the fast sodium current. Blockade is much stronger for channels that are activated (open) or inactivated than for channels that are resting. Pain fibers have a higher firing rate and longer action potential (ie, more time with the sodium channel open or inactivated) than other fiber types and therefore are more susceptible to local anesthetic action.48 These effects also occur in other conductive tissues in the heart and brain that rely on sodium current. Although sodium channel

CH3

C4H9 Amides

anesthetics consists of three major components. A lipophilic, aromatic ring is connected by an ester or amide linkage to a short alkyl, intermediate chain that is bound to a hydrophilic tertiary (or, less commonly, secondary) amine. The amine is a base (proton acceptor) that is partially charged in the physiologic pH range.

CH3

O NH

Lidocaine

C

C2H5 CH2

N C2H5

CH3

Na+

CH3

O NH

Mepivacaine

LA

C N

CH3

CH3

CH3

O NH

Bupivacaine

C N

CH3

O NH

Prilocaine CH3

C

LA

C4H9 CH

NH C3H7

CH3

FIGURE 66–1. Representative local anesthetics in common clinical use.

FIGURE 66–2. The multi-unit sodium channel is embedded in the nerve cell membrane. Local anesthetics (LA) enter the nerve cell at the exposed membranes of the Nodes of Ranvier and bind to the cytoplasmic side of the sodium channel (also located at the Node of Ranvier) and alter sodium conductance.

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blockade initially was believed to be the sole cause of systemic toxicity, the mechanisms are more complex, especially in the heart, and may occur at systemic concentrations lower than previously thought.68 Local anesthetics may interact with other cellular systems at clinically relevant concentrations. For example, lidocaine inhibited muscarinic signaling in Xenopus oocytes at less than 50% of the concentration required for sodium channel blockade.47 Growing evidence indicates that local anesthetics can directly affect many other organ systems and functions such as the coagulation, immune, and respiratory systems at concentrations much lower than those required to achieve sodium channel blockade.16,46,47 Study of these less well-described effects may help elucidate both therapeutic and toxic phenomenon that are incompletely explained.

■ PHYSICOCHEMICAL PROPERTIES The primary determinant of the onset of action of a local anesthetic is its pKa, which affects the lipophilicity of a drug (Table 66–1). All of the local anesthetics are weak bases, with a pKa between 7.8 and 9.3. At physiologic pH (7.4), xenobiotics with a lower pKa have more uncharged molecules that are free to cross the nerve cell membrane, producing a faster onset of action than xenobiotics with a higher pKa. The onset of action also is influenced by the total dose of local anesthetic administered, which affects the concentration available for diffusion. Local anesthetic potency is highly correlated with the lipid solubility of the xenobiotic. Therefore, the aromatic side of the anesthetic is the primary determinant of potency. The hydrophilic amine is important in occupying the sodium channel, which involves an ionic interaction with the charged form of the tertiary amine. The length of the intermediate chain is another determinant of local anesthetic activity, with three to seven carbon-equivalents providing maximal activity.22 Shorter or longer intermediate chain lengths are associated with rapid loss of local anesthetic action, suggesting that a critical length of separation of the aromatic group from the tertiary amine is required for sodium channel blockade to occur.

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The degree of protein binding influences the duration of action of a local anesthetic. Anesthetics with greater protein binding remain associated with the neural membrane for a longer time interval and therefore have longer durations of action.22 When high serum concentrations are achieved, a higher degree of protein binding increases the risk for cardiac toxicity.

PHARMACOKINETICS A distinction must be made between local disposition (distribution and elimination) and systemic disposition. Local distribution is influenced by several factors, including spread of local anesthetic by bulk flow, diffusion, transport via local blood vessels, and binding to local tissues. Local elimination occurs through systemic absorption, transfer into the general circulation, and local hydrolysis of amino ester anesthetics. Systemic absorption decreases the amount of local anesthetic that is available for anesthetic effect, thereby limiting the duration of the block. Systemic absorption is dependent on the avidity of binding of local anesthetics to tissues near the site of injection and on local perfusion. Both of these factors vary with the site of injection. In general, areas with greater blood flow will have more rapid and complete systemic uptake of local anesthetic therfore, intravenous (IV) > tracheal > intercostal > paracervical > epidural > brachial plexus > sciatic > subcutaneous. Because of their lipophilicity, local anesthetics readily cross cell membranes, the blood–brain barrier, and the placenta. Once absorbed, systemic tissue distribution is highly dependent on tissue perfusion. After local anesthetics enter into the venous circulation, they pass through the lungs, where significant uptake may occur, thereby lowering peak arterial concentrations. Thus, the lungs may serve as a buffer against systemic toxicity.59 This mechanism, however, has saturable kinetics. Part of the reason why most local anesthetic–induced seizures result from unintentional intravascular injection rather than absorptive uptake is that lung uptake of these drugs appears to exceed 90%.

TABLE 66–1. Pharmacologic Properties of Local Anesthetics48,100

Esters Chloroprocaine Cocaine Procaine Tetracaine Amides Bupivacaine Etidocaine Lidocaine Mepivacaine Prilocaine Ropivacaine

pKa

Protein Binding (%)

Relative Potency

Duration of Action

Approximate Maximum Allowable Subcutaneous Dose (mg/kg)

9.3 8.7 9.1 8.4

Unknown 92 5 76

Intermediate Low Low High

Short Medium Short Long

10 3 10 3

8.1 7.9 7.8 7.9 8.0 8.2

95 95 70 75 40 95

High High Low Intermediate Intermediate Intermediate

Long Long Medium Medium Medium Long

2 4 4.5 4.5 8 3.

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The very high peak venous concentrations produced by rapid injection usually are necessary to produce toxic arterial concentrations. All local anesthetics, except cocaine, cause peripheral vasodilation by direct relaxation of vascular smooth muscle. Vasodilation enhances vascular absorption of the local anesthetic. Addition of epinephrine (5 μg/mL or 1:200,000) to the local anesthetic solution decreases the rate of vascular absorption, thereby improving the depth and prolonging the duration of local action. An epinephrine local anesthetic mixture also decreases bleeding into the surgical field and serves as a marker for inadvertent intravascular injection (by producing tachycardia) when a test dose of the mixture is injected through a needle or catheter.72 Significant drawbacks to epinephrine use include uncomfortable side effects such as palpitations and tremors, local tissue ischemia, and life-threatening systemic adverse reactions in susceptible patients, such as myocardial ischemia and hypertensive crisis. Inadvertent intravascular injection of local anesthetics mixed with epinephrine can be fatal, although generally, the epinephrine in these mixtures is very dilute.63 The two classes of local anesthetics undergo metabolism by different routes (see Chap. 76). The amino esters are rapidly metabolized by plasma cholinesterase to the major metabolite, PABA. The amino amides are metabolized more slowly in the liver to a variety of metabolites that do not include PABA.21 Patients with atypical or low concentrations of plasma cholinesterase are at increased risk for systemic toxicity from ester local anesthetics. Factors that decrease hepatic blood flow or impair hepatic function increase the risk for toxic reactions to the amino amides and make management of serious reactions more difficult. The patient’s age, as it relates to liver enzyme activity and plasma protein binding, influences the rate of metabolism of local anesthetics. Whereas the lidocaine terminal half-life after IV administration averaged 80 minutes in volunteers ages 22 to 26 years, the half-life was 138 minutes in those ages 61 to 71 years80 (see Chap. 63). Newborn infants with immature hepatic enzyme systems have prolonged elimination of amino amides, which is associated with seizures when high continuous infusion rates are used.1,69 Lidocaine elimination is reduced by congestive heart failure or coadministration of xenobiotics that reduce hepatic blood flow, thus explaining the increased risk of toxicity with cimetidine and propranolol.90 Propranolol and cimetidine also potentially decrease lidocaine clearance by inhibiting hepatic mixed-function oxidase enzymes. Local anesthetics are often mixed to take advantage of desirable pharmacokinetics. Ideally, rapid-acting, relatively short-duration local anesthetics such as chloroprocaine or lidocaine can be combined with the longer latency, long-acting tetracaine or bupivacaine. In practice, the advantages of the mixtures are small, and toxicities are additive.5 Administration of one local anesthetic increases the free plasma fraction of another by displacement from protein-binding sites.51 Local anesthetics usually cannot penetrate intact skin in sufficient quantities to produce reliable anesthesia.11 Efficient skin penetration requires the combination of a high water content and a high concentration of the water-insoluble base form of the local anesthetic. This combination of properties has been achieved by mixing lidocaine and prilocaine in their base forms in a 1:1 ratio (eutectic mixture of local anesthetics [EMLA]).14 Application for at least 45 minutes is required to achieve adequate dermal analgesia. Local anesthetic uptake continues for several hours during application. A liposomal formulation of 4% lidocaine (ELA-Max) facilitates skin absorption. It is as effective as EMLA for topical anesthesia.31 In addition, a 4% tetracaine gel preparation has been used in children for topical skin anesthesia with an onset of action and efficacy at least as good as EMLA and without any systemic side effects.

CLINICAL MANIFESTATIONS OF TOXICITY ■ TOXIC REACTIONS Regional Side Effects and Tissue Toxicity At some concentration, all local anesthetics are directly cytotoxic to nerve cells. However, in clinically relevant doses, they rarely produce localized nerve damage.55,79 Significant direct neurotoxicity may result from intrathecal injection or infusion of local anesthetics for spinal anesthesia. In this setting, studies suggest lidocaine has an increased risk for both persistent lumbosacral neuropathy and a syndrome of painful but self-limited postanesthesia buttock and leg pain or dysesthesia referred to as transient neurologic symptoms.50 Nerve damage often is attributed to use of excessively concentrated solutions or inappropriate formulations. Several reports of cauda equina syndrome have been associated with use of hyperbaric 5% lidocaine solutions for spinal anesthesia. Hyperbaric solutions are more dense than cerebrospinal fluid. This neurotoxicity appears to be a phenomena that occurs when the anesthetic is injected through narrowbore needles or through continuous spinal catheters. This process may result in very high local concentrations of the anesthetic that might pool around the sacral roots because of inadequate mixing.91 The mechanism of this neurotoxic effect is unknown but is believed to be independent of sodium channel blockade.50 Because an equally effective block can be achieved with injection of larger volumes of lower concentration, 5% lidocaine should be avoided and bupivacaine used instead. Similar severe neurotoxic reactions have occurred after massive subarachnoid injection of chloroprocaine during attempted epidural anesthesia.88 The neurotoxicity initially appeared to be associated with use of the antioxidant sodium bisulfite and the low pH of the commercial solution rather than use of the anesthetic itself.108 Although chloroprocaine has been reformulated without bisulfite, new animal data suggest that it is the anesthetic that may be responsible for the neurotoxicity.104 Skeletal muscle changes are observed after intramuscular injection of local anesthetics, especially the more potent, longer-acting xenobiotics. The effect is reversible, and muscle regeneration is complete within 2 weeks after injection of local anesthetics.8

