medEssentials for the USMLE Step 1 (2012)

SAVE OFFLINE

for the USMLE Step 1 TM

FOURTH EDITION

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ALSO FROM KAPLAN MEDICAL Books USMLE® Step 1 Qbook

Flashcards USMLE® Diagnostic Test Flashcards: The 200 Questions You Need to Know for the Exam for Steps 2 & 3 USMLE® Examination Flashcards: The 200 “Most Likely Diagnosis” Questions You Will See on the Exam for Steps 2 & 3 USMLE® Pharmacology and Treatment Flashcards: The 200 Questions You’re Most Likely to See on Steps 1, 2 & 3 USMLE® Physical Findings Flashcards: The 200 Questions You’re Most Likely to See on the Exam

Online Dr. Conrad Fischer’s Comprehensive Cases Updated USMLE® Step 3 Qbank

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for the USMLE Step 1 TM

FOURTH EDITION

High-Yield Review for First- and Second-Year Medical Students

USMLE™ is a registered trademark of the Federation of State Medical Boards (FSMB) of the United States and the National Board of Medical Examiners®(NBME®), neither of which sponsors or endorses this product.

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USMLE® is a registered trademark of the Federation of State Medical Boards (FSMB) of the United States and the National Board of Medical Examiners ® (NBME® ), neither of which sponsors or endorses this product. © 2012 Kaplan, Inc. Published by Kaplan Publishing, a division of Kaplan, Inc. 395 Hudson Street New York, NY 10014 This publication is designed to provide accurate and authoritative information in regard to the subject matter covered. It is sold with the understanding that the publisher is not engaged in rendering legal, accounting, or other professional service. If legal advice or other expert assistance is required, the services of a competent professional should be sought. All rights reserved under International and Pan-American Copyright Conventions. By Payment of the required fees, you have been granted the non-exclusive, non-transferable right to access and read the text of this eBook on screen. No part of this text may be reproduced, transmitted, downloaded, decompiled, reversed engineered, or stored in or introduced into any information storage and retrieval system, in any form or by any means, whether electronic or mechanical, now known or hereinafter invented, without the express written permission of the publisher. ISBN: 978-1-60978-945-9

Review Book

LEAD AUTHORS/EDITORS

Michael S. Manley, M.D.

Leslie D. Manley, Ph.D.



Director, Basic Sciences and Step 1 Curriculum Kaplan Medical

Director, Basic Sciences and Step 1 Curriculum Kaplan Medical

CONTRIBUTORS Thomas H. Adair, Ph.D.

Robert F. Kissling III, M.D.

Professor Department of Physiology and Biophysics University of Mississippi Medical Center

John A. Kriak, Pharm.D.

John Barone, M.D. Anatomic and Clinical Pathologist

Stuart Bentley-Hibbert, M.D., Ph.D. New York Presbyterian Hospital Weill Cornell Medical Center

Steven R. Daugherty, Ph.D. Director, Education and Testing Kaplan Medical and Adjunct Professor Rush Medical College

Douglas E. Fitzovich, Ph.D. Professor of Physiology DeBusk College of Osteopathic Medicine Lincoln Memorial University

Beth Forshee, Ph.D. Assistant Professor of Physiology Lake Erie College of Osteopathic Medicine

Barbara Hansen, Ph.D. Biochemistry Faculty Kaplan Medical

President/Chief Clinical Consultant, CAMMCO, LLC

Mary J. Ruebush, Ph.D. Adjunct Professor of Medical Science, retired Montana State University Microbiology/Immunology Faculty, Kaplan Medical

Nancy Standler, M.D., Ph.D. Department of Pathology Valley View Medical Center Intermountain Healthcare

Sam Turco, Ph.D. Professor, Department of Biochemistry University of Kentucky College of Medicine

James S. White, Ph.D. Assistant Professor of Cell Biology School of Osteopathic Medicine University of Medicine and Dentistry of New Jersey Adjunct Assistant Professor of Cell and Developmental Biology University of Pennsylvania School of Medicine

Glenn C. Yiu M.D., Ph.D. Clinical Fellow in Medicine Harvard Medical School

Steven R. Harris, Ph.D Associate Dean for Academic Affairs Professor of Pharmacology University of Pikeville Kentucky College of Osteopathic Medicine

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Contents

(A more comprehensive list appears on the first page of each chapter.) How to Use medEssentials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii SECTION I: GENERAL PRINCIPLES Chapter 1: Behavioral Science . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Chapter 2: Biochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 Chapter 3: Molecular Biology, Genetics, and Cell Biology . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 Chapter 4: Immunology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 Chapter 5: Microbiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 Chapter 6: Embryology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141 Chapter 7: Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147 Chapter 8: Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153 Chapter 9: Pharmacology/Therapeutics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165 SECTION II: ORGAN SYSTEMS Chapter 1: The Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Development of the Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Peripheral Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Meninges, Ventricular System, and Venous Drainage . . . . . . . . . . . . . . . . . . . . . . . . . Neurohistology and Pathologic Correlates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Spinal Cord . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cranial Nerves and Brain Stem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Visual System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Brain Stem Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cerebellum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diencephalon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Basal Ganglia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Limbic System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cerebral Cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Blood Supply . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Seizures and Anticonvulsants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Opioid Analgesics and Related Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Local Anesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . General Anesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

183 184 186 195 198 200 204 206 212 213 214 215 217 218 222 224 226 227 228

Chapter 2: The Cardiovascular System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Embryology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

229 230 232 237 254 267

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Chapter 3: The Respiratory System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Embryology and Histology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gross Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mechanics of Breathing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gas Exchange . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

273 274 275 277 278 282 289

Chapter 4: The Renal and Urinary System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Embryology and Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

299 300 302 325 327

Chapter 5: The Gastrointestinal System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Embryology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Histology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gross Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Microbiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Additional Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

333 334 335 337 342 355 365 368

Chapter 6: The Endocrine System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endocrine System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hypothalamus and Pituitary Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Adrenal Gland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pancreas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Regulation of Calcium and Phosphate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thyroid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Growth Hormone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

369 370 370 372 379 383 386 390

Chapter 7: The Reproductive System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reproductive System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Male Reproductive System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Female Reproductive System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Female Reproductive System Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Breast Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Genitourinary System Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

393 394 396 403 412 416 419

Chapter 8: The Musculoskeletal System, Skin, and Connective Tissue . . . . . . . . . . . . . . . . Structure, Function, and Pharmacology of Muscle . . . . . . . . . . . . . . . . . . . . . . . . . . . Head and Neck Embryology and Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Upper Extremities and Back . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Musculoskeletal Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

423 424 428 431 442 451

Chapter 9: The Hematologic and Lymphoreticular System . . . . . . . . . . . . . . . . . . . . . . . . . . Hematopoiesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hemostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anticlotting Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Erythropoiesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Disorders of Red Blood Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . White Blood Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Disorders of Leukocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hematologic Changes Associated with Infectious Disease . . . . . . . . . . . . . . . . . . . . .

459 460 460 464 465 465 469 470 476

SECTION III: APPENDICES Appendix A: Essential Equations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix B: Standard Laboratory Values . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix C: Essential Diseases and Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix D: High-Yield Images . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix E: Drug List . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix F: Bacterial and Viral Algorithms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

479 485 487 501 513 533

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 541

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How to Use medEssentials

Steven R. Daugherty, Ph.D. Director, Education and Testing Kaplan Medical

Doing well on USMLE® Step 1 means mastering over 6,000 different terms, as well as countless concepts and relationships. To accomplish this, most students focus on brute memorization, trying to jam into their heads the information they think they will need and then spitting out relevant facts when exam time comes. This memorization strategy works fairly well for “recall exams,” which require you to demonstrate that you know a particular, defined set of information. Unlike most medical school exams, however, the USMLE is a “thinking exam,” requiring you to not just recognize, but apply, use, and reason with the content you have learned. Questions are drawn from the broad array of basic science knowledge, and not confined to some explicit subset. To do well—indeed, simply to pass the USMLE Step 1—you must store up information over weeks and months and then think intelligently about that material. Sheer memorization will not get you to this goal. You need a more organized and intelligent approach. To master the information you will need for Step 1, you must (1) decide what to focus on and (2) organize it in a way that fosters long-term retention. This means that you have to know what is important, and then link it together so you can think and reason as you solve the exam questions. MedEssentials for the USMLE Step 1 was created to help you master this learning process. First, it distills the mass of material you must master to emphasize the most important concepts and details. Second, it organizes the material you need to know in a way that facilitates retention and application to clinical problems. MedEssentials has already helped thousands gain a better understanding of the basics of medicine and earn better exam results. In this single volume, we have organized the high-yield USMLE information with a conscious eye towards fostering the kind of insight and understanding the current USMLE demands.

DISTILLATION When you are plowing through the stack of material you need to study for your medical school and wondering what really matters, medEssentials will serve as a guide. If it is in this book, you should know it. The purpose of medEssentials is not to cover everything you need to master, but rather to highlight and emphasize what matters most. The material included in medEssentials is the most high-yield content, selected by Kaplan Medical’s best faculty, drawing on their long years of experience preparing students for the USMLE Step 1. This faculty-selected content is then periodically reviewed by recent USMLE test-takers and rated in terms of exam relevance. Be aware that your medical school exams may contain other material not in medEssentials. We urge you to not neglect that additional content for your medical school exams. But if you are overwhelmed by the sheer volume of what you have to learn, medEssentials will ensure that you do not lose your way or neglect what is the most important.

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RETENTION AND APPLICATION Our brains are basically lazy. Old information is continually purged to make way for the new. The only things our brains hold on to for the long haul are things that we use and things that are connected.

Forget about cramming. The most common strategy for preparing for a recall exam is to cram the needed information into short-term memory and hope it lingers long enough to be used on the exam. Unfortunately, what is simply memorized is soon forgotten. The long lists of anatomic names, pharmacological substances, and pathological conditions are absorbed one day, but gone the next. Cramming information into your head may get you past today’s exam, but does not prepare you for the more complex exams or the medical practice you will face tomorrow. To solve the problems that are posed to you on USMLE Step 1, you must store up information over weeks and months, and then think intelligently to apply that material.

Don’t just sit there, do something! To be effective, study must be active. The concepts you are learning are like the clothes in your closet: We tend to hold on to clothing that we wear every day. It’s the stuff piled in the back of the closet that gets lost or tossed. Likewise, simply rereading the same thing over and over is ineffective. The key to retention is doing something with the content you want to master. Doing something with the material as you learn activates the hippocampus and amygdala. The hippocampus is a mental map that organizes information, facilitating both general comprehension and active recall. The amygdala puts an emotional tag on knowledge and events, making them stand out from the sensory stream of daily experience. When you do something with the content, it signals your brain that the content is important and activates the mental processes that allow for long-term recall. Common strategies for active learning involve taking summary notes, making charts, drawing figures or graphs, or talking with others. Each of these techniques can be beneficial, but all take a lot of time. However, recent research tells us that the simple technique of Reading, Reciting, and Reviewing can provide the same benefits of active learning in about half the time. To use this method, you first read a short section of material. Next, you cover it or look away and in your own words, recite for yourself the salient points. Finally, look back at the material and check your understanding. That’s it. Nothing complicated. This simple technique breaks you out of the boredom of endless repetition and forces you to do something concrete with the material as you encounter it. And doing something means holding on to what you are learning.

Compare and contrast for long-term retention. Blocks of content are easier to retain than scattered facts. This means you should learn content in chunks rather than as individual items. When you study, never focus on learning individual things. Rather, learn sets of things, and then learn to differentiate within the set. For instance, don’t try to learn all about a particular drug or bug. Learn classes of drugs and then the key details that let you differentiate among them. Learn groups of pathogens and then the critical differences among them based on symptoms, origins, properties, or treatments. Organize everything you learn into groupings that share common features. Once you have defined what is in the grouping, turn your attention to rehearsing how you will distinguish within the group. Note that not all details matter. The critical ones are those that help you make distinctions. Everything else is mental decoration. Details that do not help you make decisions make you feel smart, but do nothing to help you answer USMLE questions. Why study things in groupings? First, things that are connected form clusters that provide a coherent set of information and facilitate associations to other content. The cluster gives you a dual basis for understanding—learning what something is, and by contrast, what it is not. I may understand being “male” by knowing anatomic, hormonal, and developmental characteristics, but a full understanding only arrives when I am able to contrast “male” with “female.” Second, your main task on the USMLE is to say which of the presented options is “most likely,” given the information presented in the question stem (the lead-in paragraph of the question). To answer a question correctly, you have to recognize the clues in the paragraph and use these clues to guide your

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choice of an answer. The options form a cluster of possibilities. The clues in the question stem tell you which of the possible options is the “most likely” answer out of the presented possibilities. When you study by differentiating within groupings, you are anticipating the options that you will encounter and practicing how you will decide among them. Mastering this mental task has implications far beyond your USMLE score. Medical practice itself is essentially a series of multiple-choice questions. For each patient, you enter the examination room, assess available information, call to mind a set of options for how to proceed, and then pick one of the options. On the Step 1 and Step 2 CK exams, you do not have to know the options; they will be given to you. All you have to do is pick the correct choice out of the options presented. If you organize your medical knowledge as groupings and know how to differentiate within the grouping, you are organizing your thinking for medical practice as you prepare for the USMLE.

When reviewing medEssentials tables, focus on contrasts. Material in medEssentials is presented as a set of tables and diagrams. This organization of the content is the most efficient method for fostering the type of learning that the USMLE requires. Do not simply rote memorize lists of things. Let medEssentials give you the organization that allows the intelligent decision-making you will need. Review the tables in this book always with an eye toward differentiation among terms and concepts. To do this, pick two presented concepts (e.g., different pathogens, drugs, diagnoses) and rehearse how they are the same and how they are different. Once you have mastered that pair, pick another pair and repeat the process, and so on until you have rehearsed how to differentiate all of the items in the table. In other words, you should not be looking at the tables to memorize words, but to rehearse relationships. Memory fades quickly, but relationships are remembered. The key question is not, “How will I remember this?” but “How do I tell things apart?”

When reviewing medEssentials diagrams, focus on connections. Diagrams highlight distinct points of larger processes. Your task is to master not just the named points, but also the process of how you get from one to the next. So, rather than simply memorizing a sequence of steps by rote, think about the transformations or dynamic processes that lead from one step to the next. The key question is not, “What is the next step in the process?” but, “What happens to bring about the next step?” For instance, when reviewing anatomic diagrams, focus on context, not simply memorizing the name of bodily parts. What is this part connected to? What lies beside it or under it? Questions on the USMLE are likely to require the mastery of such linkages. You are trying not just to learn the pieces, but how they all fit together. MedEssentials is not a list of things to be memorized, but an organization of knowledge to allow for the retention and use of what you learn. If you use it the right way, you should find that you have a clearer understanding and enhanced confidence when applying core basic science knowledge on the USMLE, medical school exams, or even the rigors of medical practice. Remember, it’s not what you know, but how it’s organized in your brain that makes the difference! Push yourself to move beyond passive memorization to active understanding. Focus on mastering contrasts and connections, and you will know what you need to pick the best answer on exam day.

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Preface

Welcome to Kaplan Medical. This medEssentials course includes a comprehensive high-yield review book with interactive online exercises covering both first and second year medical school subjects. These tools are an excellent adjunct to your medical school curriculum and an important resource for your board preparations.

The medEssentials: High-Yield USMLE ® Step 1 Review The medEssentials review book, structured by organ system and in a compact, concise fashion, presents the most relevant and important basic medical principles with reference charts and corresponding images. Our design allows a unique level of integration between the disciplines. For example, rather than sequentially reviewing each discipline within an organ system (anatomy, physiology, pathology, and pharmacology), the book integrates important information across various disciplines for a given subtopic in one placesometimes on a single page. This way of reviewing allows you to obtain a complete, comprehensive understanding of any given topic. The first section of the book (General Principles) covers the general principles of pathology, pharmacology, physiology, behavioral science, biostatistics, biochemistry, molecular biology, cell biology, genetics, microbiology, immunology, embryology, and histology. These subjects precede the organ system chapters and serve as a comprehensive foundation for the organ-specific facts that follow. The second section of the book features the following organ systems: cardiovascular; respiratory; renal and urinary; hematologic and lymphoreticular; nervous; musculoskeletal, skin and connective tissue; gastrointestinal; endocrine; and reproductive. Each chapter includes high-yield information from the disciplines corresponding to the basic science courses taken during the first two years of medical school. Each organ system is viewed from histologic, embryologic, physiologic, pathologic, and pharmacologic perspectives. We want to hear what you think of this course. Please share with us your feedback by emailing [email protected].

Study Techniques Effective study techniques for medical school and ultimately for the board exams are about making choices. At each stage of your medical career, you need to choose study strategies that will lead you to success. Many medical students fear that not knowing all of the details may affect their clinical performance. It is natural to feel this way, but rest assured: Your ability to treat patients in these coming years will grow from mastery of concepts and by practicing your clinical skills. Your “clinical eye” will grow in time. Understanding basic mechanisms and key principles is crucial to developing the ability to apply what you know to real patients. One of the most effective strategies for studying the basic sciences is to apply the medical concepts you have learned to your imagined, future patients. For example, when studying muscle groups in anatomy, imagine yourself as a surgeon and how you would find the structures of interest. In physiology, imagine a patient asking you about cortisol, what it is and what it does. Practice explaining to a

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patient the biochemical differences between lipids, how they differ, and what this means medically. By doing so, you are simplifying the concepts, making them more memorable and clinically relevant; you are learning actively. Active use of the material that you learn increases retention and facilitates recall. Repetition makes memories. Each instance of recall produces a new memory trace, linking concepts and increasing the chance of recall in the future. Recall actually changes neuronal structures. To be truly useful, a piece of information needs to be triangulated, connected to a number of other concepts, or better yet, experienced. In other words, mere memorization is not your goal, but rather the ability to process and apply that information in a fully integrated manner. Rereading textbooks from cover to cover and underlining—yet again, in a different color—every line on every page is not an efficient way to learn. You need to focus on the material most likely to be on your exams and on the material that is considered high-yield. Begin your studies by following this simple outline: • Start every study session with a list of specific goals. • M  ake your notes richer by color-highlighting, adding notes to the diagrams, and re-summarizing what you have learned. This is your book; personalize it to get the most out of it. • A  fter reviewing your intended subject for the session, imagine how you’d teach the same concepts to someone else.

Using medEssentials: High-Yield USMLE TM Step 1 1. Learn the basic definitions and concepts central to each discipline (Section I: General Principles). The book provides the core vocabulary to understand the content of those disciplines. Terms and definitions are learned by the use of associational memory. 2. Learn central concepts for each of the subject areas and how they integrate within an organ system (Section II: Organ System). Integration of concepts and disciplines within each major organ system is the key to success in both medical school and licensing exams. Your basic mental task here is reconstructive memory, learning to recall the concepts in terms of how things fit together within an organ system. At this stage, patterns begin to emerge. The diagrams, tables, and pictures in this book are specifically designed for this stage of learning. 3. Engage in active learning by applying the concepts to scenarios, clinical settings, and mini-case presentations. This is the hardest stage of preparation, and one that most students neglect. Your task at this level is reasoning, comprehension, and deduction.

Get a Mobile Version of This Book This book comes with a free mobile download. To get your free download, follow these simple steps: 1. Go to kaptest.com/booksonline. 2. Follow the on-screen instructions. Have a copy of your book available. 3. Click on the link for directions on how to download the mobile version of medEssentials for the USMLE Step 1. Access to the mobile version is limited to the original owner of this book and is nontransferable. Kaplan is not responsible for providing access to customers who purchase or borrow used copies of this book. On behalf of Kaplan Medical, we wish you the best of success in your studies and your medical career!

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Section I

General Principles

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Behavioral Science Chapter 1 Learning and Behavior Therapy Conditioning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Types of Reinforcement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reinforcement Schedules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Learning-Based Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4 4 4 5

Child Development APGAR Scoring System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Infant Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Figures Copied and Approximate Ages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Key Developmental Terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Children’s Conceptions of Illness and Death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Child Development Milestones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7–8 Tanner Stages of Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Types of Abuse and Important Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Sleep: Physiology and Disorders Sleep Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Changes During the First Three Hours of Sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . Sleep Deprivation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sleep Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Night Terrors Versus Nightmares . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

24 25 25 25 26 27 27

Sexual Disorders Paraphilias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 Gender Identity and Preferred Sexual Partner of a Biologic Male . . . . . . . . . . . . . 28 Sexual Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Physician–Patient Relationships General Rules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30–31

Ethical and Legal Issues 10 10 11 11 12

Substance Abuse Alcohol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Drugs of Abuse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14–15

Defense Mechanisms Common Freudian Defense Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

Psychopathology Five Major Diagnostic Axes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mental Retardation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pervasive Developmental Disorders: Autism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Attention Deficit/Hyperactivity Disorder (ADHD) . . . . . . . . . . . . . . . . . . . . . . . . . . Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Antipsychotic Medications: An Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Typical Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Extrapyramidal Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Atypical Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mood Disorders: Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mood Disorder Subtypes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Normal Grief Versus Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kübler-Ross Stages of Adjustment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Electroconvulsive Therapy (ECT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lithium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Eating Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anxiety Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Sedative-Hypnotic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Important Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Somatoform Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Differentiating Somatoform Disorders from Factitious Disorders and Malingering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Personality Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Delirium Versus Dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Common Abnormalities on Neurologic Examination . . . . . . . . . . . . . . . . . . . . . . .

17 17 17 18 18 19 19 20 20 20 21 21 22 22 23 23 23 24

General Rules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31–33

Epidemiology and Biostatistics Incidence and Prevalence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .34 Types of Mortality Rates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 Screening Results in a 2 × 2 table . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 Healthy and Diseased Populations Along a Screening Dimension . . . . . . . . . . . . 34 Types of Bias in Research and Important Associations . . . . . . . . . . . . . . . . . . . . . . 35 Differentiating Observational Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 Making Decisions Using p-Values . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 Confidence Intervals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 Types of Scales in Statistics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 Types of Scales and Basic Statistical Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

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GENERAL PRINCIPLES │ 1. Behavioral Science

Learning and Behavior Therapy ►►Conditioning Classic (Respondent or Pavlovian) Conditioning UCR Unconditioned Response (salivation)

UCS Unconditioned Stimulus (sight of food)

CR Conditioned Response (salivation)

CS Conditioned Stimulus (bell)

1. Learning occurs when an old response occurs to a new stimulus. Example: A dog salivates to a bell, when previously salivation occurred only in response to meat. 2. Key stimulus (bell) must occur before the response.

Operant or Instrumental Conditioning S1

R1

1. Learning occurs when a new response occurs to an old stimulus. Example: In a Skinner box, the rat now presses the bar to obtain reinforcement.

R2 (Bar pressing)

Reinforcement

2. Key stimulus reinforcement must occur after the response.

►►Types of Reinforcement

Behavior (R)

Stimulus (S)

Add

Remove

Stops

Punishment

Extinction

Increases

Positive reinforcement

Negative reinforcement

►►Reinforcement Schedules Contingency

Schedule

Time

Behaviors

Constant

Fixed interval (FI)

Fixed ratio (FR)

Changing

Variable interval (VI)

Variable ratio (VR)

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GENERAL PRINCIPLES │ 1. Behavioral Science

►►Learning-Based Therapies On the Basis of Classic Conditioning Systematic desensitization

• Often used to treat anxiety and phobias Step 1: hierarchy of stimuli (least to most feared) Step 2: technique of muscle relaxation taught Step 3: patient relaxes in presence of each stimulus on the hierarchy • Works by replacing anxiety with relaxation, an incompatible response

Exposure (also flooding or implosion)

• Simple phobias treated by forced exposure to the feared object • Exposure maintained until fear response is extinguished

Aversive conditioning

• Properties of the original stimulus are changed to produce an aversive response • Can help reduce deviant behaviors

On the Basis of Operant Conditioning Shaping

• Achieves target behavior by reinforcing successive approximations of the desired response • Reinforcement gradually modified to move behaviors from general responses to specific responses desired

Extinction

• Discontinuing the reinforcement maintaining an undesired behavior • “Time out” with children or for test anxiety

Stimulus control

• S  ometimes stimuli inadvertently acquire control over behavior; when this is true, removal of that stimulus can extinguish the response • Example: an insomniac only permitted in bed when he/she is so tired that sleep comes almost at once

Biofeedback

• U  sing external feedback to modify internal physiologic states; often uses electronic devices to present physiologic information, e.g., heart monitor to show heart rate • Works by means of trial-and-error learning and requires repeated practice to be effective

Fading

• G  radually removing the reinforcement while: 1) without the subject discerning the difference and 2) maintaining the desired response • Example: gradually replacing postoperative painkiller with a placebo

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GENERAL PRINCIPLES │ 1. Behavioral Science

Child Development ►►Apgar Scoring System Evaluation

0 Points

1 Point

2 Points

Heart rate

0

100/min

Respiration

None

Irregular, shallow gasps

Crying

Color

Blue

Pale, blue extremities

Pink

Tone

None

Weak, passive

Active

Reflex irritability

None

Facial grimace

Active withdrawal

►►Infant Development Evidenced at birth

• • • •

Reaching and grasping behavior Ability to imitate facial expressions Ability to synchronize limb movements with speech of others Attachment behaviors, such as crying and clinging

Newborn characteristics

• Prefers: − Large, bright objects with lots of contrast − Moving objects − Curves versus lines − Complex versus simple designs − Facial stimuli (girls more than boys) • Can discriminate between language and nonlanguage stimuli • At 1 week old, the infant responds differently to the smell of mother compared with father

Smiling

• The smile develops from an innate reflex present at birth (endogenous smile) • Shows exogenous smiling in response to a face at 8 weeks • A preferential social smile, e.g., to the mother’s rather than another’s face, appears about 12 to 16 weeks

►►Figures Copied and Approximate Ages Figure Copied

Approximate Age Circle

3

Cross

4

Rectangle

412

Square

5

Triangle

6

Diamond

7

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Brain-growth spurt

• “Critical period” of great vulnerability to environmental influence • Extends from last trimester of pregnancy through first 14 postnatal months • Size of cortical cells and complexity of cell interconnections undergo their most rapid increase

Stranger anxiety

• Distress in the presence of unfamiliar people • Appears at 6 months, reaches peak at 8 months, then disappears after 12 months

Separation anxiety

• • • •

GENERAL PRINCIPLES │ 1. Behavioral Science

►►Key Developmental Terms

Distress of infant after separation from caretaker Appears at 8 to 12 months; begins to disappear at 20 to 24 months Separation anxiety disorder (school phobia) is failure to resolve separation anxiety Treatment focuses on child’s interaction with parents, not on activities in school

►►Children’s Conceptions of Illness and Death More than death, a preschool child is more likely to fear:

Separation from parents, punishment, mutilation (Freud’s castration anxiety)

When they become ill:

May interpret illness or treatment as punishment Often have all sorts of misconceptions about what is wrong with them

Until age 5:

Children usually have no conception of death as an irreversible process

Only after age 8 or 9:

Child really understands that death is universal, inevitable, and irreversible

►►Child Development Milestones Age First year of life

Year 1

Year 2

Physical and Motor Development

Social Development

Language Development

• • • •

Puts everything in mouth Sits with support (4 mo) Stands with help (8 mo) Crawls, fear of falling (9 mo)

• • • •

• • • • • •

Pincer grasp (12 mo)  ollows objects to midline (4 wk) F One-handed approach/grasp of toy Feet in mouth (5 mo) Bang and rattle stage Changes hands with toy (6 mo)

• Pat-a-cake, peek-a-boo (10 mo)

Parental figure central Issues of trust are key Stranger anxiety (6 mo) Play is solitary and exploratory

• Walks alone (13 mo) • Climbs stairs alone (18 mo) • Emergence of hand preference (18 mo) • Kicks ball, throws ball • Pats pictures in book • Stacks three cubes (18 mo)

• S  eparation anxiety (12 mo) • Dependency on parental figure (rapprochement)

• • • • • • •

• Selfish and self-centered • Imitates mannerisms and activities • May be aggressive • “No” is favorite word • Parallel play

High activity level Walks backward Can turn doorknob, unscrew lid jar Scribbles with crayon Able to aim to throw ball Stands on tiptoes (30 mo) Stacks six cubes (24 mo)

• L  aughs aloud (4 mo) • Repetitive responding (8 mo) • “mama, dada” (10 mo)

• G  reat variation in timing of language development • Uses 10 words

• Onlooker play

• • • • • •

Use of pronouns Parents understand most words Telegraphic sentences Two-word sentences Uses 250 words Identifies body parts by pointing

(Continued)

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GENERAL PRINCIPLES │ 1. Behavioral Science

►►Child Development Milestones (Cont’d.) Age Year 3

Physical and Motor Development

Social Development

Language Development

• Rides tricycle • Stacks 9 cubes (36 mo)

• Fixed gender identity • Sex-specific play

• Completes sentences • Uses 900 words

• A  lternates feet going upstairs • Bowel and bladder control (toilet training) • Draws recognizable figures • Catches ball with arms • Cuts paper with scissors

• U  nderstands “taking turns” • Knows sex and full names

• U  nderstands 4× that • Strangers can understand • R  ecognizes common objects in pictures • Can answer: “Which block is bigger?”

• Unbuttons buttons Year 4

• Alternates feet going down stairs • Hops on one foot • Grooms self (brushes teeth) • Counts fingers on hand

• Imitation of adult roles • Curiosity about sex (playing doctor) • Nightmares and monster fears

• Can tell stories • Uses prepositions • Uses plurals • Compound sentences

• Imaginary fears Year 5

• Complete sphincter control • Brain at 75% of adult weight • D  raws recognizable man with head, body, and limbs • Dresses and undresses self • Catches ball with two hands

Years 6 to 12

Years ≥12 (adolescence)

• • • • •

Boys heavier than girls Refined motor skills Rides bicycle Gains athletic skill Coordination increases

• A  dolescent “growth spurt” (girls before boys) • Onset of sexual maturity (≥10 y) • Development of primary and secondary sexual characteristics

• C  onformity to peers important • Romantic feeling for others

• A  sks the meaning of words • Abstract words elusive

• Oedipal phase

• “ Rules of the game” are key • Organized sports possible • Being team member focal for many • Separation of the sexes • Demonstrating competence is key

• S  hift from egocentric to social speech

• Identity is critical issue • Conformity most important (11 to 12 y) • Organized sports diminish for many • Cross-gender relationships

• A  dopts personal speech patterns • Communication becomes focus of relationships

• Incomplete sentences decline • Vocabulary expands geometrically (50,000 words by age 12)

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Female

Female and Male

Male

Stage

Breast

Pubic Hair

Genitalia

1

Preadolescent

None

Childhood size

2

Breast bud

Sparse, long, straight

Enlargement of scrotum/testes

3

Areolar diameter enlarges

Darker, curling, increased amount

Penis grows in length; testes continue to enlarge

4

Secondary mound; separation of contours

Course, curly, adult type

Penis grows in length/breadth, scrotum darkens, testes enlarge

5

Mature female

Adult, extends to thighs

Adult shape/size

GENERAL PRINCIPLES │ 1. Behavioral Science

►►Tanner Stages of Development

►►Types of Abuse and Important Issues Child Abuse

Elder Abuse

Spousal Abuse

Annual cases

Over 2 million

5 to 10% in population

Over 4 million

Most common type

Physical battery/neglect

Neglect

Physical battery

Likely sex of victim

Before age 5: female After age 5: male

63% female

Female

Likely sex of perpetrator

Female

Male or female

Male

Mandatory reporting?

Yes

Yes

No

Physician’s response

Protect and report

Protect and report

Counseling and information

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GENERAL PRINCIPLES │ 1. Behavioral Science

Sleep: Physiology and Disorders ►►Sleep Physiology Types of Sleep

Sleep Architecture Diagram Showing Stages of Sleep in Sequence Awake Stage 1 & REM

SLEEP

REM

NREM

Stage 2

Stages:

1

2

3

4

Stage 1 sleep and REM sleep (gray) are graphed on the same level because their EEG patterns are . very similar.

Delta

Delta Sleep

Changes of Daily Sleep Over the Life Cycle

1

2

3

4 Hours

5

6

7

8

A wake-low voltage-random fast-beta waves fast low

Drowsy-8 to 12 cps-alpha waves

Hours of Sleep 16

Awake

14

Stage 1-3 to 7 cps theta waves theta waves

12

50% REM sleep

10

25%

Stage 2-12 to 14 cps-sleep spindles and K complexes K complexes

sleep spindles 8

20%

6

4

Delta sleep-1/2 to 2 cps-delta waves>75

NREM sleep

2

0

Age 1 15 days 6 23 mo

2 3y

13 16 y

30 50 y

90 y

REM sleep-low voltage-random, fast with sawtooth waves sawtooth waves

►►Changes During the First 3 Hours of Sleep Human growth hormone (HGH)

↑

Prolactin

↑

Dopamine

↓

Serotonin

↑

Thyroid-stimulating hormone (TSH)

↓

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GENERAL PRINCIPLES │ 1. Behavioral Science

►►Sleep Deprivation Getting 5 or less hours of sleep = functioning at level of someone legally drunk Lymphocyte levels

↓

Cortisol levels

↑

Blood pressure

↑

Glucose tolerance

↓

Amygdala activation

↑

Negative mood

↑

Prefrontal cortical activity

↓

►►Sleep Disorders Disorders

Signs, Symptoms, and Issues

Treatments

Narcolepsy

• Sleep attacks • Cataplexy

• M  odafinil: nonamphetamine alternative to CNS stimulants • Traditionally treated with CNS stimulants (e.g., amphetamines)

• Hypnagogic hallucinations • Sleep paralysis • REM latency 40.0

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GENERAL PRINCIPLES │ 1. Behavioral Science

►►Anxiety Disorders Generalized anxiety disorder

• Symptoms exhibited more days than not for longer than a 6-month period – Motor tension (fidgety, jumpy) – Autonomic hyperactivity (heart pounding, sweating, chest pains), hyperventilation – Apprehension (fear, worry, rumination), difficulty concentrating – Vigilance and scanning (impatient, hyperactive, distracted) – Fatigue and sleep disturbances common, especially insomnia and restlessness • Treatment: benzodiazepines, buspirone

Specific phobias (fear of specific object, e.g., spiders, snakes)

• Anxiety when faced with identifiable object • Phobic object avoided • Persistent and disabling fear

Agoraphobia (fear of open spaces or places from which escape is difficult)

• Also sense of helplessness or humiliation • Manifest anxiety, panic-like symptoms • Travel restricted

Social phobia (fear of feeling or being stupid, shameful)

• Leads to dysfunctional circumspect behavior, e.g., inability to urinate in public washrooms • May accompany avoidant personality disorder • Discrete performance anxiety (stage fright): most common phobia; treat with paroxetine (SSRI) or atenolol or propranolol (beta blocker) • Treatment: paroxetine (SSRI) or atenolol or propranolol (beta blocker); for generalized social anxiety, use phenelzine (MAO inhibitor) or paroxetine

Obsessive–compulsive disorder

• Obsession: focusing on one thought, usually to avoid another • Compulsion: repetitive action shields person from thoughts, action “fixes” bad thought • Primary concern of patient is to not lose control •  ↑ frontal lobe metabolism, ↑ activity in the caudate nucleus • Treatment: fluoxetine, fluvoxamine, or other SSRI, clomipramine

Panic disorder

• Three attacks in 3-week period with no clear circumscribed stimulus • Abrupt onset of symptoms, peak within 10 minutes • Clinical signs: − Great apprehension and fear − Palpitations, trembling, sweating − Fear of dying or going crazy − Hyperventilation, “air hunger” − Sense of unreality • Treatment: alprazolam, clonazepam, imipramine

►►Sedative-Hypnotic Drugs Notes

Benzodiazepines

• U  sed as anxiolytics, hypnotics, anticonvulsants (diazepam, lorazepam, clonazepam), muscle relaxants, for anesthesia (e.g., midazolam) • Binds GABAA receptor and increases frequency of Cl− ion channel opening • Dose-dependent CNS depression occurs (not as much as barbiturates when used alone) • Differ in half-life and metabolism • Three BZs are not metabolized in liver: (“Out The Liver: Oxazepam, Temazepam, Lorazepam)

Barbiturates

Miscellaneous

• Used as anticonvulsants (phenobarbital, long-acting), to induce anesthesia (thiopental, short-acting) • Binds GABAA receptor and increases duration of Cl– ion channel opening

coma

medullary depression CNS Effects

Class

barbiturates

benzodiazepines

anesthesia

hypnosis

sedation, anxiolysis Increasing Sedative-Hypnotic Dose

Zolpidem, zaleplon, and eszopiclone—(all bind BZ1 receptors) and ramelteon (melatonin receptor agonist) used for sleep Buspironenonbenzodiazepine (anxiolytic)

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Generic Name

Common Uses

Alprazolam

Panic, anxiety

Chlordiazepoxide

Alcohol detoxification

Clonazepam

Panic, anxiety, seizures

Diazepam

Anxiety, insomnia, pre-op sedation, muscle relaxation

Flurazepam

Insomnia

Lorazepam

Anxiety, alcohol-related seizures

Midazolam*

Anesthesia

Oxazepam

Alcohol detoxification

Temazepam

Insomnia

Triazolam†

Insomnia

GENERAL PRINCIPLES │ 1. Behavioral Science

►►Important Benzodiazepines

*Shortest acting acting

†Short

►►Somatoform Disorders Somatization disorder

• • • •

Set of eight or more symptoms (four pain, two gastrointestinal, one sexual, one pseudoneurologic) Onset before age 30 Symptoms usually occur over period of years More common in women than in men (20 to 1)

Conversion disorder

• One or more symptoms • Altering of physical functioning, suggesting physical disorder • Usually skeletal, muscular, sensory, or some peripheral nonautonomic system, e.g., paralysis of the hand, loss of sight • Loss of functioning is real and unfeigned • Look for la belle indifference

Hypochondriasis

• • • • •

Somatoform pain disorder

• Severe, prolonged pain with no organic cause found • Pain disrupts day-to-day life • Look for secondary gain

Body dysmorphic disorder

• • • • •

Unrealistic interpretation of physical signs as abnormal Preoccupation with illness or fear of illness when none present Preoccupation persists in spite of reassurance At least 6 months’ duration Treat by simple palliative care and fostering relationship

Preoccupation with unrealistic negative evaluation of personal attractiveness Sees self as ugly or horrific when normal in appearance Preoccupation disrupts day-to-day life May seek multiple plastic surgeries or other extreme interventions May occur in eating disorders

►►Differentiating Somatoform Disorders from Factitious Disorders and Malingering* Somatoform

Factitious

Malingering

Symptom production

Unconscious

Intentional

Intentional

Motivation

Unconscious

Unconscious

Intentional

*All three may present with similar symptom profile. The key to the differential is level of patient awareness.

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GENERAL PRINCIPLES │ 1. Behavioral Science

►►Personality Disorders Types

Definition

Epidemiology

Associated Defenses

Cluster A: Odd or eccentric Paranoid

Schizoid

Schizotypal

Feelings of persecution; feels that others are conspiring to harm them; suspicious

• Men > women

Isolated lifestyle; has no longing for others (“loner”)

• Men > women

Eccentric behavior, thought, and speech

• Prevalence is 3% • Men > women

Projection

• Increased incidence in families with schizophrenia 

• Increased incidence in families with schizophrenia 

Cluster B: Dramatic and emotional Histrionic

Excessive emotion and attention seeking

• Women > men • Underdiagnosed in men

• • • •

Regression Somatization Conversion Dissociation

Narcissistic

Grandiose; overconcerned with issues of self-esteem

• Common

Fixation at subphase of separation/individualization

Borderline

Instability of mood, self-image, and relationships

• Women > men • ↑ mood disorders in families

• • • •

Antisocial

Does not recognize the rights of others

Prevalence: 3% in men; 1% in women

Superego lacunae

Splitting Projective identification Dissociation Passive-aggression

Cluster C: Anxious and fearful Avoidant

Shy or timid; fears rejection

• Common

Avoidance

• Possible deforming illness Dependent

Dependent, submissive

• Common



• Women > men • May end up as abused spouse Obsessivecompulsive

Perfectionistic and inflexible, orderly, rigid

• Men > women • ↑ concordance in identical twins

• • • •

Isolation Reaction formation Undoing Intellectualization

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Characteristics

Delirium

Dementia

History

Acute, identifiable date

Chronic, cannot be dated

Onset

Rapid

Insidious

Duration

Days to weeks

Months to years

Course

Fluctuating

Chronically progressive

Level of consciousness

Fluctuating

Normal

Orientation

Impaired periodically

Disorientation to person

Memory

Recent memory markedly impaired

Remote memories seen as recent

Perception

Visual hallucinations

Hallucinations less common

Sleep

Disrupted sleep-wake cycle

Less sleep disruption

Reversibility

Reversible

Mostly irreversible

Physiologic changes

Prominent

Minimal

Attention span

Very short

Not reduced

GENERAL PRINCIPLES │ 1. Behavioral Science

►►Delirium Versus Dementia

►►Common Abnormalities on Neurologic Examination Original Drawing

Patientʼs Drawing

Name

Localization

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GENERAL PRINCIPLES │ 1. Behavioral Science

Sexual Disorders ►►Paraphilias Pedophilia

Sexual urges toward children; most common sexual assault

Exhibitionism

Recurrent desire to expose genitals to strangers

Voyeurism

Sexual pleasure from watching others who are naked, grooming, or having sex; begins early in childhood

Sadism

Sexual pleasure derived from others’ pain

Masochism

Sexual pleasure derived from being abused or dominated

Fetishism

Sexual focus on objects, e.g., shoes, stockings Variant: transvestite fetishism (fantasies or actual dressing by heterosexual men in women’s clothing for sexual arousal)

Frotteurism

Male rubbing of genitals against fully clothed woman to achieve orgasm; subways and buses

Zoophilia

Animals preferred in sexual fantasies or practices

Coprophilia

Combining sex and defecation

Urophilia

Combining sex and urination

Necrophilia

Preferring sex with cadavers

Hypoxyphilia

Altered state of consciousness secondary to hypoxia while experiencing orgasm Variants: autoerotic asphyxiation, poppers, amyl nitrate, nitric oxide

►►Gender Identity and Preferred Sexual Partner of a Biologic Male Common Label

Gender Identity

Preferred Sexual Partner

Heterosexual

Male

Female

Transvestite fetishism

Male

Female

Gender identity disorder (transsexual)

Female

Male

Homosexual

Male

Male

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GENERAL PRINCIPLES │ 1. Behavioral Science

►►Sexual Disorders Disorders of Sexual Desire Hypoactive

Deficiency or absence of fantasies or desires, 20% of population, more common in women

Sexual aversion

Aversion to all sexual contact

Sexual Arousal Disorders Female sexual arousal disorder

• As high as 33% of females; sometimes hormonally related • Antihistamine and anticholinergic medications ↓ vaginal lubrication

Male erectile disorder (impotence)

• Primary: never able to achieve erection • Secondary: previously able to achieve erection – Up to 20% lifetime prevalence; point prevalence 3% – 50% of men treated for sexual disorders, incidence ↑ with age, more likely in smokers

Orgasm Disorders Anorgasmia (inhibited female orgasm)

• 5% of married women older than 35 have never achieved orgasm • Overall prevalence from all causes: 30% • Likelihood to have orgasm ↑ with age

Inhibited male orgasm (retarded ejaculation)

• Usually restricted to inability to orgasm in the vagina • 5% general prevalence • Differentiate from retrograde ejaculation

Premature ejaculation

• Male regularly ejaculates before or immediately after entering vagina • Treatments: stop and go technique, squeeze technique, SSRIs

Sexual Pain Disorders Dyspareunia

• Recurrent and persistent pain before, during, or after intercourse in either man or woman • More common in women • Chronic pelvic pain is a common complaint of women raped or sexually abused

Vaginismus

• Involuntary muscle constriction of the outer third of the vagina • Prevents penile insertion • Treatment: relaxation, Hegar dilators

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GENERAL PRINCIPLES │ 1. Behavioral Science

Physician–Patient Relationships ►►General Rules Think what the best physician should do, not necessarily what you have seen in practice. Rule #1:

Always place the interests of the patient first.

Make it a point to ask about and know the patient’s wishes.

Rule #2: Nothing should come between you and the patient.

• G  et rid of tables and computers. • Ask family members to leave the room if necessary. • Family should not translate for family members.

Rule #3: Tell the patient everything, even if he or she does not ask.

• The patient should know what you know and when you know it. • Information should flow through the patient to the family, not the reverse.

Rule #4: Work on long-term relationships with patients, not just short-term problems.

• Every encounter is a chance to develop a better relationship. • Good relationships mean good medical practice. • Make eye contact; both patient and physician should both be sitting, if at all possible. Arrange the setting for comfortable, close communication. If patient is in room, talk to patient, not to colleagues. The patient is always the focus.

Rule #5:

Listening is better than talking.

• When patient talks, you are learning. • Take time to listen to the patient in front of you, even if other patients or colleagues are waiting. • Ask what the patient knows before explaining.

Rule #6:

The patient is the decision-maker.

• Patients make medical decisions, physicians do not. • Negotiate, do not order.

Rule #7: Solve the problem presented; anticipate future problems.

• Find out what you need to; get the resources you need. • Change initial plans as information changes.

Rule #8: Admit to the patient when you make a mistake.

Take responsibility; don’t blame the nursing staff or a medical student.

Rule #9: Never “pass off” your patient to someone else.

• R  efer to psychiatrist or other specialist only when beyond your expertise. • Provide instruction in aspects of care, e.g., nutrition, use of medications.

Rule #10: Express empathy, then give control.

• “I’m sorry, what would you like to do?” • Important rule to remember when faced with grieving or angry patient or upset family members.

Rule #11: Agree on the problem with the patient before moving to the solution.

Informed consent requires the patient to fully understand what is wrong before treatment options are presented.

Rule #12: Be sure you understand what the patient is talking about before intervening.

Seek information before acting, clarify emotionally loaded words, begin with open-ended questions, then move to closed-ended questions.

Rule #13: Patients do not get to select inappropriate treatments.

Patients select treatments, but only from presented, appropriate choices.

Rule #14: Best answers serve multiple goals.

• T  hink about patient health, relationships, and ethics for each answer. • The best answers solve both long and short term goals.

Rule #15: Never lie.

• Do not lie to patients, their families, or insurance companies. • Do not deceive to protect a colleague.

Rule #16: Accept the health beliefs of patients and talk to them in those terms.

• Be accepting of benign folk medicine practices. Expect them. • Diagnoses need to be explained in the way patients can understand, even if not technically precise.

(Continued)

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Rule #17: Accept patients’ religious beliefs and participate, if appropriate.

Religion is a source of comfort to many. Ask about a patient’s religious beliefs if you are not sure.

Rule #18: Anything that increases communication is good.

• Take the time to talk with patients, even if others are waiting; ask why, not just what. • Seek information about the patient beyond the disease. • Ask about job, family, children, etc. • Ask “Is there anything else?”

Rule #19: Be an advocate for the patient.

• Work to get the patient what he or she needs. • Need, not payment, should decide.

Rule #20: How you do it matters as much as what you do.

• Focus on the process, not just goals. Means, not just the ends. • Do the right thing, the right way. • Treat family members with courtesy and tact, but the wishes and interests of the patient come first.

GENERAL PRINCIPLES │ 1. Behavioral Science

►►General Rules for Physician–Patient Relationships (Cont’d.)

Ethical and Legal Issues ►►General Rules Rules

Comments

Rule #1:

Competent patients have the right to refuse medical treatment.

• Patients have an almost absolute right to refuse. • Patients have almost absolute control over their own bodies.

Rule #2:

Assume that the patient is competent unless clear behavioral evidence indicates otherwise.

Competence is a legal, not a medical issue. A diagnosis, by itself, tells you little about a patient’s competence. Clear behavioral evidence would be:

Avoid going to court. Decisionmaking should occur in the clinical setting if possible.

Consider going to court only if:

Rule #3:

• Patient attempts suicide. • Patient is grossly psychotic and dysfunctional. • Patient’s physical or mental state prevents simple communication.

• T  here is intractable disagreement about a patient’s competence, who should be the surrogate, or who should make the decision about life support. • You perceive a serious conflict of interest between surrogate and patient’s interests. • Court approval of decision to terminate life support is, therefore, rarely required.

Rule #4:

When surrogates make decisions for a patient, they should use the following criteria and in this order:

1. Subjective standard • Actual intent, advance directive • What did the patient say in the past? 2. Substituted judgment • Who best represents the patient? • What would patient say if he or she could? 3. Best interests standard • Burdens versus benefits • Interests of patient, not preferences of the decision-maker

Rule #5:

If the patient is incompetent, physician may rely on advance directives.

• Advance directives can be oral. • Living will: written document expressing wishes • Health power of attorney: designating the surrogate decision-maker, “speaks with the patient’s voice”

(Continued)

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GENERAL PRINCIPLES │ 1. Behavioral Science

►►General Rules About Ethical and Legal Issues (Cont’d.) Rule #6:

Feeding tube is a medical treatment and can be withdrawn at the patient’s request.

A competent person can refuse even lifesaving hydration and nutrition. This is not considered “killing the patient,” but terminating treatment at the patient’s request.

Rule #7:

Do nothing to actively assist the patient to die sooner.

• Passive, i.e., allowing to die is okay; active, i.e., killing is not okay • But do all you can to reduce the patient’s suffering (e.g., giving pain medication).

Rule #8:

The physician decides when the patient is dead.

• W  hat if there are no more treatment options (the patient is cortically dead), and the family insists on treatment? If there are no options, there is nothing the physician can do; treatment must stop. • What if the physician thinks continued treatment is futile (the patient has shown no improvement), but the surrogate insists on continued treatment? The treatment should continue.

Rule #9:

Never abandon a patient.

• L  ack of financial resources or results are never reasons to stop the treatment of a patient. • An annoying or difficult patient is still your patient.

Rule #10: Keep the physician-patient relationship within bounds

• Intimate social contact with anyone who is or has been a patient is prohibited. • Do not date family members of patients. • Do not treat family members or write prescriptions for colleagues. • W  hen patients act inappropriately, make clear to them what appropriate behavior would be. • Any gift, beyond small tokens, should be declined.

Rule #11: Stop harm from happening

• B  eyond “do no harm”: you must stop anyone from hurting your patient OR your patient from hurting anyone else. • Stopping harm may require breaching confidentiality. • Harm can mean spreading disease, physical assault, abuse, neglect, infliction of pain, etc.

Rule #12: Always obtain informed consent.

• The patient must receive and understand five pieces of information: 1. Nature of procedure 2. Purpose or rationale 3. Benefits 4. Risks 5. Availability of alternatives • Four exceptions to informed consent: 1. Emergency 2. Waiver by patient 3. Patient is incompetent 4. Therapeutic privilege

Rule #13: Special rules apply with children.

• Children younger than 18 years are minors and are legally incompetent. • Exceptions: emancipated minors − If patient is older than 13 years and taking care of self, i.e., living alone, treat as an adult. − Marriage makes a child emancipated, as does serving in the military. − Pregnancy or having a child, in most cases, does not. • Partial emancipation − Generally age 14 and older − Consent for certain issues only: Substance drug treatment Prenatal care Sexually transmitted disease treatment Birth control

(Continued)

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Rule #14: Parents cannot withhold life- or limb-saving treatment from their children.

If parents refuse permission to treat child: 1. If immediate emergency, go ahead and treat.

Rule #15: Organ donation usually requires patient’s and family consent.

• The patient’s advance directive is key.

Rule #16: Good Samaritan Laws limit liability in nonmedical settings.

• Physician is not required to stop and help. • If help offered, shielded from liability provided: − Actions are within physician’s competence.

GENERAL PRINCIPLES │ 1. Behavioral Science

►►General Rules About Ethical and Legal Issues (Cont’d.) 2. If not immediate, but still critical (e.g., juvenile diabetes), generally the child is declared a ward of the court and the court grants permission. 3. If not life- or limb-threatening (e.g., child needs minor stitches), listen to the parents.

• Prior discussion with family members eliminates confusion regarding wishes. • If the family refuses, do not cause them stress by insisting.

− Only accepted procedures are performed. − Physician remains at scene after starting therapy until relieved by competent personnel. − No compensation changes hands. Rule #17: Confidentiality is (almost always) absolute.

• P  hysicians cannot tell anyone anything about their patient without the patient’s permission. • Physician must strive to ensure that others cannot access patient information. • Getting a consultation is permitted, as the consultant is bound by confidentiality, too. However, watch the location of the consultation. Be careful not to be overheard (e.g., in elevator or cafeteria). • If you receive a court subpoena, show up in court but do not divulge information about your patient. • If patient is a threat to self or others, the physician must break confidentiality. − Duty to warn and to protect (Tarasoff case) − A specific threat to a specific person − Suicide, homicide, and child and elder abuse are obvious threats − Infectious diseases may need to be reported to public officials or an innocent third party − Impaired drivers

Rule #18: Patients should be given the chance to state DNR (do not resuscitate) orders, and physicians should follow them.

• DNR refers only to cardiopulmonary resuscitation.

Rule #19: Committed mentally ill patients retain their rights.

• Committed mentally ill adults are legally entitled to the following: − They must have treatment available. − They can refuse treatment. − They can command a jury trial to determine “sanity.” • They lose only the civil liberty to come and go.

Rule #20: Detain patients to protect them or others.

• E  mergency detention can be effected by a physician and/or a law enforcement person for 48 hours, pending a hearing. • A physician can detain; only a judge can commit.

Rule #21: Remove from patient contact health care professionals who pose risk to patients.

Types of risks: • Infectious disease (e.g., TB) • Substance abuse • Depression (or other psychological issues) • Incompetence

Rule #22: Focus on what is the best ethical conduct, not simply the letter of the law.

The best conduct is both legal and ethical.

• Continue with ongoing treatments. • DNR decisions can be made by the patient or surrogate. • Have DNR discussions as part of your first encounter with the patient.

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GENERAL PRINCIPLES │ 1. Behavioral Science

Epidemiology and Biostatistics ►►Incidence and Prevalence Incidence

Number of new events in a specified period

Incidence rate =

Prevalence

× 10n

Number of persons exposed to risk of acquiring the condition during this period All cases of a disease at a given point/period

Prevalence rate =

Total population at risk for having the condition at a given point or period

× 10n

►►Types of Mortality Rates Crude mortality rate

Deaths ÷ population

Cause-specific mortality rate

Deaths from cause ÷ population

Cause-fatality rate

Deaths from cause ÷ number of persons with the disease/cause

Proportionate mortality rate (PMR)

Deaths from cause ÷ all deaths

►►Screening Results in a 2 × 2 Table Disease Present Screening Test Results



Absent

Totals

Positive

TP

60

FP

70

TP + FP

Negative

FN

40

TN

30

TN + FN

Totals

TP + FN

TN + FP

TP + TN + FP + FN

Sensitivity = TP/(TP + FN)

Detecting disease in population

Specificity = TN/(TN + FP)

Identifying healthy individuals in population

Positive predictive value = TP/(TP + FP)

What % of positive test results will be correct?

Negative predictive value = TN/(TN + FN)

What % of negative test results will be correct?

Accuracy = (TP + TN)/(TP + TN + FP + FN)

How good is the test overall?

Definition of abbreviations: FN, false negatives; FP, false positives; TN, true negatives; TP, true positives.

►►Healthy and Diseased Populations Along a Screening Dimension A

B

C

D

E

B, optimal sensitivity and optimal negative predictive value D, o  ptimal specificity and optimal positive predictive value

Healthy

Low

Diseased

Blood Pressures

C, h  ighest accuracy or lowest number of combined falses

High

Remember, we are looking for a cut-off score that best selects the desired group.

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Type of Bias

Definition

Important Associations

Solutions

Selection

Sample not representative

Berkson’s bias, nonrespondent bias

Random, independent sample

Measurement

The process of gathering information distorts it

Hawthorne effect

Control group/placebo group

Experimenter expectancy

Researcher’s beliefs affect outcome

Pygmalion effect

Double-blind design

Lead time

Early detection confused with increased survival

Benefits of screening

Measure “back end” survival

Recall

Subjects cannot remember accurately

Retrospective studies

Multiple sources to confirm information

Late-look

Severely diseased individuals are not uncovered

Early mortality

Stratify by severity

Confounding

Unanticipated factors obscure results

Hidden factors affect results

Multiple studies, good research design

Design

Parts of the study do not fit together

Non-comparable control group

Random assignment

GENERAL PRINCIPLES │ 1. Behavioral Science

►►Type of Bias in Research and Important Associations

►►Differentiating Observational Studies Characteristic

Cross-Sectional Studies

Case-Control Studies

Cohort Studies

Time

One time point

Retrospective

Prospective

Incidence

No

No

Yes

Prevalence

Yes

No

No

Causality

No

Yes

Yes

Role of disease

Measure disease

Begin with disease

End with disease

Assesses

Association of risk factor and disease

Many risk factors for single disease

Single risk factor affecting many diseases

Data analysis

Chi-square to assess association

Odds ratio to estimate risk

Relative and attributable risk to estimate risk

(Refer to Appendix A for equation.)

(Refer to Appendix A for relative and attributable risk equations.)

►►Making Decisions Using p-Values Possible Outcome #2

p = 0.13 (computed p value) Do NOT Reject Null Hypothesis Risk of Type II, β error p ≤ 0.05 (α-criterion)

Possible Outcome #1

p = 0.02 (computed p value) Reject Null Hypothesis Risk of Type I, α error

Statistical tests are used for making decisions. The p-value generated from the data is compared with p-value criterion selected by the investigator. If the computed value is less than the criterion value, then reject the null hypothesis, but with a chance of a type I error. If the computed value is greater than the criterion value, you should not reject the null hypothesis, but there is a chance of a type II error. Statistical power is the capacity to detect a difference if it is present. Power = 1– β. The most common way to increase power is to increase sample size.

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GENERAL PRINCIPLES │ 1. Behavioral Science

►►Confidence Intervals Confidence intervals (CI) estimate the population value based on the data from a sample. We give up precision, knowing exactly the population number, in exchange for confidence. Confidence intervals tell us that reality is most likely within the specified range. Confidence interval of the mean X ± Z

Where: X = sample mean Z = Z-score* S = standard deviation N = sample size *Z = 1.96 for 95% confidence Z = 2.58 for 99% confidence

( ) S √N

Interpretation of Confidence Intervals Confidence intervals for the mean

If the CIs for two means overlap, then they could be the same. Therefore, we have no evidence that they are different. If the CIs do not overlap, then we usually assume that they are different (statistical significance). In general, any overlap in CIs indicates no difference.

Confidence intervals for relative risk (RR) or odds ratios

If the CIs contain the number 1.0, then the population parameters compared in the ratio could be the same. Therefore, we cannot assume that they are different. If 1.0 is not included in the CI, then we assume that they are different (statistical significance). A 1.0 in the CI means that it is not significant.

►►Types of Scales in Statistics Type of Scale

Description

Key Words

Examples

Nominal (categorical)

Different groups

“This” as opposed to “that”

Gender, comparing among treatment interventions

Ordinal

Groups in sequence

Comparative quality, rank order

Olympic medals, class rank in medical school

Interval

Exact differences among groups

Quantity, mean, and standard deviation

Height, weight, blood pressure, drug dosage

Ratio

Interval + true zero point

Zero means zero

Temperature measured in degrees Kelvin

►►Types of Scales and Basic Statistical Tests Variables Name of Statistical Test

Interval

Nominal

Comment

Pearson correlation

2

0

Is there a linear relationship?

Chi-square

0

2

Any number of groups

t-test

1

1

Two groups only

One-way ANOVA

1

1

Two or more groups

Matched pairs t-test

1

1

Two groups, linked data pairs, before and after

Repeated measures ANOVA

1

1

More than two groups, linked data

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Biochemistry Chapter 2 Glycolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 The Citric Acid Cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 Oxidative Phosphorylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 Pyruvate Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 Hexose Monophosphate Shunt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 Glycogenesis and Glycogenolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 Gluconeogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 Amino Acid Structures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 Amino Acid Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .46 Amino Acid Synthesis and Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47–48 Urea Cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 Lipid Synthesis and Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50–51 Ketone Body Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 Cholesterol Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 Lipoprotein Transport and Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 Lysosomal Storage Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 Enzyme Kinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 Water-Soluble Vitamins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 Lipid-Soluble Vitamins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

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GENERAL PRINCIPLES │ 2. Biochemistry

Biochemistry ►►Glycolysis Glycolysis is a cytoplasmic pathway used by all cells to generate energy from glucose. One glucose molecule is converted into 2 pyruvate molecules, generating a net of 2 ATPs by substrate-level phosphorylation, and 2 NADHs. When oxygen is present, NADH delivers electrons to the electron transport chain in mitochondria to generate ATP by oxidative phosphorylation. Under anaerobic conditions, lactate is generated and NADH is reoxidized to NAD+. Galactose

Regulation: Three irreversible steps

Galactokinase Galactose-1-P Lactose

1

Gal-1-P uridyl transferase

Lactase

Glucose-1-P

*Controlled Enzymes Catalyzing Irreversible Steps ATP

1

*

ADP Isomerase

Glucose Sucrose

Sucrase

Glucose-6-P

+ Mg2

PFK–2

Fructose-6-P ATP

Hexokinase Glucokinase (liver)

*

2

Fructose

Fructose-1-P aldose

ADP

Dihydroxyacetone-P (DHAP)

Glycerol-3-P dehydrogenase

Isomerase

Pi Glyceraldehyde-3-P dehydrogenase

NADH

Glycerol-3-P • Triacylglycerol synthesis • Electron Shuttle

1,3-Bisphosphoglycerate (RBC)

ADP

Phosphoglycerate kinase

ATP

Liver, β-islet cells

Low Km

High Km

− G-6-P

Induced by insulin in liver

PFK-1

Fructose-1, 6-bis P

Glyceraldehyde-3-P

ETC/O2 Mitochondria

Most tissues

2

+ PFK–1 (Phosphofructokinase)

Aldolase

NAD+

Glucokinase*

ATP ADP

Fructokinase Fructose-1-P

Fructose-2,6-bis-P

Hexokinase

2,3-Bisphosphoglycerate

PFK-2

→ F-1,6-BP

→ F-2,6-BP

Rate-limiting step of glycolysis

Glycolysis regulator:

⊕ AMP ⊕ F-2,6-BP† − ATP − Citrate

⊕ Insulin − Glucagon

↑ glycolysis ↓ gluconeogenesis

3

3-Phosphoglycerate

Pyruvate kinase

Mutase

⊕ F-1,6-BP

2-Phosphoglycerate

− ATP − Alanine†

Enolase

*Glukokinase mutations may lead to a form of MODY. † Liver specific

Phosphoenolpyruvate (PEP) 3

ADP

*

Glucose Transport

Pyruvate kinase

ATP Pyruvate (aerobic)

GLUT-1 and -3: basal uptake (most cells)

Lactate (anaerobic)

GLUT-2: storage (liver); glucose sensor (β-islet) GLUT-4: ↑ by insulin (adipose, skeletal muscle); ↑ by exercise (skeletal muscle)

Disease Association Galactokinase deficiency

Galactosemia/galactosuria, cataracts in childhood (excess galactose is converted to galactitol via aldose reductase); Tx: no galactose in diet

Gal-1-P uridyl transferase deficiency

Same as above, but more severe with vomiting/diarrhea after milk ingestion, liver disease, lethargy, mental retardation; Tx: no galactose in diet

Fructokinase deficiency

Fructosuria; benign

Fructose-1-P aldolase B deficiency

Fructosuria, liver and proximal renal tubule disorder; Tx: no fructose in diet

Pyruvate kinase deficiency

Chronic hemolysis, ↑ 2,3-BPG and other glycolytic intermediates in the RBC, no Heinz bodies, autosomal recessive

Definition of abbreviations: MODY, mature-onset diabetes of the young; PFK, phosphofructokinase; RBC, red blood cell; Tx, treatment.

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►►The Citric Acid Cycle

Regulation

AcetylCoA

Citrate a

b

Oxaloacetate NADH

cis-Aconitate

h

L-Malate

Isocitrate

g

c

Fumarate FADH2

1 Isocitrate dehydrogenase (Rate-Limiting Step)

b

1 NADH + CO2

α-Ketoglutarate

f

NADH + CO2 2

d Succinyl-CoA

Succinate e GTP

Enzymes a. Citrate synthase b. Aconitase c. Isocitrate dehydrogenase d. α-Ketoglutarate dehydrogenase e. Succinyl-CoA thiokinase f. Succinate dehydrogenase g. Fumarase h. Malate dehydrogenase

⊕ ADP

− ATP − NADH

2 α-Ketoglutarate dehydrogenase*

GENERAL PRINCIPLES │ 2. Biochemistry

The citric acid cycle (tricarboxylic acid cycle) is a mitochondrial pathway that occurs only under aerobic conditions. Each acetyl-CoA generated from pyruvate is used to produce 3 NADH, 1 FADH2, and 1 GTP. Both the NADH and FADH2 deliver electrons to the electron transport chain (ETC) to generate ATP by oxidative phosphorylation.

− Succinyl CoA − ATP − NADH *Similar to pyruvate dehydrogenase complex and uses the same cofactors

Links to Other Pathways • Gluconeogenesis (malate shuttle) • Fatty acid synthesis (citrate shuttle)

Stoichiometry of the Citric Acid Cycle Acetyl-CoA + 3 NAD+ + FAD + GDP + Pi → 2 CO2 + 3 NADH + FADH2 + GTP + CoA

• A  mino acid synthesis (oxaloacetate and α-ketoglutarate) • Heme synthesis (succinyl CoA)

The only net fate of acetyl-CoA as it proceeds through the citric acid cycle is conversion to CO2. The citric acid cycle is NOT a means to convert acetyl groups to glucose. Humans lack the capacity to form glucose from acetyl-CoA.

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GENERAL PRINCIPLES │ 2. Biochemistry

►►Oxidative Phosphorylation Electron transport and the coupled synthesis of ATP are known as oxidative phosphorylation. The electron (ETC) is a series of carrier enzymes in the inner mitochondrial membrane that pass electrons, fashion, from NADH and FADH2 to oxygen, the final electron acceptor. These carriers create a proton the inner membrane, which drives the F0/F1 ATP synthase, with a net production of 3 ATPs per NADH and 2 ATPs per

transport chain in a stepwise gradient across FADH2.

Electron Transport Chain

H+

NADH

H+ FADH 2

ll

e-

l

H+ Cytosol (Intermembrane space)

CoQ

e-

H+

e-

ATP H+

02

e-

lll

V

lV

H+

ADP + P

H20

Matrix

ecytc

H+

Proton Gradient

Complex I: NADH dehydrogenase

Complex III: cytochrome b/c1

Complex II: succinate dehydrogenase

Cyt C: cytochrome c

CoQ: coenzyme Q

Complex IV: cytochrome a/a3 Complex V: Fo F1ATP synthase

Clinical Correlation Cyanide Poisoning Blocks cytochrome a/a3; cyanide from burning polyurethane (mattress/furniture stuffing); Tx: nitrites (creates methemoglobin, which binds cyanide) Inhibitors Inhibit ETC and O2 consumption Inhibit ATP synthesis • • • •

Antimycin A, piscicide (Complex I) Cyanide (cyt oxidase) Rotenone, broad-spectrum insecticides, other pesticides (Complex 1) Oligomycin (Fo) Uncouplers

Increase ETC and O2 consumption Decrease ATP synthesis Produce heat • 2,4-dinitrophenol (2,4-DNP) • Salicylate (metabolite of aspirin) • Uncoupling proteins (e.g., thermogenin)

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►►Pyruvate Metabolism GENERAL PRINCIPLES │ 2. Biochemistry

1 L  actate dehydrogenase: Anaerobic tissues: converts pyruvate to lactate, reoxidizing cytoplasmic NADH to NAD+. Liver: converts lactate to pyruvate for gluconeogenesis or for metabolism to acetyl CoA 2 Pyruvate dehydrogenase: generates acetyl-CoA for fatty acid synthesis and the citric acid cycle; complex of 3 enzymes 3 Pyruvate carboxylase: produces oxaloacetate for gluconeogenesis and the citric acid cycle 4 A  lanine aminotransferase (ALT, GPT): Muscle: converts pyruvate to alanine to transport amino groups to the liver. Liver: converts alanine to pyruvate for gluconeogenesis and delivers the amino group for urea synthesis

Regulation

Glucose

Pyruvate dehydrogenase (PDH)

Pyruvate 1 Lactate

+

H+H

NAD

+

NAD

2 CO

2

DH

Acetyl-CoA

4

+

+

+

D

NA

H

CO

2

+

AT P

3

− Acetyl-CoA

⊕ CoA

− ATP

⊕ NAD+

− NADH − glucagon

NA

Citric acid cycle

Alanine

⊕ ADP

Oxaloacetate

Fatty acid synthesis

Citric acid cycle

Cofactors: TPP (from thiamine), lipoic acid, CoA (from pantothenate), FAD (from riboflavin), NAD (from niacin) Gluconeogenesis

Stoichiometry of Pyruvate Dehydrogenase

Disease Association

Pyruvate + NAD+ + CoA → NADH + CO2 + acetyl-CoA

Pyruvate Dehydrogenase Deficiency Lactic acidosis, seizures, mental retardation, ataxia, spasticity

Cori Cycle

Muscle or RBC

glucose

glycolysis

pyruvate

lactate

pyruvate

lactate

Bloodstream Liver

glucose

gluconeogenesis

During fasting or exercise, lactate from RBCs or skeletal muscles is sent to the liver to make glucose that can be returned to the RBCs or muscle.

Definition of abbreviations: TCA, tricarboxylic acid; TPP, thiamine pyrophosphate.

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GENERAL PRINCIPLES │ 2. Biochemistry

►►Hexose Monophosphate Shunt The hexose monophosphate (HMP) shunt (pentose phosphate pathway) is a cytosolic pathway that uses glucose-6-phosphate to reduce NADP to NADPH, and synthesize ribose-5-P. NADPH is important for fatty acid and steroid biosynthesis, maintenance of reduced glutathione to protect against reactive oxygen species (ROS), and for bactericidal activity in polymorphonuclear leukocytes (PMNs). Ribose-5-P is required for nucleotide synthesis.

Regulation Glucose-6-P-dehydrogenase

Glucose NADP

NADPH

Glucose-6-P

NADP

⊕ NADP+

NADPH

6-phosphogluconate

− NADPH

Ribulose-5-P

Glucose 6-P dehydrogenase

CO2 Ribose-5-P

Nucleotide synthesis Disease Association Glucose-6-Phosphate Dehydrogenase Deficiency Episodic self-limiting hemolytic anemia induced by infection and drugs (common) or chronic hemolysis (rare); X-linked recessive; female heterozygotes have ↑ resistance to malaria

Glucose 6Phosphate

HMP Shunt

G6PDH

NADPH

Glutathione Reductase

Oxidized Glutathione

Pentose Phosphates

O2 + H2O

NADP

+

Reduced Glutathione

Glutathione Peroxidase (Se)

Oxidant Stress • infection • drugs • fava beans

H O 2

2

spontaneous

O

2

if accumulates • Hemoglobin Denaturation (Heinz bodies) • Membrane Damage (Hemolytic Anemia)

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►►Glycogenesis and Glycogenolysis

Glycogen Metabolism Glycogen

Insulin (Liver Muscle)

Glucose (Liver) +

Epinephrine (Liver and Muscle)

Glucagon (Liver)

1 +

Pi

UDP

+

Regulation

+

+

AMP Muscle

2 Glycogen Phosphorylase (and Debranching Enzyme)

1

Glycogen Synthase (and Branching Enzyme)

Glycogen synthase Liver

Skeletal Muscle

⊕ Insulin ⊕ Glucose − Glucagon − Epinephrine

⊕ Insulin − Epinephrine

GENERAL PRINCIPLES │ 2. Biochemistry

Glycogen is a branched polymer of glucose, stored primarily in liver and skeletal muscles, which can be mobilized during hypoglycemia (liver) or muscular contraction (muscles). Synthesis of glycogen (glycogenesis) is mediated by glycogen synthase, while its breakdown (glycogenolysis) is carried out by glycogen phosphorylase. Branching of the glycogen polymer occurs via a branching enzyme, which breaks an α-1,4-bond and transfers a block of glucosyl residues to create a new α-1,6-bond. This is reversed by a debranching enzyme.

UDP-Glucose PPi UTP

2 Glycogen phosphorylase

Glucose 1-P

Liver

Glucose 6-P Glycolysis (Muscle)

Glucose 6-Phosphatase (Liver)

Skeletal Muscle

⊕ glucagon

⊕ epinephrine

⊕ epinephrine − Insulin

⊕ AMP

Glucose Pyruvate

⊕ Ca2+ − ATP

Branching and Debranching Steps Glucose-6-phosphate 5

Glucose-1-phosphate 1

UDP-glucose 2

5 3

4

Storage form of glycogen 1

UDP-glucose pyrophosphorylase

4

Glycogen phosphorylase

2

Glycogen synthase

5

Debranching enzyme

3

Branching enzyme

Limit dextran

Glycogen Storage Diseases Type I: von Gierke disease (↓ glucose-6-phosphatase)

Severe fasting hypoglycemia, lactic acidosis, hepatomegaly, hyperlipidemia, hyperuricemia, short stature

Type II: Pompe disease (↓ lysosomal-α-1,4-glucosidase)

Cardiomegaly, muscle weakness, death by 2 years

Type III: Cori disease (↓ glycogen debranching enzyme)

Mild hypoglycemia; liver enlargement

Type IV: Andersen disease (↓ branching enzyme)

Infantile hypotonia, cirrhosis, death by 2 years

Type V: McArdle disease (↓ muscle glycogen phosphorylase*)

Muscle cramps/weakness during initial phase of exercise, possible rhabdomyolysis and myoglobinuria

Type VI: Hers disease (↓ hepatic glycogen phosphorylase)

Mild fasting hypoglycemia, hepatomegaly, cirrhosis

* Also known as myophosphorylase.

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GENERAL PRINCIPLES │ 2. Biochemistry

►►Gluconeogenesis Gluconeogenesis is a pathway for de novo synthesis of glucose from C3 and C4 precursors using both mitochondrial and cytosolic enzymes. Occurring only in liver, kidney, and intestinal epithelium, this pathway functions to provide glucose for the body, especially the brain and RBCs, which require glucose for energy (the brain can also use ketone bodies during fasting conditions). Gluconeogenesis occurs during fasting, as glycogen stores become depleted. Important substrates for gluconeogenesis are gluconeogenic amino acids (protein from muscle), lactate (from RBCs and muscle during anaerobic exercise), and glycerol-3-P (from triacylglycerol from adipose tissues).

Regulation

Glucose

Pi

Four irreversible steps: Glucokinase

4 Glucose-6-phosphatase

1

Glucose-6-P

Pyruvate carboxylase

Mitochondrial; requires biotin ⊕ acetyl CoA

2 PEPCK

PFK-1

3 Fructose-1,6-bisphosphatase

Cytosolic; requires GTP

Fructose-1,6-bis P

Induced by glucagon and cortisol 3

3 reversible reactions

⊕ ATP Pyruvate kinase

2

4 Glucose-6-phosphatase Lactate

Pyruvate

In endoplasmic reticulum; only in liver

Cytoplasm

‡Mediates

insulin’s inhibition and glucagon’s stimulation of this enzyme

Mitochondria Pyruvate

OAA†

− AMP − F-2,6-BP‡ (from PFK2)

Alanine

PEPCK

OAA†

Malate Shuttle

Fructose 1,6-bisphosphatase Cytosolic

PEP GDP



Glycerol-3-P

DHAP

Glyceraldehyde-3-P

GTP



Fructose-6-P

Pi

ATP ADP

Disease Association PDH

–

CO2 1

Pyruvate carboxylase (biotin)

Glucose-6-Phosphatase Deficiency (von Gierke disease) Acetyl CoA (from ß-oxidation of fatty acids)

+

Severe hypoglycemia, lactic acidosis, hepatomegaly, hyperlipidemia, hyperuricemia, short stature

Alanine Cycle Urea ATP NH2

ATP Liver

Glucose

Pyruvate (2)

Alanine (2)

Pyruvate (2)

Alanine (2)

Bloodstream Muscle

Glucose ATP

α-amino acid

A pathway by which muscles release alanine to the liver, delivering both a gluconeogenic substrate (pyruvate) and an amino group for urea synthesis

α-ketoacid

Definition of abbreviations: PEPCK, phosphoenolpyruvate carboxykinase; PFK2, phosphofructokinase 2; RBC, red blood cell. is not transported across the membrane directly. Instead, it is transported as malate in exchange for asparate via the malate shuttle.

†   OAA 

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►►Amino Acid Structures Nonpolar, Aliphatic Side Chains COO+

H3N

C

COO+

H3N

H

C

H

H

Aromatic Side Chains

COO+

H3N

C

CH3

C

H

COOH C H2N CH2

C

H

H

C

CH3

CH2

CH2

CH CH 3

CH 3

H3N

C

H

COO+

H3N

H

C

CH 2

CH 2 C

CH NH

COO+

COO+

H

CH3

Valine

H3N

C CH 2

CH

Alanine Ala

COO+

H3N

COO+

H3N

H

CH3

Glycine Gly

GENERAL PRINCIPLES │ 2. Biochemistry

Hydrophobic Amino Acids

Val OH

+

H2C

Phenylalanine

Tyrosine

Tryptophan

Phe

Tyr

Trp

CH2

CH3

Leucine

Isoleucine

Proline

Leu

Ile

Pro

Hydrophilic Amino Acids Positively Charged R Groups COO+ H3 N C H

COO +

H 3N

C

+

H3N

H

COO C

CH 2

CH2

CH2

CH 2

CH2

C

CH2

CH2

CH2

NH

+

NH3

C

-

COO +

H

H3N

C

-

H

CH2OH

+

N H

H

H

C

OH

COO

+

H3N

C

+

-

H

CH 2 SH

Serine

Threonine

Cysteine

Ser

Thr

Cys

+

NH2

-

C

CH3

+ CH

NH2

COO

H 3N

NH

C H

Negatively Charged R Groups

Polar, Uncharged R Groups

H 3N

COO C

-

H

+

H3N

COO C

-

H

COO

+

H3N

C

Arginine

Histidine

CH 2

CH2

CH 2

Lys

Arg

His

CH 2

C

CH 2

H 2N

O

H

+

H 3N

COOC

CH2

CH2

COO-

CH2

H

COO-

Aspartate

Asp

Glutamate

Glu

C H2N

CH 3

C

H

Lysine

S

-

COO +

H3 N

O

Methionine

Asparagine

Glutamine

Met

Asn

Gln

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GENERAL PRINCIPLES │ 2. Biochemistry

►►Amino Acid Derivatives Besides being the building blocks of proteins, amino acids are also precursors for various chemicals, such as hormones, neurotransmitters, and other small molecules.

Disease Association

Amino Acid

Product

Tyrosine

 hyroid hormones (T3, T4); melanin; catecholamines (dopaT mine, epinephrine)

O2

Aromatic acid O2 decarboxylase DOPA Dopamine

Tyrosine hydroxylase

Tyrosine

CO2

DHB

THB

Phenylethanolamine-NDopamine-βmethyl transferase (PNMT) hydroxylase Norepinephrine Epinephrine + Cu S-Adenosylhomocysteine SAM Ascorbate

Serotonin (5-HT); melatonin; NAD; NADP O2

Aromatic amino acid decarboxylase

Tr yptophan hydroxylase

Tr yptophan

5-OH-Tr yptophan THB

Serotonin

DHB

Glycine

CO2

Heme

Glycine Succinyl-CoA

ALA synthase

ALA dehydratase δ -Aminolevulinat e Porphobilinogen

Porphobilinogen deaminase*

Uroporphyrinogen-III †

Protoporphyrin IX Heme synthase (ferrochelatase)

Bilirubin diglucuronide

UDP-glucuronyl transferase

UDPglucuronate

UDP

Biliverdin reductase

Biliverdin

NADPH

Heme oxygenase

Heme

NADPH O2

γ-aminobutyric acid (GABA)

Glutamate

Bilirubin

Glutamate decarboxylase

γ-Aminobutyric acid (GABA)

Glutamate Arginine

Nitric oxide (NO)

NO synthase Arginine + O 2 Nitric oxide + citrulline NADPH NADP+



Histamine

Histidine

Histidine decarboxylase

Histamine

Methionine

S-adenosylmethionine (SAM; methylating agent)

Arginine, glycine, SAM

Creatine

* Also known as hydroxymethylbilane synthase;

Fe2+

Acute Intermittent Porphyria Porphobilinogen deaminase* deficiency; episodic expression, acute abdominal pain, anxiety, confusion, paranoia, muscle weakness, no photosensitivity, port-wine urine in some patients, urine excretion of ALA and PBG; autosomal dominant; onset at puberty, 15% penetrance, variable expression; more common in women

Porphyria Cutanea Tarda Uroporphyrinogen decarboxylase† deficiency; photosensitivity, skin inflammation, and blistering; cirrhosis often associated; autosomal dominant; late onset

Lead Poisoning Inhibits ALA dehydratase and ferrochelatase; microcytic sideroblastic anemia; basophilic stippling of erythrocytes; headache, nausea, memory loss, abdominal pain, diarrhea (lead colic), lead lines in gums, neuropathy (claw hand, wrist-drop), ↑ urine excretion of ALA; Tx: dimercaprol and EDTA Hemolytic Crisis

+ Ca2 +

Histidine

Carcinoid Syndrome ↑ Serotonin excretion from gastrointestinal neuroendocrine tumors (carcinoid tumors); cutaneous flushing, venous telangiectasia, diarrhea, bronchospasm, cardiac valvular lesions

Melanin

Tryptophan

Albinism Tyrosine hydroxylase (type I) or tyrosine transporter (type II) deficiency; ↓ pigmentation of skin, eyes, and hair, ↑ risk of skin cancer, visual defects

† an

Jaundice due to ↑ bilirubin from severe hemolysis; ↓ hemoglobin; ↑ reticulocytes; may result from: (1) G6PD deficiency hemolysis (2) Sickle cell crisis (3) Rh disease of newborn UDP-Glucuronyl Transferase Deficiency Jaundice due to low bilirubin conjugation; may result from: (1) Crigler-Najjar syndromes (2) Gilbert syndrome (3) Physiologic jaundice of newborn, especially premature infants

enzyme in the pathway between Uroporphyrinogen-III and Protoporphyrin IX.

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►►Amino Acid Synthesis and Metabolism

Genetic Deficiencies of Amino Acid Metabolism Valine Leucine Isoleucine

Phenylalanine

Phenylalanine hydroxylase Tetrahydrobiopterin

Phenylketonuria

Branched chain ketoacid dehydrogenase

Tyrosine Acetyl CoA Homogentisic Acid

Citrate

OAA

Homogentisate oxidase

Alkaptonuria

Maple Syrup Urine Disease

GENERAL PRINCIPLES │ 2. Biochemistry

Amino acids are required for protein synthesis. Although some amino acids can be synthesized de novo (nonessential), others (essential) must be obtained from the digestion of dietary proteins. Nonessential amino acids are synthesized from intermediates of glycolysis and the citric acid cycle or from other amino acids. Degradation of amino acids occurs by transamination of the amino group to glutamate, while the remaining carbon skeletons of the amino acids may be oxidized to CO2 + H2O, or reverted to citric acid cycle intermediates for conversion to glucose (glucogenic) or ketones (ketogenic).

Malate

Maleylacetoacetate

Fumarate

α-KG Succinyl CoA Methylmalonyl CoA mutase

Methylmalonyl CoA mutase deficiency

B12 Methylmalonyl CoA

Propionyl CoA carboxylase (Biotin) Odd-Carbon Fatty Acids

Propionyl CoA carboxylase deficiency

Propionyl CoA

α -Ketobutyrate

Threonine

Cysteine Cystathionine Homocysteine methyltransferase N5-methyl THF B12

B6

Cystathionine synthase

Homocystinuria

Homocysteine

S-Adenosylhomocysteine

Methionine

Methyl Groups for Biosynthesis • Epinephrine • N-Methylguanine cap on mRNA

ATP Pi + PPi

S-Adenosylmethionine (SAM)

Figure I-17-3. Genetic Deficiencies of Amino Acid Metabolism

(Continued)

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►►Amino Acid Synthesis and Metabolism (Cont'd.) GENERAL PRINCIPLES │ 2. Biochemistry

Precursors for Nonessential Amino Acids

Glycolysis Glucose

Phosphoglycerate Serine

Essential Amino Acids*

TCA cycle

Pyruvate

α-Ketoglutarate

Oxaloacetate

Alanine

Glutamate

Aspartate

Proline Glutamine Asparagine

Glycine Cysteine

Arginine†

Methionine

Histidine

Phenylalanine

Isoleucine

Threonine

Leucine

Tryptophan

Lysine

Valine

* Mnemonic: PVT. TIM HALL; †essential

during periods

of growth and pregnancy

Transfer of α-Amino Groups to α-Ketoglutarate Glutamate

Amino acid NH2 R

C

Ketogenic NH2

CH

R

Glucogenic and Ketogenic Amino Acids

COOH

COOH

O α-Ketoacid

Enz-PLP

HOOC

CH2 CH2 CH

Enz-PLP

HOOC

CH2 CH2 C

NH2

COOH

COOH

Leucine Lysine

Ketogenic and Glucogenic Phenylalanine Tyrosine Tryptophan Isoleucine Threonine

Glucogenic All others

O α-Ketoglutarate

Disease Association Hartnup disease

Transport protein defect with ↑ excretion of neutral amino acids; symptoms similar to pellagra; autosomal recessive

Phenylketonuria

Phenylalanine hydroxylase or dihydrobiopterin reductase deficiency → buildup of phenylalanine; tyrosine becomes essential; musty body odor, mental retardation, microcephaly, autosomal recessive; Tx: ↓ phenylalanine in diet; avoid aspartame (Nutrasweet®)

Alkaptonuria

Homogentisate oxidase deficiency (for tyrosine degradation); ↑ homogentisic acid in blood and urine (darkens when exposed to air), ochronosis (dark pigment in cartilage), arthritis in adulthood

Homocystinuria

↑ homocystine in urine. Classic homocystinuria, caused by a deficiency in cystathionine synthase, is associated with dislocated lens, deep venous thrombosis, stroke, atherosclerosis, mental retardation, and Marfan-like features. Deficiency of pyridoxine, folate, or vitamin B12 can produce a mild homocystinemia with elevated risk of atherosclerosis (previously listed symptoms absent). Methionine synthase (homocysteine methyltransferase) deficiency is extremely rare and is associated with megaloblastic anemia and mental retardation.

Cystinuria

Transport protein defect with ↑ excretion of lysine, arginine, cystine, and ornithine; excess cystine precipitates as kidney stones; Tx: acetazolamide

Maple syrup urine disease

Branched-chain ketoacid dehydrogenase deficiency; branched-chain ketoacidosis from infancy; weight loss, lethargy, alternating hypertonia/hypotonia, maple syrup odor of urine; ketosis/coma/death if untreated; Tx: ↓ valine, leucine, isoleucine in diet

Propionyl-CoA carboxylase deficiency

Neonatal ketoacidosis from blocked degradation of valine, isoleucine, methionine, threonine, and odd-carbon fatty acids; Tx: ↓ these amino acids in diet Propionyl-CoA carboxylase deficiency: neonatal metabolic acidosis; hyperammonemia; elevated propionic acid, hydroxypropionic acid, and methylcitrate; poor feeding, vomiting, lethargy, coma Methylmalonyl-CoA mutase deficiency: symptoms similar to propionyl CoA carboxylase deficiency, but accumulating metabolites differ (↑ methylmalonic acid)

Methylmalonyl-CoA mutase deficiency

Definition of abbreviation: PLP, pyridoxal-phosphate, formed from vitamin B6.

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►►Urea Cycle

Mitochondrial Matrix

HCO3– + 2 ATP + NH4+

NH4+

Portal blood (intestine) Glucose

Carbamoyl phosphate synthetase I 1 α-ketoglutarate Glutamate dehydrogenase

Carbamoyl phosphate Ornithine transcarbamoylase

Ornithine

Pyruvate NADH NAD+

Alanine (from muscle)

Citrulline Glutamate Cytosol Citrulline Argininosuccinate synthetase

Aspartate

Aspartate transaminase

AT P AMP + PP i

oxaloacetate

GENERAL PRINCIPLES │ 2. Biochemistry

Amino acids transported to the liver are transaminated to glutamate, which undergoes deamination to produce NH4+ or transamination to make aspartate. Both of these are used for synthesis of urea in the liver for excretion via the urea cycle.

α-ketoglutarate

Argininosuccinate Aspartate

Argininosuccinate lyase

Fumarate

Arginine Arginase

TCA cycle

Urea

Ornithine

Regulation 1 Carbamoyl phosphate synthase I ⊕ N-acetylglutamate* *High protein diet → ↑ glutamate in mitochondria → ↑ N-acetylglutamate

Disease Association Carbamoyl Phosphate Synthetase Deficiency

Ornithine Transcarbamoylase Deficiency

↑ [NH4+]; hyperammonemia

↑ [NH4+]; hyperammonemia

↑ blood glutamine

↑ blood glutamine

↓ BUN

↓ BUN

No increase in uracil or orotic acid

Uracil and orotic acid ↑ in blood and urine*

Cerebral edema

Cerebral edema

Lethargy, convulsions, coma, death

Lethargy, convulsions, coma, death

*OTC deficiency: ↑ carbamoyl-P stimulates pyrimidine synthesis, causing ↑ orotic acid and uracil

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GENERAL PRINCIPLES │ 2. Biochemistry

►►Lipid Synthesis and Metabolism Fatty acids are synthesized from excess glucose in the liver and transported to adipose tissues for storage. Fatty acid synthesis occurs in the cytosol and involves the transport of acetyl-CoA from the mitochondria via the citrate shuttle, carboxylation to malonyl CoA, and linking together 2 carbons per cycle to form long fatty acid chains. Synthesis stops at C16 palmitoyl-CoA, requiring 7 ATP and 14 NADPH. Metabolism of fatty acids occurs by β-oxidation, which takes place in mitochondria, and involves transport of fatty acids from the cytosol via the carnitine shuttle, then oxidative removal of 2 carbons per cycle to yield 1 NADH, 1 FADH2, and 1 acetyl-CoA.

Fatty Acid Synthesis and Oxidation Inner mitochondria membrane Mitochondrial matrix

Cytosol

Citrate shuttle pyruvate

citrate

acetyl-CoA

1 Acetyl CoA carboxylase

citrate

oxaloacetate

oxaloacetate acetyl-CoA

Fatty acid synthase

malate †

NADPH

Acetyl-CoA Other Tissues Citric Acid Cycle

Liver

Ketones

NAD

FADH2

Triglycerides and VLDL (well-fed)

Palmitoyl CoA

pyruvate

pyruvate

NADH

Malonyl CoA

AMP +PPi FAD

ATP

FA-CoA 2 Carnitine acyltransferase (CAT-1)

FA-CoA Fatty acyl CoA dehydrogenase (LCAD, MCAD)

Fatty acids from adipose (fasting)

CoA

FA-carnitine

Carnitine acyltransferase-2 (CAT-2) FA-carnitine Carnitine transporter

†

Another important source of NADPH is the HMP shunt.

Triacylglycerols (triglycerides), the storage form of fatty acids, are formed primarily in the liver and adipose tissues by attaching 3 fatty acids to a glycerol-3-P. Triacylglycerols are transported from liver to adipose as VLDL. Fatty acids from the diet are transported as chylomicrons. Both are digested by lipoprotein lipase (induced by insulin) in the capillaries of adipose and muscle. Fatty acids may be mobilized from triacylglycerols in adipose by hormone-sensitive lipase. Free fatty acids are delivered to tissues for beta oxidation.

Regulation 1 Acetyl-CoA carboxylase

2 Carnitine acyltransferase-1 (CAT-1)

Rate-limiting for fatty acid synthesis; requires biotin

Rate-limiting for fatty acid oxidation

⊕ insulin ⊕ citrate

− malonyl-CoA

− glucagon − palmitoyl-CoA

Disease Association Myopathic CAT-2/CPT-2 Deficiency Muscle aches/weakness, myoglobulinuria provoked by prolonged exercise, ↑ muscle triacylglycerols

Medium Chain Acyl-Dehydrogenase (MCAD) Deficiency Fasting hypoglycemia, no ketone bodies, dicarboxylic acidemia, C8–C10 acyl carnitines in blood, vomiting, coma, death; Tx: give IV glucose, avoid fasting, maintain high carb/low fat diet, including short chain FAs, which can be metabolized

(Continued)

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►►Lipid Synthesis and Metabolism (Cont’d.)

Glucose

DHAP

Glucose

Glucose DHAP 1 Glycerol-3-P dehydrogenase

1 Glycerol-3-P dehydrogenase

2 Glycerol kinase Glycerol Glycerol-3-P

Glycerol-3-P

VLDL

Glycerol

Glycerol

Gluconeogenesis Glycerol Glucose

Fatty Acids

Fatty Acids Albumin

3 FA CoA

TAG storage

3 FA CoA

Lipoprotein lipase VLDL

3

GENERAL PRINCIPLES │ 2. Biochemistry

Triacylglycerol (Triglyceride) Synthesis

Triacylglycerol

Triglyceride (storage)

4 Hormonesensitive lipase TAG

Fatty Acids

β-Oxidation Acetyl CoA TAG mobilization

Ketogenesis Ketone Bodies

Ketone Bodies

Muscle (Brain)

ADIPOSE

Citric Acid Cycle

LIVER

Notes 1 Glycerol-3P-dehydrogenase (adipose, liver)

Triacylglycerol synthesis from fatty acids

2 Glycerol kinase (liver only) Located on luminal membrane of endothelial cells in adipose tissue

3 Lipoprotein lipase

Regulation 3 Lipoprotein Lipase

4 Hormone sensitive lipase

Digests TGL in VLDL and chylomicrons. Fatty acids enter adipose

Mobilizes fatty acids from triacylglycerols

Induced by insulin ⊕ ApoC-II

Repressed by  insulin

⊕ Epinephrine Induced by cortisol

– insulin

Definition of abbreviations: CAT, carnitine acyltransferase (a.k.a. CPT, carnitine palmitoyl transferase); L/MCAD, long/medium chain acyldehydrogenase; TAG, triacylglycerols. Diabetic ketoacidosis results from overactive hormone-sensitive lipase often in the context of stress, trauma, or infection.

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GENERAL PRINCIPLES │ 2. Biochemistry

►►Ketone Body Metabolism During fasting, the liver converts excess acetyl-CoA from beta-oxidation of fatty acids into two ketone bodies, acetoacetate and β-hydroxybutyrate, which can be used by muscle and brain tissues. Ketosis represents a normal and advantageous response to fasting/ starvation, whereas ketoacidosis is a pathologic condition associated with diabetes and other diseases.

Disease Association

β-Oxidation FA CoA

Diabetic Ketoacidosis

Acetyl CoA HMG CoA Synthase

Excess ketone bodies in blood associated with type 1 diabetes mellitus not adequately managed with insulin, or precipitated by infection or trauma. Characterized by polyuria, dehydration, CNS depression and coma, sweet fruity breath (acetone).

HMG CoA HMG CoA Lyase Acetoacetate NADH

Liver Acetone

NAD

With the prevalence of obesity and stressful environments, ketoacidosis is now becoming more prevalent in type 2 diabetics, e.g., a diabetic in ketoacidosis cannot be assumed to be type 1.

3-Hydroxybutyrate (β-Hydroxybutyrate)

Mitochondrial Matrix Cytoplasm Acetoacetate

3-Hydroxybutyrate

Blood

Acetone

Cytoplasm

Muscle Renal Cortex Brain in Prolonged Fast

Mitochondrial Matrix Acetoacetate Activation of acetoacetate in extrahepatic tissues

Alcoholic Ketoacidosis Excess ketone bodies due to high NADH/NAD ratio in liver; symptoms same as above Note: In either type of ketoacidosis, 3-hydroxybutyrate (β-hydroxybutyrate) is the predominant ketone body formed (not detected by the urine test). Measure 3-hydroxybutyrate to more accurately evaluate ketoacidosis.

3-Hydroxybutyrate

NADH NAD

Acetoacetyl CoA

2 Acetyl CoA

Citric Acid Cycle

Figure I-16-4. Ketogenesis (Liver) and Ketogenolysis (Extrahepatic)

►►Cholesterol Synthesis Cholesterol is obtained from diet (about 20%) or synthesized de novo (about 80%). Synthesis occurs primarily in the liver for storage and bile acid synthesis, but also in adrenal cortex, ovaries, and testes for steroid hormone synthesis. Cholesterol may also be esterified into cholesterol esters by acyl-cholesterol acyl-transferase (ACAT) in cells for storage.

Regulation 1 HMG-CoA reductase

2 NADPH 3 Acetyl-CoA

HMG-CoA

HMG-CoA reductase

Rate-limiting step

Mevalonic acid

1 Cell membranes

Cholesterol

Steroids (adrenal, ovaries, testes)

Vitamin D

Bile acids (liver)

⊕ insulin

− glucagon

⊕ thyroxine

− cholesterol

Pharmacology HMG-CoA Inhibitors (“Statins”), e.g., lovastatin, pravastatin ↓ LDL; used for hypercholesterolemia; side effects: myopathy, liver dysfunction

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►►Lipoprotein Transport and Metabolism

Regulation

~ 80% HDL

Dietary fat ~ 20%

Liver Dietary Cholesterol

Intestine

Released from liver and small intestine

LDL (B-100)

Endogenous Cholesterol

Extra Hepatic Tissues

Hepatic Lipase

LCAT

(E, CII, B-48) Remnants (E, B-48)

CETP

VLDL (E, CII, B-100)

IDL (E, B-100)

HDL (cholesterol-rich)

Deliver cholesterol to liver and steroidogenic tissues via SR-B1 LP Lipase 1

LP Lipase

(Fatty acid)

1

Adipose Tissue and Muscle

Induced by insulin ⊕ ApoC-II

Type I Hypertriglyceridemia Lipoprotein lipase deficiency; ↑ triacylglycerols and chylomicrons; orange-red eruptive xanthomas, fatty liver, acute pancreatitis, abdominal pain after fatty meal; autosomal recessive

(Fatty acid)

Type II Hypercholesterolemia

Adipose Tissue and Muscle

LCAT, lecithin cholesterol acyltransferase CETP, cholesterol ester transfer protein SR-B1, scavenger receptor-B1

Classes of Lipoproteins and Important Apoproteins Lipoprotein

Functions

Apoproteins

Functions

Chylomicrons

Transport dietary triglyceride and cholesterol from intestine to tissues

apoB-48 apoC-II apoE

Secreted by epithelial cells Activates lipoprotein lipase Uptake by liver

Transports triglyceride from liver to tissues

apoB-100 apoC-II apoE

Secreted by liver Activates lipoprotein lipase Uptake of remnants by liver

Delivers cholesterol into cells

apoB-100

Uptake by liver and other tissues via LDL receptor (apoB‑100 receptor)

LDL

Hydrolyzes fatty acids from triacylglycerols from chylomicrons and VLDL

Hyperlipidemias

Chylomicrons

VLDL

1 Lipoprotein lipase

GENERAL PRINCIPLES │ 2. Biochemistry

Free fatty acids are transported by serum albumin, whereas neutral lipids (triacylglycerols and cholesterol esters) are transported by lipoproteins. Lipoproteins consist of a hydrophilic shell and a hydrophobic core and are classified by their density into chylomicrons, VLDL, LDL, and HDL.

IDL (VLDL remnants)

Picks up cholesterol from HDL to become LDL Picked up by liver

apoE

Uptake by liver

HDL

Picks up cholesterol accumulating in blood vessels Delivers cholesterol to liver and steroidogenic tissues via scavenger receptor (SR-B1) Shuttles apoC-II and apoE in blood

apoA-1

Activates LCAT to produce cholesterol esters

LDL receptor deficiency; ↑ risk of atherosclerosis and CAD, xanthomas of Achilles tendon, tuberous xanthomas on elbows, xanthelasma (lipid in eyelid), corneal arcus, homozygotes die 95%): Anti-dsDNA (40–60%) Anti-Sm (20–30%)

• Hemolytic anemia, thrombocytopenia, leukopenia • Arthritis • Skin rashes (including classic malar rash) • Renal disease • Libman-Sacks endocarditis • Serositis • Neurologic symptoms

• Females >> Males (M:F = 1:9), peak age 20–45 years, African American > Caucasian • Mechanism of injury: type II and III hypersensitivity reactions • Treatment: steroids and other immunosuppressants

Sjögren syndrome: an autoimmune disease characterized by destruction of the lacrimal and salivary glands, resulting in the inability to produce saliva or tears Antiribonucleoprotein antibodies: Anti-SS-A (Ro) Anti-SS-B (La)

• Keratoconjuctivitis sicca (dry eyes) and corneal ulcers • Xerostomia (dry mouth) • Mikulicz syndrome: enlargement of the salivary and lacrimal glands

• Females > males; age range: 30−50 years • Often associated with rheumatoid arthritis and other autoimmune diseases (e.g., SLE) • Increased risk of developing lymphoma

(Continued)

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►►Important Autoimmune Diseases (Cont’d.) Autoantibodies

Clinical Features

Comments

Diffuse Scleroderma Anti-DNA topoisomerase I antibodies (Scl-70) (70%)

Widespread skin involvement Early involvement of the visceral organs • Esophagus—dysphagia • GI tract—malabsorption • Pulmonary fibrosis—dyspnea on exertion • Cardiac fibrosis—arrhythmias • Kidney fibrosis—renal insufficiency

Raynaud phenomenon is seen in almost all patients and often preceeds other symptoms. Treatment: vasodilators, ACE inhibitors, NSAIDs, steroids, d-penicillamine

Limited scleroderma (e.g., CREST syndrome) Anticentromere antibodies

• Skin involvement of the face and hands • Late involvement of visceral organs (relatively benign clinical course)

(Calcinosis, Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly, Telangiectasia)

GENERAL PRINCIPLES │ 4. Immunology

Scleroderma (progressive systemic sclerosis): characterized by fibroblast stimulation and deposition of collagen in the skin and internal organs; females > males; age range: 20−55 years; activation of fibroblasts by growth factors/cytokines leads to fibrosis

Transplantation Immunology ►►Grafts Used in Medicine Grafts

Definition

Autologous (autografts)

Tissue is moved from one location to another in the same individual

Isograft

Transplants between genetically identical individuals (monozygotic twins)

Allograft

Transplants between genetically different members of the same species

Xenograft

Transplants between members of different species

►►Graft Rejection Reactions Type of Rejection

Time Taken

Cause

Hyperacute

Minutes to hours

Preformed anti-donor antibodies and complement (type II hypersensitivity)

Accelerated

Days

Reactivation of sensitized T cells

Acute

Days to weeks

Primary activation of T cells

Chronic

Months to years

Causes are unclear: antibodies, immune complexes, slow cellular reaction, recurrence of disease (type IV hypersensitivity)

Graft versus host

Weeks to months

Grafted bone marrow T cells attack host (type IV hypersensitivity)

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GENERAL PRINCIPLES │ 4. Immunology

Immunology Techniques in Diagnosis ►►Fluorescence Activated Cell Sorter Anti-CD4

Anti-CD8

Anti-CD20

Anti-CD3

• C  omplex mixtures of cells are treated with fluorescent dyelabeled antibodies and run through the apparatus.

Cells with fluorescent antibody

• T  he fluorescence activated cell sorter (FACS) separates the cells into populations based on their level of fluorescence with a particular dye.

Sheath fluid Laser beam

• E  ach dot on the diagram represents a cell that has bound to a fluorescent-labeled antibody.

Deflection plates

• Increasing fluorescence intensity with one dye is represented as a rise on the y-axis, and increasing fluorescence with the other dye occurs as you move right on the x-axis.

Fluorescence detector Light scatter detector

–

+

• D  ouble-labeled cells are always found in the upper right quadrant. • C  ells that have only background fluorescence with either dye are found in the lower left quadrant.

Anti-CD3 (increasing intensity of fluorescence)

Double stained

The results of flow cytometry are often shown for question analysis. Be sure to know the key CD markers and the biologic functions of the cells that possess them.

Anti-CD20

Double stained

Anti-CD4

Anti-CD8 (increasing intensity of fluorescence)

Computer-Generated Graphs

Anti-CD3

Anti-CD3

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Immunopharmacology GENERAL PRINCIPLES │ 4. Immunology

►►Recombinant Cytokines and Clinical Uses Cytokine

Clinical Uses

Aldesleukin (IL-2)

↑ Lymphocyte differentiation and ↑ NKs—used in renal cell cancer and metastatic melanoma

Oprelvekin (IL-11)

↑ Platelet formation—used in thrombocytopenia

Filgrastim (G-CSF)

↑ Granulocytes—used for bone marrow recovery

Sargramostim (GM-CSF)

↑ Granulocytes and macrophages—used for bone marrow recovery

Erythropoietin

Anemias, especially associated with renal failure

Thrombopoietin

Thrombocytopenia

Interferon-α

Hepatitis B and C, leukemias, malignant melanoma, Kaposi sarcoma

Interferon-β

Multiple sclerosis

Interferon-γ

Chronic granulomatous disease →↑ TNF

►►Immunosuppressant Agents Drug

Mechanism

Uses

Azathioprine

Converted to mercaptopurine, whose metabolites inhibit purine metabolism Cytotoxic to proliferating lymphocytes (especially T cells)

Autoimmune diseases (e.g., SLE, rheumatoid arthritis) and immunosuppression in renal allografts

Corticosteroids

↓ synthesis of prostaglandins, leukotrienes, cytokines; inhibit T-cell proliferation; at immunosuppressive doses, they are cytotoxic to some T cells

Cancer, organ transplants

Cyclophosphamide

Cytotoxic to proliferating lymphocytes (especially B cells)

• A  utoimmune diseases, bone marrow transplants • Similar cytotoxic drugs: cytarabine, dactinomycin, methotrexate, vincristine

Cyclosporine

Antibiotic that binds to cyclophilin → inhibits calcineurin (cytoplasmic phosphatase) → ↓ activation of T-cell transcription factors → ↓ IL-2, IL-3, and interferon-γ

• DOC in organ or tissue transplantation (± mycophenolate ± steroids ± cytotoxic drugs) • Side effects: peripheral neuropathy, nephrotoxicity, hyperglycemia, hypertension, hyperlipidemia, hirsutism, gingival overgrowth, cholelithiasis

Tacrolimus

Antibiotic that binds to FK-binding protein (FKBP); also inhibits calcineurin (similar to cyclosporine)

• U  sed alternatively to cyclosporine in renal and liver transplants • Side effects similar to cyclosporine

Sirolimus (rapamycin)

Inhibits T-cell activation and proliferation in response to IL-2 by binding to mTOR

Immunosuppression after kidney transplantation in conjunction with cyclosporine and corticosteroids

Mycophenolate

Inhibits de novo purine synthesis

• Kidney, liver, heart transplants • Used with cyclosporine in renal transplants to ↓ cyclosporine dose

RhD immune globulin (RhoGAMTM)

Antibody to red cell RhD antigens

Administer to RhD mother within 72 h of Rh ⊕ delivery to prevent hemolytic disease of newborn in subsequent pregnancy

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GENERAL PRINCIPLES │ 4. Immunology

►►Monoclonal Antibodies (MABs) and Clinical Uses MAB

Clinical Uses

Abciximab

Antiplatelet (acute coronary symptoms, post-angioplasty)—antagonist of IIb/IIIa receptors

Daclizumab

Kidney transplants—blocks IL-2 receptors

Infliximab

Rheumatoid arthritis and Crohn disease—binds TNF-α

Muromonab

Allograft rejection block in renal transplantsbinds CD3 on T cells

Palivizumab

Respiratory syncytial virus—blocks RSV fusion protein

Rituximab

Non-Hodgkin lymphoma—binds to CD20 antigen on B-cell surface protein

Trastuzumab

Breast cancer—antagonist to HER2/neu receptor

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Microbiology Chapter 5 General Principles of Microbiology Comparison of Medically Important Microbial Groups . . . . . . . . . . . . . . . . . . . . 112

Bacteriology Bacterial Growth Curve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 Features of Bacteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 Normal Flora Organisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 Bacterial Toxins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 Major Exotoxins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 Important Pathogenic Factors and Diagnostic Enzymes . . . . . . . . . . . . . . . . . . . . 116 Unusual Growth Requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 Bacterial Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117

Antibacterial Agents Mechanisms of Action of Antibacterial Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117 Cell Wall Synthesis Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118–119 Summary of Mechanisms of Protein Synthesis Inhibition . . . . . . . . . . . . . . . . . . . 119 Protein Synthesis Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120 Folic Acid Synthesis Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 DNA Replication Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121

Virology Viral Structure and Morphology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 DNA Viruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 RNA Viruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 Double-Stranded RNA Viruses: Reoviridae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 Positive-Sense RNA Viruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 Negative-Sense RNA Viruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134 Viral Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134 Antiviral Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135–136

Mycology Mycology: Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136 Nonsystemic Fungal Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137 Systemic Fungal Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138 Opportunistic Fungi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139 Antifungal Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140

Parasites Obligate Intracellular Parasites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122 Facultative Intracellular Parasites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122 Protozoans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122 Protozoan Parasites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 Free-Living Amebae That Occasionally Infect Humans . . . . . . . . . . . . . . . . . . . . 123 Plasmodium Life Cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 Plasmodium Species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 Antimalarial Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 Adverse Effects of Antimalarial Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 Hemoflagellates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 Miscellaneous Apicomplexa Infecting Blood or Tissues . . . . . . . . . . . . . . . . . . . . 127 Major Protozoal Infections and Drugs of Choice . . . . . . . . . . . . . . . . . . . . . . . . . 127 Metazoans: Worms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 Trematode (Fluke) Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 Gastrointestinal Cestodes (Tapeworms) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 Roundworms (Nematodes) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130 Roundworms (Nematodes) Transmitted by Eggs . . . . . . . . . . . . . . . . . . . . . . . . . 130 Roundworms (Nematodes) Transmitted by Larvae . . . . . . . . . . . . . . . . . . . . . . . 131 Filarial Nematodes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131 Drugs for Helmiathic Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131

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GENERAL PRINCIPLES │ 5. Microbiology

General Principles of Microbiology ►►Comparison of Medically Important Microbial Groups Characteristic

Viruses

Bacteria

Fungi

Parasites

Diameter

Minute (0.02–0.3 µ)

Small (0.3–2 µ)

3–10 µ

15–25 µ (trophozoites)

Cell type

Acellularno nucleus

Prokaryotic cells

Eukaryotic cells

• DNA or RNA • 1 nucleocapsid, except in segmented or diploid viruses

• DNA and RNA • 1 chromosome • No histones

• DNA and RNA • More than one chromosome

Replicates in host cells

DNA replicates continuously

G and S phases

Exons, no introns

Introns and exons

Some have polycistronic mRNA and post-translational cleavage

Mono- and polycistronic mRNA

Monocistronic RNA

Uses host organelles; obligate intracellular parasites

No membrane-bound organelles

Mitochondria and other membranebound organelles

No ribosomes

70S ribosomes (30S+50S)

80S ribosomes (40S+60S)

Replication

Make and assemble viral components

Binary fission (asexual)

Cytokinesis with mitosis/meiosis

Cellular membrane

Some are enveloped, but no membrane function

Membranes have no sterols, except Mycoplasma, which have cholesterol

Ergosterol is major sterol

Sterols, such as cholesterol

Cell wall

No cell wall

Peptidoglycan

Complex carbohydrate cell wall: chitin, glucans, or mannans

No cell wall

Note: Prions are infectious proteins (contain no nucleic acids). They are the agents of kuru, mad cow disease, etc.

Bacteriology ►►Bacterial Growth Curve Lag Phase: • Detoxifying medium • Turning on enzymes to utilize medium

Log Number of Cells

Stationary Phase

Log Phase (Logarithmic or Exponential)

Death Phase

Log Phase: • Rapid exponential growth • Generation timetime it takes one cell to divide into two • This is determined during log phase Stationary Phase: • Nutrients used up • Toxic products begin to accumulate • Number of new cells = the number of dying cells

Lag Time

Death Phase: • Nutrients gone • Toxic products kill cells • Number of cells dying exceeds the number of cells dividing

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►►Features of Bacteria GENERAL PRINCIPLES │ 5. Microbiology

Outer Membrane Protein

Capsule

LPS O-Antigen Core

Membrane Lipoteichoic Acid Cell Surface Proteins

Lipid-A

Peptidoglycan

Lipoprotein

OM

Porin

Envelope

Cell Wall Teichoic Acid

Peptidoglycan Periplasmic space Cytoplasmic IM Membrane

Cytoplasmic Membrane

Gram +

Cell Wall Synthesizing Enzymes (Penicillin Binding Proteins—PBPs)

Gram –

Envelope Structure

Gram ⊕ or –

Chemical Composition

Function

Capsule (nonessential) = slime = glycocalyx

Both Gram ⊕ and Gram –

Polysaccharide gel (except B. anthracis: poly-D-glutamate)

• Antiphagocytic • Immunogenic (except S. pyogenes and N. meningitidis, type B)

Outer membrane

Gram – only

Phospholipid/proteins LPS: • Lipid A • Polysaccharide

Hydrophobic membrane: • LPS = endotoxin • Lipid A = toxic moiety • PS = immunogenic portion

Outer membrane proteins

Attachment, virulence, etc.

Protein porins

Passive transport

Gram ⊕ (thick) Gram – (thin)

Peptidoglycanopen 3-D net of: • N-acetyl-glucosamine • N-acetyl-muramic acid • Amino acids (including DAP)

• Rigid support, cell shape, and protection from osmotic damage • Synthesis inhibited by penicillins and cephalosporins • Confers Gram reaction

Gram ⊕ only

Teichoic acids

• Immunogenic, induces TNF-α, IL-1 • Attachment

Acid-fast only

Mycolic acids

• Acid-fastness • Resistance to drying and chemicals

Periplasmic space

Gram – only

“Storage space” between the inner and outer membranes

• Enzymes to break down large molecules (b-lactamases) • Aids regulation of osmolarity

Cytoplasmic membrane = inner membrane = cell membrane = plasma membrane

Gram ⊕ Gram –

Phospholipid bilayer with many embedded proteins

• Hydrophobic cell “sac” • Selective permeability and active transport • Carrier for enzymes for: – Oxidative metabolism – Phosphorylation – Phospholipid synthesis – DNA replication – Peptidoglycan cross linkage • Penicillin binding proteins (PBPs)

Cell wall = peptidoglycan

Definition of abbreviation: DAP, diaminopimelic acid; LPS, lipopolysaccharide.

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GENERAL PRINCIPLES │ 5. Microbiology

►►Normal Flora Organisms Most infectious disease vignettes begin with the necessity to rule out the normal flora organisms that are cultured from the patient. Make sure you know those organisms that can confound a simple Gram-stain type of diagnosis, e.g., notice in the oropharynx and vagina, normal flora organisms cannot be indistinguishable from pathogens by Gram stain alone!

Common or Medically Important Organisms

Less Common but Notable Organisms

Blood, internal organs

None, generally sterile



Cutaneous surfaces

Staphylococcus epidermidis

Staphylococcus aureus, Corynebacteria (diphtheroids), streptococci, anaerobes, e.g., peptostreptococci, Candida spp.

Nose

Staphylococcus aureus

S. epidermidis, diphtheroids, assorted streptococci

Oropharynx

Viridans streptococci, including Streptococcus mutans

Assorted streptococci, nonpathogenic Neisseria, nontypeable Haemophilus influenzae, Candida albicans

Gingival crevices

Anaerobes: Bacteroides, Prevotella, Fusobacterium, Streptococcus, Actinomyces



Stomach

None



Colon (microaerophilic/ anaerobic)

Adult: Bacteroides/Prevotella (predominant organism), Escherichia, Bifidobacterium

Eubacterium, Fusobacterium, Lactobacillus, assorted gramnegative anaerobic rods Enterococcus faecalis and other streptococci

Vagina

Lactobacillus

Assorted streptococci, gram-negative rods, diphtheroids, yeasts, Veillonella (gram-negative diplococcus)

Site

►►Bacterial Toxins Endotoxin Endotoxin (lipopolysaccharide = LPS) is part of the gram-negative outer membrane. It is encoded on the chromosome. • The toxic portion is lipid A. LPS is heat stable and not strongly immunogenic, so it cannot be converted to a toxoid. • LPS activates macrophages, leading to release of TNF-α, IL-1, IL-6, and nitric oxide (NO). IL-1 is a major mediator of fever. Damage to the endothelium from bradykinin-induced vasodilation leads to shock. Coagulation (DIC) is mediated through the activation of Hageman factor. NO production causes hypotension, which contributes to shock.

Exotoxin Exotoxins are protein toxins, generally quite toxic, and secreted by bacterial cells. They are encoded on plasmids or in lysogenic phage genomes. • Exotoxins can be modified by chemicals or heat to produce a toxoid that still is immunogenic, but no longer toxic, so it can be used as a vaccine. • Most are A-B (or two) component protein toxins. B component binds to specific cell receptors to facilitate the internalization of A (the active [toxic] component)

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►►Major Exotoxins

Neurotoxins

Superantigens

cAMP inducers

Cytolysins

Toxin

Mode of Action

Role in Disease

Corynebacterium diphtheriae (⊕)

Diphtheria toxin

• A  DP ribosyl transferase inactivates eEF-2 • Targets: heart, nerves, epithelium

Inhibits eukaryotic cell protein synthesis

Pseudomonas aeruginosa ( –)

Exotoxin A

• A  DP ribosyl transferase inactivates eEF-2 • Target: liver

Inhibits eukaryotic cell protein synthesis

Shigella dysenteriae ( – )

Shiga toxin

Interferes with 60S ribosomal subunit

• Inhibits protein synthesis in eukaryotic cells • Enterotoxic, cytotoxic, and neurotoxic

Enterohemorrhagic E. coli (EHEC) ( – )

Verotoxin (shiga-like)

Interferes with 60S ribosomal subunit

Inhibits protein synthesis in eukaryotic cells

Clostridium tetani (⊕)

Tetanus toxin

Blocks release of glycine and GABA

Inhibits neurotransmission in inhibitory synapses

Clostridium botulinum (⊕)

Botulinum toxin

Blocks release of acetylcholine

Inhibits cholinergic synapses

Staphylococcus aureus (⊕)

TSST-1

• Induces IL-1, IL-6, TNF-α, IFN-γ • Decreases liver clearance of LPS

Fever, increased susceptibility to LPS, rash, shock, capillary leakage

Streptococcus pyogenes (⊕)

Exotoxin A, also called erythrogenic or pyrogenic toxin

Similar to TSST-1

Fever, increased susceptibility to LPS, rash, shock, capillary leakage, cardiotoxicity

Enterotoxigenic Escherichia coli ( – )

Heat labile toxin (LT)

LT stimulates an adenylate cyclase by ADP ribosylation of GTPbinding protein

Both LT and ST promote secretion of fluid and electrolytes from intestinal epithelium

Vibrio cholerae ( – )

Cholera toxin

Similar to E. coli LT

Profuse, watery diarrhea

Bacillus anthracis (⊕)

Anthrax toxin (3 proteins make 2 toxins)

• E  F = edema factor = adenylate cyclase • LF = lethal factor • PA = protective antigen (B component for both)

• Decreases phagocytosis • Causes edema, kills cells

Bordetella pertussis ( – )

Pertussis toxin

ADP ribosylates Gi, the negative regulator of adenylate cyclase, leading to increased cAMP

• Histamine sensitizing • Lymphocytosis promotion (inhibits chemokine receptors) • Islet activation

Clostridium perfringens (⊕)

Alpha toxin

Lecithinase

• Damages cell membranes • Myonecrosis

Staphylococcus aureus (⊕)

Alpha toxin

Pore former

Membrane becomes leaky

GENERAL PRINCIPLES │ 5. Microbiology

Protein synthesis inhibitors

Organism (Gram)

Definition of abbreviations: TSST-1, toxic shock syndrome toxin-1

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GENERAL PRINCIPLES │ 5. Microbiology

►►Important Pathogenic Factors and Diagnostic Enzymes Factor

Function

Organisms

All capsules

Antiphagocytic

Streptococcus pneumoniae, Klebsiella pneumoniae, Haemophilus influenzae, Pseudomonas aeruginosa, Neisseria meningitidis, Cryptococcus neoformans (mnemonic: some killers have pretty nice capsules) and many more

M protein

Antiphagocytic

Group A streptococci

A protein

Binds Fc of IgG to inhibit opsonization and phagocytosis

Staphylococcus aureus

Lipoteichoic acid

Attachment to host cells

All gram-positive bacteria

All pili

Attachment

Many gram-negatives

Pili of N. gonorrhoeae

Antiphagocytic, antigenic variation

N. gonorrhoeae

Hyaluronidase

Hydrolysis of ground substance

Group A streptococci

Collagenase

Hydrolysis of collagen

Clostridium perfringens, Prevotella melaninogenica

Urease

Increases pH of locale, contributes to kidney stones

Proteus, Ureaplasma, Nocardia, Cryptococcus, Helicobacter (mnemonic: PUNCH)

Kinases

Hydrolysis of fibrin

Streptococcus, Staphylococcus

Lecithinase

Destroys cell membranes

Clostridium perfringens

Heparinase

Thrombophlebitis

Bacteroides

Catalase

Destroys hydrogen peroxide (major problem for CGD patients)

• Most important: Staphylococcus, Pseudomonas, Aspergillus, Candida, Enterobacteriaceae • Most anaerobes lack catalase

IgA proteases

Destroy IgA, promote colonization of mucosal surfaces

Neisseria, Haemophilus, Streptococcus pneumoniae

Oxidase

Cytochrome c oxidase is the terminal electron acceptor

Neisseria and most gram-negatives, except the Enterobacteriaceae

Coagulase

Produces fibrin clot

Staphylococcus aureus and Yersinia pestis

►►Unusual Growth Requirements Requirements in Culture

Organism

Factors X and V

Haemophilus

Cholesterol

Mycoplasma

High salt

Staphylococcus aureus, group D enterococci and Vibrio

Cysteine

Francisella, Legionella, Brucella, and Pasteurella (mnemonic: the 4 Sisters “ELLA” worship in the Cysteine Chapel)

High temperature (42° C)

Campylobacter

Lower than atmospheric oxygen pressure (microaerophilic); special CO2 incubator

Campylobacter and Helicobacter

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►►Bacterial Genetics Homologous: The one-to-one exchange of linear extrachromosomal DNA for homologous alleles within the chromosome, using recombinase A Site-specific: The incorporation of extrachromosomal circles of DNA into another molecule of DNA using restriction endonucleases

Conjugation

The donation of chromosomal or plasmid genes from one bacterium to another through a conjugal bridge. • F+ cells have a fertility factor plasmid and serve as donors of plasmid DNA • F – cells do not have fertility factors and serve as the recipients of DNA in any cross. • Hfr cells have incorporated a fertility factor plasmid (now called episome) into their chromosome by sitespecific recombination and serve as donors of chromosomal DNA • Conjugation is the most important means of transfer of drug resistance genes in gram-negative bacilli

Transduction

The delivery of bacterial genes from one bacterium to another via a virus vector. • Generalized transduction: Transfer of any genes from one bacterium to another via an accident in the assembly of a virus with a lytic life cycle. • Specialized transduction: The transfer of bacterial chromosomal genes located near the insertion site of a temperate phage from one bacterium to another via an accident of excision. • Transduction has been shown to be the means of transfer of drug resistance to methicillin (MRSA) and imipenem (Pseudomonas).

Transformation

The uptake and incorporation of free DNA from the environment by competent cells followed by homologous recombination. • Transformation is an important means of transfer of traits in bacteria that are naturally competent (Streptococcus pneumoniae, Helicobacter, Neisseria, and Haemophilus influenzae)

Lysogeny

The stable association of DNA molecules between a bacterium and a temperate phage. • It imparts the important traits: C = Cholera toxin, O = Salmonella O antigen, B= Botulinum toxin, E = Erythrogenic toxin of Streptococcus pyogenes, D = Diphtheria toxin, S = Shiga toxin. Mnemonic: COBEDS: when 2 people share a bed, someone gets a little bit pregnant (with phage). • Bacterial cells with stably integrated temperate phage DNA are said to have undergone lysogenic conversion.

Transposon

A mobile genetic element capable of movement within a cell. • They move by a variation of site-specific recombination and are responsible for the formation of multiple drug-resistance plasmids. • VRSA has arisen because Enterococcus donated a multi-drug resistance plasmid, produced by transposition, to MRSA.

GENERAL PRINCIPLES │ 5. Microbiology

Recombination

Antibacterial Agents ►►Mechanisms of Action of Antibacterial Agents Mechanism of Action

Antibacterial Agents

Inhibition of bacterial cell-wall synthesis

Penicillins, cephalosporins, imipenem/meropenem, aztreonam, vancomycin

Inhibition of bacterial protein synthesis

Aminoglycosides, chloramphenicol, macrolides, tetracyclines, streptogramins, linezolid

Inhibition of DNA replication or transcription

Fluoroquinolones, rifampin

Inhibition of nucleic acid synthesis

Trimethoprim, flucytosine

Inhibition of folic acid synthesis

Sulfonamides, trimethoprim, pyrimethamine

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GENERAL PRINCIPLES │ 5. Microbiology

►►Cell Wall Synthesis Inhibitors Class/Example

Mechanism of Action/Resistance

Spectrum

Toxicity/Notes

Penicillins Narrow spectrum, β-lactamase sensitive: penicillin G, penicillin V Very narrow spectrum, β-lactamase resistant: methicillin, nafcillin, oxacillin

Broad spectrum, aminopenicillins, β-lactamase sensitive: ampicillin, amoxicillin

Mechanism: inhibit cross-linking of peptidoglycan component of cell wall by transpeptidases; action mediated by binding of penicillin-binding proteins (PBPs)

Gram-positives Clostridia Syphilis



Gram-positives, especially S. aureus

Resistant staph emerging “MRSA”

Resistance: production of β-lactamases, which cleave the β-lactam ring structure; change in PBPs; change in porins

Gram-positives, enterococci, H. influenzae L monocytogenes M. catarrhalis E. coli

Activity may be augmented with penicillinase β-lactamase inhibitors (e.g., clavulanic acid, sulbactam, and tazobactam)

• Gram-negatives, including Pseudomonas • Gram-positives, including enterococci (mezlocillin and piperacillin)



Extended spectrum, antipseudomonal, β-lactamase sensitive: mezlocillin, piperacillin, carbenicillin, ticarcillin, azlocillin

Cephalosporins First generation: cefazolin, cephalexin

Second generation: cefotetan, cefoxitin, cefuroxime, cefaclor

Mechanism: inhibition of cell wall formation similar to penicillins Resistance: same as penicillins

Gram-positives Proteus mirabilis E. coli Klebsiella pneumoniae Less gram-positive activity and more gram-negative activity than first generation • B. fragilis • H. influenzae • M. catarrhalis • P. mirabilis • E. coli • K. pneumoniae • Neisseria, Enterobacter

• Cross-allergenicity with penicillins occurs in 5% • Anaphylaxis, but not rash, a contraindication in penicillin-sensitive pt. • Disulfiram-like effects (cefotetan)

Third generation: ceftazidime, cefoperazone, cefotaxime, ceftriaxone

Less gram-positive activity and more gram-negative activity than second generation • Serratia sp. • Borrelia burgdorferi • H. influenzae • Neisseria • Enterobacter Some have anti-Pseudomonas activity

• Most penetrate bloodbrain barrier (not cefoperazone) • Reserved for serious infections • Disulfiram-like effects (cefoperazone)

Fourth generation: cefepime

More gram-negative activity while retaining first-generation gram-positive activity

More resistant to β- lactamases

(Continued)

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►►Cell Wall Synthesis Inhibitors (Cont’d.) Spectrum

Toxicity/Notes

Carbapenems and Monobactams Carbapenems (meropenem, imipenem)

Similar mechanism to penicillins and cephalosporins

Monobactams (aztreonam)

Gram-positives, gram-negative rods, anaerobes

• • • • •

Nephrotoxic GI distress Rash CNS toxicity Cilastatin administered concurrently with imipenem increases the drug’s half-life and reduces nephrotoxicity • Beta-lactamase resistant

Gram-negative rods

• GI distress with superinfection, vertigo, headache • Synergistic with aminoglycosides • Beta-lactamase resistant

GENERAL PRINCIPLES │ 5. Microbiology

Mechanism of Action/Resistance

Class/Example

Non-Beta Lactam Cell Wall Synthesis Inhibitors Vancomycin

Binds cell wall precursors (D-ala-D-ala muramyl pentapeptide), preventing polymerization, peptidoglycan elongation

Drug resistant gram-positives, e.g., MRSA sepsis (IV) or C. difficile (oral [not absorbed from lumen])

• Chills, fever, ototoxicity, nephrotoxicity • Flushing or “red man syndrome” upon rapid infusion • Resistant strains (VRSA, VRE) emerging

Definition of abbreviations: VRE, vancomycin-resistant enterococcus; VRSA, vancomycin-resistant Staphylococcus aureus.

ep

tide bo

*3

*4

nd

p

►►Summary of Mechanisms of Protein Synthesis Inhibition = initiating amino acid

#2 Translocation

#1

#1

= amino acid in peptide sequence

50 S m RNA

*1

"P"

= tRNA, specific for each amino acid

"A" *2

30 S sites

Event

Antibiotics and Binding Sites

Mechanism

1. Formation of initiation complex

Aminoglycosides (30S) Linezolid (50S)

Interfere with initiation codon functions—block association of 50S ribosomal subunit with mRNA-30S (bacteriostatic); misreading of code—incorporation of wrong amino acid (bactericidal)

2. Amino-acid incorporation

Tetracyclines (30S) Dalfopristin/quinupristin (50S)

Block the attachment of aminoacyl tRNA to acceptor site (bacteriostatic)

3. Formation of peptide bond

Chloramphenicol (50S)

Inhibit the activity of peptidyltransferase (bacteriostatic)

4. Translocation

Macrolides and clindamycin (50S)

Inhibit translocation of peptidyl tRNA from acceptor to donor site (bacteriostatic)

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GENERAL PRINCIPLES │ 5. Microbiology

►►Protein Synthesis Inhibitors Drug/Class

Site of Inhibition

Chloramphenicol

50S

Wide spectrum, including: • H. influenzae • N. meningitidis • Bacteroides • Rickettsia • Salmonella

Tetracyclines: • tetracycline • doxycycline • minocycline

30S

Macrolides: • erythromycin, • azithromycin • clarithromycin

Spectrum

Mechanisms of Resistance

Toxicities

Notes

Plasmid-mediated acetyltransferases that inactivate the drug

• “Gray baby” syndrome (↓ glucuronyl transferase in neonates) • Aplastic anemia/bone marrow suppression • GI irritation

• Toxicity limits clinical use • Reserved for severe Salmonella and bacterial meningitis in blactam–sensitive patients

Gram ⊕ and Gram – : • Rickettsia • Chlamydia • Mycoplasma • H. pylori • Brucella • Vibrio

Plasmid-mediated efflux pumps and reduced uptake via transport systems

• GI irritation • Tooth enamel dysplasia • Bone growth irregularities • Hepatotoxicity • Photosensitivity • Vestibular toxicity

• Fanconi syndrome with expired tetracycline • Oral absorption limited by multivalent cations

50S

Gram ⊕, some Gram – : • Chlamydia • Mycoplasma • Ureaplasma • Legionella • Campylobacter

Methylation of binding site on 50S; increased efflux from multidrug exporters

• • • • •

Useful in atypical pneumonia

Ketolides • Telithromycin

50S

Similar spectrum to macrolides

Many macrolideresistant strains are susceptible to ketolides

• Severe hepatotoxicity • Visual disturbances • Fainting

Its use is limited because of toxicity

Clindamycin

50S

Narrow spectrum: Gram ⊕, anaerobes

Methylation of binding site on 50S

• GI irritation • Skin rash • C. difficile superinfection



Aminoglycosides: • gentamicin • neomycin • tobramycin • streptomycin

30S

Gram – rods, aerobic only

Plasmid-mediated group transferases

Ototoxicity, nephrotoxicity

Neomycin for bowel prep (stays in bowel lumen)

Oxazolidinones: • linezolid

50S

Gram ⊕ cocci

Resistance rare

• Thrombocytopenia, neutropenia, esp. in immunocompromised • MAO inhibition (dietary and drug restrictions)

No cross-resistance with other protein synthesis inhibitors, so often reserved for resistant infections

GI irritation Cholestasis Hepatitis Skin rashes ↓ CYP3A4 (except azithromycin)

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►►Folic Acid Synthesis Inhibitors Trimethoprim and pyrimethamine inhibit

Dihydropteroate Synthase

Dihydrofolate Reductase

Dihydropteroic Acid

Pteridine + PABA

Class/Drug

Mechanism of Action

Spectrum

+ Glutamate

Dihydrofolic Acid

Mechanism of Resistance

GENERAL PRINCIPLES │ 5. Microbiology

Sulfonamides inhibit

Tetrahydrofolic Acid

Toxicity

Notes

Sulfonamides

PABA antimetabolite inhibits bacterial dihydropteroate synthase, thus curbing folate synthesis

Gram – , gram ⊕, Chlamydia, Nocardia

Decreased accumulation of drugs, decreased affinity of drug for dihydropteroate synthase

• Hypersensitivity • Hemolytic anemia in G6PD-deficient • Nephrotoxicity • Kernicterus in newborns

Combined with trimethoprim for increased efficacy

Trimethoprim

Inhibits bacterial dihydrofolate reductase, thus inhibiting folate synthesis

H. influenzae M. catarrhalis

Production of bacterial dihydrofolate reductase with decreased affinity for drug

• Megaloblastic anemia • Leukopenia • Granulocytopenia

• Adverse effects may be reduced by concurrent folinic acid • Good for UTIs because it is excreted in urine unchanged

►►DNA Replication Inhibitors Class/Drug Fluoroquinolones: • ciprofloxacin • ofloxacin • levofloxacin • moxifloxacin

Mechanism of Action

Spectrum

Interfere with bacterial DNA topoisomerase II and IV (DNA gyrase), resulting in inhibition of DNA synthesis

Gram – rods, Neisseria, occasional gram ⊕

Mechanism of Resistance • Decreased intracellular drug concentrations through efflux pumps and altered porins • Alteration of drug’s binding site

Toxicity

Notes

• • • •

Contraindicated in pregnancy due to cartilage formation abnormalities in animal studies

GI distress Skin rash Superinfection Tendonitis and tendon rupture

►►Miscellaneous Class/Drug Metronidazole

Mechanism of Action When reduced, interferes with nucleic acid synthesis (bactericidal)

Spectrum

Mechanism of Resistance

Anaerobes (except Actinomyces)

Rare plasmamediated resistance

Toxicity

Notes

• GI distress • Disulfiram-like reaction with alcohol • Peripheral neuropathy, ataxia

• Strong metallic taste • DOC in pseudomembranous colitis

Definition of abbreviations: DOC, drug of choice; G6PD, glucose-6-phosphate dehydrogenase; PABA, para-aminobenzoic acid; UTI, urinary tract Infection.

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GENERAL PRINCIPLES │ 5. Microbiology

Parasites ►►Obligate Intracellular Parasites • Cannot be cultured on inert media. Intracellular organisms (both obligate and facultative) are protected from antibody and complement. Intracellular pathogens tend to elicit cell-mediated immune responses, so end pathologic lesion is frequently a granuloma • All rickettsiae, chlamydiae, Mycobacterium leprae • All viruses • Plasmodium, Toxoplasma gondii, Babesia, Leishmania, Trypanosoma cruzi (amastigotes in cardiac muscle)

►►Facultative Intracellular Parasites Live inside phagocytic cells in the body, but can be cultured on inert media • Francisella tularensis • Listeria monocytogenes • Mycobacterium tuberculosis • Brucella species • Nontuberculous mycobacteria • Salmonella typhi • Legionella pneumophila • Yersinia pestis • Nocardia • Borrelia burgdorferi • Histoplasma capsulatum

►►Protozoans Common Name

Amebae

Flagellates

Apicomplexa (Intracellular)

Important genera

Entamoeba Naegleria Acanthamoeba

Luminal (Gut, UG) Trichomonas Giardia

Blood/Tissue Plasmodium Toxoplasma Babesia

Hemoflagellates Leishmania Trypanosoma

Intestinal Cryptosporidium Isospora

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►►Protozoan Parasites

Entamoeba histolytica

Disease/Organs Most Affected • Amebiasis: dysentery • Inverted, flask-shaped lesions in large intestine with extension to peritoneum and liver, lungs, brain, and heart • Blood and pus in stool • Liver abscesses

Form/Transmission

Diagnosis

• Cysts • Fecal-oral transmission: water, fresh fruits, and vegetables • Travel to tropics

• Trophozoites or cysts (with 4 nuclei) in stool

• Nuclei have sharp central karyosome and fine chromatin “spokes”

• Serology Giardia lamblia

Giardiasis: Ventral sucking disk attaches to lining of duodenal wall, causing a fatty, foulsmelling diarrhea (diarrhea → malabsorption in duodenum, jejunum)

• Cysts • Fecal (human, beaver, muskrat, etc.), oral transmission: water, food, day care, oral-anal sex • Campers and hikers

• Trophozoites or cysts in stool or fecal antigen test (replaces “string” test)

GENERAL PRINCIPLES │ 5. Microbiology

Species

• “Falling leaf” motility Cryptosporidium spp.

Cryptosporidiosis: transient diarrhea in healthy; severe in immunocompromised hosts

• Cysts • Undercooked meat, water; not killed by chlorination

Acid fast oocysts in stool: biopsy shows dots (cysts) in intestinal glands

Trichomonas vaginalis (urogenital)

Trichomoniasis: frothy green, unpleasant smelling vaginal discharge, itching, burning vaginitis

• Trophozoites • Sexual

Motile trophozoites in methylene blue wet mount

►►Free-Living Amebae That Occasionally Infect Humans Species

Disease/Locale

Form/Transmission

Diagnosis

Naegleria

Primary amebic meningoencephalitis (PAM): severe prefrontal headache, nausea, high fever, often an altered sense of smell; often fatal

• Free-living amebae picked up while swimming or diving in very warm fresh water • Penetrates cribriform plate

• Motile trophozoites in CSF • Culture on plates seeded with gram – bacteria; amebae will leave trails

Acanthamoeba

Keratitis; GAE in immunocompromised patients; insidious onset but progressive to death

• Free-living amebae in contaminated contact lens solution (airborne cysts) • Not certain for GAE; inhalation or contact with contaminated soil or water

• Star-shaped cysts on biopsy; rarely seen in CSF • Culture as above

Definition of abbreviations: CSF, cerebrospinal fluid; GAE, granulomatous amaebic encephalitis.

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GENERAL PRINCIPLES │ 5. Microbiology

►►Plasmodium Life Cycle Each Plasmodium has two distinct hosts: • A vertebrate, such as the human (intermediate host), where asexual phase (schizogony) takes place in the liver and red blood cells • An arthropod (definitive) host (Anopheles mosquito), where gametogony (sexual phase) and sporogony take place Disease is caused by a variety of mechanisms, including metabolism of hemoglobin and lysis of infected cells, leading to anemia and to agglutination of the infected RBCs. Paroxysms (chills, fever spike, and malarial rigors) occur when the infected RBCs are lysed, liberating a new crop of merozoites.

Cycle in Mosquito Ruptured oocyst

Migrate to salivary gland

Stomach Lumen

Zygote

Exoerythrocytic

Sporozoites migrate into the bloodstream

Hypnozoites (sleeping forms) P. vivax+ P. ovale Liver reLapse

Sporozoites invade the parenchymal cells of the liver

Penetrates stomach wall and divides

Fertilization

Division to form primary tissue schizont

Liver

Maturation Division ted ges s in itoes e t y toc osqu me m Ga y the b

Blood Some merozoites differentiate into sexual forms

Erythrocytic Schizont Trophozoite

Asexual cycle determines the time between febrile episodes

io Invas

n

ry t of E

te cy hro

Cycle in Humans

Erythrocytic

Definition of abbreviation: RBCs, red blood cells.

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►►Plasmodium Species Disease

Important Features

Blood Smears

Liver Stages

Plasmodium vivax

Benign tertian

48-hour fever spikes

Enlarged host cells; ameboid trophozoites

Persistent hypnozoites Relapse*

Plasmodium ovale

Benign tertian

48-hour fever spikes

Oval, jagged, infected RBCs

Persistent hypnozoites Relapse

Plasmodium malariae

Quartan or malarial

72-hour fever spikes; recrudescence*

Bar and band forms; rosette schizonts

No persistent stage*

Plasmodium falciparum

Malignant tertian

Irregular fever spikes; causes cerebral malaria; most dangerous

Multiple ring forms crescent-shaped gametes

No persistent stage*

GENERAL PRINCIPLES │ 5. Microbiology

Species

Definition of abbreviations: PO, by mouth; RBCs, red blood cells. *Recrudescence is a recurrence of symptoms from low levels of organisms remaining in red cells. Relapse is an exacerbation from liver stages (hypnozoites). †Use quinine sulfate plus pyrimethamine-sulfadoxine.

►►Antimalarial Drugs 1. Suppressive (to avoid infection) 2. Therapeutic (eliminate erythrocytic) 3. Radical cure (eliminate exoerythrocytic) 4. Gametocidal (destruction of gametocytes) Successful treatment is accomplished with chloroquine followed by primaquine. Chloroquine therapy is suppressive, therapeutic, and gametocidal, whereas primaquine eliminates the exoerythrocytic form.

Chloroquine-Sensitive Malaria P. falciparum

Chloroquine

P. malariae

Chloroquine

P. vivax

Chloroquine plus primaquine

P. ovale

Chloroquine plus primaquine

Chloroquine-Resistant Malaria Prophylaxis: mefloquine; backup drugs: doxycycline, atovaquone-proguanil Treatment: quinine ± either doxycycline, clindamycin, or pyrimethamine

►►Adverse Effects of Antimalarial Drugs Drug

Side Effects

Contraindications and Cautions

Chloroquine, hydroxychloroquine

GI distress, pruritus, headache, dizziness, hemolysis, retinopathy

Avoid in psoriasis

Mefloquine

NVD, dizziness, syncope, extrasystoles, CNS effects (rare)

Avoid in seizures, psychiatric disorders, and in cardiac conduction defects

Primaquine

GI distress, headache, dizziness, neutropenia, hemolysis

Avoid in pregnancy, G6PD deficiency, and autoimmune disorders

Quinine

GI distress, cinchonism, CNS effects, hemolysis, hematotoxicity

Avoid in pregnancy

Definition of abbreviations: CNS, central nervous system; GI, gastrointestinal; G6PD, glucose-6-phosphate dehydrogenase; NVD, nausea, vomiting, diarrhea.

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GENERAL PRINCIPLES │ 5. Microbiology

►►Hemoflagellates Trypomastigote

Hemoflagellates (Trypanosomes and Leishmania) infect blood and tissues. They are found in: • Human blood as trypomastigotes with flagellum and an undulating membrane. • Intracellular as amastigotes (oval cells having neither the flagellum nor undulating membrane). Leishmania spp. have only amastigotes in the human.

Vector/Form/ Transmission

Amastigote Flagellar pocket

Nucleus

Species

Disease

Diagnosis

Trypanosoma cruzi*

• Chagas disease (American trypanosomiasis) • Latin America • Swelling around eye (Romaña’s sign): common early sign • Cardiac muscle (dilated cardiomyopathy), megaesophagus, megacolon

Reduviid bug (kissing or cone bug) passes trypomastigote in feces

Blood films, trypomastigotes

Trypanosoma brucei gambiense Trypanosoma b. rhodesiense

• African sleeping sickness (African trypanosomiasis) • Antigenic variation

Trypomastigote in saliva of tsetse fly

• Trypomastigotes in blood films, CSF • High immunoglobulin levels in CSF

Leishmania donovani† complex

• Visceral leishmaniasis • Kala-azar

Sandfly bite

Amastigotes in macrophages in bone marrow, liver, spleen

Leishmania (about 15 different species)

Cutaneous leishmaniasis (Oriental sore, etc.)

Sandfly bite

Amastigotes in macrophages in cutaneous lesions

Leishmania braziliensis complex

Mucocutaneous leishmaniasis

Sandfly bite

Same

Definition of abbreviations: CSF, cerebrospinal fluid. *T. cruzi: An estimated 0.5 million Americans are infected, creating some risk of transfusion transmission in the United States. In babies, acute infections are often serious and involve the CNS. In older children and adults, mild acute infections may become chronic with the risk of development of cardiomyopathy and heart failure. † All Leishmania: intracellular, sandfly vector, stibogluconate

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►►Miscellaneous Apicomplexa Infecting Blood or Tissues Disease/Locale of Origin

Transmission

Diagnosis

Babesia (primarily a disease of cattle) Humans: Babesia microti, WA1 and MO1 strains

Babesiosis (hemolytic, malaria-like) Same range as Lyme: N.E., N. Central, California, and N.W. United States

• Ixodes tick • Coinfections with Borrelia and Ehrlichia

Giemsa stain of blood smear

Toxoplasma gondii

• Most common parasitic disease • Infections after birth are most commonly asymptomatic or mild; may mimic mononucleosis • Produces severe disease in AIDS or other immunocompromised (ring-enhancing lesions in brain) • Primary maternal infection during pregnancy may infect fetus: −  Severe congenital infections (intracerebral calcifications, chorioretinitis, hydro- or microcephaly, seizures) if Toxoplasma crosses the placenta early −  Later term congenital infection may produce progressive blindness

Cat is essential definitive host; many other animals are intermediate hosts

Serology: High IgM or rising IgM acute infection

GENERAL PRINCIPLES │ 5. Microbiology

Species

Mode: • Raw meat in U.S.; pork is #1 • Contact with cat feces

►►Major Protozoal Infections and Drugs of Choice Infection

Drug of Choice

Comments

Amebiasis

Metronidazole

Diloxanide for noninvasive intestinal amebiasis

Giardiasis

Metronidazole or furazolidone



Trichomoniasis

Metronidazole

Treat both partners

Toxoplasmosis

Pyrimethamine and sulfadiazine

TMP-SMX is also prophylactic against Pneumocystis jiroveci in AIDS

Leishmaniasis

Stibogluconate



Trypanosomiasis

• Nifurtimox (Chagas disease) • Arsenicals, pentamidine, suramin (African sleeping sickness)



►►Metazoans: Worms* Phylum

Flatworms (Platyhelminthes)

Roundworms (Nemathelminthes)

Class (common name)

Trematodes (flukes)

Cestodes (tapeworms)

Nematodes† (roundworms)

Genera

Fasciola Fasciolopsis Paragonimus Clonorchis Schistosoma

Diphyllobothrium Hymenolepis Taenia Echinococcus

Necator Enterobius W uchereria/Brugia Ascaris and Ancylostoma Toxocara, Trichuris, and Trichinella W Onchocerca Dracunculus Eyeworm (Loa loa) Strongyloides

*Metazoans also include the Arthropoda, which serve mainly as intermediate hosts (the crustaceans) or as vectors of disease (the Arachnida and Insecta). †Nematodes mnemonic (turn the “W” upside down)

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GENERAL PRINCIPLES │ 5. Microbiology

►►Trematode (Fluke) Diseases Trematodes: • Are commonly called flukes, which are generally flat and fleshy, leaf-shaped worms • Are hermaphroditic, except for Schistosoma, which has separate males and females • Have complicated life cycles occurring in two or more hosts • Have operculated eggs (except for Schistosoma) • The first intermediate hosts are snails

Progression in Humans

Organism

Common Name

Acquisition

Schistosoma mansoni

Intestinal schistosomiasis

Contact with water; skin penetration

Skin penetration (itching) → mature in veins of mesentery → eggs cause granulomas in liver (portal hypertension and liver fibrosis in chronic cases)

Schistosoma haematobium

Vesicular schistosomiasis

Contact with water; skin penetration

Skin penetration (itching) → mature in bladder veins; chronic infection has high association with bladder carcinoma in Egypt and Africa

Nonhuman schistosomes

Swimmer’s itch

Contact with water; skin penetration (Great Lakes)

Penetrate skin, producing dermatitis without further development in humans; itching is most intense at 2 to 3 days



Clonorchis sinensis

Chinese liver fluke

Raw fish ingestion

Inflammation of biliary tract, pigmented gallstones, cholangiocarcinoma

Operculated eggs

Paragonimus westermani

Lung fluke

Raw crabs, crayfish

Hemoptysis, secondary bacterial infection of lung

Operculated eggs

S. japonicum

Important Ova

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►►Gastrointestinal Cestodes (Tapeworms)

Human Host Type

Disease/Organ Involvement/ Symptoms (Sx)

Water, vegetation, food contaminated with eggs Autoinfection

IH

Cysticercosis/eggs → larva develop in brain, eye, heart, lung, etc. Epilepsy with onset after age 20

Biopsy

Rare/raw pork containing the cysticerci ingested by humans

DH

• Intestinal tapeworm • Sx: same as for Taenia saginata

Proglottids or eggs in feces

Drinking pond water containing copepods (crustaceans) carrying the larval forms or frog/snake poultices

IH

Sparganosis/larvae penetrate intestinal wall and encyst

Biopsy

Rare, raw pickled fish containing a sparganum

DH

Intestinal tapeworm (up to 10 meters)/small intestine, megaloblastic anemia

Proglottids or eggs in feces

Ingestion of eggs

IH

Hydatid cyst disease; liver and lung, where cysts containing brood capsules develop

Imaging, serology

Cestode (Common Name)

Form/ Transmission

Taenia solium (pork tapeworm) IH: swine; rare: humans DH: humans,developing and Slavic countries

Diphyllobothrium latum (fish tapeworm) 2 IHs: crustaceans → fish; rare: humans DH: humans/mammals; cool lake regions

Echinococcus granulosus IH: herbivores; rare: humans

Diagnosis

GENERAL PRINCIPLES │ 5. Microbiology

• Consist of three basic portions: the head or scolex; a “neck” section, which produces the proglottids; and the segments or proglottids, which mature as they move away from the scolex • Are diagnosed by finding eggs or proglottids in the feces • Have complex life cycles involving extraintestinal larval forms in intermediate hosts; when humans are intermediate host, these infections are generally more serious than intestinal infections with adult tapeworms

DH: carnivores in sheepraising areas Definition of abbreviations: IH, intermediate host; DH, definitive host.

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GENERAL PRINCIPLES │ 5. Microbiology

►►Roundworms (Nematodes) Roundworms are transmitted by: • Ingestion of eggs (Enterobius, Ascaris, or Trichuris) • Direct invasion of skin by larval forms (Necator, Ancylostoma, or Strongyloides) • Ingestion of meat containing larvae (Trichinella) • Infection involving insects transmitting the larvae with bites (Wuchereria, Loa loa, Mansonella, Onchocerca, and Dracunculus)

►►Roundworms (Nematodes) Transmitted By Eggs Disease/Organs Most Affected

Form/Transmission

Pinworms, large intestine, perianal itching

• Eggs/person to person • Autoinfection

• Scotch tape swab of perianal area • Ova have flattened side with larvae inside

Trichuris trichiura

Whipworm cecum, appendicitis, and rectal prolapse

Eggs ingested

Barrel-shaped eggs with bipolar plugs in stools

Ascaris lumbricoides

Ascariasis Ingest egg → larvae migrate through lungs (cough) and mature in small intestine; may obstruct intestine or bile duct

Eggs ingested

Bile stained, knobby eggs

Species Enterobius vermicularis

Diagnosis

(Most frequent helminth parasite in U.S.)

(Most common helminth worldwide; largest roundworm)

Adult 35 to 40 cm Toxocara canis or cati (Dog/cat ascarids)

Visceral larva migrans Larvae wander aimlessly until they die, cause inflammation

Eggs ingested/from handling puppies or from eating dirt in yard (pica)

Clinical findings and serology

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►►Roundworms (Nematodes) Transmitted by Larvae Disease/Organs

Form/Transmission

Diagnosis

Necator americanus (New World hookworm)

Hookworm infection Lung migration → pneumonitis Bloodsucking → anemia

Filariform larva penetrates intact skin of bare feet

Fecal larvae (up to 13 mm) and ova: oval, transparent with 2–8 cell-stage visible inside Fecal occult blood may be present

Ancylostoma braziliense Ancylostoma caninum (dog and cat hookworms)

Cutaneous larva migrans/ intense skin itching, snake-like tracks

Filariform larva penetrates intact skin but cannot mature in humans

Usually a presumptive diagnosis; exposure

Strongyloides stercoralis

Threadworm strongyloidiasis: Early: pneumonitis, abdominal pain, diarrhea Later: malabsorption, ulcers, bloody stools

Filariform larva penetrates intact skin; autoinfection leads to indefinite infections unless treated

Larvae in stool, serology

Trichinella spiralis

Trichinosis: larvae encyst in muscle → pain

Viable encysted larvae in meat are consumed: wildgame meat

Muscle biopsy; clinical findings: fever, myalgia, splinter hemorrhages, eosinophilia

Species

Disease

Transmission/Vector

Diagnosis

Wuchereria bancrofti; Brugia malayi

Elephantiasis

Mosquito

Microfilariae in blood, eosinophilia

Loa loa (African eye worm)

Pruritus, calabar swellings

Chrysops, mango flies

Microfilariae in blood, eosinophilia

Onchocerca volvulus

River blindness, itchy “leopard” rash

Blackflies

Skin snips from calabar swellings

Dracunculus medinensis (Guinea worm, fiery serpent)

Creeping eruptions, ulcerations, rash

Drinking water with infected copepods

Increased IgE; worm eruption from skin

GENERAL PRINCIPLES │ 5. Microbiology

Species

►►Filarial Nematodes

►►Drugs for Helminthic Infections Most intestinal nematodes (worms)

• Mebendazole (↓ glucose uptake and ↓ microtubular structure) • Pyrantel pamoate (NM agonist → spastic paralysis)

Most cestodes (tapeworms) and trematodes (flukes)

• Praziquantel (↑ Ca2+ influx, ↑ vacuolization)

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GENERAL PRINCIPLES │ 5. Microbiology

Virology ►►Viral Structure and Morphology The Basic Virion

Viral Structure Helical

Icosahedral

DNA or RNA + Structural proteins = Nucleocapsid (naked capsid virus)

Naked capsid virus (No naked helical viruses)

Nucleocapsid

Nucleocapsid + Host membrane with viral specified glycoproteins* = Enveloped virus

Enveloped icosahedral capsid virus

*critical for infectiousness of viral progeny

Enveloped helical virus

Lipid bilayer

Glycoprotein

►►DNA Viruses General Comments About DNA Viruses: • All are double-stranded except Parvo • All are icosahedral except Pox, which are brick-shaped complex • All replicate in the nucleus except Pox

Virus Family

DNA Type

Polymerase

Envelope

Area of Replication

Major Viruses

Parvovirus

ssDNA

No

Naked

Nucleus

B19

Papilloma

dsDNA Circular

No

Naked

Nucleus

Papilloma

Polyomavirus

dsDNA Circular

No

Naked

Nucleus

Polyoma

Adenovirus

dsDNA Linear

No

Naked

Nucleus

Adenovirus

Hepadnavirus

Partially dsDNA Circular

Yes

Enveloped

Nucleus via RNA intermediate

HBV

Herpesvirus

dsDNA Linear

No

Enveloped Nuclear

Nucleus, assembled in nucleus

HSV, VZV, EBV, CMV HHV-6, HHV-8

Poxvirus

dsDNA Linear

Yes

Enveloped

Cytoplasm

Variola, vaccinia Molluscum contagiosum

Definition of abbreviations: CMV, cytomegalovirus; ds, double-stranded; EBV, Epstein-Barr virus; HBV, hepatitis B virus; HSV, herpes simplex virus; ss, single-stranded; VZV, varicella-zoster virus. Note: Viruses are listed from top to bottom in order of increasing size. If you know them in this order, then you can remember that the smallest 4 are naked (wearing more clothing makes you larger). Mnemonic: Pardon PaPa As He Has Pox Mnemonic: Naked viruses PAPP (you need to be naked for a Pap smear)

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►►RNA Viruses GENERAL PRINCIPLES │ 5. Microbiology

General Comments About RNA Viruses: • All are single-stranded except Reo • Most are enveloped. Only naked ones are Hepe, Calici, Pico, and Reo (Mnemonic: Help! CPR!) • Some are segmented; Mnemonic: ROBA: Reo, Orthomyxo, Bunya, and Arena – ROBA sounds like ROBOT • Positive sense RNA = (+)RNA (can be used itself as mRNA) • Negative sense RNA = (–)RNA – Complementary to mRNA – Cannot be used as mRNA – Requires virion-associated, RNA-dependent RNA polymerase (as part of mature virus) • Others that carry a polymerase are Reo, Arena, and Retro

►►Double-Stranded RNA Viruses: Reoviridae Reovirus

RNA Structure

Polymerase

Envelope

Shape

Major viruses

• Linear dsRNA • 10−11 segments

Yes

Naked

• Icosahedral • Double shelled

• Reovirus • Rotavirus

►►Positive-Sense RNA Viruses Family

RNA Structure

Polymerase

Envelope

Shape

Area of Replication

Calicivirus

• ss⊕RNA, linear • Nonsegmented

No

Naked

Icosahedral

Cytoplasm

• Norwalk • Norolike

Hepevirus

• ss⊕RNA, linear • Nonsegmented

No

Naked

Icosahedral

Cytoplasm

Hepatitis E

Picornavirus

• ss⊕RNA, linear • Nonsegmented

No

Naked

Icosahedral

Cytoplasm

• Polio, ECHO, Entero • Rhino, coxsackie • Hepatitis A

Flavivirus

• ss⊕RNA, linear • Nonsegmented

No

Enveloped

Icosahedral

Cytoplasm

Yellow fever, dengue, SLE, hepatitis C, West Nile virus

Togavirus

• ss⊕RNA, linear • Nonsegmented

No

Enveloped

Icosahedral

Cytoplasm

Rubella WEE, EEE, VEE

Coronavirus

• ss⊕RNA, linear • Nonsegmented

No

Enveloped

Helical

Cytoplasm

Coronaviruses SARS agent

Retrovirus

• Diploid • ss⊕RNA, linear • Nonsegmented

RNAdependent DNA polymerase

Enveloped

Icosahedral or truncated conical

Nucleus

HIV HTLV Sarcoma

Major Viruses

Definition of abbreviations: EEE, eastern equine encephalitis; HIV, human immunodeficiency virus; HTLV, human T-cell lymphocytotropic virus; VEE, Venezuelan equine encephalitis; WEE, Western equine encephalitis. Mnemonic: Again from smallest (top) to largest (bottom): Call Henry, Pico, and Flo To Come Rightaway Mnemonic: Picornaviruses: PEE Co Rn A viruses (Polio, Entero, Echo, Coxsackie, Rhino, Hep A)

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GENERAL PRINCIPLES │ 5. Microbiology

►►Negative-Sense RNA Viruses Virus

RNA

Polymerase

Envelope

Shape

Area Where Multiplies

Paramyxovirus

• ss – RNA, linear • Nonsegmented

Yes

Yes

Helical

Cytoplasm

Mumps, measles RSV, parainfluenza

Rhabdovirus

• ss – RNA, linear • Nonsegmented

Yes

Yes

Bulletshaped, helical

Cytoplasm

Rabies, VSV

Filovirus

• ss – RNA, linear • Nonsegmented

Yes

Yes

Helical

Cytoplasm

Marburg, Ebola

Orthomyxovirus

• ss – RNA, linear • 8 segments

Yes

Yes

Helical

Cytoplasm and nucleus

Influenza

Bunyavirus

• ss – RNA, linear to circular • 3 segments, ambisense

Yes

Yes

Helical

Cytoplasm

California and LaCrosse encephalitis, Hantavirus

Arenavirus

• ss – RNA, circular, • 2 segments: 1 – sense, 1 ambisense

Yes

Yes

Helical

Cytoplasm

Lymphocytic choriomeningitis virus, Lassa fever

Major Viruses

Definition of abbreviations: ds, double-stranded; RSV, respiratory syncytial virus; ss, single-stranded; VSV, vesicular stomatitis virus. Mnemonic (in order of increasing size): Pain Results From Our Bunions Always (Pain is a negative thing!) Or, to remind you of life-cycle: Bring A Polymerase Or Fail Replication

►►Viral Genetics Phenotypic mixing

• Related viruses coinfect cell (virus A and virus B) • Resulting proteins on the surface are a mixture capsid of AB around nucleic acid of either A or B

Phenotypic masking

• Related viruses coinfect cell (virus A and virus B) • Capsid of proteins of virus A form around nucleic acid of B

Complementation

• Two related defective viruses infect the same cell; if they are defective in different genes, viral progeny (still with mutated DNA) will be formed • If they are defective in the same gene, no progeny will be formed • Coinfection of hepatitis B and D is a clinical example of complementation where HBV supplies the needed surface antigen for hepatitis D

Genetic reassortment (genetic shift)

• Two different strains of a segmented RNA virus infect the same cell. • Major new genetic combinations are produced through “shuffling,” resulting in stable and dramatic changes • This results in pandemics of disease

Genetic drift

• Minor antigenic changes from mutation • Occurs in many viruses, particularly RNA types • Most noted in HIV and influenza

Viral vectors

• Recombinant viruses are produced that have combinations of human replacement genes with the defective viral nucleic acid

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►►Antiviral Agents

Class/Agent

Mechanism of Action

Spectrum/Clinical Applications

Mechanism(s) of Resistance

Toxicity/Notes

ANTIHERPETICS Acyclovir Famciclovir Valacyclovir

Inhibit viral DNA polymerases Activated by viral thymidine kinase (TK); • Famciclovir is oral prodrug converted to penciclovir • Valacyclovir is oral prodrug of acyclovir • Mechanism of penciclovir same as acyclovir

HSV, VZV (esp. famciclovir, valacyclovir)

Decreased activity or loss of thymidine kinase/DNA polymerase

• F  airly well-tolerated (esp. oral), some nausea/vomiting • IV use associated with seizure, delirium, crystalluria (maintain hydration) • Famciclovir and valacyclovir have much greater oral bioavailability and longer t 1/2 than acyclovir

Ganciclovir

Similar to acyclovir

CMV (e.g., CMV retinitis), HSV, VZV

Similar to acyclovir

Dose-limiting leukopenia, thrombocytopenia; crystalluria (maintain hydration)

Foscarnet

Inhibits DNA and RNA polymerases; does not require activation by kinases (may be effective in acyclovir-, ganciclovir-resistant strains)

• C  MV retinitis in AIDS patients • Acyclovir-resistant mucocutaneous HSV in immuno­ compromised patients

Block viral penetration/ uncoating of influenza A virus via interaction with viral M2 protein

• Influenza A (prophylaxis) • Amantadine also used in Parkinson disease to stimulate dopamine release

Oseltamivir Zanamivir

Inhibit neuraminidases made by influenza A and B (enzymes that promote virion release and prevent clumping of these virions), decreasing viral spread

Prophylaxis, but may ↓ duration of flu symptoms by 2-3 days

Ribavirin

Inhibits viral RNA synthesis by altering the nucleotide pools and normal messenger RNA formation

Influenza A & B, Parainfluenza, RSV, paramyxoviruses HCV (combined with α−interferon), HIV

ANTI-INFLUENZA DRUGS Amantadine Rimantadine

GENERAL PRINCIPLES │ 5. Microbiology

As viruses rely on host machinery to produce viral products, selectivity must be achieved by targeting minute differences in viral enzymes. This may be accomplished at any stage in the viral “life cycle” including adsorption, penetration, nucleic acid synthesis, late protein synthesis, protein processing, viral product packaging, and viral release.