■ SYSTEMIC SIDE EFFECTS AND TOXICITY Allergic Reactions Allergic reactions to local anesthetics are extremely rare. Fewer than 1% of all adverse drug reactions caused by local anesthetics are immunoglobulin (Ig)E-mediated.39 In one study designed to determine the prevalence of true local anesthetic allergy in patients referred to an allergy clinic for suspected hypersensitivity, skin prick and intradermal testing results were negative for all 236 subjects tested.9 As noted, the amino esters are responsible for the majority of true allergic reactions. When hydrolyzed, the amino ester local anesthetics produce PABA, a known allergen (see Chap. 55). Cross-sensitivity to other amino ester anesthetics is common. Some multidose commercial preparations of amino amides may contain the preservative methylparabens, which is chemically related to PABA and is the most likely cause of the much rarer allergic reaction to amino amides or seeming allergic responses to both the amides and esters. Preservative-free amino amides, including lidocaine, can be used safely in patients who have reactions to drug preparations containing methylparabens unless the patient is specifically sensitive to lidocaine. Again, if the patient with a history of allergic reaction to a particular drug requires a local anesthetic, a paraben preservative-free drug from the opposite class can be chosen because there is no cross-reactivity between the amides and esters. Methemoglobinemia Methemoglobinemia is reported frequently as an adverse effect of topical and oropharyngeal benzocaine use and occasionally with lidocaine, tetracaine, or prilocaine use. The diagnosis can be established by direct measurement of methemoglobin percent with a

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cooximeter. Most reports of methemoglobinemia associated with local anesthetics are the result of an excessive dose, a break in the normal mucosal barrier for topical anesthetics, or a deficiency of a congenital reducing enzyme such as methemoglobin reductase (see Chap. 127). Benzocaine is metabolized to aniline and then further metabolized to phenylhydroxylamine and nitrobenzene, which are both potent oxidizing agents (see Chap. 127). Although reports describe methemoglobinemia resulting from standard doses of benzocaine topical oropharyngeal spray given for laryngoscopy or gastrointestinal upper endoscopy,29,75 affected patients commonly have abnormal mucosal integrity, as occurs with thrush or mucositis. Prilocaine is an amino ester local anesthetic primarily used in obstetric anesthesia because of its rapid onset of action and low systemic toxicity in both the mother and fetus. Use of large doses of prilocaine may lead to the development of methemoglobinemia.45,61 Prilocaine is an aniline derivative that, when metabolized in the liver, produces ortho-toluidine, another oxidizing agent.45 A direct relationship exists between the amount of epidural prilocaine administered and the incidence of methemoglobinemia. A dose greater than approximately 8 mg/kg is generally necessary to produce symptoms, which may not become apparent until several hours after epidural administration of the drug. Standard doses of EMLA cream used for circumcision in term neonates are associated with minimal production of methemoglobin, but risks may be increased in neonates with metabolic disorders.102 EMLA-associated methemoglobinemia has been reported in children and rarely in adults.41 When clinically indicated, affected patients with symptomatic methemoglobinemia should be treated with IV methylene blue (see Chap. 127 and Antidotes in Depth A41: Methylene Blue). Other Reactions The most common adverse reactions to local anesthetics are vasovagal reactions.106 Systemic Toxicity Systemic toxicity for all local anesthetics correlates with serum concentrations. Factors that determine the concentration include (1) dose; (2) rate of administration; (3) site of injection (absorption occurs more rapidly and completely from vascular areas, such with neck blocks and intercostal blocks); (4) the presence or absence of a vasoconstrictor; and (5) the degree of tissue–protein binding, fat solubility, and pKa of the local anesthetic.73 The brain and heart are the primary target organs for systemic toxicity because of their rich perfusion, moderate tissue–blood partition coefficients, lack of diffusion limitations, and presence of cells that rely on voltage-gated sodium channels to produce an action potential. Recommendations for maximal local anesthetic doses designed to minimize the risk for systemic toxic reactions have been published.100 These maximal recommended doses aim to prevent infiltration of excessive drug. However, because most episodes of systemic toxicity from local anesthetics, with the exception of methemoglobinemia from topical drug, occur secondary to unintentional intravascular injection rather than from overdosage, limiting the maximal dose will not prevent most toxic systemic reactions.97 Toxicity is also related to the metabolism for a given local anesthetic. The rapidity of elimination from the plasma influences the total dose delivered to the CNS or heart. The amino esters are rapidly hydrolyzed in the plasma and eliminated, explaining their relatively low potential for systemic toxicity. The amino amides have a much greater potential for producing systemic toxicity because termination of the therapeutic effect of these drugs is achieved through redistribution and slower metabolic inactivation.35 Another factor that creates difficulty in specifying the minimal toxic plasma concentration of lidocaine results from the fact that its N-dealkylated metabolites are pharmacologically active. Although these factors make it difficult to establish safe doses of local anesthetics, Table 66–2 summarizes the estimates of minimal toxic intravenous doses of various local anesthetics.

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TABLE 66–2. Toxic Doses of Local Anesthetics Local Anesthetic Procaine Chloroprocaine Tetracaine Lidocaine Mepivacaine Bupivacaine Etidocaine

Minimum IV Toxic Dose of Local Anesthetic in Humans (mg/kg) 19.2 22.8 2.5 6.4 9.8 1.6 3.4

IV, intravenous.

Central Nervous System Toxicity Systemic toxicity in humans usually presents as CNS abnormalities. IV infusion studies in volunteers have demonstrated an inverse relationship between the anesthetic potency of various local anesthetics and the dosage required to induce signs of CNS toxicity.98 A similar relationship exists between the convulsive concentration of various local anesthetics and their relative anesthetic potency. In humans, seizures are reported at serum concentrations of approximately 2 to 4 μg/mL for bupivacaine and etidocaine. Concentrations in excess of 10 μg/mL are usually required for production of seizures when less-potent drugs such as lidocaine are administered. Despite the strong relationship between local anesthetic potency and CNS toxicity, several other factors influence the CNS effects, including the rate of injection, drug interactions, and acid–base status.24 The rapidity with which a particular serum concentration is achieved influences the toxicity of the anesthetic. Volunteers could tolerate an average dose of 236 mg of etidocaine and a serum concentration of 3 μg/mL before onset of CNS symptoms when the anesthetic was infused at a rate of 10 mg/min. However, when the infusion rate was increased to 20 mg/min, the same individuals could tolerate only an average of 161 mg of the drug, which produced a serum concentration of approximately 2 μg/mL.96 Centrally acting local anesthetics can modify the clinical presentation of a systemic toxic reaction. In general, whereas CNS-depressant drugs minimize the signs and symptoms of CNS excitation, they increase the threshold for local anesthetic–induced seizures. Flumazenil increases the sensitivity of the CNS to the amino amide anesthetics.13 Both metabolic and respiratory acidoses increase local anesthetic– induced CNS toxicity. Acidemia decreases plasma protein binding, increasing the amount of free drug available for CNS diffusion despite promoting the charged form of the amine. The convulsive threshold of various local anesthetics is inversely related to arterial PCO2.26,32,33 Hypercarbia may lower the seizure threshold by several mechanisms: (1) increased cerebral blood flow, which increases drug delivery to the CNS; (2) increased conversion of the drug base to the active cation in the presence of decreased intracellular pH; and (3) decreased plasma protein binding, which increases the amount of free drug available for diffusion into the brain.15,26,32,33 A gradually increasing serum lidocaine concentration produces a common pattern of symptoms and signs (Fig. 66–3). In an awake patient, the initial symptoms are subjective and include tinnitus, lightheadedness, circumoral numbness, disorientation, confusion, auditory and visual disturbances, and lethargy. Subjective side effects occur at serum concentrations between 3 and 6 μg/mL. Significant

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The Clinical Basis of Medical Toxicology

Serum conc (μg/mL)

24

Cardiac arrest

20 16 12 8 4

Respiratory arrest Coma Convulsions Unconsciousness Muscular twitching Visual and auditory disturbances Lightheadedness Numbness of tongue

0 FIGURE 66–3. Relationship of signs and symptoms of toxicity to serum lidocaine concentrations.

psychological effects of local anesthetics have also been reported. Near-death experiences and delusions of actual death are described as specific symptoms of local anesthetic toxicity.64 Thus, the appearance of psychologic symptoms during administration of local anesthetics should not be disregarded as unrelated nervous reactions or effects of sedatives given as premedication but rather as a possible early sign of CNS toxicity. Objective signs, usually excitatory, then develop and include shivering, tremors, and ultimately generalized tonic–clonic seizures. Objective CNS toxicity usually is evident at concentrations between 5 and 9 μg/ mL. Seizures may occur at concentrations above 10 μg/mL, with higher concentrations producing coma, apnea, and cardiovascular collapse. The excitatory phase has a wide range of intensity and duration, depending on the chemical properties of the local anesthetic. With the highly lipophilic, highly protein-bound drugs, the excitement phase is brief and mild. Toxicity from a large IV bolus of bupivacaine may present without any CNS excitement and with bradycardia, cyanosis, and coma as the first signs.93 Rapid intravascular injection of lidocaine may produce a brief excitatory phase followed by generalized CNS depression with respiratory arrest. Seizures may follow even a small dose injected into the vertebral or carotid artery (as may occur during stellate ganglion block).54 A relative overdose produces a slower onset of symptoms (usually within 5–15 minutes of drug injection), with irritability progressing into seizures. The mechanism of the initial CNS excitation involves a selective block of cerebral cortical inhibitory pathways in the amygdala.103,107 The resulting increase in unopposed excitatory activity leads to seizures. As the concentration increases further, both inhibitory and excitatory neurons are blocked, and generalized CNS depression ensues.

■ TREATMENT OF LOCAL ANESTHETIC CENTRAL NERVOUS SYSTEM TOXICITY At the first sign of possible CNS toxicity, administration of the drug must be discontinued. One hundred percent oxygen should be supplied immediately, and ventilation should be supported if necessary. Patients with minor symptoms usually do not require treatment, provided adequate respiratory and cardiovascular functions are maintained. The patient must be followed closely so that progression to more severe effects can be detected. Although most seizures caused by local anesthetics are selflimited, they should be treated quickly because the hypoxia and acidosis produced by prolonged seizures may increase both CNS

and cardiovascular toxicity.76,78 Intubation is not mandatory, and the decision to intubate must be individualized. Maintaining adequate ventilation is of proven value, but modest hyperventilation in theory might decrease CNS toxicity. By decreasing CNS extraction of drug, lowering extracellular potassium, and hyperpolarizing the neuronal cell membrane, normalizing (lowering) PCO2 may decrease the affinity or accelerate separation of the local anesthetic from the sodium channel. Barbiturates and benzodiazepines have been used for treatment of local anesthetic–induced seizures. An induction dose of thiopental, which is readily available to the anesthesiologist or an IV benzodiazepine such as lorazepam, can rapidly terminate a seizure, but either of these medication groups can also exacerbate circulatory and respiratory depression.24,71 Propofol 1 mg/kg IV was as effective as thiopental 2 mg/kg IV in stopping bupivacaineinduced seizures in rats and has been used successfully in a patient with uncontrolled muscle twitching secondary to local anesthetic toxicity.10,43 However, propofol may cause significant bradydysrhythmias and even asystole, especially when used with other xenobiotics that cause bradycardia. Whether propofol interacts with local anesthetics to enhance their bradydysrhythmic effects is not known, and it is not possible to generally recommend propofol over barbiturates and benzodiazepines for treatment of local anesthetic CNS toxicity. Neuromuscular blocking agents have been proposed as adjunctive treatment for local anesthetic–induced seizures. They block muscular activity, decreasing oxygen demand and lactic acid production. However, neuromuscular blocking agents should never be used to treat seizures per se because they have no anticonvulsant effect and can make clinical diagnosis of ongoing seizures problematic by abolishing muscle contractions. To avoid this potentially lethal complication, chemical paralysis should be used only to facilitate endotracheal intubation if needed. Use of short-acting neuromuscular blockers is desirable to allow for subsequent repeated neurologic assessments. Succinylcholine may not be ideal because of its significant side effects, including hyperkalemia and dysrhythmias. Newer short-acting nondepolarizing neuromuscular blockers with less potential for cardiac side effects, such as rocuronium, should be considered (see Chap. 68). When severe systemic toxicity occurs, the cardiovascular system must be monitored closely because cardiovascular depression may go unnoticed while the seizures are being treated. Because local anesthetic– induced myocardial depression may occur even with preserved blood pressure, it is important to be aware of early signs of cardiac toxicity, including electrocardiographic (ECG) changes. If toxicity results from an oral ingestion, activated charcoal is generally indicated, but its benefits are unproven. If the patient has presented for care immediately after ingestion, orogastric lavage with a nasogastric tube may be considered. Induction of emesis is contraindicated even after oral administration because of the risk of seizures and aspiration. Contaminated mucous membranes should be washed off. Hemodialysis is not of proven utility and may be impractical, as is hemoperfusion. Cardiovascular Toxicity Cardiovascular side effects are the most feared manifestations of local anesthetic toxicity. Shock and cardiovascular collapse may be related to effects on vascular tone, inotropy, and dysrhythmias related to indirect CNS and direct cardiac and vascular effects of the local anesthetic. Animal studies and clinical observations clearly demonstrate that for most local anesthetics, CNS toxicity develops at lower serum concentrations (exception: bupivacaine) than those needed to produce cardiac toxicity, that is, they have a high CV:CNS toxicity ratio.54,77,78,93 When cardiac toxicity occurs, management may be exceedingly difficult. Some of the discrepancy between the incidence of CNS and cardiac toxicity may result from a detection bias. Not only can the treating physicians fail to recognize cardiac effects because of

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preoccupation with CNS manifestations of toxicity, but significant early cardiac toxicity may be quite subtle. An experimental study attempting to identify early warning signs of bupivacaine-induced cardiac toxicity in pigs evaluated bupivacaine-induced changes in cardiac output, heart rate, blood pressure, and ECG.83 A 40% reduction in cardiac output was not associated without significant change in heart rate or blood pressure, the latter secondary to a direct vasoconstrictive effect of bupivacaine at the concentrations produced. 17 Changes in systemic vascular tone induced by local anesthetics may be mediated by direct effect on vascular smooth muscle or indirectly via effects on spinal cord sympathetic outflow. Predictably, sympathetic blockade after spinal anesthesia or epidural anesthesia above the T5 dermatome results in peripheral venodilation and arterial dilation. Shock may result when high doses of anesthetic are used in hypovolemic patients. Local anesthetics have a biphasic effect on peripheral vascular smooth muscle. Whereas lower doses produce direct vasoconstriction, higher doses are associated with severe cardiovascular toxicity and cause vasodilation, contributing to cardiovascular collapse. All local anesthetics directly produce a dose-dependent decrease in cardiac contractility, with the effects roughly proportional to their peripheral anesthetic effect. Although the classic anesthetic action of sodium channel blockade in heart muscle accounts in large part for the negative inotropy by affecting excitation–contraction coupling, it does not explain the entire difference in myocardial depression produced by different anesthetics.28 Poorly understood effects on calcium handling or effects of the intracellular drug directly on contractile proteins or mitochondrial function may be operable.28 Blockade of the fast sodium channels of cardiac myocytes decreases maximum upstroke velocity (Vmax) of the action potential (see Chap. 22 and 23 and Fig. 63–1). This effect slows impulse conduction in the sinoatrial and atrioventricular (AV) nodes, the His-Purkinje system, and atrial and ventricular muscle.20 These changes are reflected on ECG by increases in PR interval and QRS duration. At progressively higher anesthetic concentrations, hypotension, sinus arrest with junctional rhythm, and eventually cardiac arrest occur.4 Asystole has been described in patients who received unintentional IV bolus injections of 800 to 1000 mg of lidocaine.4,34 Cardiovascular toxicity of local anesthetics usually occurs after a sudden increase in serum concentration, as in unintentional intravascular injection. Cardiovascular toxicity is rare in other circumstances because large doses are necessary to produce this effect and because CNS toxicity precedes cardiovascular events, thus providing a warning. Cardiac toxicity usually is not observed with lidocaine use in humans until the serum lidocaine concentration greatly exceeds 10 μg/mL unless the patient is also receiving xenobiotics that depress sinus and AV nodal conduction such as calcium channel blockers, β-adrenergic antagonists, or cardioactive steroids. Bupivacaine is significantly more cardiotoxic than most other local anesthetics commonly used. Inadvertent intravascular injection produces near-simultaneous signs of CNS and cardiovascular toxicity. Animal studies have compared the dosage or serum concentrations of local anesthetics required to produce irreversible circulatory collapse with those necessary to produce seizures.25,77,78 This cardiovascular collapse/CNS toxicity (CC/CNS) ratio for lidocaine is approximately 7; therefore, CNS toxicity should become evident well before potentially cardiotoxic concentrations are reached. In contrast, the CC/CNS ratio for bupivacaine is 3.7. Bupivacaine produces myocardial depression out of proportion to its anesthetic potency and, more importantly, may cause refractory ventricular dysrhythmias.95 Enhanced cardiovascular toxicity may relate to enhanced CNS effects at cardiovascular centers,105 direct effects on myocyte metabolism, and important differences related to sodium channel blockade. Although lidocaine and bupivacaine both block sodium channels in the open or inactivated states lidocaine quickly dissociates from the channel at diastolic potentials, allowing

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rapid recovery from block during diastole (fast on–fast off). Therefore, sodium channel blockade with lidocaine is much more pronounced at rapid heart rates (accounting for the antidysrhythmic effects for ventricular tachycardia).63 On the other hand, at high concentrations, bupivacaine rapidly binds to and slowly dissociates from sodium channels (fast on–slow off), with significant block accumulating at all physiologic heart rates.20 Accordingly, at heart rates of 60 to 150 beats/min, approximately 70 times more lidocaine is needed than bupivacaine to produce an equal effect on Vmax. Enhanced conduction block in Purkinje fibers and ventricular muscle cells can set up a reentrant circuit responsible for the ventricular tachydysrhythmias induced by bupivacaine.70 Bupivacaine, a potent and long-acting amide anesthetic, has the highest potential for cardiovascular toxicity, which can be refractory to conventional therapy. Inadvertent intravascular injection produces nearsimultaneous signs of CNS and cardiovascular toxicity. Bupivacaine has an asymmetrically substituted carbon, and the kinetics of sodium channel binding are stereospecific.56 The S (levo)-enantiomer levobupivacaine is significantly less cardiotoxic than the R (dextro)-enantiomer despite having similar anesthetic properties.6,68 Consequently, bupivacaine, the racemic mixture of both enantiomers, is more cardiotoxic than levobupivacaine, which contains only the levo-enantiomer.40 The stereospecific effect on sodium channels seems to differ between the heart and the peripheral nerves because the local anesthetic potency of levobupivacaine is the same as, or perhaps even greater than, that of bupivacaine.30,81 Ropivacaine is a pure enantiomer and is less cardiotoxic than bupivacaine, but it is also slightly less potent as an analgesic.85,86 Effects other than sodium channel blockade may contribute to cardiotoxicity. Lipophilic local anesthetics such as bupivacaine may directly impair mitochondrial energy transduction via two mechanisms: (1) uncoupling of oxygen consumption and adenosine triphosphate (ATP) synthesis and (2) inhibition of complex I in the respiratory chain.101 This effect is related to the lipophilic properties of the drug rather than to stereospecific effects on ion channels. Lidocaine has no effect on mitochondrial respiration, and ropivacaine has less effect than bupivacaine.114 There is no difference between the two bupivacaine enantiomers. These effects occur with higher concentrations of the local anesthetic, as occur after unintentional intravascular injection. Low-dose bupivacaine-induced cardiotoxic effects have been described in humans under certain circumstances and at concentrations that are not associated with seizure activity in pigs.52,113 Severe cardiac toxicity is described after injection of a small subcutaneous dose of bupivacaine in a patient with secondary carnitine deficiency.113 Myocytes are highly dependent on oxidation of fatty acids for energy turnover. Interference with this mechanism via bupivacaine-induced inhibition of carnitineacylcarnitine translocase has been proposed to contribute to the cardiotoxicity of lipophilic local anesthetics113 (see Chap. 47 and Fig. 47–2 and Antidote in Depth A21: Intravenous Fat Emulsion). Bupivacaine may produce dysrhythmias by blocking GABAergic neurons that tonically inhibit the autonomic nervous system.44 In addition to its other effects on the heart, bupivacaine may induce a marked decrease in cardiac contractility by altering Ca2+ release from sarcoplasmic reticulum.62 In a large series of patients receiving bupivacaine, systemic toxicity occurred in only 15 of 11,080 nerve blocks.74 Of these patients, 80% convulsed; the other 20% had milder symptoms. A series of cases was described in which bupivacaine use, particularly at 0.75% concentration, was associated with severe cardiovascular depression, ventricular dysrhythmias, and even death. Pregnant women were disproportionately affected. Some of these patients required prolonged and difficult resuscitation.89 In 1983, 49 incidents of cardiac arrest or ventricular tachycardia that occurred over a 10-year period were presented to the U.S. FDA Anesthetic and Life Support Advisory Committee. Among these cases, 0.75% bupivacaine was used in 27 obstetric patients with 10 deaths, and 0.5% bupivacaine was used in eight obstetric patients

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TABLE 66–3. Types of Local Anesthetic Reactions Cause

Major Clinical Features

Local anesthetic toxicity (intravascular injection) Reaction to catecholamine Vasovagal reaction

Immediate seizure or cardiac toxicity

Allergic reaction High spinal or epidural block

Tachycardia, hypertension, headache Bradycardia, rapid onset and recovery, hypotension, pallor Anaphylaxis Bradycardia, hypotension, respiratory distress, respiratory arrest

with six deaths. Among the 14 nonobstetric patients, five died. The overall mortality was 21 of 49 (43%). Partly as a result of these reports, in 1984, the U.S. FDA withdrew approval of bupivacaine 0.75% for use as obstetric anesthesia.89 Acid–base and electrolyte status influence the cardiac toxicity of a given drug because all depressant properties are potentiated by acidosis, hypoxia, or hypercarbia.12 Table 66–3 outlines the spectrum of acute local anesthetic reactions.