• D  ose limiting nephrotoxicity • Electrolyte imbalance (can lead to seizures)

Current isolates are resistant Resistance due to mutations in M2 protein (no cross resistance to neuraminidase inhibitors) Mutations to viral neuraminidase

Unknown

• A  taxia • Increased seizure activity • Dizziness & hypotension • Rimantadine better tolerated in elderly Oseltamivir: oral prodrug; GI discomfort Zanamivir: inhalational drug; cough, bronchospasm in asthmatics Dose-dependent hemolytic anemia

(Continued)

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GENERAL PRINCIPLES │ 5. Microbiology

►►Antiviral Agents (Cont’d.) Class/Agent

Mechanism of Action

Spectrum/Clinical Applications

Mechanism(s) of Resistance

Toxicity/Notes

HIV THERAPY: For details on HIV therapy, see Ch. 4, General Principles of Immunology

Interferons✝

Interferons are a class of related proteins with antiviral, antiproliferative, and immune regulating activity. They induce the synthesis of a number of antiviral proteins (e.g., RNAse and a protein kinase) that protect the cell against subsequent challenges by a variety of viruses.

• • • •

 epatitis B & C H  aposi sarcoma K  eukemias L Malignant

Anti-interferon antibodies are seen with prolonged use

melanoma

• Interferons can cause influenza-like symptoms, especially in the first week of therapy • Bone marrow suppression • Profound fatigue, myalgia, weight loss, and increased susceptibility to bacterial infections • Depression is seen in up to 20% of patients

Definition of abbreviations: CMV, cytomegalovirus; HCV, hepatitis C virus; HSV, herpes simplex virus; RSV, respiratory syncytial virus; VZV, varicella zoster virus. ✝ For more information on interferons and other immunosuppressants, see Chapter 4, General Principles of Immunology

Mycology ►►Mycology: Overview Fungi are eukaryotic organisms with complex carbohydrate cell walls (the reason they frequently calcify in chronic infections) and ergosterol as their major membrane sterol (which is targeted with nystatin and the imidazoles). Morphologic and geographic clues are very important in determining the identity of the organism. Fungi come in two basic forms

• Hyphaefilamentous forms may either have cross walls (septate) or lack them (aseptate) • Yeastssingle-celled oval/round forms • Dimorphic fungimay convert from hyphal to yeast forms (key examples: Histoplasma, Blastomyces, Coccidioides, and Sporothrix). Mnemonic: Heat Changes Body Shape: yeast in the heat, mold in the cold

Pseudohyphae

• Hyphae formed by budding off yeasts; formed by Candida albicans; the basis of the germ tube test for diagnosis of invasive C. albicans

Spores are used for reproduction and dissemination

• • • •

Conidiaasexual spores form off hyphae Blastoconidiaasexual spores like buds on yeasts Arthroconidiaasexual spores formed with joints between Spherules with endosporessexual spores in tissues (Coccidioides)

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►►Nonsystemic Fungal Infections Disease

Notes

Malassezia furfur

Pityriasis or tinea versicolor

• Superficial infection of keratinized cells • Hypopigmented spots on the chest/back (blotchy suntan) • KOH mount of skin scales: “spaghetti and meatballs,” yeast clusters and short, curved septate hyphae • Treatment is topical selenium sulfide; recurs.

Fungemia

• In premature infants

Cutaneous or mucocutaneous candidiasis

• Causes oral thrush and vulvovaginitis in immunocompetent individuals • Source of opportunistic infections in hospitalized and immunocompromised (see Opportunistic Mycoses)

Candida albicans, Candida spp.

Pseudohyphae

Budding Yeasts

Germ Tubes

True Hyphae

Trichophyton, Microsporum, Epidermophyton

Tinea (capitis, barbae, corporis, cruris, pedis)

• • • •

Sporothrix schenckii

• Sporotrichosis (rose gardener’s disease)

Dimorphic fungus: • Environmental form: hyphae with rosettes and sleeves of conidia • Tissue form: cigar-shaped yeast

Hyphae with sleeves

GENERAL PRINCIPLES │ 5. Microbiology

Organism

Infects skin, hair, and nails Monomorphic filamentous fungi KOH mount shows arthroconidia, hyphae Pruritic lesions with serpiginous borders and central clearing

• Pulmonary sporotrichosis (in alcoholics/ homeless)

or rosettes of conidia

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GENERAL PRINCIPLES │ 5. Microbiology

►►Systemic Fungal Infections Organism

Disease

Notes General Comments

Histoplasma Coccidioides Blastomyces

• Acute pulmonary (asymptomatic or selfresolving in about 95% of the cases) • Chronic pulmonary • Disseminated infections

Diagnosis: • Sputum cytology (calcofluor white staining helpful) • Sputum cultures on blood agar and special fungal media (inhibitory mold agar, Sabouraud’s agar) • Peripheral blood cultures are useful for Histoplasma because it circulates in RES cells

Specific Organisms Histoplasma capsulatum

Fungus flu (a pneumonia) • Asymptomatic or flu-like • Hepatosplenomegaly may be present • May disseminate in AIDS patient

Dimorphic fungus: • Environmental form: hyphae with microconidia and tuberculate macroconidia − Endemic region: Eastern Great Lakes, Ohio, Mississippi, and Missouri River beds − Found in soil (dust) enriched with bird or bat feces (caves, chicken coops) • Tissue form: small intracellular yeasts with narrow neck on bud; no capsule • Facultative intracellular parasite found in RES cells (tiny; can get 30 or so in a human cell)

Coccidioides immitis

Coccidioidomycosis (San Joaquin Valley fever)

• Dimorphic fungus • Asymptomatic to self-resolving pneumonia • Desert bumps (erythema nodosum) • Pulmonary lesions may calcify • May disseminate in AIDS and immunocompromised (meningitis, mucocutaneous lesions) • Has a tendency to disseminate in third trimester of pregnancy

(endospores/spherules)

(arthroconidia) Blastomyces dermatitidis

Blastomycosis

• • • • •

Dimorphic fungus Environmental form: hyphae with conidia Tissue form: broad-based budding yeast Pulmonary disease Disseminated disease

Definition of abbreviations: RES, reticuloendothelial.

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►►Opportunistic Fungi • Allergic bronchopulmonary aspergillosis/asthma, cystic fibrosis • Fungus ball: free in preformed lung cavities • Invasive aspergillosis/severe neutropenia, CGD, CF, burns − Invades tissues, causing infarcts and hemorrhage

• Dichotomously branching

GENERAL PRINCIPLES │ 5. Microbiology

Aspergillus fumigatus

• Generally acute angles • Septate • Compost pits, moldy marijuana • May cause disease in immunocompromised patients

Treatment: itraconazole, amphotericin B; depends on severity of infection

− Nasal colonization →pneumonia or meningitis −  Cellulitis/in burn patients; may also disseminate Candida albicans (and other spp. of Candida)

• Involvement of the oral cavity and digestive tract • Septicemia, endocarditis in IV drug abusers • Mucocutaneous candidiasis

Diagnosis: • KOH: pseudohyphae, true hyphae, budding yeasts • Septicemia: culture lab identification: biochemical tests/formation of germ tubes Treatment: • Topical imidazoles or oral imidazoles; nystatin • Disseminated: amphotericin B or fluconazole

Cryptococcus neoformans

• Meningitis/Hodgkin, AIDS (the dominant meningitis) • Acute pulmonary (usually asymptomatic)/pigeon breeders

• • •

Encapsulated yeast (monomorphic) Environmental source: Soil enriched with pigeon droppings Diagnosis of meningitis: CSF − Detect capsular antigen in CSF (by latex particle agglutination or counter immunoelectrophoresis) − India ink mount (misses 50%) of CSF sediment to find budding yeasts with capsular “halos” − Cultures (urease ⊕ yeast) • Treatment: amphotericin B plus flucytosine until afebrile and culture – , then fluconazole

Mucor, Rhizopus, Absidia (Zygomycophyta family)

Rhinocerebral infection (mucormycosis) caused by Mucor (or other Zygomycophyta)

• Nonseptate, filamentous fungi • Characterized by paranasal swelling, necrotic tissues, hemorrhagic exudates from nose and eyes, mental lethargy • Occurs in ketoacidotic diabetic patients and leukemic patients • These fungi penetrate without respect to anatomic barriers, progressing rapidly from sinuses into brain tissue • Diagnosis: KOH of tissue; broad, ribbon-like nonseptate hyphae with about 90° angles on branches • Treatment: débride necrotic tissue and start amphotericin B fast; high fatality rate because of rapid growth and invasion

Pneumocystis jiroveci (formerly carinii)

Pneumonia in AIDS patients, malnourished babies, premature neonates, other immunocompromised

• An exudate with foamy or honeycomb appearance on H & E stain • Patchy infiltrative (ground-glass appearance) on x-ray • Diagnosis: silver-staining cysts in bronchial alveolar lavage fluids or biopsy • Treatment: trimethoprim/sulfamethoxazole, pentamidine

Definition of abbreviations: CF, cystic fibrosis; CSF, cerebrospinal fluid; CGD, chronic granulomatous disease; KOH, potassium hydroxide.

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GENERAL PRINCIPLES │ 5. Microbiology

►►Antifungal Agents Because fungi are eukaryotic, finding selectively toxic antifungal agents is difficult. Consequently, treating fungal infections poses a clinical challenge, especially in immunocompromised patients. Fungal cell membranes contain ergosterol, a sterol not found in mammalian tissue. Thus, this difference provides the basis for most systemically administered antifungal agents. Class/Agent

Mechanism of Action

Spectrum/Clinical Use

Mechanism(s) of Resistance

Toxicity/Notes

Agents for Systemic Infections Amphotericin B

Binds ergosterol, causing formation of artificial pores, thus altering membrane permeability, killing the cell

Widest antifungal spectrum: Aspergillus Coccidioides Blastomyces Candida albicans Cryptococcus Histoplasma Mucor Sporothrix schenckii

Very uncommon; ↓ or structurally altered ergosterol

• Fever and chills (“cytokine storm”) • Nephrotoxicity limits dosing (cumulative over lifetime) • Reversible anemia (secondary to ↓ erythropoietin) • Arrhythmias • IV only

Flucytosine

Permease allows entry, deaminated to 5-FU, then converted to 5-FdUMP (thymidylate synthase inhibitor)

Narrow spectrum: Cryptococcus C  andida albicans (systemic)

Rapid if used as a single agent; ↓ activity of fungal permeases and deaminases

• Reversible bone marrow suppression • Alopecia • Typically combined with amphotericin B or fluconazole

Azoles: fluconazole, itraconazole, voriconazole, ketoconazole

Inhibit synthesis of ergosterol, leading to altered membrane permeability

Varies: Candida Coccidioides Cryptococcus Aspergillus Histoplasma

↓ sensitivity of target enzymes

• • • • •

Echinocandin/ caspofungin

Inhibits synthesis of β-1,2 glycan, a component of fungal cell walls

Candida Aspergillus



• Not very toxic • Headache • Infusion-related reactions

Vomiting and diarrhea Skin rash Hepatotoxicity (rare) Gynecomastia ↓ P450

Systemic Agents for Superficial Infections Griseofulvin

• Uptake by energydependent transport • Interferes with microtubule formation in dermatophytes • May inhibit polymerization of nucleic acids

• Dermatophytes of the hair and scalp • Accumulates in keratin

Terbinafine

Inhibits squalene epoxidase (for sterol biosynthesis)

Accumulates in keratin, used in onychomycosis

Azoles (see above)







Topical Nystatin

Disrupts membrane by binding ergosterol

↓ in transport/uptake

• • • • • • •

Confusion and vertigo Headache Blurred vision Nausea/vomiting ↑ P450 GI irritation Disulfiram-like reaction with ethanol

• • • •

GI irritation Rash Headache Taste disturbance



Antifungals ✝

Candida, especially in oral candidiasis (thrush)

Same as amphotericin B

• Contact dermatitis • Stevens-Johnson syndrome

✝ Topical azoles, such as miconazole and clotrimazole are also widely used.

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Embryology Chapter 6 General Principles of Embyrology Early Embryology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142–144 Germ-Layer Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144 Placenta . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145 Twinning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145 Teratogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146

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GENERAL PRINCIPLES │ 6. Embryology

General Principles of Embryology ►►Early Embryology Week 1

sis

ito

:m

ge ava

Fertilization occurs in the ampulla of the uterine tube when the male and female pronuclei fuse to form a zygote. At fertilization, the secondary oocyte rapidly completes meiosis II.

Cle

Day 2 2-cell Blastula

Day 3 4-cell Blastula

Embryoblast (Embryo) Day 4

Trophoblast (Placenta)

Morula Day 5 (46, 2N) Zygote

Blastocyst

Day 1

Day 6 (Implantation begins)

Fertilization

Ovary Zona pellcida

Corona radiata cells Secondary oocyte arrested in metaphase of meiosis II

Cytotrophoblast Ampulla of oviduct

Blastocyst cavity Embryoblast Syncytiotrophoblast

During the first 4 to 5 days of the first week, the zygote undergoes rapid mitotic division (cleavage) in the oviduct to form a blastula, consisting of increasingly smaller blastomeres. This becomes the morula (32-cell stage). A blastocyst forms as fluid develops in the morula. The blastocyst consists of an inner cell mass known as the embryoblast, and the outer cell mass known as the trophoblast becomes the placenta. At the end of the first week, the trophoblast differentiates into the cytotrophoblast and syncytiotrophoblast and then implantation begins. Implantation usually occurs in the posterior superior wall of the uterus.

Figure II-2-1. Week 1

Clinical Correlation: Ectopic Pregnancy

Tubal

The most common form of ectopic pregnancy Usually occurs when the blastocyst implants within the ampulla of the uterine tube because of delayed transport Risk factors: endometriosis, pelvic inflammatory disease (PID), tubular pelvic surgery, or exposure to diethylstilbestrol (DES) Clinical signs: abnormal or brisk uterine bleeding, sudden onset of abdominal pain that may be confused with appendicitis, missed menstrual period (e.g., LMP 60 days ago), positive human chorionic gonadotropin (hCG) test, culdocentesis showing intraperitoneal blood, positive sonogram

Abdominal

Most commonly occurs in the rectouterine pouch (pouch of Douglas) (Continued)

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►►Early Embryology (Cont’d.) Week 2

Epiblast

Bilaminar disk

Lacuna spaces

The embryoblast differentiates into the epiblast and hypoblast, forming a bilaminar embryonic disk. The epiblast forms the amniotic cavity, and hypoblast cells migrate from the primary yolk sac.

Endometrial blood vessel

Endometrial gland

Syncytiotrophoblast • Implantation • hCG

Prechordal plate

Connecting stalk

Chorionic cavity Yolk sac Amniotic cavity

Primary villi

The prechordal plate, formed from fusion of epiblast and hypoblast cells, is the site of the future mouth. Extraembryonic mesoderm is derived from the epiblast. Extraembryonic somatic mesoderm lines the cytotrophoblast, forms the connecting stalk, and covers the amnion. Extraembryonic visceral mesoderm covers the yolk sac.

GENERAL PRINCIPLES │ 6. Embryology

Hypoblast

The connecting stalk suspends the conceptus within the chorionic cavity. The wall of the chorionic cavity is called the chorion, consisting of extraembryonic somatic mesoderm, the cytotrophoblast, and the syncytiotrophoblast.

Chorion Extraembryonic mesoderm Cytotrophoblast • Primary villi

Clinical Correlation

Figure II-3-1. Week 2

Human chorionic gonadotropin (hCG) is a glycoprotein produced by the syncytiotrophoblast. It stimulates progesterone production by the corpus luteum. hCG can be assayed in maternal blood or urine and is the basis for early pregnancy testing. hCG is detectable throughout pregnancy. Low hCG levels may predict a spontaneous abortion or ectopic pregnancy. High hCG levels may predict a multiple pregnancy, hydatidiform mole, or gestational trophoblastic disease. (Continued)

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►►Early Embryology (Cont’d.) GENERAL PRINCIPLES │ 6. Embryology

Weeks 3 Through 8

A

Third week: gastrulation and early development of nervous and cardiovascular systems; corresponds to first missed period

Cranial Prechordal plate

Gastrulationa process that produces the three primary germ layers: ectoderm, mesoderm, and endoderm; begins with the formation of the primitive streak within the epiblast

Primitive node Primitive pit

B

Primitive streak

Cranial

Primitive node & streak Epiblast (Ectoderm)

Cloacal membrane

Amnion Caudal

Notochord Yolk sac

Ectoderm → neuroectoderm and neural crest cells Mesoderm → paraxial mesoderm (35 pairs of somites), intermediate mesoderm, and lateral mesoderm All major organ systems begin to develop during the embryonic period (Weeks 3–8). By the end of this period, the embryo begins to look human.

Hypoblast Mesoderm Endoderm

Figure II-4-1. Week 3

Clinical Correlation

Sacrococcygeal teratoma: a tumor that arises from remnants of the primitive streak; often contains various types of tissue (bone, nerve, hair, etc.). Chordoma: a tumor that arises from remnants of the notochord, found either intracranially or in the sacral region Caudal dysplasia (sirenomelia): a constellation of syndromes ranging from minor lesions of the lower vertebrae to complete fusion of lower limbs. Occurs as a result of abnormal gastrulation, in which migration of mesoderm is disturbed. Associated with VATER (vertebral defects, anal atresia, tracheoesophageal fistula, and renal defects) or VACTERL (vertebral defects, anal atresia, cardiovascular defects, tracheoesophageal fistula, renal defects, and upper limb defects) Hydatidiform mole: results from the partial or complete replacement of the trophoblast by dilated villi • In a complete mole, there is no embryo; a haploid sperm fertilizes a blighted ovum and reduplicates so that the karyotype is 46,XX, with all chromosomes of paternal origin. In a partial mole, there is a haploid set of maternal chromosomes and usually two sets of paternal chromosomes so that the typical karyotype is 69,XXY. • Molar pregnancies have high levels of hCG, and 20% develop into a malignant trophoblastic disease, including choriocarcinoma.

►►Germ-Layer Derivatives Ectoderm Surface ectoderm

Epidermis, hair, nails, inner and external ear, tooth enamel, lens of eye, anterior pituitary (from Rathke pouch), major salivary, sweat, and mammary glands; epithelial lining of nasal and oral cavities and ear

Neuroectoderm

CNS (brain and spinal cord), retina and optic nerve, pineal gland, neurohypophysis, astrocytes, oligodendrocytes, ependymal cells

Neural crest

Adrenal medulla, ganglia (sensory, autonomic), melanocytes, Schwann cells, meninges (pia, arachnoid), pharyngeal arch cartilage, bones of the skull, odontoblasts, parafollicular (C) cells, laryngeal cartilage, aorticopulmonary septum, endocardial cushions (abnormal development can lead to many congenital defects)

Mesoderm

Muscle (smooth, cardiac, skeletal), connective tissue, serous membranes, bone and cartilage, blood and blood vessels, lymphatics, cardiovascular organs, adrenal cortex, gonads and internal reproductive organs, spleen, kidney and ureter, dura mater

Endoderm

Epithelial parts: GI tract, tonsils, thymus, pharynx, larynx, trachea, bronchi, lungs, urinary bladder, urethra, tympanic cavity, auditory tube and other pharyngeal pouches Parenchyma: liver, pancreas, tonsils, thyroid, parathyroids, glands of GI tract, submandibular and sublingual glands

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►►Placenta GENERAL PRINCIPLES │ 6. Embryology

The placenta permits exchange of nutrients and waste products between maternal and fetal circulations.

Umbilical arteries (2) Umbilical vein (1)

Maternal blood

Syncytiotrophoblast Chorionic plate

Fetal

Villus

Maternal

Decidua basalis

Myometrium Perimetrium Uterine vein Uterine artery

Fetal component

Chorionic plate and villi Syncytiotrophoblast: outer layer of chorionic villi; secretes hCG Cytotrophoblast: inner layer of chorionic villi

Maternal component

Decidua basalis: Maternal blood vessels from the decidua conduct blood into the intervillous spaces of the placenta, where floating villi are present

Placental barrier

The syncytiotrophoblast, cytotrophoblast, basement membrane, fetal capillary endothelium separate the maternal and fetal blood

Umbilical cord

1 umbilical vein supplies oxygenated blood from the placenta to the fetus 2 umbilical arteries carries deoxygenated blood back from the fetus to the placenta Urachus: Removes nitrogenous waste from the fetal bladder

►►Twinning The type of twinning depends on the point in time in which cleavage occurs. If the twinning occurs very early on (before the chorion forms), two separate chorions will form (dichorionic). All other possible types of twins are monochorionic because the chorion has already formed. Fraternal twins are dizygotic and identical twins are monozygotic. Placental morphology

Time of cleavage

Type of twin

Dichorionic diamniotic

Very early (Days 1–3)

Fraternal or identical

Monochorionic diamniotic

Early (Days 4–8)

Identical

Monochorionic monoamniotic

Later (Days 8–13): identical Even later (Days 13–15): conjoined

Identical, conjoined

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►►Teratogens GENERAL PRINCIPLES │ 6. Embryology

ACE inhibitors; ARBS Aminoglycosides Androgens Anticonvulsants

Folate antagonists Lithium Radiation Tetracyclines

Renal damage CN VIII toxicity Masculinization of female fetus Neural tube defects (carbamazepine, valproic acid), phenytoin (fetal hydantoin syndrome); multiple congenital defects Congenital goiter, hypothyroidism Vaginal clear cell adenocarcinoma; vaginal adenosis Fetal alcohol syndrome (e.g., growth retardation, facial abnormalities, microcephaly, cardiac defects) Multiple congenital anomalies Ebstein anomaly Multiple abnormalities Discoloration of teeth

Thalidomide Warfarin Vitamin A excess; vitamin A derivatives

Phocomelia (limb reduction defects) Bone and cartilage abnormalities, hemorrhage, etc. Multiple abnormalities, e.g., cleft palate, cardiac abnormalities, mental retardation

Antithyroid drugs Diethylstilbestrol (DES) Ethanol

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Physiology Chapter 7 Physiologic Terminology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Transport . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diffusion Kinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fluid Volume Compartments and Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary of Volume and Osmolarity Changes of Body Fluids . . . . . . . . . . . . . . Membrane Potentials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Action Potential . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

148 148 149 149 150 151 152

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GENERAL PRINCIPLES │ 7. Physiology

►►Physiologic Terminology Equilibrium

Equilibrium occurs when the balance of opposing forces has reached the lowest free energy state, and as a result, a given variable has reached a constant value.

Steady state

Steady state is a condition in which a variable is maintained within narrow limits by regulating an opposing activity. This process requires energy.

Negative feedback

This is a common system that acts to oppose changes in the internal environment. Negative feedback systems promote stability and act to restore steady-state function after a perturbation.

Positive feedback

This is a less common system (also called a vicious cycle) that acts to magnify a change in the internal environment; the initial change in a system is increased as a result of feedback activity. In a viable organism, any positive feedback system is ultimately overridden by one or more negative feedback systems.

Negative Feedback Example

Positive Feedback Example

Follicular Phase

Pre-ovulatory Phase

Gonadotropin-releasing hormone

Gonadotropin-releasing hormone

Luteinizing hormone

Luteinizing hormone

Estradiol

Estradiol

The figures above show the negative feedback relationship between estrogens and the gonadotropins that dominates during the follicular phase, which transforms into a positive feedback relationship, producing the LH surge prior to ovulation. Solid arrows show direct relationships (stimulation) and dashed arrows show inverse relationships (inhibition).

►►Transport Type of Transport

Energy Source

Example

Other Characteristics

Clinical Correlation

Simple diffusion

Passive

Pulmonary gases



Pulmonary edema decreases diffusion

Carrier-mediated or facilitated diffusion

Passive

Glucose uptake by muscle

• Insulin controls carrier population • Chemical specificity

Insulin-dependent glucose uptake impaired in diabetes mellitus

Primary active transport

Direct use of ATP

Na+/K+-ATPase

Antiport (countertransport)

Inhibition by cardiac glycosides

Ca2+-ATPase

Regulates cellular Ca2+

Deficiency causes neuromuscular disorders

Na+-glucose in kidney

Symport (cotransport)

Osmotic diuresis results when transporters saturated

Na+-H+ exchange

Antiport (countertransport)

Renal tubular acidosis

Secondary active transport

Electrochemical gradient for sodium is most common driving force

Key Points • Passive processes are directly related to concentration gradients. • Active processes create or increase a concentration gradient and thus depend upon metabolic energy. • Both carrier-mediated facilitated diffusion and active transport can be saturated; maximum transport rate depends on population and activity of transport molecules. • Primary active transport proteins have an ATPase as part of their structure. • Most secondary active transport depends upon the electrochemical gradient of sodium ions, which in turn depends on the activity of the primary active transporter, sodium-potassium ATPase.

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►►Diffusion Kinetics

Influx

Si m

pl e

Concentration

di ff

us io n

Carriermediated transport

r, a

lula

cel

a Intr

e ctiv

Extracellular

lar,

llu race

Facilitated diffusion

Int

Extracellular concentration

rt

spo

tran

sive

pas

Time

Assumption: intracellular concentration is negligible

Facilitated diffusion increases transport rate above that capable with simple diffusion, but has saturation kinetics (left). Active transport can produce a concentration gradient, and passive processes will lead to an equilibrium state (right).

GENERAL PRINCIPLES │ 7. Physiology

The rate is estimated by Fick’s law of diffusion: J = −DA(∆C/∆X) J = net flux, D = diffusion coefficient, A = surface area, ∆C = concentration or pressure gradient, ∆X = diffusion distance Changes in surface area or diffusion distance are most important in disease states (e.g., the decrease in surface area caused by destruction of alveoli in emphysema or the decreased diffusion of oxygen during pulmonary edema related to increased diffusion distance).

Simple diffusion

Assumption: extracellular concentration does not change

►►Fluid Volume Compartments and Distribution % of Body Weight

Fraction of TBW

Markers Used to Measure Volume

Primary Cations

Primary Anions

Total body water (TBW)

60

1.0

Tritiated H2O D2O, antipyrine





Intracellular fluid volume (ICF)

40

²⁄³

TBW – ECF*

K+

Organic phosphates; protein

Extracellular fluid volume (ECF)

20

¹⁄³

Inulin Mannitol

Na+

Cl− HCO3−

Plasma

5

¹⁄¹² (¼ of ECF)

RISA Evans blue

Na+

Cl− HCO3− Plasma proteins

Interstitial fluid

15

¼ (¾ of ECF)

ECF-plasma volume*

Na+

Cl− HCO3−

Principles of Fluid Distribution 1. Osmolarity of the ICF and ECF are equal. 2. Intracellular volume changes only when extracellular osmolarity changes. 3. All substances enter or leave the body by passing through the extracellular compartment.

Measurement of Fluid Volumes Volume =

Mass Concentration

Example: 100 mg of inulin is infused. After equilibration, its concentration = 0.01 mg/mL. What is patient’s ECF volume? Answer: ECF = 100 mg/0.01 mg/mL = 10,000 mL, or 10 L

Osmolarity and Mass 1. P  lasma osmolarity in mOsm/L can be quickly estimated as twice the plasma sodium concentration in mmol/L. More rigorously, plasma osmolarity (mOsm/L) = (2 × serum sodium [mEq/L]) + (BUN [mg/dL]/2.8) + (glucose [mg/dL]/18). 2. Mass of solutes in the TBW, ICF, or ECF in mOsm is calculated by the relevant volume multiplied by the osmolarity. Definition of abbreviation: RISA, radio-iodinated serum albumin. *Indirect measurement

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GENERAL PRINCIPLES │ 7. Physiology

►►Summary of Volume and Osmolarity Changes of Body Fluids Body osmolarity and intracellular and extracellular fluid volumes change in clinically relevant situations. The Darrow-Yannet diagram (right) represents this information. The y-axis is solute concentration or osmolarity. The x-axis is the volume of ICF and ECF. The solid line represents the control state, and the dashed line represents changes in volume or osmolarity. In this example, osmolarity ↓, ICF volume ↑, and ECF volume ↓.

Concentration of Solute

ICF

volume

ECF Volume

Body Osmolarity

ICF Volume

Diarrhea, hemorrhage, vomiting

↓

No change

No change

Isosmotic volume expansion (gain of isotonic fluid)

Isotonic saline infusion

↑

No change

No change

Hyperosmotic volume contraction (loss of water)

Dehydration, diabetes insipidus

↓

↑

↓

Hyperosmotic volume expansion (gain of NaCl)

Excessive NaCl intake, hypertonic mannitol, chronic aldosterone excess

↑

↑

↓

Hyposmotic volume contraction (loss of NaCl)

Adrenal insufficiency

↓

↓

↑

Hyposmotic volume expansion (gain of water)

SIADH, water intoxication

↑

↓

↑

Type

Examples

Isosmotic volume contraction (loss of isotonic fluid)

ECF

o

volume

D-Y Diagram

Definiton of abbreviation: SIADH, syndrome of inappropriate antidiuretic hormone.

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►►Membrane Potentials Amount of voltage needed to balance the chemical force due to its concentration gradient The Nernst equation can determine this. For a monovalent cation: Ex =

[X]o 60 mV log10 ; Ex = equilibrium potential, [X] = ion concentration (out and in), Z = charge [X]i Z

(Na+ = 1, Cl– = –1, Ca2+ = 2) Resting membrane (RM) potential

Chord conductance equation

• RM is the potential difference across a cell membrane in millivolts (mV); −70 mV is typical. • RM occurs because of an unequal distribution of ions between the ICF and ECF and the selective permeability of the membrane to ions. Proteins (anions) in cells that do not diffuse help establish the electrical potential across the membrane. • The relative effect of an ion on the membrane potential is in proportion to the conductance or permeability of that ion. The greater the conductance, the closer the membrane will approach the equilibrium potential of that ion. • The resting potential of cells is negative inside. Hyperpolarization occurs when the membrane potential becomes more negative. Depolarization occurs when the membrane potential becomes less negative or even positive. Em = (gK/Σg × EK) + (gNa/Σg × ENa) + (gCl/Σg × ECl)

GENERAL PRINCIPLES │ 7. Physiology

Equilibrium potential

Em = membrane potential in mV; g = conductance of individual ion; Σg = total conductance of cell membrane; E = equilibrium potential of individual ion from Nernst equation • Used to calculate membrane potential; useful to evaluate effects of ion conductance and concentrations; explains action potential, synaptic potentials, and electrolyte disorders

Properties of ions in a typical neuron

Ion

Extracellular (mM)

Intracellular (mM)

Equilibrium Potential (mV)

Conductance

Na+

150.0

15.0

+60

Very low

K+

5.5

150.0

−90

High

Cl−

125.0

9.0

−70

High

• Because potassium and chloride have a high conductance, their equilibrium potentials dominate the membrane potential, so the inside of the cell is negative. • Changes in EC K+ can produce large changes in the membrane potential: ↑ EC K+ → depolarization; ↓ EC K+ → hyperpolarization. • Changes in EC Na+ have little effect on membrane potential, but an increase in Na+ conductance → depolarization. Definition of abbreviation: EC, extracellular.

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►►Action Potential GENERAL PRINCIPLES │ 7. Physiology

Absolute refractory period

Relative refractory period Sodium equilibrium potential

60 mV

Action potential

0 mV

Sodium conductance

Potassium conductance

– 70 mV

Resting equilibrium potential

– 90 mV

Potassium equilibrium potential

Time

The action potentials (AP) of excitable cells involve the opening and closing of voltage-gated channels for sodium, potassium, and in some cells, calcium. The figure above shows a neuronal AP. The opening of a channel increases conductance. Steps are shown below. • Inward currents depolarize the membrane potential to threshold. • Voltage-gated Na+ channels open, causing an inward Na+ current. The membrane potential approaches the Na+ equilibrium potential. These channels can be blocked by tetrodotoxin. • These Na+ channels close rapidly (inactivation), even though the membrane is still depolarized. • Depolarization slowly opens K+ channels, increasing K+ conductance (outward current), leading to repolarization. • Absolute refractory period: An AP cannot be elicited because Na+ channels are closed. • Relative refractory period: Only a greater than normal stimulus can produce an AP because the K+ conductance is still higher than at rest. • The Na+-K+ pump restores ion concentrations. It is electrogenic (3 Na+ pumped out for every 2 K+ pumped in).

Clinical Correlations Calcium has a low resting conductance and does not contribute to the resting potential. It has a very positive equilibrium potential, so when conductance increases (e.g., cardiac and smooth muscle cells), depolarization occurs. Calcium concentration affects the action potentials and force of contraction of cardiac and smooth muscle. Hypercalcemia stabilizes excitable membranes, leading to flaccid paralysis of skeletal muscle. Hypocalcemia destabilizes membranes, leading to spontaneous action potentials and spasms. Abnormal increases and decreases of extracellular potassium have severe consequences for cardiac conduction and rhythm. Renal and gastrointestinal disorders are likely to cause abnormalities of electrolytes and alteration of resting potentials and action potentials.

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Pathology Chapter 8 Cellular Injury and Adaptation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154 Direct and Indirect Results of Reversible Cell Injury . . . . . . . . . . . . . . . . . . . . . . . As the Degree of Cellular Injury Worsens... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Irreversible Injury and Cell Death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Apoptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Adaptive Cellular Responses to Injury (Potentially Reversible) . . . . . . . . . . . . . .

155 155 155 156 156

Regeneration and Repair Capacity of Cells to Regenerate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Wound Healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Connective Tissue Components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Growth Factors and Cytokines Involved in Growth Repair . . . . . . . . . . . . . . . . . Connective Tissue Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

157 157 157 157 157

Staining Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 Amyloidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 Neoplasia Basic Terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159 Selected Risk Factors for Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159 Mechanisms of Carcinogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160–161 Oncogenic Viruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161 Serum Tumor Markers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162 Paraneoplastic Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162 Grading and Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163 Cancer Incidence and Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163

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GENERAL PRINCIPLES │ 8. Pathology

Cellular Injury and Adaptation Homeostatic cell Metabolic changes Ischemia Toxins, etc.

Changing conditions in the cell’s environment can produce changes from adaptation to injury or even cell death. The cellular response to injury depends on the type, duration, and severity of injury, the type of cell injured, metabolic state, and ability to adapt.

Adaptation Reversible changes

Injury Irreversible changes

Causes

Examples

Hypoxia (most common)

• Ischemia (e.g., arteriosclerosis, thromboembolus) • Cardiopulmonary failure • Severe anemia

Infections

Viruses, bacteria, parasites, rickettsiae, fungi, prions

Immunologic reactions

• Hypersensitivity reactions • Autoimmune

Congenital/metabolic disorders

• Inborn errors of metabolism (e.g., phenylketonuria, galactosemia, glycogen storage diseases)

Chemical injury

• • • •

Physical injury

Trauma, burns, frostbite, radiation

Nutritional or vitamin imbalance

• • • •

Drugs (e.g., therapeutic, drugs of abuse) Poisons Pollution Occupational exposure (e.g., CCl4, CO, asbestos)

Inadequate calorie/protein intake (e.g., marasmus, kwashiorkor, anorexia nervosa) Excess caloric intake (e.g., obesity, atherosclerosis) Vitamin deficiencies Hypervitaminosis

Important Mechanisms of Cell Injury .– ],

Protective Factors Against Free Radicals [OH.],

• Oxygen-free radicals (superoxide [O2 hydroxyl radical hydrogen peroxide [H2O2]) damage DNA, proteins, lipid membranes, and circulating lipids (LDL) by peroxidation

1. Antioxidants—vitamins A, E, and C

• Decreased oxidative phosphorylation

4. Catalase—hydrogen peroxide → oxygen and water

• ATP depletion

2. Superoxide dismutase—superoxide → hydrogen peroxide 3. Glutathione peroxidase—hydroxyl ions or hydrogen peroxide → water

• Increased cell-membrane permeability • Influx of calcium—activates a wide spectrum of enzymes: proteases, ATPases, phospholipases, endonucleases • Mitochondrial dysfunction, formation of mitochondrial permeability transition (MPT) channels • Release of cytochrome c is a trigger for apoptosis

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►►Direct and Indirect Results of Reversible Cell Injury Consequences

Pathophysiologic Correlates

Decreased synthesis of ATP by oxidative phosphorylation

Decreased function of Na+/K+ ATPase → influx of Na+ and water, efflux of K+, and swelling of the ER

Cellular swelling (hydropic swelling), swelling of endoplasmic reticulum, membrane blebs, myelin figures

Increased glycolysis → glycogen depletion

Increased lactic acid production → decreased intracellular pH

Tissue acidosis

Ribosomes detach from rough ER

Decreased protein synthesis

Lipid deposition (fatty change)

►►As the Degree of Cellular Injury Worsens . . . Severe plasma membrane damage

Massive influx of calcium, efflux of intracellular enzymes and proteins into the circulation

Markers of cellular damage detectable in serum (LDH, CK, ALT, AST, troponin, etc.)

Calcium influx into mitochondria

Irreparable damage to oxidative phosphorylation

Mitochondrial densities

Lysosomal contents leak out

Lysosomal hydrolases are activated intracellularly

Autolysis, heterolysis, nuclear changes (pyknosis, karyorrhexis, karyolysis)

GENERAL PRINCIPLES │ 8. Pathology

Direct Result

►►Irreversible Injury and Cell Death Morphologic Pattern

Characteristics

Coagulative necrosis

Most common (e.g., heart, liver, kidney) Proteins denatured, nucleus is lost, but cellular shape is maintained

Liquefactive necrosis

Abscesses, brain infarcts, pancreatic necrosis Cellular destruction by hydrolytic enzymes

Caseous necrosis

Seen in tuberculosis Combination of coagulation and liquefaction necrosis → soft, friable, and “cottage-cheese–like” appearance

Fat necrosis

Caused by the action of lipases on fatty tissue (e.g., with pancreatic damage) Chalky white appearance

Fibrinoid necrosis

Eosinophilic homogeneous appearance—resembles fibrin

Gangrenous necrosis

Common sites: lower limbs, gallbladder, GI tract, and testes Dry gangrene—coagulative necrosis Wet gangrene—liquefactive necrosis

Apoptosis

A specialized form of programmed cell death, an active process under genetic control Often affects only single cells or small groups of cells Mediated by a cascade of caspases (digest nuclear and cytoskeletal proteins and activate endonucleases)

Myocardial ischemia is a good example of cellular injury and death. Myocardial Ischemia

Decreased Oxidative Phosphorylation

Na+ K+ ATPase pump

Influx of Na+ Efflux of K+

Cell Swelling Endoplasmic Reticulum Swelling Loss of Microvilli Membrane Blebs

Ribosomal Detachment

Glycolysis

Glycogen

Lactic Acid

Protein Synthesis

Severe Membrane Damage

Influx of Ca2+

Cytoplasmic Enzyme Leak Out of Cell (i.e., CK-MB)

pH

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GENERAL PRINCIPLES │ 8. Pathology

►►Apoptosis Morphology

Stimuli for Apoptosis

Genetic Regulation

Physiologic Examples

Pathologic Examples

• Cells shrink, cytoplasm is dense and eosinophilic • Nuclear chromatin condenses, then fragments • Cell membrane blebs • Cell fragments (apoptotic bodies) are phagocytized by adjacent cells or macrophages • Lack of inflammatory response

• Cell injury and DNA damage • Lack of hormones, cytokines, or growth factors • Receptor-ligand signals: –  Fas binding to Fas ligand – Tumor necrosis factor (TNF) binding to TNF receptor 1 (TNFR1)

• bcl-2 (inhibits apoptosis) • p-53 (stimulates apoptosis)

• Embryogenesis— organogenesis and development • Hormone-dependent apoptosis (menstrual cycle) • Selective death of lymphocytes in thymus

• Viral hepatitis (Councilman body) • Graft versus host disease • Cystic fibrosis (CF)—duct obstruction and pancreatic atrophy

►►Adaptive Cellular Responses to Injury (Potentially Reversible) Types

Definitions

Causes

Atrophy

Decrease in cell size and functional ability. Cells shrink; lipofuscin granules can be seen microscopically. EM— autophagosomes

• • • • •

Hypertrophy

An increase in cell size and functional ability mediated by growth factors, cytokines, and other trophic stimuli, leading to increased expression of genes and increased protein synthesis. May coexist with hyperplasia.

• Increased mechanical demand, e.g., striated muscle of weight lifters, cardiac muscle in hypertension • Increased endocrine stimulation, e.g., puberty, pregnancy, lactation

Hyperplasia

An increase in the number of cells in a tissue or organ, mediated by growth factors, cytokines, and other trophic stimuli. Increased expression of growth-promoting genes (proto-oncogenes), increased DNA synthesis, and cell division

Physiologic causes: • Compensatory (e.g., after partial hepatectomy) • Hormonal stimulation (e.g., breast development at puberty) • Antigenic stimulation (e.g., lymphoid hyperplasia) Pathologic causes: • Endometrial hyperplasia • Prostatic hyperplasia of aging

Metaplasia

A reversible change of one cell type to another

Irritation

Dysplasia

An abnormal proliferation of cells characterized by changes in cell size, shape, and loss of cellular organization; premalignant, e.g., cervical dysplasia

Similar to stimuli that produce cancer (e.g., HPV, esophageal reflux)

Deceased workload/disuse Ischemia Lack of hormonal or neural stimulation Malnutrition Aging

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Regeneration and Repair GENERAL PRINCIPLES │ 8. Pathology

Wound healing involves regeneration of cells in a damaged tissue, along with repair of the connective tissue matrix.

►►Capacity of Cells to Regenerate Cell Type

Properties

Examples

Labile

Regenerate throughout life

Skin and mucosal lining cells Hematopoietic cells Stem cells

Stable

Replicate at a low level throughout life Have the capacity to divide if stimulated by some initiating event

Hepatocytes Proximal tubule cells Endothelium

Permanent

Cannot replicate

Neurons and cardiac muscle

►►Wound Healing Growth Factors and Cytokines Involved in Growth Repair • Transforming growth factor α (TGF-α) • Platelet-derived growth factor (PDGF) • Fibroblast growth factor (FGF) • Vascular endothelial growth factor (VEGF) • Epidermal growth factor (EGF) • Tumor necrosis factor α (TNF-α) and IL-1

Primary Union (healing by first intention) Occurs with clean wounds when there has been little tissue damage and wound edges are closely approximated, e.g., a surgical incision Secondary Union (healing by second intention) Occurs in wounds that have large tissue defects (the two skin edges are not in contact): • Granulation tissue fills in the defects • Often accompanied by significant wound contraction; may produce large residual scar Keloids

►►Connective Tissue Components Collagen production requires vitamin C (wound healing impaired in scurvy) and copper. Different types of collagen are found in different body sites. • Type I collagen is the most common form. • Type II collagen is found in cartilage. • T  ype III collagen is an immature form found in granulation tissue. • T  ype IV collage is found in basement membranes. Other extracellular matrix components include: – adhesion molecules – proteoglycans – glycosaminoglycans

Occur as result of excessive scar collagen deposition/ hypertrophy, especially in dark-skinned people

Connective Tissue Diseases Scurvy Vitamin C deficiency first affecting collagen with highest hydroxyproline content, such as that found in blood vessels. Thus, an early symptom is bleeding gums.

Ehlers-Danlos (ED) Syndrome Defect in collagen synthesis or structure. There are many types. ED type IV is a defect in type III collagen. Osteogenesis Imperfecta Defect in collagen type I

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GENERAL PRINCIPLES │ 8. Pathology

Staining Methods Stain

Cell Type/Component

Hematoxylin (stains blue to purple)

Nuclei, nucleoli, bacteria, calcium

Eosin (stains pink to red)

Cytoplasm, collagen, fibrin, RBCs, thyroid colloid

Prussian blue

Iron

Congo red

Amyloid

Periodic acid-Schiff (PAS)

Glycogen, mucin, mucoprotein, glycoprotein, as well as fungi

Gram stain

Microorganisms

Trichrome

Collagen

Reticulin

Reticular fibers in loose connective tissue

Immunohistochemical (antibody) stains: • Cytokeratin

• Epithelial cells

• Vimentin

• Connective tissue

• Desmin

• Muscle

• Prostate-specific antigen (PSA)

• Prostate

• S-100, neuron specific enolase, neurofilament

• Neurons, neuronally derived, neural crest−derived growths

• GFAP

• Glial cells (including astrocytes)

• Tartrate-resistant acid phosphatase (TRAP)

• Hairy cell leukemia

• Bombesin

• Small cell lung cancer, carotid body tumor

Definition of abbreviations: GFAP, glial fibrillary acidic protein.

Amyloidosis An accumulation of various insoluble fibrillar in various tissues. It stains with Congo red and shows apple-green birefringence with polarized light.

Disease

Major Fibril Protein

Precursor Protein

Primary amyloidosis (e.g., plasma cell disorders)

AL

Kappa or lambda chains

Secondary amyloidosis (e.g., neoplasia, rheumatoid arthritis, SLE, TB, Crohn disease, osteomyelitis, familial Mediterranean fever)

AA

Serum amyloid associated (SAA)

Renal hemodialysis

Ab2M

b2 microglobin

Senile cerebral amyloidosis

Ab

b-amyloid precursor protein

Cardiac amyloidosis

ATTR

Transthyretin

Medullary carcinoma of thyroid

A Cal

Calcitonin

Type 2 diabetes, pancreatic islet-cell tumors

A Amylin

Amylin

Definition of abbreviations: ATTR, amyloid transthyretin; SLE, systemic lupus erythematosus; TB, tuberculosis.

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Neoplasia GENERAL PRINCIPLES │ 8. Pathology

Carcinogenesis is a multistep process involving multiple genetic changes from inherited germ-line mutations or acquired mutations, leading to monoclonal expansion of a mutated cell. Progression of epithelial cancer: normal epithelium → atypical hyperplasia → dysplasia → carcinoma in situ → invasion, metastasis (collagenases, hydrolases aid in penetration of barriers, such as basement membrane)

►►Basic Terms Anaplasia

Loss of cell differentiation and tissue organization

Atypical hyperplasia

Increased cell number with morphologic abnormalities

Carcinoma

Malignant tumor of epithelium

Carcinoma in situ

Malignant tumor of epithelium that does not penetrate basement membrane to underlying tissue

Desmoplasia

Excessive fibrous tissue formation in tumor stroma

Dysplasia

Abnormal atypical cellular proliferation

Metaplasia

Replacement of one type of adult cell or tissue by another (within the same germ cell line) that is not normally present in that site

Metastasis

Secondary, discontinuous malignant growth (spread), such as a lung metastasis of a colon carcinoma

Sarcoma

A mesenchymal (nonepithelial) malignant tumor

►►Selected Risk Factors for Cancer Geographic/Racial

Stomach cancer (Japan); hepatocellular carcinoma (Asia)

Occupational/Environmental exposures

Aflatoxin: hepatocellular carcinoma Alkylating agents: leukemia, lymphoma, other cancers Aromatic “−amines” and “azo−” dyes: hepatocellular carcinoma Arsenic: squamous cell carcinomas of skin and lung, angiosarcoma of liver Asbestos: bronchogenic carcinoma, mesothelioma Benzene: leukemia

Age

Increases risk of most cancers (exceptions: Wilms, etc.)

Hereditary predisposition

Familial retinoblastoma; multiple endocrine neoplasia, familial polyposis coli

Acquired risk factors

Cervical dysplasia, endometrial hyperplasia, cirrhosis, ulcerative colitis, chronic atrophic gastritis

Chromium and nickel: bronchogenic carcinoma Cigarette smoke: multiple malignancies CCl4: fatty change and centrilobular necrosis of the liver Ionizing radiation: thyroid cancer, leukemia Naphthylamine: bladder cancer Nitrosamines: gastric cancer Polycyclic aromatic hydrocarbons: bronchogenic carcinoma Ultraviolet exposure: skin cancers Vinyl chloride: angiosarcoma of liver

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►►Mechanisms of Carcinogenesis GENERAL PRINCIPLES │ 8. Pathology

There are many proposed mechanisms of carcinogenesis. The most important mutations involve growth-promoting genes (proto-oncogenes), growth-inhibiting tumor suppressor genes, and genes regulating apoptosis.

Clinically Important Oncogenes Proto-oncogenes are normal cellular genes involved with growth and cellular differentiation. Oncogenes are derived from proto-oncogenes by changing the gene sequence (resulting in a new gene product, oncoprotein) or a loss of gene regulation → overexpression of the normal gene product. Oncogenes lack regulatory control and are overexpressed → unregulated cellular proliferation.

Oncogene

Tumor

Gene Product

Mechanism of Activation

Growth factor hst-1/int-2

Cancer of the stomach, breast, bladder, and melanoma

Fibroblast growth factor

Overexpression

sis

Astrocytoma

Platelet-derived growth factor

Overexpression

Growth factor receptor Epidermal growth factor receptor

Overexpression

Breast, ovary, lung

Epidermal growth factor receptor

Amplification

erb-B3

Breast

Epidermal growth factor receptor

Overexpression

ret

MEN II and III, familial thyroid (medullary) cancer

Glial neurotrophic factor receptor

Point mutation

erb-B1

SCC of lung

erb-B2

Signal transduction proteins abl

CML, ALL

bcr-abl fusion protein with tyrosine kinase activity

Translocation t(9;22)

Ki-ras

Lung, pancreas, and colon

GTP-binding protein

Point mutation

c-myc

Burkitt lymphoma

Nuclear regulatory protein

Translocation t(8;14)

L-myc

Small cell lung carcinoma

Nuclear regulatory protein

Amplification

N-myc

Neuroblastoma

Nuclear regulatory protein

Amplification

Cell-cycle regulatory proteins bcl-1

Mantle cell lymphoma

Cyclin D1 protein

Translocation t(11;14)

CDK4

Melanoma, glioblastoma multiforme

Cyclin-dependent kinase

Amplification

c-kit

Gastrointestinal stromal tumor (GIST)

KIT (also called CD117) is a stem cell factor receptor, a receptor tyrosine kinase

Overexpression or mutation

Definition of abbreviations: ALL, acute lymphocytic leukemia; CML, chronic myelogenous leukemia; MEN, multiple endocrine neoplasia; SCC, squamous cell carcinoma. (Continued)

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►►Mechanisms of Carcinogenesis (Cont’d.) Inactivation of Tumor Suppressor Genes

Gene

Chromosome

Tumors

VHL

3p25

Von Hippel-Lindau disease, renal cell carcinoma

WT-1

11p13

Wilms tumor

WT-2

11p15

Wilms tumor

Rb

13q14

Retinoblastoma, osteosarcoma

p53

17p13.1

Lung, breast, colon, etc.

BRCA-1

17q12-21

Hereditary breast and ovary cancers

BRCA-2

13q12-13

Hereditary breast cancer

APC

5q21

Adenomatous polyps and colon cancer

DCC

18q21

Colon cancer

NF-1

17q11.2

Neurofibromas

NF-2

22q12

Acoustic neuromas, meningiomas

p16

9p

Melanoma

DPC4

18q21

Pancreatic cancer

bcl-2 • Prevents apoptosis • Overexpressed in follicular lymphomas t(14:18) (chromosome 14 [immunoglobulin heavy chain gene]; chromosome 18 [bcl-2]) bax, bad, bcl-xS, bid • Promote apoptosis • p 53 promotes apoptosis in mutated cells by stimulating bax synthesis; inactivation → failure of apoptosis c-myc • Promotes cellular proliferation • When associated with p53 → promotes apoptosis; when associated with bcl-2 → inhibits apoptosis

GENERAL PRINCIPLES │ 8. Pathology

Tumor suppressor genes encode proteins that regulate and suppress cell proliferation by inhibiting progression through the cell cycle. Inactivation of these genes → uncontrolled cellular proliferation.

Failure of Apoptosis Is Another Cause of Cancer

►►Oncogenic Viruses Specific virus

Human T-cell leukemia virus (HTLV1)*

Hepatitis B (HBV) Hepatitis C (HCV)*

Epstein-Barr

Human papilloma virus (types 16, 18 in genital sites)

Human herpesvirus 8 (HHV-8)

Associated disease

Adult T-cell leukemia/ lymphoma

Hepatocellular carcinoma

Burkitt lymphoma, B-cell lymphoma, nasopharyngeal carcinoma

Cervical, vulvar, vaginal, penile, and anal carcinoma; some head and neck cancers

Kaposi sarcoma

*RNA oncogenic viruses (all other are DNA).

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►►Serum Tumor Markers GENERAL PRINCIPLES │ 8. Pathology

These are usually normal cellular components that are increased in neoplasms but may also be elevated in non-neoplastic conditions. Can be used for screening, monitoring of treatment efficacy, and detecting recurrence.

Marker

Associated Cancers

α-fetoprotein (AFP)

Hepatocellular carcinoma, nonseminomatous testicular germ-cell tumors

β-human chorionic gonadotropin (hCG)

Trophoblastic tumors, choriocarcinoma

Calcitonin

Medullary carcinoma of the thyroid

Carcinoembryonic antigen (CEA)

Carcinomas of the lung, pancreas, stomach, breast, colon

CA-125

Ovarian epithelial carcinoma

CA19-9

Pancreatic adenocarcinoma

Placental alkaline phosphatase

Seminoma

Prostatic acid phosphatase

Prostate cancer

Prostate-specific antigen (PSA)

Prostate cancer

S-100

Melanoma, neural-derived tumors, astrocytoma

►►Paraneoplastic Syndromes Syndrome

Neoplasm

Mechanism

Carcinoid syndrome

Carcinoid tumor (metastatic, bronchial, ovarian)

Serotonin, bradykinin

Cushing syndrome

Small cell carcinoma of the lung, neural tumors

ACTH, ACTH-like peptide

Hypercalcemia

Squamous cell carcinoma of the lung; breast, renal, and ovarian carcinomas

PTH-related peptide, TGF-α, TNF, IL-1

Lambert-Eaton myasthenic syndrome

Small cell carcinoma of the lung

Antibodies against presynaptic voltage-gated Ca2+ channels at the neuromuscular junction

Polycythemia

Renal cell carcinoma, hepatocellular carcinoma, cerebellar hemangioblastoma

Erythropoietin

SIADH

Small cell carcinoma of the lung; intracranial neoplasms

ADH

Definition of abbreviations: ACTH, adrenocorticotropic hormone; IL, interleukin; TGF, transforming growth factor; TNF, tumor necrosis factor; PTH, parathyroid hormone; SIADH, syndrome of inappropriate antidiuretic hormone

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►►Grading and Staging • An estimate of the cytologic malignancy of a tumor, including the degree of anaplasia and number of mitoses. • Nuclear size, chromatin content, nucleoli, and nuclear-to-cytoplasmic ratio are all used.

Stage

• T  he clinical estimate of the extent of spread of a malignant tumor. Low stage means a localized tumor. Stage rises as tumors spread locally then metastasize. • TNM is typically used; T = size of tumor; N = node involvement; M = metastases

►►Cancer Incidence and Mortality Incidence

Mortality

Males

Females

Prostate: 29%

Breast: 30%

Lung and bronchus: 14%

Lung and bronchus: 14%

Colon and rectum: 9%

Colon and rectum: 9%

Males

Females

Lung and bronchus: 28%

Lung and bronchus: 26%

Prostate: 11%

Breast: 15%

Colon and rectum: 8%

Colon and rectum: 9%

GENERAL PRINCIPLES │ 8. Pathology

Grade

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Pharmacology/Therapeutics Chapter 9 Pharmacokinetics Key Concepts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166–167

Drug Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167 Pharmacodynamics Key Concepts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168 Signal Transduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169

Toxicology Management of the Poisoned Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170 Signs, Symptoms, and Treatments for Common Toxic Syndromes . . . . . . . . . . . 170 Signs, Symptoms, and Treatments for Heavy Metal Poisoning . . . . . . . . . . . . . . . 171 Summary of Antidotes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172

Autacoids Histamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 Serotonin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174 Angiotensin II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175

Antineoplastic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176–177 Natural Medicinals and Nutrional Supplements Natural Medicinals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178 Purified Nutritional Supplements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178

Drug Development and Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179

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GENERAL PRINCIPLES │ 9. Pharm/Therapeutics

Pharmacokinetics ►►Key Concepts Volume of distribution (apparent)

Vd =

• V  d estimates the fluid volume into which the drug has distributed (one needs to extrapolate plasma concentration at time zero). • The lower the C0, the higher the Vd, and vice versa (i.e., inversely related). • Drugs stored in nonfluid compartments like fat may have a Vd greater than TBW (e.g., lipid-soluble drugs, thiopental). • Drugs that bind strongly to plasma proteins have a Vd that approaches plasma volume. • Approximate Vd values (weight 70 kg) plasma volume (3 L), blood (5 L), extracellular fluid (12−14 L), TBW (40−42 L)

Dose C0

C0= plasma concentration at time zero

Clearance Cl =

Elimination

Clearance is the theoretical volume of blood totally cleared of drug/unit time. It represents the ratio of drug elimination to its plasma concentration. For a drug with first-order elimination, clearance is constant.

Rate of drug elimination Plasma drug concentration

Elimination is synonymous with termination of drug action. The two primary mechanisms are hepatic metabolism to inactive metabolites or renal excretion. First-Order Elimination A constant fraction of drug is eliminated with time.

Units of Drug

Most drugs have first-order elimination.

Zero Order

Units of Drug

First Order

Zero-Order Elimination

Bioavailability (F)

Half-life is the time it takes for the amount or concentration of a drug to fall to 50% of a previous estimate. It is constant for drugs eliminated by firstorder kinetics.

0.7 × Vd Cl

Plasma drug concentrations remain relatively constant over time. As a rule, it takes 4 to 5 half-lives to achieve steady state (rise in concentration: 50% at 1 half-life; 75% at 2 half-lives; 87.5% at 3 half-lives; 93.75% at 4 halflives. For elimination, decline in concentration is similar: 50% remains at 1 half-life; 25% at 2 half-lives; 12.5% at 3 half-lives; 6.25% at 4 half-lives.) Plasma Drug Concentration

Steady state

t1/2 =

Examples: ethanol (except at low blood levels), phenytoin, and aspirin (high doses) Time

Time

Half-life

A constant amount of drug is eliminated with time. Half-life is not applicable.

intravascular dose (e.g., IV bolus)

The fraction of the administered drug that reaches the systemic circulation.

F=

extravascular dose (e.g., oral)

�

AUCPO (AUC = area under the curve, AUCIV PO = oral, IV = intravenous)

By definition, intravenous drug administration has an F of 1 (100%).

Time

Definition of abbreviations: AUC, area under the curve; F, bioavailability; IV, intravenously; PO, by mouth; TBW, total body weight. (Continued)

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First-pass effect

Maintenance dose

With oral administration, drugs are absorbed into the portal circulation and initially distributed to the liver. For some drugs, their rapid hepatic metabolism decreases bioavailability. This can be avoided by giving the drug by an alternate route (e.g., sublingual, transdermal). MD =

Loading dose LD =

Cl × CP

A maintenance dose is given to maintain a relatively constant plasma concentration. It is equal to the rate of elimination.

F

If therapeutic plasma concentrations are needed quickly and the Vd is large, a loading dose may be given to produce the desired drug levels (fill up the Vd) without the typical delay of 4 to 5 half-lives.

Vd × CP F

Definition of abbreviation: CP, desired plasma concentration

Drug Metabolism Biotransformation is the conversion of drugs to more water-soluble drugs that can be more readily excreted. There are two main types of metabolic reactions: phase I and phase II. Phase I

The parent drug becomes more water-soluble by oxidation, reduction, or hydrolysis by cytochrome P450 isozymes (also called mixed function oxidases) located in smooth endoplasmic reticulum in liver, and in the GI, lungs, and kidney to a lesser extent. Often the drug is converted to compounds with little or no pharmacologic activity; in other instances, the metabolites retain pharmacologic activity.

CYP450

Substrate Example

Inducers

Inhibitors

Genetic Polymorphisms

1A2

Theophylline Acetaminophen

Aromatic hydrocarbons (smoke) Cruciferous vegetables

Quinolones

No

2C9

Phenytoin Warfarin

General inducers*

—

Yes

2D6

Many cardiovascular and CNS drugs

None known

Haloperidol

Yes

3A4

60% of drugs in PDR

General inducers*

Phase II

Conjugation reactions may follow phase I or can occur on the parent drug. Examples include glucuronidation, acetylation, sulfation, glutathione conjugation, and methylation. Phase II reactions lead to inactive molecules, which are polar and usually renally excreted. All phase II reactions use enzymes called transferases.

GENERAL PRINCIPLES │ 9. Pharm/Therapeutics

►►Key Concepts (Cont'd.)

Macrolides

Quinidine General inhibitors† Grapefruit juice

No

Definition of abbreviations: PDR; Physician's Desk Reference. * General inducers: anticonvulsants (barbiturates, phenytoin, carbamazepine), antibiotics (rifampin), chronic alcohol, glucocorticoids. † General inhibitors: antiulcer medications (cimetidine, omeprazole), antibiotics (erythromycin, clarithomycin, macrolides) protease inhibitors, azole antifungals, acute alcohol.

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►►Key Concepts Agonist

An agonist is a drug that binds to a receptor and activates it.

Partial agonist

A partial agonist is a drug that binds to a receptor but does not elicit a 100% response. It will elicit a partial response when administered alone. When administered with a full agonist, it acts as an antagonist because it displaces the full agonist from the receptor.

Graded dose− response curve

A graded dose−response curve depicts increasing responses to increasing drug doses.

% Response

B

Efficacy

GENERAL PRINCIPLES │ 9. Pharm/Therapeutics

Pharmacodynamics

A

C

Log Dose of Drug Potency

Competitive antagonist % Response

Noncompetitive antagonist

control

100

competitive

noncompetitive

A competitive antagonist binds to the receptor without activating the effector system. It can be overcome by increasing the agonist dose. This is seen as a parallel right shift in the dose−response curve. A noncompetitive antagonist binds to the receptor without activating the effector system. It cannot be overcome by increasing the agonist dose. This is seen as a downward shift in the dose−response curve.

Log Dose of Drug

Kd

Potency: the measure of how much drug is required to produce a given effect. It is typically expressed as the concentration that can elicit a 50% response (EC50). Efficacy: the maximal effect a drug can produce. It is also known as maximal efficacy. A partial agonist has a lower efficacy than a full agonist. It can be less potent (C) or more potent (A) than a full agonist (B). (See figure to left.)

Figure I-2-4. D-R Curves of Antagonists and Potentiators

The concentration of drug that binds to 50% of the receptors

Physiologic antagonist

Substances that produce opposing physiologic effects, but do not exert their mechanism of action at the same receptor

Quantal dose− response curve

A quantal dose−response curve depicts the dose of drug needed to produce a predetermined response in a population. It is the percent of population responding versus log (dose).

Therapeutic index (TI) % of population responding

100

Therapeutic effect

Death

The therapeutic index is the ratio of the drug dose required to produce a toxic or lethal effect to the dose needed for a therapeutic effect.

TI =

50

0

Log [drug] ED50

LD50

TD50 LD50 or ED50 ED50

ED50, TD50, and LD50 are the median effective, toxic, and lethal doses in 50% of the studied population, respectively. � ↑ TI, safe drug; ↓ TI, unsafe drug

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G-protein−coupled receptors*

These receptors consist of one polypeptide with seven-transmembrane−spanning regions. When bound by an agonist, the trimeric (α, β, γ) GTP-binding protein (G protein) is activated. The α component usually interacts with the effector molecules. The most common G proteins and their receptors are as follows: G protein

Receptors

Effector

Second messenger response

Gs

β1, β2,D1, H2, V2

Adenylyl cyclase

↑ cAMP

Gi

α2, M2, D2

Adenylyl cyclase

↓ cAMP

Gq

α1, M1, M3, H1, V1

Phospholipase C

↑ IP3 (↑ Cai2+), DAG

Ligand-gated channels

Activation of receptors within ion channels may directly open the channel, e.g., nicotinic ACh (Na+/ K+), GABAA (Cl−), NMDA (Ca2+/Na+) receptors, or may regulate the ion channel’s response to an agonist, e.g., benzodiazepine or barbiturate sites on the GABAA receptor.

Intracellular receptors

Lipid-soluble agents diffuse across the plasma membrane to bind intracellular receptors (e.g., steroid receptors, thyroid receptors). This permits receptor binding to nuclear DNA sequences that modify gene expression.

Ligand-regulated transmembrane enzymes*

These receptors have extracellular ligand binding sites and intracellular catalytic sites. Ligand binding causes dimerization and activates the enzyme activity (often a tyrosine kinase). Examples: insulin and growth factor receptors.

Transmembrane receptors that activate a separate tyrosine kinase

These also form dimers when activated, then activate a separate cytoplasmic tyrosine kinase (Janus kinases; JAKs). The kinase phosphorylates STAT factors (signal transducers and activators of transcription). STAT dimers then regulate transcription. Examples: cytokine and growth hormone receptors.

GENERAL PRINCIPLES │ 9. Pharm/Therapeutics

►►Signal Transduction

* Figures of these pathways can be found on pages 84–85, Cell Signaling.

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GENERAL PRINCIPLES │ 9. Pharm/Therapeutics

Toxicology ►►Management of the Poisoned Patient There are many facets of managing the poisoned patient, including supportive care, poison identification, decontamination, enhancing elimination, and administration of antidotes. Decontamination

Syrup of ipecac (induces vomiting), gastric lavage (“stomach pumping”), activated charcoal (absorbs drug)

Enhancing elimination

• Many drugs are weak acids or bases and can be in nonionized or ionized forms. Nonionized drugs are lipid soluble (cross membranes); ionized drugs are water soluble (renally excreted) • The urine pH can be manipulated to increase drug elimination  -COOH ↔ R-COO– + H+ (e.g., aspirin) Weak acid: R (Increase excretion by giving bicarbonate to trap drug in basic environment) Weak base: R  -NH+3 ↔ R-NH2 + H+ (e.g., amphetamines) (Increase excretion with NH4Cl to trap drug in acidic environment)

►►Signs, Symptoms, and Treatments for Common Toxic Syndromes Compounds

Signs and Symptoms of Toxicity

Treatment

AChE inhibitors

Miosis, salivation, sweating, GI cramps, diarrhea, seizures, anxiety/agitation, muscle fasciculations followed by muscle paralysis (including diaphragm), respiratory failure, coma

Respiratory support; atropine plus pralidoxime (2-PAM, AChE-reactivating agent for organophosphate inhibitors)

Atropine and muscarinic blockers

↑ HR, ↑ BP, hyperthermia (hot, dry skin), ↓ GI motility, urinary retention, mydriasis, delirium, hallucinations, seizures, coma

Control CV symptoms and hyperthermia plus physostigmine (crosses BBB)

Carbon monoxide (>10% carboxyHb)

Headache, dizziness, nausea/vomiting, shortness of breath, chest pain, ↑ HR, ↓ BP, arrhythmias, confusion, coma

Hyperbaric O2 and decontamination

CNS stimulants

Anxiety/agitation, hyperthermia (warm, sweaty skin), mydriasis, ↑ HR, ↑ BP, psychosis, seizures

Control CV symptoms, hyperthermia, and seizures; BZs or antipsychotics may be beneficial

Opioid analgesics

Lethargy, sedation, coma, ↓ HR, ↓ BP, miosis, hypoventilation, respiratory failure, ↓ GI motility

Ventilatory support; naloxone at frequent intervals

Salicylates

Confusion, lethargy, hyperventilation, ototoxicity, hyperthermia, dehydration, hypokalemia, acid-base disturbances, seizures, coma

Correct acidosis and electrolytes, urinary alkalinization, possible hemodialysis

Sedative-hypnotics and ethanol

Disinhibition, lethargy, stupor, coma, ataxia, nystagmus, hypothermia, respiratory failure

Ventilatory support—flumazenil if BZs implicated

SSRIs

Agitation, confusion, coma, muscle rigidity, hyperthermia, seizures, autonomic instability

Control hyperthermia and seizures—possible use of cyproheptadine and BZs

Tricyclic antidepressants

Mydriasis, hyperthermia (hot, dry skin), 3 Cs (convulsions, coma, and cardiotoxicity)

Control seizures and hyperthermia, correct acidosis plus possible antiarrhythmics

Definition of abbreviations: AChE, acetylcholinesterase; BBB, blood−brain barrier; BP, blood pressure; BZs, benzodiazepines; CNS, central nervous system; CV, cardiovascular; GI, gastrointestinal; HR, heart rate; SSRIs, selective serotonin reuptake inhibitors.

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Metals

Source

Signs and Symptoms

Treatment*

Arsenic

Wood preservatives, insecticides, occupational, environmental

Acute: GI distress, garlic breath, “rice water” stools, hypotension Chronic: paresthesias, stocking-glove neuropathy, pallor from anemia, skin Arsine gas: headache, N/V, abdominal pain, dyspnea, jaundice

Dimercaprol, penicillamine, succimer Supportive care

Iron

Iron supplements, multivitamin supplements

Occurs mainly in children; severe GI distress, GI bleeding, hepatocellular injury, seizures, shock, coma

Deferoxamine

Lead

Tap water, leaded paint chips, glazed kitchenware, etc.

Acute: abdominal (colic, N/V), CNS (headaches, ataxia, seizures, coma, encephalopathy) Chronic: anemia (inhibits heme synthesis), neuropathy (wristdrop), GI symptoms, nephropathy, developmental delays, growth retardation, decreased fertility, stillbirths

EDTA, dimercaprol, succimer

Mercury

Dental amalgams, electroplating, batteries, wood preservatives, occupational, contaminated foods, old thermometers

Acute: vapor inhalation (elemental)—chest pain, dyspnea, pneumonitis, confusion Acute: tremors, gingivitis, CNS disturbances, GI distress, renal failure Chronic: renal failure, dementia, acrodynia Organic: CNS (paresthesias, auditory and visual loss, movement disorders)

Dimercaprol, penicillamine, succimer

GENERAL PRINCIPLES │ 9. Pharm/Therapeutics

►►Signs, Symptoms, and Treatments for Heavy Metal Poisoning

Definition of abbreviations: CNS, central nervous system; GI, gastrointestinal; EDTA, ethylenediaminetetraacetic acid; N/V, nausea and vomiting. *Need to remove patient from source; decontamination is also important part of management.

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GENERAL PRINCIPLES │ 9. Pharm/Therapeutics

►►Summary of Antidotes Antidote

Type of Poisoning

Acetylcysteine

Acetaminophen

Atropine

AChE inhibitors

Deferoxamine

Iron

Digoxin antibodies

Digoxin

Dimercaprol (BAL)

Arsenic, mercury (inorganic, elemental), lead (with EDTA if severe poisoning); succimer and unithiol now used more frequently

EDTA

Primarily for lead poisoning

Esmolol

Theophylline, caffeine, β agonists

Ethanol

Methanol, ethylene glycol

Flumazenil

Benzodiazepines, zolpidem, suggested for zaleplon

Fomepizole

Methanol, ethylene glycol

Glucagon

β blockers

Naloxone

Opioid analgesics

Oxygen

Carbon monoxide

Penicillamine

Copper, Wilson disease, adjunctive in iron and arsenic intoxication

Physostigmine

Anticholinergics: atropine, antihistamine, antiparkinsonian—not tricyclic antidepressants

Pralidoxime (2-PAM)

Organophosphate cholinesterase inhibitors

Protamine

Heparins

Succimer

Lead, arsenic, mercury

Vitamin K

Warfarin and coumarin anticoagulants

Activated charcoal

Nonspecific: all oral poisonings except Fe, CN, Li, solvents, mineral acids, or corrosives

Definition of abbreviations: AChE, acetylcholinesterase; EDTA, edetate calcium disodium, ethylenediaminetetraacetic acid.

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Autacoids are endogenously produced substances that do not fit well in other classifications such as hormones or neurotransmitters. The autacoids include histamine, serotonin, vasoactive peptides, and prostaglandins (see page 54).

►►Histamine Synthesis

Histidine

Location

Circulating basophils and tissue mast cells, GI tract, skin, lung

Degranulation

• L  iberation of histamine from mast cells via IgE-mediated hypersensitivity reactions, trauma, drugs, and venoms • ↓ cAMP favors release; ↑ cAMP (via β-adrenergic and glucocorticoid stimulation) ↓ release • Other substances released include kallikrein, kinins, prostaglandins, SRS-A

Histidine decarboxylase

Histamine

Histamine Receptors Receptor

Second Messenger

Distribution

Action

H1

Gq; ↑ IP3, DAG

Smooth muscle

Vasodilation (via NO), ↑ bronchoconstriction, activates nociceptive receptors

H2

Gs; ↑ cAMP

Stomach, smooth muscle

↑ gastric acid secretion

GENERAL PRINCIPLES │ 9. Pharm/Therapeutics

Autacoids

Pharmacologic Agents Agent

Mechanism of Action

Clinical Uses

Notes/Toxicity

H1 antagonists: Diphenhydramine Promethazine Chlorpheniramine Hydroxyzine Fexofenadine* Loratadine* Cetirizine*

Competitively inhibit H1 receptors

• Allergic reactions • Motion sickness • OTC: sleep aids and cold medications

• M  uscarinic block (sedation, dry mouth)

H2 antagonists: Cimetidine Ranitidine Famotidine Nizatidine

Competitively inhibit H2 receptors → reduce gastric acid secretion†

• Peptic ulcer disease† • GERD • Zollinger Ellison syndrome

Cimetidine: P450 inhibition, antiandrogen effect

Definition of abbreviations: GERD, gastroesophageal reflux disease; GI, gastrointestinal; IgE, immunoglobulin E; SRS-A, slow-reacting substance of anaphylaxis. *No CNS entry (less sedating) and no muscarinic block; loratadine (Claritin), fexofenadine (Allegra), cetirizine (Zyrtec) †Not as efficacious as proton pump inhibitors

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GENERAL PRINCIPLES │ 9. Pharm/Therapeutics

►►Serotonin Synthesis and degradation



Location

Enterochromaffin cells in the gut, CNS neurons, platelets (primarily just storage)

Tryptophan hydroxylase

Tryptophan

5HT

MAOA

5HIAA

Serotonin Receptors Receptor

Second Messenger

Action

5HT1(A, B, D, E, F)

Gi; ↓ cAMP

• CNS • Behavioral effects (sleep, feeding, thermoregulation, anxiety) • Vasoconstriction

5HT2(A, B, C)

Gq; ↑ IP3, DAG

• • • •

5HT3

Ion channel

• CNS (area postrema), PNS • Emesis • Anxiety

5HT4

Gs; ↑ cAMP

• CNS: neuronal excitation • GI motility

CNS Behavioral effects Smooth muscle contraction Platelet aggregation

Pharmacologic Agents Agent

Mechanism of Action

Clinical Uses

Notes/Toxicity

Sumatriptan Naratriptan Other “-triptans”

5HT1D agonist

Migraine headaches



Buspirone

5HT1A partial agonist

Anxiety disorders

Lower addiction potential than other drugs like benzodiazepines

Ondansetron Granisetron Other “-setrons”

5HT3 antagonist

Emesis

Mainly for postoperative or chemotherapyinduced nausea and vomiting

SSRIs: Citalopram Fluoxetine Fluvoxamine Paroxetine Sertraline

Selectively block 5HT reuptake

• Anxiety disorders • Depression

• Sexual dysfunction • Drug interactions: serotonin syndrome with MAO inhibitors, TCAs, meperidine, and St. John’s wort

Ergot alkaloids: Ergonovine Ergotamine Methysergide Bromocriptine* LSD

Agonists, partial agonists, and antagonists at 5HT and α-adrenergic receptors; some are agonists at DA receptors*

• P  ostpartum hemorrhage (ergonovine, ergotamine) • Migraine headaches (ergotamine [for acute attacks], methysergide [prophylaxis]) • Parkinson disease, hyperprolactinemia (bromocriptine, pergolide) • Abuse (LSD)

Ergotism (“St. Anthony’s Fire”): − Mental disorientation − Hallucination − Convulsions − Muscle cramps − Dry gangrene of extremities

MAO inhibitors: Phenelzine Tranylcypromine

Inhibit metabolism of 5HT, NE, and DA by MAO

Depression

• Non-selective MAO inhibitors • Tyramine (red wine, cheese) ingestion → hypertensive crisis

Definition of abbreviations: DA, dopamine; 5-HT, 5-hydroxytrypamine; 5-HIAA, 5-hydroxyindoleacetic acid; LSD, d-lysergic acid diethylamide; MAO, monoamine oxidase; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressants.

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GENERAL PRINCIPLES │ 9. Pharm/Therapeutics

►►Angiotensin II Synthesis and Actions Angiotensinogen (from liver)

Renin (kidney)

Angiotensin I

AngiotensinConverting Enzyme (lungs)

Angiotensin II Adrenal cortex

AT-1 receptors

Aldosterone secretion

Bradykinin

inactivation blood vessels

Vasoconstriction

Pharmacologic Agents Agent

Mechanism of Action

Clinical Uses

Notes/Toxicity

ACE Inhibitors

Inhibits conversion of AT-I to AT-II by ACE

• • • •

• • • • • • •

Captopril Enalapril* Benazepril*

AT1-receptor antagonists:

Also inhibits the inactivation of bradykinins by kininase II, potentiating their vasodilatory effect

Aliskiren

Dry cough Angioedema Hypotension Acute renal failure ↓ Aldosterone Hyperkalemia Fetal renal toxicity; contraindicated in pregnancy

Competitively inhibit receptor for AT-II

• Hypertension • CHF • Diabetic nephropathy

• Common alternative to ACE-inhibitors if patient cannot tolerate adverse reactions (e.g., cough) • Does not block BK degradation • Similar BP effects and toxicity profile as ACE inhibitors (but no cough)

Blocks formation of AT-I (and therefore AT-II) via renin inhibition

Hypertension

• Similar BP effects as ACE inhibitors • Does not block BK degradation • Headache, diarrhea

Losartan Valsartan

Renin inhibitor:

Hypertension CHF Myocardial infarction Diabetic nephropathy

Definition of abbreviations: ACE, angiotensin-converting enzyme; AT-I, angiotensin I; AT-II, angiotensin II; BK, bradykinin; CHF, congestive heart failure. *Ester prodrugs of ACE inhibitor converted to active form by liver

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GENERAL PRINCIPLES │ 9. Pharm/Therapeutics

Antineoplastic Agents These agents are used to treat various neoplasms. Although the mechanism of action varies, each agent hinders cell replication in some way. Specificity relies on differential effect between neoplastic cells and normal tissue. The mechanism of action may be cell-cycle specific (affecting cells in all stages except G0) or cell-cycle nonspecific.

Class

Mechanism

Indications

Toxicities

Antimetabolites

Cell-cycle specific (CCS). Inhibit synthesis of nucleic acids and thus protein synthesis.

Methotrexate

• A  folic acid analog that inhibits dihydrofolate reductase; decreased dTMP levels hinder DNA synthesis and thus protein synthesis • S-phase specific

Neoplastic indications: leukemia, lymphomas, breast cancer, choriocarcinoma Nonneoplastic indications: rheumatoid arthritis, psoriasis, termination of pregnancy (e.g., ectopic)

Suppresses bone marrow reversibly; folinic acid (leucovorin) is used to “rescue”; fatty change in liver

5-Fluorouracil (5-FU)

• P  yrimidine antimetabolite is converted to 5-F-dUMP, which when bound to folic acid, inhibits thymidylate synthase. This prevents dTMP synthesis, thus inhibiting DNA and protein synthesis. • S-phase specific

Breast, ovarian, colon, head and neck cancers, basal cell carcinomas and keratoses (use topically)

Irreversible myelosuppression and photosensitivity, GI irritation, alopecia

Cytarabine (Ara-C)

• Pyrimidine antimetabolite • Inhibits DNA polymerases • S-phase specific

Acute leukemias

BMS, GI irritation, ↑ doses → neurotoxicity

6-Mercaptopurine (6-MP)

• A  ctivated by hypoxanthineguanine phosphoribosyltransferase (HGPRT) • Inhibits purine synthesis, inhibiting nucleic acid synthesis • S-phase specific

Aacute leukemias, CML, nonHodgkin lymphoma

• B  MS, hepatotoxicitycoadministration with allopurinol increases toxicity (6-MP metabolized by xanthine oxidase) • Azathioprine forms 6-MP

Alkylating Agents Busulfan

Cell cycle-nonspecific (CCNS). This class of agents causes alkylation of DNA, leading to cross-linking, abnormal base pairing, or DNA strand breakage. Alkylates DNA

CML

Pulmonary fibrosis, hyperpigmentation, and adrenal insufficiency

Cyclophosphamide

Alkylates DNAattacks guanine N7, induces cross-linking

Non-Hodgkin lymphoma; ovarian and breast cancers; neuroblastoma

BMS and hemorrhagic cystitis (can be ↓ by mesna, which traps acrolein, a toxic metabolite)

Nitrosoureas (lomustine, carmustine)

• Alkylates DNA • Crosses blood–brain barrier

Brain tumors

Neurologic

Definition of abbreviations: BMS, bone marrow suppression; CML, chronic myelogenous leukemia.

(Continued)

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Class

Mechanism

Indications

Toxicities

Cisplatin, carboplatin

Alkylates DNA

Testicular, bladder, lung, and ovarian carcinomas

Nephrotoxic, neurotoxicity (deafness, tinnitus)

Procarbazine

Alkylates DNA

Hodgkin disease (MOPP*)

BMS, pulmonary toxicity, neurotoxic, leukemogenic

Antibiotics

Structurally dissimilar subclass of drugs. Mechanisms of action vary.

Doxorubicin

Intercalates DNA, creating breaks. Hinders DNA replication and transcription.

Hodgkin lymphoma (ABVD†), breast, endometrial, lung, ovarian CAs, myeloma, sarcomas

Cardiotoxicdexrazoxane (treatment to inhibit free radical formation; may protect against cardiotoxicity), BMS, alopecia, GI distress

Bleomycin

• Generates free radicals → DNA strand scission • G2 phase

Lymphomas, testicular, skin CA

Pulmonary fibrosis, mucocutaneous reactions (blisters, alopecia), hypersensitivity reactions

Hormones/ Hormone Antagonists

May inhibit hormone-dependent tumor growth.

Prednisone

Induces apoptosis of lymphoid cells

Chronic lymphocytic leukemia (CLL), Hodgkin lymphoma (MOPP*), autoimmune disease

Typical symptoms of glucocorticoid excess, including Cushing syndrome

Tamoxifen

Selective estrogen receptor modulator (SERM). Prevents estrogen from binding estrogen receptor– positive breast CA cells, leading to involution of estrogen-dependent tumors.

Breast cancer

Hot flashes, increased risk of endometrial carcinoma

Plant Alkaloids

GENERAL PRINCIPLES │ 9. Pharm/Therapeutics

►►Antineoplastic Agents (Cont’d.)

Cell-cycle specific drugs. Most prevent the assembly of microtubules and the formation of the mitotic spindle.

Vinblastine

• Inhibits microtubule/ spindle formation • M-phase specific

Lymphoma, Wilms tumor, choriocarcinoma

BMS

Vincristine

• Inhibits microtubule/ spindle formation • M-phase specific

Same as vinblastine, MOPP* (is Oncovin)

Neurotoxic, GI distress

Paclitaxel

• S  tabilizes microtubules so that spindle cannot break down • M-phase specific

Ovarian and breast carcinomas

BMS

Etoposide

• Inhibits topoisomerase II, ↑ DNA degradation • Late S/early G2 phase

Small cell carcinoma, prostate cancer, testicular carcinoma

BMS, GI irritation, alopecia

†ABVD: Adriamycin® (doxoribicin), bleomycin, vinblastine, decarbazine *MOPP: mechlorethamine, vincristine (Oncovin®), procarbazine, prednisone

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GENERAL PRINCIPLES │ 9. Pharm/Therapeutics

Natural Medicinals and Nutritional Supplements Please note that these substances are not FDA-approved for any conditions and there are variable amounts of evidence regarding efficacy. However, many of your patients may be taking herbal medicines such as these, and familiarity with these agents is useful.

►►Natural Medicinals Name

Medicinal Use(s)

Possible Mechanism(s)

Side Effects/Interactions

Echinacea

↓ Cold symptoms

↑ ILs and TNF

GI distress, dizziness, headache

Ephedra (Ma Huang)

Bronchodilator, cold symptoms, mild CNS stimulant

Indirect acting sympathomimetic

Insomnia, palpitations, tachycardia; higher doses: hypertension, cardiac arrhythmias, toxic psychosis

Garlic

↓ Cholesterol, atherosclerosis

Inhibits HMG-CoA reductase and ACE

Allergies, hypotension, antiplatelet actions; caution advised when used with anticoagulants

Gingko

Intermittent claudication; cognitive improvement

Antioxidant, free radical scavenger, ↑ NO

Anxiety, GI distress, insomnia, antiplatelet actions; caution advised when used with anticoagulants

Ginseng

Possible ↑ in mental and physical performance

Unknown

Insomnia, nervousness, hypertension, mastalgia, vaginal bleeding

Milk thistle

Limits hepatic injury from Amanita mushroom poisoning, viral hepatitis, alcohol, acetaminophen

Inhibits P450

None reported

Saw palmetto

BPH treatment

5α-reductase inhibitor and androgen receptor antagonist

GI pain, ↓ libido, headache, hypertension

St. John’s wort

Depression

May enhance brain 5HT functions

Major drug interactions: serotonin syndrome with SSRIs, MAOIs; induces P450, leading to ↓ effects of multiple drugs

►►Purified Nutritional Supplements Name

Medicinal Use(s)

Side Effects

Coenzyme Q10 (ubiquinone)

Hypertension, coronary artery disease, chronic stable angina, CHF

Well-tolerated, some GI disturbance

Dehydroepiandrosterone (DHEA)

Androgen precursor advocated for treatment of AIDS ( ↑ CD4 in females), Alzheimer disease and “aging,” diabetes, hypercholesterolemia, and SLE ( ↓ in symptoms and “flare-ups” in females)

Females: androgenization and concern regarding CV disease and breast cancer

Glucosamine

Osteoarthritis

Well tolerated, some GI disturbances

Melatonin

Serotonin derivative used for “jet-lag” and sleep disorders

Drowsiness, sedation, headache. Contraindicated in pregnancy, in women trying to conceive (↓ LH), and in nursing mothers (↓ prolactin)

Males: feminization in young and concern in elderly regarding BPH and cancer

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Preclinical

IND

Phase 1

Phase 2

Phase 3

NDA

Phase 4

In vitro testing; animal testing (at least 2 different species)

Proposal to the FDA for human testing; includes preclinical data and proposals for the clinical trials

25-50 normal volunteers✝

100-200 patients

1000-5000 patients; double-blind studies used

Request to market new agent

Post-marketing surveillance (if FDA approved NDA)

Safety and pharmacokinetics

Efficacy

Efficacy, side effects

Biologic activity and safety

Physicians report toxicities that may be now apparent with a larger sample size.

*Definition of abbreviations: IND: Investigational New Drug application; NDA: New Drug Application ✝ If the agent is known to be toxic (e.g., antineoplastic, AIDS drug), volunteer patients will be used instead

GENERAL PRINCIPLES │ 9. Pharm/Therapeutics

Drug Development and Testing

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Section II

Organ Systems

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The Nervous System Chapter 1 Development of the Nervous System Central Nervous System Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184 Congenital Malformations of the Nervous System . . . . . . . . . . . . . . . . . . . . . . . . 185

Peripheral Nervous System Autonomic and Somatic Nervous Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186 Parasympathetic and Sympathetic Nervous Systems . . . . . . . . . . . . . . . . . . . . . . 186 Parasympathetic = Craniosacral Outflow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187 Sympathetic = Thoracolumbar Outflow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187 Autonomic Effects on Organ Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187–188 Cholinergic Transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189 Cholinergic Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189–191 Predominant Tone and the Effect of Ganglionic Blockers . . . . . . . . . . . . . . . . . . 191 Adrenergic Transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192 Adrenergic Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193–194 Meninges and Meningeal Spaces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195 Meningitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195 Organisms Causing Bacterial Meningitis by Age Group . . . . . . . . . . . . . . . . . . . . 195 CSF Parameters in Meningitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196 Viral Encephalitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196 Ventricular System and Venous Drainage . . . . . . . . . . . . . . . . . . . . . . . . . . . 196–197 Hydrocephalus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197

Neurohistology and Pathologic Correlates Cell Types of the Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198 Disorders of Myelination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198–199 Tumors of the CNS and PNS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199 Primary Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199

Spinal Cord 200 201 201 202 202 202 203 203

Cranial Nerves and Brain Stem Cranial Nerves: Functional Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204–205 Skull Base Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205

Visual System Visual Field Defects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anatomy of the Eye and Glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pharmacology of the Eye . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Drugs Used to Treat Glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pupillary Light Reflex Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

208 208 209 210 210 211

Brain Stem Lesions Medulla . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212 Pons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212 Midbrain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213

Cerebellum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213 Diencephalon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214 Basal Ganglia

Meninges, Ventricular System, and Venous Drainage

General Spinal Cord Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Descending Pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Upper Versus Lower Motor Neuron Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Commonly Tested Muscle Stretch Reflexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ascending Pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dorsal Column-Medial Lemniscus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anterolateral (Spinothalamic) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Classic Spinal Cord Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Accommodation-Convergence Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Correlations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Eye Movement Control Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Trigeminal Nerve (V)/Facial Nerve (VII) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vestibular System (VIII) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Auditory System (VIII) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

206 206 207 207 207

Basal Ganglia Components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215 Diseases of the Basal Ganglia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216 Treatment for Parkinson Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216

Limbic System Limbic Structures and Functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217 Clinical Correlations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217

Cerebral Cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218 Key Features of Lobes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alzheimer Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Creutzfeldt-Jakob Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pick Disease (Lobar Atrophy) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CNS Trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cerebral Herniations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

219 220 220 220 220 221 221 221 221

Blood Supply . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222–223 Cerebrovascular Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224

Seizures and Anticonvulsants Seizures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224 Anticonvulsants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225 Newer Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225

Opioid Analgesics and Related Drugs Individual Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226 Characteristics of Opioid Analgesics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227

Local Anesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227 General Anesthetics Inhalational Anesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228 Intravenous Anesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228

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ORGAN SYSTEMS │ 1. The Nervous System

Development of the Nervous System Neurulation

Neural plate

• N  eurulation begins in the third week of fetal development. • The notochord induces the overlying ectoderm to form the neural plate. • By end of the third week, neural folds grow over midline and fuse to form neural tube. • During closure, neural crest cells form from neuroectoderm.

Neuroectoderm

Neural groove

Notochordal process Ectoderm

Neural fold

A

Mesoderm

A

Endoderm

Notochord (induces formation of the nervous system) Neural groove

Neural crest

B Day 18

• N  eural tube → brain and spinal cord (plus lower motoneurons, preganglionic neurons) • Brain stem and spinal cord have an alar plate (sensory) and a basal plate (motor); plates are separated by the sulcus limitans. • Neural tube → 3 primary vesicles → 5 primary vesicles

Neural fold Rostral neuropore (closes at day 25)

Neural crest

C

Failure to close results in anencephaly, causing polyhydraminos and increased alpha-feto protein

B C D

• N  eural crest → sensory and postganglionic neurons

Day 22

Alar plate (sensory)

Basal plate (motor) Neural crest

Caudal neuropore (closes at 27D)

• P  eripheral NS (PNS): cranial nerves (12 pairs) and spinal nerves (31 pairs)

Neural tube

D

Failure to close results in spina bifida and increased alphafeto protein

►►Central Nervous System Development Adult Derivatives 5 secondary vesicles

Structures

Telencephalon 3 primary vesicles Forebrain Midbrain Hindbrain Neural tube

Spinal cord

Telencephalon

Cerebral hemispheres, most of basal ganglia

Lateral ventricle

Diencephalon

Thalamus, hypothalamus, subthalamus, epithalamus (pineal gland), retina

Third ventricle

Mesencephalon

Midbrain

Cerebral aqueduct

Metencephalon

Pons, cerebellum

Fourth ventricle

Myelencephalon

Medulla

Diencephalon Mesencephalon Metencephalon

Brain stem

Myelencephalon Spinal cord

Ventricles

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►►Congenital Malformations of the Nervous System Types

Description

Anencephaly

—

Failure of anterior neuropore to close Brain does not develop Incompatible with life Increased AFP

Spina bifida

Skin

Dura and arachnoid Subarachnoid space Spinal cord

Vertebral body

Failure of posterior neuropore to close Spina bifida occulta (Figure A)

Vertebral arch

Spina bifida with meningocele (Figure B)

Meninges protrude throughSpinal vertebral defect cord Increase in AFP

Mildest form Skin fail to form around spinal cord No increase in AFP Asymptomatic Dura and arachnoid

Muscle Vertebrae

Subarachnoid space Vertebral body

Vertebral arch

Spina Muscle

bifida with meningomyelocele (Figure C)

Skin

Vertebral arch

A

Skin

Meninges and spinal cord protrude through vertebral defect Increase in AFP

Dura and arachnoid

Spina bifida with myeloschisis (Figure D)

Muscle

Muscle

ORGAN SYSTEMS │ 1. The Nervous System

Vertebral arch

Condition

Subarachnoid space Most severe Spinal cordcord Spinal

Increase Vertebral bodyin

B

can be seen externally AFP

C

D

Dura and arachnoid Subarachnoid space Spinal cord Vertebral body

Arnold-Chiari malformation

Type I

Most common Mostly asymptomatic Downward displacement of cerebellar tonsils through foramen magnum

Type II

More often symptomatic Downward displacement of cerebellar vermis and medulla through foramen magnum Compression of IV ventricle → obstructive hydrocephaly Frequent lumbar meningomyelocele Frequent association with syringomyelia

Dandy-Walker malformation

Failure of foramina of Luschka and Magendie to open → dilation of IV ventricle Agenesis of cerebellar vermis and splenium of the corpus callosum

Hydrocephalus

Most often caused by stenosis of cerebral aqueduct CSF accumulates in ventricles and subarachnoid space Increased head circumference

Holoprosencephaly

Incomplete separation of cerebral hemispheres One ventricle in telencephalon Seen in trisomy 13 (Patau)

Definition of abbreviation: AFP, a-fetoprotein.

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►►Autonomic and Somatic Nervous Systems • Somatic NS: 1 neuron (from spinal cord → effector organ)

Craniosacral

PANS

Thoraciclumbar

SANS

CNS

Postganglionic neuron

Preganglionic neuron

ACh NN

various organs

ACh M

heart, smooth muscle, glands

α NE or β

various organs

ACh NN

ACh NN

ACh M Neurohumoral transmission

ACh NN

Motor neuron

heart, smooth muscle, glands sweat glands piloerector muscles

α Epi or β

various organs

ACh NM

skeletal muscle

Adrenal medulla

SOMATIC

ORGAN SYSTEMS │ 1. The Nervous System

Peripheral Nervous System

transported via blood

• Autonomic NS: 2 neurons (from spinal cord → effector organ) – Preganglionic neuron: cell body in CNS – Postganglionic neuron: cell body in ganglia in PNS –  Parasympathetic: long preganglionic, short postganglionic – Sympathetic: short preganglionic, long postganglionic (except adrenal medulla)

Definition of abbreviations: NN, neuronal nicotinic receptor; NM, muscle nicotinic receptor; NE, norepinephrine; M, muscarinic receptor; ACh, acetylcholine.

Neuromuscular junction

Note: Arrows indicate lesion sites that result in Horner syndrome.

►►Parasympathetic Nervous System Pupillary sphincter Ciliary m.

1. Ciliary ganglion

►►Sympathetic Nervous System Hypothalamus

2. Submandibular VI ganglion

Submandibular gland Sublingual gland 3. Pterygopalatine VII ganglion a Lacrimal gland Nasal mucosa VIII Oral mucosa

III IV

Head (sweat glands, dilator pupillae m., superior tarsal m.)

III

Midbrain

IV V

V

Pons

VII VI VIII IX X XI

IX

Parotid gland

Medulla

X

4. Otic ganglion

C1 Terminal ganglia

Viscera of the thorax and abdomen (foregut and midgut)

XI

Descending hypothalamic fibers (drive all preganglionic sympathetic neurons)

Internal carotid a. External carotid a. X

Superior cervical ganglion Middle cervical ganglion Vertebral ganglion Cervicothoracic ganglion T1

Heart, trachea, bronchi, lungs (Thorax)

T1

Smooth muscle and glands of the foregut and midgut

* * *

Thoracic splanchnic nerves

Prevertebral ganglia

Smooth muscle and glands of the hindgut and pelvic viscera

L1 L1

Preganglionic Postganglionic

Terminal ganglia

L2 Lumbar Prevertebral ganglia splanchnic nerves Sympathetic chain

Hindgut and pelvic viscera (including the bladder, erectile tissue, and rectum) Pelvic splanchnics

S2 S3 S4



Gray rami *Rejoin branches of spinal nerve

Note: Arrows indicate lesion sites that result in Horner syndrome.

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►►Sympathetic = Thoracolumbar Outflow

Origin

Site of Synapse

Innervation

Origin

Site of Synapse

Innervation

Cranial nerves III, VII, IX

4 cranial ganglia (ciliary, submandibular, pterygopalatine, otic)

Glands and smooth muscle of the head

Spinal cord levels T1–L2

Sympathetic chain ganglia (paravertebral ganglia)

Smooth and cardiac muscle and glands of body wall and limbs; head and thoracic viscera

Cranial nerve X

Terminal ganglia (in or near the walls of viscera)

Viscera of the neck, thorax, foregut, and midgut

Thoracic splanchnic nerves T5–T12

Prevertebral ganglia (collateral; e.g., celiac, aorticorenal superior mesenteric ganglia)

Smooth muscle and glands of the foregut and midgut

Pelvic splanchnic nerves (S2, S3, S4)

Terminal ganglia (in or near the walls of viscera)

Hindgut and pelvic viscera (including bladder, rectum, and erectile tissue)

Lumbar splanchnic nerves L1, L2

Prevertebral ganglia (collateral; e.g., inferior mesenteric and pelvic ganglia)

Smooth muscle and glands of the pelvic viscera and hindgut

ORGAN SYSTEMS │ 1. The Nervous System

►►Parasympathetic = Craniosacral Outflow

►►Autonomic Effects on Organ Systems As a general rule, the sympathetic autonomic nervous system (SANS) mediates “fight or flight” responses, such as increasing heart rate and contractility, dilating airways and pupils, inhibiting GI and GU functions, and directing blood flow away from skin and GI tract and toward skeletal muscles. In contrast, the parasympathetic autonomic nervous system (PANS) causes the body to “rest and digest,” reducing heart rate and contractility, contracting airways and pupils, inducing secretion from lacrimal and salivary glands, and promoting GI and GU motility. Blood vessels are solely innervated by SANS nerve fibers.

Sympathetic “Fight or Flight” Organ

Action

Parasympathetic “Rest and Digest” Receptor

Action

Receptor

Cardiovascular Heart SA node Atria AV node Ventricles

↑ heart rate ↑ contractility ↑ conduction velocity and automaticity1 ↑ contractility

β1, (β2)

↓ heart rate ↓ contractility ↓ conduction velocity and automaticity1 ↓ contractility (slight)

M2

Arterioles2 Veins

Contract: ↑ resistance Contract: ↑ venous pressure

α1 α1

 

(M3)3 

Kidney

Renin release

β1





β2

Contract: ↑ resistance

M3

Respiratory Bronchiolar smooth muscle

Relax: ↓ resistance

(Continued) 1 When

acting as a pacemaker; otherwise, the SA node suppresses automaticity in these cells receptors that mediate relaxation and decrease resistance are also present on coronary arteries and arterioles. Low doses of 2 epinephrine (or β2 agonists) act selectively on β2 receptors and can decrease systemic vascular resistance, but increased sympathetic tone increases systemic vascular resistance because vasoconstriction dominates. 3 M receptors are on vascular endothelium (not smooth muscle, like the adrenergic receptors) and cause vasodilation via nitric oxide 3 (NO) generation; this has little physiologic significance because vasculature is not innervated by PANS, but is more important with muscarinic agonist administration. 2β 

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ORGAN SYSTEMS │ 1. The Nervous System

►►Autonomic Effects on Organ Systems (Cont’d.) Sympathetic “Fight or Flight” Organ

Action

Parasympathetic “Rest and Digest” Receptor

Action

Receptor

Gastrointestinal GI smooth muscle Walls Sphincters Glandular secretion

α2,4 β2 α1 

↓ GI motility Contracts 

↑ GI motility Relaxes Increases

M3 M3 M3

β2, α β2, α

 

 

β3





Relaxes Contracts

β2 α1

Contracts Relaxes

M3 M3

Uterus, pregnant

Relaxes Contracts

β2 α

 Contracts

 M3

Penis, seminal vesicles

Ejaculation

α

Erection

M

—

—

 Contracts (constricts pupil) Contractsnear vision

 M3 M3

Liver

Gluconeogenesis Glycogenolysis

Fat cells

Lipolysis Genitourinary

Bladder Walls Sphincters

Skin Sweat glands

M,5 α6

Secretion Eye

Radial dilator muscle Pupillary sphincter muscle Ciliary muscle 4 Probably

Contracts (dilates pupil)  Relaxesfar vision

α1  β

via inhibition of cholinergic nerve terminals

5 Generalized 6 Localized

(e.g., palms of hands)

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►►Cholinergic Transmission

Choline + Acetyl CoA Choline acetyltransferase (ChAT)

uptake 3

Choline Ca2+ influx initiates release

ACh

Receptor

Signal

Function

NM

Cation channel

Stimulates skeletal muscle contraction (somatic)

NN

Cation channel

Stimulates autonomic ganglia and adrenal medulla

M1

↑ IP3, DAG (Gq)

↑ gastric acid secretion from parietal cells; CNS and PNS effects

M2

↓ cAMP (Gi)

↓ heart rate and contractility

M3

↑ IP3, DAG (Gq)

↑ smooth muscle contraction (e.g., GI, GU, bronchial, pupillary constriction); ↑ secretions; vascular endothelium (dilation via NO)

Autoreceptor 4

release 5

ACh

2

Acetylcholinesterase (AChE)

Choline + Acetate

muscarinic

1 nicotinic receptors

ORGAN SYSTEMS │ 1. The Nervous System

Acetylcholine (ACh) is synthesized from acetate and choline in synaptic nerve terminals via choline acetyltransferase (ChAT) and stored in synaptic vesicles and released by Ca2+ influx upon depolarization. The uptake of choline into the nerve terminal is the ratelimiting step of ACh synthesis and can be blocked by hemicholinium. ACh then binds to postsynaptic receptors to elicit somatic (NM) or autonomic (NN and M) effects. Signal termination occurs by degradation of ACh by acetylcholinesterase (AChE).

effector cells

Definition of abbreviations: DAG, diacylglycerol; GI, gastrointestinal; GU, genitourinary; IP3, inositol triphosphate. Note: The numbers in the figure correspond to the numbers in the table below.

►►Cholinergic Pharmacology Mechanism of Action

Agent

Clinical Uses

Other Notes and Toxicity

1 ACh receptor Nicotinic (NM) agonist/antagonists (skeletal muscle)

(See neuromuscular blockers, page 427.)

Nicotinic (NN) antagonists (ganglion blockers)

Hexamethonium Mecamylamine

Rarely used due to toxicities

Blocks both SANS and PANS; effectively reduces predominant tone (see table below)

Cholinergic agonists

Bethanechol (M)

Ileus (postop/neurogenic) Urinary retention

Heart block, cardiac arrest Syncope

Methacholine (M)

Diagnosis of bronchial hyperreactivity in asthma

Partially sensitive to cholinesterase (others listed here are resistant)

Pilocarpine (M)

Glaucoma (topical) Xerostomia



Carbachol (B)

Glaucoma (topical)



Nicotine (N)

Smoking deterrence



M = muscarinic N = nicotinic B = both

(Continued)

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ORGAN SYSTEMS │ 1. The Nervous System

►►Cholinergic Pharmacology (Cont’d.) Mechanism of Action

Agent

Clinical Uses

Other Notes and Toxicity

Muscarinic antagonists

Atropine

Counteracts cholinergic toxicity Antidiarrheal Mydriatic agent for eye exams Reversal of sinus bradycardia and heart block

Mydriasis and cycloplegia (blind as a bat) Decreased secretions (dry as a bone) Vasodilation (red as a beet) Delirium and hallucinations (mad as a hatter) Hyperthermia Tachycardia Urinary retention and constipation Sedation, amnesia

Homatropine Cyclopentolate Tropicamide

Ophthalmology (topical), for mydriasis

—

Ipratropium

Asthma and COPD

Localized effect because is a quaternary amine; few antimuscarinic side effects

Scopolamine

Motion-sickness Antiemetic

(See side effects for atropine.)

Benztropine Trihexyphenidyl Biperiden

Parkinsonism Acute extrapyramidal symptoms from neuroleptics

Glycopyrrolate Dicyclomine

Reduces hypermotility in GI and GU tracts

Edrophonium

Diagnosis of myasthenia gravis

Seizures

Tertiary amines:

Physostigmine

Glaucoma Reversal of anticholinergic toxicity

Carbamylating inhibitor Seizures

Quaternary amines:

Neostigmine Pyridostigmine Ambenonium

Ileus, urinary retention Myasthenia gravis Reversal of nondepolarizing neuromuscular blockers

Carbamylating inhibitors

Donepezil Tacrine Rivastigmine Galantamine

Alzheimer disease

Hepatotoxicity GI bleeding

Class known as “Belladonna” alkaloids (meaning “beautiful lady”) from their origin from Atropa belladonna, which was used to dilate pupils (believed to make women look more attractive).

Other drugs with antimuscarinic effects: • • • • • •

Antihistamines Tricyclics Antipsychotics Quinidine Amantadine Meperidine

2 Metabolism of ACh (AChE inhibitors) Short-acting:

Lipid-soluble:

(Continued)

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►►Cholinergic Pharmacology (Cont’d.) Agent

Clinical Uses

Echothiophate

Glaucoma

• Long-acting and irreversible

Malathion Parathion

Insecticide

• Causes time-dependent aging, which permanently inactivates AChE

Sarin VX

Nerve agents (chemical warfare)

Organophosphates:

ORGAN SYSTEMS │ 1. The Nervous System

Mechanism of Action

Other Notes and Toxicity

Mnemonic: DUMBBELSS Diarrhea Urination Miosis Bradycardia Bronchoconstriction Excitation (CNS and muscle) Lacrimation Salivation Sweating Acute treatment with atropine and pralidoxime (2-PAM) to regenerate AChE before aging occurs

3 Reuptake inhibitors

Hemicholinium

Only used in research settings

Blocks choline reuptake, slowing ACh synthesis

4 Vesicular transport  inhibitors

Vesamicol

Only used in research settings

Blocks ACh uptake into vesicles, preventing storage and leading to ACh depletion

5 Vesicle release inhibitors

Botulinum toxin

Blepharospasm Strabismus/Hyperhydrosis Cervical dystonia Cosmetic (removes wrinkles)

Prevents fusion of cholinergic vesicles to membrane, thereby inhibiting ACh release

Definition of abbreviations: ACh, acetylcholine; AChE, acetylcholinesterase; ChAT, choline acetyltransferase; COPD, chronic obstructive pulmonary disorder.

►►Predominant Tone and the Effect of Ganglionic Blockers The effects of ganglionic blockers can be easily predicted if you know the predominant autonomic tone to a particular effector organ. The effect of the blockade will be the opposite of what the predominant tone causes. In general, the predominant tone to blood vessels and sweat glands is sympathetic, and most everything else is parasympathetic. Site

Predominant Tone

Effect of Ganglionic Blockade

Arterioles

Sympathetic

Dilation (↓ blood pressure)

Veins

Sympathetic

Dilation (↓ venous return)

Heart

Parasympathetic

↑ heart rate

GI tract

Parasympathetic

↓ motility and secretions

Eye

Parasympathetic

Pupillary dilation, focus to far vision

Urinary bladder

Parasympathetic

Urinary retention

Salivary glands

Parasympathetic

Dry mouth

Sweat glands

Sympathetic (cholinergic)

Anhidrosis

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ORGAN SYSTEMS │ 1. The Nervous System

►►Adrenergic Transmission Norepinephrine (NE), epinephrine (EPI), and dopamine are part of the catecholamine family, which are synthesized from tyrosine. The first step of the synthetic pathway is carried out by tyrosine hydroxylase; it is also the rate-limiting step. NE levels inside the presynaptic terminal may also be regulated by metabolism by monoamine oxidase (MAO). Once released, NE binds to various adrenergic receptors to transmit its signal. NE primarily binds α1, α2, and β1 receptors, whereas EPI (released by the adrenal medulla) binds α1, α2, β1, and β2 receptors. Reuptake (especially uptake-1) and diffusion are most important in the termination of action of NE (and DA). Metabolism occurs via catechol-O-methyltransferase ([COMT] extracellular) and MAO (intracellular). Metabolites such as metanephrine, normetanephrine, vanillylmandelic acid (VMA) can be measured in the urine and are used in the diagnosis of diseases such as pheochromocytoma. 4

Tyrosine

Dopa

Hydroxylase

Tyrosine

Dopa Decarboxylase Dopamine Dopamine β Hydroxylase Norepinephrine (NE)

MAO 2

NE Mobile Pool NE

5

3

α2 receptors +

7 Exocytosis Reuptake NE + alpha

2

COMT

1

receptors

Metabolites + beta

EFFECTOR CELLS

Receptor

Signal

Function

α1

↑ IP3, DAG (Gq)

↑ smooth muscle contraction (in vascular walls, radial dilator muscle [eye], and GI and bladder sphincters); ↑ glycogenolysis in liver

α2

↓ cAMP (Gi)

Inhibits neurotransmitter release; inhibits insulin release and lipolysis

β1

↑ cAMP (Gs)

↑ heart rate and contractility; ↑ AV conduction velocity; ↑ renin secretion

β2 β3

↑ smooth muscle relaxation (in vascular, bronchial, GI, and bladder walls); ↑ glycogenolysis in liver, ↑ insulin release ↑ lipolysis from adipose tissues Mnemonic: You can get an adrenaline rush from a QISSS (GqGiGsGsGs).

Definition of abbreviations: DAG, diacylglycerol; GI, gastrointestinal; GU, genitourinary; IP3, inositol triphosphate. Note: The numbers in the figure correspond to the numbers in the following table.

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►►Adrenergic Pharmacology Agent

Clinical Uses

Other Notes and Toxicity

α1: Phenylephrine

Nasal congestion Vasoconstriction Mydriasis (topical)

—

α1: Methoxamine

Paroxysmal supraventricular tachycardia

Bradycardia (vagal reflex)

α2: C  lonidine Methyldopa

Hypertension

Decreases sympathetic outflow Methyldopa: prodrug converted to methylnorepinephrine

Nonselective: Phentolamine

Pheochromocytoma

Reversible, competitive inhibitor Postural hypotension, reflex tachycardia

Nonselective: Phenoxybenzamine

Pheochromocytoma

Irreversible inhibitor Postural hypotension, reflex tachycardia

α1: P  razosin Doxazosin Terazosin Tamsulosin

Hypertension Benign prostatic hypertrophy

Postural hypotension on first dose

α2: Yohimbine

Impotence Postural hypotension

Clinical use limited

α2: Mirtazapine

Depression

May also block 5HT receptors

β1 = β2: Isoproterenol

Bronchospasm Heart block and bradyarrhythmias

Clinical use limited ↓ BP, ↑ HR Arrhythmias

β1 > β2: Dobutamine

Acute heart failure

—

β2: Albuterol Terbutaline Metaproterenol Salmeterol

Asthma

Tachycardia, skeletal muscle tremor Pulmonary delivery to minimize side effects Salmeterol is long-acting Suppress premature labor (terbutaline)

β1: A  cebutolol Atenolol Esmolol Metoprolol

Hypertension Angina Chronic heart failure (carvedilol, metoprolol) Arrhythmia Glaucoma (timolol) Migraine, tremor, thyrotoxicosis (propanolol)

Sedation Decreases libido Bradycardia β1 selectivity safer in asthma, diabetes, and vascular diseases Pindolol and acebutolol have intrinsic sympathomimetic activity (useful in asthmatics); should not be used in patients with recent MI

CHF (carvedilol) Hypertension (labetalol)

Similar to above Liver damage (labetalol)

ORGAN SYSTEMS │ 1. The Nervous System

Mechanism of Action 1 Adrenergic receptor α-adrenergic agonists

α-adrenergic antagonists

β-adrenergic agonists

β-adrenergic antagonists

Nonselective: Pindolol Propranolol Nadolol Timolol α and β: Labetalol Carvedilol

Definition of abbreviation: CHF, congestive heart failure.

(Continued)

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ORGAN SYSTEMS │ 1. The Nervous System

►►Adrenergic Pharmacology (Cont’d.) Mechanism of Action

Agent

Clinical Uses

Other Notes and Toxicity

Phenelzine Tranylcypromine

Depression

Nonselective MAO-A/B inhibitors Tyramine (red wine, cheese) ingestion → hypertensive crisis Insomnia Postural hypotension MAO-AIs: moclobemide (reversible), clorgyline available in Europe

Selegiline Rasagiline

Parkinson disease

Selective MAO-B inhibitor

Entacapone Tolcapone

Parkinson disease



Cocaine

Local anesthesia Abuse

Inhibits monoamine reuptake Addiction

Amitriptyline Imipramine Desipramine Nortriptyline

Depression

Inhibits monoamine reuptake Sedation Postural hypotension Tachycardia Atropine-like effects

α-Methyltyrosine (metyrosine)

Hypertension

Inhibits tyrosine hydroxylase

Reserpine

Hypertension

Inhibits monoamine vesicular uptake, leading to neurotransmitter depletion Sedation, depression

Guanethidine

Hypertension

Inhibits NE release from sympathetic nerve endings Requires neuronal uptake to work, so interferes with other drugs that require uptake carrier (e.g., cocaine, amphetamine, cyclic antidepressants)

Amphetamine Methylphenidate

Narcolepsy and ADHD

Displaces NE from mobile pool Addiction Restlessness and rebound fatigue

Ephedrine Pseudoephedrine

For vasoconstriction

Displaces NE from mobile pool Pseudoephedrine: OTC for nasal congestion

2 Metabolism MAO inhibitors MAO-A: mainly liver but Anywhere MAO-B: mainly in Brain

COMT inhibitors

3 Reuptake inhibitors Tricyclic antidepressants

4 Synthesis inhibitors

Only for hypertension associated with pheochromocytoma

5 Drugs affecting release Adrenergic neuron blockers

Indirect-acting sympathomimetics

Definition of abbreviations: ADHD, attention deficit and hyperactivity disorder; COMT, catechol-O-methyltransferase; MAO, monoamine oxidase; NE, norepinephrine; OTC, over the counter.

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►►Meninges and Meningeal Spaces The meninges consist of three connective tissue membranes that surround the brain and spinal cord. Meningeal spaces are spaces or potential spaces adjacent to the meninges.

Meninges

Meningeal Space

Anatomic Description

Clinical Correlate

Epidural space

Tight potential space between dura and skull Contains middle meningeal artery

Epidural hematoma Temporal bone fracture → rupture of middle meningeal artery Lens-shaped biconvex hematoma

Dura

Tough outer layer; dense connective tissue Subdural space

Arachnoid

Contains bridging veins

ORGAN SYSTEMS │ 1. The Nervous System

Meninges, Ventricular System, and Venous Drainage

Subdural hematoma Rupture of bridging veins Crescent-shaped hematoma

Delicate, nonvascular connective tissue Subarachnoid space

Pia

Contains CSF Ends at S2 vertebra

Subarachnoid hemorrhage “Worst headache of my life” Often caused by berry aneurysms Lumbar puncture between L4, L5 discs

Thin, highly vascular connective tissue Adheres to brain and spinal cord

►►Meningitis (infection of the meninges, especially the pia and arachnoid) Acute purulent (bacterial) meningitis

• Headache, fever, nuchal rigidity, obtundation; coma may occur • Meninges opaque; neutrophilic exudate present • Sequelae: hydrocephalus, herniation, cranial nerve impairment

Acute aseptic (viral) meningitis

• L  eptomeningeal inflammation (lymphomonocytic infiltrates) due to viruses (Enterovirus most frequent) • Fever, signs of meningeal irritation, depressed consciousness, but low mortality

Mycobacterial meningoencephalitis

• Can be caused by Mycobacterium tuberculosis or atypical mycobacteria • Usually involves the basal surface of the brain with tuberculomas within the brain and dura mater • Frequent in AIDS patients, particularly by Mycobacterium avium-intracellulare (MAI)

Fungal meningoencephalitis

• Candida, Aspergillus, Cryptococcus, and Mucor species most frequent agents • Aspergillus and Mucor attack blood vessels → vasculitis, rupture of blood vessels, and hemorrhage • Cryptococcus causes diffuse meningoencephalitis

►►Organisms Causing Bacterial Meningitis by Age Group Neonates

Infants/Children

Adolescents/Young Adults

Elderly

Group B streptococci Escherichia coli Listeria monocytogenes

Haemophilus influenzae B (if not vaccinated) Streptococcus pneumoniae Neisseria meningitidis

Neisseria meningitidis

Streptococcus pneumoniae Listeria monocytogenes

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ORGAN SYSTEMS │ 1. The Nervous System

►►CSF Parameters in Meningitis Proteins (mg/dL)

Pressure (mm H2O)

45–85 (50–70% of blood glucose)

15–45

70–180

Up to 90,000 neutrophils

Decreased (50)

Markedly elevated

Aseptic (viral)

100–1,000 most lymphocytes

Normal

Increased (>50)

Slightly elevated

Granulomatous (mycobacterial/fungal)

100–1,000 most lymphocytes

Decreased (50)

Moderately elevated

Condition

Cells/µl

Glucose (mg/dL)

Normal values

larger fibers; myelinated fibers > unmyelinated fibers. Modality blocked: autonomic and pain > touch/pressure > motor. There are two main classes: amides and esters.

Amides (metabolized in liver) Bupivacaine Etidocaine Ropivacaine Lidocaine (M)* Mepivacaine Prilocaine (M)

(L) (L) (L)

Esters (metabolized by plasma cholinesterases) Tetracaine Cocaine Procaine Benzocaine‡

(L) (M)† (S)

(M)

Notes Duration of action can be increased by coadministration of a vasoconstrictor (e.g., epinephrine) to limit blood flow Hint: Amide drugs have two “i”s, and ester drugs have one “i” in their names.

Side Effects 1.  Neurotoxicity: lightheadedness, nystagmus, restlessness, convulsions 2.  Cardiovascular toxicity: ↓ CV parameters (except cocaine which ↑ HR and BP); bupivacaine especially notable for CV toxicity 3.  Allergic reaction: esters via PABA formation; switch to amides if allergic to esters

Definition of abbreviations: L, long acting; M, medium acting; S, short acting. *Also a IB antiarrhythmic †Primarily used topically; sympathomimetic; drug of abuse (schedule II) ‡Topical only

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ORGAN SYSTEMS │ 1. The Nervous System

General Anesthetics The ideal general anesthetic produces unconsciousness, analgesia, skeletal muscle relaxation, loss of reflexes, and amnesia. There are two broad classes of general anesthetics: inhalational and intravenous.

►►Inhalational Anesthetics Definitions • Solubility: blood:gas partition coefficient • Minimum alveolar anesthetic concentration (MAC): the minimal alveolar concentration at which 50% of patients do not respond to a standardized painful stimulus. MAC ∝ 1/potency

General Principles • D  rugs with a ↑ solubility have slow induction and recovery times (if it is soluble in blood, then it takes longer to achieve the partial pressure required for anesthesia). • Drugs with a ↓ solubility have rapid induction and recovery times (if it is not very soluble in blood, it quickly achieves the partial pressure required for anesthesia). • Anesthesia is terminated by redistribution of the agent from the brain to the blood. • Anesthetics that undergo hepatic metabolism tend be more toxic.

General Side Effects • Sometimes when administered with muscle relaxants (especially succinylcholine) → malignant hyperthermia. Treat with dantrolene. • Most ↓ BP moderately.

Anesthetic

Solubility

MAC (%)

Metabolism (%)

Unique Side Effects/Properties

Nitrous oxide

0.5

>100

0

Low potency; because the MAC is >100, it cannot provide complete anesthesia; good for induction; good analgesia and amnesia

Desflurane

0.4

6.5

70

Nephrotoxicity

►►Intravenous Anesthetics Drug Class

Agents

Unique Properties

Barbiturates

Thiopental, methohexital

Redistribution from brain terminates effects, but hepatic metabolism is required for elimination; used mainly for induction or short procedures; hyperalgesic; ↓ respiration, cardiac function, and cerebral blood flow

Benzodiazepines

Midazolam

Good amnesic; respiratory depression (can be reversed with flumazenil)

Dissociative

Ketamine

Patient remains conscious, but has amnesia, catatonia, and analgesia; related to phencyclidine (PCP)—causes emergence reactions (hallucinations, excitation, disorientation); CV stimulant

Opioids

Fentanyl, alfentanil, remifentanil, morphine

Chest wall rigidity, respiratory depression (can reverse with naloxone); neuroleptanesthesia: fentanyl + droperidol + nitrous oxide

Miscellaneous

Propofol, etomidate

Propofolrapid induction, antiemetic Etomidaterapid induction; minimal CV or respiratory effects; pain and myoclonus on injection; nausea

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The Cardiovascular System Chapter 2 Embryology Development of the Heart Tube . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230 Adult Structures Derived from the Dilatations of the Primitive Heart . . . . . . . . . 230 Atrial Septum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .230 Ventricular Septum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 Aorticopulmonary Septum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 Fetal Circulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232

Cardiovascular Anatomy Structures of the Mediastinum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232 Arterial Supply to the Heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 Chambers and Valves of the Heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233–234 Borders of the Heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234 Cross-Sectional Anatomy of the Thorax . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235 Conducting System of the Heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236 Associations of Common Traumatic Injuries with Vessel and Nerve Damage . . . . . 236

Cardiovascular Physiology Comparison of Cardiac Action Potentials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237 Cardiac Action Potentials-Ionic Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237 Important Implications of Ion Currents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237 Refractory Periods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238 Basic Principles of the Electrocardiogram . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238 Sequence of Myocardial Excitation and Conduction . . . . . . . . . . . . . . . . . . . . . . 238 Principles of the Electrocardiogram (EKG or ECG) . . . . . . . . . . . . . . . . . . . . . . . . 239 Important Rhythms to Recognize . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240 Evolution of an Infarction: Signs on the EKG . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240 Identifying Location of an Infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240 Mean Electrical Axis (MEA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 Cardiac Mechanical Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242 Cardiac Performance: Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242 Cardiac and Vascular Function Curves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242 Cardiovascular Responses in Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243 Cardiac and Vascular Function Curves: Examples . . . . . . . . . . . . . . . . . . . . . . . . 243 The Cardiac Cycle: the Wigger’s Diagram . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244 Cardiac Pressure–Volume Loops (PV Loops) . . . . . . . . . . . . . . . . . . . . . . . . 245–246 The Cardiac Valves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246

Cardiovascular Pathology Congenital Abnormalities of the Heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254–255 Obstructive Congenital Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255 Ischemic Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256 Myocardial Infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256 Appearance of Infarcted Myocardium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257 Rheumatic Fever and Rheumatic Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . 257 Congestive Heart Failure (CHF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258 Shock . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258 Endocarditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259 Myocarditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259 Valvular Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260 Cardiomyopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260 Pericardial Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261 Pericardial Effusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261 Cardiac Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261 Vasculitides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262–263 Additional Vascular Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264 Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265 Aneurysm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265 Venous Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265 Vascular Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266 Edema and Shock . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266

Cardiovascular Pharmacology Antiarrhythmic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267–268 Antihypertensives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269–270 Antianginal Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271 Drugs Used in Heart Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271–272 Antihyperlipidemics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272

Valvular Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247 Hemodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248–249 Area-Velocity Relationship . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249 Pressures of the Cardiovascular System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249 Factors That Control Filtration and Reabsorption in Capillaries . . . . . . . . . . . . . . 250 Factors That Alter Capillary Flow and Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . 251 Wall Tension: Law of Laplace . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251 Autonomic Control of Heart and Circulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252 Control of Organ Blood Flow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252 Autoregulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252 Basics of Integrated Control of Arterial Pressure and Cardiac Output . . . . . . . . . 253 Selected Applications of the Diagram . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253

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ORGAN SYSTEMS │ 2. The Cardiovascular System

Cardiovascular Embryology ►►Development of the Heart Tube Arterial

Truncus Arteriosus

The primitive heart tube is formed from lateral plate mesoderm. The primitive heart tube undergoes dextral looping (bends to the right) and forms five dilatations. Four of the five dilatations become subdivided by a septum. Most of the common congenital cardiac anomalies result from defects in the formation of these septa.

Bulbus Cordis

Primitive Ventricle Primitive Atrium Sinus Venosus Venous

►►Adult Structures Derived from the Dilatations of the Primitive Heart Embryonic Dilatation

Adult Structure

Truncus arteriosus (neural crest)

Aorta Pulmonary trunk

Bulbus cordis

Smooth part of right ventricle (conus arteriosus) Smooth part of left ventricle (aortic vestibule)

Primitive ventricle

Trabeculated part of right ventricle Trabeculated part of left ventricle

Primitive atrium

Trabeculated part of right atrium Trabeculated part of left atrium

Sinus venosus (the only dilatation that does not become subdivided by a septum)

Right—smooth part of right atrium (sinus venarum) Left—coronary sinus Oblique vein of left atrium

►►Atrial Septum Formation of the Atrial Septum Septum primum (SP) Foramen primum (FP)

Septum secundum (SS)

Atrioventricular septum (AV) (endocardial cushions) SP FP

Foramen secundum (FS)

SS

FS

AV

SP FP

AV

Foramen ovale (FO)

Atrial septal defects are called ASDs. Secundum-type ASDs are caused by excessive resorption of the SP or reduced size of the SS or both. This results in an opening between the right and left atria. If the ASD is small, clinical symptoms may be delayed as late as age 30. This is the most clinically significant ASD. The foramen ovale (FO) is the fetal communication between the right and left atria. It remains patent in up to 25% of normal individuals throughout life, although paradoxical emboli may pass through a large patent FO. Premature closure of the FO is the closure of the FO during prenatal life. This results in hypertrophy of the right side of the heart and underdevelopment of the left side.

Membranous part Interventricular septum Muscular part

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ORGAN SYSTEMS │ 2. The Cardiovascular System

►►Ventricular Septum Membranous Interventricular Septum

Atrioventricular Canal

a b c

Muscular Interventricular Septum



A membranous ventricular septal defect (VSD) is caused by the failure of the membranous interventricular septum to develop, and it results in left-to-right shunting of blood through the interventricular foramen. Patients with left-to-right shunting complain of excessive fatigue upon exertion. Left-to-right shunting of blood is not cyanotic but causes increased blood flow and pressure to the lungs (pulmonary hypertension). Pulmonary hypertension causes marked proliferation of the tunica intima and media of pulmonary muscular arteries and arterioles. Ultimately, the pulmonary resistance becomes higher than systemic resistance and causes right-to-left shunting of blood and “late” cyanosis. At this stage, the condition is called Eisenmenger complex. VSD is the most common congenital cardiac anomaly.

Figure legend: a, right bulbar ridge; b, left bulbar ridge; c, AV cushions.

►►Aorticopulmonary Septum

Neural crest cells migrate into the truncal and bulbar ridges of the truncus arteriosus, which grow in a spiral fashion and fuse to form the aorticopulmonary (AP) septum. The AP septum divides the truncus arteriosus into the aorta (dark gray) and pulmonary trunk (light gray).

Transposition of the Great Vessels Occurs when the AP septum fails to develop in a spiral fashion and results in the aorta opening into the right ventricle and the pulmonary trunk opening into the left ventricle. This causes right-to-left shunting of blood with resultant cyanosis. Infants born alive with this defect must have other defects (like a PDA or VSD) that allow mixing of oxygenated and deoxygenated blood.

Tetralogy of Fallot Occurs when the AP septum fails to align properly and results in (1) pulmonary stenosis, (2) overriding aorta, (3) interventricular septal defect, and (4) right ventricular hypertrophy. This causes right-to-left shunting of blood with resultant “early” cyanosis, which is usually present at birth. Tetralogy of Fallot is the most common congenital cyanotic cardiac anomaly.

Persistent Truncus Arteriosus Occurs when there is only partial development of the AP septum. This results in a condition in which only one large vessel leaves the heart and receives blood from both the right and left ventricles. This causes right-to-left shunting of blood with resultant cyanosis. This defect is always accompanied by membranous ventricular septal defect.

Definition of abbreviation: PDA, patent ductus arteriosus.

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Clinical Correlation

65% 22

Fetus

18

Left atrium

40%

Normally, the ductus arteriosus closes within a few hours after birth, via smooth muscle contraction, to form the ligamentum arteriosum. Patent ductus arteriosus (PDA) occurs when the ductus arteriosus (connection between the pulmonary trunk and aorta) fails to close after birth.

20

Ductus arteriosus

50%

O2 Content (mL/dL)

ORGAN SYSTEMS │ 2. The Cardiovascular System

►►Fetal Circulation

16 14

Mother

12 10

Superior vena cava

Pulmonary artery

Foramen ovale

Left ventricle

8 6 4 2

Right atrium

0 0

Right ventricle

10

20

30

40

50

60

70

80

90 100

PO2 (mm Hg) 60%

67%

Inferior vena cava

Prostaglandin E and intrauterine or neonatal asphyxia sustain the patency of the ductus arteriosus.

Aorta

26%

Ductus venosus Portal vein

26% Liver

80%

Umbilical vein

From placenta To placenta

Prostaglandin inhibitors (e.g., indomethacin), acetylcholine, histamine, and catecholamines promote closure of the ductus arteriosus. PDA is common in premature infants and cases of maternal rubella infection. It causes a leftto-right shunting of blood. (Note: During fetal development, the ductus arteriosus is a right-toleft shunt).

Right and left umbilical arteries

In the fetal circulation, the ductus venosus allows fetal blood to bypass the liver, and the foramen ovale and the ductus arteriosus allow fetal blood to bypass the lungs. Note the sites where the oxygen saturation level of fetal blood is the highest (umbilical vein) and the lowest (ductus arteriosus).

Cardiovascular Anatomy ►►Structures of the Mediastinum

The thoracic cavity is divided into the superior mediastinum above the plane of the sternal angle and the inferior mediastinum (anterior, middle, and posterior mediastina) below that sternal plane. The superior mediastinum contains the thymic remnants, superior vena cava and its brachiocephalic tributaries, aortic arch and its branches, trachea, esophagus, thoracic duct, and the vagus and phrenic nerves. The anterior mediastinum is anterior to the heart and contains remnants of the thymus. The middle mediastinum contains the heart and great vessels, and the posterior mediastinum contains the thoracic aorta, esophagus, thoracic duct, azygos veins, and the vagus nerves. The inferior vena cava passes through the diaphragm at the caval hiatus at the level of the eighth thoracic vertebra; the esophagus through the esophageal hiatus at the tenth thoracic vertebra; and the aorta courses through the aortic hiatus at the level of the twelfth thoracic vertebra.

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Arterial supply to the heart muscle is provided by the right and left coronary arteries, which are branches of the ascending aorta. The right coronary artery supplies the right atrium, the right ventricle, the sinoatrial and atrioventricular nodes, and parts of the left atrium and left ventricle. The distal branch of the right coronary artery (in 70% of subjects, “right dominant”) is the posterior interventricular artery that supplies, in part, the posterior aspect of the interventricular septum. The left coronary artery supplies most of the left ventricle, the left atrium, and the anterior part of the interventricular septum. The two main branches of the left coronary artery are the anterior interventricular artery (LAD) and the circumflex artery.

Left coronary artery Circumflex artery

Right coronary artery

Left anterior descending artery (LAD) Diagonal artery

Marginal artery

Posterior interventricular artery

In a myocardial infarction, the LAD is obstructed in 50% of cases, the right coronary in 30%, and the circumflex artery in 20% of cases.

ORGAN SYSTEMS │ 2. The Cardiovascular System

►►Arterial Supply to the Heart

►►Chambers and Valves of the Heart Right Atrium

Pulmonic valve

Aortic valve

Left atrium Mitral valve

Right atrium Tricuspid valve Right ventricle

Left ventricle

The right atrium receives venous blood from the entire body (except for blood from the pulmonary veins). The auricle is derived from the fetal atrium; it has rough myocardium known as pectinate muscles. The sinus venarum is the smooth-walled portion of the atrium, which receives blood from the superior and inferior venae cavae. The crista terminalis is the vertical ridge that separates the smooth from the rough portion of the right atrium; it extends longitudinally from the superior vena cava to the inferior vena cava. The SA node is in the upper part of the crista terminalis. The right AV (tricuspid valve) communicates with the right ventricle.

Right Ventricle The right ventricle receives blood from the right atrium via the tricuspid valve; outflow is to the pulmonary trunk via the pulmonary semilunar valve. The trabeculae carneae are the ridges of myocardium in the ventricular wall. The papillary muscles project into the cavity of the ventricle and attach to cusps of the AV valve by the strands of the chordae tendineae. Papillary muscles contract during ventricular contraction to keep the cusps of the AV valves closed. The chordae tendineae control closure of the valve during contraction of the ventricle. The infundibulum is the smooth area of the right ventricle leading to the pulmonary valve. Left Atrium The left atrium receives oxygenated blood from the lungs via the pulmonary veins. There are four openings: the upper right and left and the lower right and left pulmonary veins. The left AV orifice is guarded by the mitral (bicuspid) valve; it allows oxygenated blood to pass from the left atrium into the left ventricle.

(Continued)

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ORGAN SYSTEMS │ 2. The Cardiovascular System

►►Chambers and Valves of the Heart (Cont’d.) Left Ventricle Blood enters from the left atrium through the mitral valve and is pumped out to the aorta through the aortic valve. Trabeculae carneae, the ridges of myocardium in the ventricular wall, are normally three times thicker than those of the right ventricle. Papillary muscles (usually two large ones) are attached by the chordae tendineae to the cusps of the bicuspid valve. The aortic vestibule leads to the aortic semilunar valve and ascending aorta; the right and left coronary arteries originate from the right and left aortic sinuses at the root of the ascending aorta.

Clinical Correlation Murmurs Murmurs in valvular heart disease result when there is valvular insufficiency or a stenotic valve. For most of ventricular systole, the mitral valve should be closed and the aortic valve should be open, so that “common systolic valvular defects” include mitral insufficiency and aortic stenosis. For most of ventricular diastole, the mitral valve should be open and the aortic valve should be closed, so that “common diastolic valvular defects” include mitral stenosis and aortic insufficiency.

►►Borders of the Heart Superior vena cava

Ligamentum arteriosum Left pulmonary artery

Right pulmonary artery

Pulmonary trunk Left atrium

Right pulmonary veins

Left pulmonary veins Left ventricle

Right atrium

The external surface of the heart consists of several borders:

• • • •

the right border is formed by the right atrium the left border is formed by the left ventricle the base formed by the two atria the apex at the tip of the left ventricle

The anterior surface is formed by the right ventricle. The posterior surface is formed mainly by the left atrium. A diaphragmatic surface is formed primarily by the left ventricle.

Inferior vena cava Apex Right ventricle

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ORGAN SYSTEMS │ 2. The Cardiovascular System

►►Cross-Sectional Anatomy of the Thorax Right Brachiocephalic Vein

Manubrium

Brachiocephalic Trunk Left Common Carotid Artery Trachea

Superior Vena Cava

Ascending Aorta

Bifurcation of Trachea

Descending Aorta

Esophagus

Left Subclavian Artery

T2 Vertebra

Ribs

Ribs

Scapula

Chest: CT, T4

Chest: CT, T2 Right Pulmonary Artery

Superior Vena Cava

Body of Sternum

Ascending Aorta

Scapula

T4 Vertebra

Right Atrium

Pulmonary Trunk

Right Ventricle

Left Ventricle

Descending Aorta

T6 Vertebra

T5 Vertebra

Spinal Cord

Chest: CT, T5

Spinal Cord

Descending Aorta

Esophagus

Left Atrium

Chest: CT, T6

Images copyright 2005 DxR Development Group Inc. All rights reserved.

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ORGAN SYSTEMS │ 2. The Cardiovascular System

►►Conducting System of the Heart

Atrioventricular node (AV node)

Superior vena cava

Left atrium

Sinoatrial node (SA node)

Pulmonary veins His bundle Left ventricle

Right atrium

Bundle branches

Right ventricle

The sinoatrial node initiates the impulse for cardiac contraction. The atrioventricular node receives the impulse from the sinoatrial node and transmits that impulse to the ventricles through the bundle of His. The bundle divides into the right and left bundle branches and Purkinje fibers to the two ventricles. Sympathetic innervation from the T1 to T5 spinal cord segments increases the heart rate, while the parasympathetics by way of the vagus nerves slow the heart rate.

Inferior vena cava Purkinje fibers

►►Associations of Common Traumatic Injuries with Vessel and Nerve Damage

Subclavian artery

Brachiocephalic trunk

External iliac artery

Clavicle

Inguinal ligament Femoral artery

Axillary artery 1

Anterior humeral circumflex artery Lacerates posterior humeral circumflex artery (may lesion axillary n.)

Surgical neck fracture of humerus

Superior thoracic artery Thoracoacromial artery

Teres major Midshaft fracture of humerus Supra-condylar fracture of humerus

Aortic arch

Pectoralis minor

Lacerates profunda brachii artery (may lesion radial n.)

Lateral circumflex artery Medial circumflex artery (Major source of blood supply to head of femur)

Deep femoral artery (Supplies anterior and posterior thigh and shaft of femur)

Lateral thoracic artery

Lacerates brachial artery (may lesion median n.)

Medial epicondyle fracture

Radial collateral artery

Superior ulnar collateral artery (may lesion ulnar n.)

Subscapular artery (anastomoses with suprascapular artery to provide collateral circulation around the axillary artery)

Popliteal artery

Popliteal artery

Anterior tibial artery

Inferior ulnar collateral artery Radial artery

Common interosseus artery Ulnar artery

Posterior tibial artery (Compressed with tibial nerve in posterior compartment syndrome)

Anterior tibial artery (Compressed with deep fibular nerve in anterior compartment syndrome)

Peroneal artery

Deep palmar arch

Superficial palmar arch

Medial plantar artery

Dorsalis pedis artery

Lateral plantar artery Plantar arch artery

Anterior

Posterior

Figure III-5-3. Arterial Supply to the Lower Limb

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ORGAN SYSTEMS │ 2. The Cardiovascular System

Cardiovascular Physiology ►►Comparison of Cardiac Action Comparison of cardiac action potentials Potentials Em (mV)

+20 0

-100

1

2

Ventricle

0

3 4

4

0

Unique Cardiac Ion Channels iK

Delayed rectifier; slow to open/close; depolarization opens

iK1

Inward rectifier; open at rest; depolarization closes it

L-type

Ca2+, slow channel, long acting; depolarization opens

if

Na+; “funny channel”; repolarization opens it; causes the pacemaker spontaneous depolarization

Ionic Basis of Ventricular AP

SA node 0

Em (mV)

►►Cardiac Action Potentials—Ionic Mechanisms

3

4

1

4

Ionic Basis of SA Node AP Slow Response (SA node) Cell Action Potential and its Ionic Basis

2

0

200 msec

-80

0

-65

4

-90

4

4

gNa+

gK+

gCa++

Conductances show changes only, and do not reflect absolute values or relative values of different ions.

CURRENTS

4

Em (mV)

0

3

Conductances

-100

0

Em (mV)

Atrium

2

3

0 4

iK

OUTWARD

1

0

3

INWARD

Em (mV)

+20

if iCa

►►Important Implications of Ion Currents

Conductances show changes only and do not reflect absolute values of different ions.

Ventricles and Atria

SA Node and AV Node

Force development Ca2+ current of plateau (phase 2) has major influence

Phase 4resting potential ↑ gK+ occurs via iK1 channels iK channels are closing or closed

Phase 4pacemaker ↑ gNa+ via if “funny channel” High gK+ but ↓ as iK channels close

Phase 0upstroke ↑ gNa+ via typical fast Na+ channels ↓ gK+ as iK1 channels close

Phase 0upstroke ↑ gCa2+ via T-type (fast, transient) channels, then L-type (slow) open

Phase 1rapid partial repolarization ↓ gNa+ as fast channels close ↑ gK+ transiently via iKto

No phase 1 because no fast sodium channels

Phase 2plateau ↑ gCa2+: slow (L-type) channels at end of phase 2, ↑ gK+ via iK channels

Phase 2 usually absent

Phase 3repolarization ↓ gCa2+ as L-type channels close ↑ gK+ via iK; then iK1 opens

Phase 3repolarization ↓ gCa2+ as slow channels close ↑ gK+ via iK channels

Timing/heart rate if is increased by sympathetics → increased heart rate; parasympathetics increase gK+ → decreased heart rate Premature beats Action potential amplitude and shape not all-or-none; early beats abnormal with low force Susceptible period Arrhythmia risk high during relative refractory period

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Summation is difficult to achieve in cardiac muscle and tetany does not occur. In fact, the abnormal shape of action potentials initiated during the relative refractory period reduces calcium influx and thus contractile force, as shown.

Muscle Twitch Versus Refractory Periods

+30

Effect of AP Initiation During the Relative Refractory Period 100 msec

Muscle Twitch Force

Relative refractory period

0

-100

Em (mV)

+40

Effective refractory period

millivolts

ORGAN SYSTEMS │ 2. The Cardiovascular System

►►Refractory Periods

0 1 3

2

4

-100 4 3 2

Active Force

1 0 100

Time

200

300 Time (msec)

400

►►Basic Principles of the Electrocardiogram A moving wave of depolarization in the heart produces a positive deflection as it moves toward the positive terminals of the ECG electrodes. A depolarizing wave moving away from the positive (toward the negative) terminals produces a negative deflection. A wave of depolarization moving at right angles to the axis of the electrode terminals produces no deflection. Upon repolarization, the reverse occurs.

►►Sequence of Myocardial Excitation and Conduction

R

R PR Interval

ST segment

P

T QS

QRS duration

T

P QS

QT interval

Event/Tissue

Electrocardiogram

Sinoatrial node (SA) depolarizes (primary pacemaker)

Beginning of P wave

Conduction of depolarization through atrial muscle

P wave

Conduction through atrioventricular node (AV)

Between P wave and QRS complex (PR interval)

Conduction through His-Purkinje system and ventricular septum

QRS complex begins

Ventricular depolarization apex to base; septum to lateral wall; endocardial to epicardial

QRS complex

Ventricles are in the plateau phase of depolarization

ST segment

Repolarization of ventricles in reverse sequence

T wave

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ORGAN SYSTEMS │ 2. The Cardiovascular System

Important ECG Values PR interval

0.12–0.20 sec

Length measures AV conduction time

QRS duration

0.20 sec); 1:1 correspondence; P wave:R wave

Second degree Mobitz I (Wenckebach)

Progressively increased PR interval; then dropped (missing) QRS and then repeat of sequence

Second degree Mobitz II

Regular but prolonged PR interval; unexpected dropped QRS; may be a regular pattern, such as 2:1 = 2 P waves:1 QRS complex or 3:1, etc.

Third degree (complete)

No correlation of P waves and QRS complexes; usually high atrial rate and lower ventricular rate

Premature ventricular contraction (PVC)

Large, wide QRS complex originates in ectopic focus of irritability in ventricle; may indicate hypoxia

Ventricular tachycardia

Repeated large, wide QRS complexes like PVCs; Rate 150−250/min; acts like prolonged sequence of PVCs

Ventricular fibrillation

Total loss of rhythmic contraction; totally erratic shape

►►Evolution of an Infarction: Signs on the EKG Features to observe

QRS complex

Presence of prominent Q waves in leads where normally absent: infarct damage

ST segment

Elevation or depression: acute injury

T wave

Inversion; e.g., downward in lead where usually positive: acute ischemia

Acute myocardial infarction (MI)

Minutes to a few days

ST segment elevation or depression Inverted T waves Prominent Q waves

Resolving infarction (healing)

Weeks to months

Inverted T waves Prominent Q waves

Stable (old) MI

Months to years

Prominent Q waves as result of MI persist for the rest of life

Caution: Not all infarctions produce Q waves. Inverted T waves and/or ST abnormalities should always be investigated, even in absence of significant Q waves.

►►Identifying Location of an Infarction Location

Principal Feature of ECG

Vessel Involvement

Posterior

Large R with ST depression in V1 and V2: Mirror test or reversed transillumination

Right coronary artery

Lateral

Q waves in lateral leads I and AVL

Circumflex coronary artery

Inferior

Q waves in inferior leads II, III & AVF

Right or left coronary artery

Anterior

Q waves in V1, V2, V3 & V4

Anterior descending coronary artery

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ORGAN SYSTEMS │ 2. The Cardiovascular System

►►Mean Electrical Axis (MEA) Definition

• O  verall direction and force (vector) of the events of ventricular depolarization: obtained by vector sum of net voltage of two leads or by quadrant method using leads I and aVF • MEA tends to shift toward large mass and away from an MI

Normal axis

• Expected in the absence of cardiac disease • R wave: lead I, +; lead II, +; lead III, +

Left axis deviation

• • • •

May indicate left heart enlargement, as in hypertrophy or left dilated failure Abnormally prolonged (slow) left ventricular conduction Right heart MI, expiration, obesity, lying down R wave: lead I, +; lead II, +; lead III, –

Right axis deviation

• • • •

Right ventricular hypertrophy or dilation Prolonged right conduction Left heart MI, inspiration, tall lanky people, standing up R wave: lead I, –; lead II, +; lead III, +

Extreme right axis deviation

Difficult interpretation; one example: depolarization proceeding from abnormal focus in LV apex

Einthoven’s Triangle: Leads I, II, and III* –90° –120

Vector Cardiogram lead aVF -

lead l -

+

– II

III

+

left axis deviation

lead l +

Voltages: lead l + lead l + lead aVF+ normal axis

lead l -

normal

0 I

+180 –

+

extreme right axis deviation right axis deviation

I

–

lead aVF -

–60

+120 III

+90° aVF

Essentials of the EKG Heart rate Rhythm

+60 II

lead aVF +

lead aVF +

lead aVF -

lead aVF -

lead l +

lead l -

lead aVF + Voltages: lead l+ lead aVFleft axis deviation

lead l -

lead l +

lead aVF + Voltages lead l lead aVF+ right axis deviation

Axis deviation Hypertrophy Infarction *The figure adds aVF because the quadrant method of determining axis uses leads I and aVF.

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ORGAN SYSTEMS │ 2. The Cardiovascular System

►►Cardiac Mechanical Performance Factor

Definition

Effects

Preload

Cardiac muscle cell length (sarcomere length) before contraction begins

↑ preload causes ↑ active force development up to a limit

Afterload

Load on the heart during ejection of blood from the ventricle

↑ afterload ↓ the volume of blood ejected during a beat

Contractility

Capacity of the heart to produce active force at a specified preload

High contractility ↑ ability to work Low contractility ↓ ability to work

Rate

Heart rate (HR): number of cardiac cycles per minute

↑ output of blood per minute, but ↓ output per beat; very high rate (>≈150/min) ↓ output

►►Cardiac Performance: Definitions Stroke volume (SV)

Blood ejected from ventricle per beat = EDV – ESV

End diastolic volume (EDV)

Volume of blood in ventricle at end of diastole; the preload

End systolic volume (ESV)

Volume of blood remaining in ventricle at end of systole

Cardiac output (CO)

Volume of blood per minute pumped by the heart; CO = SV × HR

Ejection fraction (EF)

Measure of contractility: EF = SV/EDV

Left ventricular dP/dT (mm Hg/sec)

Measure of contractility: maximum rate of change of pressure during isovolumic contraction

►►Cardiac and Vascular Function Curves Cardiac function curve (CFC)

• CFC generated by controlling preload and measuring cardiac output, stroke volume or other measure of systolic performance • ↑ preload improves actin-myosin interdigitation and thus ↑ SV, CO, etc. • CFC shifts up with ↑ contractility; down with ↓ contractility; so a new curve is produced when contractility changes • Moving to a different point on the same CFC is a change only of preload: moving to a different CFC is change of contractility

Vascular function curve (VFC)

• VFC relates venous return to right atrial pressure

Equilibrium point

Cardiac output is determined by both CFC and VFC. Intersection of the CFC and VFC is the stable operating point; if contractility or blood volume changes, the system will operate at the intersection of the two new curves.

• ↑ blood volume shifts VFC up, ↓ volume shifts VFC down

►►Cardiovascular Responses in Exercise Heart Rate

TPR

MAP

Cardiac Output

Aerobic, Dynamic

Increased

Decreased

Minimal change

Increased

Anaerobic, Static

Increased

Increased

Increased

Increased, unchanged, or decreased*

*Cardiac output during static or anaerobic exercise is highly dependent on the type and intensity of exercise. Definition of abbreviations: MAP, mean arterial pressure; TPR, total peripheral resistance.

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ORGAN SYSTEMS │ 2. The Cardiovascular System

►►Cardiac and Vascular Function Curves: Examples Stability of Typical CFC and VFC

Changes in Blood Volume 10

8

C

B

Cardiac Function Curve

D

6

A 4 Equilibrium Point

2

Cardiac Output (L/min)

Cardiac Output (L/min)

10

6 Initial Point 4

-2

0

2 4 6 8 Central Venous Pressure (mmHg)

No r

2

Vascular Function Curve

m al Vo lu m

e

Hemorrhage 0

0

Increased blood volume

8

-2

0

10

2 4 6 8 Central Venous Pressure (mmHg)

10

Diagram shows that cardiac output (CO, 5 L/min) changes only transiently when CFC and VFC are not changed. Point A: venous pressure is increased from 3 to 6 mm Hg because of sudden removal of blood from arterial system and injection into venous system. This causes CO to increase to point B. CO then returns to equilibrium point in steps (B → C, C → D) as blood is pumped from venous system back to arterial system.

Increased blood volume (e.g., transfusion) shifts the VFC upward, which increases preload. Increased CO follows. Decreased blood volume (e.g., hemorrhage) shifts the VFC downward, which decreases preload. Decreased CO follows. Increases and decreases in preload produce increases and decreases in CO by the Frank-Starling mechanism.

Sympathetic Stimulation of Heart

Changes in CO After Heart Failure

Cardiac Output (L/min)

Cardiac Output (L/min)

8

B D

6

C A

4

Moderate H

Initial Point -2

0

2 4 6 8 Central Venous Pressure (mmHg)

6

Increased contractility by cardiac sympathetic nerve stimulation shifts the CFC upward (dashed line); however, this does not change the VFC. The initial large increase in CO (point B) returns to point D on the VFC as blood is transferred from the venous system to the arterial system.

ve

Ex

tre

re

yp

er

A 4

m

e

Vo l

Normal

um

e

Compensated Failure C Decompensated

B

0

10

Se

Vo l vo um Normal V e le ol m um ia e

8

2

2 0

Progressive Changes of Heart Failure

10

10

-2

0

D

2 4 6 8 Central Venous Pressure (mmHg)

E

10

Reduced contractility shifts CO down (point B), but preload immediately increases to intersect with the normal volume curve as shown. Within hours to days, blood volume increases, shifting VFC upward, and point C becomes the equilibrium point. With progressive failure, blood volume cannot increase enough to maintain CO at a normal level. (point D). Blood volume continues to increase, which overstretches the heart (point E).

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Pressure (mmHg)

Aortic

Diastasis

Slow ventricular filling

Rapid ventricular filling

Isovol. relax.

Ejection

Isovol. contract.

Atrial Systole 120

aortic valve closes

aortic valve opens

mitral valve closes Ventricular

0

mitral valve opens

left atrial pressure

Aortic Blood Flow (L/min)

5 aortic flow is measured at the root, or origin

0 40

Ventricular Volume (ml)

ORGAN SYSTEMS │ 2. The Cardiovascular System

►►The Cardiac Cycle: the Wigger’s Diagram

20

Heart Sounds Venous Pulse (mmHg) Electrocardiogram

1

4 a

6

2

c

3

v

R

0

T

P Q 0.0

0.1

P

S 0.2

0.3

0.4 Time (sec)

0.5

0.6

0.7

0.8

Left ventricular pressure

Systole: begins at isovolumic contraction, ends at beginning of isovolumic relaxation: two phases are isovolumic contraction and ventricular ejection

Diastole: begins at beginning of isovolumic relaxation and ends at onset of isovolumic contraction: two phases are isovolumic relaxation and ventricular filling

Aortic pressure

Maximum is systolic pressure. During ejection, aortic pressure is slightly below ventricular pressure.

Minimum is diastolic pressure. Pressure falls during diastole as blood flows from aorta into capillaries and then veins.

Left atrial pressure

Systole; isolated from ventricular pressure because mitral valve is closed

Diastole, blood flows from atrium into ventricle because mitral valve is open. Note mitral closed during isovolumic relaxation.

Aortic flow (measured at root)

Systolic ejection begins when ventricular pressure exceeds aortic diastolic and aortic valve opens.

Ejection ends when rapidly falling ventricular pressure causes aortic valve to close.

Ventricular volume

Maximum at end of diastole; does not change during isovolumic contraction because mitral and aortic valves are closed.

Minimum at end of ejection phase; does not change during isovolumic relaxation (both valves closed).

Heart sounds

Systole: S1 caused by sound of mitral closure

S2 caused by sound of aortic valve closure

Venous pulse

Rises with atrial systole

Drops as atrium fills

EKG

QRS begins before isovolumic contraction

T wave begins during late ejection phase

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Phase

Pressure

Volume

Filling

Slightly ↑

Large ↑; point C = EDV

Isovolumic contraction

Rapid ↑; maximum dp/dt

No change, valves closed

Ejection

Continues to rise

↓ as ejection proceeds

Isovolumic relaxation

Rapid ↓

No change, valves closed

Applications Area within loop = stroke work output

Increase work by ↑ stroke volume (volume work) or by ↑ LVP (pressure work)

Decreased blood volume (hemorrhage, dehydration, urination)

Line C−D shift left (↓ preload); ↓ stroke volume ↓ stroke work

Increase in contractility (sympathetics, or β-adrenergic drugs, digitalis)

Line F−A shifts left (↓ ESV) a major effect; slight ↓ EDV; overall ↑ stroke volume, ↑ stroke work

Decreased contractility, as in heart failure

Loop shifts to right and systolic pressure is lower: ↑↑ ESV, ↑ EDP, ↓ SV, ↓ stroke work

Volume expansion (normal heart)

Line C−D shifts right (↑ EDV); ↑ SV; ↑ stroke work

150

E

aortic valve opens

F 100

100

aortic valve closes Stroke Volume

D

50 mitral valve opens mitral valve closes 0 0

A

B 50 100 Left Ventricular Volume (ml)

A–B: rapid filling B–C: reduced or slower filling C: end diastolic volume (EDV) C–D: isovolumic contraction

C

150

D–F: ejection phase F: end systolic volume (ESV)

F–A: isovolumic relaxation

• Area within loop = stroke work • Increase work by ↑ stroke volume (volume work) or by ↑ LVP (pressure work)



Increased Blood Volume

150

Blood Volume Changes

Left Ventricular Pressure (mm Hg)

Left Ventricular Pressure (mm Hg)

Normal PV Curve

ORGAN SYSTEMS │ 2. The Cardiovascular System

►►Cardiac Pressure–Volume Loops (PV Loops)

Stroke Volume 50 Hemorrhage 0 0

50 100 Left Ventricular Volume (ml)

150

• Decreased blood volume (hemorrhage, dehydration): Line C–D shifts left (↓ preload); ↓ stroke volume, ↓ stroke work • Volume expansion (normal heart): Line C–D shifts right (↑ EDV), ↑ SV, ↑ stroke work • Diastolic dysfunction tends to ↓ EDV despite ↑ EDP • Systolic dysfunction tends to ↑ ESV and ↓ systolic LVP

(Continued)

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Increased Afterload

Decreased Afterload

Progressive Heart Failure 150

Left Ventricular Pressure

Decreased Afterload

100

150

100 Stroke Volume

Stroke Volume 50

Left Ventricular Pressure

150 Increased Afterload

Left Ventricular Pressure

ORGAN SYSTEMS │ 2. The Cardiovascular System

►►Cardiac Pressure–Volume Loops (PV Loops; Cont’d.)

100

0 0

50 100 Left Ventricular Volume (ml)

50 100 Left Ventricular Volume (ml)

150

150

With increased afterload (e.g., ↑ aortic pressure), the velocity of shortening and the distance shortened are both decreased. Thus, ESV increases, causing SV to decrease.

Decreased afterload produces the opposite changes as increased afterload. Thus, ESV decreases and SV increases.

B

C

50

50

0 0

Normal (A)

D

0 0

50 100 150 Left Ventricular Volume (ml) A. Normal left ventricular function. B. Immediate effec of reduced contractility, no compensation. C. Compensated LV failure: SV is partially restored because of moderately increased preload. D. A: Decompensated failure: despite extreme increases Normal of preload, SV of remains low, and in fact the heart is B: Acutethe loss contractility without beingcompensation overly stretched, so additional "compensation" is actually harmful.

C: Compensated LV failure (SV partially restored because of moderate increase in preload) D: Decompensated failure (SV remains low despite ↑↑↑ in preload) Overall: Curves shift to the right and systolic pressures ↓. Heart failure: ↑↑↑ ESV, ↑ EDV, ↓ SV, ↓ stroke work

►►The Cardiac Valves Mitral

Between LA and LV

Open during filling

Closed during ventricular systole and isovolumic relaxation

Aortic

Between LV and aorta

Open during ejection

Closed during diastole and isovolumic contraction

Tricuspid

Between RA and RV

Open during filling

Closed during ventricular systole and isovolumic relaxation

Pulmonic

Between RV and pulmonary artery

Open during ejection

Closed during diastole and isovolumic contraction

Both Valves Closed

Isovolumic Relaxation

Left Ventricular Volume

Isovolumic Contraction

Aortic Valve

Time OPEN

Mitral Valve OPEN

First Heart Sound mitral closure

OPEN

Second Heart Sound aortic and pulmonic closure

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ORGAN SYSTEMS │ 2. The Cardiovascular System

►►Valvular Disorders Aortic Stenosis

Aortic Regurgitation

160

90

Pressure (mm Hg)

Pressure (mm Hg)

160

Aortic Pressure

40

Atrial Pressure Ventricular Pressure

0

Aortic Pressure

Atrial Pressure Ventricular Pressure

0

SM

• Discrepancy of systolic LV and systolic aortic pressures • Causes crescendo-decrescendo systolic murmur

• D  iastolic aortic P decreases rapidly as blood flows back into ventricle; ventricular diastolic P is elevated. • Causes diastolic murmur

Mitral Valve Stenosis

Mitral Regurgitation

120

100 Pressure (mm Hg)

Aortic Pressure

20 0

Atrial Pressure

Pressure (mm Hg)

Aortic Pressure 80

Ventricular Pressure Atrial Pressure Ventricular Pressure

0 SM

• Discrepancy of diastolic LVP and left atrial P during filling • Causes diastolic murmur

• Incompetent valve allows backflow into left atrium during ventricular systole • Causes systolic murmur

Definition of abbreviation: SM, systolic murmur.

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ORGAN SYSTEMS │ 2. The Cardiovascular System

►►Hemodynamics Poiseuille’s equation: Q = (P1 – P2)/R Series circuits: RT = R1 + R2 + R3 …..Rn

Parallel circuits: I/RT = 1/R1 + 1/R2 +1/R3... ..1/Rn

• Flow (Q); P1 (input pressure); P2 (output pressure); R (resistance); (P1 − P2) = pressure gradient • ↑ pressure gradient → ↑ flow • ↑ resistance → ↓ flow • RT = total resistance • Flow is equal at all points in series circuit; pressure drops across each resistor • Adding more resistors in series increases RT. Pressure drop increases along circuit with constant flow, and flow decreases with constant input pressure (P1). • Various types of blood vessels lie in series. • Flow divided between parallel resistors • RT is always lower than the lowest resistor • Adding more resistors in parallel decreases RT. • Produces low resistance circuit • Organs lie in parallel

Pi Q

Series system Q equal at all points Pressure drops across each resistor P2 P1 R1

R2

R3

Q

Q

Q

Po Q

Pi = input pressure Po = output pressure Pi - Po = (Pi -P1) + (P1-P2) + (P2 - Po) RT = (Pi - Po) /Q Pi - Po = (Pi - P1) + (P1 - P2) +(P2 - Po) R Q 1 Q Q Q

Q RT = R1 +1 R2 + R3 QT

R2

P1

R3

Q2

P2

QT

Q3 QT = Q1 + Q2 + Q3 1 = 1 + 1 + 1 RT = R1 R2 R3

Hydraulic Resistance Equation: R = (P1 – P2)/Q = 8ηl/πr4

• • • •

η = viscosity; l = length; r = radius Viscosity ↑ by ↑ hematocrit Viscosity ↓ in anemia l is usually constant; r changes greatly for normal regulation and in disease.

• 2× radius = 1/16 R → 16 × flow • ½ radius = 16 × R → 1/16 × flow • Control of radius is the dominant mechanism to control resistance.

Pulse pressure (PP): PP = SP – DP

• Compliance: systemic veins > pulmonary circuit > systemic arteries (volume of blood is in same order)

Right Atrium

Vena Cavae

120

• S  P = systolic pressure; DP = diastolic pressure ↓ compliance (e.g., arteriosclerosis) → ↑ SP and ↓ DP, so PP ↑

Veins

C = ∆V / ∆P

• ∆V = volume change; ∆P = pressure change • High compliance means vessels easily distended by blood. • Elasticity is inverse of compliance; vessels are stiff when elasticity is high

Venules

Compliance (C):

mmHg

TPR = (MAP – RAP)/CO

Capillaries

• Mean arterial pressure (MAP); right atrial pressure (RAP) • Pressure gradient is between aorta and right atrium. • TPR is calculated from MAP and cardiac output (CO). RAP is assumed to be 0 mm Hg, unless specified. • TPR is also known as SVR (systemic vascular resistance) Arterioles

Total peripheral resistance equation

Arteries

• Resistance of peripheral circuit: aorta → right atrium • TPR ↑ by sympathetics, angiotensin II, and other vasoconstrictors • Highest TPRs in arterioles; also main site of blood flow regulation

Aorta

Total peripheral resistance (TPR)

80

40

0

• MAP = diastolic + 1/3 (pulse pressure) • MAP = 80 + 1/3(120 – 80) = 80 = 13 = 93 mm Hg

(Continued)

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•

Cardiac output (Fick method)

• CO = VO2 /(Ca – Cv)

• Used to measure cardiac output; most accurate if Ca is pulmonary venous and Cv is pulmonary arterial

•

• V  O2 = oxygen consumption, Ca = arterial oxygen content, Cv = venous oxygen content

• A  ssuming total flow is equal in all vessel types, velocity increases as radius decreases. • T  he aorta is a single large vessel, but its total area is small compared with numerous capillaries in parallel. • If low capillary velocity allows adequate time for diffusion, exchange is perfusion limited. • If velocity is high, metabolic exchange may become diffusion limited.