LABORATORY STUDIES In cases of possible local anesthetic toxicity, an ECG should be obtained to detect dysrhythmias and conduction disturbances. Serum electrolytes, blood urea nitrogen (BUN), creatinine, and arterial blood gas analysis should be obtained to help assess the cause of cardiac dysrhythmias. A methemoglobin percent should be obtained in patients in whom methemoglobinemia is suspected clinically. Rapid, sensitive assays are available for measuring concentrations of lidocaine and its monoethylglycylxylidide (MEGX) metabolite. When properly interpreted, the results of these assays may be used to prevent lidocaine toxicity and to identify lidocaine toxicity in the nontherapeutic setting. Assays for determining serum concentrations of other local anesthetics are not routinely available. Treatment should never be delayed while waiting for results of xenobiotic concentration determinations.

TREATMENT ■ TREATMENT OF LOCAL ANESTHETIC CARDIAC TOXICITY Treatment of cardiovascular complications of local anesthetics is complicated by the complex effects of local anesthetics on the heart. Initial therapy should focus on correcting the physiologic derangements that may potentiate the cardiac toxicity of local anesthetics, including hypoxemia, acidosis, and hyperkalemia.12,92 Prompt support of ventilation and circulation limits hypoxia and acidosis. Early recognition of potential cardiac toxicity is critical to achieving a good outcome because patients with cardiac toxicity that goes unrecognized for any interval are more difficult to resuscitate.7 If a potentially massive intravascular local anesthetic injection is suspected, maximizing oxygenation of the patient before cardiovascular collapse occurs is critical.

■ INTRAVENOUS FAT EMULSIONS While investigating the relationship between lipid metabolism and bupivacaine toxicity (described above), a rat study of bupivacaineinduced asystolic arrest showed that pretreatment with IV fat emulsion

(IFE) increased the toxic dose of bupivacaine by 50%. In addition, a dose of bupivacaine that was uniformly fatal in control rats showed universal survival in animals that also received fat emulsion.117 Subsequent studies with experimental models of local anesthetic toxicity have demonstrated accelerated return of cardiac function after IFE both in intact animals and the isolated heart.115,116 In clinical reports, epinephrine has limited efficacy in the treatment of cardiac arrest that occurs from bupivacaine toxicity. This could possibly be secondary to inhibition of intracellular cyclic adenosine monophosphate production by bupivacaine. The efficacy of IFE was compared with epinephrine for resuscitation of bupivacaine-induced cardiovascular collapse in a rodent model.112 IFE led to improved recovery. A 20% IFE was successfully used to resuscitate a patient from a prolonged cardiac arrest caused by bupivacaine toxicity. The patient rapidly stabilized with IFE after failing to improve with 20 minutes of advanced cardiopulmonary resuscitation (CPR).94 Subsequently, several case reports have been published describing successful use of IFE (in various formulations) to treat patients in cardiac arrest after regional anesthesia with various local anesthetic agents, including bupivacaine, ropivacaine, and levobupivacaine.49,58,109 The mechanism by which IFE reverses local anesthetic toxicity is uncertain. One of the hypotheses is that the exogenous fat emulsion provides a competing source for binding of lipid-soluble local anesthetics, a circulating lipid sink. This view is supported by a study that demonstrated decreased cardiac bupivacaine concentrations after IFE.116 Another possibility is that the fat emulsion load might overwhelm the inhibition of the carnitine acylcarnitine translocase by mass action and thereby increase the myocardial energy supply, making the heart more likely to respond to resuscitation. In addition, IFE has positive inotropic effects in isolated heart preparations and reversed bupivacaine-induced cardiac depression at lipid levels less than those needed to reduce aqueous bupivacaine concentration.99 The limited clinical data suggest that an IV bolus of fat emulsion may be lifesaving in patients with refractory cardiovascular collapse secondary to local anesthetic overdose. Optimal dosing is uncertain.110 Suggested dosing for a patient in cardiac arrest is 1.5 mL/kg bolus of 20% IFE over 1 minute while continuing chest compressions followed by 15 mL/kg/min for 30 to 60 minutes. If there is evidence of recovery, dosing should be changed to a continuous infusion of 20% IFE at a rate of 0.25 mL/kg/min [15 mL/kg/h] given until hemodynamic recovery, which can be increased as indicated.111 IFE should be given after signs of local anesthetic toxicity become manifest110 (see Antidote in Depth A21: Intravenous Fat Emulsion). In addition to lipid therapy, standard advanced cardiac life support (ACLS) protocols should be generally followed when dealing with most episodes of local anesthetic cardiac toxicity. Hypotension in sinus rhythm results from both peripheral vasodilation and myocardial depression and should be treated with α- and β-adrenergic agonists. Vasopressin may be administered during CPR in addition to epinephrine. Atropine supplemented with electrical pacing should be used to treat bradycardia. The effectiveness of epinephrine in reversing local anesthetic–induced cardiac depression is inconsistent in various animal models. The dysrhythmic effects of epinephrine are of particular concern. Amrinone, a phosphodiesterase III inhibitor, was evaluated for treatment of bupivacaine-induced cardiac toxicity.38,57 Anesthetized pigs with cardiovascular collapse induced by bupivacaine infusion survived when they were treated with amrinone; all of the control animals died of irreversible cardiac arrest.57 A phosphodiesterase III inhibitor would be a good choice for reversing bupivacaine-induced cardiac depression.96 Bupivacaine-induced dysrhythmias often are refractory to cardioversion, defibrillation, and pharmacologic treatment. Lidocaine, phenytoin, magnesium, bretylium, amiodarone, calcium channel blockers, and combined therapy with clonidine and dobutamine have all been

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used in animal models with variable results.27,65,67 Therapy for bupivacaine toxicity should be directed toward dissociating bupivacaine from the myocardial sodium channel, thereby reversing the drug’s effects on cardiac conduction. Lidocaine competes with bupivacaine for cardiac sodium channels and at high doses may displace it. Anecdotal reports suggest that lidocaine has occasionally helped in this application.23 However, concern persists about additive CNS effects when lidocaine is used to treat bupivacaine cardiac toxicity, and we do not recommend its routine use. With toxicity from the longer-acting, highly lipid-soluble, proteinbound amide local anesthetics (bupivacaine and etidocaine), if the patient does not respond promptly to therapy, CPR can be expected to be difficult and prolonged (1–2 hours) before depression of the cardiac conduction system spontaneously reverses as a result of redistribution and metabolism of the drugs.2,87 Vital organ perfusion is seriously compromised during CPR despite optimal chest compression. The significance of this problem increases with the duration of resuscitation; therefore, rapid initiation of cardiopulmonary bypass should be considered, if practical. Its use has resulted in a successful outcome in some cases of lidocaine and bupivacaine overdose.37,60 Cardiopulmonary bypass provides circulatory support that is far superior to that provided by closed-chest cardiac massage. The improved perfusion prevents tissue hypoxia and the development of metabolic acidosis, which in turn decreases the binding of local anesthetics to myocardial sodium channel receptors. Hepatic blood flow is better maintained, enhancing local anesthetic metabolism, and increased myocardial blood flow helps redistribute local anesthetics out of the myocardium.60 Cardiac pacing was used successfully for treatment of cardiac arrest after unintentional administration of a 2 g bolus of lidocaine into a cardiopulmonary bypass circuit as the patient was being removed from bypass.82 Pharmacologic therapy was unsuccessful, and resumption of bypass was necessary. Forty-five minutes after the injection, AV pacing restored perfusion and permitted discontinuation of bypass. Use of sodium bicarbonate early in resuscitation to prevent acidosismediated potentiation of cardiac toxicity may have been beneficial in some cases,23 but paradoxical effects on intracellular pH during CPR suggest against its use in the absence of strong experimental or clinical data. In another canine model, an infusion of 2 mL/kg 50% dextrose plus 1 Unit/kg insulin was superior to saline or dextrose alone in reversing bupivacaine-induced cardiac depression.19 (see A18: Insulin Euglycemia) Effects on potassium current, calcium handling, and myocardial energy utilization all may have contributed to the salutatory effects of the insulin infusion.

■ PREVENTION OF SYSTEMIC TOXICITY OF LOCAL ANESTHETICS Despite the development of new, relatively less toxic amide local anesthetics such as levobupivacaine and ropivacaine, severe CNS and cardiovascular effects are not eliminated. Several cases of ropivacaineinduced cardiac arrest have been reported.18,49,53 In these cases, patients with both asystolic arrest and ventricular fibrillation–associated arrest were successfully resuscitated. Nonetheless, it is clear that prevention is more prudent and effective than treatment of toxicity. The keys to prevention are to use the lowest possible anesthetic concentration and volume consistent with effective anesthesia and to avoid a significant intravascular injection. The latter is accomplished by careful, slow aspiration of a needle or catheter before injection; injection of a small test dose of anesthetic mixed with epinephrine to assess a cardiovascular response if injection is intravascular; and use of slow, fractional dosing of large-volume injections with vigilance for early signs of CNS and cardiac toxicity.

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SUMMARY Local anesthetics are frequently used xenobiotics that provide surgical analgesia and acute and chronic pain relief. The analgesic effect of local anesthetics is primarily caused by inhibition of neural conductance secondary to sodium channel blockade. Systemic toxicity, which primarily affects the heart and brain, is also largely related to sodium channel blockade. Severe systemic toxicity usually occurs secondary to inadvertent intravascular injection. In most cases of systemic toxicity, CNS manifestations precede cardiovascular events. If cardiovascular collapse and cardiac arrest occur, resuscitation may be difficult and prolonged. A novel therapy of IV fat emulsion is shown to reverse, by uncertain mechanisms, local anesthetic toxicity. Cardiopulmonary bypass may be useful because it provides cardiovascular support, limits exacerbating factors such as tissue hypoxia and acidosis, and improves hepatic blood flow, thereby increasing local anesthetic metabolism. Avoidance of intravascular injection and vigilance for early signs of CNS and cardiac toxicity are keys to preventing serious adverse events.

ACKNOWLEDGMENT Staffan Wahlander contributed to this chapter is a previous edition.