Cross sectional Area (cm2)

Right Atrium

Vena Cavae

Veins

Venules

Capillaries

Arterioles

Aorta

• V∝ 1/cross sectional area • V ∝1/r2, • V = velocity; r = radius

Arteries

►►Area-Velocity Relationship

4000

50

2000

25

0

= cross sectional area = mean velocity

Mean Velocity (cm/sec)

ORGAN SYSTEMS │ 2. The Cardiovascular System

►►Hemodynamics (Cont’d.)

0

►►Pressures of the Cardiovascular System Lungs

Pulmonary Artery

Pulmonary Vein RA

RV

Systemic Veins

LA

• The cardiac output and stroke volume of the left and right heart are nearly equal. • The mean pressures are different because the systemic resistance is about 6× higher.

LV Aorta & Systemic Arteries

• The pulse pressure in the pulmonary circulation is lower because its compliance is higher.

Peripheral Organs

Pressures in the Pulmonary Circulation (mm Hg)

Pressures in the Systemic Circulation (mm Hg)

Right ventricle

25/0

Left ventricle

Pulmonary artery

25/8

Aorta 120/80

Mean pulmonary artery

14

MAP 93

120/0

Capillary 7–9

Capillary: skeletal Renal glomerular

6 cm in diameter will rupture within 10 years

Syphilitic

Syphilitic obliterative endarteritis of vasa vasorum

Ascending aorta (aortic root)

May dilate the aortic valve ring, causing aortic insufficiency

Marfan syndrome

Lack of fibrillin leads to poor elastin function

Ascending aorta (aortic root)

May dilate the aortic valve ring, causing aortic insufficiency

Dissecting aneurysm (aortic dissection)

Hypertension, cystic medial necrosis (e.g., Marfan syndrome)

Blood enters intimal tear in aortic wall and spreads through media

Presents with severe tearing pain

Berry aneurysm

Congenital; some associated with adult polycystic kidney disease

Classic location: Circle of Willis

Rupture leads to subarachnoid hemorrhage

►►Venous Disease Deep vein thrombosis

Involves deep leg veins

Major complication: pulmonary embolus

Varicose veins

Dilated, tortuous veins caused by increased intraluminal pressure

• Superficial veins of legs • Hemorrhoids • Esophageal varices

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ORGAN SYSTEMS │ 2. The Cardiovascular System

►►Vascular Tumors Angiosarcoma

• Malignant vascular tumor with a high mortality • Occurs most commonly in skin, breast, liver, soft tissues

Glomus tumor

• Small, painful tumors most often found under fingernails

Hemangioma

• Common, benign tumors that may involve skin, mucous membranes, or internal organs

Hemangioblastoma

• Associated with von Hippel-Lindau disease • Tends to involve the central nervous system and retina

Kaposi sarcoma

• Low-grade malignancy of endothelial cells • Viral etiology: human herpesvirus 8 (HHV8) • Most often seen in AIDS patients in the U.S.

►►Edema and Shock Edema

• F  luid is maintained with vessels via balance between hydrostatic pressure (“pushing fluid out”) and oncotic pressure (“pulling fluid in”). • Most causes of edema can be related to either increased hydrostatic pressure or reduced plasma osmotic pressure. Other causes included lymphatic obstruction, sodium retention. • Clinically, may see pitting edema in extremities (dependent) or massive generalized edema (anasarca).

Increased Hydrostatic Pressure Local: deep vein thrombosis Generalized: congestive heart failure

Reduced Plasma Osmotic Pressure Cirrhosis, nephrotic syndrome, protein losing enteropathy

Shock

Three major variants: cardiogenic, septic, and hypovolemic

Type

Comments

Heart Rate

Systemic Vascular Resistance

Cardiac Output

Cardiogenic

Intrinsic pump failure. As the heart fails, stroke volume decreases, with compensatory increases in heart rate and systemic vascular resistance.

↑

↑

↓

Septic

Endotoxin mediated. Massive peripheral vasodilation with a decrease in systemic vascular resistance. There is peripheral pooling of blood (decreased effective circulatory volume). The heart compensates with an increase in heart rate.

↑

↓

↑

Hypovolemic

Blood loss. The effective circulatory volume decreases through actual loss. The heart is able to attempt to compensate with an increase in heart rate.

↑

↑

Unchanged

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►►Antiarrhythmic Drugs Drugs

Mechanism of Action

Effect

Indications

Toxicities

Notes

Class I: Na+ Channel Blockers (Local Anesthetics) These agents block the open or inactivated channel preferentially and therefore block frequently depolarized (e.g., abnormal) tissue better (use dependence; state dependence). Class I drugs are subdivided into three groups based on their effect on AP duration. Class IA quinidine procainamide disopyramide

Class IB lidocaine mexiletine tocainide

Class IC flecainide propafenone encainide

• ↓ Na+ influx

• ↓  K+ efflux (↑ AP duration, ↑ ERP, slows conduction)

Atrial and ventricular arrhythmias

• Q  uinidine: cinchonism (headache, tinnitus, vertigo), ↑ QT interval, torsades de pointes, autoimmune reactions (e.g., thrombocytopenia) • Procainamide: reversible SLE-like syndrome

• H  yperkalemia enhances cardiotoxic effects • Quinidine enhances digoxin toxicity

• ↓  Na+ influx in ischemic or depolarized Purkinje and ventricular tissue (little effect on atrial or normal tissue) • Shortens phase 3 repolarization

• ↓ AP duration • Prolongs diastole

Ventricular arrhythmias (e.g., post MI, digitalis toxicity)

CNS toxicity

Hyperkalemia enhances cardiotoxic effects

• ↓ Na+ influx

• No effect on AP duration • Slows conduction velocity • Increase QRS duration

Refractory ventricular arrhythmias (used as last resort)

Proarrhythmic

Can precipitate cardiac arrest and sudden death in patients with preexisting cardiac abnormalities

• S  lows phase 0 depolarization in His-Purkinje fibers and cardiac muscle

• M  arkedly slows phase 0 depolarization in His-Purkinje fibers and cardiac muscle

ORGAN SYSTEMS │ 2. The Cardiovascular System

Cardiovascular Pharmacology

Class II: Beta Blockers These drugs slow AV conduction. propranolol metoprolol esmolol

• β  -adrenoreceptor blockade − ↓ cAMP − ↓ Ca2+ current • ↓ phase 0 depolarization in AV node • ↓ phase 4 depolarization in SA node

• ↓ AV node conduction • ↑ PR interval

• SVT • P  ost-MI arrhythmia prophylaxis

Impotence, bradycardia, depression, worsens asthma

• U  sed post MI; has a protective effect • May mask premonitory signs of hypoglycemia • Esmolol-very short acting

(Continued)

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ORGAN SYSTEMS │ 2. The Cardiovascular System

►►Antiarrhythmic Drugs (Cont'd.) Drugs

Mechanism of Action

Effect

Indications

Toxicities

Notes

Class III: K+ Channel Blockers These agents prolong the AP and increase the ERP. sotalol ibutilide dofetilide amiodarone

↓ K+ current (delayed rectifier current), prolonging phase 3 repolarization of AP

• ↑  AP duration • ↑ERP

Atrial fibrillation/ flutter, ventricular arrhythmias, refractory arrhythmias

• G  eneral: torsade de pointes, sinus bradycardia • Amiodarone: pulmonary fibrosis, hepatotoxicity, cutaneous, photosensitivity, corneal deposits, thyroid dysfunction • Bretylium: new arrhythmias, ↓ BP • Sotalol: excessive β blockade

• S  otalol: also class II

Class IV: Ca2+ Channel Blockers By blocking L-type Ca2+ channels, these agents slow AV node conduction. verapamil diltiazem

Block L-type Ca2+ channels

Decreased conductivity SA/AV nodes

• A  trial fibrillation/ flutter • Atrial automaticities • AV nodal reentry

Constipation, dizziness, flushing, AV block, strong negative inotropic effect, hypotension



Unclassified Adenosine: used for AV nodal arrhythmias; extremely short acting Mg2+: used in digitalis-induced arrhythmias, torsade de pointes K+: used in digitalis-induced arrhythmias; ↓ other ectopic pacemakers Digoxin: used in rapid atrial flutter/fibrillation, AV nodal reentrant arrhythmias

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Class

Drugs

Mechanism

Side Effects/Notes

SYMPATHOPLEGICS α1 antagonists

Prazosin Doxazosin Terazosin

Block α1 receptors on arterioles and venules

Orthostatic hypotension and syncope, especially with the first dose

α2 agonists

Clonidine

Decrease sympathetic outflow by stimulating α2 receptors in the CNS

Rebound hypertension, dry mouth, sedation, bradyarrhythmias

Methyldopa

Sedation, hemolytic anemia; it is a prodrug that is converted to α-methyl norepinephrine

β blockers

Propranolol Atenolol Metoprolol, others

Block postsynaptic β receptors

CV disturbances, impotence, sleep disturbances, sedation, asthma

Postganglionic sympathetic terminal blockers

Reserpine

Destroys adrenergic synaptic vesicles, decreasing NE release

Rarely used; depression, sedation, dry mouth, edema, bradycardia, night terrors

Guanethidine

Depletes NE and blocks NE release

Rarely used; orthostatic hypotension, sexual dysfunction; uses uptake site to enter nerve terminal

Hexamethonium Mecamylamine

Ganglionic nicotinic antagonists that inhibit postganglionic sympathetic neurons

Rarely used; side effects result from blocking both sympathetic and parasympathetic tone

Ganglionic blockers

ORGAN SYSTEMS │ 2. The Cardiovascular System

►►Antihypertensives

VASODILATORS Ca2+

channel blockers

Amlodipine Diltiazem Nifedipine Verapamil

Block L-type Ca2+ channels in cardiac and smooth muscle

Constipation, edema, headache, bradycardia, GI disturbances, dizziness, AV block, CHF, tachycardia (nifedipine)

Drugs acting through nitric oxide (NO)

Hydralazine

Release endothelial NO → stimulation of smooth muscle guanylate cyclase → ↑ cGMP

Reversible lupus erythematosus-like syndrome, edema; arteriolar dilation

Drugs acting by opening K+ channels

Minoxidil

Open K+ channels → hyperpolarization of vascular smooth muscle

For severe hypertension; hirsutism, pericardial effusion, edema

Vasodilate renal vessels

For hypertensive emergencies

D1 agonist

Nitroprusside

Diazoxide Fenoldopam

For hypertensive emergencies, arteriolar and venous dilation; cyanide poisoning

For hypertensive emergencies; hypoglycemia

INHIBITORS OF ANGIOTENSIN Angiotensinconverting enzyme inhibitors (ACEIs)

Captopril Enalapril Fosinopril Ramipril Lisinopril

Block formation of angiotensin II, leading also to a ↓ in aldosterone

Dry cough, hyperkalemia, angioedema, renal damage in preexisting renal disease; contraindicated in pregnancy (fetal renal damage)

Angiotensin II receptor blockers (ARBs)

Losartan Valsartan Candesartan

Block angiotensin II at AT1 receptor; ↓ in aldosterone

Renal damage in preexisting renal disease, hyperkalemia; contraindicated in pregnancy (fetal renal damage)

Renin inhibitor

Aliskiren

↓ angiotensin I (and therefore ATII and aldosterone)

Hyperkalemia

(Continued)

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ORGAN SYSTEMS │ 2. The Cardiovascular System

►►Antihypertensives (Cont’d.) Class

Drugs

Mechanism

Side Effects/Notes DIURETICS

Thiazides

Hydrochlorothiazide Metolazone

Inhibit Na+/Cl- transporter

Useful in mild hypertension; ↓ K+, ↓ Mg2+, ↑ Ca2+, ↓ Na+, ↑ uric acid, ↑ glucose, ↑ LDL cholesterol, ↑ triglycerides

Loop diuretics

Furosemide

Inhibit Na+/K+/2Cltransporter

Used in moderate to severe hypertension; ↓ K+, ↓  Mg2+, ↓ Ca2+, ↓ Na+, ↑ uric acid, ↑ glucose, ↑ LDL cholesterol, ↑ triglycerides

Aldosterone antagonists

Spironolactone

Aldosterone antagonist in the distal convoluted tubule

Hyperkalemia, metabolic acidosis, gynecomastia; can be safely used in pregnancy

Concomitant Disease States Disease State

Agents Initially Indicated

Agents Contraindicated

Other Notes

Pregnancy

Methyldopa Hydralazine

ACE; ARB

Diabetes

ACEI, ARB

BB (high dose)

Additional treatment with lower-dose BB is acceptable. Diuretics are also good secondary agents

Heart Failure

ACEI

BB (high dose), verapamil; diltiazem

Additional treatment with BB (low dose), ARB, diuretics (all classes); can use select CBs (amlodipine, felodipine)

COPD / Asthma

CB

BB (Non-selective high dose)

ACE not recommended due to chronic cough side effect

Chronic Kidney Disease

ACEI, ARB

Benign Prostatic Hypertrophy

Alpha blockers

Severe Depression

Loop diuretics can be used; do not use other diuretics in renal insufficiency

BB, reserpine, methyldopa

Post-MI

BB, spironolactone, verapamil, diltiazem

Recurrent Stroke Prevention

Diuretics, ACEI

ACEI also acceptable

Definition of Abbreviations: ACEI, Angiotensin-Converting Enzyme Inhibitor; ARB, Angiotensin Receptor Blocker; BB, Beta Blocker; CB, Calcium Channel Blocker

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Angina pectoris, the primary symptom of ischemic heart disease, occurs in periods of inadequate oxygen delivery to the myocardium. Classically, this symptom is described as a crushing, pressure-like pain that occurs during periods of exertion. Strategies used to treat this condition include: − increasing oxygen delivery through increased perfusion − decreasing myocardial oxygen demands

Drug Class Nitrates (nitroglycerin, isosorbide dinitrate)

Calcium Channel Blockers (nifedipine, verapamil, diltiazem)

Beta blockers (propranolol, atenolol, metoprolol)

Molecular mechanism

Generation of endothelial NO activates GC → ↑ cGMP → dephosphorylates MLCK → relaxation of vascular smooth muscle

Inhibits voltage-gated “L-type” Ca2+ channels and ↓ Ca2+ influx in cardiac and vascular smooth muscle → ↓ muscle contractility

β-adrenergic antagonism

Physiologic mechanism

• V  enodilation → ↓ preload → ↓ afterload • ↓ myocardial O2 demand

• Arteriolar vasodilation → ↓ afterload • ↓ myocardial O2 demand • ↓ AV node conduction velocity

↓ contractility, ↓ HR, ↓ BP (mild), ↓ myocardial O2 demand, ↓ AV node conduction velocity

Indications

Acute angina (nitroglycerin), pulmonary edema

Angina, HTN, SVT (except nifedipine)

Angina, HTN, arrhythmia

Adverse effects

Reflex tachycardia, orthostatic hypotension, headache, tachyphylaxis

Cardiac depression, peripheral edema, constipation

Impotence, depression, bradycardia

Notes

Contraindicated in patients taking sildenafil → hypotension and sudden death

Selectivity for vascular Ca2+ channels: Nifedipine > diltiazem > verapamil

Non-CV indications include migraine, familial tremor, stage fright, thyrotoxicosis, glaucoma; beta blockers with ISA are contraindicated in angina/MI patients

Verapamil primarily affects myocardium

ORGAN SYSTEMS │ 2. The Cardiovascular System

►►Antianginal Drugs

Definition of abbreviations: AV, atrioventricular; cGMP, cyclic guanosine monophosphate; GC, guanylate cyclase; HTN, hypertension; ISA, intrinsic sympathomimetic activity; SVT, supraventricular tachycardia.

►►Drugs Used in Heart Failure Heart failure results when tissue demands for circulation cannot be met by an ailing myocardium. Inadequate cardiac output secondary to decreased contractility leads to decreased exercise tolerance and muscle fatigue. Neurohumoral responses to this physiologic shortcoming play an integral role in the pathogenesis of heart failure; thus, drugs used to treat this condition may be aimed at these responses. Physiologically, these drugs may reduce afterload, reduce preload, or increase contractility. Drug Class

Mechanism of Action

Effects

Indications

Toxicities

Notes

ACE inhibitors

Inhibits angiotensinconverting enzyme (ACE) → ↓ angiotensin II and ↑ bradykinin

• D  ecreased aldosterone → ↓ fluid retention

• CHF • Post-MI to prevent pathologic remodeling • Hypertension • Chronic renal disease

Dry cough, hypotension, proteinuria, fetal renal toxicity, angioedema

• C  ornerstone of CHF therapy • Prophylactic in post-MI because they oppose “remodeling” that leads to heart failure

• C  HF (because ↑ contractility) • Atrial fibrillation (because ↓ AV conduction)

Yellow vision, nausea, vomiting, diarrhea, anorexia, hallucination, lifethreatening arrhythmias

• H  ypokalemia enhances toxicity • Quinidine → ↑ dig toxicity (↓ dig clearance) • Digoxin antibodies (FAb fragments) used in overdose • Digoxin does not improve survival following MI

captopril enalapril lisinopril

Cardiac glycosides digoxin

• V  asodilation → ↓ preload and afterload Inhibits Na+/K+ ATPase → ↑ intracellular Na+ → ↓ Na+ gradient → ↓ Na+-Ca2+ exchange → ↑ intracellular Ca2+

• Increased myocardial Ca2+ → increased contractility • Delayed conduction at AV node. (parasympathomimetic effect)

(Continued)

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ORGAN SYSTEMS │ 2. The Cardiovascular System

►►Drugs Used in Heart Failure (Cont’d.) Drug Class

Mechanism of Action

Effects

Indications

Toxicities

Notes

Angiotensin II−receptor blockers

Block angiotensin II receptors

Same as ACE inhibitors

Same as ACE inhibitors

Fetal renal toxicity, no cough

Not as well studied as ACEIs, but seem to have same efficacy

↑ nitric oxide → cGMP → vasodilation

Nitroglycerin, isosorbide dinitrate: predominantly venodilators

CHF, HTN, angina, pulmonary edema

Tachycardia, headache hypotension

• N  itroprusside, nitroglycerin (extended release): used in acute HF • Hydralazine, isosorbide dinitrate: used in chronic HF

losartan candesartan Vasodilators nitroglycerin nitroprusside isosorbide dinitrate hydralazine Beta-receptor antagonists carvedilol labetalol metoprolol Beta-1 agonists dobutamine dopamine Diuretics

Nitroprusside: dilation of arteries = veins

These agents were once contraindicated in heart failure; now they are used to reduce the progression of mild to moderate heart failure. • Carvedilol, labetalol: nonselective β antagonist, α1 antagonist • Metoprolol: β1 antagonist • Contraindicated in patients with asthma or severe bradycardia Used in acute heart failure Dopamine: ↓ dose → improves renal blood flow; moderate dose: stimulates myocardial contractility; ↑ doses → vasoconstrictor (alpha1 receptors); used for cardiogenic shock Dobutamine: β1 selective Used to reduce symptoms of fluid retention (pulmonary congestion, edema); loop diuretics most effective, thiazides can be effective in mild cases

►►Antihyperlipidemics Drug Class/Agents

Mechanism

Side Effects/Comments

HMG-CoA Reductase Inhibitors (“-statins”: lovastatin, atorvastatin, fluvastatin pravastatin, simvastatin, rosuvastatin,)

Inhibit rate-limiting step in cholesterol synthesis ↓ Liver cholesterol ↑ LDL-receptor expression ↓ LDL ↑ HDL ↓ VLDL synthesis ↓ Triglycerides

• • • • •

Bile Acid Sequestrants (cholestyramine, colestipol, colesevelam)

↓ Enterohepatic recirculation of bile salts, leading to: ↑ Synthesis of new bile salts by liver ↓ Liver cholesterol ↑ LDL-receptor expression ↓ LDL

• G  I disturbances • Malabsorption of lipid-soluble vitamins • ↓ Absorption of drugs (e.g., warfarin, thiazides, digoxin, pravastatin, fluvastatin)

Niacin

Liver: ↓ VLDL synthesis Adipose tissue: ↓ lipolysis ↓ VLDL ↓ LDL ↑ HDL ↓ Triglycerides

Flushing (↓ by aspirin and over time), pruritus, hepatoxicity

Fibrates (gemfibrozil, fenofibrate)

Ligands for PPAR-α → activation of lipoprotein lipases ↓ Triglycerides ↓ VLDL and IDL Modest ↓ LDL

• G  allstones • Myopathy (especially when combined with reductase inhibitors) • Can ↑ LDL in some patients, so often combined with other cholesterol-lowering agents

Ezetimibe

Blocks intestinal absorption of cholesterol ↓ LDL

Possible ↑ of hepatotoxicity with reductase inhibitors

 yalgia, myopathy (check creatine kinase) M Rhabdomyolysis ↑ serum aminotransferases Teratogenic P450 inhibitors can ↑ risk of hepatotoxicity, myopathy

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The Respiratory System Chapter 3 Respiratory Embryology and Histology

Respiratory Pathology

Development of the Respiratory System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274 The Alveoli and Blood-Gas Barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274

Gross Anatomy Pharynx and Related Areas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Larynx . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Intrinsic Muscles of the Larynx . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pleura and Pleural Cavities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

275 275 275 276

Respiratory Physiology Lung Volumes and Capacities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277 Dead Space and Ventilation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277–278

Ear, Nose, Throat, and Upper Respiratory System Infections . . . . . . . . . . . . 289–290 Middle Respiratory Tract Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290 Pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291–292 Granulomatous Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293 Obstructive Lung Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293–294 Drugs for Asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294 Restrictive Lung Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295 Respiratory Distress Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .295 Tumors of the Lung and Pleura . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296 Diseases of the Pleura . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297 Pulmonary Vascular Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297

Mechanics of Breathing Muscles of Breathing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Elastic Properties of the Lung . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Elastic Properties of the Lung and Chest Wall . . . . . . . . . . . . . . . . . . . . . . . . . . . . Surface Tension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Airway Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Breathing Cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pulmonary Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary of Classic Lung Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

278 278 279 279 279 280 281 281

Gas Exchange Partial Pressures of O2 and CO2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diffusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oxygen Transport and the Hemoglobin–O2 Dissociation Curve . . . . . . . . . . . . . Additional Changes the Hemoglobin–O2 Dissociation Curve . . . . . . . . . . . . . . . CO2 Transport . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pulmonary Blood Flow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ventilation-Perfusion Relationships . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Disorders That Affect Arterial Oxygen Pressure or Content . . . . . . . . . . . . . . . . . Control of Ventilation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chemoreceptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Response to High Altitude . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

282 283 284 284 285 285 286 287 288 288 288

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ORGAN SYSTEMS │ 3. The Respiratory System

Respiratory Embryology and Histology ►►Development of the Respiratory System

The respiratory (laryngotracheal) diverticulum forms in the ventral wall of the foregut. The lung bud forms at the distal end of the diverticulum and divides into two bronchial buds. These branch into the main bronchi, lobar bronchi, and segmental bronchi. The right bud divides into three main bronchi, and the left divides into two. The tracheoesophageal septum divides the foregut into the esophagus and trachea.

Clinical Correlate A tracheoesophageal fistula is an abnormal communication between the trachea and esophagus caused by a malformation of the tracheoesophageal septum. 90% occur between the esophagus and distal third of the trachea. It is generally associated with esophageal atresia and polyhydramnios. Symptoms include gagging and cyanosis after feeding and the reflux of gastric contents into the lungs, causing pneumonitis.

►►The Alveoli and Blood-Gas Barrier Alveolar macrophage Type I cell

Alveolar macrophage Alveolus

Connective tissue

The conducting zone of the lungs does not participate in gas exchange and is anatomic dead space. It is composed of the trachea, bronchi, bronchioles, and terminal bronchioles. The trachea and bronchi contain pseudostratified ciliated columnar cells and goblet cells (secrete mucous). Bronchioles and terminal bronchioles contain ciliated epithelial cells and Clara cells (which secrete a surfactant-like substance, aid in detoxification, and are stem cells for the ciliated cells). The respiratory zone carries out gas exchange and consists of respiratory bronchioles, alveolar ducts, and alveoli.

Type II cells Capillary

Endothelial cell

Red blood cell

Alveolus

Type I cell Basal lamina Endothelial cell

Capillary

Terminal bronchioles divide into respiratory bronchioles, which contain alveoli and branch to form alveolar ducts. The ducts terminate in alveolar sacs and are lined by squamous alveolar epithelium. Alveoli are thin-walled sacs responsible for gas exchange. They contain: • T  ype I epithelial cells, which provide a thin surface for gas exchange. • Type II epithelial cells, which produce surfactant. • A  lveolar macrophages, which are derived from monocytes and remove particles and other irritants via phagocytosis. There are approximately 300 million alveoli in each lung.

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►►Pharynx and Related Areas The pharynx is a passageway shared by the digestive and respiratory systems. It has lateral, posterior, and medial walls throughout but is open anteriorly in its upper regions (nasopharynx, oropharynx), communicating with the nasal cavity and the oral cavity. The nasopharynx is the region of the pharynx located directly posterior to the nasal cavity. It communicates with the nasal cavity through the choanae (i.e., posterior nasal apertures). The oropharynx is the region of the pharynx located directly posterior to the oral cavity. It communicates with the oral cavity through a space called the fauces. The fauces are bounded by two folds, consisting of mucosa and muscle, known as the anterior and posterior pillars. • The anterior pillar of the fauces, also known as the palatoglossal fold, contains the palatoglossus muscle. • The posterior pillar of the fauces, also known as the palatopharyngeal fold, contains the palatopharyngeus muscle. • The tonsillar bed is the space between the pillars that houses the palatine tonsil. The laryngopharynx is the region of the pharynx that surrounds the larynx. It extends from the tip of the epiglottis to the cricoid cartilage. Its lateral extensions are known as the piriform recesses.

ORGAN SYSTEMS │3. The Respiratory System

Gross Anatomy

►►The Larynx Thyroid cartilage Vocalis muscle Vocal ligament Thyroarytenoid muscle (↓ tension) Posterior cricoarytenoid muscle

Lateral arytenoid muscle

Action of posterior cricoarytenoid muscle (abduction of vocal ligament)

Action of lateral cricoarytenoid muscle (adduction of vocal ligament)

Hyoid bone Corniculate cartilage

Thyroid cartilage

Arytenoid cartilage Transverse arytenoid muscle

Cricoid cartilage

Posterior cricoarytenoid muscle

The larynx is the voice box. It also maintains a patent airway and acts as a sphincter during lifting and pushing. Skeleton of the larynx: • Three unpaired laryngeal cartilages (i.e., thyroid, cricoid, epiglottis) and three paired cartilages (i.e., arytenoid, cuneiform, corniculate) • The fibroelastic membranes include the thyrohyoid membrane and the cricothyroid membrane (conus elasticus).The free, upper border of the latter is specialized to form the vocal ligament on either side.

Cricothyroid muscle (↑ tension)

Trachea

Posterior

Lateral

►►Intrinsic Muscles of the Larynx* Muscle

Function

Posterior cricoarytenoid

Abducts vocal fold

Lateral cricoarytenoid

Adducts vocal fold

Cricothyroid

Tenses vocal fold

Thyroarytenoid (including vocalis)

Relaxes vocal fold

Thyroepiglotticus

Opens laryngeal inlet

Aryepiglotticus

Closes laryngeal inlet

Oblique and transverse arytenoids

Close laryngeal inlet

*Note that the cricothyroid is innervated by the external laryngeal nerve, a branch of the superior laryngeal branch of the vagus nerve. All other intrinsic laryngeal muscles are supplied by the recurrent laryngeal branch of the vagus nerve.

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ORGAN SYSTEMS │ 3. The Respiratory System

►►Pleura and Pleural Cavities Parietal pleura lines the inner surface of the thoracic cavity; visceral pleura follows the contours of the lung itself. Inflammation of the central part of the diaphragmatic pleura may produce pain referred to the shoulder (phrenic nerve; C3, C4, and C5).

Costomediastinal recess

Right lung

Left lung

Superior lobe

Superior lobe

Anterior view

Middle lobe Inferior lobe

Inferior lobe

Costodiaphragmatic recesses

Diaphragm

Costodiaphragmatic recess

Mediastinum

Posterior view

• T  he costal line of reflection is where the costal pleura becomes continuous with the diaphragmatic pleura from Rib 8 in the midclavicular line, to Rib 10 in the midaxillary line, and to Rib 12 lateral to the vertebral column. • Costodiaphragmatic recesses are spaces below the inferior borders of the lungs where costal and diaphragmatic pleurae are in contact. • The costomediastinal recess is a space where the left costal and mediastinal parietal pleurae meet, leaving a space due to the cardiac notch of the left lung. This space is occupied by the lingula of the left lung during inspiration.

Structure of the Lungs • The right lung is divided by the oblique and horizontal fissures into three lobes: superior, middle, and inferior. • The left lung has only one fissure, the oblique, which divides the lung into upper and lower lobes. The lingula of the upper lobe corresponds to the middle lobe of the right lung. • Bronchopulmonary segments of the lung are supplied by the segmental (tertiary) bronchus, artery, and vein. There are 10 on the right and eight on the left.

Arterial Supply • R  ight and left pulmonary arteries arise from the pulmonary trunk. The pulmonary arteries deliver deoxygenated blood to the lungs from the right side of the heart. • Bronchial arteries supply the bronchi and nonrespiratory portions of the lung. They are usually branches of the thoracic aorta.

Venous Drainage • There are four pulmonary veins: superior right and left and inferior right and left. • Pulmonary veins carry oxygenated blood to the left atrium of the heart. • The bronchial veins drain to the azygos system. They share drainage from the bronchi with the pulmonary veins.

Lymphatic Drainage • Superficial drainage is to the bronchopulmonary nodes; from there, drainage is to the tracheobronchial nodes. • Deep drainage is to the pulmonary nodes; from there, drainage is to the bronchopulmonary nodes. • Bronchomediastinal lymph trunks drain to the right lymphatic and the thoracic ducts.

Innervation of Lungs • Anterior and posterior pulmonary plexuses are formed by vagal (parasympathetic) and sympathetic fibers. • Parasympathetic stimulation has a bronchoconstrictive effect. • Sympathetic stimulation has a bronchodilator effect.

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►►Lung Volumes and Capacities Vt

Tidal volume

Air inspired and expired in normal breathing

TLC

Total lung capacity

Volume in lungs with maximal inspiration

FRC

Functional residual capacity

Volume in lungs at end of quiet, passive expiration; the equilibrium point of the system

RV

Residual volume

Volume at end of maximal forced expiration

Tidal volume

VC

Vital capacity

Volume expired from maximal inspiration to maximal expiration

Expiratory reserve volume

IRV

Inspiratory reserve volume

The volume inspired with a maximal inspiratory effort in excess of the tidal volume

ERV

Expiratory reserve volume

The volume expelled with an active expiratory effort after passive expiration

IC

Inspiratory capacity

The volume of air inspired with a maximal inspiratory effort after passive expiration

6 5

4

Inspiratory reserve Inspiratory volume capacity Vital capacity

Liters

3

2 1

Total lung capacity

Functional residual capacity

Residual volume

0

ORGAN SYSTEMS │3. The Respiratory System

Respiratory Physiology

Note: FRC and RV cannot be measured with a spirometer. Spirometry can only measure changes in volume.

►►Dead Space and Ventilation VT = 500 ml

VD = 150 ml

VD

End of Inspiration

VA = VT - VD VA Contains CO2

VA = 350 ml

Vd = dead space (no gas exchange) Anatomic Vd = conducting airways Alveolar Vd = alveoli with poor blood flow (ventilated but not perfused) Physiologic Vd = anatomic + alveolar dead space

Standard Symbols = alveolar a = arterial V = volume • V = minute ventilation P = pressure Paco2 = alveolar pressure of CO2 Paco2 = arterial pressure of CO2 Peco2 = Pco2 in expired air a

Abbreviation

Name

Definition

Normal Values

Vd

Dead space

Volume that does not exchange gas with blood

150 mL

Va

Alveolar volume

Portion of tidal volume that reaches alveoli during inspiration

350 mL

Vt

Tidal volume: Vt = Va + Vd

Amount of gas inhaled and exhaled during normal breathing – the sum of dead space volume and alveolar volume

500 mL

n

Respiratory frequency

Breaths/minute

15/min

Total ventilation: Vtn = Van + Vdn • • • Ve = Va + Vd

Total ventilation per minute Vtn = (350 mL × 15/min) + (150 mL × 15/min) = 7,500 mL/min • Ve = 5,250 mL/min + 2,250 mL/min = 7,500 mL/min

7,500 mL/min

•

Ve

(Continued)

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ORGAN SYSTEMS │ 3. The Respiratory System

►►Dead Space and Ventilation (Cont’d.) •

Va

Alveolar ventilation • Va = (Vt – Vd) × n

Amount of inspired air that reaches the alveoli each minute. It is the effective part of ventilation.

5,250 mL/min

The adequacy of alveolar ventilation can be determined from the concentration of expired carbon dioxide. • • Vco2 = CO2 production (generally assume is normal and constant) • ↑ alveolar ventilation → ↓ Paco2 • ↓ alveolar ventilation → ↑ Paco2

•

Vco2 • V a = Pco × K 2

Physiologic Dead Space

VD PaCO 2 − PECO 2 = VT PaCO 2

All expired CO2 comes from alveolar gas, not from dead space gas. Therefore, the fraction shows the dilution of CO2 by the dead space. In the normal individual, anatomic dead space = physiologic dead space, and Vd/ Vt = 0.2−0.35. In lung disease, this number can increase.

Mechanics of Breathing

�

►►Muscles of Breathing Muscles of inspiration

• Diaphragm—most important • Other muscles of inspiration are used primarily during exercise or in diseases that increase airway resistance (e.g., asthma): − External intercostal muscles (move ribs upward and outward) − Accessory muscles (elevate first two ribs and sternum)

Muscles of expiration

• Expiration is passive during quiet breathing. • Muscles of expiration are used during exercise or increased airway resistance (e.g., asthma): − Abdominal muscles (help push diaphragm up during exercise or increased airway resistance) − Internal intercostal muscles (pull ribs downward and inward)

►►Elastic Properties of the Lung Pressure-Volume Curve Lung Compliance 6,000

5,000

ph

4,000

Em

Change of lung volume (ml)

yse

ma

• Compliance (∆V/∆P) is used to estimate the distensibility of the lungs. It is inversely related to elasticity (tendency of a material to recoil when stretched). •  The steeper the slope, the higher the compliance. The flatter the slope, the lower the compliance (stiffer). •  Normal curve: Compliance = ∆V/∆P = 800 mL/4 cm H2O = 200 mL/cm H2O Atelectasis requires an extreme effort to open collapsed alveoli. •  •  Compliance of lungs also ↑ with age.

al

m

or

3,000

N

2,000

ir

sp

Re

ry

o at

es

str

Di

e

m

ro

nd

y sS

∆V = 800

1,000 ∆P = 4

0

4

Atelectasis (collapse) 8

16 20 12 24 Airway Pressure (cmH2O)

28

32

Clinical Correlation: Changes in Lung Compliance ↑ Compliance

Emphysema

• Less elastic recoil of lungs, so FRC ↑ • Chest wall expands and becomes barrel-shaped • Also, ↑ RV, ↑ TLC, ↓ FVC, ↑ Raw

↓ Compliance*

Fibrosis, respiratory distress syndrome

• Tendency of lungs to collapse ↑, so FRC ↓ • Also, ↓↓ TLC, ↓ RV, ↓↓ FVC

Definition of abbreviation: Raw, airway resistance. *Restrictive lung disease: a condition that reduces the ability to inflate the lungs (e.g., ↓ compliance).

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At FRC the forces (see arrows) are in equilibrium

100 Vital Capacity 80 %

a

em

ys ph

Che st W all

Em

60

t es

ng

&

l,

al W

r No

al

m

b Fi

Emphysema

s

si

ro

Ch

Lu

FRC Lun g

40

The figure to the left shows the pressure−volume relationships of the lung, the chest wall, and the lung and chest wall together. • At FRC, the system is at equilibrium and the airway pressure = 0 cm H2O. At FRC, the elastic recoil of the lungs tends to collapse the lungs. The tendency of the lungs to collapse is balanced exactly by the tendency of the chest wall to spring outward. • The result of the opposing forces of the lungs and chest wall cause the intrapleural pressure (Pip) to be negative (a vacuum). The Pip is the pressure in the intrapleural space, which lies between the lungs and chest wall.

20

Clinical Correlation Fibrosis

0

_20

_10

0

+10

+20

+30

If sufficient air is introduced into the intrapleural space, the Pip becomes atmospheric (0 mm Hg), and the lungs and chest wall follow their normal tendencies: the lungs collapse and the chest wall expands. This is a pneumothorax.

ORGAN SYSTEMS │3. The Respiratory System

►►Elastic Properties of the Lung and Chest Wall

Airway Pressure (cmH2O)

►►Surface Tension • T  he attractive forces between adjacent molecules of liquid are stronger than those between liquid and gas, creating a collapsing pressure.

P

• • • •

T/r Psmall > Plarge

Laplace’s Law: P =

2T

, where P = collapsing pressure T = surface tension r = radius of alveoli Large alveoli (↑r) have low collapsing pressures (easy to keep open). Small alveoli (↓r) have high collapsing pressures (difficult to keep open). Surfactant reduces surface tension (T). With ↓ surfactant (e.g., premature infants), � smaller alveoli tend to collapse (atelectasis).

r

• Surfactant, produced by type II alveolar cells, ↑ compliance.

►►Airway Resistance Airflow

Q= Airway resistance

�

Changes in airway � resistance

R=

∆P R

8hl pr

4

where Q = airflow ∆P = pressure gradient R = airway resistance where R = resistance η = viscosity of inspired gas l = airway length r = airway radius Medium-sized bronchi are the major sites of airway resistance (not the smaller airways because there are so many of them).

• Bronchial smooth muscle: − Parasympathetic nervous system → bronchoconstriction via M3 muscarinic receptors (↑ resistance) − Sympathetic nervous system → bronchodilation via β2 receptors (↓ resistance) • Lung volume: ↑ lung volume → ↓ resistance (greater radial traction on airways) ↓ lung volume → ↑ resistance • Viscosity or density of inspired gas: ↑ density → ↑ resistance (deep sea diving) ↓ density → ↓ resistance (breathing helium)

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ORGAN SYSTEMS │ 3. The Respiratory System

►►The Breathing Cycle 0.5

Inspiration

At rest (FRC): Pa = Patm = 0 mm Hg

Expiration

Inspiration

0.4 0.3 VT

0.2 0.1

Change in Lung Volume (l)

0 -5

Intrapleural Pressure (cmH2O)

-6

FRC

1. Inspiratory muscles contract. 2. Thoracic volume ↑. 3. Pip becomes more negative. 4. Lungs expand (also causes Pip to be more negative because of ↑ elastic recoil). 5. Pa becomes negative. 6. Air flows in down pressure gradient (Patm − Pa). Expiration

-7 -8 + 0.5 Flow (l/sec) 0

1. Muscles relax. 2. Thoracic volume ↓. 3. Pip is less negative. 4. Lungs recoil inward (also causes Pip to be less negative). 5. Pa becomes positive. 6. Air flows out down pressure gradient (Pa − Patm).

Clinical Correlation

_ 0.5

+1

0

Alveolar Pressure (cmH2O)

Obstructive lung disease: a condition that causes an abnormal increase in Raw. Chronic obstructive pulmonary disease (COPD) such as emphysema → destruction of elastic tissue → ↑ lung compliance → collapse of airways on expiration (dynamic compression). This occurs in normal individuals during a forced expiration but can occur during normal expiration in COPD. COPD patients learn to expire slowly and with pursed lips.

_1 +30

_11

+38 +19

Definition of abbreviations: FRC, functional residual capacity; Pa, alveolar pressure; Patm, atmospheric pressure.

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Normal

Obstructive Disease

Restrictive Disease

7

7

ORGAN SYSTEMS │3. The Respiratory System

►►Pulmonary Disease

7

FEV1

FEV1

4 FVC 3

FVC

Lung Volume (liters)

5

Lung Volume (liters)

Lung Volume (liters)

6

6

6

5 4 3

5 4 FEV1

3

FVC 2

2

2

1

1

1

0

0

0 1 second

1 second

FEV1 = 80% (or 0.80) FVC

FEV1 = 50% FVC

• Forced vital capacity (FVC) is the volume of air that can be expired with a maximal effort after a maximal inspiration. • Forced expiratory volume 1 (FEV1) is the volume of gas expired during the first second.

1 second

FVC

FRC

TLC

RV

FEV1 = 88% FVC

FVC

FRC

TLC

RV

TLC

RV

FRC

FVC

FEV1

Obstructive pattern

↑

↑↑

↑↑

NC or ↓

↓↓

↓↓

↓ FEV1/FVC with ↑ TLC

Restrictive pattern

↓↓

↓

↓

↓↓

↓

NC or ↑

↓ FVC with ↓ TLC

FEV1/FVC

Most Diagnostic

Definition of abbreviation: NC, no change.

►►Summary of Classic Lung Diseases Disease

Pattern

Characteristics

Asthma

Obstructive

Raw is ↑ and expiration is impaired. All measures of expiration are ↓ (FVC, FEV1, FEV1/FVC). Air is trapped →↑ FRC.

COPD

Obstructive

• Combination of chronic bronchitis and emphysema • There is ↑ compliance, and expiration is impaired. Air is trapped →↑ FRC. “Blue bloaters” (mainly bronchitis): impaired alveolar ventilation → severe hypoxemia with −  cyanosis and ↑ Paco2. They are blue and edematous from right heart failure. “Pink puffers” (mainly emphysema): alveolar ventilation is maintained, so they have −  normal Paco2 and only mild hypoxemia. They have a reddish complexion and breathe with pursed lips at an ↑ respiratory rate.

Fibrosis

Restrictive

• There is ↓ compliance, and inspiration is impaired. • All lung volumes are decreased, but because FEV1 decreases less than FVC, FEV1/FVC may be increased or normal.

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ORGAN SYSTEMS │ 3. The Respiratory System

Gas Exchange ►►Partial Pressures of O2 and CO2 Dalton’s Law of Partial Pressures: Partial pressure (pgas) = total pressure (Pt) × fractional gas concentration (Fgas) Alveolar gas equation: Pao2 =Pio2 − Pco2/R • • Alveolar ventilation equation: Va = Vco2 × K/Paco2; (K = Pb − Ph2o = 760 − 47 = 713)

.

Alveolar Ventilation (VA)

160 mm Hg

Ambient PO2 = F(Patm)

150 mm Hg

PIO2 = F(Patm – 47) I = Inspired

PAO2 = 100 mm Hg PACO2 = 40 mm Hg End Capillary PvO2 = 40 mm Hg PvCO2 = 45 mm Hg

PO2 = 100 mm Hg PCO2 = 40 mm Hg

.

Pulmonary Capillary Blood Flow (Qc)

Systemic Arterial PaO2 = 95 mm Hg PaCO2 = 40 mm Hg

A = alveolar, a = systemic arterial

Equation

O2

CO2

0.21

0

0.21 (760) = 160

0

Dry inspired air (any altitude)

Fgas

Dry air at sea level

Pgas = Fgas × Pb

Inspired, humidified tracheal air (Pio2)

Pgas = Fgas × (Pb – Ph2o)

0.21 (760 − 47) = 150

0

O2: Pao2 = Pio2 − Paco2/R

150 – 40/0.8 = 100

(280 mL/min × 713)/5,000 mL/min = 40

Alveolar air (Pagas)

•

CO2: Vco2K/R Systemic arterial blood (Pagas)

—

100 (completely equilibrates with alveolar O2 if no lung disease)

40 (CO2 is from pulmonary capillaries and equilibrates with alveolar gas)

Mixed venous blood (Pvco 2)

—

40 (O2 has diffused from arterial blood into tissues)

45 (CO2 has diffused from tissues to venous blood)

All pressures are expressed in mm Hg. Definition of abbreviations: K, constant; Paco2, partial pressure of alveolar carbon dioxide; Pao2, partial pressure of alveolar oxygen; Pb, • barometric pressure; Ph2o, water vapor pressure; Pio2, partial pressure of inspired oxygen; Vco2, CO2 production; R, respiratory exchange ratio.

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Fick’s Law of Diffusion

• Vgas ∝ D(P1 – P2) × A/T where Vgas = diffusion of gas, D = diffusion coefficient of a specific gas, A = surface area, T = thickness. • A and T are physical factors that change mainly in disease. • D of CO2 >>> O2

Time course in pulmonary capillary

Normal Cardiac Output

Intense Exercise

Alveolar

PO2 in blood (mmHg)

100 Normal Abnormal

50

Grossly Abnormal Venous

0

0.25 0.50 Time in capillary (sec)

Perfusion-Limited Gases Gases that equilibrate between the alveolar gas and pulmonary capillaries are perfusion-limited. The amount of gas transferred is not dependent on the properties of the blood-gas barrier. • O2 (under normal conditions) • N2O (nitrous oxide) • CO2

• A  red blood cell remains in capillary for 0.75 seconds (s) • Equilibrium is reached in 0.25 s in normal lung at resting state. • Exercise reduces equilibration time, but there is still enough reserve for full equilibration of oxygen in a healthy individual.

ORGAN SYSTEMS │3. The Respiratory System

►►Diffusion

0.75

Diffusion-Limited Gases Gases that do not equilibrate between the alveolar gas and the pulmonary capillaries are diffusion-limited. The amount of gas transferred is dependent on the properties of the blood-gas barrier. • O2: − Blood-gas barrier is thickened in fibrosis. − Surface area is ↓ in emphysema. − Intense exercise ↓ time for equilibration in pulmonary capillaries (can occur in normal lungs). − Low O2 gas mixture (less partial pressure gradient, can occur in normal lungs) • CO: Binds so avidly to Hb, Paco does not ↑ much. Used to measure the pulmonary diffusing capacity.

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Total O2 content at high pressure includes dissolved O2

20

Temperature PCO2 H+ 2,3-DPG

80

16

Hb-O2

60

12

40

8

20

4

0

20

60 80 100 PO2 (mmHg)

40

120

140

Key Pressures

Key Saturation %

Pao2 = 100 mm Hg

Almost 100% saturated

Pv- o2 = 40 mm Hg

75% saturated

P50 = 27 mm Hg

50% saturated

O2 Content (ml/100ml)

100

Hemoglobin saturation (%)

ORGAN SYSTEMS │ 3. The Respiratory System

►►Oxygen Transport and the Hemoglobin−O2 Dissociation Curve

600

• Each hemoglobin (Hb) molecule has four subunits. • Each subunit has a heme moiety with an iron in the ferrous state (Fe2+), and two α and two β polypeptide chains. • O2 capacity: maximal amount of O2 that can bind to Hb • O2 content*: Total O2 in blood (bound + dissolved) = (O2 capacity × % saturation) + dissolved O2

= (1.39 × Hb ×

Sat ) + 0.003 PO2 100

• C  ontent reflects O2 bound to Hb (the amount of O2 that is dissolved is trivial compared to bound). • Partial pressure reflects dissolved O2.

Shift to Right (↑ P50) • Facilitates unloading • ↑ temperature, ↑ Pco2, ↓ pH, ↑ 2,3-DPG • Exercising muscle is hot, acidic, and hypercarbic

Shift to Left (↓ P50) • Facilitates loading • ↓ temperature, ↓ Pco2, ↑ pH, ↓ 2,3-DPG • CO poisoning

Definition of abbreviations: Hb, hemoglobin concentration; Sat, saturation; P50, Po2 at 50% saturation. *1.39 mL of O2 binds 1 g of Hb (some texts use 1.34 or 1.36).

►►Additional Changes in the Hemoglobin–O2 Dissociation Curve ia

Polycythem

Arterial content increase Normal Hb = 15

20

Arterial content decrease

16 O2 Content (vol%)

100% sat.

Anemia

Normal

O2 Content (vol%)

24

CO

12

100% sat. 8

38°C pH = 7.40

100% sat.

PO2 in Blood (mm Hg)

CO poisoning is dangerous for three reasons:

4

P50 0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 PO2 (mm Hg)

• Polycythemia and anemia change arterial O2 content.

1. CO left-shifts the curve (↓ P50), causing ↓ O2 unloading in tissues. 2. CO has 240 times greater affinity for Hb as O2, thus ↓ the O2 content of blood. 3. CO inhibits cytochrome oxidase

• Pao2 and P50 remain the same.

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ORGAN SYSTEMS │3. The Respiratory System

►►CO2 Transport CO2

CO2

Plasma

CO2 + H2O H2CO3 Carbonic Anhydrase Hb - CO2

–

Cl

HCO3

–

+ – H + HCO3

Hb - H Red Blood Cell

Forms of CO2 Percentages reflect contribution in arterial blood. 1. HCO3− = 90% 2. Carbamino compounds (combination of CO2 with proteins, especially Hb) = 5% 3. Dissolved CO2 = 5%

►►Pulmonary Blood Flow Resistance (R)

Very low

Compliance

Very high

Pressures

Very low compared with systemic circulation

Effect of Pao2

• • • •

Gravity

Upright posture: greatest flow in base; lowest in apex

Filter

Removes small clots from circulation

Vasoactive substances

Converts angiotensin I → AII; inactivates bradykinin; removes prostaglandin E2 and F2α and leukotrienes

Alveolar hypoxia → vasoconstriction. This is a local effect and the opposite of other organs, where hypoxia → vasodilation. This directs blood away from hypoxic alveoli to better ventilated areas This is also why fetal pulmonary vascular resistance is so high. Pulmonary resistance ↓ when the first breath oxygenates the alveoli, causing pulmonary blood flow to rise.

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• •

•

•

V/Q: the ratio of alveolar ventilation (V) to pulmonary blood flow (Q).

0.15

Fraction of total

ORGAN SYSTEMS │ 3. The Respiratory System

►►Ventilation−Perfusion Relationships

3 Blood flow Q

0.10 0.05

VA/Q

2

VA Ventilation

VA/Q 1

Base

• B  lood flow is lowest at the apex and highest at the base (gravity effect). • V  entilation is lowest at the apex and highest at the base. • T  he change in ventilation is not as great as blood • • flow, so the V/Q ratio is highest at the apex and lowest at the base.

Apex

Middle

• •

Changes in V/Q

O2 = 150 mm Hg CO2 = 0 mm Hg

A good way to remember the changes in partial • • pressures due to alterations in V/Q is to think of the most extreme cases.

CO2 = 45 O2 = 40

O2 = 40 CO2 = 45

O2 = 100

O2 = 150

CO2 = 40

CO2 = 0

• •

If ventilation is 0 (airways blocked), V/Q = 0 (a •  shunt). No gas exchange occurs and the Pao2 and Paco2 are the same as mixed venous blood. • •

normal ventilation

obstruction of ventilation

obstruction of arterial vessel

•  If perfusion is 0 (embolism), V/Q = ∞ (dead space). No gas exchange occurs and Pao2 and Paco2 are the same as inspired air.

� of Changes Summary

Shunt VA/Q = 0 Base Optimum

45

PCO2 (mmHg)

Apex

Low V /Q A

40

Hig

30

•

Va • Q • • Va/Q Po2 Pco2

hV A /Q

20 10 0 40

50

60

70

80

100 110 90 PO2 (mmHg)

120

130

140

Apex ↓↓ ↓↓↓ ↑↑

Base ↑ ↑↑ ↓

↑ ↓

↓ ↑

VA/Q = 150 Dead space

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Notes

Pao2

Paco2

Cao2

A-a*

Response to Supplemental O2 N

Hypoventilation1

Drugs (e.g., opiates, barbiturates), head trauma, chest wall dysfunction

↓

↑

↓

NC

↑ Pao2; ↑ Cao2

↓ inspired pO2

↑ altitude

↓

↓2

↓

NC

↑ Pao2; ↑ Cao2

↓

↑

↑ Pao2; ↑ Cao2

Diffusion limitation3

Pao2 and Pao2 do not fully equilibrate

↓

NC2

Shunt4

Venous blood mixes with arterial system, bypassing ventilated areas of lung

↓

NC2

↓

↑

Poor

V/Q mismatch

Ventilation and perfusion are mismatched in the lung

↓

NC2

↓

↑

↑ Pao2; ↑ Cao2

CO poisoning

Exhaust fumes

NC

NC

↓

NC

↑ Pao2; NC in Cao25

↓ [Hb]

Anemia

NC

NC

↓

NC

↑ Pao2; NC in Cao26

•

ORGAN SYSTEMS │3. The Respiratory System

►►Disorders That Affect Arterial Oxygen Pressure or Content

Definition of abbreviation: NC, no change or minimal response. *An increase in the A-a gradient indicates a problem with gas exchange. N Warning: Supplemental O2 in CNS depression and lung disease can shut off the hypoxic drive to ventilation and cause cessation of spontaneous breathing. • 1Hypoventilation: ↓ V a, so ↑ Paco2 → ↓ Pao2 →↓ Pao2 (As ↑ CO2 diffuses into alveoli from blood, it displaces O2.) 2Result of hypoxia-induced increase of ventilation 3Diffusion limitation causes disease (blood-gas barrier has less surface area or is thickened), ↓ transit time during intense exercise, exercise at high altitude 4Abnormal shunts (often congenital, e.g., Tetralogy of Fallot) 5Slow response of Cao due to extremely high affinity of Hb for carbon monoxide 2 6Can only increase dissolved O because Hb is saturated at normal Pao . 2 2

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ORGAN SYSTEMS │ 3. The Respiratory System

►►Control of Ventilation Brain Stem Respiratory Centers Medulla

Rhythm generator

Inspiratory center: generates breathing rhythm Expiratory center: not active during normal, passive expiration; involved in active expiration (e.g., exercise)

Pons

Regulates medulla

Apneustic center: stimulates prolonged inspiration Pneumotaxic center: terminates inspiration

Cortex

Conscious and emotional response

Lesions above the pons eliminate voluntary control, but basic breathing pattern remains intact.

►►Chemoreceptors Central (Medulla) Chemoreceptors (Respond to Changes in pH of CSF)

Peripheral Chemoreceptors (Carotid and Aortic Bodies)

O2

No response

• ↓  Pao2 (5 years old

Slow growth on Eaton medium, cold agglutinins

Mycoplasma pneumoniae, viruses

Release of O2 radicals causes necrosis of epithelium

Symptomatic

Definition of abbreviations: Ag, antigens; NAD, nicotinamide adenine dinucleotide; RSV, respiratory syncytial virus.

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Lobar pneumonia and bronchopneumonia—acute inflammation and consolidation (solidification) of the lung due to an extracellular bacterial agent. Lobar affects entire lobe (opacification = consolidation on x-ray); bronchopneumonia (patchy consolidation around bronchioles on x-ray). Associated with high fever and productive cough. Interstitial (atypical) pneumonia causes interstitial pneumonitis without consolidation and can be due to viral agents (influenza virus; parainfluenza; RSV, especially in young children; adenovirus; CMV, especially in immunocompromised; varicella), Mycoplasma pneumoniae, and Pneumocytis jiroveci. Clinical: • Fever and chills • Cough (may be productive) • Tachypnea • Pleuritic chest pain • Decreased breath sounds, rales, and dullness to percussion • Elevated WBC count with a left shift

Diagnosis

Most Common Causative Agents

Adults (including alcoholics), rustcolored sputum Lobar pneumonia or less commonly, bronchopneumonia

Gram ⊕ diplococcus, α hemolytic, catalase – lysed by bile, inhibited by Optochin

Neutropenic patients, burn patients, CGD, CF

Type of Infection

Case Vignette/ Key Clues

Pneumonia— typical

Pneumonia— atypical

Pathogenesis

Treatment

Streptococcus pneumoniae, Haemophilus influenzae (much less common)

Capsule antiphagocytic IgA protease

Third-generation cephalosporin, azithromycin

Gram – rod, oxidase ⊕, bluegreen pigments

Pseudomonas aeruginosa

Opportunist

Sensitivity testing required

Foul-smelling sputum, aspiration possible

Culture of sputum

Anaerobes, mixed infection (Bacteroides, Fusobacterium, Peptococcus)

Aspiration of vomitus → enzyme damage → anaerobic foci

Empiric antibiotic therapy (amoxicillin/ clavulanate, gentamicin)

Alcoholic with aspiration, facultative anaerobic, gram – bacterium with huge capsule, currant jelly sputum

Gram – rod, lactose fermenting, oxidase –

Klebsiella pneumoniae

Capsule protects against phagocytosis

Susceptibility testing necessary

Poorly nourished, unvaccinated baby/ child; giant cell pneumonia with hemorrhagic rash, Koplik spots

Serology

Measles: malnourishment ↑ risk of pneumonia and blindness

Cytolysis in lymph nodes, skin, mucosa

Supportive

Pneumonia teens/ young adults; bad hacking, dry cough “walking pneumonia”

Serology, cold agglutinins

Mycoplasma pneumoniae (most common cause of pneumonia in school-age children)

ORGAN SYSTEMS │3. The Respiratory System

►►Pneumonia

Syncytia → giant cell pneumonia

Adhesin causes adhesion to mucus; oxygen radicals cause necrosis of epithelium

Doxycycline, azithromycin

(Continued)

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ORGAN SYSTEMS │ 3. The Respiratory System

►►Pneumonia (Cont’d.) Type of Infection

Case Vignette/ Key Clues

Pneumonia— atypical (cont’d.)

Air-conditioning exposure, common showers, especially >50 years, heavy smoker, drinker

Direct fluorescent antibody

Bird exposure ± hepatitis

Acute pneumonia or chronic cough with weight loss, night sweats

Sudden acute respiratory syndromes

Diagnosis

Most Common Causative Agents

Pathogenesis

Treatment

Legionella spp.

Intracellular in macrophages

Macrolide

Direct fluorescent antibody, intracytoplasmic inclusions

Chlamydophilia psittaci

Obligate intracellular

Tetracycline, erythromycin

AIDS patients with staccato cough; “ground glass” x-ray; biopsy: honeycomb exudate with silver staining cysts; premature infants

Silver-staining cysts in alveolar lavage

Pneumocystis jiroveci (carinii)

Attaches to type I pneumocytes, causes excess replication of type II pneumocytes

Trimethoprim sulfamethoxazole

Primary influenza pneumonia Secondary (bacterial)

Virus culture

Influenza virus

Cytolysis in respiratory tract; cytokines contribute; secondary infections common

Oseltamivar, zanamivar

Over 55 years, HIV ⊕, or immigrant from developing country

Auramine-rhodamine stain of sputum acidfast bacilli

Mycobacterium tuberculosis

Facultative intracellular parasite → cell-mediated immunity and DTH

Multidrug therapy

Dusty environment with bird or bat fecal contamination (Missouri chicken farmers, Ohio river)

Intracellular yeast cells in sputum

Histoplasma capsulatum

Facultative intracellular

Amphotericin B

Desert sand S.W. United States

Endospores in spherules in tissues

Coccidioides immitis

Acute, chronic lung infection, dissemination

Amphotericin B

Rotting, contaminated wood, same endemic focus as Histoplasma and east coast states

Broad-based budding yeast cells in sputum or skin

Blastomyces dermatitidis

Acute, chronic lung infection, dissemination

Ketoconazole

Travel to Far East, Toronto, winter, early spring

Serology, virus, isolation

SARS agent

Replication in cells of upper respiratory tree

None

“Four Corners” region (CO, UT, NM, AZ), spring, inhalation rodent urine

Serology, virus, isolation

Hantavirus (Sin Nombre)

Virus disseminates to CNS, liver, kidneys, endothelium

Ribavirin

Definition of abbreviations: CGD, chronic granulomatous disease; CMV, cytomegalovirus; CF, cystic fibrosis; DTH, delayed-type hypersensitivity; RSV, respiratory syncytial virus.

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Tuberculosis Causes caseating granulomas containing acid-fast mycobacteria; transmission is by inhalation of aerosolized bacilli; increasing incidence in the U.S., secondary to AIDS − Primary tuberculosis (initial exposure) can produce a Ghon complex, characterized by a subpleural caseous granuloma above or below the lobar fissure, accompanied by hilar lymph node granulomas. − Secondary tuberculosis (reactivation or reinfection) tends to involve the lung apex. − Progressive pulmonary tuberculosis can take the forms of cavitary tuberculosis, miliary pulmonary tuberculosis, and tuberculous bronchopneumonia. Miliary tuberculosis can also spread to involve other body sites. Clinical: fevers and night sweats, weight loss, cough, hemoptysis, positive skin test (PPD)

Sarcoidosis Sarcoidosis is a granulomatous disease of unknown etiology; affects females > males, ages 20–60; most common in African American women. Noncaseating granulomas occur in any organ of the body; hilar and mediastinal adenopathy are typical. Clinical: Cough, shortness of breath, fatigue, malaise, skin lesions, eye irritation or pain, fever/night sweats Labs:  ↑ serum angiotensin-converting enzyme (ACE)  Schaumann bodies: laminated calcifications  Asteroid bodies: stellate giant-cell cytoplasmic inclusions

ORGAN SYSTEMS │3. The Respiratory System

►►Granulomatous Diseases

►►Obstructive Lung Disease Increased resistance to airflow secondary to obstruction of airways Chronic obstructive pulmonary disease (COPD) includes chronic bronchitis, emphysema, asthma, and bronchiectasis.

Disease

Characteristics

Clinical Findings

Chronic bronchitis

• P  ersistent cough and copious sputum production for at least 3 months each year in 2 consecutive years • Highly associated with smoking (90%)

• C  ough, sputum production, dyspnea, frequent infections • Hypoxia, cyanosis, weight gain

Emphysema

• A  ssociated with destruction of alveolar septa, resulting in enlarged air spaces and a loss of elastic recoil, and producing overinflated, enlarged lungs • Thought to be due to protease/antiprotease imbalance Gross: • Overinflated, enlarged lungs • Enlarged, grossly visible air spaces • Formation of apical blebs and bullae (centriacinar type)

• P  rogressive dyspnea • Pursing of lips and use of accessory muscles to breathe • Barrel chest • Weight loss

Centriacinar (centrilobular) emphysema

• • • •

 roximal respiratory bronchioles involved P Most common type (95%) Associated with smoking Worst in apical segments of upper lobes

Panacinar (panlobular) emphysema

• • • •

 ntire acinus involved; distal alveoli spared E Less common Alpha-1-antitrypsin deficiency Distribution: entire lung; worse in bases of lower lobes

Asthma

• D  ue to hyperreactive airways, resulting in episodic bronchospasm, producing wheezing, severe dyspnea, and coughing. • Inflammation, edema, hypertrophy of mucous glands with goblet cell hyperplasia and mucus plugs are characteristic findings. • Hypertrophy of bronchial wall smooth muscle, thickened basement membranes

(Continued)

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ORGAN SYSTEMS │ 3. The Respiratory System

►►Obstructive Lung Disease (Cont’d.) Extrinsic asthma

• • • • •

 ype I hypersensitivity reaction T Allergic (atopic)—most common type Childhood and young adults; ⊕ family history Allergens: pollen, dust, food, molds, animal dander, etc. Occupational exposure: fumes, gases, and chemicals

Intrinsic asthma

• • • • • •

 nknown mechanism U Respiratory infections (usually viral) Stress Exercise Cold temperatures Drug induced (aspirin)

Bronchiectasis

• A  n abnormal permanent airway dilatation due to chronic necrotizing infection • Most patients have underlying lung disease, such as bronchial obstruction, necrotizing pneumonias, cystic fibrosis, or Kartagener syndrome.

►►Drugs for Asthma Class

Agents

Mechanism

Comments

Bronchodilators β2 agonists

Albuterol Terbutaline Metaproterenol Salmeterol Formoterol

Stimulate β2 receptors → ↑ cAMP → smooth muscle relaxation

• G  enerally have the advantage of minimal cardiac side effects • Most often used as inhalants • Salmeterol and formoterol are long-acting agents, so are useful for prophylaxis • Cause skeletal muscle tremors; some CV side effects (tachycardia, arrhythmias) can still occur

Non-selective β agonists

Epinephrine (α1,α2,β1,β2) Isoproterenol (β1, β2)

Stimulate β2 receptors → ↑ cAMP → smooth muscle relaxation

• N  ot used as much as the β2 agonists • Epinephrine is used for acute asthma attacks and for anaphylaxis

Muscarinic antagonists

Ipratropium Tiotropium

Block muscarinic receptors, inhibiting vagally induced bronchoconstriction

• U  sed as an inhalant; there are minimal systemic side effects • Used in asthma and COPD • β2 agonists are generally preferred for acute bronchospasm • These are useful in COPD because it decreases bronchial secretions and has fewer CV side effects • Tiotropium is longer-acting

Methylxanthines

Theophylline

Inhibit PDE; block adenosine receptors

• A  vailable orally • Major use is for asthma (although β2 agonists are first-line)

Leukotriene Antagonists Leukotriene antagonists

Zafirlukast Montelukast

Block LTD4 (and LTE4) leukotriene receptors

5-lipoxygenase inhibitors

Zileuton

Block leukotriene synthesis

• O  rally active; not used for acute asthma episodes • Prevents exercise-, antigen-, and aspirininduced asthma

Anti-inflammatory Agents Corticosteroids

Beclomethasone Prednisone, prednisolone Others

Inhibit phospholipase A2 → ↓ arachidonic acid synthesis

• ↓  inflammation and edema • Used orally and inhaled • IV use in status asthmaticus

Release inhibitors

Cromolyn Nedocromil

Inhibit mast cell degranulation

• C  an prevent allergy-induced bronchoconstriction • Available as nasal spray, oral, eye drops

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ORGAN SYSTEMS │3. The Respiratory System

►►Restrictive Lung Disease (Decreased Lung Volumes and Capacities) Examples Chest wall disorders: obesity, kyphoscoliosis, polio, etc. Intrinsic lung disease: Adult respiratory distress syndrome (ARDS) Neonatal respiratory distress syndrome (NRDS) Pneumoconioses (silicosis, asbestosis, “black lung” disease from coal dust) Sarcoidosis Idiopathic pulmonary fibrosis (Hamman-Rich syndrome) Goodpasture syndrome Wegener granulomatosis Eosinophilic granuloma Collagen-vascular diseases Hypersensitivity pneumonitis Drug exposure

►►Respiratory Distress Syndromes Adult Respiratory Distress Syndrome (ARDS) • Diffuse damage to the alveolar epithelium and capillaries, resulting in progressive respiratory failure unresponsive to oxygen therapy • Causes: shock, sepsis, trauma, gastric aspiration, radiation, oxygen toxicity, drugs, pulmonary infections, and many others • Clinical presentation: dyspnea, tachypnea, hypoxemia, cyanosis, and use of accessory respiratory muscles  − X-ray: bilateral lung opacity (“white out”)  − Gross: heavy, stiff, noncompliant lungs  − Micro:  Interstitial and intra-alveolar edema   Interstitial inflammation   Loss of type I pneumocytes   Hyaline membrane formation  − Overall mortality 50%

Neonatal Respiratory Distress Syndrome (NRDS) Also known as hyaline membrane disease of newborns. Causes respiratory distress within hours of birth and is seen in infants with deficiency of surfactant secondary to prematurity (gestational age of female

Central

• Invasive nests of squamous cells, intercellular bridges (desmosomes); keratin production (“squamous pearls”) • Hyperparathyroidism secondary to increased secretion of parathyroid related peptide

Small cell (oat cell) carcinoma/20%

Strongly related; male > female

Central

• V  ery aggressive; micro: small round cells • Frequently associated with paraneoplastic syndromes, including production of ACTH (Cushing syndrome), ADH, and parathyroid related peptide

—

—

Large anaplastic cells without evidence of differentiation

—

Bronchial

May produce carcinoid syndrome

Large cell/10% Carcinoid/ Ex = net reabsorption of X; Fx < Ex = net secretion of X

►►Examples Using Mass Balance to Evaluate Renal Processing of a Solute Data

Calculations

Conclusions

• • • •

GFR = 100 mL/min [Subst.]plasma = 1 µg/mL • V = 2 mL/min [Subst.]urine = 75 µg/mL

F = 100 × 1 = 100 µg/min E = 2 × 75 = 150 µg/min

Subst. must be secreted because the amount excreted is > the amount filtered. S ≈ 50 µg/min*

• • • •

GFR = 100 mL/min [Subst.]plasma = 3 µg/mL • V = 1 mL/min [Subst.]urine = 100 µg/mL

F = 100 × 3 = 300 µg/min E = 1 × 100 = 100 µg/min

Subst. must be reabsorbed because the amount filtered is > the amount excreted. R ≈ 200 µg/min†

• • • •

GFR = 100 mL/min [Subst.]plasma = 2 µg/mL • V = 4 mL/min [Subst.]urine = 50 µg/mL

F = 100 × 2 = 200 µg/min E = 4 × 50 = 200 µg/min

Subst. is neither secreted nor reabsorbed because the amount excreted = the amount filtered.¶

Definition of abbreviation: Subst., substance. *Assumes no reabsorption †Assumes no secretion ¶Still possible that S = R, but this is unlikely.

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Definition

Volume of plasma from which a substance is removed (cleared) per unit time

Concept

Relates the excretion of a substance to its concentration in plasma

Calculation

Cs = (Us × V)/Ps

Application: GFR

• Inulin clearance can be used to calculate GFR. • Rationale: inulin is filtered, but is neither secreted nor reabsorbed. Therefore,

•

where, Cs = clearance of substance, Us = urine concentration of • substance, V = urine flow, Ps = plasma concentration of substance

Clearance of inulin = (U

•

[inulin]

× V)/P[inulin] = GFR

• C  reatinine clearance is the best clinical measure of GFR because it is produced continually by the body and is freely filtered but not reabsorbed. Creatinine is partially secreted, but its clearance is still a reasonable clinical estimate of GFR. Application: Renal plasma flow (RPF)

Para-aminohippuric acid (PAH) is filtered and secreted; at low doses it is almost completely cleared from blood flowing through the kidneys during a single pass. Therefore, PAH clearance = RPF. However, PAH clearance is a measure of plasma flow rather than blood flow. Renal blood flow (RBF) can be calculated as follows:

ORGAN SYSTEMS │ 4. The Renal/Urinary System

►►Clearance and Its Applications

RBF = RPF / (1 – hematocrit), using hematocrit as decimal proportion, e.g., 0.40

Renal blood flow (RBF) Application: Free water clearance (Ch2o)

• C  h2o is not a true clearance. It is the volume of water that would have to be added to or removed from urine to make the urine isoosmotic to plasma. • Ch2o is the difference between water excretion (urine flow) and osmolar clearance. Thus: •

•

•

Ch2o = V – Cosm = V – (Uosm × V)/Posm • P  ositive Ch2o: Urine is hypotonic, ADH is low, “free water” has been removed from body, and plasma osmolarity is being increased. • Negative Ch2o: Urine is hypertonic, ADH is high, water is being conserved, and plasma osmolarity is being decreased. • Use Ch2o to evaluate whether urine osmolarity is appropriate. If Posm is elevated, Ch2o should be negative to compensate; if Posm is low, Ch2o should be positive. Definition of abbreviation: ADH, antidiuretic hormone.

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(Approximately 1 million nephrons/kidney) Sequence of Fluid Flow in a Nephron

Cortex

Structure Proximal tubule Bowman's capsule

Distal tubule

Collecting duct

Outer zone

Medulla

ORGAN SYSTEMS │ 4. The Renal/Urinary System

►►Structure of the Nephron

Inner zone

Loop of Henle

Basic Function

Bowman capsule

Formation of filtrate

Proximal tubule (PT)

Reabsorption of H2O, solutes; some secretion

Descending thin loop of Henle (DTL)

Reabsorption of H2O, no solute transport

Ascending thin loop of Henle (ATL)

Reabsorption of solutes, not water

Thick ascending loop of Henle (TAL)

Reabsorption of solutes, not water

Early distal tubule (EDT)

Reabsorption of solutes; special sensory region

Late distal tubule (LDT); cortical collecting duct (CCD)

Reabsorption of solutes and water; regulation of acid−base status

Medullary collecting duct (MCD)

Reabsorption of H2O; final control of urine volume and osmolarity

►►Association of Blood Vessels With the Nephron LDT = late distal tubule CCD = cortical collecting duct PTC

To renal vein

LDT Renal artery AA = afferent arteriole EA = efferent arteriole JGA = juxtaglomerular BC apparatus BC = Bowman's capsule GC = glomerular capillaries EDT = early distal tubule

AA

JGA EDT EA CCD

GC

PTC PT PT = proximal tubule PTC PTC = paratubular PT capillaries DTL = thin descending loop of Henle ATL = ascending thin loop TAL = thick ascending loop MCD = medullary collecting duct

TAL

DTL ATL

MCD

Each tubular segment has a blood supply that allows exchange of water and/or solute.

Sequence of Blood Flow in Nephrons Blood Vessel

Tubular Segment

Afferent arteriole

No exchange

Glomerular capillaries

Bowman capsule

Efferent arteriole

No exchange

Peritubular capillaries

Sequence: proximal tubule → loop of Henle → distal tubule → collecting duct

Vasa recta: specialized portion of peritubular capillaries that perfuse medulla 1−2% of blood flow

Loop of Henle, collecting duct

vasa recta

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ORGAN SYSTEMS │ 4. The Renal/Urinary System

►►The Juxtaglomerular Apparatus (JGA) The juxtaglomerular apparatus includes the site of filtration (Bowman capsule [BC] and glomerular capillaries), as well as the arterioles and macula densa tubule cells found at the end of the thick ascending limb. Macula densa cells sense tubular fluid NaCl and contribute to autoregulation and regulation of renin secretion.

AA = afferent arteriole EA = efferent arteriole MD = macula densa EA

AA

Filtration Bowman capsule

A pouch wrapped around capillaries

Podocytes

Specialized cells of BC, which help prevent protein filtration

Glomerular capillaries (GC)

Fenestrated, which allows rapid filtration of water and small solutes, but prevents protein filtration

...

...

...

...

MD .. ....

...

EN

...

...... ...

EGM

..... ...... .....

Filtration = GFR = Kf[(PGC – PBC) – (πGC – πBC)]

G

(same forces as discussed in CV)

PE FP

BS EN = endothelium BS = Bowman's Space FP = Foot Process of Podocyte PE = Parietal Epithelium

M Basement Membrane EN Podocyte cell body

Kf

Filtration coefficient is high for H2O, electrolytes, small solutes

PGC

Remains high along GC due to very low GC resistance, favoring filtration

PBC

Remains low unless urinary tract obstruction is present

πGC

Rises along GC due to high filtration, until filtration ceases in distal capillary; reduced with low plasma protein

πBC

≈ zero normally, proteinuria increases it

Proximal Tubule EGM = extraglomerular mesangial cells M = mesangial cells G = granular cell

Filtration Fraction = GFR/RPF Ranges from 15−30%, usually ≈20% • Nonrenal capillary filtration fraction ≈1−2% • Nonrenal Pcap falls along capillary due to capillary resistance, so filtration only occurs at proximal end and reabsorption occurs distally.

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An isolated change in renal perfusion pressure between 75 and 175 mm Hg will not change RBF or GFR significantly because autoregulation maintains RBF at a constant level by adjusting afferent and efferent arteriolar resistances. Autoregulation occurs via a myogenic response and tubuloglomerular feedback.

Mechanisms of Autoregulation

0

0

5

200

RBF

4 3

100

GFR

flow

500

Autoregulatory range

2

ine

1000

6

Ur

Renal blood flow (ml/min)

1500

↓ arterial pressure causes GFR to ↓, which in turn ↓ delivery of NaCl to macula densa. This results in an ↑ in efferent arteriolar resistance and a ↓ in afferent arteriolar resistance, both of which ↑ GFR to a normal level. The ↑ in efferent arteriolar resistance occurs in response to ↑ levels of angiotensin II.

Tubuloglomerular feedback (TGF)

Urine flow or Sodium Excretion (X Normal)

7

↑ arterial pressure stretches vessel wall, which ↑ calcium movement into smooth muscle cells, causing them to contract.

Myogenic

Glomerular Filtration Rate (ml/min)

ORGAN SYSTEMS │ 4. The Renal/Urinary System

►►Autoregulation of GFR and RBF

1 50 100 150 200 Mean arterial pressure (mm Hg)

Autoregulatory range

Between approximately 75−175 mm Hg mean arterial pressure (MAP)

Renal shutdown

Lower than 50 mm Hg MAP; both GFR and RBF are very low; kidney shuts down

0

►►Regulation of Filtration (GFR and RBF) Vessel

Constriction

Dilation

Pcap

GFR

RBF

Pcap

GFR

RBF

Afferent arteriole

↓

↓

↓

↑

↑

↑

Efferent arteriole

↑

↑

↓

↓

↓

↑

►►Tubular Function: Reabsorption and Secretion Active Facilitated Transporters Display Maximum Transport (Tmax) Rates Transport maximum

Tmax = mass of solute per time transported when carriers saturated

Limited carrier population

Transport mediated by these carriers is saturable under pathophysiologic conditions, e.g., glucose transporters

Reabsorption < Tmax

None of solute in urine until filtered load > Tmax

Secretion < Tmax

All of solute delivered in plasma appears in urine until delivery > Tmax

Interpretation

Reduced Tmax for glucose indicates reduced number of functioning nephrons

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ORGAN SYSTEMS │ 4. The Renal/Urinary System

Estimation of Tmax by Graphical Interpretation Glucose Excretion (mg/min)

300

Theoretical

200 100

The solid line represents the theoretical relationship between glucose filtered load (FL) and glucose excretion (E). Actually, some glucose appears in the urine below the Tmax due to competition for binding sites. When the filtered load > Tmax, E = FL − Tmax.

Splay Tmax

0

100

0

200

300

400

600

500

Glucose filtered load (mg/min) Select a point on linear portion:



FLglucose = 500 mg/min; Eglucose = 200 mg/min

Reabsorption = excretion – filtered load

Rglucose = 200 mg/min – 500 mg/min = −300 mg/min

Tmax = 300 mg/min reabsorption

Therefore, Rglucose = Tmax , and carriers are saturated

Proximal Tubule First Half of the Proximal Tubule FIRST HALF OF THE PROXIMAL TUBULE Tubular Fluid

Second Half of the Proximal Tubule

Na+ Transport, Second Half of Proximal Tubule Blood

+ Capillary

Na+ K+

H+ H+

+ HCO3-

CA

H2O

+ CO2

CA CO2

ATP

+ H2O

Na+

HCO3-

Na+ ClNa+ H+

Wall

HCO3-

Blood

Tubular Fluid

H-Anion Anion Cl-

+

Na+

H-Anion Cl-

Na+

ATP

Na+ K+

K+ Cl-

Na+ Cl-

Na+ Na+ Glucose

ATP K+ Glucose

Sodium secondary active symporters also for amino acids,

− reabsorption is depicted at the top of the lactate and 3phosphate. 1) NaHCO diagram. 2) The Na+-glucose symporter is depicted in the bottom cell; other symporters reabsorb amino acids, lactate, and phosphate.

Reabsorption of sodium and chloride are related by parallel operation of sodium antiport with hydrogen and chloride antiport with anions. The

Thehydrogen processes the left figureand continue on inspecies the second half the andinanion combine, the neutral reenters theofcell, proximal tubule and others are added: splits and the hydrogen and anion contribute again to entry of sodium and chloride. The anion may be OH-, formate, oxalate, bicarbonate or

3) Secondary active NaCl reabsorption is mediated by the parallel sulfate. The reabsorption of chloride contributes to a lumen-positive operation of the Na+/H+ antiport and Cl−/anion antiport (e.g., potential. The high concentration of chloride causes diffusion of chloride − OH , formate, oxalate, sulfate). H+ plus anion associate into the through tight andfluid this contributes the positiveinto charge. neutralthe acid injunctions the tubular and diffusetopassively the cell, where they dissociate again to move through the antiports. 4) Water follows non-Cl− solute reabsorption in the first half of the PT and increases tubular fluid [Cl−]. Passive Cl− diffusion pulls Na+ electrically after it, but creates a small negative electrical potential in the tubular lumen.