REFERENCES 1. Agarwal R, Gutlove D, Lockhart C. Seizures occurring in pediatric patients receiving continuous infusion of bupivacaine. Anesth Analg. 1992;75: 284-286. 2. Albright G. Cardiac arrest following regional anesthesia with etidocaine or bupivacaine. Anesthesiology. 1979;51:285-287. 3. Ash-Bernal R, Wise R, Wright S. Acquired methemoglobinemia—a retrospective series of 138 cases at 2 teaching hospitals. Medicine. 2004;83: 265-273. 4. Babui E, Garcia-Rubi D, Estanol B. Inadvertent massive lidocaine overdose causing temporary complete heart block in myocardial infarction. Am Heart J. 1981;102:801-803. 5. Badgwell J. Cardiovascular and central nervous system effects of co-administered lidocaine and bupivacaine in piglets. Reg Anesth. 1991;16:89-94. 6. Bardsley H, Gristwood R, Baker H, et al. A comparison of the cardiovascular effects of levobupivacaine and rac-bupivacaine following intravenous administration to healthy volunteers. Br J Clin Pharmacol. 1998;46: 245-249. 7. Batra MS, Bridenbaugh LD, Caldwell RD, Hecker BR. Bupivacaine cardiotoxicity in a pregnant patient with mitral valve prolapse: an example of an improperly administered epidural block. Anesthesiology. 1984;60:170-171. 8. Benoit P, Belt WD. Some effects of local anesthetic agents on skeletal muscle. Exp Neurol. 1972;34:264–278. 9. Berkun Y, Ben-Zvi A, Levy Y, et al. Evaluation of adverse reactions to local anesthetics: experience with 236 patients. Ann Allergy Asthma Immunol. 2003;91:342-345. 10. Bishop D, Johnstone R. Lidocaine toxicity treated with low-dose propofol. Anesthesiology. 1993;78:788-789. 11. Bonadio W. TAC: a review. Pediatr Emerg Care. 1989;5:128-130. 12. Bosnjak Z, Stowe D, Kampine J. Comparison of lidocaine and bupivacaine depression of sinoatrial node activity during hypoxia and acidosis in adult and neonatal guinea pigs. Anesth Analg. 1986;65:911-917. 13. Bruguerolle B, Emperaire N. Local anesthetic-induced toxicity may be modified by low-dose flumazenil. Life Sci. 1992;50:185-187. 14. Buckley MM, Benfield P. Eutectic lidocaine/prilocaine cream: a review of the topical anaesthetic/analgesic efficacy of a eutectic mixture of local anaesthetics (EMLA). Drugs. 1993;46:126-151. 15. Burney R, DiFazio C, Foster J. Effects of pH on protein binding of lidocaine. Anesth Analg. 1978;57:478-480. 16. Butterworth JF, Strichartz G. Molecular mechanisms of local anesthesia: a review. Anesthesiology. 1990;72:711-734. 17. Chang KS, Morrow DR, Kuzume K, et al. Bupivacaine inhibits baroreflex control of heart rate in conscious rats. Anesthesiology. 2000; 92:197-207.

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18. Chazalon P, Tourtier J, Villevielle T, et al. Ropivacaine-induced cardiac arrest after peripheral nerve block: successful resuscitation. Anesthesiology. 2003; 99:1253-1254. 19. Cho H, Lee J, Chung I, et al. Insulin reverses bupivacaine-induced cardiac depression in dogs. Anesth Analg. 2000;91:1096-1102. 20. Clarkson C, Hondeghem LM. Mechanism for bupivacaine depression of cardiac conduction: fast block of sodium channels during the action potential with slow recovery from block during diastole. Anesthesiology. 1985;62:396-405. 21. Covino BG. New developments in the field of local anesthetics and the scientific basis for their clinical use. Acta Anaesth Scand. 1982;26:242-249. 22. Covino BG. Pharmacology of local anesthetic agents. Br J Anaesth. 1986;58: 701-716. 23. Davis N, de Jong R. Successful resuscitation following massive bupivacaine overdose. Anesth Analg. 1982;61:62-64. 24. de Jong R, Heavner J. Local anesthetic seizure prevention: diazepam versus pentobarbital. Anesthesiology. 1972;36:449-457. 25. de Jong R, Ronfeld R, DeRosa R. Cardiovascular effects of convulsant and supraconvulsant doses of amide local anesthetics. Anesth Analg. 1982;61:3-9. 26. de Jong R, Wagman I, Prince D. Effect of carbon dioxide on the cortical seizure threshold to lidocaine. Exp Neurol. 1967;17:221-232. 27. de la Coussaye J, Bassoul B, Brugada J, et al. Reversal of electrophysiologic and hemodynamic effects induced by high-dose of bupivacaine by the combination of clonidine and dobutamine in anesthetized dogs. Anesth Analg. 1992;74:703-711. 28. de la Coussaye J, Bassoul B, Albat B, et al. Experimental evidence in favor of role of intracellular actions of bupivacaine in myocardial depression. Anesth Analg. 1992;74:698-702. 29. Dinneen S, Mohr D, Fairbanks V. Methemoglobinemia from topically applied anesthetic spray. Mayo Clin Proc. 1994;69:886-888. 30. Dyhre H, Lang M, Wallin R, et al. The duration of action of bupivacaine, levobupivacaine, ropivacaine, and pethidine in peripheral nerve block in the rat. Acta Anaesthesiol Scand. 1997;41:1345-1352. 31. Eichenfeld LA. clinical study to evaluate the efficacy of ELA-Max (4% liposomal lidocaine) as compared with eutectic mixture of local anesthetics cream for pain reduction of venipuncture in children. Pediatrics. 2002;109:1093-1099. 32. Englesson S. The influence of acid-base changes on central nervous system toxicity of local anesthetic agents. I. An experimental study in cats. Acta Anaesthesiol Scand. 1974;18:79-87. 33. Englesson S. The influence of acid-base changes on central nervous system toxicity of local anesthetic agents: II. Acta Anaesthesiol Scand. 1974;18: 88-103. 34. Finkelstein F, Kreeft J. Massive lidocaine poisoning. N Engl J Med. 1979;301:50. 35. Foldes FF, Davidson GM, Duncalf D, Kuwabara S. The intravenous toxicity of local anesthetic agents in man. Clin Pharm Ther. 1965;6:328-335. 36. Franz D, Perry R. Mechanisms for differential block among single myelinated and nonmyelinated axons by procaine. J Physiol. 1974;236:193-210. 37. Freedman M, Gal J, Freed C. Extracorporeal pump assistance—novel treatment for acute lidocaine poisoning. Eur J Clin Pharmacol. 1982;22:129-135. 38. Fujita Y. Amrinone reverses bupivacaine-induced regional myocardial dysfunction. Acta Anaesthesiol Scand. 1996;40:47-52. 39. Giovannitti JA, Bennett CR. Assessment of allergy to local anesthetics. J Am Dent Assoc. 1979;98:701-706. 40. Graf BM, Martin E, Bosnjak ZJ, et al. Stereospecific effect of bupivacaine isomers on atrioventricular conduction in the isolated perfused guinea pig heart. Anesthesiology. 1997;86:410-419. 41. Hahn I, Hoffman RS, Nelson LS. EMLA-induced methemoglobinemia (metHb) and systemic topical anesthetic toxicity. J Emerg Med. 2004; 26: 85-88. 42. Halsted WS. Practical comments on the use and abuse of cocaine suggested by its invariably successful employment in more than a thousand minor surgical operations. N Y Med J. 1885;42:294. 43. Heavner J, Arthur J, Zou J, et al. Comparison of propofol with thiopentone for treatment of bupivacaine-induced seizures in rats. Br J Anaesth. 1993;71:715-719. 44. Heavner JE. Cardiac dysrhythmias induced by infusion of local anesthetics into the lateral ventricle of cats. Anesth Analg. 1986;65:133-138. 45. Hjelm M, Holmdahl M. Biochemical effects of aromatic amines II. Cyanosis methemoglobinemia and Heinz-body formation induced by a local anaesthetic agent (prilocaine). Acta Anaesthesiol Scand. 1965; 2:99-120.

46. Hollmann MW, Durieux ME. Local anesthetics and the inflammatory response: a new therapeutic indication? Anesthesiology. 2000;93:858-875. 47. Hollmann MW, Fisher LG, Byforf AM, et al. Local anesthetic inhibition of m1 muscarinic acetylcholine signaling. Anesthesiology. 2000; 93:497-509. 48. Hondeghem L, Miller R. Local Anesthetics, Basic and Clinical Pharmacology, 4th ed. Stamford, CT: Appleton and Lange; 1989:315-322. 49. Huet O, Eyrolle L, Mazoit J, et al. Cardiac arrest after injection of ropivacaine for posterior lumbar plexus blockade. Anesthesiology. 2003;99: 1451-1453. 50. Johnson M. Potential neurotoxicity of spinal anesthesia with lidocaine. Mayo Clin Proc. 2000;75:921-932. 51. Jorfeldt L, Lewis DH, Lofstrom JB, Post C. Lung uptake of lidocaine in man as influenced by anaesthesia, mepivacaine infusion or lung insufficiency. Acta Anaesth Scand. 1983;27:5-9. 52. Kasten G, Martin S. Successful cardiovascular resuscitation after massive intravenous bupivacaine overdosage in anesthetized dogs. Anesth Analg. 1985;64:491-497. 53. Klein S, Pierce T, Rubin Y, et al. Successful resuscitation after ropivacaineinduced ventricular fibrillation. Anesth Analg. 2004;97:901-903. 54. Kozody R, Ready L, Barsa J, Murphy T. Dose requirements of local anesthetic to produce grand mal seizure during stellate ganglion block. Can Anaesth Soc J. 1982;29:489-491. 55. Lambert L, Lambert D, Strichartz G. Irreversible conduction block in isolated nerve by high concentrations of local anesthetics. Anesthesiology. 1994;80:1082-1093. 56. Lee-Son S, Wang GK, Concus A, et al. Stereoselective inhibition of neuronal sodium channels by local anesthetics: evidence for two sites of action? Anesthesiology. 1992;77:324-335. 57. Lindgren L, Randell T, Suzuki N, et al. The effect of amrinone on recovery from severe bupivacaine intoxication in pigs. Anesthesiology. 1992;77: 309-315. 58. Litz RJ, Roessel T, Heler AR, Stehr SN. Reversal of central nervous system and cardiac toxicity after local anesthetic intoxication by lipid emulsion injection. Anesth Analg. 2008;106:1575-1577. 59. Lofstrom JB. Physiologic disposition of local anesthetics. Reg Anesth. 1982;7:33-38. 60. Long W, Rosenblum S, Grady I. Successful resuscitation of bupivacaineinduced cardiac arrest using cardiopulmonary bypass. Anesth Analg. 1989;69: 403-406. 61. Lund P, Cwik J. Propitocaine (citanest) and methemoglobinemia. Anesthesiology. 1965;26:569-571. 62. Lynch C III. Depression of myocardial contractility in vitro by bupivacaine, etidocaine, and lidocaine. Anesth Analg. 1986;65:551-559. 63. Mallampati SR, Liu P, Knapp RM. Convulsions and ventricular tachycardia from bupivacaine with epinephrine: successful resuscitation. Anesth Analg. 1984;63:856-859. 64. Marsch SCU, Schaefer HG, Castelli I. Unusual psychological manifestation of systemic local anesthetic toxicity. Anesthesiology. 1998;88:531-533. 65. Matsuda F, Kinney W, Wright W, Kambam J. Nicardipine reduces the cardio-respiratory toxicity of intravenously administered bupivacaine in rats. Can J Anaesth. 1990;37:920-923. 66. Mattison JB. Cocaine poisoning. Med Surg Rep. 1891;60:645-650. 67. Maxwell L, Martin L, Yaster M. Bupivacaine-induced cardiac toxicity in neonates: successful treatment with intravenous phenytoin. Anesthesiology. 1994;80:682-686. 68. Mazoit JX, Decaux A, Bouaziz H, et al. Comparative ventricular electrophysiologic effect of racemic bupivacaine, levobupivacaine, and ropivacaine on the isolated rabbit heart. Anesthesiology. 2000;92:784-792. 69. McCloskey J, Haun S, Deshpande J. Bupivacaine toxicity secondary to continuous caudal epidural infusion in children. Anesth Analg. 1992;75:287-290. 70. Moller R, Covino B. Cardiac electrophysiologic effects of lidocaine and bupivacaine. Anesth Analg. 1988;67:107-114. 71. Moore D, Balfour R, Fitzgibbons D. Convulsive arterial plasma levels of bupivacaine and the response to diazepam therapy. Anesthesiology. 1979;50:454-456. 72. Moore DC, Batra M. The components of an effective test dose prior to epidural block. Anesthesiology. 1981;55:693-696. 73. Moore DC, Bridenbaugh LD, Thompson GE, et al. Factors determining dosages of amide-type local anesthetic drugs. Anesthesiology. 1977;47: 263-268. 74. Moore DC, Bridenbaugh LD, Thompson GE, et al. Bupivacaine: a review of 11,080 cases. Anesth Analg. 1978;57:42-53.