(Continued)

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ORGAN SYSTEMS │ 4. The Renal/Urinary System

Proximal Tubule (Cont'd.) Substance

Action

Mechanism

Water

67% reabsorbed

• Simple diffusion; filtration forces favor reabsorption • Solute reabsorption creates osmotic gradient, water follows it; paracellular and transcellular • Cell membranes permeable to water

Na+

67% reabsorbed

• N  a+/K+-ATPase in the basolateral membrane creates an electrochemical gradient; secondary active transport, luminal (apical) surface; co- and countertransport • Simple diffusion, paracellular

Glucose, lactate, amino acids, phosphate

≈100% reabsorbed

• S  econdary active transport at the luminal (apical) surface; cotransport with Na+; Na+ electrochemical gradient provides the power • Transport maximum processes (see below)

H+

Secreted

Primary ATPase and secondary active antiport with Na+

HCO3−

≈100% reabsorbed

Reabsorbed as CO2 at the apical surface; facilitated diffusion and exchange with Cl− on basolateral surface; carbonic anhydrase located at the apical surface and intracellularly

Cl−

≈67% reabsorbed

• T  ranscellular: at the apical surface, exchange with anions; at the basolateral surface, facilitated diffusion and symport with K+ • Paracellular, simple diffusion

Ca2+

≈70% reabsorbed

80% of proximal tubule reabsorption paracellular; 20% transcellular

Organic cations, anions

Mainly secreted

Various mechanisms

Loop of Henle: Overview Descending Thin Limb (DTL)

Ascending Thin Limb (ATL)

Thick Ascending Limb (TAL)

H 2O

Reabsorbs 15% of GFR

Impermeable

Impermeable

Solutes

Diffuse into tubule

Slight active reabsorption

Reabsorbs 25% FL of NaCl, K+; 20% FL of Ca2+; 50−60% FL of Mg2+

Tubular fluid volume

Decreases

No change

No change

Tubular fluid osmolarity

Increases; DTL is called the “concentrating segment”

Decreases

Decreases below normal plasma; TAL is called the “diluting segment”

Definition of abbreviation: FL, filtered load.

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ORGAN SYSTEMS │ 4. The Renal/Urinary System

Thick Ascending Loop of Henle

Thick Ascending Limb of the Loop of Henle

Mechanisms of Solute Transport, Thick Ascending Loop of Henle

Blood

Tubular Fluid

+

Na+

Reabsorption: • Symport with Cl− and K+ • Antiport with H+ • Paracellular due to electrical force

K+

Reabsorption: • Paracellular reabsorption (electrical force) • Symport with Na+ and Cl−

Ca2+

Reabsorption: • Paracellular (electrical force) • Transcellular, apical surface, simple diffusion • Basolateral Ca2+-ATPase, Na+-Ca2+ exchange • 2H+/Ca2+ ATPase antiport; parathyroid hormone stimulates

Mg2+

Reabsorption: • Paracellular (electrical force) • Transcellular, active transport

H+

Secretion: • Na+/H+ exchange, NH4+

Capillary Na+ 2ClK+

Na+

ATP

K+ H+ CA CO2

+

Wall

Cl- K+ HCO3-

+ H2O

Na+ K+ Ca2+ Mg2+

HCO3-

Ca++ ATP

Ca++

H2O

Na+

Ca++ Ca++

+

3Na+

2H+

“Diluting segment”: reabsorption of solutes without reabsorption of water produces hyperosmotic interstitium of medulla; needed for descending loop water reabsorption and collecting duct ability to regulate water reabsorption

Positive potential in the lumen contributes to reabsorption of cations via paracellular route. There is no reabsorption of water in this segment. CA = carbonic anhydrase

Distal Tubule and Collecting Duct Overview

Tubular Fluid Volume

Tubular Fluid Osmolarity

Tubular Fluid Solutes

Delivered from TAL

≈15% of GFR

Hypotonic at ≈1/2 POSM

• ≈10% FL of NaCl, K+, and Ca2+ • ≈5% FL of HCO3−

Early distal convoluted tubule (EDT)

No H2O reabsorbed

Hypotonic at ≈1/3 POSM

• R  eabsorb ≈5% FL of NaCl via apical Na+-Cl− symporter (NCC) in secondary active transport inhibited by thiazide diuretics • Reabsorb ≈10% FL of Ca2+ via secondary active transport stimulated by parathyroid hormone (PTH) and indirectly by thiazide diuretics

Late distal tubule (LTD) and cortical collecting duct (CCD)

H2O reabsorption regulated by antidiuretic hormone (ADH)

Varies primarily with H2O reabsorption

• R  eabsorb ≈4% of FL of NaCl via active transport regulated by aldosterone • Reabsorb ≈5% FL of HCO3− via active transport regulated by aldosterone • Secretion of K+ determines total excretion; active secretion regulated by aldosterone

Medullary collecting duct (MCD)

H2O reabsorption regulated by ADH

Varies primarily with H2O reabsorption

Reabsorb ≈60% of FL of urea passively via transporter regulated by ADH; urea reabsorption is needed for medullary osmolarity

Definition of abbreviation: FL, filtered load. *Some refer to the LDT as the connecting tubule.

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ORGAN SYSTEMS │ 4. The Renal/Urinary System

►►Renal Regulation of Excretion of Water and Solutes Overview Steady-State Balance (maintained by renal regulation of excretion)

Fractional E = (Excreted)/(Filtered)

Major Regulators of Renal Excretion

Range Typical Water

Volume liquid drunk/day = Eh2o

0.5−14%

Solute

Osmols generated as water soluble wastes = Eosmoles



NaCl

Amount NaCl eaten/day = ENaCl

0.1−5%

≈0.5−1%

• A  ldosterone acting on LDT and CCD; renal SNS tone acting on PT • Angiotensin II on multiple segments • Atrial natriuretic peptide, etc.

K+

Amount K+ eaten/day ≈EK+

1−80%

≈15%

• A  ldosterone acting on LDT and CCD; other factors described later

Ca2+

Amount Ca2+ absorbed from GI/day = ECa2+

0.1−3%

≈1%

Parathyroid hormone (PTH) acting on DCT

HCO3−

• New HCO3− added to blood/day = net acid excretion (NAE) = (Eammonium)+ (Eh2po4−) – (Ebicarbonate)

HCO3−

≈0%

Aldosterone acting on LDT and CCD; plasma pH and other factors described later

H2PO4−

≈20%

20% − 80%

≈40%

• NAE determines [HCO3−]plasma Urea

Amount generated/day = Eurea

≈1% ≈1.5%

Antidiuretic hormone (ADH) acting on LDT and collecting duct Major osmoles excreted are salts, acids, and nitrogenous wastes; excrete ≈600−900 mOsm/day

Synthesis depends on protein metabolism; regulated by ADH acting on medullary collecting duct

Definition of abbreviations: CCD, cortical collecting duct.

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ORGAN SYSTEMS │ 4. The Renal/Urinary System

Regulation of Urine Osmolarity and Urine Flow: Antidiuretic Hormone (ADH) Effect of Plasma ADH on Urine Osmolarity, Urine and Total Solute Excretion Effect Flow, of plasma [ADH] on urine osmolarity, flow rate

Collecting Duct

Tubular Fluid

Collecting Duct

and total solute excretion

Max Blood

Urine osmolarity

Capillary H2O

Absence of ADH

Wall

Total solute excretion Urine flow rate Min 0

Vesicles Containing

Fusion of

H2O

vesicles that

contain H2O H2O channels

H2O

ATP A AC R D H cAMP

Phosphoproteins H2O

The ADH-receptor complex on the basolateral membrane activates adenylate cyclase. cAMP activates a kinase that phosphorylates proteins involved in movement of vesicles and fusion with the membrane. The resulting channels allow diffusion of water across the apical membrane.

Max

Urine Osmolarity Versus Urine Flow

Presence of ADH Protein Kinase

1200 Urine Osmolarity (mOsm/L)

Water Channels

Plasma [ADH]

1000 800 600 400 200 0

0

1

2 3 4 Urine flow (ml/min)

5

In the normal system, urine flow and osmolarity have an inverse relationship.

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ORGAN SYSTEMS │ 4. The Renal/Urinary System

Loop of Henle and the Countercurrent Mechanism Antidiuresis (Presence of ADH)

Vasa recta

Nephron

Interstitial osmolality mOsm/Kg

Cortex

300 H2O 300 NaCl

Medulla

H2O H2O NaCl

H2O 600

NaCl

H2O

H2O Solute

H2O

Solute H2O H2O

NaCl

In the presence of ADH, the collecting duct is permeable to water. Because of the high osmolarity of the medulla, water is reabsorbed, so the urine volume is small and the urine concentration is the same as the medulla (hyperosmotic).

H2O 1200 Urea

Vasa recta

• Only 1−2% of renal blood flow • Reabsorbed solutes “trapped” in medulla

Balance of solutes and water

• In total loop, more solute than H2O reabsorbed • Produces hyperosmotic interstitium of medulla

Descending thin loop

• Fluid enters isoosmotic with normal plasma • H2O reabsorption → ↓volume with ↑ osmolarity

Ascending loop

• Solute reabsorption only, not H2O → hypoosmotic tubular fluid • Accumulation of solutes in interstitium of medulla

Collecting duct

• With ADH, collecting duct permeable to H2O and urea • As duct passes through hyperosmotic interstitium, reabsorption of H2O → small volume of concentrated urine • Negative CH2O; dilutes plasma

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Vasa recta

Nephron

Interstitial osmolality mOsm/Kg

Cortex

300 300 NaCl

Medulla

H2O

NaCl 400

H2O

In the absence of ADH, the collecting duct is impermeable to water, so urine flow is high and the urine is dilute. Note that medullary osmolality is also lower than when ADH is present.

NaCl H2O Solute

H2O

Solute H2O

500

NaCl

ORGAN SYSTEMS │ 4. The Renal/Urinary System

Loop of Henle and the Countercurrent Mechanism Water-Induced Diuresis (Absence of ADH)

600

H2O

Urea

Vasa recta

• ↑ blood flow with lower-than-normal osmolarity • Washes out solutes, medullary osmolarity reduced

Balance of solutes and water

Medullary osmolarity still higher than normal plasma, but not as high as during antidiuresis

Descending thin loop

Less H2O is reabsorbed because the medulla is not as concentrated as during antidiuresis

Ascending loop

Solute reabsorption continues, but a significant portion of solutes that are reabsorbed are washed into the vasa recta

Collecting duct

• • • •

Without ADH, the collecting duct is impermeable to H2O and urea No H2O reabsorption because tubular fluid passes through medulla ↑ urine flow,↓ urine osmolarity Positive CH2O; acts to concentrate plasma

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152 ADH-Thirst Control System Blocked

148 Plasma Na+ (mEq/L)

ORGAN SYSTEMS │ 4. The Renal/Urinary System

Regulation of Plasma Osmolarity by ADH

ADH secretion is increased by elevated plasma sodium or osmolarity and decreased by high blood volume or high pressure. This acts as a negative feedback system to control plasma osmolarity. (See Antidiuretic Hormone and Control of Osmolarity and Volume in the Endocrine section.)

144

Calculation of Plasma Osmolality (mOsm/kg solution) Plasma osmolality = 2 (plasma [Na+]) + [glucose mg/dL]/18 + [urea mg/dL]/2.8

Normal 140

Example: sodium = 145 mEq/L, glucose = 180 mg/dL, urea = 28 mg/dL Plasma osmolality = 290 + 10 + 10 = 310 mOsm/kg

136

0

30 60 90 120 150 Na+ intake per day (mEq)

180

However: plasma Na+ dominates control of ADH because of its osmotic effect; urea and glucose usually irrelevant. Note: glucose may be important part of urine osmolality (especially in diabetes); when present, it causes osmotic diuresis.

Normal function of the control system for ADH secretion and water consumption prevents large changes of plasma sodium concentration. Loss of this system causes plasma sodium concentration to increase in proportion to sodium intake.

Control Signals for Na+ and H2O Excretion System Renal sympathetic nerves

Renin−angiotensin II−aldosterone

Atrial natriuretic peptide (ANP)

ADH

Action

Segment/Site

↓ GFR

Afferent arteriole constriction

↑ NaCl reabsorption

Proximal, TAL, DT, CD → ↑ H2O reabsorption (except TAL, due to impermeability of water)

Angio II → ↑ NaCl reabsorption

Proximal → ↑ H2O reabsorption

Aldosterone →↑ NaCl reabsorption

TAL, DT, CD →↑ H2O reabsorption (except TAL, due to impermeability of water)

↑ GFR

Glomerulus

↓ renin, angio II, aldosterone

JGA and adrenal cortex

↓ NaCl and H2O reabsorption

CD (urodilatin* assists)

↓ ADH secretion and actions

Posterior pituitary and CD

↑ permeability to H2O

CD → ↑ H2O reabsorption → ↓ urine flow and ↑ urine osmolarity

*Urodilatin is a peptide produced by DT and CD when blood pressure/volume increase. Very potent inhibition of NaCl and water reabsorption, but only local action; it does not circulate.

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Disorder

ECF Volume

Blood Pressure

[Na+]plasma

Urine Volume and Osmolarity

Arterial pH

[K+]plasma

Diabetes insipidus∗

↓

↑

↔ or ↓

↑ volume ↓ osmolarity

↑

↓ (↑ aldosterone and alkalosis)

SIADH

↑

↓

↑ or ↔

↓ volume ↑ osmolarity

↓

↑ (but negative balance)

Aldosterone deficiency (primary)

↓

↓

↓

↑ volume ↑ osmolarity

↓

↑ positive balance

Aldosterone excess (primary)

↑

↑

↑

↓ volume ↓ osmolarity

↑

↓ negative balance

Polydipsia

↑

↓

↔

↑ volume ↓ osmolarity

↓

↑ balance variable

Water deprivation (dehydration)

↓

↑

↓

↓ volume ↑ osmolarity

↑

↑, ↓, ↔ depends on multiple factors

ORGAN SYSTEMS │ 4. The Renal/Urinary System

Disorders of Solute and Water Regulation

Definition of abbreviation: SIADH, syndrome of inappropriate (excessive) ADH secretion. ∗ADH deficiency is called primary, central, or neurogenic; ↓ renal response to ADH is nephrogenic. Distinguish by response to administration of ADH; ↑ urine osmolarity in response to ADH injection indicates primary.

Osmotic Diuresis Cause

Effect

Excessive solute in tubular fluid

Decrease reabsorption of H2O

Diabetic ketoacidosis

• Glucose and ketones in urine → polyuria, K+ wasting • Na+ loss → hyponatremia

Starvation and alcoholic ketoacidosis

Ketonuria → polyuria, K+ wasting, hyponatremia

Osmotic diuretics (mannitol, carbonic anhydrase inhibitors)

Inhibit proximal tubule H2O reabsorption → diuresis, K+ wasting (due to ↑ flow)

Loop diuretics (furosemide) and distal tubule diuretics (thiazides)

Inhibit NaCl reabsorption →↑ tubular solutes → diuresis and K+ wasting

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K+ secretion (pmol/min)

ORGAN SYSTEMS │ 4. The Renal/Urinary System

Causes of Increased Potassium Excretion Tubular Flow and K+ Secretion Tubular flow and K+ secretion 200 150

Factor

High K+ diet

100 Normal K+ diet Low K+ diet

50 0 0

Mechanism K+

↑ Tubular flow

Washes

↑ Tubular load of Na+

Stimulates DT Na+ pump →↑ tubular cells K+

↑ Plasma K+

↑ FL and →↑ aldosterone →↑ K+ secretion

Aldosterone on DT

↑ Apical permeability K+ ↑ Na+ pump →↑ DT cell K+ →↑ K+ secretion

Metabolic alkalosis

↑ Tubular cell K+ →↑ secretion of K+

Chronic metabolic acidosis

Osmotic diuresis and ↑ aldosterone

out of tubular cells

30 10 20 40 Tubular flow rate (nL/min)

• Shaded bar: normal flow range • High flow → high secretion • Flow is not a normal control mechanism; changes are pathologic.

Effects of Volume Expansion and Contraction on K+ Secretion Volume Expansion

Volume Contraction Volume Contraction

Volume Expansion

arterial baroreceptors Atrial Volume

Angiotensin II Na+, H2O Excretion

K+ secretion

ADH

Chronic

Urodilatin

Metabolic Acidosis

Angiotensin II

Brain Integration

Aldosterone

renin

Sympathetic Activity

ANP

Urodilatin

Brain Integration

ADH

Atrial Volume

Sympathetic Activity

ANP

arterial baroreceptors

renin

Na+, H2O Excretion

K+ secretion

Aldosterone

Metabolic Alkalosis

Volume expansion causes acidosis due to responses that ↓ reabsorption of bicarbonate in proximal tubule and ↓ aldosterone. Volume contraction causes alkalosis due to ↑ proximal tubular reabsorption of bicarbonate and ↑ aldosterone. Both can cause K+ wasting because metabolic alkalosis and chronic metabolic acidosis both ↑ K+ secretion in distal tubule and collecting duct.

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ORGAN SYSTEMS │ 4. The Renal/Urinary System

Effects of Metabolic Alkalosis and Acidosis on K+ Excretion Metabolic Alkalosis

Metabolic Acidosis Acute

Metabolic Alkalosis Potassium shift into cells Increased [K+] tubular cells Hypokalemia

Chronic Skeletal Muscle Cell

Distal Tubule and Collecting Duct Principal Cells Na-K ATPase Activity

K+ secretion

[K+]i

Increased K+ secretion

K+ permeabilty apical membrane

Filtered Load K+

Negative K+ balance

NaCl and H2O Reabsorption H+/K+ Exchange

ECV Aldosterone Distal Tubule and Collecting Duct Principal Cells

Na-K ATPase Activity [K+]i

K+ Excretion

Both acute and chronic metabolic alkalosis cause hypokalemia with a negative potassium balance.

Tubule Fluid Flow Rate

Plasma [K+]

K+ Excretion

Increased K+ excretion

Proximal Tubule Cell

K+ permeabilty apical membrane

K+ secretion

ECV = Effective circulating volume Acute

Chronic

Acute ( 7.40

Acidosis

Alkalosis

_ HCO3 < 24 mEq/L PCO2 > 40 mm Hg

Metabolic Acidosis

PCO2 < 40 mm Hg

Respiratory Compensation 1.2 mm Hg PCO2 for each_1 mEq/L HCO3

Respiratory Acidosis _

HCO3

> 24 mEq/L

Metabolic Compensation _ 3.5 mEq/L HCO3 for each 10 mm Hg PCO2

_ HCO3 > 24 mEq/L

PCO2 < 40 mm Hg

Metabolic Alkalosis

Respiratory Alkalosis

PCO2 > 40 mm Hg

_ HCO3 < 24 mEq/L

Respiratory Compensation 0.7 mm Hg per 1 mEq/L

PCO2 _ HCO3

Metabolic Compensation _ 0.5 mEq/L HCO3 per 10 mm Hg PCO2

1. What is the pH? Acidotic or alkalotic? 2. What is the respiratory contribution? Acidosis, alkalosis, or no change? 3. What is the metabolic contribution? Acidosis, alkalosis, or no change? 4. What causes the acid–base disorder? Ans: the factor (respiratory or metabolic) that would produce the abnormal pH. 5. Is there compensation? Did the other factor change in the direction that would help offset the disorder?

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ORGAN SYSTEMS │ 4. The Renal/Urinary System

Use of the Plasma Anion Gap (PAG) Use

To determine whether the cause of a metabolic acidosis is due to ↑ concentration of nonvolatile acid

Discriminates

Whether the primary disorder is loss of bicarbonate in urine or feces

Principle

Cations = anions in plasma, if all were measured; commonly measure Na+, Cl−, and HCO3−; metabolic acids are not measured. So there is a gap between cations and anions as measured.

Calculation

PAG = [Na+] − ([Cl− ] + [HCO3−]); normal = 12 ± 2

Interpretation ↑ PAG

Excess molecules of acid, e.g., diabetic ketoacidosis, aspirin, lactic acidosis, etc.

Non-anion gap acidosis (normal PAG)

Acidosis due to loss of bicarbonate in urine or diarrhea results in hyperchloremic acidosis; kidneys reabsorb excess Cl− in replacement for bicarbonate

Urinary Anion Gap (UAG) Principle

Hard to measure NH4+ in urine, but it is the major form of acid excreted Cations = anions in urine, if all are measured

Ions measured

Na+, K+, Cl–: anions > cations because did not measure NH4+

UAG calculation

UAG = [Na+] + [K+] − [Cl− ]

Interpretation of negative

Kidneys are excreting acid

Interpretation of positive

Kidneys are excreting base

In acidosis

UAG should be negative if kidneys are compensating appropriately

In alkalosis

UAG should be positive if kidneys are compensating appropriately

Sample case: Arterial: pH = 7.15, Paco2 = 30 mm Hg, [HCO3−] = 10 mEq/L, Cl− = 100 mEq/L, Na+ = 145 mEq/L Urine: Na+ = 100 mEq/L, K+ = 90 mEq/L, Cl− = 140 mEq/L Diagnosis: metabolic acidosis with respiratory compensation; PAG = 35; therefore, grossly excessive acid in the body. Diagnosis is either non-renal metabolic acidosis or renal failure with low GFR (e.g., uremia). UAG is only reliable for measuring urine acid excretion in normal anion gap metabolic acidosis, such as to discriminate renal tubular acidosis (RTA) vs. non-renal causes. Avoid in high PAG acidosis.

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ORGAN SYSTEMS │ 4. The Renal/Urinary System

Renal Pharmacology ►►Diuretics: Mechanisms Proximal convoluted tubule (PCT) Glomerulus bases

active secretion 120 ml/min

Na+

(10%)

HCO–3 (>95%) (reabsorption)

Lumen

Cl– ADH antagonist

PTH sensitive

6

Ca2+

5

Na+ (60%) Cl– (45%)

1

K+ Ca2+ Mg2+

H2O

Cortex

Distal convoluted tubule (DCT)

4 acids

2

K+, H+ Na+ ( adults

Membranous glomerulonephritis

Nephrotic syndrome; adults > children

Usually normal renal function; may respond to steroids

May respond to steroids Membranoproliferative glomerulonephritis

Variable: mild proteinuria, mixed nephritic/ nephrotic, or frank nephrotic syndrome Poor response to steroids

Type II: immune complex and alternate complement pathway Focal segmental glomerulosclerosis

Nephrotic syndrome (most common cause in adults) Poor prognosis; rarely responds to steroids

Definition of abbreviations: ASO, antistreptolysin O.

Immunologic; aggressive variant of lipoid nephrosis; IV drug use; HIV nephropathy

“C3 nephritic factor”

Focal and segmental sclerosis and hyalinization

Epithelial damage; loss of foot processes

IgM and C3 focal deposits

(Continued)

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ORGAN SYSTEMS │ 4. The Renal/Urinary System

►►Glomerular Diseases (Cont'd.) Type

Clinical Presentation

Mechanism

Light Microscopy

Electron Microscopy

Immunofluorescence

Goodpasture syndrome

RPGN + pulmonary hemorrhage

Anti-GBM antibodies (type II hyper­ sensitivity)

Crescents; mesangial proliferation in early cases

GBM disruption; no deposits

Linear IgG and C3

Immunologic

Crescents

Variable, ± deposits; all have GBM ruptures

Granular or linear

Immunologic

Proliferation limited to certain segments of particular glomeruli

Variable; may show mesangial deposits

Variable; may show mesangial deposits

Unknown

Variable: normal or segmental/ mesangial proliferation or crescentic

Mesangial deposits

Mesangial IgA deposition

Nonenzymatic glycosylation causes glomerular basement membrane thickening and mesangial matrix expansion

Capillary basement membrane thickening; diffuse and nodular glomerular sclerosis (KimmelstielWilson)

Thickened glomerular basement membrane and welldemarcated, roughly round nodules in the glomeruli

Not really helpful; may show non-specific immunoglobulin G deposition along the basement membrane

Variable

Hyalinized glomeruli

Not specific

Negative or granular

Amyloid deposition, often accompanying diseases e.g., multiple myeloma, chronic infections, tuberculosis, and rheumatoid arthritis

Eosinophilic amorphous deposits in glomeruli and interstitium that show apple-green birefringence when stained with Congo Red

Fibrillar depositions of amyloid material

Immuno­ fluorescence is not usually helpful

X-linked disorder of collagen

Segmental and focal glomerulo­ sclerosis, tubular atrophy, interstitial fibrosis, chronic inflammation

Thickening (sometimes thinning) and splitting the basement membrane

Immuno­ fluorescence for individual chains of type IV collagen can be diagnostic

Often poor prognosis; may respond to steroids, plasmapherisis, cytotoxic agents Idiopathic RPGN

RPGN; may follow flu-like syndrome Extremely poor prognosis

Focal proliferative glomerulonephritis

Primary focal glomerulonephritis or part of multisystem disease; may be subclinical or present with hematuria, proteinuria, nephrotic syndrome Variable prognosis

IgA nephropathy (Berger disease)

Variable: recurrent hematuria, mild proteinuria, nephrotic syndrome; children and young adults Usually slowly progressive course

Diabetic glomerulopathy

Microscopic proteinuria; or can eventually cause nephrotic syndrome Prognosis variable, depends on diabetic control

Chronic glomerulonephritis

Chronic renal failure; may follow a variety of acute glomerulopathies Poor prognosis

Amyloidosis

Nephrotic syndrome Prognosis variable, depends in underlying condition

Alport syndrome

Hematuria, proteinuria, which slowly progress to renal failure; deafness; ocular disorders Renal failure common by age 50

Definition of abbreviations: ASLO, antistreptolysin O; GBM, glomerular basement membrane; RPGN, rapidly progressive glomerulonephritis.

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Acute Tubular Necrosis (ATN)

Most common cause of acute renal failure; associated with reversible injury to the tubular epithelium; excellent prognosis if patient survives disease responsible for the ATN

Ischemic ATN

• Most common cause of ATN • ↓ blood flow caused by severe renal vasoconstriction, hypotension, or shock

Nephrotoxic ATN

Caused by heavy metals such as mercury, drugs, and myoglobin

Four Phases of ATN Initial phase

36 hours: after precipitating event occurs

Oliguric phase

10 days: ↓ urine output; uremia, fluid overload, and hyperkalemia may occur

Diuretic phase

2−3 weeks: gradual ↑ in urine volume (up to 3 L/day); hypokalemia, electrolyte imbalances, and infection may occur

Recovery phase

3 weeks: improved concentrating ability, restoration of tubular function; normalization of BUN and creatinine

ORGAN SYSTEMS │ 4. The Renal/Urinary System

►►Tubular Diseases of the Kidney

►►Tubulointerstitial Diseases of the Kidney Pyelonephritis

• Infection of the renal pelvis, tubules, and interstitium • Ascending infection is the most common route with organisms from the patient’s fecal flora; hematogenous infection is much less common. • Etiologic agents usually gram-negative bacilli (e.g., E. coli, Proteus, and Klebsiella). E. coli pili mediate adherence, motility aids movement against flow of urine. Proteus (urease, alkaline urine, struvite stones), Klebsiella (large capsule)

Acute pyelonephritis

• Risk factors: urinary obstruction, vesicoureteral reflux, pregnancy, instrumentation, diabetes mellitus • Under 40 more common in women (shorter urethra); over 40, ↑ incidence in men due to benign prostatic hypertrophy • Symptoms: fever, malaise, dysuria, frequency, urgency, and costovertebral angle (CVA) tenderness. Fever, CVA tenderness, and WBC casts distinguish pyelonephritis from cystitis. • Urine: many WBCs and WBC casts • Gross: scattered yellow microabscesses on the renal surface • Micro: foci of interstitial suppurative necrosis and tubular necrosis • Blunting of the calyces may be seen on intravenous pyelogram

Chronic pyelonephritis

• • • • • •

Acute allergic interstitial nephritis

• Hypersensitivity reaction to infection or drugs (e.g., NSAIDs, penicillin, methicillin) • Leads to interstitial edema with a mononuclear infiltrate • Presents 2 weeks after exposure with hematuria, pyuria, eosinophilia, and azotemia

Analgesic nephritis

Interstitial nephritis and renal papillary necrosis, induced by large doses of analgesics

Gouty nephropathy

• Urate crystals in tubules, inducing tophus formation and a chronic inflammatory reaction • Note: Urate crystals appear as birefringent, needle-shaped crystals on light microscopy.

Acute urate nephropathy

• Precipitation of crystals in the collecting ducts, causing obstruction • Seen in lymphoma and leukemia, especially after chemotherapy

Multiple myeloma

Bence-Jones proteins are directly toxic to tubular epithelium

Diffuse cortical necrosis

• Generalized infarction of both kidneys; preferentially involves the renal cortex • Seen in settings of obstetric catastrophes (abruptio placentae) and shock • Mechanism thought to be a combination of vasospasm and DIC

Reflux nephropathy most common cause Interstitial parenchymal scarring deforms the calyces and pelvis Symptoms: onset can be insidious or acute; present with renal failure and hypertension Gross: irregular scarring and deformed calyces with overlying corticomedullary scarring Micro: chronic inflammation with tubular atrophy Pyelogram diagnostic

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ORGAN SYSTEMS │ 4. The Renal/Urinary System

►►Vascular Diseases of the Kidney Ischemia

• Caused by embolization of mural thrombi usually left side of heart or aorta • Gross: sharply demarcated, wedge-shaped pale regions, which undergo necrosis with subsequent scarring • Symptoms: infarcts may be asymptomatic or may cause pain, hematuria, and hypertension

Renal vein thrombosis

• • • • • •

Thrombosis of one or both renal veins may occur Associated with the nephrotic syndrome, particularly membranous glomerulonephritis Renal cell carcinoma may also provoke renal vein thrombosis as a result of direct invasion by tumor Presents with hematuria, flank pain, and renal failure Gross: kidney enlarged Micro: hemorrhagic infarction of renal tissue

►►Urolithiasis • Affects 6% of the population; men > women • Renal colic may occur if small stones pass into the ureter, where they may also cause hematuria and urinary obstruction and predispose to infection Calcium stones

• 75% of stones; most patients have hypercalciuria without hypercalcemia • Calcium stones are radiopaque; they are the only ones that can be seen on x-ray

Magnesiumammonium phosphate stones

• 15% of stones; occur after infection by urease-producing bacteria, such as Proteus • Urine becomes alkaline, resulting in precipitation of magnesium-ammonium phosphate salts; may form large stones (e.g., staghorn calculi)

Uric acid stones

Seen in gout, leukemia, and in patients with acidic urine

Cystine stones

• Very rare • Associated with an autosomal recessive amino acid transport disorder, leading to cystinuria • Most stones are unilateral and formed in calyx, pelvis, bladder

►►Obstructive Uropathy and Hydronephrosis Hydronephrosis

• M  ultiple etiologies, including stones, benign prostatic hypertrophy, pregnancy, neurogenic bladder, tumor, inflammation, and posterior urethral valves • Persistence of glomerular filtration despite urinary obstruction, causing dilation of calyces and pelvis. High pressure in the collecting system causes atrophy and ischemia. • Gross: dilatation of the pelvis and calyces with blunting of renal pyramids • Symptoms: − Unilateral: may remain asymptomatic as the kidney atrophies − Bilateral incomplete: loses concentrating ability, causing urinary frequency, polyuria and nocturia − Bilateral complete: causes anuria, uremia, and death if untreated

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ORGAN SYSTEMS │ 4. The Renal/Urinary System

►►Tumors of the Kidney Benign Cortical adenomas

• Common finding at autopsy • Gross: yellow, encapsulated cortical nodules • Micro: may be identical to renal cell carcinoma, distinguished by size

Angiomyolipomas

• Hamartomas, composed of fat, smooth muscle, and blood vessels • Particularly common in patients with tuberous sclerosis

Malignant Renal cell carcinomas

• • • •

• • • • •

90% of all renal cancers in adults; seen in ages 50–70 with no sex predilection Moderate association with smoking and a familial predisposition Occurs in 2/3 of patients with von Hippel-Lindau disease Symptoms: “classic” triad of hematuria, palpable mass, and costovertebral pain (10% of cases); hematuria in middle-aged patient should raise concern Gross: most common in the upper pole; usually solitary, with areas of necrosis and hemorrhage; often invades the renal vein and extends into the vena cava and heart Micro: polygonal clear cells with abundant clear cytoplasm Genetics: often associated with loss of function of VHL gene and activation of the MET oncogene Paraneoplastic syndrome: polycythemia, hypercalcemia, Cushing syndrome, etc. High incidence of metastasis on initial presentation 5-year survival depends on stage, especially poor (25–50%) if tumor extends into the renal vein

Wilms tumor (nephroblastoma)

• • • • • •

Common childhood malignancy with peak incidence at age 2 Symptoms: abdominal mass and hypertension, nausea, hematuria, intestinal obstruction May be associated with other congenital anomalies Gross: very large, demarcated masses; most are unilateral, but may be bilateral if familial Micro: embryonic glomerular and tubular structures surrounded by mesenchymal spindle cells 90% survival rate when patients are treated with surgery, chemotherapy, radiotherapy

Transitional cell carcinoma

• Can involve the epithelium of the renal pelvis • Histology similar to transitional cell carcinoma of the bladder, but is less common • Can present with hematuria

•

►►Anomalies of the Ureters Double ureters

• F  orm when two same-sided ureters join at some point before the junction to the bladder or enter the bladder separately • Associated with double renal pelvises or an abnormally large kidney

Ureteral Obstruction in Hydroureter and Hydronephrosis Internal obstruction

• R  enal calculi are most common cause; usually impact at the ureteropelvic junction, entrance to the bladder, and where they cross iliac vessels • Other causes: strictures, tumors

External obstruction

• P  elvic tumors may compress or invade the ureteral wall; sclerosing retroperitonitis, a fibrosis of retroperitoneal structures, can cause obstruction. • Pregnancy may cause obstruction and may also cause dilation (secondary to progesterone).

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ORGAN SYSTEMS │ 4. The Renal/Urinary System

►►Pathology of the Bladder Diverticula

• Pouch-like evaginations of the bladder wall • Occur in older men and women and may lead to urinary stasis and therefore infection

Exstrophy of bladder

• C  aused by absence of the anterior musculature of the bladder and abdominal wall; developmental failure of downgrowth of mesoderm over the anterior bladder • Site of severe chronic infections, with ↑ incidence of adenocarcinoma

Patent urachus

• Fistula that connects the bladder with the umbilicus • Isolated persistence of the central urachus termed a urachal cyst • Carcinomas may develop in these cysts

Infectious cystitis

• Cystitis causes frequency, urgency, dysuria, and suprapubic pain • Causative organisms: E. coli, Staphylococcus saprophyticus (associated with intercourse), Proteus, Klebsiella (esp. in diabetics), Pseudomonas (capsule is antiphagocytic, exotoxin A inhibits EF-2, esp. in patients with structural abnormalities and antibiotic usage), Enterococcus (esp. in males with prostate problems) • No WBC casts in urine (as compared with pyelonephritis) • Systemic signs, such as fever and chills, are also uncommon with lower urinary tract infections; CVA tenderness usually absent

Hemorrhagic cystitis

Marked mucosal hemorrhage secondary to viruses, radiation, or chemotherapy (cyclophosphamide, protect with mesna)

Cystitis emphysematosa

• Submucosal gas bubbles • Occurs mostly in diabetics

Bladder obstruction

• Men: benign prostatic hyperplasia or carcinoma most common cause • Women: cystocele of the bladder most common cause • Gross: thickening, hypertrophy, and trabeculation of the smooth muscle bladder wall

Carcinoma of the bladder

• Transitional cell carcinoma: 90% of primary bladder neoplasms • Risk factors: Smoking, occupational exposure (e.g., naphthylamine), infection with Schistosoma haematobium (more commonly associated with squamous cell carcinoma) • 3% of all cancer deaths in the United States - peak incidence between 40 and 60 years of age. • Usually presents with painless hematuria, may also cause dysuria, urgency, frequency, hydronephrosis, and pyelonephritis. • P  rognosis: Determined by grade and stage at the time of diagnosis; high incidence of recurrence at multiple locations.

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The Gastrointestinal System Chapter 5 Embryology of the Gastrointestinal System

Gastrointestinal Pathology

Development of the Gastrointestinal Tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334 Adult Structures Derived from Each of the Three Divisions of the Primitive Gut Tube . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335

Gastrointestinal Histology Layers of the Digestive Tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335 Histology of Specific Regions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336

Gross Anatomy Abdominal Viscera . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Abdominal Aorta and Celiac Circulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . Superior and Inferior Mesenteric Arteries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hepatic Portal Circulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

337 338 339

340 Inferior Vena Cava (IVC) and Tributaries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340 Cross-Sectional Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341

Gastrointestinal Physiology Appetite . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342 Saliva . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342 Swallowing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343 The Stomach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343 The Small Intestine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344 The Large Intestine (Colon) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345 Vomiting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345 Antiemetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346 Emetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346 Gastrointestinal Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346–347 Gastric Secretions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348 Mechanism of Gastric H+ Secretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348 Drugs for Peptic Ulcer Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349 Phases of Gastric Secretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349 Pancreatic Secretions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350 Hepatic Excretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351–352 Digestion and Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352–354

Lesions of the Oral Cavity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355 Esophageal Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355–356 Stomach Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 356 Small Intestine Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357 Appendix Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 358 Large Intestine Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 358 Inflammatory Bowel Disease: Crohn Disease Versus Ulcerative Colitis . . . . . . . . 359 Exocrine Pancreas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359 Congenital Hepatic Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360 Common patterns of Liver Disease Presentation . . . . . . . . . . . . . . . . . . . . . . . . . 360 Acquired Hepatic Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361 Hepatic Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362 Hepatic Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362 Characteristics of Viral Hepatitides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363 Serology of Heptatitis B Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364 Biliary Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364

Gastrointestinal Microbiology Microbial Diarrhea: Organisms Causing Inflammatory Diarrhea/Dysentery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365 Microbial Diarrhea: Organisms Causing Noninflammatory Diarrhea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 366–367 Diarrhea by Intoxication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367

Additional Pharmacology Antidiarrheals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Laxatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Drugs That Stimulate Gastrointestinal Motility . . . . . . . . . . . . . . . . . . . . . . . . . . . Miscellaneous Gastrointestinal Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

368 368 368 368

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ORGAN SYSTEMS │ 5. The Gastrointestinal System

Embryology of the Gastrointestinal System ►►Development of the Gastrointestinal Tract

Amniotic cavity (AM)

Yolk sac (YS)

Stomach Hepatic diverticulum

AM

Lateral body fold

YS

Vitelline duct

Yolk stalk

Vitelline duct Cloaca

Coelom Gut tube

2 3 4

Esophagus Lung bud

Gall bladder

Allantois AM

Pharyngeal pouches 1

Foregut

90 Rotation

Midgut

270 Rotation

Hindgut Septation Celiac Ventral Dorsal pancreatic artery Inferior Superior pancreatic bud mesenteric mesenteric bud artery artery

The primitive gut tube is formed by incorporation of the yolk sac into the embryo during cranial–caudal and lateral folding. • T  he epithelial lining and glands of the mucosa are derived from endoderm. The epithelial lining of the gut tube proliferates rapidly and obliterates the lumen, followed by recanalization. • The lamina propria, muscularis mucosa, submucosa, muscularis externa, and adventitia/serosa are derived from mesoderm. The primitive gut tube is divided into the foregut, midgut, and hindgut, each supplied by a specific artery, each receiving a slightly different autonomic innervation, and each having slightly different relationships to a mesentery.

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Foregut

Midgut

Hindgut

Artery: celiac

Artery: superior mesenteric

Artery: inferior mesenteric

Parasympathetic innervation: vagus nerves

Parasympathetic innervation: vagus nerves

Parasympathetic innervation: pelvic splanchnic nerves

Sympathetic innervation: greater splanchnic nerves, T5−T9*

Sympathetic innervation: lesser and lowest splanchnic nerves, T9−T12*

Sympathetic innervation: lumbar splanchnic nerves L1−L2*

Foregut Derivatives

Midgut Derivatives

Hindgut Derivatives

Esophagus Stomach Duodenum (first and second parts) Liver Pancreas Biliary apparatus Gall bladder Pharyngeal pouches† Lungs† Thyroid† Spleen‡

Duodenum (second, third, and fourth parts) Jejunum Ileum Cecum Appendix Ascending colon Transverse colon (proximal two thirds)

Transverse colon (distal third) Descending colon Sigmoid colon Rectum Anal canal (above pectinate line)

ORGAN SYSTEMS │ 5. The Gastrointestinal System

►►Adult Structures Derived from Each of the Three Divisions of the Primitive Gut Tube

*Referred painstimulation of visceral pain fibers that innervate a gastrointestinal structure results in a dull, aching, poorly localized pain that is referred over the T5 through L1 dermatomes. The sites of referred pain generally correspond to the spinal cord segments that provide the sympathetic innervation to the affected gastrointestinal structure. †Derivatives of endoderm, but not supplied by the celiac artery or innervated as above. ‡Spleen is not a foregut derivative, but is supplied by the celiac artery.

Gastrointestinal Histology ►►Layers of the Digestive Tract

Serosa Muscularis externa Submucosa Mucosa Epithelium Lamina propria Muscularis mucosa

Submucosal plexus (Meissner plexus): a collection of ganglia and interneurons of the enteric nervous system (ENS), predominantly responsible for regulating epithelial function and some circular smooth muscle function Myenteric plexus (Auerbach plexus): a collection of ganglia and interneurons of the enteric nervous system (ENS), predominantly responsible for regulating longitudinal and some circular smooth muscle function

Note that the first third of esophageal muscle is skeletal, the middle third is mixed skeletal and smooth, and the final third is smooth muscle. Also, the stomach smooth muscle contains an oblique layer between the submucosa and circular layer of smooth muscle.

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ORGAN SYSTEMS │ 5. The Gastrointestinal System

►►Histology of Specific Regions Region

Major Characteristics

Mucosal Cell Types at Surface

Function of Surface Mucosal Cells

Esophagus

• N  onkeratinized stratified squamous epithelium • Skeletal muscle in muscularis externa (upper 1/3) • Smooth muscle (lower 1/3)





Stomach (body and fundus)

Rugae: shallow pits; deep glands

Mucous cells

Chief cells Parietal cells Enteroendocrine (EE) cells

Secrete mucus; form protective layer against acid; tight junctions between these cells probably contribute to the acid barrier of the epithelium. Secrete pepsinogen and lipase precursor Secrete HCl and intrinsic factor Secrete a variety of peptide hormones

Pylorus

Deep pits; shallow branched glands

Mucous cells Parietal cells EE cells

Same as above Same as above High concentration of gastrin

Small intestine

Villi, plicae, and crypts

Columnar absorptive cells

Contain numerous microvilli that greatly increase the luminal surface area, facilitating absorption

Duodenum

Brunner glands, which discharge alkaline secretion

Goblet cells

Secrete acid glycoproteins that protect mucosal linings Contains granules that contain lysozyme. May play a role in regulating intestinal flora High concentration of cells that secrete cholecystokinin and secretin

Paneth cells

EE cells Jejunum

Villi, well developed plica, crypts

Same cell types as found in the duodenal epithelium

Same as above

Ileum

Aggregations of lymph nodules called Peyer patches

M cells found over lymphatic nodules and Peyer patches

Endocytose and transport antigen from the lumen to lymphoid cells

Large intestine

Lacks villi, crypts

Mainly mucus-secreting and absorptive cells

Transports Na+ (actively) and water (passively) out of lumen

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►►Abdominal Viscera Common bile duct

Epiploic foramen

Omental bursa (lesser peritoneal sac)

Portal vein

Viscera are classified as:

Greater peritoneal sac

Liver

Lesser omentum Gastrosplenic ligament

Stomach IVC

Major Peritoneal Organs (suspended by a mesentery) Stomach Liver and gallbladder Spleen Foregut duodenum Tail of pancreas Jejunum Ileum Appendix Transverse colon

Proper hepatic artery

A Spl

Splenorenal ligament

Kidney

Major Secondary Retroperitoneal Organs (lost a mesentery during development) Midgut duodenum Head, neck, and body of pancreas Ascending colon Descending colon Upper rectum

• Peritoneal organshave a mesentery and are almost completely enclosed in peritoneum. These organs are mobile. • Retroperitoneal organsare partially covered with peritoneum and are immobile or fixed organs.

ORGAN SYSTEMS │ 5. The Gastrointestinal System

Gross Anatomy

This figure is a cross-section of the abdomen that shows the greater and lesser peritoneal sacs and associated abdominal viscera.

Major Primary Retroperitoneal Organs (never had a mesentery) Kidneys Adrenal glands Ureter Aorta Inferior vena cava Lower rectum Anal canal

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ORGAN SYSTEMS │ 5. The Gastrointestinal System

►►The Abdominal Aorta and Celiac Circulation Inferior phrenic Celiac Superior mesenteric

Middle suprarenal

Proper hepatic artery

Renal

Gastroduodenal artery Common hepatic artery

Left gastric artery Splenic artery

Gonadal Lumbars

Inferior mesenteric

Median sacral

Gastroepiploic artery

Common iliac

Internal iliac External iliac

Inferior pancreaticoduodenal artery

Superior mesenteric artery

Clinical Correlations In an occlusion of the celiac artery at its origin from the abdominal aorta, collateral circulation may develop in the head of the pancreas by way of anastomoses between the pancreaticoduodenal branches of both the superior mesenteric and the gastroduodenal arteries. Branches of the celiac circulation may be subject to erosion if an ulcer penetrates the posterior wall of the stomach or the posterior wall of the duodenum. • The splenic artery may be subject to erosion by a penetrating ulcer of the posterior wall of the stomach. • The left gastric artery may be subject to erosion by a penetrating ulcer of the lesser curvature of the stomach. • The gastroduodenal artery may be subject to erosion by a penetrating ulcer of the posterior wall of the first part of the duodenum. Patients with a penetrating ulcer may have pain referred to the shoulder, which occurs when air escapes through the ulcer and stimulates the peritoneum covering the inferior aspect of the diaphragm. The contents of a penetrating ulcer of the posterior wall of the stomach or the duodenum may enter the omental bursa. Hematemesis may result from bleeding into the lumen of the esophagus, stomach, or duodenum proximal to the ligament of Treitz. Hematemesis is commonly caused by a duodenal ulcer, a gastric ulcer, or esophageal varices.

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Superior Mesenteric Artery Distribution

Inferior Mesenteric Artery Distribution

Transverse colon Middle colic artery

Inferior pancreaticoduodenal artery

Right colic artery Ileocolic artery

Superior mesenteric artery

Inferior mesenteric artery Descending colon

First jejunal artery

Left colic artery

Ascending colon

ORGAN SYSTEMS │ 5. The Gastrointestinal System

►►Superior and Inferior Mesenteric Arteries

Sigmoid arteries

Intestinal arteries (jejunal and ileal)

Superior rectal artery

Sigmoid colon

Rectum

Clinical Correlation • Common sites of ischemic bowel infarction are in the transverse colon near the splenic flexure and in the rectum. • Infarction of the transverse colon occurs between the distal parts of the middle colic branches of the superior mesenteric and left colic branches of the inferior mesenteric arteries. • Infarction of the rectum occurs between the distal parts of the superior rectal branches of the inferior mesenteric artery and the middle rectal branches of the internal iliac artery.

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ORGAN SYSTEMS │ 5. The Gastrointestinal System

►►Hepatic Portal Circulation Clinical Correlation

Portal vein

Gastric vein

Splenic vein

Superior mesenteric vein Inferior mesenteric vein

Patients with cirrhosis of the liver may develop portal hypertension, in which venous blood from gastrointestinal structures, which normally enters the liver by way of the portal vein, is forced to flow in the retrograde direction in tributaries of the portal vein. Retrograde flow forces portal venous blood into tributaries of the superior or inferior vena cava; portacaval anastomoses are established at these sites, permitting portal venous blood to bypass the liver.

Sites of Anastomoses

Portal

Caval

Clinical Signs

1. Umbilicus

Paraumbilical veins

Superficial veins of the anterior abdominal wall

Caput medusa

2. Rectum

Superior rectal veins (inferior mesenteric vein)

Middle and inferior rectal veins (internal iliac vein)

Internal hemorrhoids

3. Esophagus

Gastric veins

Veins of the lower esophagus, which drain into the azygos system

Esophageal varices

4. Retroperitoneal organs

Tributaries of the superior and inferior mesenteric veins

Veins of the posterior abdominal wall

Not clinically relevant

►►Inferior Vena Cava (IVC) and Tributaries Hepatic veins Inferior phrenic vein

Right suprarenal vein Right renal vein Right gonadal vein

Left suprarenal vein Left renal vein Left gonadal vein

The inferior vena cava is formed at about the level of the L5 vertebra by the union of the common iliac veins. It ascends just to the right of the midline. On the right, the renal, adrenal, and gonadal veins drain directly into the inferior vena cava. On the left, only the left renal vein drains directly into the inferior vena cava; the left gonadal and the left adrenal veins drain into the left renal vein. The left renal vein crosses the anterior aspect of the aorta just inferior to the origin of the superior mesenteric artery.

Clinical Correlation Common iliac vein Median sacral vein

The left renal vein may be compressed by an aneurysm of the superior mesenteric artery as the vein crosses anterior to the aorta. Patients with compression of the left renal vein may have renal and adrenal hypertension on the left, and, in males, a varicocele on the left.

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ORGAN SYSTEMS │ 5. The Gastrointestinal System

►►Cross-Sectional Anatomy Abdomen: CT, T11

Abdomen: CT, L1

Diaphragm Aorta

Liver

Stomach

Inferior Vena Cava

Liver

Pancreas

Superior Mesenteric Splenic Artery Vein

Spleen

Spleen

Right Kidney

Abdomen: CT, L2 Superior Mesenteric Ascending Vein Colon Duodenum

Right Kidney

Renal Pelvis

Inferior Vena Cava

Superior Mesenteric Artery Jejunum

Descending Aorta Colon

Inferior Vena Cava

Portal Vein

Aorta

Left Kidney

Left Adrenal Gland

Abdomen: CT, S1 Sigmoid Colon

Gluteus Medius

Left Common Iliac Vein

Gluteus Maximus

Left Common Iliac Artery

Ureter

Psoas Major

Iliacus

Images copyright 2005 DxR Development Group Inc. All rights reserved.

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ORGAN SYSTEMS │ 5. The Gastrointestinal System

Gastrointestinal Physiology ►►Appetite Appetite is primarily regulated by two regions of the hypothalamus: a feeding center and a satiety center. Normally, the feeding center is active, but is transiently inhibited by the satiety center.

Hypothalamus Location

Stimulation

Destruction

Feeding center

Lateral hypothalamic area

Feeding

Anorexia

Satiety center

Ventromedial nucleus of hypothalamus

Cessation of feeding

Hypothalamic obesity syndrome

Hormones That May Affect Appetite Cholecystokinin (CCK)

• Released from I-cells in the mucosa of the small intestine • CCK-A receptors are in the periphery • CCK-B receptors are in the brainboth reduce appetite when stimulated

Calcitonin

• Released mainly from the thyroid gland • Has also been reported to decrease appetite by an unknown mechanism

Ghrelin

• ↑ levels provoke hunger • Levels rise during fasting

Leptin

• Promotes satiety • Levels ↑ after meals and ↓ with fasting

Mechanical Distention • Distention of the alimentary tract inhibits appetite, whereas the contractions of an empty stomach stimulate it. • Some satiety is derived from mastication and swallowing alone.

Miscellaneous Other factors that help to determine appetite and body weight include body levels of fat and genetic factors.

►►Saliva Salivary glands Submandibular Parotid Sublingual

• Produce approximately 1.5 L/day of saliva • The presence of food in the mouth, the taste, smell, sight, or thought of food, or the stimulation of vagal afferents at the distal end of the esophagus increase the production of saliva.

Functions

• Initial triglyceride digestion (lingual lipase) • Initial starch digestion (α-amylase) • Lubrication

Composition

Ions: HCO3− 3× [plasma]; K+ 7 × [plasma]; Na+ 0.1 × [plasma]; Cl− 0.15 × [plasma] Enzymes: α-amylase, lingual lipase Hypotonic pH: 7–8 Flow rate: alters the composition Antibacterial: lysozyme, lactoferrin, defensins, IgA

Regulation

Parasympathetic

↑ synthesis and secretion of watery saliva via muscarinic receptor stimulation (anticholinergics → dry mouth)

Sympathetic

↑ synthesis and secretion of viscous saliva via β-adrenergic receptor stimulation

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Swallowing is a reflex action coordinated in the swallowing center in the medulla. Afferents are carried by the glossopharyngeal (CN IX) and vagus (CN X) nerves. Food is moved to the esophagus by the movement of tongue (hypoglossal nerve, CN XII) and the palatal and pharyngeal muscles (CNs IX and X). 1. Initiation of swallowing occurs voluntarily when the mouth is closed on a bolus of food and the tongue propels it from the oral cavity into the pharynx. 2. Involuntary contraction of the pharynx advances the bolus into the esophagus. 3. Automatic closure of the glottis during swallowing inhibits breathing and prevents aspiration. 4. Relaxation of the upper esophageal sphincter (UES) allows food to enter the esophagus. 5. Peristaltic contraction of the esophagus propels food toward the lower esophageal sphincter (LES), the muscle at the gastroesophageal junction. 6. The LES is tonically contracted, relaxing on swallowing. Relaxation of the LES is mediated via the vagus nerve; VIP (vasoactive inhibitory peptide) is the major neurotransmitter causing LES relaxation.

Clinical Correlation Achalasia

Pathologic inability of the LES to relax during swallowing. Food accumulates in the esophagus, sometimes causing megaesophagus.

Gastric reflux

LES tone is low, allowing acid reflux into the esophagus; can lead to gastroesophageal reflux disease (GERD).

ORGAN SYSTEMS │ 5. The Gastrointestinal System

►►Swallowing

►►The Stomach • The stomach has three layers of smooth muscle: longitudinal (outer, for peristalsis), circular (for mixing), and oblique (inner). • The stomach is composed of the fundus, body, and antrum. • Receptive relaxation mediated by VIP occurs in the fundus. As the stomach fills, a vagovagal-mediated receptive relaxation occurs, allowing storage. • The bolus of swallowed food received by the stomach is further macerated and mixed with HCl, mucus, and pepsin. The food (chyme) is then discharged at a controlled rate into the duodenum. Only a small amount of chemical digestion actually occurs in the stomach.

Gastric Motility • A pacemaker within the greater curvature produces a basal electric rhythm (BER) of 3 to 5 waves/min. • The magnitude of the gastric contractions are increased by parasympathetic and decreased by sympathetic stimulation. • Migrating motor complexes (MMC) are propulsive contractions initiated during fasting that begin in the stomach and move undigested material from the stomach and small intestine into the colon. They repeat every 90 to 120 minutes and are mediated by motilin. This housekeeping function lowers the bacterial count in the gut.

Gastric Emptying • The pylorus is continuous with the circular muscle layer and acts as a “valve” to control gastric emptying. • The contractions of the stomach (peristalsis) propel chyme through the pylorus at a regulated rate. • Pyloric sphincter contraction at the time of antral contraction limits the movement of chyme into the duodenum and promotes mixing by forceful regurgitation of antral contents back into the fundus (retropulsion). • Gastric emptying is delayed by: − Fat/protein in the duodenum stimulating CCK release, which increases gastric distensibility − H+ in the duodenum via neural reflexes − Stomach contents that are hypertonic or hypotonic Definition of abbreviation: VIP, vasoactive intestinal peptide.

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ORGAN SYSTEMS │ 5. The Gastrointestinal System

►►The Small Intestine Striated border

• T  he small intestine participates in the digestion and absorption of nutrients. It has specialized villi on the epithelial surface to aid in this function.

Capillary (shown with red blood cell) Lymphatic lacteal

Villus

• T  he duodenum is the proximal pyloric end of the small intestine. Distal to the duodenum is the jejunum, and then the ileum.

Goblet cells

• In the small intestine, the chyme from the stomach is mixed with mucosal cell secretions, exocrine pancreatic juice, and bile.

Myofibroblast

Enterocytes

• M  ucus production occurs in surface epithelial cells throughout the gastrointestinal tract, Brunner glands in the duodenum, and goblet cells in the mucosa throughout the intestine.

Crypt

Paneth cells Lamina propria

Smooth muscle Muscularis mucosae

• M  ucus functions include lubrication of the gastrointestinal tract, binding bacteria, and trapping immunoglobulins where they have access to pathogens. • T  he rate of mucus secretion is increased by cholinergic stimulation, chemical irritation, and physical irritation.

Clinical Correlate Any compromise of the mucous protection can lead to significant damage and irritation of the gastrointestinal tract, leading to gastritis, duodenitis, or even peptic ulcer disease.

Intestinal Motility • Small bowel slow waves move caudally in the circular smooth muscle. The rate slows from approximately 12/min in the jejunum to approximately 9/min in the ileum. • Segmentation contractions are ring-like contractions that mix intestinal contents. They occur at random “nodes” along the intestine. These relax, and then new nodes are formed at the former internodes. This action moves the chyme back and forth, increasing mucosal exposure to the chyme. • Peristalsis is a reflex response initiated by stretching of the lumen of the gut. There is contraction of muscle at the oral end and relaxation of muscle at the caudal end, thus propelling the contents caudally. Although peristalsis is modulated by autonomic input, it can occur even in isolated loops of small bowel with no extrinsic innervation. − The intrinsic control system senses stretch with calcitonin gene-related polypeptide neurons (CGRP). − The contractile wave is initiated by acetylcholine (ACh) and substance P. − The relaxation caudal to the stimulus is initiated by nitric oxide (NO) and VIP. • Parasympathetic stimulation ↑ contractions and sympathetic stimulation ↓ contractions. • The gastroileal reflex is caused by food in the stomach, which stimulates peristalsis in the ileum and relaxes the ileocecal valve. This delivers intestinal contents to the large intestine. • Small intestinal secretions are generally alkaline, serving to neutralize the acidic nature of the chyme entering from the pylorus.

Clinical Correlation Peristalsis is activated by the parasympathetic system. For those suffering from decreased intestinal motility manifesting as constipation (paralytic ileus, diabetic gastroparesis), dopaminergic and cholinergic agents are often used (e.g., metoclopramide).

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General Features • T  he colon is larger in diameter and shorter in length than is the small intestine. Fecal material moves from the cecum, through the colon (ascending, transverse, descending, and sigmoid colons), rectum, and anal canal. • T  hree longitudinal bands of muscle, the teniae coli, constitute the outer layer. Because the colon is longer than these bands, pouching occurs, creating haustra between the teniae and giving the colon its characteristic “caterpillar” appearance. • The mucosa has no villi, and mucus is secreted by short, inward-projecting colonic glands. • Abundant lymphoid follicles are found in the cecum and appendix and more sparsely elsewhere. • The major functions of the colon are reabsorption of fluid and electrolytes and temporary storage of feces.

Colonic Motility • P  eristaltic waves briefly open the normally closed ileocecal valve, passing a small amount of chyme into the cecum. Peristalsis also advances the chyme in the colon. Slow waves, approximately 2/min, are initiated at the ileocecal valve and increase to approximately 6/min at the sigmoid colon. • Segmentation contractions mix the contents of the colon back and forth. • M  ass movement contractions are found only in the colon. Constriction of long lengths of colon propels large amounts of chyme distally toward the anus. Mass movements propel feces into the rectum. Distention of the rectum with feces initiates the defecation reflex.

ORGAN SYSTEMS │ 5. The Gastrointestinal System

►►The Large Intestine (Colon)

Absorption The mucosa of the colon has great absorptive capability. secreted into the colon.

Na+

is actively transported with water following, and K+ and HCO3– are

Defecation Feces

Contains undigested plant fibers, bacteria, inorganic matter, and water. Nondietary material (e.g., sloughed-off mucosa) constitutes a large portion of the feces. In normal feces, 30% of the solids may be bacteria. Bacteria synthesize vitamin K, B-complex vitamins, and folic acid, split urea to NH3, and produce small organic acids from unabsorbed fat and carbohydrate.

Defecation

Rectal distention with feces activates intrinsic and cord reflexes that cause relaxation of the internal anal sphincter (smooth muscle) and produce the urge to defecate. If the external anal sphincter (skeletal muscle innervated by the pudendal nerve) is then voluntarily relaxed, and intra-abdominal pressure is increased via the Valsalva maneuver, defecation occurs. If the external sphincter is held contracted, the urge to defecate temporarily diminishes.

Gastrocolic reflex

Distention of the stomach by food increases the frequency of mass movements and produces the urge to defecate. This reflex is mediated by parasympathetic nerves.

►►Vomiting Vomiting occurs in three phases: nausea, retching, and vomiting. • N  auseahypersalivation, decreased gastric tone, increased duodenal and proximal jejunal tone → reflux of contents into stomach • RetchingGastric contents travel to the esophagus. Retching occurs if upper esophageal sphincter (UES) remains closed. • VomitingIf pressure increases enough to open the UES, vomiting occurs; vomiting can be triggered by oropharyngeal stimulation, gastric overdistention and gastroparesis, vestibular stimulation, or input from the chemoreceptor trigger zone, located in the area postrema in the floor of the fourth ventricle, which stimulates the medullary vomiting center.

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ORGAN SYSTEMS │ 5. The Gastrointestinal System

►►Antiemetics Drug Class

Agents

Comments

5HT3 antagonists

Ondansetron Granisetron, dolasetron

May act in chemoreceptor trigger zone and in peripheral sites

DA antagonists

Phenothiazine, metoclopramide*

Block D2 receptors in chemoreceptor trigger zone

Cannabinoids

Dronabinol

Active ingredient in marijuana

►►Emetics Ipecac

• Locally irritates the GI tract and stimulates the chemoreceptor trigger zone • If emesis does not occur in 15-20 min, lavage must be used to remove ipecac

Apomorphine

• Dopamine-receptor agonist that stimulates the chemoreceptor trigger zone • Vomiting should occur within 5 min

*Also a prokinetic agent

►►Gastrointestinal Hormones Gastrointestinal hormones are released into the systemic circulation after physiologic stimulation (e.g., by food in gut), can exert their effects independent of the nervous system when administered exogenously, and have been chemically identified and synthesized. The five gastrointestinal hormones include secretin, gastrin, cholecystokinin (CCK), gastric inhibitory peptide (GIP), and motilin.

Hormone

Source

Stimulus

Actions

Gastrin*, ‡

G cells of gastric antrum

• S  mall peptides, amino acids, Ca2+ in lumen of stomach • Vagus (via GRP) • Stomach distension • Inhibited by: H+ in lumen of antrum

• • • •

CCK*

I cells of duodenum and jejunum

• F  atty acids, monoglycerides • Small peptides and amino acids

• S  timulates gallbladder contraction and relaxes sphincter of Oddi • ↑ pancreatic enzyme secretion • Augments secretin-induced stimulation of pancreatic HCO3− • Inhibits gastric emptying • Trophic effect on exocrine pancreas/gallbladder

Secretin†

S cells of duodenum

• ↓ pH in duodenal lumen • Fatty acids in duodenal lumen

• • • •

GIP†

K cells of duodenum and jejunum

Glucose, fatty acids, amino acids

• ↑ insulin release • ↓ gastric H+ secretion

Motilin

Enterochromaffin cells in duodenum and jejunum

Absence of food for >2 hours

Initiates MMC motility pattern in stomach and small intestine

↑ HCl secretion by parietal cells Trophic effects on GI mucosa ↑ pepsinogen secretion by chief cells ↑ histamine secretion by ECL cells

↑ pancreatic HCO3− secretion (neutralizes H+) Trophic effect on exocrine pancreas ↑ bile production ↓ gastric H+ secretion

(Continued)

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ORGAN SYSTEMS │ 5. The Gastrointestinal System

►►Gastrointestinal Hormones (Cont'd.) Paracrines/ Neurocrines Somatostatin

Source

Stimulus

Actions

D cells throughout GI tract

↓ pH in lumen

• ↓ gallbladder contraction, pancreatic

secretion

• ↓ gastric acid and pepsinogen secretion • ↓ small intestinal fluid secretion • ↓ ACh release from the myenteric plexus

and decreases motility

• ↓ α-cell release of glucagon, and β-cell

release of insulin in pancreatic islet cells

Histamine VIP†, ¶

Enterochromaffin cells

• Gastrin • ACh

↑ gastric acid secretion (directly, and potentiates gastrin and vagal stimulation)

Neurons in GI tract

• Vagal stimulation

• Relaxation of intestinal smooth muscle,

• Intestinal distention

including sphincters • ↑ Pancreatic HCO3− secretion • Stimulates intestinal secretion of

electrolytes and H2O GRP

Vagal nerve endings

Cephalic stimulation, gastric distension

Stimulates gastrin release from G cells

Pancreatic polypeptide

F cells of pancreas, small intestine

Protein, fat, glucose in lumen

↓ pancreatic secretion

Enteroglucagon

L cells of intestine



• ↓ gastric, pancreatic secretions • ↑ insulin release

Definition of abbreviations: ECL, enterochromaffin-like cells; GIP, gastric inhibitory peptide; GRP, gastrin-releasing peptide. *Member of gastrin-CCK family †Member of secretin-glucagon family Clinical Correlates: ‡Zollinger-Ellison syndrome (gastrinoma)non-β islet-cell pancreatic tumor that produces gastrin, leading to ↑ in gastric acid secretion and development of peptic ulcer disease ¶VIPomatumor of non-α, non-β islet cells of the pancreas that secretes VIP, causing watery diarrhea

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ORGAN SYSTEMS │ 5. The Gastrointestinal System

►►Gastric Secretions Secretion Product

Cell Type

Region of Stomach

Stimulus for Secretion

Inhibitors of Secretion

Action of Secretory Product

HCl

Parietal (oxyntic) cells

Body/fundus

• Gastrin • ACh (from vagus) • Histamine

• Low pH inhibits (by inhibiting gastrin) • Prostaglandins • Chyme in duodenum (via GIP and secretin)

• Kills pathogens • Activates pepsinogen to pepsin

Intrinsic factor

Necessary for vitamin B12 absorption by the ileum; forms complex with vitamin B12

Pepsinogen (zymogen, precursor of pepsin)

Chief cells

Body/fundus

• ACh (from vagus) • Gastrin • HCl

H+ (via somatostatin)

• C  onverted to pepsin by ↓ pH and pepsin (autocatalytic) • Digests up to 20% of proteins

Gastrin

G cells

Antrum

• Small peptides/aa • Vagus (via GRP) • Stomach distention

H+ (via somatostatin)

• ↑  HCl secretion (parietal cells) • ↑ pepsinogen secretion (chief cells) • ↑ histamine secretion by ECL cells

Mucus

Mucous cells

Entire stomach

ACh (from vagus)

Forms gel on mucosa to protect mucosa from HCl and pepsin; traps HCO3− to help neutralize acid

Definition of abbreviations: aa, amino acids; ECL, enterochromaffin-like cells.

►►Mechanism of Gastric H+ Secretion Parietal cell

Interstitial fluid Na+

Gastric lumen K+

CO2 + H2O K+

Carbonic anhydrase

K+

H2CO3

K+ H+

CI– HCO3–

• In the parietal cell, CO2 and H2O are converted by carbonic anhydrase to H+ and HCO3−. • H+ is secreted into the lumen of the stomach by H+-K+ pump (H+/K+− ATPase). Cl− is secreted with H+. • HCO3− is absorbed into the bloodstream in exchange for Cl −. • After a meal, enough H+ may be secreted to raise the pH of systemic blood and turn the urine alkaline (“alkaline tide”). The three primary triggers of H+ secretion are: • ACh (from vagus), via the M3 muscarinic receptor

HCO3–

+

H+

CI–

• Histamine, via the H2 histamine receptor • Gastrin, via unidentified receptor

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Drug Class

Agents

Comments

Antacids

Magnesium hydroxide, aluminum hydroxide, calcium carbonate

Magnesium: laxative effect Aluminum hydroxide: constipating effect

H2 antagonists

Cimetidine, ranitidine, famotidine, nizatidine

• Useful in PUD, GERD, Zollinger-Ellison syndrome, but not as effective as proton pump inhibitors • Cimetidine inhibits hepatic drug metabolizing enzymes and has antiandrogen effects

Proton pump inhibitors

Omeprazole, lansoprazole, esomeprazole, pantoprazole, rabeprazole

• Irreversibly inactivate H+/K+-ATPase, thus blocking H+ secretion. • Work very well—useful in PUD, Zollinger-Ellison syndrome, and GERD

Mucosal protective agents

Sucralfate

Polymerizes in the stomach and forms protective coating over ulcer beds.

Misoprostol

PGE1 derivative used for peptic ulcers caused by NSAIDs

Antibiotics

Macrolides, metronidazole, tetracyclines (various combinations)

To treat H. pylori

ORGAN SYSTEMS │ 5. The Gastrointestinal System

►►Drugs for Peptic Ulcer Disease

Definition of abbreviations: GERD, gastroesophageal reflux disorder; PGE1, prostaglandin E1; NSAIDs, nonsteroidal antiinflammatory drugs; PUD, peptic ulcer disease.

►►Phases of Gastric Secretion Cephalic phase

The smell, sight, thought, or chewing of food can increase gastric secretion via parasympathetic (vagal) pathways. Responsible for approximately 30% of acid secreted.

Gastric phase

Food in the stomach ↑ secretion. The greatest effects occur with proteins and peptides, leading to gastrin release (alcohol and caffeine also exert a strong effect). Gastric distention initiates vagovagal reflexes. Accounts for approximately 60% of acid secreted.

Intestinal phase

Protein digestion products in the duodenum stimulate duodenal gastrin secretion. In addition, absorbed amino acids act to stimulate H+ secretion by parietal cells. The intestinal phase accounts for less than 10% of the gastric secretory response to a meal.

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ORGAN SYSTEMS │ 5. The Gastrointestinal System

►►Pancreatic Secretions The exocrine secretions of the pancreas are produced by the acinar cells, which contain numerous enzyme-containing granules in their cytoplasm, and by the ductal cells, which secrete HCO3–. The secretions reach the duodenum via the pancreatic duct. Bicarbonate (HCO3−)

• HCO3– in the duodenum neutralizes HCl in chyme entering from the stomach. This also deactivates pepsin. • When H+ enters the duodenum, S cells secrete secretin, which acts on pancreatic ductal cells to increase HCO3– production. • HCO3– is produced by the action of carbonic anhydrase on CO2 and H2O in the pancreatic ductal cells. HCO3– is secreted into the lumen of the duct in exchange for Cl–.

Pancreatic enzymes

• Approximately 15 enzymes are produced by the pancreas, which are responsible for digesting proteins, carbohydrates, lipids, and nucleic acids. • When small peptides, amino acids, and fatty acids enter the duodenum, CCK is released by I cells, stimulating pancreatic enzyme secretion. • ACh (via vagovagal reflexes) also stimulates enzyme secretion and potentiates the action of secretin. • Protection of pancreatic acinar cells against self-digestion: Proteolytic enzymes are secreted as inactive precursors, which are activated in the gut lumen. For example, −  the duodenal brush border enzyme, enterokinase, converts trypsinogen to the active enzyme, trypsin. Trypsin then catalyzes the formation of more trypsin and activates chymotrypsinogen, procarboxypeptidase, and prophospholipases A and B. Ribonucleases, amylase, and lipase do not exist as proenzymes. − Produce enzyme inhibitors to inactivate trace amounts of active enzyme formed within.

Enzyme

Reaction Catalyzed

Proteases: Trypsin Chymotrypsin Carboxypeptidase

Proteins → peptides Proteins → peptides Peptides → amino acids

Polysaccharidase: Amylase

Starch and glycogen → maltose, maltotriose, and α-limit dextrins

Lipases: Phospholipases A and B Esterases Triacylglycerol lipases

Phospholipids → phosphate, fatty acids, and glycerol Cholesterol esters → free cholesterol and fatty acids Triglycerides → fatty acids and monoglycerides

Nucleases: Ribonuclease Deoxyribonuclease

RNA → ribonucleotides DNA → deoxyribonucleotides

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Physiologic roles

• Excretion of bilirubin, cholesterol, drugs, and toxins • Promotion of intestinal lipid absorption • Delivery of IgA to small intestine

Components of bile

• B  ilecomposed of bile salts, phospholipids, cholesterol, bilirubin (bile pigments), water, and electrolytes Formation of Bile • B  ile, produced by hepatocytes, drains into hepatic ducts and is stored in the gallbladder for later release. • Primary bile acids (cholic and chenodeoxycholic acids) are made from cholesterol in the liver. Secondary bile acids (deoxycholic and lithocholic) are products of bacterial metabolism of primary bile acids in the gut. • All bile acids must be conjugated with glycine or taurine to form their bile salt before being secreted into bile. • Above a critical micellar concentration, bile salts form micelles. Electrolytes and H2O are also added to the bile.

LIVER Micelles

Glycine Taurine Primary Bile Salts

form

1. Cholic Acid 2. Chenodeoxycholic Acid

Conjugation

Liver Fats e.g., cholesterol phospholipid Conjugated Bilirubin (aqueous soluble)

Primary Bile Acid Production

cholesterol Glucuronic Acid Conjugation

Blood Bilirubin

Secretin HCO 3– and Fluid

1.

Bilirubin (lipid soluble)

Micelles

Micelles

GALL BLADDER fatsoluble material

2.

Bile Pigments Conjugated Bilirubin

3.

Salts and H 2O

Enterohepatic Circulation

Contraction stimulated by CCK

Na+ — active transport K+

, Cl–, H 2O — follow Na+

Sphincter of Oddi

Active transport of 1 or 2 bile salts

micelles for dig. and absor. lipid 0

1 bile salts

0

2 bile salts

DUODENUM bile pigments

to feces

Figure X-1-7

• M  icelles are water soluble-spheres with a lipid-soluble interior. • Micelles are vital in the digestion, transport, and absorption of lipid-soluble substances from the duodenum to the distal ileum, where bile salts are actively reabsorbed and recycled (enterohepatic circulation). • A lack of reabsorbing mechanisms or distal ileal disease can lead to deficiency of bile salts. This can lead to malabsorption, gallstones, and steatorrhea.

Gallbladder

(95%)

CCK relaxes

ORGAN SYSTEMS │ 5. The Gastrointestinal System

►►Hepatic Excretion

Distal ileum

• T  he gallbladder concentrates and stores bile for release during meals. • During the interdigestive period, the sphincter of Oddi is closed and the gallbladder is relaxed, allowing it to fill with bile. • Bile is concentrated in the gallbladder by water and electrolyte absorption. • Small peptides and fatty acids in the duodenum cause CCK secretion, which causes gallbladder contraction and relaxation of the sphincter of Oddi. ACh also aids in this process. (Continued)

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ORGAN SYSTEMS │ 5. The Gastrointestinal System

►►Hepatic Excretion (Cont'd.) Bilirubin

• Bilirubin is a product of heme metabolism. • It is taken up by hepatocytes and conjugated with glucuronic acid prior to secretion into bile. This gives bile a golden yellow color. In the large intestine, bilirubin is deconjugated and metabolized by bacteria to form urobilinogens (colorless). Some of the urobilinogens are reabsorbed; most of the reabsorbed urobilinogens are secreted into bile, with the remainder excreted in the urine. • Most urobilinogen remains in the gut and is further reduced to pigmented compounds (stercobilins and urobilins) and excreted in feces. Stercobilins give a brown color to feces. • Jaundice (yellowing of the skin and whites of the eyes) is a result of elevated bilirubin.

Regulation of bile secretion

• S  ecretin stimulates the secretion of bile high in HCO3– content from the biliary ductules, but does not alter bile salt output. • Secretion of bile salts by hepatocytes is directly proportional to hepatic portal vein concentration of bile salts.

►►Digestion and Absorption • Carbohydrates, lipids, and proteins are digested and absorbed in the small intestine. • The brush border of the small intestine increases surface area, greatly facilitating absorption of nutrients.

Carbohydrate digestion

Must be converted to monosaccharides in order to be absorbed

Mouth • Salivary amylase normally hydrolyzes approximately 10 to 20% of ingested starch. • It hydrolyzes only α-(1:4)-glycosidic linkages to maltose, maltotriose, and α-limit dextrins.

Intestine • Pancreatic amylase is found in the highest concentration in the duodenal lumen, where it rapidly hydrolyzes starch to oligosaccharides, maltose, maltotriose, and α-limit dextrins. • Maltase, α-dextrinase, lactase, sucrase, and isomaltase are found in the brush border, with the highest concentrations in the mid-jejunum and proximal ileum. − α-dextrinase: cleaves terminal α-1,4 bonds, producing free glucose − Lactase: converts lactose to glucose and galactose − Sucrase: converts sucrose to glucose and fructose − Maltase: converts maltose and maltotriose to 2 and 3 glucose units, respectively. • The monosaccharide end products (glucose, galactose, and fructose) are readily absorbed from the small intestine, primarily in the jejunum.

Clinical Correlation • Lactase deficiency causes an inability to digest lactose into glucose and galactose. • Consequence: ↑ osmotic load, giving rise to osmotic diarrhea and flatulence. • Very common in African Americans, Asians, and Mediterraneans, and to a lesser degree, in Europeans/Americans.

Carbohydrate absorption

Luminal Membrane • G  lucose and galactose compete for transport across the brush border by a Na+-dependent coporter (SGLT-1). Na+ moves down its gradient into the enterocyte and the sugars move up their concentration gradients into the enterocyte (secondarily active). A Na+-K+ ATPase in the basolateral membrane helps maintain the Na+ gradient (by keeping intracellular Na+ low). • Fructose: facilitated diffusion (down its concentration gradient) via GLUT-5 transporter

Basolateral Membrane Glucose, galactose, and fructose are transported across the basolateral membrane via facilitated diffusion (GLUT2 transporter). (Continued)

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ORGAN SYSTEMS │ 5. The Gastrointestinal System

►►Digestion and Absorption (Cont'd.) Lipid digestion

Stomach • Fatty materials are pulverized to decrease particle size and increase surface area. • CCK slows gastric emptying to allow enough time for digestion and absorption in the small intestine.

Small Intestine • Bile acid micelles emulsify fat. • Pancreatic lipases digest fat. • Fats are hydrolyzed by pancreatic lipases to free fatty acids, monoacylglycerols, and other lipids (e.g., cholesterol, and fat-soluble vitamins A, D, E, K), which collect in micelles.

Lipid absorption

• M  icelles carry products of fat digestion in the aqueous fluid of the gut lumen to the brush border, where they can diffuse into the enterocyte. • Enterocytes re-esterify the fatty acids to form triacylglycerols, phospholipids, and cholesteryl esters, which are incorporated with apoproteins into chylomicrons. • Chylomicrons are released by exocytosis into the intercellular spaces, where they enter the lacteals of the lymphatic system. They then enter the venous circulation via the thoracic duct. • Glycerol diffuses into portal blood and is either oxidized for energy or stored as glycogen. • Triacylglycerols with medium- and short-chain fatty acids are hydrolyzed quickly and do not require micelle formation for absorption. They undergo little re-esterification and are absorbed directly into the portal venous system.

Clinical Correlation Abetalipoproteinemia results from a deficiency of apoprotein B, causing an inability to transport chylomicrons out of intestinal cells.

Protein digestion

Stomach Pepsin begins protein digestion in the stomach. It functions best at pH 2 and is irreversibly deactivated above pH 5; therefore, it will be inactivated in the duodenum. Pepsin is not an essential enzyme.

Small Intestine Protein digestion continues with pancreatic proteases (trypsin, chymotrypsin, elastase, carboxypeptidases A and B) activated by brush border peptidases. These are essential enzymes.

Protein absorption

Luminal Membrane • Protein products can be absorbed as amino acids, dipeptides, and tripeptides. • Amino acids are absorbed via Na+-dependent amino acid cotransport. Many different transport systems have been identified, e.g., carriers for neutral, basic, acidic, and imino amino acids. • Dipeptides and tripeptides are absorbed via an H+-dependent cotransport mechanism.

Basal Membrane • Dipeptides and tripeptides are hydrolyzed to amino acids intracellularly. • Amino acids are transported to the blood by facilitated diffusion.

Clinical Correlation Hartnup disease is a disorder in which neutral amino acids cannot be absorbed.

Water and electrolyte absorption

The absorption of water and electrolytes occurs mainly in the small intestine. Approximately 5–10 liters of fluid must be absorbed daily (intake and secretion), with 80–90% being absorbed in the small intestine at a maximal rate of 700 mL/h.

(Continued)

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ORGAN SYSTEMS │ 5. The Gastrointestinal System

►►Digestion and Absorption (Cont'd.) NaCl

• In the proximal intestine, there is Na+ -H+ exchange, Na+-glucose or Na+-amino acid cotransport, Na+-Cl− cotransport, and passive diffusion through Na+ channels. • In the colon, passive diffusion through Na+ channels is more important and is stimulated by aldosterone. • Cl− is absorbed via Na+-Cl− cotransport, Cl−-HCO3− exchange, and passive diffusion.

K+

• K+ absorption occurs in the small intestine by passive diffusion. • K+ is secreted in the colon (stimulated by aldosterone).

Ca2+

• Absorption in the small intestine is via a vitamin D-dependent carrier. • Vitamin D deficiency → ↓ Ca2+ absorption → osteomalacia (adults) and rickets (children).

H 2O

• Secondary to solute absorption • Isoosmotic absorption in gallbladder and small intestine; permeability is lower in colon.

Iron

• Absorbed as free Fe2+ or as heme iron, primarily in the duodenum • Fe2+ is bound to transferrin in the blood.

Vitamins

• Fat-soluble (A, D, E, K)incorporated into micelles and absorbed • Water solubleusually via Na+-dependent cotransporters • Vitamin B12absorption occurs in ileum and is transported while bound to intrinsic factor; ↓ intrinsic factor (gastrectomy) → pernicious anemia

H2O, electrolyte secretion

Secretion occurs in crypts. Cl− is the main ion secreted, via cAMP-regulated channels in the luminal membrane.

Clinical Correlation Cholera toxin stimulates adenylate cyclase → ↑ cAMP → open Cl− channels; Na+ and H2O follow → secretory diarrhea.

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ORGAN SYSTEMS │ 5. The Gastrointestinal System

Gastrointestinal Pathology ►►Lesions of the Oral Cavity Leukoplakia

• White plaques on oral mucosa, produced by hyperkeratosis of the epithelium • 10% have epithelial dysplasia, a precancerous lesion • Predisposing factors: smoking, smokeless tobacco, alcohol abuse, chronic friction, and irritants

Erythroplakia

• Flat, smooth, and red. • Significant numbers of atypical epithelial cells • High risk of malignant transformation

Hairy leukoplakia

• Wrinkled patches on side of tongue • Epstein-Barr virus associated • No malignant transformation

Lichen planus

White reticulate lesions on the buccal mucosa and tongue

Tumors of the Oral Cavity Benign tumors

Hemangiomas, hamartomas, fibromas, lipomas, adenomas, papillomas, neurofibromas, and nevi

Malignant tumors

• Squamous carcinoma most common. Peak incidence from ages 40–70 years. • Associated with tobacco and alcohol use, particularly when used together • Lower lip most common site, but may affect floor of mouth and tongue

►►Esophageal Pathology Achalasia

• • • •

Lack of relaxation of the LES secondary to loss of myenteric plexus Most common ages: 30−50. Symptoms: dysphagia, regurgitation, aspiration, chest pain Can be idiopathic, secondary to Chagas disease (Trypanosoma cruzi), or malignancy

Barrett esophagus

• Gastric or intestinal columnar epithelium replaces normal squamous epithelium • Occurs with chronic insult, usually reflux (increases risk of adenocarcinoma 30–40 times)

Boerhaave syndrome

• Violent retching causes potentially fatal esophageal rupture

Diverticula

• Sac-like protrusions of one or more layers of the pharyngeal or esophageal wall • Zenker diverticula: − Occur at the junction of the pharynx and esophagus in elderly men − Symptoms: dysphagia and regurgitation of undigested food soon after ingestion • Traction diverticula: true diverticula in mid-esophagus; usually asymptomatic

Esophageal carcinoma

• • • • •

Esophageal strictures

• N  arrowing of the esophagus, often as a result of fibrosis after severe inflammation. Caused by reflux, Herpes virus, Cytomegalovirus, Candida, chemical burns (e.g., lye ingestion). • Carcinoma should be ruled out

Esophageal varices

• Dilated tortuous vessels of the esophageal venous plexus resulting from portal hypertension • Esophageal varices are prone to bleeding; may be life-threatening

Most are adenocarcinomas occurring after 50 and have male:female ratio of 4:1 Incidence higher in northern Iran, Central Asia Associated with smoking, alcohol, nitrosamines, achalasia, Barrett esophagus, and vitamin A deficiency Presents with dysphagia (first to solids) Liver and lung most common sites of metastasis; poor prognosis

(Continued)

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ORGAN SYSTEMS │ 5. The Gastrointestinal System

►►Esophageal Pathology (Cont'd.) Esophagitis

• M  ost common cause is reflux; other causes include infections (Herpes virus, Cytomegalovirus, Candida) and eosinophilic esophagitis

Hernia

Sliding

90% of cases, gastroesophageal junction above diaphragm, associated with reflux

Paraesophageal

Gastric cardia above diaphragm, gastroesophageal junction remains in the abdomen; herniated organ at risk for strangulation and infarction

Mallory-Weiss tears

Occur at gastroesophageal junction secondary to recurrent forceful vomiting, usually seen in alcoholics

Schatzki rings

Mucosal rings at the squamocolumnar junction below the aortic arch

Tracheoesophageal fistula

• Usually esophageal blind pouch with a fistula between the lower segment of the esophagus and trachea • Associated with congenital heart disease and other gastrointestinal malformations

Webs

• Mucosal folds in the upper esophagus above the aortic arch • Plummer-Vinson syndrome: dysphagia, glossitis, iron-deficiency anemia, and esophageal webs

Definition of abbreviation: LES, lower esophageal sphincter.

►►Stomach Pathology Acute gastritis (erosive)

Can be caused by alcohol, aspirin, smoking, shock, steroids, and uremia Patients experience heartburn, epigastric pain, nausea, vomiting, and hematemesis

Chronic gastritis Fundal (type A)

Autoimmune; associated with pernicious anemia, achlorhydria, and intrinsic factor deficiency

Antral (type B)

Caused by Helicobacter pylori and is most common form of chronic gastritis in U.S.

Carcinoma

• Risk factors: genetic predisposition, diet, hypochlorhydria, pernicious anemia, and nitrosamines • Usually asymptomatic until late, then presents with anorexia, weight loss, anemia, epigastric pain. Virchow node (left supraclavicular lymph node) common site of metastasis • Pathology: 50% arise in the antrum and pylorus • Linitis plastica: infiltrating gastric carcinoma with a diffuse fibrous response • Histology: signet ring cells characteristic of gastric carcinoma

Hypertrophic gastropathy

• Menetrier disease: markedly thickened rugae due to hyperplastic superficial mucus glands with atrophy of deeper glands • Hypertrophic-hypersecretory gastropathy: hyperplasia of parietal and chief cells in gastric glands • Excessive gastrin secretion (e.g., gastrinoma, Zollinger-Ellison syndrome): produces gastric gland hyperplasia. Risk of peptic ulcer disease.

Peptic ulcers

• Common locations: proximal duodenum, stomach, and esophagus • H. pylori infection important etiologic factor. Modification of acid secretion coupled with antibiotic therapy that eradicates H. pylori is apparently curative in most patients. • Symptoms: episodic epigastric pain; complications: hemorrhage, perforation • Duodenal ulcers do not become malignant. Gastric ulcers only rarely • Stress ulcers: burns → Curling ulcers; CNS trauma → Cushing ulcers

Pyloric stenosis

• Congenital hypertrophy of pyloric muscle • Classic case: firstborn boy, presenting with projectile vomiting 3–4 weeks after birth; associated with a palpable “olive” mass in epigastric region • Treatment: surgical

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Celiac sprue

• Allergic reaction to the gliadin component of gluten; genetic predisposition • Predisposes to neoplasm, especially lymphoma • Pathology: atrophy of villi in the jejunum; affects only proximal small bowel

Congenital anomalies

• M  eckel diverticulum: persistent omphalomesenteric vitelline duct. Located near ileocecal valve. May contain ectopic gastric, pancreatic, or endometrial tissue, which may produce ulceration • Vitelline fistula: direct connection between the intestinal lumen and the outside of the body at the umbilicus due to persistence of the vitelline duct. Associated with drainage of meconium from the umbilicus • Atresia: congenital absence of a region of bowel (e.g., duodenal atresia); polyhydramnios, obstruction, and bile-stained vomiting in neonate • Stenosis: narrowing that may cause obstruction • Omphalocele: when the midgut loop fails to return to the abdominal cavity, forming a light gray shiny sac at the base of the umbilical cord filled with loops of small intestine • Gastroschisis: A failure of the lateral body folds to fuse causes extrusion of the intestines through a open defect in the abdominal wall that is usually to the right of the umbilicus; unlike omphalocele, the intestines are exposed to the open air rather than being covered with a membrane.

Hernias

• C  ause 15% of small intestinal obstruction, most commonly at the inguinal and femoral canals • Inguinal hernias – Indirect inguinal hernia: the intestinal loop goes through the internal (deep) inguinal ring, external (superficial) inguinal ring, and into the scrotum. Much more common in males; may present in infancy if there is a failure of the processus vaginalis to close. – Direct inguinal hernia: the intestinal loop protrudes through the inguinal (Hesselbach’s) triangle to cause a bulge in the abdominal wall medial to the inferior epigastric artery. Hesselbach’s triangle is defined by the inferior epigastric artery, the lateral border of the rectus abdominus, and the inguinal ligament. The typical patient is an older man, and the hernia is covered by the external spermatic fascia. • Femoral hernia: the intestinal loop protrudes below the inguinal ligament through the femoral canal below and lateral to the pubic tubercle. More common in women. This type of hernia is particularly likely to produce a dangerous bowel incarceration. • Diaphragmatic hernia: infants with defective development of pleuroperitoneal membrane may have intestines and other abdominal structures herniated into the thorax; potentially fatal because of impairment of lung expansion

Ischemic bowel disease

• T  hrombosis or embolism of the superior mesenteric artery accounts for approximately 50% of cases; venous thrombosis for 25% of cases • Internal hernias can strangulate entrapped loops of bowel • Usually after age 60 and presents with abdominal pain, nausea, and vomiting

Intussusception

• Telescoping of one segment of bowel into another • More common in infants and children; may be reduced with a diagnostic barium enema • In adults, lead point usually an intraluminal mass; usually requires surgery

Lymphoma

• Usually non-Hodgkin, large cell, diffuse type • In immunosuppressed patients, the incidence of primary lymphomas of small intestine is increasing. • MALToma: often follicular and follow a more benign course; associated with H. pylori infection; may regress after antibiotic therapy.

Necrotizing enterocolitis

• L  ife-threatening acute, necrotizing inflammation of the small and large intestines • Usually in premature or low birth weight neonates • Peak incidence when babies start oral foods at 2 to 4 days, but can occur any time in first three months of life • If surgical treatment is required, it may cause short bowel syndrome

Tropical sprue

• Unknown etiology; high incidence in the tropics; especially Vietnam, Puerto Rico • Pathology: similar to changes in celiac disease, but affects entire length of small bowel

Volvulus

• Twisting of the bowel about its mesenteric base; may cause obstruction and infarction • May be associated with malrotation of the midgut • Typical patient is elderly

Whipple disease

• Rare, periodic acid-Schiff (PAS)–positive macrophages in the lamina propria of intestines • Caused by small bacilli (Tropheryma whippelii); more common in men (10:1)

ORGAN SYSTEMS │ 5. The Gastrointestinal System

►►Small Intestine Pathology

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ORGAN SYSTEMS │ 5. The Gastrointestinal System

►►Appendix Pathology Appendicitis

• T  he vermiform appendix may become inflamed as a result of either an obstruction by stool, which forms a fecalith (common in adults), or hyperplasia of its lymphatic tissue (common in children). • An inflamed appendix may stimulate visceral pain fibers, which course back in the lesser splanchnic nerves and result in colicky pain referred over the umbilical region.

►►Large Intestine Pathology Angiodysplasia

• Dilated tortuous vessels of the right colon → lower gastrointestinal bleeding in elderly • Highest incidence in the cecum

Diverticular disease

• Multiple outpouchings of colon present in 30–50% of adults; higher incidence with ↑ age • Presents with pain and fever

Hirschsprung disease

• Absence of ganglion cells of Meissner and Auerbach plexus in distal colon • Produces markedly distended colon, proximal to aganglionic portion • Failure to pass meconium, with constipation, vomiting, and abdominal distention

Imperforate anus

Failure of perforation of the membrane that separates endodermal hindgut from ectodermal anal dimple

Polyps Tubular adenomas

• Pedunculated polyps; 75% of adenomatous polyps • Sporadic or familial; average age of onset is 60; most occur in left colon • Cancer occurs in approximately 4% of patients

Villous adenomas

• Largest, least common polyps; usually sessile • 1/3 cancerous

Tubulovillous adenomas

• Combined tubular and villous elements • Increased villous elements →↑ likelihood of malignant transformation

Polyposis Syndromes Peutz-Jeghers syndrome

• Autosomal dominant; involves entire gastrointestinal tract; melanin pigmentation of the buccal mucosa • Polypshamartomas; not premalignant

Turcot syndrome

Colonic polyps associated with brain tumors

Familial multiple polyposis

• Autosomal dominant; appearance of polyps during adolescence • Start in rectosigmoid area and spread to cover entire colon • Virtually all patients develop cancers; prophylactic total colectomy recommended

Gardner syndrome

• Colonic polyps associated with desmoid tumors • Risk of colon cancer nearly 100%

Malignant Tumors Adenocarcinoma

• • • • • • •

98% of all colonic cancers; third most common tumor in both women and men; peak incidence in 60s Symptoms: rectal bleeding, change in bowel habits, weakness, malaise, and weight loss Tumor spreads by direct extension and metastasis to nodes, liver, lungs, bones Carcinoembryonic antigen (CEA) tumor marker helps to monitor tumor recurrence after surgery 75% of tumors in rectum, sigmoid colon Left-sided lesions: annular constriction, infiltration of the wall, obstruction Right-sided lesions: often bulky, polypoid, protuberant masses; rarely obstruct because fecal stream is liquid on right side

Squamous cell carcinoma

• Occur in anal region, associated with papilloma viruses • Incidence rising in homosexual men with AIDS

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Crohn Disease

Ulcerative Colitis

Most common site

Terminal ileum

Rectum

Distribution

Mouth to anus

Rectum → colon; “backwash” ileitis

Spread

Discontinuous/“skip”

Continuous

Gross features

Focal ulceration with intervening normal mucosa, linear fissures, cobblestone appearance, thickened bowel wall, “creeping fat”

Extensive ulceration, pseudopolyps

Micro

Noncaseating granulomas

Crypt abscesses

Inflammation

Transmural

Limited to mucosa and submucosa

Complications

Strictures, “string sign” on barium studies, obstruction, abscesses, fistulas, sinus tracts

Toxic megacolon

Genetic association

Family history of any type of inflammatory bowel disease is associated with increased risk.

Extraintestinal manifestations

Less common

Common (e.g., arthritis, spondylitis [HLA B27 positive], primary sclerosing cholangitis, erythema nodosum, pyoderma gangrenosum)

Cancer risk

Slight 1–3%

5–25%

ORGAN SYSTEMS │ 5. The Gastrointestinal System

►►Inflammatory Bowel Disease: Crohn Disease Versus Ulcerative Colitis

►►Exocrine Pancreas Acute hemorrhagic pancreatitis

• Diffuse necrosis of the pancreas by release of activated enzymes • Most often associated with alcoholism and biliary tract disease • Symptoms: sudden onset of acute, continuous, and intense abdominal pain, often radiating to back; accompanied by nausea, vomiting, and fever → frequently results in shock • Lab values: high amylase, high lipase (elevated after 3–4 days), leukocytosis • Gross: gray areas of enzymatic destruction, white areas of fat necrosis, red areas of hemorrhage

Chronic pancreatitis

• Remitting and relapsing episodes of mild pancreatitis → progressive pancreatic damage • X-rays reveal calcifications in pancreas • Chronic pancreatitis may result in pseudocyst formation, diabetes, steatorrhea

Pseudocysts

• Possible sequelae of pancreatitis or trauma • Up to 10 cm in diameter with a fibrous capsule; no epithelial lining or direct communication with ducts

Carcinoma

• Risk factors: smoking, high-fat diet, chemical exposure • Commonly develop in head of the pancreas, may result in compression of bile duct and main pancreatic duct → obstructive jaundice • Asymptomatic until late in course, then weight loss, abdominal pain (classically, epigastric pain radiating to back), jaundice, weakness, anorexia; Trousseau syndrome (migratory thrombophlebitis) often seen • Very poor prognosis

Cystic fibrosis

• A  utosomal recessive; CFTR (cystic fibrosis transmembrane conductance regulator protein) gene located on chromosome 7; D508 is a common mutation • Defective chloride channel: secretion of very thick mucus and high sodium and chloride levels in sweat • 10% present with meconium ileus (most present during first year with steatorrhea, pulmonary infections, and obstructive pulmonary disease) • Pseudomonas aeruginosa is most common etiologic agent; blue-green sputum • Median survival age 37; mortality most often due to pulmonary infections

Annular pancreas

Occurs when the ventral and dorsal pancreatic buds form a ring around the duodenum → obstruction of the duodenum

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ORGAN SYSTEMS │ 5. The Gastrointestinal System

►►Congenital Hepatic Diseases Extrahepatic biliary atresia

• Incomplete recanalization → cholestasis, cirrhosis, portal hypertension • Within first weeks of life: jaundice, dark urine, light stools, hepatosplenomegaly

Intrahepatic biliary atresia

• Diminished number of bile ducts; sometimes associated with α-1-antitrypsin deficiency • Presents in infancy with cholestasis, pruritus, growth retardation, ↑ serum lipids • Icterus visible when serum bilirubin exceeds 2 mg/dL (true in any case of jaundice)

Conjugated hyperbilirubinemia

• D  ubin-Johnson syndrome: benign conjugated hyperbilirubinemia due to impaired transport; liver grossly black • Rotor syndrome: asymptomatic, similar to Dubin-Johnson, but the liver not pigmented

Unconjugated hyperbilirubinemia

• Can be due to hemolysis, diffuse hepatocellular damage, enzymatic defect • Gilbert syndrome: autosomal recessive disease; deficiency of glucuronyl transferase; benign • Crigler-Najjar syndrome: −  Type 1: autosomal recessive with complete absence of glucuronyl transferase, marked unconjugated hyperbilirubinemia, severe kernicterus, death − Type 2: autosomal dominant with mild deficiency of glucuronyl transferase; no kernicterus

►►Common Patterns of Liver Disease Presentation Cholestasis

• Impaired excretion of conjugated bilirubin; can have chalky stool • Intrahepatic: viral hepatitis, cirrhosis, drug toxicity • Extrahepatic: gallstones, carcinoma of bile ducts, ampulla of Vater or head of pancreas

Hepatic failure

Causes jaundice, encephalopathy, renal failure, palmar erythema, spider angiomas, gynecomastia, testicular atrophy, prolonged prothrombin time, hypoalbuminemia

Chronic passive congestion

• Associated with right heart failure • Pathology: congestion of central veins and centrilobular hepatic sinusoids (known as “nutmeg liver”)

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ORGAN SYSTEMS │ 5. The Gastrointestinal System

►►Acquired Hepatic Diseases Alcoholic liver disease

• Three major forms: 1) fatty liver, 2) alcoholic hepatitis, 3) alcoholic cirrhosis Fatty liver

• Yellow, greasy liver • Accumulation of lipids within hepatocytes • Potentially reversible

Alcoholic hepatitis

• Alcoholic hepatitis usually associated with fatty change; occasionally seen with cirrhosis • Results from a heavy drinking binge • Note: Mallory bodies may be seen, but may also be seen in Wilson disease, hepatocellular carcinoma, and primary biliary cirrhosis • AST/ALT > 2.0 indicates alcoholic liver disease

Cirrhosis

• Third leading cause of death in the 25- to 65-year-old age group • Leading etiologies: alcoholism and hepatitis C

Alpha-1-antitrypsin deficiency

• Autosomal recessive; characterized by deficiency of a protease inhibitor • Results in pulmonary emphysema and hepatic damage (cirrhosis)

Budd-Chiari syndrome

• Congestive liver disease secondary to thrombosis of the inferior vena cava or hepatic veins • Causes “nutmeg liver” (also seen in right heart failure) with centrilobular congestion and necrosis • May develop rapidly or slowly; more likely to be fatal if it develops rapidly

Hemochromatosis

• P  rimary form autosomal recessive inheritance; secondary form usually related to multiple blood transfusions • Deposits of iron in the liver, pancreas, heart, adrenal, skin “bronze diabetes” • Also seen: cardiac arrhythmias, gonadal insufficiency, arthropathy • High incidence of hepatocellular carcinoma

Portal hypertension

• Intrahepatic: most common cause and usually secondary to cirrhosis of the liver; other causes: schistosomiasis, sarcoid • Posthepatic: right-sided heart failure, Budd-Chiari syndrome • Prehepatic: portal vein obstruction • Clinical: ascites, portosystemic shunts that form hemorrhoids, esophageal varices, periumbilical varices (caput medusae), encephalopathy, splenomegaly • Additionally, impaired estrogen metabolism: gynecomastia, gonadal atrophy, amenorrhea in females, spider angiomata, palmar erythema

Primary biliary cirrhosis

• • • •

Secondary biliary cirrhosis

• Longstanding large bile duct obstruction, stasis of bile, inflammation, secondary infection, and scarring • Usually presents with jaundice

Reye syndrome

• Usually affects children between 6 months and 15 years of age • Characterized by fatty change in the liver, edematous encephalopathy • Etiology: unclear; frequently preceded by a mild upper respiratory infection, varicella, influenza A or B infection • Also associated with aspirin administration at levels not ordinarily toxic

Sclerosing cholangitis

• Chronic fibrosing inflammatory disease of the extrahepatic and larger intrahepatic bile ducts • Associated with inflammatory bowel disease; predisposition for cholangiocarcinoma

Wilson disease (hepatolenticular degeneration)

• Autosomal recessiveinadequate excretion of copper • Clinical: rarely manifests before age 6, then presents with weakness, jaundice, fever, angiomas, and eventually portal hypertension; CNS manifestations: tremor, rigidity, disorders of affect and thought • Labs: low serum ceruloplasmin; ↑ urinary copper excretion • Pathology: macronodular cirrhosis, degenerative changes in the lenticular nuclei of brain, pathognomonic Kayser-Fleischer rings, a deposition of copper in Descemet membrane of the corneal limbus

Autoimmune etiology; causes sclerosing cholangitis, cholangiolitis Associated with other autoimmune diseases; primarily affects middle-aged women Presents with fatigue and pruritus; elevated alkaline phosphatase Antimitochondrial antibody in over 90% of patients

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ORGAN SYSTEMS │ 5. The Gastrointestinal System

►►Hepatic Tumors Liver cell adenoma (benign)

• ↑ incidence with anabolic steroid and oral contraceptive use • Forms a mass, which may be mistaken for carcinoma, or may rupture (especially during pregnancy)

Nodular hyperplasia (benign)

• Appears as solitary nodule that often has a fibrous capsule and bile ductules • Stellate fibrous core usually present • Nodular regenerative hyperplasiamultiple nodules composed of normal hepatocytes with loss of normal architecture

Cholangiocarcinomas

• • • •

Hepatoblastoma

• Rare, malignant neoplasm of children • Hepatomegaly, vomiting, diarrhea, weight loss, elevated serum levels of AFP

Hepatocellular carcinoma

• 9  0% of primary liver neoplasms; strongly associated with cirrhosis, HCV and HBV infections • Clinical: tender hepatomegaly, ascites, weight loss, fever, polycythemia, hypoglycemia • Alpha-fetoprotein is present in 50–90% of patients’ serum (AFP also found with other forms of liver disease, pregnancy, fetal neural tube defects, germ-cell carcinomas of the ovaries and testes) • Death due to gastrointestinal bleed and liver failure; generally, metastases first occur in lungs

10% of primary liver neoplasms; associated with primary sclerosing cholangitis In developing countries, also associated with infection with Clonorchis sinensis (liver fluke) Clinical: weight loss, jaundice, pruritus 50% metastasize to lungs, bones, adrenals, and brain, exhibiting both hematogenous and lymphatic spread

►►Hepatic Infections Acute viral hepatitis

• Can be icteric or anicteric • Symptoms: malaise, anorexia, fever, nausea, upper abdominal pain, hepatomegaly • Labs: elevated transaminases

Chronic hepatitis

• 5  –10% of HBV infections and well over 50% of HCV; other etiologies: drug toxicity, Wilson disease, alcohol, α-1-antitrypsin deficiency, autoimmune hepatitis • Histology: chronic inflammation with hepatocyte destruction, cirrhosis, liver failure

Fulminant hepatitis

• Massive hepatic necrosis and progressive hepatic dysfunction; mortality of 25–90% • Etiologies: HBV, HCV, delta virus (HDV) superinfection, HEV, chloroform, carbon tetrachloride, certain mushrooms, acetaminophen overdose • Pathology: progressive shrinkage of liver as parenchyma is destroyed

Liver abscesses

Pyogenic: • E. coli, Klebsiella, Streptococcus, Staphylococcus; ascending cholangitis most common cause • Seeding of liver due to bacteremia another potential cause Parasitic: • Entamoeba histolytica: especially in men over age 40 following intestinal disease; thick, brown abscess fluid • Ascaris lumbricoides: can cause blockage of bile ducts, eosinophilia, verminous abscesses

Parasitic infections

• Schistosomiasis: splenomegaly, portal hypertension, ascites • Amebiasis: Entamoeba histolytica, bloody diarrhea, pain, fever, jaundice, hepatomegaly

Definition of abbreviations: HBV, hepatitis B virus; HCV, hepatitis C virus.

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Hepatitis A

Hepatitis B

Hepatitis C

Hepatitis D

Hepatitis E

Nucleic acid

RNA (Picornavirus)

DNA (Hepadnavirus)

RNA (Flavivirus)

RNA

RNA (Hepevirus)

Characteristics

• 5  0% seropositivity in people >50 • Clinical disease: mild or asymptomatic; rare after childhood

• W  orldwide carrier rate 300 million • 300,000 new infections/year in U.S.

• 1  50,000 new cases/year in U.S. • Most important cause of transfusionrelated hepatitis

• R  eplication defective • Dependent on HBV coinfection for multiplication

Fulminant hepatitis 0.3−3%; 20% in pregnant women

Transmission

• F  ecal-oral, raw shellfish (concentrate virus) • Not shed in semen, saliva, urine • Shed in stool 2 weeks before onset of jaundice and 1 week after

• P  arenteral, close personal contact • Transfusion • Dialysis • Needle-sticks • IV drug use • Male homosexual activity

• P  arenteral, close personal contact • Route of transmission undetermined in 40–50% of cases

Parenteral, close personal contact

• Waterborne • Young adults

Incubation

2−6 weeks

4−26 weeks

2−26 weeks

4−7 weeks in superinfection

2−8 weeks

Carrier state

None

1% blood donors

1%

1−10% in drug addicts

Unknown

Progression to chronic hepatitis

None

5−10% acute infections, 90% in infants

>80%

• <  5% in coinfection* • 80% superinfection†

None

Increased risk of hepatocellular carcinoma

No

Yes

Yes

Yes, same as for B

Unknown, although not likely

Diagnosis

IgM against HAV

 BcAb is the • H 1st antibody, HBsAg indicates current infection • HBeAg indicates infectivity

ELISA for HCV Abs

Ab to Delta Agent plus HBsAg

ELISA for HEV Abs

ORGAN SYSTEMS │ 5. The Gastrointestinal System

►►Characteristics of Viral Hepatitides

*Coinfection: hepatitis B and delta agent acquired at the same time delta agent acquired during chronic hepatitis B infection

†Superinfection:

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Acute Hepatitis B

Chronic Hepatitis B

Jaundice Symptoms HBs* Window

Anti-HBs

Fatigue

Anti-HBc

[

ORGAN SYSTEMS │ 5. The Gastrointestinal System

►►Serology of Hepatitis B Infection

Anti-HBc HBsAg

HBsAg

Anti-HBe

HBeAg

HBeAg Virus Shedding

Anti-HBe

Virus Shedding

Liver Enzymes 1

2

3

4

5

6

Months After Exposure

12

24

Liver Enzymes 1

2

3 4 5 Months

6

1

2

3

4

5 6 Years

7

8

9

Time After Exposure

*The window is the time between the disappearance of the HBsAg and before antibody to the surface antigen is detected.

►►Biliary Disease Cholelithiasis (gallstones)

• 2  0% of women and 8% of men in U.S.; rare before age 20, but seen in 25% of persons >60 years • Most stones remain in gallbladder and are asymptomatic • Famous “4 Fs”: fat, female, fertile (multiparous), older than 40 years

Three Types of Stones Cholesterol Stones Pure cholesterol stones are radiolucent, solitary, 1–5 cm (diameter), yellow, more common in Northern Europeans Pigment Stones • Small, black, multiple, and radiolucent; high incidence in Asians • Associated with hemolytic disease, e.g., hereditary spherocytosis • Cholelithiasis occurs in the young; think of hereditary spherocytosis, sickle cell disease, or other chronic hemolytic process Mixed Stones • 80% of all stones and associated with chronic cholecystitis • Composed of cholesterol and calcium bilirubinate

Carcinoma of gallbladder

• Disease asymptomatic until late • Symptoms: dull abdominal pain, mass, weight loss, anorexia • Pathology: typically involves fundus and neck; 90% differentiated or undifferentiated adenocarcinomas • Poor prognosis, with 3% 5-year survival rate • Risk factors: cholelithiasis and cholecystitis (in up to 90% of patients), porcelain gallbladder (due to calcium deposition in gallbladder wall); occurs predominantly in elderly

Carcinoma of bile ducts (cholangiocarcinoma)

• • • •

Not associated with gallstones Men are affected more frequently; usually elderly Symptoms: obstructive jaundice Risk factors: chronic inflammation, infections, (e.g., liver flukes), ulcerative colitis

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►►Microbial Diarrhea: Organisms Causing Inflammatory Diarrhea/Dysentery (Invasive Organisms Eliciting Blood, Pus In Stool, Fever)

Organism

Most Common Sources

Common Age Group Infected

Incubation Period

Pathogenesis/ Vignette Clues

Diagnosis

Treatment

Campylobacter jejuni

Poultry, domestic animals, water

All

3–5 days

Invades epithelium, RBC and WBC in stools (most common bacterial diarrhea in U.S.)

Oxidase ⊕, gram – , curved rod, seagullwings shape; grows at 42°C; microaerophile

• Treatment for severe cases only • Erythromycin for invasive disease

Salmonella spp.

Poultry, domestic animals, water

All

8–48 hours

Penetrates to lamina propria of ileocecal region → PMN response and prostaglandin synthesis, which stimulates cAMP

Gram – , motile rods; encapsulated, oxidase –

• S  evere cases only • Sensitivity testing required

Shigella spp.

Water, no animal reservoirs, fecal-oral transmission

All

1–7 days

Shallow mucosal ulcerations and dysentery; septicemia rare

Gram – rod; nonlactose fermenting; nonmotile

• S  evere cases only • Fluoroquinolones, trimethoprimsulfamethoxazole

Yersinia enterocolitica

Milk, wild and domestic animals, fecal-oral

All

2–7 days

Cold-climate pseudoappendicitis; heat-stable enterotoxin; arthritis may occur

Gram – , motile rod; nonencapsulated, oxidase – ; urease ⊕; bipolar staining; best growth at 25°C

• S  evere cases only • Aminoglycosides, trimethoprimsulfamethoxazole

Clostridium difficile

Associated with antibiotic use

Pt. on antibiotics

NA

Pt. on antibiotic (clindamycin)

Gram ⊕ rod; anaerobic spore former

Switch antibiotic; metronidazole

Enteroinvasive E. coli

Food, water, fecal-oral

Adults

2–3 days

Similar to Shigella

Gram – rod; motile, lactose fermenter; serotyping compares O, H, K antigens

Sensitivity testing required

Entamoeba histolytica

Food, water, fecal-oral

All

2–4 weeks

Trophozoites invade colon; flask-like lesions, extraintestinal abscesses (liver); travelers to Mexico

Motile trophozoites or quadrinucleate cysts

Metronidazole

ORGAN SYSTEMS │ 5. The Gastrointestinal System

Gastrointestinal Microbiology

Definition of abbreviation: Pt., patient.

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ORGAN SYSTEMS │ 5. The Gastrointestinal System

►►Microbial Diarrhea: Organisms Causing Noninflammatory Diarrhea (Noninvasive Organisms: No Blood, Pus In Stool) Most Common Sources

Common Age Group Infected

Rotaviruses

Day care, water, fecaloral

Norwalk virus Norovirus (Norwalk-like)

Incubation Period

Pathogenesis/ Vignette Clues

Infants and toddlers

1–3 days

Water, food, fecal-oral

Older kids and adults

Adenovirus 40/41

Nosocomial

Clostridium perfringens

Organism

Diagnosis

Treatment

Microvilli of small intestine blunted; dehydration

Diagnosis by exclusion: dsRNA naked, doubleshelled, icosahedral (Reovirus family)

Supportive

18–48 hours

Blunting of microvilli; “cruise ship” diarrhea

Diagnosis by exclusion: ⊕ ssRNA, naked, icosahedral (Calicivirus family)

Supportive

Young kids, immuno­ compromised

7–8 days

Death of enteric cells causes diarrhea

Diagnosis by exclusion: naked, dsDNA, icosahedral

No specific therapy

Beef, poultry, gravies, Mexican food

All

8–24 hours

Enterotoxin

Anaerobic, gram ⊕ rods, sporeforming, Nagler reaction

Not indicated

Vibrio cholerae

Water, food, fecal-oral

All ages

9–72 hours

• T  oxin stimulates adenylate cyclase • Rice water stools

Curved, gram – rod; oxidase ⊕; “shooting-star” motility

Oral rehydration therapy; tetracycline shortens symptoms

Vibrio parahaemolyticus

Raw or undercooked shellfish

Anyone eating raw shellfish

5–92 hours

Self-limited gastroenteritis mimicking cholera

Curved, gram – rod; oxidase ⊕; “shooting-star” mobility

Not indicated

Enterotoxigenic E. coli (ETEC)

Water, uncooked fruits and vegetables

All ages

12–72 hours

Heat labile toxin (LT) stimulates adenylate cyclase; stable toxin stimulates guanylate cyclase

Gram – rod; motile; lactose fermenter; serotyping compares O, H, K antigens

Sensitivity testing required

Enteropathogenic E. coli (EPEC)

Food, water, fecal-oral

Infants in developing countries

2–6 days

Adherence to enterocytes through pili → damage to adjoining microvilli

Gram – rod; motile; lactose fermenter; serotyping compares O, H, K antigens

Sensitivity testing required

Enterohemorrhagic E. coli (EHEC)

Food, fecal-oral (hamburger)

50% 35 years; tends to involve shaft of the penis and scrotum Gross: thick, ulcerated plaque Micro: squamous cell carcinoma in situ

Squamous cell carcinoma

1% of cancers in men in the United States, usually age 40–70. Usually slow growing and non-painful; patients often delay seeking medical attention. Circumcision decreases the incidence. Human Papilloma virus (types 16 and 18) infection is closely associated. Gross: Plaque progressing to an ulcerated papule or fungating growth. Metastases can go to local lymph nodes.

Peyronie disease

Curved penis due to fibrosis of the tunica albuginea (Continued)

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ORGAN SYSTEMS │ 7. The Reproductive System

►►Diseases of the Penis and Prostate (Cont’d.) Diseases of the Prostate Prostatic carcinoma

• • • • • • • • •

Most common cancer in men; usually occurs after age 50, and the incidence increases with age Associated with race (more common in African Americans than in Caucasians, relatively rare in Asians) May present with urinary problems or a palpable mass on rectal examination Prostate cancer more common than lung cancer, but lung cancer is bigger killer Metastases may occur via the lymphatic or hematogenous route Bone commonly involved with osteoblastic metastases, typically in the pelvis and lower vertebrae Elevated PSA, together with an enlarged prostate on digital rectal exam, highly suggestive of carcinoma Most patients present with advanced disease and have a 10-year survival rate of 7 ng/mL ...................

10.0-14.0 kPa 4.4-5.9 kPa [H + ] 36-44 nmol/L 3.8-6.1 mmol/L < 6.6 mmol/L < 5 µg/L > 7 µg/L

76-390 mg/dL ........................................................ 0-380 IU/mL ......................................................... 650-1500 mg/dL .................................................... 40-345 mg/dL ........................................................ 50-170 µg/dL ......................................................... 45-90 U/L .............................................................. Male: 6-23 mIU/mL ............................................. Female: follicular phase 5-30 mIU/mL ............ midcycle 75-150 mIU/mL ............................. postmenopause 30-200 mIU/mL .................. 275-295 mOsmol/kg ............................................. 230-630 pg/mL ...................................................... 20-70 U/L .............................................................. 3.0-4.5 mg/dL ....................................................... < 20 ng/mL ...........................................................

0.76-3.90 g/L 0-380 kIU/mL 6.5-15 g/L 0.4-3.45 g/L 9-30 µmol/L 45-90 U/L 6-23 U/L 5-30 U/L 75-150 U/L 30-200 U/L 275-295 mOsmol/kg 230-630 ng/L 20-70 U/L 1.0-1.5 mmol/L < 20 µg/L

6.0-7.8 g/dL ........................................................... 3.5-5.5 g/dL ........................................................... 2.3-3.5 g/dL ........................................................... 0.5-5.0 µU/mL ...................................................... 8-30% of administered dose/24 h ....................... 5-12 µg/dL ............................................................. 35-160 mg/dL ........................................................ 115-190 ng/dL ....................................................... 25-35% .................................................................. 7-18 mg/dL ............................................................ 3.0-8.2 mg/dL .......................................................

60-78 g/L 35-55 g/L 23-35 g/L 0.5-5.0 mU/L 0.08-0.30/24 h 64-155 nmol/L 0.4-1.81 mmol/L 1.8-2.9 nmol/L 0.25-0.35 1.2-3.0 mmol urea/L 0.18-0.48 mmol/L

(*) Included in the Biochemical Profile (SMA-12)

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APPENDICES │ B. Lab Values

CEREBROSPINAL FLUID Cell count ........................................................................... Chloride .............................................................................. Gamma globulin ................................................................ Glucose ............................................................................... Pressure .............................................................................. Proteins, total ..................................................................... HEMATOLOGIC Bleeding time (template) .................................................. Erythrocyte count ............................................................. Hematocrit ......................................................................... Hemoglobin, blood ............................................................ Hemoglobin, plasma ......................................................... Leukocyte count and differential Leukocyte count ......................................................... Segmented neutrophils .............................................. Band forms .................................................................. Eosinophils .................................................................. Basophils ..................................................................... Lymphocytes ............................................................... Monocytes ................................................................... Mean corpuscular hemoglobin ....................................... Mean corpuscular hemoglobin concentration .............. Mean corpuscular volume ............................................... Partial thromboplastin time (nonactivated) ................... Platelet count ..................................................................... Prothrombin time .............................................................. Reticulocyte count ............................................................ Sedimentation rate, erythrocyte (Westergren) Thrombin time ................................................................... Volume Plasma .......................................................................... Red cell ........................................................................

SWEAT Chloride .............................................................................. URINE Calcium .............................................................................. Chloride .............................................................................. Creatinine clearance ........................................................ Estriol, total (in pregnancy) 30 weeks ...................................................................... 35 weeks ...................................................................... 40 weeks ...................................................................... 17-Hydroxycorticosteroids ................................................ 17-Ketosteroids, total ......................................................... Osmolality ........................................................................... Oxalate ................................................................................ Potassium ........................................................................... Proteins, total ..................................................................... Sodium ................................................................................ Uric acid .............................................................................

REFERENCE RANGE

SI REFERENCE INTERVALS

0-5 cells/mm3 ................................................................................................................. 118-132 mmol/L ................................................... 3-12% total proteins ............................................ 40-70 mg/dL .......................................................... 70-180 mm H2O .................................................... < 40 mg/dL ...........................................................

0-5 x 106/L 118-132 mmol/L 0.03-0.12 2.2-3.9 mmol/L 70-180 mm H2O < 0.40 g/L

2-7 minutes ........................................................... Male: 4.3-5.9 million/mm3 ..................................................................... Female: 3.5-5.5 million/mm 3 ............................................................ Male: 41-53% ....................................................... Female: 36-46% ................................................... Male: 13.5-17.5 g/dL ........................................... Female: 12.0-16.0 g/dL ....................................... 1-4 mg/dL ..............................................................

2-7 minutes 4.3-5.9 x 1012/L 3.5-5.5 x 1012/L 0.41-0.53 0.36-0.46 2.09-2.71 mmol/L 1.86-2.48 mmol/L 0.16-0.62 mol/L

4500-11,000/mm3 ..................................................................................................... 54-62% .................................................................. 3-5% ...................................................................... 1-3% ...................................................................... 0-0.75% ................................................................. 25-33% .................................................................. 3-7% ...................................................................... 25.4-34.6 pg/cell ................................................... 31-36% Hb/cell .................................................... 80-100 m 3 ......................................................................................................................... 60-85 seconds ....................................................... 150,000-400,000/mm3 ....................................................................................... 11-15 seconds ....................................................... 0.5-1.5% of red cells ........................................... Male: 0-15 mm/h ................................................. Female: 0-20 mm/h ............................................. < 2 seconds deviation from control ...................

4.5-11.0 x 109/L 0.54-0.62 0.03-0.05 0.01-0.03 0-0.0075 0.25-0.33 0.03-0.07 0.39-0.54 fmol/cell 4.81-5.58 mmol Hb/L 80-100 fl 60-85 seconds 150-400 x 109/L 11-15 seconds 0.005-0.015 0-15 mm/h 0-20 mm/h < 2 seconds deviation from control

Male: 25-43 mL/kg ............................................... Female: 28-45 mL/kg .......................................... Male: 20-36 mL/kg ............................................... Female: 19-31 mL/kg ..........................................

0.025-0.043 L/kg 0.028-0.045 L/kg 0.020-0.036 L/kg 0.019-0.031 L/kg

0-35 mmol/L .........................................................

0-35 mmol/L

100-300 mg/24 h ................................................... Varies with intake ............................................... Male: 97-137 mL/min .......................................... Female: 88-128 mL/min .....................................

2.5-7.5 mmol/24 h Varies with intake

6-18 mg/24 h ......................................................... 9-28 mg/24 h ......................................................... 13-42 mg/24 h ....................................................... Male: 3.0-10.0 mg/24 h ....................................... Female: 2.0-8.0 mg/24 h ..................................... Male: 8-20 mg/24 h ............................................. Female: 6-15 mg/24 h ......................................... 50-1400 mOsmol/kg ............................................. 8-40 g/mL ........................................................... Varies with diet ................................................... < 150 mg/24 h ...................................................... Varies with diet ................................................... Varies with diet ...................................................

21-62 mol/24 h 31-97 mol/24 h 45-146 mol/24 h 8.2-27.6 mol/24 h 5.5-22.0 mol/24 h 28-70 mol/24 h 21-52 mol/24 h 90-445 mol/L Varies with diet < 0.15 g/24 h Varies with diet Varies with diet

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Appendix C

Essential Diseases and Findings ►►Essential Eponyms (Diseases and Findings) Name

Description

Addison disease

Primary adrenocortical insufficiency

Albright syndrome

Young girls with short stature, polyostotic fibrous dysplasia, precocious puberty, café-aulait spots

Alport syndrome

Progressive hereditary nephritis with sensorineural deafness

Argyll-Robertson pupil

Small, irregular pupils that react poorly to light in neurosyphilis (accommodation is preserved)

Arnold-Chiari malformation

Congenital herniation of cerebellar tonsils and vermis through the foramen magnum; may compress medulla or cervical cord

Aschoff bodies

Painless nodules in rheumatic fever

Auer rods

Intracytoplasmic inclusions in acute myelogenous leukemia

Babinski sign

Upward moving great toe when sole stroked; indicates upper motor neuron lesion

Baker’s cyst

Popliteal fossa cyst in rheumatoid arthritis

Bartter syndrome

Hypokalemia, metabolic alkalosis, elevated renin and aldosterone, normal to low blood pressure

Becker muscular dystrophy

Less severe than Duchenne, also due to defective dystrophin

Bell’s palsy

Facial paralysis due to lower motor neuron CN VII palsy

Bence Jones protein

Kappa or lambda immunoglobin light chains in urine of patients with multiple myeloma or Waldenström macroglobulinemia

Berger disease

IgA nephropathy; most common form of primary glomerulonephritis

Bernard-Soulier disease

Thrombocytopenia, large platelets; defect in platelet adhesion

Birbeck granules

Intracellular “tennis racket”–shaped structures in histiocytosis X (eosinophilic granuloma)

Bouchard’s nodes

PIP swelling in osteoarthritis secondary to osteophytes

Brushfield spots

Ring of iris spots in Down syndrome

Bruton disease

X-linked agammaglobulinemia; mature B cells absent

Budd-Chiari syndrome

Posthepatic venous thrombosis causing occlusion of hepatic vein or inferior vena cava

Buerger disease

Small/medium artery vasculitis, especially in young male smokers

Burkitt lymphoma

EBV-associated lymphoma with 8:14 translocation (starry sky appearance)

Burton’s lines

Blue discoloration of gums in lead poisoning (Continued)

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APPENDICES │ C. Diseases/Findings

►►Essential Eponyms (Diseases and Findings) (Cont'd.) Name

Description

Caisson disease

Gas emboli in divers

Call-Exner bodies

Small spaces with eosinophilic material in granulosa-theca cell tumor of ovary

Chagas disease

Infection with Trypanosoma cruzi (Central and South America)

Charcot’s triad #1

Nystagmus, intention tremor, and scanning speech; suggests multiple sclerosis

Charcot’s triad #2

Jaundice, RUQ pain, and fever; suggests cholangitis

Charcot-Leyden crystals

Crystals in sputum made of eosinophil membranes; suggests bronchial asthma

Chediak-Higashi disease

Phagocyte deficiency related to abnormally large granules in neutrophils

Cheyne-Stokes respirations

Terminal pattern of respirations with increasing breaths followed by apnea; indicates central apnea in coronary heart disease and increased intracranial pressure

Chvostek’s sign

Facial musical spasm on tapping; indicates hypocalcemia

Codman’s triangle on x-ray

Subperiosteal new bone formation; suggests osteosarcoma

Cori disease

Liver and muscle glycogen storage disease due to debranching enzyme deficiency

Councilman bodies

Eosinophilic intracytoplasmic balls in hepatocytes; suggests toxic or viral hepatitis

Cowdry type A bodies

Intranuclear inclusions; suggests herpesvirus infection

Crigler-Najjar syndrome

Mild (type 2) to life-threatening (type 1) congenital unconjugated hyperbilirubinemia

Curling ulcer

Acute gastric ulcer secondary to severe burns

Curschmann’s spirals

Coiled mucinous fibrils found in sputum in bronchial asthma

Cushing ulcer

Gastric ulcer produced by increased intracranial pressure

Donovan bodies

Intracellular bacteria in granuloma inguinale

Dressler syndrome

Fibrinous pericarditis developing after myocardial infarction

Dubin-Johnson syndrome

Benign black liver secondary to congenital conjugated hyperbilirubinemia

Duchenne muscular dystrophy

X-linked recessive muscle dysfunction secondary to deleted dystrophin gene

Edwards syndrome

Trisomy 18; causes “rocker bottom” feet, low-set ears, and heart disease

Eisenmenger’s complex

Uncorrected left-to-right cardiac shunt causes late right-to-left shunt with late cyanosis

Erb-Duchenne palsy

“Waiter’s tip” hand secondary to superior trunk brachial plexus injury

Fanconi syndrome

Kidney dysfunction secondary to proximal tubular reabsorption defect

Gardner syndrome

Constellation of colon polyps with osteomas and soft tissue tumors

Gaucher disease

Glucocerebrosidase deficiency leading to potentially fatal glucocerebroside accumulation in multiple organs, notably spleen, liver, marrow, and brain

Ghon focus

Small lung lesion of early tuberculosis

Gilbert syndrome

Benign congenital unconjugated bilirubinemia (mostly just scares doctors)

Goodpasture syndrome

Anti-basement membrane antibodies; causes pulmonary and kidney bleeding (Continued)

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Name

Description

Gower’s maneuver

Child using arms to help with leg weakness when trying to stand; suggests Duchenne muscular dystrophy

Guillain-Barré syndrome

Autoimmune peripheral nerve damage causing life-threatening paralysis

Hand-Schüller-Christian disease

Chronic, progressive, potentially fatal histiocytosis in which macrophages attack a child’s body

Heberden’s nodes

Osteophytes at DIP; suggests osteoarthritis

Heinz bodies

Red cell inclusions in G6PD deficiency

Henoch-Schönlein purpura

Hypersensitivity vasculitis causing hemorrhagic urticaria and arthritis

Homer-Wright rosette

Microscopic finding of a ring of neural cells suggesting neuroblastoma

Horner syndrome

Dysfunction of oculosympathetic pathway; ptosis, miosis, hemianhidrosis, apparent enophthalmos; causes include Pancoast tumor, lateral medullary syndrome

Howell-Jolly bodies

Red cell inclusions of DNA suggesting hyposplenism

Huntington disease

Autosomal-dominant caudate degeneration causing chorea and psychiatric problems

Janeway lesions

Hemorrhagic nodules in palms or soles; suggest endocarditis

Jarisch-Herxheimer reaction

Overaggressive treatment of infection causing endotoxin release with possible shock; classic example is syphilis

Job syndrome

Poor delayed hypersensitivity with neutrophil chemotaxis abnormality causing hyper-IgE with skin abscesses and other infections

Kaposi sarcoma

HHV-8 infection in AIDS patients causing vascular sarcoma

Kartagener syndrome

Dynein defect causes defective cilia, leading to bronchiectasis

Kayser-Fleischer rings

Green to golden copper deposits in iris around pupil; suggest Wilson disease

Kimmelstiel-Wilson nodules

Acellular glomerular nodules; suggest diabetic nephropathy

Klüver-Bucy syndrome

Bilateral amygdala lesions causing bizarre behavior with tendency to put anything in the mouth

Koplik spots

Minute white specks in buccal mucosa that may be first sign of measles

Krukenberg tumor

Gastric adenocarcinoma with ovarian metastases

Kussmaul ventilation

Diabetic ketoacidosis causes rapid, deep breathing to blow off CO2

Lesch-Nyhan syndrome

X-linked HGPRT deficiency causing high uric acid levels with risk of brain damage

Lewy bodies

Round intracytoplasmic inclusions in neurons; seen in Parkinson disease

Libman-Sacks disease

Noninfectious endocarditis in SLE

Lines of Zahn

White streaks in arterial thrombus

Lisch nodules

Brown iris lesions in neurofibromatosis

Mallory bodies

Ropy cytoplasmic inclusions in hepatocytes in alcoholic liver disease

APPENDICES │ C. Diseases/Findings

►►Essential Eponyms (Diseases and Findings) (Cont'd.)

(Continued)

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APPENDICES │ C. Diseases/Findings

►►Essential Eponyms (Diseases and Findings) (Cont'd.) Name

Description

Mallory-Weiss syndrome

Esophagogastric lacerations with profuse bleeding secondary to heavy vomiting, forcing part of stomach into esophagus

McArdle disease

Muscle phosphorylase deficiency causing glycogen storage disease with prominent muscular symptoms

McBurney’s point

Appendicitis is suggested by tenderness on palpation on a line between the anterior superior spine of the ilium and the umbilicus

Negri bodies

Neuron inclusions on electron microscopy in rabies

Niemann-Pick disease

Potentially fatal sphingomyelinase deficiency causing sphingomyelin deposition in brain and other organs, cherry-red macula spot, and neurologic problems

Osler’s nodes

Pea-sized nodules on palms and soles suggesting endocarditis

Pancoast tumor

Apical lung cancer causing Horner syndrome

Parinaud syndrome

Dorsal midbrain syndrome often caused by compression by pineal gland; paralysis of upward gaze, may compress cerebral aqueduct → noncommunicating hydrocephalus

Parkinson disease

Motor disorder (resting tremor, rigidity) secondary to nigrostriatal dopamine depletion

Peutz-Jeghers syndrome

Benign autosomal-dominant colon polyposis syndrome

Peyronie disease

Penis deviates on erection secondary to fibrosis

Pick bodies

Round, silver-staining cytoplasmic structures in neurons in Pick disease; contain tau protein

Pick cells

Swollen (balloon) cells found in Pick disease; may contain Pick bodies

Pick disease

Frontal and temporal atrophy; progressive dementia; similar to Alzheimer disease but has a shorter course

Plummer-Vinson syndrome

Esophageal webs with iron deficiency anemia

Pompe disease

Lysosomal glucosidase deficiency causing cardiomegaly

Pott disease

Tuberculosis of the vertebrae

Raynaud syndrome

Recurrent vasospasm in extremities causing hand or foot color changes

Reed-Sternberg cells

Large binucleate tumor cells in Hodgkin disease

Reid index

Increased Reid index means thick mucous glands in bronchus and suggests chronic bronchitis

Reinke crystals

Crystals seen in Leydig cell tumors on microscopy

Reiter syndrome

Nongonococcal urethritis causes immune response, leading to conjunctivitis and arthritis

Roth spots

Retinal hemorrhages; suggest endocarditis

Rotor syndrome

Fairly benign congenital conjugated hyperbilirubinemia

Russell bodies

Round plasma cell inclusions that suggest multiple myeloma

Schiller-Duval bodies

Glomerulus-like microscopic structures in yolk sac tumors (Continued)

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APPENDICES │ C. Diseases/Findings

►►Essential Eponyms (Diseases and Findings) (Cont'd.) Name

Description

Sézary syndrome

Cutaneous form of T-cell lymphoma with marked generalized erythema

Sheehan syndrome

Postpartum pituitary necrosis leading to massive hormonal deficits

Sipple syndrome

MEN type IIa; medullary thyroid carcinoma, pheochromocytoma, and parathyroid disease

Sjögren syndrome

Autoimmune attack on salivary glands with dry eyes, dry mouth, and arthritis

Spitz nevus

Childhood spindle cell lesion that looks like melanoma but has better prognosis

Trousseau’s sign of hypocalcemia

Carpal spasm

Trousseau’s sign of malignancy

Migratory thrombophlebitis suggesting visceral (pancreatic) carcinoma

Virchow’s node

Left supraclavicular node enlargement suggesting metastatic gastric carcinoma

Virchow’s triad

Combination of blood stasis, endothelial damage, and hypercoagulation causes venous clots with risk of pulmonary embolism

von Recklinghausen neurologic disease

Neurofibromatosis

von Recklinghausen bone disease

Osteitis fibrosa cystica

Wallenberg syndrome

Lateral medullary syndrome caused by PICA occlusion; causes contralateral pain/ temperature deficits in body, ipsilateral pain/temperature deficits in face, dysphagia, vestibular dysfunction, ipsilateral Horner syndrome

Waterhouse-Friderichsen syndrome

Adrenal hemorrhage complicating meningococcemia

Weber syndrome

Medial midbrain syndrome; ipsilateral oculomotor paralysis, contralateral spastic paralysis, contralateral lower facial weakness

Wermer syndrome

MEN type I; parathyroid tumors, endocrine pancreatic tumors, and pituitary gland tumors

Whipple disease

Tropheryma whippelii causes malabsorption syndrome

Wilson disease

Altered copper metabolism causes damage to liver and brain; Kayser-Fleischer rings

Zenker’s diverticulum

Lower esophageal diverticulum

Zollinger-Ellison syndrome

Gastrin-secreting tumor causing peptic ulcers

►►Eye Findings on Physical Examination Finding

Classic Disease Association (Notes)

Argyll Robertson pupil

Tertiary (neuro) syphilis; loss of light reflex constriction; accommodation is preserved; classic form bilateral

Blue sclera

Osteogenesis imperfecta, types I and II (fatal) Also may be seen in Ehlers-Danlos syndrome, pseudoxanthoma elasticum, Marfan syndrome

Brushfield spots

Down syndrome (ring of white spots around periphery of iris; trisomy 21)

Charcot’s triad #1

Multiple sclerosis (nystagmus, intention tremor, scanning speech; triad #2 is for cholangitis: jaundice, fever, rigors, pain) (Continued)

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APPENDICES │ C. Diseases/Findings

►►Eye Findings on Physical Examination (Cont'd.) Finding

Classic Disease Association (Notes)

Cherry-red spot

Tay-Sachs, Niemann-Pick, central retinal artery occlusion (retinal pallor contrasting with strikingly red macular spot)

Cotton-wool spots

Chronic hypertension (small areas of yellowish-white discoloration in the retina)

Horner syndrome

Impaired sympathetic innervation to eye (ptosis, miosis, anhidrosis, and apparent enophthalmos; numerous causes, including vascular, traumatic, congenital, Pancoast tumor, other tumors)

Internuclear ophthalmoplegia (INO)

Multiple sclerosis (disorder of lateral conjugate gaze; affected eye cannot adduct and nystagmus occurs in the abducting eye; convergence is intact)

Kayser-Fleischer rings

Wilson disease (greenish or golden copper deposits in crescent or ring in Descemet’s membrane)

Lens dislocation

Marfan syndrome (can be accompanied by aortic dissection and joint hyperflexibility)

Lisch nodules

Neurofibromatosis type I (tan hamartomas on the iris)

Roth spots

Bacterial endocarditis (hemorrhage in retina with a white center; also seen in leukemia, diabetes, collagen-vascular diseases)

►►Skin Findings Finding

Classic Disease Association (Notes)

Adenoma sebaceum

Tuberous sclerosis (raised, erythematous papules on the face, especially around the nose)

Anesthesia

Leprosy (skin may be blotchy, red, or thickened)

Bullae (tense) 

Bullous pemphigoid

Bullae (flaccid, rupturing)

Pemphigus

Brown-black lesion with fuzzy edge

Melanoma (depth of lesion most important prognostic indicator)

Butterfly rash

Systemic lupus erythematosus (nose and cheeks)

Café-au-lait spots

Neurofibromatosis (light brown spots, often over 1 cm)

Chancre

Primary syphilis (painless ulcer, usually on genitalia)

Chancroid

Haemophilus ducreyi (painful ulcer, usually on genitalia)

Condylomata lata

Secondary syphilis (smooth, flat, painless genital lesions; scrapings may show spirochetes with darkfield microscopy)

Dermatitis, dementia, diarrhea

Pellagra caused by niacin deficiency

Dog or cat bite

Pasteurella multocida

Elastic skin

Ehlers-Danlos syndrome

Erythema chronicum migrans

Lyme disease (expanding red ring with central clearing at tick bite site)

Generalized hyperpigmentation

Addison disease (primary adrenal insufficiency)

Kaposi sarcoma

AIDS (usually slightly raised violaceous papules or plaques) (Continued)

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APPENDICES │ C. Diseases/Findings

►►Skin Findings (Cont'd.) Finding

Classic Disease Association (Notes)

Port wine stain

Hemangioma (large, purplish lesion on face)

Rash on palms and soles

Secondary syphilis, Rocky Mountain spotted fever

Silvery, scaly plaques

Psoriasis (knees, elbows, scalp)

Slapped cheeks

Erythema infectiosum (fifth disease, parvovirus B19)

Vesicles, small painful

Herpes, dermatitis herpetiformis

►►Extremity Findings on Physical Examination Finding

Classic Disease Association (Notes)

Arachnodactyly

Marfan syndrome (very long fingers and toes)

Babinski sign

Upper motor neuron lesion (stimulation of sole of foot → upgoing great toe)

Baker’s cyst

Rheumatoid arthritis (cyst in popliteal fossa)

Bouchard’s node

Osteoarthritis (PIP osteophytes)

Boutonniere deformity

Rheumatoid arthritis (finger flexed at PIP and hyperextended at DIP)

Calf pseudohypertrophy

Duchenne muscular dystrophy (replacement of muscle with fat and connective tissue)

Heberden’s nodes

Osteoarthritis (DIP enlargement because of osteophytes)

Janeway lesions

Endocarditis (hemorrhagic nodules in palms or soles)

Osler’s nodes

Endocarditis (tender nodules on palms and soles)

Palpable purpura

Henoch-Schönlein purpura (legs and buttocks)

Rash affecting palms and soles

Secondary syphilis, Rocky Mountain spotted fever

Raynaud syndrome

Recurrent vasospasm (pale to blue to red on hands or feet)

Simian crease

Down syndrome (single long crease across palm; trisomy 21)

Splinter hemorrhage

Infective endocarditis, trauma (found under fingernails)

Tendon xanthomas

Familial hypercholesterolemia (classically Achilles tendon)

Tophi

Gout (hard nodules composed of uric acid)

►►Radiologic Findings Finding

Classic Disease Association (Notes)

Bamboo spine

Ankylosing spondylitis (rigid spine with fused joints)

Boot-shaped heart

Right ventricular hypertrophy; tetralogy of Fallot (upturned ventricular apex and large pulmonary artery make the “boot”)

Codman’s triangle

Osteosarcoma (new subperiosteal bone lifts periosteum)

(Continued)

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APPENDICES │ C. Diseases/Findings

►►Radiologic Findings (Cont'd.) Finding

Classic Disease Association (Notes)

Double-bubble sign

Duodenal atresia, also duodenal stenosis, duodenal webs, annular pancreas, malrotation of the gut (two air-filled structures in upper abdomen, with little or no air distally)

“Hair on end” or “crew-cut”

Beta thalassemia, sickle cell anemia (extramedullary hematopoiesis below periosteum leads to formation of bony spicules = “hair” on outside of bone)

Mammillary body atrophy

Wernicke encephalopathy (memory loss)

Periosteal elevation

Pyogenic osteomyelitis (elevation due to subperiosteal inflammation; this may be the earliest radiologic sign of osteomyelitis)

“Punched out” (lytic) lesions of bone

Multiple myeloma

Rib notching

Coarctation of aorta (dilated aorta before coarctation puts chronic pressure on ribs)

Soap bubble

Giant cell tumor of bone (lytic expansile lesion)

String sign

Crohn disease (small bowel follow-through shows very narrow lumen, typically in terminal ileum)

►►Auscultation Findings Sound

Possible Causes Systolic Murmurs

Soft systolic ejection murmurs

May be normal in infants, children, pregnancy

Systolic ejection murmur (right 2nd interspace) 

Aortic stenosis

Systolic ejection murmur (mid to lower left sternal border)

Hypertrophic obstructive cardiomyopathy

Systolic ejection murmur (left 2nd interspace) 

Pulmonic stenosis

Systolic ejection murmur (apex, can increase through systole)

Mitral regurgitation

Systolic ejection murmur (lower left sternal border, increases with inspiration)

Tricuspid regurgitation

Holosystolic ejection murmur (left fourth interspace)

Ventricular septal defect

Diastolic Murmurs Diastolic murmur (apex)

Mitral stenosis

Diastolic murmur (left 4th interspace)

Tricuspid stenosis

Decrescendo diastolic murmur (left 4th interspace)

Aortic regurgitation (see also Austin-Flint murmur)

Austin-Flint murmur (mid-to-late-diastolic rumble/low-frequency murmur over apex)

Severe aortic regurgitation

Decrescendo diastolic murmur (right sternal edge and left 2nd interspace)

Pulmonic regurgitation (Continued)

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APPENDICES │ C. Diseases/Findings

►►Auscultation Findings (Cont'd.) Sound

Possible Causes Continuous Murmurs

Continuous murmur (left 2nd interspace below median end of clavicle)

Patent ductus arteriosus

Continuous murmur (centrally at 3rd interspace level)

Aorticopulmonary window defect

Continuous murmur (peripheral body sites) 

Systemic arteriovenous connections

Miscellaneous Findings Loud S1

Mitral stenosis

Soft or absent S1 

Mitral regurgitation if valve is stiff

Late aortic valve closure in S2 

Left bundle branch block, aortic stenosis

Late pulmonic valve closure in S2 

Atrial septal defect, right bundle branch block

Fixed split S2 during respiration

Atrial septal defect

Paradoxical splitting of S2

Left bundle branch block (also some cases of aortic stenosis and patent ductus)

Single S2

Badly damaged aortic valve (regurgitation, stenosis, or atresia)

Early systolic click 

Congenital aortic or pulmonic valve stenosis, severe pulmonary hypertension

Changing systolic clicks with position

Myxomatous degeneration of mitral or tricuspid valves

S3 (pericardial knock) 

Dilated and noncompliant left (strongest on expiration) or right (strongest on inspiration) ventricle, normal in kids

S4

Right (strongest on inspiration) or left (strongest on expiration) ventricular dysfunction (myocardial ischemia or early myocardial infarction)

Summation gallop (combined S3 and S4)

Tachycardic patient with right or left ventricular dysfunction

Diastolic knock

Constricting pericardium

Mitral opening snap

Mitral stenosis

►►Genetic Associations Finding

Classic Disease Association (Notes)

5p–

Cri-du-chat syndrome (cat-like cry, feeding problems, abnormal mental development)

45,XO

Turner syndrome (infertile female, webbed neck, coarctation of aorta)

47,XXY

Klinefelter syndrome (male with small testes and eunuchoid habitus)

CFTR

Cystic fibrosis (chloride channel gene, chromosome 7, recurrent pneumonia, pancreatic exocrine insufficiency)

FBN1 gene (codes for fibrillin)

Marfan syndrome (chromosome 15, tall stature, hyperextensible joints, dissecting aortic aneurysm)

(Continued)

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APPENDICES │ C. Diseases/Findings

►►Genetic Associations (Cont'd.) Finding

Classic Disease Association (Notes)

NF1

Neurofibromatosis type I (von Recklinghausen disease, chromosome 17, neurofibromas, café-au-lait spots)

NF2

Neurofibromatosis type II (bilateral acoustic neurofibromatosis, chromosome 22)

t(8;14)

Burkitt lymphoma (c-myc)

t(9;22)

CML and occasionally AML (Philadelphia chromosome, bcr-abl hybrid)

t(14;18)

Many follicular lymphomas (bcl-2)

Trisomy 13

Patau syndrome (microcephaly, mental retardation, cleft palate, polydactyly, heart malformations)

Trisomy 18

Edwards syndrome (rocker bottom feet, microcephaly, mental retardation, multiple organ defects)

Trisomy 21

Down syndrome (most common chromosomal disorder, older maternal age, mental retardation, early Alzheimer disease)

VHL

von Hippel-Lindau (chromosome 3, hemangioblastomas, renal cell carcinoma)

XYY

XYY syndrome (very tall male with increased risk of behavior problems)

►►Microscopic Findings Finding

Classic Disease Association (Notes)

Auer rods

Acute myelogenous leukemia, particularly promyelocytic (rods in white blood cell cytoplasm)

Basophilic stippling

Lead poisoning (dots in erythrocytes)

Birbeck granules on EM

Histiocytosis X (eosinophilic granuloma)

Call-Exner bodies

Granulosa-theca cell tumor of ovary (ring of cells with pink fluid in center)

Cerebriform nuclei

Mycosis fungoides (cutaneous T-cell lymphoma)

Clue cells

Gardnerella vaginitis (bacteria on epithelial cells)

Councilman bodies

Toxic or viral hepatitis (pink, round cytoplasmic inclusion in hepatocytes)

Cowdry type A bodies

Herpes (intranuclear eosinophilic inclusions)

Crescents in Bowman’s capsule

Rapidly progressive crescentic glomerulonephritis

Curschmann’s spirals

Bronchial asthma (coiled mucinous fibrils found in sputum)

Depigmentation of neurons in substantia nigra

Parkinson disease (degeneration of dopaminergic nigrostriatal neurons)

Donovan bodies

Granuloma inguinale (oval, rod-shaped organisms in cells)

Ferruginous bodies

Asbestosis (rod-shaped structures with crystals on them)

Heinz bodies

G6PD deficiency (red cell inclusions)

Homer Wright rosettes

Neuroblastoma (ring of neural cells)

Howell-Jowell bodies

Splenectomy or nonfunctioning spleen (blue-black erythrocyte inclusions)

Hypersegmented neutrophils

Macrocytic anemia (vitamin B12 or folate deficiency) (Continued)

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APPENDICES │ C. Diseases/Findings

►►Microscopic Findings (Cont'd.) Finding

Classic Disease Association (Notes)

Hypochromic microcytosis

Iron deficiency anemia, lead poisoning

Keratin pearls

Squamous cell carcinoma (concentric layers of keratin)

Kimmelsteil-Wilson nodules

Diabetic nephropathy (acellular nodules in glomerulus)

Koilocytes

HPV infections such as condyloma, cervical dysplasia (look for perinuclear halo)

Lewy bodies

Parkinson disease (round, pink nodules in neuronal cytoplasm)

Mallory bodies

Alcoholic liver disease (ropy, pink cytoplasmic structures in hepatocytes)

Needle-shaped, negatively birefringent crystals

Gout (uric acid)

Negri bodies

Rabies (large viral inclusions in neurons, see on Emergency Medicine)

Neurofibrillary tangles

Alzheimer disease (tangles of fibers in neuron cytoplasm)

Owl’s eye nuclei

Cytomegalovirus (due to virus particles in nucleus)

Pick bodies

Pick disease (silver protein deposits in neurons)

Pseudopalisading tumor cell arrangement

Glioblastoma multiforme (foci of necrosis surrounded by intact tumor cells)

Pseudorosettes

Ewing sarcoma (rings of cells with central vessel)

Reed-Sternberg cells

Hodgkin lymphoma (large binucleate cell with large nucleoli)

Reinke crystals

Leydig cell tumor (rectangular crystals, ovary or testes)

Renal epithelial casts in urine

Acute toxicity/viral (epithelial casts reflect tubular damage)

Rhomboid crystals in joint fluid, positively birefringent

Pseudogout (calcium pyrophosphate crystals)

Rouleaux

Multiple myeloma (stacked erythrocytes)

Russell bodies

Multiple myeloma (hyaline spheres in plasma cells)

Schiller-Duval bodies

Yolk sac tumor (look like glomeruli)

Senile plaques

Alzheimer disease (extracellular amyloid)

Signet ring cells

Gastric carcinoma (have nucleus compressed to one side of cell)

Smudge cells

Chronic lymphocytic leukemia (smashed lymphocyte)

Spike and dome on EM

Membranous glomerulonephritis (irregular dense deposits with basement membrane material between deposits)

“Starry sky” pattern

Burkitt lymphoma (sheets of small lymphocytes with scattered histiocytes as “stars”)

Subepithelial humps on Emergency Medicine

Poststreptococcal glomerulonephritis

Sulfur granules

Actinomyces israeli (clusters of bacteria)

Tram track appearance on light microscopy

Membranoproliferative glomerulonephritis (double contour capillary loops)

Waxy casts in urine

Chronic end-stage renal disease

WBC casts in urine

Acute pyelonephritis

WBCs in urine

Acute cystitis (heavy neutrophilic infiltrate)

“Wire loop” lesion

Lupus nephritis (thickened capillary basement membrane)

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APPENDICES │ C. Diseases/Findings

►►Classic Antibody Findings Finding

Classic Disease Association (Notes)

Anti-basement membrane

Goodpasture syndrome

Anticentromere

Scleroderma (CREST syndrome)

Anti-double stranded DNA (ANA antibodies)

Systemic lupus erythematosus (type III hypersensitivity-immune complexes)

Antiepithelial cell

Pemphigus vulgaris

Antigliadin

Celiac disease

Antihistone

Drug-induced SLE

Anti-IgG 

Rheumatoid arthritis (rheumatoid factor)

Antimitochondrial

Primary biliary cirrhosis

Antineutrophil

Vasculitis

Antiplatelet

Idiopathic thrombocytopenic purpura

C-ANCA, P-ANCA

Wegener granulomatosis (C-ANCA), polyarteritis nodosa (mostly P-ANCA, but can have both)

CLL

Mycoplasma pneumoniae, mononucleosis, lymphoma, CLL

►►Abnormal Erythrocytes on Peripheral Smear Finding

Classic Disease Association (Notes)

Acanthocytes (spur cells)

Abetalipoproteinemia (severe burns, liver disease, hypothyroidism)

Basophilic stippling

Lead poisoning (thalassemia)

Bite cells and Heinz bodies

Glucose-6-phosphate dehydrogenase deficiency (spleen removes Heinz bodies, leading to “bitten” appearance of RBCs)

Dacrocytes (teardrop cells)

Scarring of bone marrow (myelophthisis), splenic dysfunction

Echinocytes (burr cells)

Often drying artifact, uremia

Elliptocytes (ovalocytes)

Hereditary elliptocytosis (iron deficiency, thalassemia, myelophthisis)

Howell-Jolly bodies and Cabot rings

Splenic dysfunction (thalassemia)

Macrocytes (large cells)

Vitamin B12 and folate deficiency (myelodysplastic syndromes, liver disease)

Microcytes (small cells)

Iron deficiency anemia (thalassemia and some cases of anemia of chronic disease)

Pappenheimer bodies

Sideroblastic anemia (splenic dysfunction)

Rouleaux formation

Multiple myeloma (RBCs stacked like coins)

Schistocytes

Intravascular hemolysis (fragmented cells)

Spherocytes

Hereditary spherocytosis (extravascular hemolysis)

Stomatocytes

Hereditary stomatocytosis (alcoholism)

Target cells

Liver disease, thalassemia (HbC, occasionally in iron deficiency)

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Finding

Classic Disease Association (Notes)

Bilobed neutrophil nuclei

Pelger-Huet anomaly

Cerebriform nuclei (convoluted appearance to nucleus)

Mycosis fungoides (cutaneous T-cell lymphoma)

Dohle bodies

Sepsis, May-Hegglin anomaly (pale blue, oval cytoplasmic inclusions that can be near cytoplasmic membrane of neutrophils)

Giant platelets

Bernard-Soulier syndrome

Hypersegmented neutrophil nuclei

Megaloblastic (macrocytic) anemia

Large blue granules in cytoplasm of all white blood cells

Alder-Reilly anomaly

Large eosinophilic granules in neutrophil cytoplasm

Chediak-Higashi syndrome

Toxic granulation

Sepsis (medium-to-large sized dark blue granulations in neutrophil cytoplasm)

APPENDICES │ C. Diseases/Findings

►►Abnormalities of White Blood Cells and Platelets on Peripheral Smear

►►Serum Enzymes Enzyme

Classic Associated Conditions

Alanine aminotransferase (ALT)

Liver damage

Alkaline phosphatase (Alk phos)

Bone, biliary, and placental disease

Amylase

Pancreatic and salivary disease

Angiotensin-converting enzyme (ACE) 

Sarcoidosis (also primary biliary cirrhosis, Gaucher disease, leprosy)

Aspartate aminotransferase (AST)

Acute myocardial infarction, liver disease

Creatinine kinase (CK) CK-MB

Myocardial infarction (early 2–8 h), severe skeletal muscle injury

Elastase-1

Pancreatic disease

Lactate dehydrogenase (LDH) LD1>LD2 High LD4 and LD5 High LD1 And LD5

Acute myocardial infarction (early), hemolysis, renal infarction Liver damage (also skeletal muscle damage) Acute myocardial infarction complicated by liver congestion; alcoholic liver disease complicated by megaloblastic anemia

Lipase

Pancreatic disease

Myoglobin

Myocardial infarction (early, but nonspecific)

Troponin I

Myocardial infarction (elevates as early as 3 h post MI, then stays elevated up to 9 days after MI)

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Appendix D Renal Pathology

1. Hyperplastic arteriolitis of kidney in malignant hypertension. Smooth muscle cell proliferation and collagen deposition of arterioles and interlobular artery walls result in concentric intimal thickening. This is often referred to as “onion-skinning” because of the concentric appearance.

2. Papillary necrosis is mostly seen in diabetic patients and in those with urinary tract obstruction. Necrotic tissue shows coagulative necrosis with preservation of the tubule outline. Tubular lumens are necrotic as a result of an extension of infection along the tubular lumens.

3. Color reversal of the cortex following hypotensive disease

4. Kidney amyloid deposition, Congo red stain, polarized light microscopy. The photomicrograph shows a glomerulus in the kidney after staining with Congo red. When viewed under polarized light, the amyloid produces a characteristic green birefringence. This property is thought to be due to the structure of the amyloid protein. (Source: Katsumi Miyai, M.D., Ph.D.)

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APPENDICES │ D. High-Yield Images

Renal Pathology (Cont’d )

5. Nephrosclerosis of the kidney due to malignant hypertension. Pinpoint petechial hemorrhages can be seen on the surface of the kidney. This results from ruptured arterioles, giving the kidney a “flea-bitten” appearance.

8. Poststreptococcal glomerulonephritis. Glomeruli are enlarged and hypercellular due to both infiltration of leukocytes and endothelial and mesangial proliferation. Subepithelial humps would be seen on electron microscopy (not shown here).

6. Fibrinoid necrosis of arterioles in malignant hypertension. Injury to the renal arterioles results in fibrinogen and platelet deposition and focal necrosis of cells in the vessel wall. This is seen as eosinophilic granular changes occuring in affected blood vessel walls.

9. Fibrinoid necrosis in the kidney. This kidney photomicrograph is from a patient with malignant hypertension, and it shows the characteristic features of fibrinoid necrosis. The arteriole wall (top right) is devoid of nuclei and has an amorphous pink appearance from protein deposition.

7. Nodular glomerulosclerosis in a diabetic patient. Also called Kimmelstiel-Wilson disease, this pathology results in PAS-positive glomerular nodules in the peripheral capillary loops.

10. Autosomal dominant polycystic kidney disease. The kidney is enlarged and the parenchyma is extensively replaced by cysts of varying sizes. Some of the darker-colored cysts contain hemorrhagic fluid.

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Cardiac Pathology APPENDICES │ D. High-Yield Images

14. Fibrinous pericarditis is the most common form of pericarditis and is composed of fibrinous exudates. It is associated with myocardial infarction and uremia.

11. Microscopic features of myocardial infarction. A 1-day-old infarct (top two images) shows coagulative necrosis with wavy fibers, edematous tissue, and scattered neutrophils. A 7- to 10-day-old infarct (bottom image) reveals the absence of necrotic myocytes because of phagocytosis.

15. Rheumatic heart disease. The characteristic microscopic lesion is an Aschoff body, a focal area of eosinophilic fibrinoid necrosis surrounded by inflammatory cells. 12. Infective (bacterial) endocarditis of the atrial valve. Bulky vegetations containing fibrin, inflammatory cells, and bacteria are deposited on the heart valves. Sometimes vegetations can erode into the myocardium and cause ring abscesses. Typically, subacute endocarditis has less valvular destruction than is found in acute endocarditis.

16. Dilated cardiomyopathy (DCM). In DCM, the heart is usually enlarged and flabby with dilatation of all chambers. The myocardial wall thins as the heart enlarges, resulting in impaired contractility (systolic dysfunction). 13. Nonbacterial thrombotic endocarditis (NBTE) is characterized by the deposition of small masses of fibrin platelets on the leaflets of the cardiac valves. In contrast to infective endocarditis, these vegetations contain no microorganisms. It is often related to cancer or sepsis and is significant because of the potential for embolization of the deposits, with resultant infarcts in secondary locations. Copyright 2005 DxR Development Group Inc. All rights reserved.

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APPENDICES │ D. High-Yield Images

Cardiac Pathology (Cont’d )

17. Cardiac hypertrophy. The heart exhibits concentric hypertrophy of the left ventricle and is from a patient with a history of hypertension. The left ventricle wall is thickened and has areas of white fibrosis consistent with prior ischemic injury.

18. Lines of Zahn. Alternating pale pink bands of platelets with fibrin and red bands of red blood cells form a true thrombus.

Gastrointestinal Pathology

19. Giardia lamblia trophozoites are pear-shaped binucleated parasites. Trophozoites are noninvasive but can result in blunting of the intestinal villi.

20. Adenocarcinoma of the esophagus. Adenocarcinomas arising from the distal esophagus are usually found in Barrett esophagus. Most of these tumors are mucin-producing, glandular tumors.

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21. Chronic active hepatitis and cirrhosis from hepatitis C: inflammation in the portal tracts with predominantly lymphocytes and macrophages. There is bile duct damage and septal and bridging fibrosis.

22. Hemochromatosis of the liver. Prominent hemosiderin deposition can be seen in the cytoplasm of these hepatocytes.

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Gastrointestinal Pathology (Cont’d )

Hematologic/Lymphoreticular APPENDICES │ D. High-Yield Images

23. Fatty liver, nonalcoholic. Defects in any of the steps in uptake, catabolism, or secretion of fatty acids in the liver can result in steatosis. Fat vacuoles enlarge until the nucleus is displaced into the periphery of the hepatocyte.

24. Carcinoid, small intestine. The small intestine is the most common location for a carcinoid tumor (the appendix is the second). The tumor cells are uniform in appearance and have a scant pink granular cytoplasm and a round-to-oval stippled nucleus. Electron microscopy will reveal (not shown here) membrane-bound secretory granules with dense cores.

25. Invasive adenocarcinoma of the colon. The malignant cells have a distinctive signet ring appearance from intracellular mucin vacuoles, which displace the nucleus to the side of the cell. This subtype is considered a more aggressive form of adenocarcinoma.

26. ANA immunofluorescence, centromere pattern. Antinuclear antibodies (ANA) are a sensitive (yet not specific) indicator of autoimmune diseases, such as SLE, scleroderma, and Sjögren syndrome. The pattern of fluorescence suggests the type of antibody in the patient’s serum, as each pattern is associated with specificity to different nuclear components.

27. Lymph node, sarcoid. Classic lesions on microscopic appearance are noncaseating granulomas with epithelioid cells and occasional giant cells (Langhans cells).

28. Bone marrow myelofibrosis. Marrow spaces become obliterated by fibrosis. This results in extensive extramedullary hematopoiesis principally in the spleen.

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APPENDICES │ D. High-Yield Images

Nervous System

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29. Metastatic disease to the brain. Metastatic lesions account for 25% of intracranial tumors. Metastases form sharply demarcated masses usually with surrounding edema. The most common location is at the gray matter−white matter junction.

32. Neurofibrillary tangles within a neuron in Alzheimer disease. These tangles are bundles of paired filaments in the cytoplasm (abnormally hyperphosphorylated tau proteins). A senile plaque is seen in the center.

30. Subarachnoid hemorrhage. This kind of hemorrhage may result from a ruptured intracranial aneurysm, trauma, or other vascular malformation. Irrespective of the etiology, there is an increased risk of injury after the hemorrhage due to vessel spasm in surrounding vessels that may involve the circle of Willis.

33. Lewy bodies in a substantia nigra neuron of Parkinson disease. These eosinophilic cytoplasmic filament inclusions are composed of α-synuclein. Lewy bodies may also be found in cholinergic cells of the basal nucleus of Meynert.

31. Dural meningioma. Meningiomas are well-defined, rounded masses that compress the underlying brain. The tumor may extend into the overlying bone. Characteristic microscopic features include a whorled pattern of cell growth and psammoma bodies.

34. Berry aneurysm of the circle of Willis. Aneurysms occur on the anterior circle of Willis in 80% of cases. The anterior communicating artery and middle cerebral artery trifurcation are the most common locations. Sudden onset of severe headache is often the first symptom of aneurysm rupture.

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Nervous System (Cont’d )

Musculoskeletal and Skin Pathology APPENDICES │ D. High-Yield Images

35. Progressive multifocal leukoencephalopathy is caused by the JC polyomavirus, which primarily infects oligodendrocytes and results in demyelination. Lesions or patchy white matter destruction has affected the entire lobe of this brain.

38. Muscle polymyositis. Inflammatory cells are found in the endomysium, and both necrotic and regenerating muscle fibers are scattered throughout the fascicle.