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Chapter 66

75. Moore T, Walsh C, Cohen M. Reported adverse event cases of methemoglobinemia associated with benzocaine products. Arch Intern Med. 2004;164: 1192-1196. 76. Morishima H, Corvino B. Toxicity and distribution of lidocaine in nonasphyxiated and asphyxiated baboon fetuses. Anesthesiology. 1981;54:182-186. 77. Morishima H, Pederson H, Finster M, et al. Bupivacaine toxicity in pregnant and nonpregnant ewes. Anesthesiology. 1985;63:134-139. 78. Morishima H, Pederson H, Finster M, et al. Toxicity of lidocaine in adult, newborn, and fetal sheep. Anesthesiology. 1981;55:57-61. 79. Myers RR, Kalichman MW, Reisner LS, et al. Neurotoxicity of local anesthetics: altered perineural permeability, edema, and nerve fiber injury. Anesthesiology. 1986;64:29-35. 80. Nation R, Triggs E, Selig M. Lignocaine kinetics in cardiac and aged subjects. Br J Clin Pharmacol. 1977;4:439-445. 81. Nau C, Vogel W, Hempelmann G, et al. Stereoselectivity of bupivacaine in local anesthetic-sensitive ion channels of peripheral nerve. Anesthesiology. 1999;91:786-795. 82. Noble J, Kennedy D, Latimer R, et al. Massive lignocaine overdose during cardiopulmonary bypass: successful treatment with cardiac pacing. Br J Anaesth. 1984;56:1439-1441. 83. Nystrom EUM, Heavner JE, Buffington CW. Blood pressure is maintained despite profound myocardial depression during acute bupivacaine overdose in pigs. Anesth Analg. 1999;88:1143-1148. 84. Peterson RC. History of cocaine. NIDA Res Monogr. 1977;13:17-34. 85. Pitkanen M, Feldman HS, Arthur GR, et al. Chronotropic and inotropic effects of ropivacaine, bupivacaine, and lidocaine in the spontaneously beating and electrically paced isolated perfused rabbit heart. Reg Anesth Pain Med. 1992;17:183-192. 86. Polley LS, Columb MO, Naughton NN, et al. Relative analgesic potencies of ropivacaine and bupivacaine for epidural analgesia in labor: implications for therapeutic indexes. Anesthesiology. 1999;90:944-950. 87. Prentiss J. Cardiac arrest following caudal anesthesia. Anesthesiology. 1979;50:51-53. 88. Reisner LS, Hochman BN, Plumer MH. Persistent neurologic deficit and adhesive arachnoiditis following intrathecal 2-chloroprocaine injection. Anesth Analg. 1980;59:452-454. 89. Reiz S, Nath S. Cardiotoxicity of local anesthetic agents. Br J Anaesth. 1986;58:736-746. 90. Reynolds F. Adverse effects of local anaesthetics. Br J Anaesth. 1987;59:78-95. 91. Rigler M, Drasner K, Krejcie T, et al. Cauda equina syndrome after continuous spinal anesthesia. Anesth Analg. 1991;72:275-281. 92. Rosen M, Thigpen J, Schnider S, et al. Bupivacaine-induced cardiotoxicity in hypoxic and acidotic sheep. Anesth Analg. 1985;64:1089-1096. 93. Rosenberg PH, Kalso EA, Tuominen MK, Linden HB. Acute bupivacaine toxicity as a result of venous leakage under the tourniquet cuff during a bier block. Anesthesiology. 1983;58:95-98. 94. Rosenblatt MA, Abel M, Fischer GW, et al. Successful use of a 20% lipid emulsion to resuscitate a patient after a presumed bupivacaine-related cardiac arrest. Anesthesiology. 2006;105:217-218. 95. Saitoh K, Hirabayashi Y, Shimizu R, Fukuda H. Amrinone is superior to epinephrine in reversing bupivacaine-induced cardiovascular depression in sevoflurane-anesthetized cats. Anesthesiology. 1995;83:127-133. 96. Scott DB. Evaluation of the toxicity of local anaesthetic agents in man. Br J Anaesth. 1975;47:56-61.

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97. Scott DB. “Maximal recommended doses” of local anaesthetic drugs. Br J Anaesth. 1989;63:373-374. 98. Scott DB. Toxicity caused by local anaesthetic drugs. Br J Anaesth. 1981;53: 553-554. 99. Stehr SN, Pexa A, Hannack S, et al. The effects of lipid infusion on myocardial function and bioenergetics in l-bupivacaine toxicity in the isolated rat heart. Anesth Analg. 2007;104:186-192. 100. Strichartz GR, Berde CB. Local anesthetics. In: Miller RD, ed. Anesthesia, 4th ed. New York: Churchill Livingstone; 1994:489-521. 101. Sztark F, Malgat M, Dabadie P, et al. Comparison of the effects of bupivacaine and ropivacaine on heart cell mitochondrial bioenergetics. Anesthesiology. 1998;88:1340-1349. 102. Taddio A, Stevens B, Craig K, et al. Efficacy and safety of lidocaine prilocaine cream for pain during circumcision. N Engl J Med. 1997; 336:1197-1201. 103. Tanaka K, Yamasaki M. Blocking of cortical inhibitory synapses by intravenous lidocaine. Nature. 1966;209:207-208. 104. Taniguchi M, Bollen A, Drasner K. Sodium bisulfite: scapegoat for chloroprocaine neurotoxicity? Anesthesiology. 2004;100:85-91. 105. Thomas R, Behbehani M, Coyle D, et al. Cardiovascular toxicity of local anesthetics: an alternative hypothesis. Anesth Analg. 1986;65: 444-450. 106. Verrill PJ. Adverse reactions to local anesthetics and vasoconstrictor drugs. Practitioner. 1975;214:380-387. 107. Wagman IH, de Jong RH, Prince DA. Effects of lidocaine on the central nervous system. Anesthesiology. 1967;28:155-172. 108. Wang BC, Hillman DE, Spielholz NI, et al. Chronic neurologic deficits and Nesacaine: an effect of the anesthetic 2-chloroprocaine or the antioxidant sodium bisulfite? Anesth Analg. 1984;63:445-447. 109. Warren JA, Thoma RB, Georgescu A, Shah SJ. Intravenous lipid infusion in the successful resuscitation of local anesthetic-induced cardiovascular collapse after supraclavicular brachial plexus block. Anesth Analg. 2008;106:1578-1580. 110. Weinberg GL. Lipid infusion therapy. Translation to clinical practice. Anesth Analg. 2008;106:1340-1342. 111. Weinberg GL. Lipid rescue—caveats and recommendations for the “Silver Bullet.” [letter]. Reg Anesth Pain Med. 2004;29:74-75. 112. Weinberg GL, Gregorio GD, Ripper R, et al. Resuscitation with lipid versus epinephrine in a rat model of bupivacaine overdose. Anesthesiology. 2008; 108:907-913. 113. Weinberg GL, Laurito C, Geldner P, et al. Malignant ventricular dysrhythmias in a patient with isovaleric acidemia receiving general and local anesthesia for suction lipectomy. J Clin Anesth. 1997;9:668-670. 114. Weinberg GL, Palmer JW, VadeBoncourer TR, et al. Bupivacaine inhibits acylcarnitine exchange in cardiac mitochondria. Anesthesiology. 2000;92: 523-528. 115. Weinberg G, Ripper R, Feinstein D, et al. Lipid emulsion infusion rescues dogs from bupivacaine-induced cardiac toxicity. Reg Anesth Pain Med. 2003; 28:198-202. 116. Weinberg G, Ripper R, Murphy P, et al. Lipid infusion accelerates removal of bupivacaine and recovery from bupivacaine toxicity in the isolated rat heart. Reg Anesth Pain Med. 2006;31:296-303. 117. Weinberg GL, VadeBoncouer T, Ramaraju GA, et al. Pretreatment or resuscitation with a lipid infusion shifts the dose-response to bupivacaineinduced asystole in rats. Anesthesiology. 1998:88:1071-1075.

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A N T I D O T E S I N D E P T H ( A 21 ) INTRAVENOUS FAT EMULSIONS Theodore C. Bania Intravenous fat emulsion (IFE) has been used as a source of parenteral nutrition for over 40 years. More recently, IFE has also been used as a diluent for intravenous drug delivery of highly lipophilic xenobiotics such as propofol and liposomal amphotericin. The use of IFE as an antidote is most extensively studied for the treatment of local anesthetic toxicity, specifically from bupivacaine, but new applications that are being investigated and reported on include the treatment of overdose from lipophilic drugs such as calcium channel blockers, cyclic antidepressants, clomipramine, and beta adrenergic antagonists, to name a few.

PHARMACOLOGY Intravenous fat emulsion is composed of two types of lipids, triglycerides and phospholipids. Triglycerides are hydrophobic molecules that are formed when three fatty acids are linked to one glycerol. The fatty acid chain length varies, producing different triglycerides. The main triglycerides in IFE are linoleic, linolenic, oleic, palmitic, and stearic acids, and concentrations of these vary slightly in the different commercially available fat emulsions. These long-chain triglycerides (12 or more carbons) are extracted from safflower oil and/or soybean oil depending on the brand of the emulsion.42 Newer fat emulsions contain long-chain triglycerides in addition to medium-chain triglycerides (6–12 carbons) derived from coconut, olive, and fish oils but are currently not available in the United States.46 Phospholipids contain two fatty acids bound to glycerol along with a phosphoric acid moiety at the third hydroxyl (Fig A21–1). Phospholipids are amphipathic, that is, the nonpolar fatty acids are hydrophobic while the polar phosphate head is hydrophilic. This imparts important pharmacological properties to this carrier molecule, allowing it to solubilize nonpolar xenobiotics into the aqueous serum. The phospholipids in IFE are extracted from egg yolks. The lipids in IFE are dispersed in the serum by forming an emulsion of small lipid droplets. To create the emulsion droplets, the phospholipids form a layer around a triglyceride core. The hydrophobic fatty acid component of the phospholipid molecule is directed toward the triglycerides while the hydrophilic glycerol component is directed outward away from the triglyceride core. The presence of small amounts of glycerol, which is hydrophilic, allows the lipid droplets to be suspended as an emulsion in water and serum. Intravenous fat emulsion is a white, milky liquid. It is sterile and nonpyrogenic with a pH of about 8 (range 6 to 9). IFEs are isotonic solutions (260–310 mOsm/L) and are available in 5%, 10%, 20%, and 30% solutions. The 30% solution should be diluted before administration. IFE can be delivered through a peripheral or central vein.42

Intravenous fat emulsions have different globule sizes depending on their uses.7 Microemulsions (mean droplet size less than 0.1 μm) are used for drug delivery. Mini-emulsions (mean droplet size greater than 0.1 μm but less than 1.0 μm) are used for parenteral nutrition. Droplet sizes in commercially available nutritional IFEs range from 0.4 to 0.5 μm. After intravenous administration, IFEs are found in the serum as chylomicronlike lipid droplets that turn the serum turbid or milky. Macro-emulsions (mean droplet size greater than 1.0 μm) are used for chemoembolization. These macro-emulsions contain antineoplastics that are delivered intraarterially directly into the tumor blood supply. The lipid droplets occlude the artery and slowly release the antineoplastic. Lipid droplets that are less than 1 μm are primarily removed from circulation as they pass through the capillaries of adipose tissue and the liver. The capillary endothelium in these tissues contains lipoprotein lipase, which hydrolyzes triglycerides releasing fatty acids and glycerol that then diffuses into the cells. Fatty acids also enter the cardiac myocyte either by passive diffusion or protein-mediated transport.39 Once inside the cells, fatty acids are used as energy or resynthesized into triglycerides and stored. For use as energy, triglycerides are transported into the mitochondria by carnitine palmitoyl transferase, where they undergo β oxidation sequentially releasing acetylcoenzyme A (acetyl-CoA) as the fatty acid chain is reduced in length. These acetylCoA molecules enter the Krebs cycle, where they ultimately generate adenosine triphosphate (ATP) (see Fig. 12-3 and 12-8). Although glucose, lactate, and fatty acid metabolism may ultimately lead to the production of acetyl-CoA, fatty acid metabolism produces the largest amount of energy. For example, 1 mol of glucose produces 38 ATP while 1 mol of stearic acid produces 146 ATPs55 and the metabolism of longer fatty acid chains may produce more ATP. The half-life of IFE is 30 to 60 minutes, and can vary substantially depending on the patient’s clinical state, dose of IFE, and droplet size.8 Larger droplet sizes have slower clearances, and are removed by reticuloendothelial phagocytosis. These larger droplets are more likely to induce an inflammatory response, obstruct the microvasculature, and produce capillary fat emboli.

MECHANISM OF ACTION The mechanisms of action of IFE in toxicology are not clearly understood. There are currently three proposed mechanisms of action of IFE in toxicology: modulation of intracellular metabolism, a lipid sink or sponge mechanism, and activation of ion channels. In experimental models of poisoning from xenobiotics that alter intracellular energy metabolism, toxicity was successfully treated with IFE, suggesting that repairing or circumventing this dysfunction may be involved. Bupivacaine blocks carnitine-dependent mitochondrial lipid transport and inhibits adenosine triphosphatase (ATPase) synthetase in the electron transport chain.6,51 Verapamil also inhibits intracellular processing of fatty acids,20,21 but it inhibits insulin release and produces insulin resistance as well.21 The cyclic antidepressant amitriptyline depresses human myocardial contraction independent of an effect on conduction16 and inhibits medium- and short-chain fatty acid metabolism.48 Propranolol changes intracellular energy from primarily fatty acid to carbohydrate-dependent metabolism.28

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Antidotes in Depth

Phosphoglycerol head Cholesterol Extracellular fluid Lipid tail Intracellular fluid

Phospholipid Hydrophilic

R Phosphate group

H Glycerol head

H

C

H H H H H H H

O–

P

H

O

C

C

O

H

C H C H C H C H C H C H C H C H

O

O

H

Ester linkage O

H

O

C H C H C H C H C H C H C H C

C H C H C H C H C H C H C H C H

O H H H H H H H H H H H H H H H

H

C H C H C H C H C H C H C H C

H H H H H H H

H

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ischemia resulted in improved systolic wall thickening. In the same canine model, pretreatment with oxfenicine, which blocks carnitine palmitoyl transferase one blocked the beneficial effect of IFE.20 This implies that the effects of IFE on myocardial contraction following ischemia are mediated by mitochondrial metabolism. To determine if this is the mechanism of action in verapamil toxicity, rodents were pretreated with oxfenicine or control solution and had verapamil toxicity induced. Both groups were then resuscitated with IFE.1 There was no significant difference in survival time and mean arterial pressure between the oxfenicine-treated and control groups. This implies that in verapamil toxicity IFE works by a mechanism other than supplying energy to the mitochondria. In the lipid sink/sponge mechanism, IFE soaks up lipid-soluble xenobiotic and removes it from the site of toxicity. In a slight variation of this mechanism, IFE may pull the xenobiotic out of the aqueous plasma, which bathes the tissue, and into a nonaqueous part of the plasma that is not in contact with the site of toxicity. IFE may also change the distribution of lipid-soluble xenobiotics and deposit them away from the site of toxicity into an area with high lipid content. There is some experimental support for this lipid/sponge mechanism. In an isolated heart model, hearts were perfused with bupivacaine until asystole and then treated with control or IFE. The IFE-treated hearts had a faster recovery from asystole, lower concentration of bupivacaine in the tissue, and higher concentrations of bupivacaine in the venous effluent.52 In a successful resuscitation from bupropion overdose, bupropion concentrations increased dramatically after administration of IFE.36 These findings in the experimental model and case report can be explained by the lipid sink/sponge model, where IFE pulls a xenobiotic out of tissue stores. However, the increased concentrations in both could also be explained by an increased perfusion of tissues with the return of circulation and release of the drug. Stronger evidence for the lipid sink/sponge mechanism comes from a pharmacokinetic study of clomipramine concentrations following infusion of IFE. In a rabbit model of clomipramine-induced hypotension, IFE resulted in a more rapid increase in blood pressure compared with saline.15 These hemodynamic effects were associated with an increased concentration and decreased volume of distribution of clomipramine. Additionally, IFE may activate ion, particularly Ca2+, channels. Fatty acids directly activate myocardial calcium channels and induce a dosedependent increase in the Ca2+ current. Oleic, linoleic, and linolenic acids act directly on the Ca2+ channel to increase Ca2+ current.18 Unfortunately, there is no direct support for this mechanism of action of IFE. Despite the lack of studies on mechanisms of action, the lipid sink/ sponge model is the most likely hypothesis since beneficial effects from IFE are most frequently noted for lipid-soluble xenobiotics. Other mechanisms may be consequential and the mechanism of action may vary for different xenobiotics.

Fatty acid tails Hydrophobic

EFFICACY IN POISONING

FIGURE A21–1. Biologic membranes are comprised of phospolipids that have a hyrophilic phosphoglycerol “head” and hydrophobic fatty acid “tails.” .

■ EXPERIMENTAL MODELS

Theoretically, adding excess fatty acids may overcome blocked or inhibited enzymes by mass action, providing energy to an energy “starved” heart, reversing toxicity. There is limited experimental evidence to support a modulation of intracellular energy metabolism as the mechanism of action of the IFE for poisoning. The only evidence to support this mechanism comes from IFE effect in reversing myocardial depression resulting from myocardial ischemia.43 In a canine model of 10 minutes of regional myocardial ischemia, treatment with IFE after

IFE was first studied as an antidote to bupivacaine toxicity and then evaluated for calcium channel blockers, cyclic antidepressants, and β-adrenergic antagonist toxicity. In a rodent model, pretreatment with IFE (10%–30%) followed by a continuous infusion of bupivacaine (10 mg/kg/min) increased the dose of bupivacaine needed to induce asystole.53 In the second part of this study, bupivacaine was infused into rodents until the development of cardiac arrest. Rodents were resuscitated with IFE (30% IFE, 7.5 mL/kg bolus then 3 mL/kg/min for 2 minutes) or an equivalent volume of saline. Animals were more successfully resuscitated with IFE from a larger dose of bupivacaine then

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Part C

The Clinical Basis of Medical Toxicology

when saline treated. The LD50 for saline resuscitation was 12.5 mg/kg, whereas the LD50 for IFE resuscitation was 18.5 mg/kg. In a larger animal model, bupivacaine was administered until cardiac arrest and then the animal was resuscitated with IFE (20% IFE, 4 mL/kg bolus, then 0.5 mL/kg/min for 10 minutes) or saline. Intravenous fat emulsion resulted in a dramatic improvement in survival as six of six survived following IFE versus none in the control (zero of six).49,50 In a controlled study of rodents given a continuous infusion of verapamil, treatment with 12.4-mL/kg bolus of 20% IFE resulted in an increase in heart rate and survival compared with control.41 In a larger animal model of verapamil toxicity where animals were also treated with calcium and atropine, 7 mL/kg of 20% IFE over 30 minutes resulted in improved blood pressure and survival.2 In an experimental model of clomipramine toxicity,14 rabbits were given clomipramine until mean arterial pressure decreased to 50% of baseline. They were then treated with sodium bicarbonate (3 mL/kg of 8.4%), IFE (12 mL/kg of 20%), or sodium chloride (12 mL/kg of 0.9%). Intravenous fat emulsion resulted in an increase in mean arterial pressure over sodium chloride and NaHCO3. In a second part of this study, clomipramine was administered until cardiovascular collapse followed by resuscitation with NaHCO3 (2 mL/kg of 8.4%) or IFE (8 mL/kg of 20%) delivered over 2 minutes. Intravenous fat emulsion resulted in improved survival (four of four) whereas NaHCO3 resulted in no resuscitations (zero of four). In a rodent model with a constant infusion of propranolol, IFE decreased QRS prolongation, but the study was underpowered to detect an effect on heart rate or survival.5 In another rodent and rabbit model of propranolol toxicity, IFE resulted in an increase in blood pressure.4,13

CLINICAL CASE REPORTS Based upon the experimental evidence in bupivacaine toxicity, IFE was subsequently successfully used in several reported human cases of cardiovascular collapse from local anesthetic overdose. Previously, cardiopulmonary bypass was the only effective treatment for these patients, as most cases were refractory to standard cardiac resuscitative measures (see Chap. 66). The first reported case occurred in a patient who developed cardiac arrest after the inadvertent intravenous administration of bupivacaine and mepivacaine during an interscalene block.32 The patient was treated with cardiopulmonary resuscitation (CPR) and advanced cardiac life support (ACLS) for 20 minutes, but only had return of spontaneous circulation after administration of the first dose of IFE (100 mL of 20% IFE followed by 0.5 mL/kg/min for 2 hours). The second successfully treated case occurred when a patient developed asystole after inadvertent intravenous administration of ropivacaine during an axillary plexus block.25 The patient received CPR and ACLS and had return of spontaneous circulation 10 minutes after administration of IFE (100 mL of 20% or 2 mL/kg followed by an infusion at 10 mL/min for an additional dose of 100 mL of IFE). Additionally, a 60-year-old man with diabetes, coronary artery disease, and end-stage renal failure became unresponsive and developed ventricular fibrillation and torsades de pointes after administration of mepivacaine and bupivacaine for a supraclavicular brachial plexus block. The patient was treated with CPR and ACLS for 10 minutes and then was treated with IFE (250 mL of 20% over 30 minutes). He had return of pulse and blood pressure 11 minutes later.47 In addition to its use during resuscitation, IFE has been used to treat milder symptoms of local anesthetic toxicity such as central nervous system symptoms and dysrhythmias without loss of pulse. A patient developed agitation, dizziness, unresponsiveness, and atrial premature

contractions and bigeminy after administration of mepivacaine and prilocaine for a brachial plexus block. The patient was only treated with IFE (1 mL/kg of 20%, repeated at 3 minutes for a total of 100 mL, followed by a continuous infusion of 0.25 mL/kg/min or 14 mL/min) and had rapid resolution of his dysrhythmia and regained consciousness.26 A 75-year-old patient developed seizure, wide complex dysrhythmia, and hypotension following administration of levobupivacaine for a lumbar plexus block. The patient was treated with propofol and metaraminol and IFE (20%, 100 mL over 5 minutes). During the IFE infusion, the QRS narrowed and blood pressure and electrocardiogram (ECG) normalized within 10 minutes.10 A 13-year-old patient developed ventricular tachycardia at 150 beats/min after being administered lidocaine with epinephrine and ropivacaine for a lumbar plexus block. The patient was only treated with IFE (150 mL or 3 mL/kg of 20% IFE over 3 minutes) and reverted to a normal QRS complex within 2 minutes.27 Intravenous fat emulsion has also been successfully used to resuscitate a 17-year-old patient with prolonged cardiovascular collapse after overdose of bupropion and lamotrigine. In this remarkable case the patient, who had seizures and hypotension, received ACLS and CPR for 70 minutes and had return of spontaneous circulation after administration of IFE (a bolus of 100 mL of 20%).36 Although the optimal dosing regimen for human poisonings remains undefined, several animal models of high-dose IFE have been performed. In a rodent and canine model of verapamil toxicity, 12.4- and 7-mL/kg boluses of 20% IFE were given,3,41 and in a rabbit model of clomipramine, 12 mL/kg of 20% IFE was used.42 These animal models used large doses of xenobiotic and were designed to produce a rapid onset of toxicity, so it is difficult to extrapolate from these models to typical human cases. However, the onset of action of IFE in these models was relatively rapid with effects occurring within 5 minutes for clomipramine, and 25 to 30 minutes for verapamil. Higher doses of IFE also are more effective than lower doses. In a model of verpamil toxicity, higher doses of IFE were more effective in improving blood pressure, acidemia, and survival than lower doses of IFE up to a maximum of 18.6 mL/kg of 20% IFE. Higher doses improved hemodynamic parameters transiently but may have also resulted in overall decreased survival times.31

DOSING The dose of IFE administered depends on the implicated xenobiotic and the patient’s clinical condition. Dosing is best defined for local anesthetic toxicity, specifically bupivacaine, with generalization of this dosing regimen to poisoning by other local anesthetics and other xenobiotics. The recommended dose of 20% IFE is 1.5-mL/kg bolus followed by 0.25 mL/kg/min or 15 mL/kg/h to run for 30 to 60 minutes.11,49 The bolus can be repeated several times for persistent asystole, and the infusion rate can be increased if blood pressure decreases. For local anesthetic poisoning, earlier recommendations limited use of IFE only if standard resuscitative measures failed. As a result of the experimental evidence and many successful case reports, some authors are recommending adding IFE at the first signs of local anesthetic toxicity or, in the setting of cardiovascular collapse, to use IFE concomitantly with CPR and ACLS.54 Generalization of this practice to other xenobiotics is not currently studied or recommended. Some authors are also recommending that IFE be stored for easy and rapid access in operating rooms or in areas where local anesthetics are frequently used.33 Most case reports documenting successful treatment of local anesthetic toxicity with lipids have been with Intralipid®; however, other parenteral lipid formulations such as Medialipid® (a mixture of 50%

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long-chain triglycerides and 50% medium-chain triglycerides; Braun, Germany)27 and Liposyn III® (Hospira Inc., Lake Forest, IL)47 have also been successful, suggesting that all currently available parenteral lipid products will be as effective. Propofol is formulated as a 10% lipid emulsion, but it is not recommended for use a lipid rescue agent50 because of the adverse effect of the propofol from the dose needed as a lipid rescue agent. For bupivacaine toxicity, 1.5-mL/kg bolus of 20% IFE is recommended which equates to 3 mL/kg of the 10% lipid emulsion in the propofol solution. As normal dose of propofol (1%) for general anesthesia is 2.5 mg/kg or 0.25 mL/kg.34 Using propofol as a lipid rescue agent would deliver a bolus of 12 times the recommended dose of propofol. This would exacerbate any drug-induced hypotension and bradycardia. Experimental evidence indicates that IFE may be potentially beneficial in verapamil,2,31,41 clomipramine,14,15 and propranolol4,13 toxicity and this may be extrapolated to other lipid-soluble calcium channel blockers, cyclic antidepressants, or β-adrenergic antagonists. These xenobiotics will usually demonstrate continued absorption, longer duration of toxicity, severe hypotension, and either dysrhythmias or bradycardia over several hours or days. The precise indications and dose of IFE for these situations has not been studied. It may occasionally be necessary to administer a continuous infusion of IFE following initial resuscitation. The dose of IFE used for nutrition is generally considered a safe dose, except for the potential complications described above. Currently, the nutritional dose of IFE is 1 to 2 g/kg/d or 5 to 10 mL/kg/d of 20% IFE, which is administered over 6 to 24 hours.8,33 The dose can be increased daily up to 3 g/kg/d. This dose and rate is less than the dose recommended for bupivacaine toxicity (1.5 mL/kg bolus of 20% IFE followed by 15 mL/kg/h for 30 to 60 minutes)11 and less than the doses used in experimental models for other xenobiotic toxicity. Based on the current data available from animal models, if IFE is used for severe xenobiotic-induced toxicity other than for that of local anesthetics, the safest dosing would be to start with the low dose suggested for bupivacaine toxicity and titrate up, every hour, if hemodynamic parameters continue to worsen.

ADVERSE EFFECTS AND CONTRAINDICATIONS There have been no reported adverse effects attributed to IFE in the case reports of IFE use in local anesthetic or bupropion toxicity. With the doses used in these cases and the short durations of administration, most patients recovered fully without any significant adverse effects.10,25-27,33,36,47 Based on these case reports, a dose of 1.5-mL/kg bolus of 20% IFE followed by 0.25 mL/kg/min or 15 mL/kg/h to run for 30 to 60 minutes appears to be safe in bupivacaine-induced cardiac arrest and severe toxicity. Because of the limited number of case reports, toxicity from IFE remains a concern. Pulmonary toxicity has been reported when IFE is used as a source of parenteral nutrition. In patients with acute respiratory distress syndrome (ARDS), 500 mL of 20% IFE administered over 8 hours resulted in an increase in pulmonary artery pressures, pulmonary shunting, pulmonary vascular resistance, and a decrease in partial pressure of oxygen in the alveoli/fraction of inspired oxygen (Pao2/ Fio2).45 Similar results were found in patients with ARDS administered 500 mL of 10% IFE over 4 hours resulting in an increase in pulmonary shunting and a decrease in the fraction of Pao2/Fio2.19 The pulmonary effect of IFE in ARDS may be related to the rate of infusion. In patients with ARDS, 500 mL of 20% IFE infused over 5 hours resulted in an increase in pulmonary pressures, and slower infusion over 10 hours

Intravenous Fat Emulsions

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had no effect on pulmonary pressures.29 There are conflicting results of the effects of IFE in patients without ARDS. In septic and nonseptic patients without ARDS, 500 mL of 20% IFE administered over 10 hours resulted in an increase in pulmonary artery pressures and pulmonary shunting.44 In patients with chronic obstructive pulmonary disease (COPD) and pneumonia, 500 mL of 10% IFE administered over 4 hours did not have any pulmonary effects, and in a group of healthy postoperative patients this dose actually decreased pulmonary shunting and increased Pao2/Fio2 ratio.19 In these studies, when pulmonary effects occurred they were mild and resolved after the IFE infusion was stopped or within 3 to 4 hours. Larger doses may result in clinically significant toxicity and more prolonged effect. However, studies using fat emulsions with mediumchain triglycerides have shown less pulmonary toxicity.9,37 There are two mechanisms by which IFE may cause pulmonary toxicity. IFE may occlude the pulmonary vasculature with micro–fat emboli. This is supported by the finding of macrophages containing lipid droplets in the bronchial alveolar lavage fluid of ARDS patients treated with IFE.24 Experimental evidence also supports the possibility that the high concentrations of linoleic acid in IFE are converted to arachidonic acid and then into vasoactive prostaglandins. Indomethacin, an inhibitor of prostaglandin synthesis, prevented any pulmonary vascular effect caused by IFE in a sheep model.30 In addition to pulmonary toxicity, large dose and/or more rapid infusion of IFE have the potential to induce a fat overload syndrome. The fat overload syndrome is characterized by hyperlipemia, fever, fat infiltration, hepatomegaly, jaundice, splenomegaly, anemia, leukopenia, thrombocytopenia, coagulation disturbances, seizures, and coma. Multiple end-organ dysfunction is attributed to inadequate clearance of lipids and sludging in the lungs, brain, kidney, retina, and liver.7,8,12,17,22,24,34,35,40 Because of the rapid redistribution of most local anesthetics, prolonged IFE infusion should not be required (see Chap. 66). However, many other lipid-soluble xenobiotics have a long duration of toxicity and prolonged IFE infusions may be recommended, resulting in a fat overload syndrome. Intravenous fat emulsion has the potential to increase gastrointestinal absorption of lipid-soluble xenobiotics. Although this is only currently a theoretical concern, the excessive xenobiotic would likely be partitioned into the IFE and thus be unlikely to result in additional toxicity. Intravenous fat emulsion also has the potential to interact with other antidotes being used. If an antidote is lipid soluble, it may be incorporated by the IFE and result in decreased effectiveness. This is a theoretical concern, and there are no clinical data supporting this concern. IFE has been used with several medications during resuscitation from bupivacaine toxicity including epinephrine, atropine, amiodarone, vasopressin, sodium bicarbonate, magnesium sulfate, calcium chloride, naloxone, and metaraminol.10,25,32,36,47 The combined use of IFE and high-dose insulin-euglycemia was evaluated in a model of severe verapamil toxicity and there was no improvement in hemodynamics, metabolic parameters