36. Temporal lobe abscess. A cerebral abscess is seen here on the right temporal lobe.

39. Melanoma cells are larger than normal nevus cells. They contain large nuclei with irregular contours, clumped chromatin, and prominent red nucleoli.

37. Epidural hematoma. This noncontrast CT shows the typical hyperdense convex or lens-shaped appearance of an acute epidural hematoma. A midline shift to the left can also be seen. (Source: Andrew Mullins)

40. Rickets. This radiograph of a child with rickets depicts outward curvature (bowing) of the femur and tibia due to inadequate mineralization of bone. (Source: Paul M. Michaud) Copyright 2005 DxR Development Group Inc. All rights reserved.

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APPENDICES │ D. High-Yield Images

Pulmonary Pathology

41. Cavitary lung abscess in the setting of prior tuberculosis scar tissue

44. Panacinar emphysema. Emphysema is characterized by abnormally large alveoli separated by thin septa. These alveoli are permanently enlarged due to alveolar wall destruction. This type of emphysema more commonly affects the lower zones and anterior margins of the lung and is associated with a-1 AT deficiency.

42. Pulmonary Infarction. This lung is from a patient with a history of a recent pulmonary embolus. There is a wedge-shaped hemorrhagic infarction. At the apex of the wedge are several arteries containing pulmonary emboli. (Source: Katsumi Miyai, M.D., Ph.D.)

45. Pulmonary embolism, saddle embolus. A large majority of pulmonary emboli arise from deep venous leg thrombi. They pass through larger vascular channels until they lodge in smaller arteries of the lung. In this case, a large embolus occludes the bifurcation of the pulmonary artery (saddle embolus) and has caused sudden death in the patient.

43. Mycobacterium tuberculosis, acid fast stain. An acid fast stain is used to diagnose the presence of mycobacteria in tissue and cytologic preparations. Many thin, red, rod-like M. tuberculosis organisms are shown here.

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Reproductive Pathology APPENDICES │ D. High-Yield Images

46. Atypical ductal hyperplasia of the breast. The duct is filled with columnar and rounded cells. The appearance is similar to lobular carcinoma in situ (LCIS), except that the atypia is limited in extent and the cells do not completely fill the ductal spaces. There is an increased risk of developing breast carcinoma when these lesions are identified.

49. Condyloma acuminata is a benign tumor of stratified squamous epithelium caused by sexually transmitted HPV. Characteristic histologic features are acanthosis, parakeratosis, hyperkeratosis, and nuclear atypia with vacuolization (koilocytes).

50. Fibroadenomas of the breast are sharply demarcated mobile masses within the breast. It is the most common benign tumor of the female breast and is more common in women under 30 years old. 47. HER2-positive breast carcinoma. Breast cancers are routinely assayed for the HER2/neu gene using fluorescent in situ hybridization (FISH) and protein using immunohistochemistry (brown stain). These tests predict the clinical responses to antibodies targeted to the protein. Carcinomas that are HER2-positive tend to be poorly differentiated.

48. Paget disease of the nipple. Presents as an erythematous scaly crust in a unilateral nipple. Malignant (“Paget”) cells extend from the ductal system into the skin of the nipple. There is an increased incidence of underlying invasive carcinoma.

51. Bicornuate uterus. A heart-shaped uterus results from an incomplete fusion of the Müllerian or paramesonephric ducts. This abnormality is the most common type of uterine malformation.

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APPENDICES │ D. High-Yield Images

Reproductive Pathology (Cont’d )

52. Hydatidiform mole, gross specimen. Numerous swollen (hydropic) villi are shown here. 55. Complete hydatidiform mole. A complete hydatidiform mole shows hydropic swelling of most chorionic villi, trophoblast hyperplasia (arrow), and little-to-no vascularization of the villi. The majority of complete moles result from the fertilization by a single sperm of an egg that has lost its chromosomes.

53. Prostate cancer. Small malignant cells with enlarged nuclei and dark cytoplasm make up this abnormal prostate gland. Perineural invasion by malignant cells is shown here (arrow).

56. CMV infection of the placenta. Placental villitis occurs with hydropic change within the placenta with congenital cytomegalovirus (CMV) infection. An enlarged cell with mauve intranuclear inclusions is seen here, which is typical for congenital cytomegalovirus infection. Congenital infection with CMV is a common cause for hydrops fetalis.

54. Normal placental villi

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Normal Hematology APPENDICES │ D. High-Yield Images

57. Normal red blood cell on peripheral smear 60. Eosinophil. These cells are most numerous in the blood during parasitic infections and allergic diseases.

61. Lymphocyte on peripheral blood smear 58. Segmented neutrophil. These are the first cells in acute inflammation and have two types of lysosomal granules: azurophilic (primary) granules and specific (secondary). An increase of these cells found on peripheral smear indicates bacterial infections, inflammation, trauma, and hemorrhage.

62. Monocyte. These are the precursors of phagocytic cells (macrophages, osteoclasts, Kupffer cells).

59. Basophil. These cells are involved in type I hypersensitivity and have large basophilic and metachromatic granules. An increase in basophils on a peripheral smear is seen in viral infections, urticaria, postsplenectomy, and hematologic malignancies. 63. Plasma cell on peripheral blood smear Copyright 2005 DxR Development Group Inc. All rights reserved.

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APPENDICES │ D. High-Yield Images

Abnormal Hematology

68. Spherocytes. These cells are near-spherical in shape and have no area of central pallor as seen in normal red blood cells. Spherocytes are found in hereditary spherocytosis, hemolytic anemia, and severe burns. 64. Acanthocytes. Red blood cells show many spicules on the surface of the cell. This can be seen in abetalipoproteinemia.

69. Target cells are erythrocytes with central staining and an inner ring and outer rim of pallor. They are seen in liver disease, thalassemia, or sickle cell disease.

65. Rouleaux formation. Red blood cells appear to stack on each other in long chains. This results in a high erythrocyte sedimentation rate (ESR).

70. Smudge cells are leukocytes that have been damaged during preparation of the peripheral blood smear. This usually occurs because of the fragility of the cell and is seen in chronic lymphocytic leukemia (CLL).

66. Schistocytes. These red blood cells are fragmented due to mechanical trauma (fibrin bands) and are seen in intravascular hemolysis.

71. Hairy cells are characterized by fine, irregular pseudopods at the cell surface and immature nuclear features. These cells are found only in hairy cell leukemia.

67. Sickle cells. Sickle cell anemia is an inherited blood disease in which the red blood cells produce abnormal hemoglobin. The abnormal hemoglobin causes crescent or sickle-shaped deformities.

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72. Hodgkin disease, Reed-Sternberg cell. A classic Reed-Sternberg cell has two nuclear lobes, large inclusion-like nucleoli, and abundant cytoplasm. These cells are essential in the histologic diagnosis of Hodgkin lymphoma.

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Appendix E

Drug List This drug table is designed for reference. Do not attempt to memorize it; we suggest you use this as a starting point to create your own personal drug list. Many of the most commonly used drugs are presented, but the list is not exhaustive. Also remember that most drugs have more side effects than noted in this table. We have included brand names in addition to the generic names—even though brand names are not tested on the USMLE—because you will be exposed to many brand names during your clinical years. Generic Name (Brand Name) • Primary Use

Therapeutic Class and Mechanism

Most Common Adverse Effects

Acebutolol (Sectral®)

β1-adrenoreceptor blocker with mild intrinsic sympathomimetic activity

Hypoglycemic unawareness, bradycardia, hypotension, use with caution in asthmatics (not completely β1 selective), impotence

• Pain, fever, headache

Nonopiate, nonsalicylate, non-NSAID analgesic/antipyretic

Hepatic failure in overdose situation (treat with N-acetylcysteine)

Acetazolamide (Diamox®)

Carbonic anhydrase inhibitor

Hypochloremic metabolic acidosis, renal stones, hypokalemia, paresthesias, hyperammonemia/hepatic encephalopathy in cirrhotic patients

Antiviral (inhibits viral DNA polymerases)

Seizures in overdose, nephrotoxicity (crystalluria)

Antiasthma (β2-receptor agonist)

Tremor, tachycardia, CNS stimulation, hypertension

Bisphosphonate

Esophageal ulcers, esophagitis, abdominal pain, gastric reflux, dysphagia

Xanthine oxidase inhibitor (irreversible suicide inhibitor)

Rash that can progress to StevensJohnson syndrome, and/or generalized vasculitis, irreversible hepatotoxicity

• Anxiety

Benzodiazepine, sedative/hypnotic (increases frequency of GABAA-receptor opening)

Drowsiness, dizziness, amnesia, decreased motor skills, dependence, respiratory depression with high doses (can be reversed with flumazenil)

Alteplase (t-PA; Activase®)

Tissue-plasminogen activator

Bleeding

Potassium-sparing diuretic (blocks Na+ channels in cortical collecting tubules)

Hyperkalemia

• Hypertension, ventricular arrhythmias

Acetaminophen (Tylenol®)

• Glaucoma, high altitude sickness, edema if accompanied by metabolic alkalosis, urinary alkalization Acyclovir (Zovirax®) • Herpes simplex Albuterol (Proventil®) • Asthma Alendronate (Fosamax®) • Osteoporosis Allopurinol (Zyloprim®) • Gout Alprazolam (Xanax®)

• Acute myocardial infarction, stroke, pulmonary embolism Amiloride (Midamor®) • Hypertension, congestive heart failure

(Continued)

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APPENDICES │ E. Drug List

Generic Name (Brand Name) • Primary Use

Therapeutic Class and Mechanism

Most Common Adverse Effects

Amiodarone (Cordarone®)

Antiarrhythmic (class III)

Pulmonary fibrosis, deposits in skin, photosensitivity, thyroid dysfunction

• Depression, anxiety

Tricyclic antidepressant (blocks norepinephrine [NE] and serotonin [5HT] reuptake)

Strong antimuscarinic side effects (e.g., urinary retention, tachycardia, increased intraocular pressure), cardiac arrhythmias on overdose

Amlodipine (Norvasc®)

Calcium channel blocker

Dizziness, edema, somnolence, palpitations

Beta-lactam antibiotic (penicillin)

Diarrhea, maculopapular rash (especially in patients with mononucleosis), pseudomembranous colitis, anaphylactic reactions

Beta-lactam antibiotic (penicillin)/ beta-lactamase inhibitor

Diarrhea, maculopapular rash (especially in patients with mononucleosis), pseudomembranous colitis, anaphylactic reactions

Stimulant

CNS stimulation, tachycardia, cardiac arrhythmias, dependence

Antifungal (binds ergosterol)

Chills and fevers, hypotension, nephrotoxicity (dose-limiting)

Beta-lactam antibiotic (penicillin)

Diarrhea, maculopapular rash (especially in patients with mononucleosis), pseudomembranous colitis, anaphylactic reactions

Aromatase inhibitor (decreases estrogen synthesis)

Hot flushes, fatigue

Atypical antipsychotic

Fewer extrapyramidal side effects than typical antipsychotics

NSAID, salicylate; analgesic, antipyretic, antiplatelet, antiinflammatory (irreversibly inhibits COX-1/COX-2)

Gastric ulcers/bleeding, hypersensitivity, bronchoconstriction, nephrotoxicity, Reye syndrome; high doses: tinnitus, hyperventilation, acid/base disorders

Antihypertensive (β1 antagonist)

Hypoglycemic unawareness, use with caution in asthmatics (not completely β1 selective), bradycardia, hypotension, impotence

Norepinephrine (NE)–reuptake inhibitor

CNS stimulation, agitation, mood swings, potential increase in suicidal ideation

HMG-CoA reductase inhibitor

Hepatic dysfunction, rhabdomyolysis, myalgia, myopathy

• Cardiac arrhythmias Amitriptyline (Elavil®)

• Hypertension, coronary artery disease Amoxicillin (Trimox®) • Respiratory tract infections, otic infections, urinary tract infections Amoxicillin/potassium clavulanate (Augmentin®) • Respiratory tract infections, otic infections, urinary tract infections Amphetamine mixed salts (Adderall®) • Treatment of attention deficit hyperactivity disorder Amphotericin B • Systemic mycoses Ampicillin (Omnipen®) • Urinary tract infections, upper respiratory tract infections Anastrozole (Arimidex®) • Estrogen-dependent breast cancer in postmenopausal women Aripiprazole (Abilify®) • Schizophrenia, bipolar disorder Aspirin (many name brands) • Pain/fever/headache, prevention of clotting with myocardial infarction/ transient ischemic attack Atenolol (Tenormin®) • Hypertension, angina pectoris due to coronary atherosclerosis, acute myocardial infarction Atomoxetine (Strattera®) • Attention deficit hyperactivity disorder Atorvastatin (Lipitor®) • Hyperlipidemia, hypertriglyceridemia

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Generic Name (Brand Name) Therapeutic Class and Mechanism

Most Common Adverse Effects

Azithromycin (Zithromax®)

Macrolide (azalide) antibiotic

Gastrointestinal distress, does not inhibit P450

Muscle relaxant/spasmolytic (GABAB agonist)

Drowsiness, dizziness, mental confusion, incoordination

ACE inhibitor

Cough, angioedema, hyperkalemia, neutropenia (rare)

Anticholinergic (muscarinic antagonist)

Strong antimuscarinic side effects (e.g., dry mouth, tachycardia, urinary retention, worsening of glaucoma, paralytic ileus, hyperthermia)

Antineoplastic (antibiotic)

Pulmonary fibrosis

Spasmolytic (prevents ACh release)

Weakness of injected and adjacent muscles

Antiglaucoma agent (α2 agonist; decreases aqueous humor secretion)

Conjunctivitis, ocular itching

Dopamine agonist

Dyskinesias, nausea/vomiting, behavioral effects, postural hypotension

Corticosteroid

Oral candidiasis

Corticosteroid

Epistaxis (nosebleed)

Local anesthetic (amide)

Cardiovascular toxicity, various CNS symptoms (excitation or depression, dizziness, seizures), allergic reactions

Antidepressant (heterocyclic)

Seizures, anxiety, insomnia, mania

Nonbenzodiazepine, nonbarbiturate anxiolytic; partial agonist at 5-HT1A receptors

Dizziness, nervousness

Antiheadache; barbiturate

Drowsiness, may be habit forming

Angiotensin II–receptor (type AT1) antagonist

Hypotension, increased potassium, contraindicated in pregnancy

• Respiratory tract infections Baclofen (Lioresal®) • Muscle spasticity secondary to multiple sclerosis, spinal cord injury Benazepril (Lotensin®) • Hypertension, congestive heart failure, diabetic nephropathy Benztropine (Cogentin®) • Parkinsonism, extrapyramidal disorders due to neuroleptics Bleomycin (Blenoxane®)

APPENDICES │ E. Drug List

• Primary Use

• Hodgkin disease; testicular, ovarian, and bladder cancers Botulinum toxin (Botox®) • Spastic disorders, local muscle spasms, cosmetic (wrinkle reduction) Brimonidine (Alphagan P®) • Open-angle glaucoma, ocular hypertension Bromocriptine (Parlodel®) • Parkinsonism, hyperprolactinemia Budesonide (Pulmicort®) • Asthma Budesonide nasal spray (Rhinocort Aqua®) • Allergic rhinitis Bupivacaine (Marcaine®) • Local anesthesia Bupropion (Wellbutrin®) • Depression, smoking cessation Buspirone (BuSpar®) • Generalized anxiety disorder Butalbital (with acetaminophen/caffeine; Fioricet®; with aspirin/caffine, Fiorinal®) • Tension headaches Candesartan (Atacand®) • Hypertension, heart failure

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APPENDICES │ E. Drug List

Generic Name (Brand Name) • Primary Use

Therapeutic Class and Mechanism

Most Common Adverse Effects

Captopril (Capoten®) • Hypertension, congestive heart failure, diabetic nephropathy

ACE inhibitor (prototype; others in class include benazepril, enalapril, lisinopril, quinapril, ramipril)

Cough, angioedema, hyperkalemia, neutropenia (rare)

Carbamazepine (Tegretol®)

Anticonvulsant

Ataxia, diplopia, blood dyscrasias, P450 inducer, teratogen

Skeletal muscle relaxant

a1 block (postural hypotension, tachycardia), mental confusion, drowsiness, incoordination

Mixed α1/β receptor antagonist

Heart failure, hypoglycemic unawareness, bronchospasm in asthmatics, bradycardia, hypotension, impotence

NSAID (specific COX-2 inhibitor)

Increased risk of serious cardiovascular thrombotic events (myocardial infarction and stroke), gastrointestinal bleeding, ulceration, hepatic and renal dysfunction

Beta-lactam antibiotic (gram-positive infections [except Enterococci and Listeria], some enterics; not for CNS infections)

Anaphylaxis, serum sickness, rashes, diarrhea, pseudomembranous colitis; may potentiate renal toxicity of aminoglycosides; the N-methylthiotetrazole side chain found in cefamandole, cefotetan, and cefoperazone is associated with hypoprothrombinemia and intolerance to ethanol

• Seizures, trigeminal neuralgia Carisoprodol (Soma®) • Painful musculoskeletal conditions Carvedilol (Coreg®) • Heart failure, hypertension Celecoxib (Celebrex®) • Pain and inflammation secondary to a variety of conditions (osteoarthritis, rheumatoid arthritis, others) First-generation cephalosporins Cefadroxil (Duricef®), cefazolin (Ancef®, Kefzol®), cephalexin (Keflex®)

Second-generation cephalosporins Cefaclor (Ceclor®), cefonicid (Monocid®), cefotetan (Cefotan®), cefoxitin (Mefoxin®), cefprozil (Cefzil®) and cefuroxime (Ceftin®, Zinacef®) Third-generation cephalosporins Cefdinir (Omnicef®), cefixime (Suprax®), cefotaxime (Claforan®), cefpodoxime (Vantin®), ceftazidime (Fortaz®, Tazidime®, Tazicef®), ceftibuten (Cedax®), ceftizoxime (Cefizox®) and ceftriaxone (Rocephin®) Fourth-generation cephalosporins Cefepime (Maxipime®) Cetirizine (Zyrtec®)

Beta-lactam antibiotic (less gram-positive activity and more gram-negative activity than first generation; not for CNS infections [except cefuroxime])

Beta-lactam antibiotic (less gram-positive activity and more gram-negative activity than second generation; usually reserved for serious infections; ceftriaxone is drug of choice for gonococcal infections; also used for late-stage Lyme disease)

Beta-lactam antibiotic (more gram-negative activity and same gram-positive activity as first generation)

• Seasonal allergic rhinitis

Histamine H1-receptor antagonist (second generation)

Fewer CNS side effects than firstgeneration antihistamines

Cholestyramine (Questran®)

Antihyperlipidemic

Constipation

Antimalarial

Gastrointestinal distress, rash, visual and auditory impairment, peripheral neuropathy

• Hyperlipidemia Chloroquine (Aralen®) • Malaria

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Generic Name (Brand Name) Therapeutic Class and Mechanism

Most Common Adverse Effects

Cimetidine (Tagamet®)

Histamine H2-receptor antagonist

Potent P450 inhibitor, gynecomastia, decreased libido

Fluoroquinolone antibiotic (bacteriocidal inhibitor of topoisomerases)

Gastrointestinal distress, CNS dysfunction, superinfection, collagen dysfunction, pregnancy category D

Antineoplastic (alkylating agent)

Nausea/vomiting, neurotoxic, nephrotoxic

• Depression

Selective serotonin reuptake inhibitor (SSRI) antidepressant

CNS stimulation, sexual dysfunction, serotonin syndrome, seizures in overdose; drug interactions with MAOIs, TCAs, meperidine

Clarithromycin (Biaxin®)

Macrolide antibiotic

P450 inhibitor, pseudomembranous colitis

Fertility agent (blocks estrogen receptors in pituitary, induces ovulation)

Multiple births

• Obsessive-compulsive disorder, depression

Tricyclic antidepressant; norephinephrine (NE) and serotonin (5HT) reuptake inhibitor

Strong antimuscarinic side effects (e.g., cardiac arrhythmias, urinary retention, tachycardia, increased intraocular pressure, cognitive impairment)

Clonidine (Catapres®)

Antihypertensive (α2-agonist)

Sedation, rebound hypertension if stopped suddenly

Benzodiazepine, sedative/hypnotic, anticonvulsant (increases frequency of opening of GABAA receptor)

Drowsiness, dizziness, amnesia, respiratory depression

• Reduction of antithrombotic events

Antiplatelet agent, blocks ADP receptors on platelets

Bleeding, thrombotic thrombocytopenic purpura, neutropenia

Clozapine (Clozaril®)

Atypical antipsychotic

Agranulocytosis (requires weekly WBC count), seizures

Opioid analgesic/acetaminophen combination

Respiratory depression, euphoria, constipation, pruritus, dependence

Inhibits microtubule assembly

Gastrointestinal distress, hepatic and renal damage

Mast cell stabilizer

Cough, throat irritation when inhaled

Skeletal muscle relaxant

Antimuscarinic side effects, drowsiness

• Peptic ulcer disease, gastroesophageal reflux disease, Zollinger-Ellison Ciprofloxacin (Cipro®) • Urinary tract infections, chronic bacterial prostatitis, respiratory tract infections, many others Cisplatin (Platinol®)

APPENDICES │ E. Drug List

• Primary Use

• Testicular, bladder, lung, and ovarian cancers Citalopram (Celexa®)

• Respiratory tract infections Clomiphene (Clomid®) • Infertility Clomipramine (Anafranil®)

• Hypertension, opioid withdrawal Clonazepam (Klonopin®) • Seizures, panic disorder Clopidogrel (Plavix®)

• Schizophrenia in patients unresponsive to other agents Codeine/Acetaminophen (Tylenol® #2, #3 and #4 [least codeine in #2, most in #4]) • Moderate-to-severe pain Colchicine (Colchicine®) • Gout Cromolyn (intranasal: NasalCrom®, inhalational: Intal®, oral: Crolom®, ophthalmic: Opticrom®) • Asthma, allergies Cyclobenzaprine (Flexeril®) • Treatment of muscle spasm

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APPENDICES │ E. Drug List

Generic Name (Brand Name) • Primary Use

Therapeutic Class and Mechanism

Most Common Adverse Effects

Cyclophosphamide (Cytoxan®)

Antineoplastic (alkylating agent)

Bone marrow suppression, hemorrhagic cystitis (use mesna), gastrointestinal distress, alopecia

Immunosuppressant (binds cyclophilin)

Nephrotoxicity, peripheral neuropathy, hypertension, hirsutism, gingival hyperplasia Related to skeletal muscle relaxation

• Malignant hyperthermia, neuroleptic malignant syndrome (unlabeled use)

Skeletal muscle relaxant (blocks Ca2+ release from sarcoplasmic reticulum by blocking the ryanodine receptor)

Desmopressin (DDAVP®)

Synthetic vasopressin

Hyponatremia, decreased plasma osmolality, seizures

Stimulant

CNS stimulation, tachycardia, cardiac arrhythmias, dependence

Benzodiazepine; sedative/hypnotic, anticonvulsant (increases frequency of opening of GABAA receptor)

Respiratory depression, somnolence, dizziness, dependence

• Heart failure, atrial arrhythmias

Cardiac glycoside, antiarrhythmic, inhibits Na+/K+-ATPase

Arrhythmias, visual defects (green-yellow halos), nausea

Diltiazem (Cardizem®)

Calcium channel blocker

Peripheral edema, dizziness, bradycardia, AV block, hypotension

Antihistamine (first generation)

Antimuscarinic side effects, sedation

Antidiarrheal (diphenoxylate: weak opioid; atropine: antimuscarinic)

Atropine is added to prevent abuse; side effects related to constipation, some CNS effects

Anti-Alzheimer disease (reversible cholinesterase inhibitor)

Gastrointestinal (diarrhea, nausea, vomiting, increased gastric acid secretion), bradycardia or heart block

• Shock

Sympathomimetic amine vasopressor (low dose: increases renal blood flow; moderate dose: positive inotropic effects)

Multiple (careful monitoring of patient’s vitals required)

Doxazosin (Cardura®)

α1 antagonist

Orthostatic hypotension and syncope, particularly as a “first-dose effect,” tachycardia

• Depression, resistant pruritus

Tricyclic antidepressant (norephineprhine [NE] and serotonin [5HT] reuptake blocker)

Strong antimuscarinic side effects (urinary retention, tachycardia, increased intraocular pressure, cognitive impairment), cardiac arrhythmias

Doxorubicin (Doxil®)

Antineoplastic (anthracycline antibiotic)

Cardiotoxicity (dexrazoxane may protect), myelosuppression, alopecia, gastrointestinal distress

• Lymphomas, ovarian and breast cancer, neuroblastoma Cyclosporine (Restasis®) • Immunosuppressant for organ transplants Dantrolene (Dantrium®)

• Central diabetes insipidus, primary nocturnal enuresis Dextroamphetamine (Dexedrine®) • ADHD, narcolepsy Diazepam (Valium®) • Status epilepticus, anxiety disorders, acute alcohol withdrawal, muscle spasms Digoxin (Lanoxin®)

• Hypertension, arrhythmias, angina Diphenhydramine (Benadryl®) • Allergies, motion sickness Diphenoxylate/Atropine (Lomotil®) • Diarrhea Donepezil (Aricept®) • Mild-to-moderate dementia of Alzheimer disease Dopamine

• Benign prostatic hypertrophy, hypertension Doxepin (Sinequan®)

• Cancer

(Continued)

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Generic Name (Brand Name)

APPENDICES │ E. Drug List

• Primary Use

Therapeutic Class and Mechanism

Most Common Adverse Effects

Doxycycline (many name brands)

Tetracycline antibiotic

Photosensitivity and skin reactions, gastrointestinal distress, dental enamel dysplasia, decreased bone growth

Serotonin and norepinephrine reuptake inhibitor (SNRI)

Nausea, sleep disorders, dizziness, dry mouth, anxiety, hypomania

Cholinesterase inhibitor (reversible, shortacting)

Bradycardia

• HIV infection

Nonnucleoside, reverse transcriptase inhibitor (NNRTI); used in combination regimens

CNS dysfunction, skin rash, elevated plasma cholesterol

Enalapril (Vasotec®)

ACE inhibitor

Cough, angioedema, hyperkalemia, neutropenia (rare)

• Prevention of thrombosis

Anticoagulant; enhancer of antithrombin III activity; low molecular weight (LMW) heparin

Bleeding, much lower incidence of thrombocytopenia than heparin

Entacapone (Comtan®)

Antiparkinson (COMT inhibitor)

Exacerbates the effects of levodopa

Macrolide antibiotic

Potent P450 inhibitor, gastrointestinal distress, arrhythmia

Selective serotonin reuptake inhibitor (SSRI) antidepressant

Serotonin syndrome, somnolence, insomnia, tachycardia, postural hypotension, paresthesias, sexual dysfunction

Proton pump inhibitor

Gastrointestinal side effects, dizziness, headache

Estrogen-receptor agonist

Nausea, breast tenderness, endometrial hyperplasia, biliary disease, clot formation

Tumor necrosis factor (TNF) inhibitor, immunosuppressant, DMARD (diseasemodifiying antirheumatic drug)

Infections, injection site infections

Anticonvulsant (blocks T-type Ca2+ channels)

Gastrointestinal distress

• Prostatitis, sinusitis, Chlamydia, pelvic inflammatory disease, acne, prophylaxis against anthrax Duloxetine (Cymbalta®) • Major depressive disorder, diabetic peripheral neuropathic pain, generalized anxiety disorder Edrophonium (Enlon®) • Diagnosis of myasthenia gravis Efavirenz (Sustiva®)

• Hypertension, congestive heart failure, diabetic nephropathy Enoxaparin (Lovenox®)

• Parkinson disease Erythromycin (E-Mycin®) • Upper respiratory tract infections (including Mycoplasma and Legionella), skin infections, Chlamydia Escitalopram (Lexapro®) • Depression, anxiety disorders, obsessive-compulsive disorder Esomeprazole (Nexium®) • Peptic ulcer disease, gastroesophageal reflux disease, Zollinger-Ellison Estrogens (various preparations and combinations) • Contraception, hormone-replacement therapy, osteoporosis, female hypogonadism, dysmenorrhea Etanercept (Enbrel®) • Rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis Ethosuximide (Zarontin®) • Absence seizures

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APPENDICES │ E. Drug List

Generic Name (Brand Name) • Primary Use

Therapeutic Class and Mechanism

Most Common Adverse Effects

Ezetimibe (Zetia®)

Antihyperlipidemic (inhibits absorption of dietary cholesterol)

Diarrhea, myalgia, myopathy (rare)

• Hyperlipidemia Famciclovir (Famvir®)

Antiviral (inhibits viral DNA polymerases)

Fatigue

• Herpes simplex Famotidine (Pepcid®)

Histamine H2-receptor antagonist

• Peptic ulcer disease, gastroesophageal reflux disease, Zollinger-Ellison Felodipine (Plendil®)

Calcium channel blocker

Headache, dizziness, reflex tachycardia, gingival hyperplasia

Analgesic (opioid agonist)

Respiratory depression, constipation, miosis, emesis, pruritus, dependence

Antihyperlipidemic (fibric acid derivative; ligand for peroxisome proliferator-activated receptor-alpha [PPAR-α])

Gastrointestinal distress, gallstones, myopathy (especially in combination with statins), elevated liver enzymes

Histamine H1-receptor antagonist (second generation)

Fewer CNS side effects than firstgeneration antihistamines

Granulocyte colony-stimulating factor (G-CSF), cytokine

Bone pain, splenomegaly, splenic rupture (rare)

5α-reductase inhibitor

Pregnancy category X, impotence, hypotension

Mineralocorticoid

Hypertension, edema

Conazole antifungal (inhibits 14-α-demethylase, preventing the conversion of lanosterol to ergosterol)

Hepatic dysfunction, decreased steroid synthesis, inhibits CYP3A4

Corticosteroid; antiasthmatic

Epistaxis, pharyngitis, angioedema, upper respiratory infection

Benzodiazepine-receptor antagonist

Seizures

Selective serotonin reuptake inhibitor (SSRI) antidepressant

CNS stimulation, sexual dysfunction, gastrointestinal distress, serotonin syndrome, seizures in overdose; drug interactions with MAOIs, TCAs, meperidine

Androgen-receptor antagonist

Hepatotoxicity

HMG-CoA reductase inhibitor; antihyperlipidemic

Myalgia, myopathy, rhabdomyolysis, hepatic dysfunction, elevated transaminases

• Hypertension Fentanyl (Duragesic®) • Moderate-to-severe pain Fenofibrate (TriCor®) • Hypertriglyceridemia, hypercholesterolemia Fexofenadine (Allegra®) • Seasonal allergic rhinitis Filgrastim (Neupogen®) • Neutropenia (e.g., chemotherapy, bone marrow transplant) Finasteride (Proscar®) • Benign prostatic hyperplasia, male pattern baldness Fludrocortisone (Florinef®) • Hypotension Fluconazole (Diflucan®) • Esophageal and invasive candidiasis, coccidiomycosis, cryptococcal meningitis Fluticasone (Floven®) • Asthma Flumazenil (Romazicon®) • Benzodiazepine overdose Fluoxetine (Prozac®) • Depression, obsessive-compulsive disorder, anxiety disorders, bulimia Flutamide (Eulexin®) • Prostatic carcinoma Fluvastatin (Lescol®) • Hypercholesterolemia

(Continued)

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Generic Name (Brand Name) Therapeutic Class and Mechanism

Most Common Adverse Effects

Fluvoxamine (Luvox®)

Selective serotonin reuptake inhibitor (SSRI) antidepressant

CNS stimulation, sexual dysfunction, serotonin syndrome, seizures in overdose

Broad-spectrum, bactericidal antibiotic

Diarrhea

ACE inhibitor

Cough, angioedema, hyperkalemia

• Edema and hypertension

Loop diuretic (blocks Na+/K+/2Cl– transporter in thick ascending limb)

Hypokalemia, hypocalcemia, hyperuricemia, hyponatremia, tinnitus, and hearing loss

Gabapentin (Neurontin®)

Anticonvulsant

Dizziness, somnolence

Antiviral (inhibits viral DNA polymerases)

Myelosuppression, fever, rash

Gemfibrozil (Lopid®)

Antihyperlipidemic (fibric acid derivative; ligand for peroxisome proliferator-activated receptor-alpha [PPAR-α])

Gastrointestinal distress, gallstones, myopathy (especially in combination with statins), elevated liver enzymes

Gentamicin (Garamycin®)

Aminoglycoside antibiotic

Ototoxicity, nephrotoxicity, muscle weakness (caused by ↓ acetylcholine release)

Immune-modifying agent

Injection site reaction, chest pain

Oral hypoglycemic agent, sulfonylurea

Hypoglycemia, weight gain, rash

Oral hypoglycemic agent, sulfonylurea

Hypoglycemia, weight gain, rash

Oral hypoglycemic agent, sulfonylurea

Hypoglycemia, weight gain, rash

Antiemetic (5HT3 antagonist)

Headache, dizziness

Antipsychotic, butyrophenone (blocks dopamine D2 receptors; high potency)

Extrapyramidal symptoms, tardive dyskinesia, hyperprolactinemia, neuroleptic malignant syndrome, fewer autonomic side effects than low-potency neuroleptics

• Depression, obsessive-compulsive disorder Fosfomycin (Monurol®) • UTIs Fosinopril (Monopril®) • Hypertension, heart failure, diabetic nephropathy Furosemide (Lasix®)

APPENDICES │ E. Drug List

• Primary Use

• Epilepsy, postherpetic neuralgia, diabetic peripheral neuropathy Ganciclovir (Cytovene®) • CMV, HSV, VZV infections

• Severe gram-negative infections Glatiramer (Copaxone®) • Relapsing-remitting multiple sclerosis Glimepiride (Amaryl®) • Type 2 diabetes mellitus Glipizide (Glucotrol®) • Type 2 diabetes mellitus Glyburide (Micronase®, DiaBeta®, Glynase®) • Type 2 diabetes mellitus Granisetron (Kytril®) • Nausea/vomiting Haloperidol (Haldol®) • Schizophrenia, Tourette syndrome

(Continued)

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APPENDICES │ E. Drug List

Generic Name (Brand Name) • Primary Use

Therapeutic Class and Mechanism

Most Common Adverse Effects

Halothane (Fluothane®)

General inhalational anesthetic

Cardiovascular and respiratory depression, sensitizes heart to catecholamines, hepatitis

Anticoagulant (enhances antithrombin III activity)

Bleeding, thrombocytopenia; antidote is protamine

Antihypertensive and thiazide diuretic (inhibits Na+/Cl– transporter in distal convoluted tubule)

Hypokalemia, hypercalcemia, hyperuricemia, hyperglycemia, hyperlipidemia, possible sulfonamide allergenicity

• Hypertension

Antihypertensive (vasodilator; releases nitric oxide from endothelial cells)

Systemic lupus erythematosus–like syndrome, tachycardia, salt/H2O retention

Hydrocodone (Vicodin®)

Opioid analgesic

Respiratory depression, euphoria, constipation, nausea, pruritus, dependence

NSAID (nonselective COX inhibitor)

Increased risk of serious cardiovascular thrombotic events, bleeding, gastrointestinal ulceration

Imipenem: carbapenem antibiotic; cilastatin: renal dehydropeptidase inhibitor (prevents inactivation of imipenem)

Allergy (cross-allergenicity with penicillins), gastrointestinal distress, seizures

• Depression

Tricyclic antidepressant (norepinephrine [NE] and serotonin [5HT] reuptake blocker)

Strong anticholinergic side effects (e.g., urinary retention, tachycardia, increased intraocular pressure), cardiac arrhythmias on overdose

Indinavir (Crixivan®)

Protease inhibitor

Nephrolithiasis, hematologic abnormalities, inhibition of P450

• Arthritis, acute inflammation

Antiinflammatory, NSAID (nonspecific COX inhibitor)

Gastrointestinal bleeding, increased risk of thrombotic events, renal toxicity

Interferon-α (INF-α; Roferon-A®, Intron-A®)

Interferon

Flu-like symptoms, depression, bone marrow suppression

Interferon

Flu-like symptoms, depression, bone marrow suppression

Interferon

Flu-like symptoms, depression, bone marrow suppression

Anticholinergic bronchodilator (muscarinic antagonist)

Quaternary amine, so there is little systemic absorption

Angiotensin II–receptor (type AT1) antagonist

Hypotension, increased BUN and potassium, contraindicated in pregnancy

• General anesthesia Heparin (many brand names) • Prevention of thrombosis Hydrochlorothiazide (HydroDIURIL®) • Edema and hypertension

Hydralazine (Apresoline®)

• Moderate-to-severe pain Ibuprofen (Motrin®) • Osteoarthritis, rheumatoid arthritis, inflammatory conditions, mild-tomoderate pain, antipyretic Imipenem-cilastatin (Primaxin®) • For severe infections, e.g., respiratory, intraabdominal, others Imipramine (Tofranil®)

• HIV infection Indomethacin (Indocin®)

• Hepatitis B and C, leukemias, melanoma, Kaposi sarcoma Interferon-β (INF-β; Avonex®, Refib®) • Multiple sclerosis Interferon-γ (INF-γ; Actimmune®) • Chronic granulomatous disease Ipratropium (Atrovent®) • Bronchospasm associated with chronic obstructive pulmonary disease Irbesartan (Avapro®) • Hypertension, heart failure, diabetic neuropathy

(Continued)

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Generic Name (Brand Name) Therapeutic Class and Mechanism

Most Common Adverse Effects

Isoniazid (INH; Nydrazid®)

Antimycobacterial

Hepatotoxicity, hemolysis (in G6PD deficiency, peripheral neuropathy; reversed by pyridoxine)

Nonspecific β agonist

Tremor, angina, arrhythmia

Nitrate vasodilator

Hypotension, tachycardia, headache

Retinoid

Pregnancy category X, depression, suicidal ideation, decreased night vision, dry mouth

• Blastomycoses, sporotrichoses, others

Conazole antifungal (inhibits 14-α-demethylase, preventing the conversion of lanosterol to ergosterol)

Hepatic dysfunction, decreased steroid synthesis, inhibits CYP3A4

Ivermectin (Stromectol®)

Anthelmintic

Hypotension, headache, muscle aches

Conazole antifungal (inhibits 14-α-demethylase, preventing the conversion of lanosterol to ergosterol)

Hepatic dysfunction, decreased steroid synthesis, inhibits CYP3A4

• HIV infection, hepatitis B

Antiretroviral, nucleoside reverse transcriptase inhibitor (NRTI)

Least toxic of the NRTIs, some headache, gastrointestinal distress

Lamotrigine (Lamictal®)

Anticonvulsant

Stevens-Johnson syndrome, lifethreatening rash, sedation, ataxia

• Tuberculosis Isoproterenol (Isuprel®) • Heart block, bronchospasm Isosorbide (dinitrate [Isordil®]; mononitrate [Imdur®]) • Angina pectoris Isotretinoin (Accutane®) • Severe cystic acne Itraconazole (Sporanox®)

APPENDICES │ E. Drug List

• Primary Use

• Strongyloides, onchocerciasis Ketoconazole (Nizoral®) • Blastomyces, Histoplasma, Candida, other Lamivudine (3TC) (Epivir®)

• Partial seizures, adjunctive for other seizure types, bipolar disorder Lansoprazole (Prevacid®) • Ulcers, gastroesophageal reflux disease, Zollinger-Ellison Latanoprost (Xalatan®)

Proton pump inhibitor (irreversible blocker of H+/K+ ATPase on parietal cells)

PGF2α agonist

Eyelash changes, iris pigmentation changes

DMARD, pyrimidine synthesis inhibitor (inhibits dihydroorotate dehydrogenase)

Diarrhea, elevated hepatic enzymes, alopecia, rash

Gonadotropin-releasing hormone (GnRH) analog (others in class include goserelin, nafarelin)

Bone pain, gynecomastia, impotence, testicular atrophy, hematuria

Levodopa: dopamine precursor; carbidopa: peripheral dopa decarboxylase inhibitor

Dyskinesias, behavioral changes, hypotension, on-off phenomena

Fluoroquinolone antibiotic (bacteriocidal inhibitor of topoisomerases)

Gastrointestinal distress, CNS dysfunction, superinfection, collagen dysfunction, pregnancy category D

• Open-angle glaucoma, ocular hypertension Leflunomide (Arava®) • Rheumatoid arthritis Leuprolide (Lupron Depot®) • Advanced prostatic cancer Levodopa-carbidopa (Sinemet®) • Parkinsonism Levofloxacin (Levaquin®) • Urinary tract infections, chronic bacterial prostatitis, respiratory tract infections, many others

(Continued)

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APPENDICES │ E. Drug List

Generic Name (Brand Name) • Primary Use

Therapeutic Class and Mechanism

Most Common Adverse Effects

Levothyroxine (Synthroid®)

Synthetic T4

Symptoms of hyperthyroidism

ACE inhibitor

Cough, angioedema, hyperkalemia

Antimanic

Nephrogenic diabetes insipidus, tremor, goiter, seizures, teratogen

Histamine H1 receptor antagonist (second generation)

Fewer CNS side effects than firstgeneration antihistamines

Benzodiazepine, sedative/hypnotic (increases frequency of GABAA receptor opening)

Drowsiness, dizziness, amnesia, respiratory depression

Angiotensin II–receptor (type AT1) antagonist (prototype; other “-sartans” include candesartan, irbesartan, olmesartan, telmisartan, valsartan)

Hypotension, increased BUN and potassium, contraindication in pregnancy

HMG-CoA reductase inhibitor, antihyperlipidemic (prototype; other “-statins” include atorvastatin, fluvastatin, pravastatin, rosuvastatin, simvastatin)

Myalgia, myopathy, rhabdomyolysis, hepatic dysfunction, elevated transaminases

Osmotic diuretic

Extracellular fluid volume expansion causing hyponatremia, nausea, headache

Anthelminthic

Gastrointestinal distress

Antiemetic (H1 antagonist)

Dizziness, drowsiness

Progestin

Thromboembolic disorders, myocardial infarction, galactorrhea

NMDA-receptor antagonist

Dizziness

Opioid analgesic

Seizures, typical opioid side effects (no miosis), dangerous in combination with SSRIs and MAOIs, antimuscarinic

Antiinflammatory

Gastrointestinal distress, dizziness

Antiasthmatic (β2-receptor agonist)

CNS stimulation, hypertension, tachycardia

• Hypothyroidism Lisinopril (Prinivil® and Zestril®) • Hypertension, congestive heart failure, diabetic nephropathy Lithium (Eskalith®) • Bipolar disease Loratadine (Claritin®) • Seasonal allergic rhinitis Lorazepam (Ativan®) • Anxiety Losartan (Cozaar®) • Hypertension, diabetic neuropathy, heart failure Lovastatin (Mevacor®) • Hypercholesterolemia

Mannitol (Osmitrol®) • Increased intracranial pressure, to promote diuresis in renal failure, increased intraocular pressure (narrow-angle glaucoma), to promote excretion of renal toxins Mebendazole (Vermox®) • Whipworm, pinworm infections Meclizine (Antivert®) • Motion sickness Medroxyprogesterone (Provera®) • Contraceptive injection, hormonereplacement therapy Memantine (Namenda®) • Alzheimer disease Meperidine (Demerol®) • Moderate-to-severe pain Mesalamine (Canasa®) • Inflammatory bowel disease Metaproterenol (Alupent®) • Asthma

(Continued)

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Generic Name (Brand Name)

APPENDICES │ E. Drug List

• Primary Use

Therapeutic Class and Mechanism

Most Common Adverse Effects

Metformin (Glucophage®)

Antidiabetic, biguanide

Lactic acidosis

Opioid analgesic

Respiratory depression, euphoria, constipation, pruritus, dependence

• Neoplastic disease, arthritis, psoriasis

Antineoplastic, immunosuppressant (inhibits dihydrofolic reductase)

Myelosuppression, gastrointestinal distress, crystalluria (leucovorin rescue used to lower toxicity)

Methylphenidate (Ritalin®)

Stimulant

CNS stimulation, tachycardia, cardiac arrhythmias

Antiemetic, prokinetic agent, dopamine antagonist

Extrapyramidal side effects, hyperprolactinemia

Antihypertensive (β1-anatgonist)

Heart failure, hypoglycemic unawareness, use with caution in asthmatics (not completely β1 selective), bradycardia, hypotension, impotence

Trichomonacide, antiprotozoal, and antibacterial agent

Disulfiram-like reaction, neuropathy, metallic taste, reversible neutropenia, seizures

Conazole antifungal

Allergic contact dermatitis

Progestin and glucocorticoid antagonist/ abortifacient

Vaginal bleeding, infection, sepsis

Antidepressant a2 agonist

Weight gain, sedation

Antiulcer medication (prostaglandin E1 agonist)

Diarrhea, miscarriage

• Prevention of NSAID-induced ulcers Mometasone (Elocon®)

Topical corticosteroid, antiinflammatory

HPA-axis suppression, increased topical infection (bacterial, viral, and fungal)

Corticosteroid

Epistaxis, pharyngitis, angioedema, upper respiratory tract infection

Antiasthma (for prevention, not to reverse acute attacks), selective antagonist of leukotriene D4 (LTD4) receptors

Gastrointestinal disturbances, hypersensitivity reactions

• Type 2 diabetes mellitus Methadone (Dolophine®) • Maintenance treatment and detoxification of opioid addiction, moderate-to-severe pain Methotrexate (Trexall®)

• Attention deficit hyperactivity disorder Metoclopramide (Reglan®) • Gastroesophageal reflux disease, diabetic gastroparesis, nausea/ vomiting Metoprolol (Lopressor®, Toprol XL®) • Hypertension, angina pectoris, heart failure Metronidazole (Flagyl®) • Trichomoniasis, amebiasis, giardiasis, anaerobic bacterial infections, numerous other infections Miconazole (Monistat-3® and -7®) • Vulvovaginal candidiasis, topical fungal infections Mifepristone (RU486®) • Abortifacient, postcoital contraceptive Mirtazapine (Remeron®) • Major depressive disorder Misoprostol (Cytotec®)

• Inflammatory and pruritic manifestations of corticosteroidresponsive dermatoses Mometasone (Nasonex®) • Allergic rhinitis Montelukast (Singulair®) • Asthma • Allergies

(Continued)

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APPENDICES │ E. Drug List

Generic Name (Brand Name) • Primary Use

Therapeutic Class and Mechanism

Most Common Adverse Effects

Morphine (MS Contin®)

Opioid analgesic/narcotic analgesic

Respiratory depression, euphoria, constipation, pruritus, dependence

Topical antibiotic

Contact dermatitis

Immunosuppressant (inosine monophosphate dehydrogenase [IMPDH] inhibitor)

Myelosuppression

Penicillinase-resistant penicillin

Penicillin allergy

• Pain

Opioid, mixed agonist/antagonist (stimulates kappa, weak mu antagonist)

Sedation, CNS effects; less respiratory depression, less analgesia, and less abuse potential than strong mu agonists

Naloxone (Narcan®)

Opioid antagonist

Short half-life may necessitate multiple doses

Opioid antagonist

Longer half-life than naloxone, can cause abstinence symptoms

NSAID

Increased risk of serious cardiovascular thrombotic events, bleeding, gastrointestinal ulceration

Mast cell stabilizer

Coughing, airway irritation

Antidepressant (heterocyclic)

Hepatotoxicity, P450 inhibitor

Protease inhibitor

Diarrhea, P450 inhibitor

Cholinesterase inhibitor (quaternary amine)

Excess cholinomimetic effects

• HIV infection

Antiretroviral, nonnucleoside reverse transcriptase inhibitor (NNRTI)

Fatal hepatotoxicity, Stevens-Johnson syndrome, toxic epidermal necrolysis

Niacin (Niaspan®)

Antihyperlipidemic

Flushing, hepatotoxicity

Dihydropyridine calcium channel blocker

Orthostatic hypotension, tachycardia, dizziness, peripheral edema, syncope, gingival hyperplasia

Urinary antiseptic

Hypersensitivity pneumonitis

• Moderate-to-severe pain Mupirocin (Bactroban®) • Impetigo, methicillin-resistant Staphylococcus aureus (MRSA) Mycophenolate mofetil (CellCept®) • Prophylaxis of organ rejection in patients receiving allogenic renal, cardiac, or hepatic transplants Nafcillin (Unipen®) • Staphylococcal infections Nalbuphine (Nubain®)

• Used to reverse acute opioid overdose Naltrexone (ReVia®) • Decreases alcohol cravings, used in opioid dependence Naproxen (Naprosyn®, Naprelan®) • Osteoarthritis, inflammatory conditions, rheumatoid arthritis, pain Nedocromil (Tilade®) • Asthma Nefazodone (Serzone®) • Depression Nelfinavir (Viracept®) • HIV infection Neostigmine (Prostigmin®) • Myasthenia gravis, reversal of neuromuscular blockade Nevirapine (Viramune®)

• Hypercholesterolemia Nifedipine (Procardia®, Adalat CC®) • Angina, hypertension Nitrofurantoin (Macrodantin®, Macrobid®) • Urinary tract infections (Continued)

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Generic Name (Brand Name) Therapeutic Class and Mechanism

Most Common Adverse Effects

Nitroglycerin (Nitro-Dur®, Nitro-Bid®, Nitrostat®)

Antianginal vasodilator, nitrate

Tachycardia, hypotension, headache

Atypical antipsychotic (blocks 5HT2 receptors)

Increased mortality in elderly with dementia-related psychosis, postural hypotension

APPENDICES │ E. Drug List

• Primary Use

• Angina Olanzapine (Zyprexa®) • Schizophrenia Omeprazole (Prilosec®) • Ulcers, gastroesophageal reflux disease, Zollinger-Ellison

Ondansetron (Zofran®)

Proton pump inhibitor (irreversible blocker of H+/K+-ATPase on parietal cells; prototype, “-prazoles” include esomeprazole, lansoprazole, pantoprazole, rabeprazole) Antiemetics, (5HT3 antagonist; prototype, others in class include granisetron, dolasetron)

Headache, dizziness

• Nausea/vomiting Orlistat (Xenical®)

Antiobesity, pancreatic lipase inhibitor

Steatorrhea, flatulence, bloating

Benzodiazepine; sedative/hypnotic, anticonvulsant (increases frequency of opening of GABAA receptor)

Respiratory depression, somnolence, dizziness

Genitourinary smooth muscle relaxant, antimuscarinic

Typical antimuscarinic side effects

Opioid analgesic

Respiratory depression, euphoria, constipation, pruritus, dependence

• Obesity Oxazepam (Serax®) • Anxiety, alcohol withdrawal Oxybutynin (Ditropan XL®) • Urinary incontinence Oxycodone (sustained-release, OxyContin®; with aspirin: Percodan®, with acetaminophen: Percocet®) • Moderate to severe pain Pantoprazole (Protonix®) • Ulcers, gastroesophageal reflux disease, Zollinger-Ellison Paroxetine (Paxil®)

Proton pump inhibitor (irreversible blocker of H+/K+-ATPase on parietal cells)

Selective serotonin reuptake inhibitor (SSRI) antidepressant

CNS stimulation, sexual dysfunction, gastrointestinal distress, serotonin syndrome, seizures in overdose; drug interactions with MAOIs, TCAs, meperidine

Beta-lactam antibiotic

Allergic reactions, anaphylaxis, drug fever, Stevens-Johnson syndrome, pseudomembranous colitis

Antidepressant, irreversible and nonselective monoamine oxidase (MAO) inhibitor

Hypertensive crisis with tyraminecontaining foods and indirect-acting sympathomimetics, serotonin syndrome with serotonergic drugs, e.g., SSRIs

• Seizures, preanesthetics, insomnia

Sedative hypnotic, anticonvulsant, longacting barbiturate (increases duration of GABAA-receptor opening)

Sedation, P450 induction, dependence, additive with other CNS depressants

Phenoxybenzamine (Dibenzyline®)

Irreversible α-adrenergic antagonist

Hypotension, gastrointestinal distress

• Depression, obsessive-compulsive disorder, anxiety disorders, bulimia Penicillin G, penicillin V (many brand names) • Numerous bacterial infections Phenelzine (Nardil®) • Depression

Phenobarbital (Pb®)

• Pheochromocytoma (Continued)

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APPENDICES │ E. Drug List

Generic Name (Brand Name) • Primary Use

Therapeutic Class and Mechanism

Most Common Adverse Effects

Phenytoin (Dilantin®)

Anticonvulsant (hydantoin)

Gingival hyperplasia, sedation, diplopia, hirsutism, teratogen

Cholinesterase inhibitor (tertiary amine)

Muscarinic effects (diarrhea, urination, miosis, bronchoconstriction, bradycardia, excitation, lacrimation, salivation, sweating [DUMBBELSS])

Antiglaucoma (muscarinic agonist)

Muscarinic agonist effects

Nonselective β-adrenergic antagonist with intrinsic sympathomimetic activity

Heart failure, hypoglycemic unawareness, bronchospasm in asthmatics, bradycardia, hypotension, impotence

Thiazolidinedione; stimulates peroxisome proliferator-activator receptors (PPARs)

Cardiovascular toxicity

• Type 2 diabetes mellitus Piroxicam (Feldene®)

NSAID

Increased risk of serious cardiovascular thrombotic events, bleeding, gastrointestinal ulceration

HMG-CoA reductase inhibitor, antihyperlipidemic

Myalgia, myopathy, rhabdomyolysis, hepatic dysfunction, elevated transaminases

Antiinflammatory, glucocorticosteroid, immunosuppressant

Sodium retention, fluid retention, potassium loss, hypokalemic alkalosis, peptic ulcer disease, cushingoid state, osteoporosis

GABA analog

Somnolence

• Ventricular arrhythmias

Class IA antiarrhythmic (Na+ and K+ channel blocker)

Lupus erythematosus–like syndrome, hematoxicity, hypotension, cardiovascular effects (torsades)

Prochlorperazine (Compazine®)

Phenothiazine antiemetic

Extrapyramidal side effects, lowers seizure threshold, neuroleptic malignant syndrome

Nonselective β-adrenergic antagonist

Heart failure, hypoglycemic unawareness, bronchospasm in asthmatics, bradycardia, hypotension, impotence

Antithyroid agent (blocks tyrosine iodination, inhibits coupling)

Rash, immune reactions (rare)

• Hyperthyroidism Quetiapine (Seroquel®)

Atypical antipsychotic

Increased suicidal risk, somnolence, hypotension, tachycardia

• Generalized tonic-clonic and complex partial seizures Physostigmine (Antilirium®) • Anticholinergic overdose, glaucoma

Pilocarpine (Isopto Carpine®) • Glaucoma Pindolol (Visken®) • Hypertension Pioglitazone HCl (Actos®)

• Osteoarthritis, inflammatory conditions, rheumatoid arthritis Pravastatin (Pravachol®) • Hypercholesterolemia Prednisone (Deltasone®) • Inflammatory conditions, immunosuppressive Pregabalin (Lyrica®) • Neuropathic pain associated with diabetic peripheral neuropathy, seizures Procainamide (Procanbid®)

• Nausea/vomiting Propranolol (Inderal®) • Hypertension, angina, arrhythmias, hyperthyroidism, migraine, benign essential tremor Propylthiouracil (PTU) (generic)

• Schizophrenia, bipolar disorder

(Continued)

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Generic Name (Brand Name) Therapeutic Class and Mechanism

Most Common Adverse Effects

Quinidine (Quinaglute®, Quinidix®)

Class IA antiarrythmic (Na+ and K+ channel blocker)

Cinchonism (Gastrointestinal symptoms, tinnitus, visual disturbances, CNS excitation), torsade

• Atrial and ventricular arrythmias Rabeprazole (AcipHex®) • Ulcers, gastroesophageal reflux disease, Zollinger-Ellison Raloxifene (Evista®)

APPENDICES │ E. Drug List

• Primary Use

Proton pump inhibitor (irreversible blocker of H+/K+-ATPase on parietal cells)

Selective estrogen-receptor modulator (SERM)

Hot flashes, leg cramps, blood clots

• Osteoporosis Ramipril (Altace®)

ACE inhibitor

Cough, angioedema, hyperkalemia

• Hypertension, congestive heart failure, diabetic nephropathy Ranitidine (Zantac®)

Histamine H2-receptor antagonist

• Peptic ulcer disease, gastroesophageal reflux disease, Zollinger-Ellison Rifampin (Rifadin®)

Antitubercular agent (inhibits DNAdependent RNA polymerase)

Hepatotoxicity, induces P450

• Tuberculosis Risedronate (Actonel®)

Bisphosphonate

Esophageal ulcers, esophagitis, abdominal pain, gastric reflux, dysphagia

Atypical antipsychotic

Fewer extrapyramidal side effects than typical neuroleptics, postural hypotension, dizziness, stroke

Dopamine-receptor agonist

Sedation, dyskinesias, nausea/vomiting

• Type 2 diabetes mellitus

Thiazolidinedione, stimulates peroxisome proliferator-activator receptors (PPARs)

Hypoglycemia and weight gain may occur, cardiovascular toxicity

Rosuvastatin (Crestor®)

HMG-CoA reductase inhibitor

Hepatic dysfunction, rhabdomyolysis, myalgia, myopathy

Bronchodilator (β2-receptor agonist; long acting)

CNS stimulation, hypertension, tachycardia

Antiparkinson (MAOB inhibitor)

CNS stimulation, insomnia, dyskinesias

Selective serotonin reuptake inhibitor (SSRI) antidepressant

CNS stimulation, sexual dysfunction, gastrointestinaI distress, serotonin syndrome, seizures in overdose; drug interactions with MAOIs, TCAs, meperidine

• Osteoporosis Risperidone (Risperdal®) • Schizophrenia Ropinirole (Requip®) • Parkinson disease, restless legs syndrome Rosiglitazone (Avandia®)

• Hyperlipidemia, hypertriglyceridemia Salmeterol (Serevent®) • Asthma, chronic obstructive pulmonary disease Selegiline (Eldepryl®) • Parkinson disease Sertraline (Zoloft®) • Depression, obsessive-compulsive disorder, anxiety disorders, bulimia

(Continued)

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APPENDICES │ E. Drug List

Generic Name (Brand Name) • Primary Use

Therapeutic Class and Mechanism

Most Common Adverse Effects

Sildenafil (Viagra®)

Cyclic guanosine monophosphate (cGMP)–specific phosphodiesterase type 5 (PDE5) inhibitor

Postural hypotension, tachycardia, myocardial infarction, priapism, vision loss

HMG-CoA reductase inhibitor, antihyperlipidemic

Myalgia, myopathy, rhabdomyolysis, hepatic dysfunction, elevated transaminases

Potassium-sparing diuretic, aldosterone receptor antagonist, androgen receptor antagonist

Gynecomastia, hyperkalemia, dilutional hyponatremia

Antiretroviral, nucleoside reverse transcriptase inhibitor (NRTI)

Peripheral neuropathy (dose-limiting)

• Muscle relaxation (adjunct to surgery, intubation)

Depolarizing muscle relaxant (short duration, metabolized by plasma cholinesterases)

May have role in malignant hyperthermia, muscle pain, hyperkalemia

Sulfasalazine (Azulfidine®)

Antiinflammatory (derivative of mesalazine)

Gastrointestinal distress, dizziness

Antimigraine (abortive); selective 5-hydroxytryptamine1D (5-HT1D)–receptor agonist

Coronary artery vasospasm, hypertension, tachycardia, chest or throat pain/pressure, myocardial infarction, stroke, cerebral hemorrhage, asthenia

Cyclic guanosine monophosphate (cGMP)–specific phosphodiesterase type 5 (PDE5) inhibitor

Postural hypotension, tachycardia, myocardial infarction, priapism, vision loss

Selective estrogen-receptor modulator (SERM)

Hot flushes, increased risk of venous thrombosis

α1A-adrenergic antagonist (prostate selective)

Orthostatic hypotension, syncope (firstdose response), hypotension, tachycardia, fewer side effects than pure a1-adrenergic antagonists

• Insomnia

Benzodiazepine; sedative/hypnotic (increases frequency of GABAA-receptor opening)

Drowsiness, dizziness, amnesia, respiratory depression

Terazosin (Hytrin®)

α1-adrenergic antagonist

Orthostatic hypotension and syncope, particularly as a “first-dose effect,” tachycardia

Antifungal (inhibits squalene epoxidase)

Gastrointestinal distress, headache, hepatotoxicity

Tetracycline antibiotic

Teratogenicity (tooth developmental problems, bone hypoplasia, hepatic failure), photosensitivity, pseudomembranous colitis, renal toxicity, maculopapular and erythematous rashes

• Erectile dysfunction Simvastatin (Zocor®) • Hyperlipidemia, hypertriglyceridemia Spironolactone (Aldactone®) • Primary hyperaldosteronism, edematous conditions, CHF, hypertension, hypokalemia, female hirsutism Stavudine (d4T) (Zerit®) • HIV Infection Succinylcholine (Anectine®)

• Inflammatory bowel disease Sumatriptan (Imitrex®) • Migraine

Tadalafil (Cialis®) • Erectile dysfunction Tamoxifen (Nolvadex®) • Metastatic breast cancer, prevention of breast cancer in high-risk patients Tamsulosin (Flomax®) • Benign prostatic hypertrophy

Temazepam (Restoril®)

• Benign prostatic hypertrophy, hypertension Terbinafine (Lamisil®) • Onychomycosis Tetracycline (Achromycin®) • Acne, Chlamydia, numerous sexually transmitted infections, Rocky Mountain spotted fever, many others

(Continued)

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Generic Name (Brand Name) Therapeutic Class and Mechanism

Most Common Adverse Effects

Theophylline (Theo-Dur®)

Bronchodilator, methylxanthine, phosphodiesterase inhibitor, adenosine antagonist

Insomnia, tremor, gastrointestinal distress

• Chronic asthma, chronic obstructive pulmonary disease Timolol (ophthalmic: Timoptic®, Betimol®; oral: Blocadren®)

Antiglaucoma, antihypertensive; nonselective β-adrenergic antagonist

Heart failure, hypoglycemic unawareness, bronchospasm in asthmatics, bradycardia, hypotension, impotence

Muscarinic antagonist

Antimuscarinic side effects (e.g., tachycardia, dry mouth, urinary retention)

Anticonvulsant, antimigraine

Cognitive deficits, fatigue, renal stones, anorexia

Centrally acting synthetic opioid analgesic, inhibits serotonin (5HT) and norepinephrine reuptake

Seizures, dizziness, constipation

• Moderate-to-moderately severe pain Trazodone (Deseryl®)

Antidepressant (heterocyclic)

Priapism, sedation, cardiac arrhythmias

Antiacne (vitamin A derivative)

Irritation, erythema, peeling, dryness, burning/stinging Hyperkalemia

• Edema, hypertension

Potassium-sparing diuretic (Na+ channel blocker in collecting duct)

Trihexyphenidyl (Artane®)

Anticholinergic (muscarinic antagonist)

Strong antimuscarinic side effects (e.g., dry mouth, tachycardia, urinary retention, worsening of glaucoma, paralytic ileus, hyperthermia)

Combination blocks folic acid synthesis

Toxicity primarily due to sulfonamide; hypersensitivity, hematologic disorders, kernicterus, competes for plasma proteins

Antiviral (inhibits viral DNA polymerases)

Confusion, hallucinations, seizures, thrombotic thrombocytopenic purpura/ hemolytic uremic syndrome, especially with high doses in AIDS patients

Anticonvulsant/antimanic (inhibits T-type Ca2+ channels, blocks Na+ channels)

Hepatic failure (rare but can be fatal), teratogenicity (neural tube defects), P450 inhibitor

Angiotensin II–receptor (type 1 AT1) antagonist

Hypotension, increased BUN and potassium, contraindicated in pregnancy

Antibiotic (glycopeptide bacteriocidal; inhibits cell wall synthesis)

Red man syndrome, ototoxicity, nephrotoxicity, hypersensitivity

• Glaucoma, hypertension Tolterodine tartrate (Detrol®) • Urinary incontinence Topiramate (Topamax®) • Epilepsy, migraine Tramadol (Ultram®)

APPENDICES │ E. Drug List

• Primary Use

• Depression Tretinoin (Retin-A®) • Acne vulgaris Triamterene (Dyrenium®)

• Control of extrapyramidal disorders, Parkinson disease Trimethoprim/sulfamethoxazole (Bactrim®, Septra®) • Urinary tract infections, Pneumocystis jiroveci infections, many gramnegative bacteria, CA-MRSA Valacyclovir (Valtrex®) • Herpes simplex

Valproic acid (Depakote®) • Epilepsy, mania, migraine prophylaxis Valsartan (Diovan®) • Hypertension, heart failure Vancomycin (Vancocin®) • Severe infections caused by susceptible strains of methicillinresistant (beta-lactam–resistant) staphylococci and other serious grampositive infections

(Continued)

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APPENDICES │ E. Drug List

Generic Name (Brand Name) • Primary Use

Therapeutic Class and Mechanism

Most Common Adverse Effects

Venlafaxine (Effexor®)

Antidepressant (heterocyclic)/inhibits norepinephrine [NE] and serotonin [5HT] uptake

Somnolence, nausea, impotence, tachycardia, CNS stimulation

Vasodilator and cardiac depressant, calcium channel blocker (blocks L-type calcium channels)

Strong negative inotropic effects, hypotension, atrioventricular block, heart failure, constipation

Antineoplastic/M phase–specific agent (inhibits mitotic spindle formation)

Myelosuppression, alopecia, gastrointestinal distress

Antineoplastic/M phase–specific agent (inhibits mitotic spindle formation)

Peripheral neuropathy, alopecia, gastrointestinal distress

Anticoagulant (vitamin K–dependent clotting factor inhibitor)

Bleeding, contraindicated in pregnancy, multiple drug interactions with P450 inducers or inhibitors

Antiasthma (for prevention, not to reverse acute attacks), selective antagonist of leukotriene D4 and E4 (LTD4 and LTE4) receptors

Hepatic failure

• HIV infection

Nucleoside reverse transcriptase inhibitor (NRTI); formerly called azidothymidine (AZT)

Bone marrow suppression leading to anemia and neutropenia (may require transfusions), headache, asthenia, myalgia, gastrointestinal distress; all NRTIs may cause lactic acidemia and hepatomegaly with steatosis

Zileuton (Zyflo®)

5-lipoxygenase inhibitor

Dyspepsia, elevation of liver function tests

Antimigraine (abortive)/selective 5-hydroxytryptamine1D (5-HT1D)– receptor agonist

Coronary artery vasospasm, hypertension, tachycardia, chest or throat pain/pressure, myocardial infarction, stroke, cerebral hemorrhage, asthenia

Nonbenzodiazepine hypnotic; binds BZ1 site on the GABAA receptor; can be reversed by flumazenil

Daytime drowsiness, dizziness, abnormal behaviors

• Depression Verapamil (Calan®, Verelan®) • Hypertension, arrhythmias, angina, prophylaxis of paroxysmal supraventricular tachycardia (PSVT) Vinblastine (Velban®) • Lymphomas, neuroblastoma, testicular carcinoma, Kaposi sarcoma Vincristine (Oncovin®) • Leukemias, lymphomas, Wilms tumor Warfarin (Coumadin®) • Coagulation disorders, venous thrombosis, pulmonary embolism, atrial fibrillation, stroke, systemic embolism after myocardial infarction Zafirlukast (Accolate®) • Asthma

Zidovudine (ZDV; Retrovir®)

• Asthma (prophylaxis, chronic treatment) Zolmitriptan (Zomig®) • Migraine

Zolpidem (Ambien®) • Insomnia

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Appendix F

Bacterial Algorithms COCCI

+

-

GRAM STRAIN

Staphylococcus sp

Neisseria sp

Streptococcus sp

+

-

CATALASE

Staphylococcus sp

+

S

N. meningitidis

NOVOBIOCIN

S. epidermidis

R

N. gonorrhoeae

Streptococcus sp

GAMMA-HEMOLYTIC Group D

BETA-HEMOLYTIC Complete (clear) Hemolysis

Partial (green) Hemolysis

OPTOCHIN

-

S. saprophyticus

ALPHA-HEMOLYTIC

S

MALTOSE

fermentation

-

COAGULASE

S. aureus

+

R

S

BACITRACIN

S. pneumoniae Viridians group Group A S. sanguis S. pyogenes S. mutans

Usually NO Hemolysis

R

Group B S. agalactiae

+ E. faecalis

Growth in 6.5% NaCI

-

S. bovis

(Continued)

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APPENDICES │ F. Algorithms

►►Bacterial Algorithms (Cont’d.)

Gram +

COCCI

Gram –

Staphylococcus sp S. aureus

• Coagulase (+) • Protein A • β-Lactamase (many) • Beta-hemolytic • Heat-stable enterotoxins • CAMP test hemolysin • Salt-tolerant • Mannitol salt agar • Yellow/gold pigment • Normal in nose, skin • Toxic Shock synd • Scalded Skin synd • Abscesses • Food poisoning (2–6 h) • Acute endocarditis • IV drug users • Acute osteomyelitis • DOC: MSSA: Nafcillin • MRSA: Vancomycin • VRSA: quinupristin

S. pneumoniae • Lancet-shaped • Capsule • Quellung (+) • IgA protease • Lysed by bile • Normal in URT • #1 for pneumonia >60 yr • #1 for adult meningitis • #1 Otitis media in kids • DOC: Macrolides, ceftriaxone, amoxicillin • ~20% Pen resist. • Vaccine for elderly (23 serotypes) • Vaccine pediatric (13 serotypes conjugated to protein)

S. epidermidis

• Coagulase(-) • Non-hemolytic • "Plastic" adherence • Normal in skin, nose, mouth, gut • Subacute endocarditis in IV drug users • Catheter, prosthetic device infections • Novobiocin sensitive

S. saprophyticus

• Coagulase(-) • Non-hemolytic • UTI in sexually active adolescents • Novobiocin resistant

N. meningitidis

• Polysaccharide capsule • β-Lactamase (rare) • Pili • Colonizes URT • WaterhouseFriderichsen synd. • Tetravalent vaccine • Utilizes maltose • DOC: cefotaxime, ceftriaxone

Gram + Streptococcus sp Viridans group S. sanguis S. mutans • Dextrans: Adherence dental caries • Normal in oropharynx • Subacute endocarditis (Post-dental work or poor dental hygiene) • DOC: penicillin + aminoglycosides

Also • Moraxella • Veillonella • Eikenella • Kingella

Neisseria sp

• Kidney-bean-shaped • Catalase (+) • Oxidase (+), black • IgA protease • Endotoxin present • Utilize glucose aerobically • Chocolate agar • Candle jar, CO2

Group A S. pyogenes • Capsule of hyaluronic acid • M protein • Streptolysin O • Streptolysin S • Streptokinase • Hyaluronidase • Erythrogenic toxin (SPE-A) • Rheumatic fever • Post-Strep acute GN • Cellulitis • Impetigo • DOC: Penicillin G/V

Group B S. agalactiae • CAMP Test (+) (incomplete hemolysin) • C carbohydrate • Hydrolyzes hippurate • Salt-tolerant • Colonizes vagina in 15–20% • Screen preg treat with ab. ↓ meningitis • #1 for neonatal meningitis (↓ing) • DOC: Ampicillin + aminoglycoside

Group D E. faecalis • Enterococcus • C carbohydrate • Hydrolyzes bile esculin with black complex • Salt-tolerant • Normal in colon, gut • UTI • Bilary tract infections • Post-op endocarditis • Opportunistic infxns • DOC: Sensitivity testing

N. gonorrhoeae

• No capsule • β-Lactamase • Pili • Probe • Thayer-Martin medium • DOC: Ceftriaxone PLUS Tetracycline for Chlamydia • No vaccine • Does not utilize maltose

Group D S. bovis • Non-enterococcal • C carbohydrate • Hydrolyzes bile esculin with black complex

(Continued)

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APPENDICES │ F. Algorithms

►►Bacterial Algorithms (Cont’d.) GRAM (+) RODS NON-SPORE-FORMING

Aerobic Motile

Non-Motile

L. monocytogenes

C. diphtheriae

• Tumbling motility • "Jets" from cell to cell • Fac intracellular organism • Beta-hemolytic • Cold enrichment • Sepsis • Crosses placenta • Meningitis Renal transplant Neonatal Cancer • DOC: Ampicillin and Gentamicin for IC

• Club-shaped • "Chinese Characters" • Exotoxin (ADP-R of EF-2) Heart, Nerves • Volutin granules on Loeffler's medium • Tellurite: black colonies • ELEK test • Gray pseudomembrane • Myocarditis • Recrnt larngl nerve palsy • DOC: Antitoxin PLUS Erythromycin • Toxoid vaccine

N. asteroides

• Filaments to rods • Urease (+) • Partially acid-fast • Cavitary bronchopulmonary • Multiple brain abscesses • Mycetoma (granules) • DOC: Sulfonamides

Anaerobic A. israelii

• Rods with branching • Non-motile • Not restricted by anatomical boundaries • Sulfur "granules" in exudates from sinus tract • Normal in mouth and female genitourinary tract • Cervicofacial (lumpy jaw) • IUD-associated infections • Solitary brain abscess • Mycetoma • Rx: Penicillin pus drainage

SPORE-FORMING Aerobic Motile

B. cereus

• Heat-stable exotoxin: vomiting increase cAMP • Heat-labile toxin: diarrhea • Reheated fried rice • Food poisoning (2–18 h) • Symptomatic Rx

Anaerobic Non-Motile

B. anthracis

• Poly-D-glutamate capsule • Spores • In R-E cells • Toxin: Protective Ag Lethal factor Edema factor (an adenylate cyclase) • Painless skin ulcer 95% • Black eschar • Striking local edema • Woolsorter's disease Pneumonia • DOC: Ciprofloxacin or doxycycline

Non-Motile

Motile C. tetani

• Terminal spores • Exotoxin Tetanospasmin Inhibits GABA Glycine • Tetanus Spastic paralysis • DOC: hyperimmune globulin, Penicillin PLUS spasmolytic • Toxoid vaccine

C. botulinum

• Neurotoxin heat-labile Blocks ACh release • Flaccid paralysis • Canned-food poisoning • Trivalent antitoxin • DOC: antitoxin PLUS Penicillin • Infant botulism human hyperimmune serum, no drugs

C. difficile

• Nosocomial • Diarrhea to pseudomembranous colitis • Antibiotic (Clindamycin) usage • Yellow plaques • Colon • Toxins A + B • DOC: Change or stop antibiotic

C. perfringens

• Subterminal spore • Alpha lecithinase= Phospholipase C • Enterotoxin • Stormy fermentation • Double-zone hemolysis • Egg yolk agar • Normal in colon • Food poisoning • Gas gangrene • Myonecrosis • High mortality • DOC: Penicillin G + Clindamycin PLUS debridement

(Continued)

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APPENDICES │ F. Algorithms

►►Bacterial Algorithms (Cont’d.) GRAM (-) RODS & SPIROCHETES

Facultative Anaerobes

AEROBES B. pertussis • Adhesion to cell via hemagglutinin and pertussis toxin • Adenylate cyclase txn (local edema) • Tracheal toxin • Dermanecrosis toxin • Endotoxin - Lipid X, A ADP-R of GNBP • Bordet-Gengou agar • Regan-Lowe agar • Whooping cough • DOC: Erythromycin • Vaccine toxoid and filamentous hemagglutinin

Brucella sp • In R-E cells • Endotoxin • Requires CYS, CO2 • Unpasteurized milk • Undulant Fever Bang's disease Malta fever • B. abortus cattle, mild • B. suis pigs suppurative, chronic • B. melitensis goats severe, acute • DOC: rifampin and doxycycline

F. tularensis • In R-E cells • Requires CYS • Dermacentor tick bite Transovarian trans. • Aerosol • Rabbits, rodents • Granulomatous rxn • Tularemia - AR, MO, TX • Live, attntd vaccine • DOC: Streptomycin

Coxiella burnetti

L. pneumophila

P. aeruginosa

• Obligate intracellular bacteria • Q fever-atyp pneumo, hepatitis • Urine, feces, amniotic fluid, placenta-airborne, resistant to drying • Reservoir: cats, domestic livestock, high titers in pregnant • Weil-Felix test negative • No rash

• Water-loving air conditioning • Requires CYS & Fe • Buffered Charcoal Yeast agar • Dieterle silver stain • Stains poorly Gram (-) • Atypical pneumonia • Mental confusion • Diarrhea • DOC: Erythromycin • Not contagious

• Slime-layer • Grape-like odor • Exotoxin A: ADP-R of eEF-2 Liver • Oxidase (+) • Pigments pyocyanin, pyoverdin • Transient colonization In 10% of normal pop • Osteomyelitis in drug abusers • Pneumonia in cystic fibrosis • Nosocomial infections Burn patients Neutropenic patients • Ecthyma gangrenosum • DOC: Penicillin PLUS Aminoglycoside

SPIROCHETES ANAEROBES Bacteroides sp • B. fragilis - obligate • Modified LPS, capsules • Predominant colonic flora • Normal in oropharynx, vagina • Predisposing factors: surgery, trauma chronic disease (cancer) • Septicemia, peritonitis aspiration pneumonia • Prevotella melaninogenica Human oropharynx • Fusobacterium (combined w/ Treponema microdentium) Vincent's angina Trench mouth • DOC: Metronidazole OR Clindamycin OR Cefoxitin

Treponema sp • T. pallidum - Syphilis Obligate parasite • 1˚- PAINLESS chancre, infectious • 2˚- Rash infectious • 3˚- Gummas, CVS, CNS • Congenital: stillbirths, malformed • VDRL & RPR - Screening tests • Reagin ab - xrxn with Cardiolipin • FTA-ABS (immunofluorescence) specific test • Dark-field microscopy • DOC: Benzathine Penicillin

• Thin-Walled • Spiral-Shaped • Axial Filaments • Jarisch-Herxheimer Rxn

Borrelia sp • Microaerophillic • Giemsa stain • B. burgdorferi Lyme disease (I. scapularis), I. pacificus Reservoirs: mice, deer CT, WI, CA Erythema Migrans Target lesions • B. recurrentis Relapsing fever Vector: body louse Antigenic variation • DOC: Penicillin or azithromycin

Leptospira sp • Dark-field microscopy • Contaminated water Animal urine • Fever, jaundice, uremia • Non-icteric Leptospirosis Meningitis - No PMN in CSF uveitis, rash • Icteric Leptospirosis Weil's disease Renal failure, myocarditis • DOC: Penicillin G or doxycycline

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Other Gram (–) RODS

FACULTATIVE ANAEROBES P. multocida • Requires CYS • Animal bites (cats & dogs) • Cellulitis with Lymphadenitis • DOC: Amoxicillin/Clav (prophylaxis)

H. influenzae

Vibrio sp

• Polyribitol capsule • Quellung (+) • IgA protease • Requires X (Hemin), V (NAD) • Normal in nasopharynx and conjunctiva • Pathogenic in kids: type B • Meningitis in 1–2 yr • Otitis media, pneumonia • Acute epiglottitis • DOC: Cefotaxime/Ceftriaxone • Prev: HIB vaccine, Rifampin

ENTEROBACTERIACEAE - Ferment Glucose - Oxidase (-), Catalase (+) - Reduce Nitrates to Nitrites

• Polar flagella, comma-shaped • Enterotoxin (Choleragen) ADP-R, increase cAMP • Catalase (+), Oxidase (+) • Alkaline culture (TCBS) • Classic cholera O1 • Biotypes: El Tor, Cholerae • Rice-water stools • Most severe dehydration • Rx: fluid & electrolytes tetracycline for contacts • V. parahaemolyticus Catalase (-), salt-tolerant Raw seafood • V. vulnificus Brackish water • Oysters Cellulitis, Septicemia DOC: tetracycline

E. coli

K. pneumoniae • Capsule • Quellung (+) • Pneumonia Currant jelly septum Chronic lung disease Alcoholism Aspiration • UTI Nosocomial Catheterization • DOC: Cephalosporin +/– aminoglycoside

K. granulomatis

• Painless, soft genital lesions • Granuloma inguinale • Caribbean and New Guinea • DOC: TMP-SMX

Also: • Gardnerella • Capnocytophaga • Actinobacillus • Cardiobacterium

• Microaerophilic • Polar flagella • Comma or S-shaped • Oxidase (+), Catalase (+) • Skirrow's agar CO2 • Invasive • H. pylori 37˚C, urease(+) gastritis, ulcers carcinoma • DOC: omeprazole + amoxicillin + clarithromycin • C. jejuni 42˚C enterocolitis #1 bacterial diarrhea U.S.A. • “Gull-Wings” • C. fetus escapes GIT • DOC: Erythromycin, fluoroquinolones

Non-Lactose-Fermenting

Lactose-Fermenting • Normal in colon • #1 for UTI P-pili, X-Adhesins • Nosocomial infections • Neonatal meningitis (K1 ) • ETEC • Traveler's Drha Toxins: LT, ST • EIEC • Invasive • EHEC • VTEC 0157:H7 Hemorrhagic colitis Hemolytic uremic S Does not ferment Sorbitol • EPEC Plasmid-coded EAF • EAEC Fimbriae/biofilm • DAEC Infants Bacteria in microvilli • DOC: Ampicillin or Sulfonamides Cephalosporins

Campylobacter sp Helicobacter sp

APPENDICES │ F. Algorithms

►►Bacterial Algorithms (Cont’d.)

Motile and H2 S-Producing Proteus sp. • Swarming motility • Indole (+), Urease (+) • UTI, Septicemia • Staghorn calculi • DOC: Fluoroquinolones

Salmonella enterica subsp.

Non-Motile and Non-H2 S-Producing Shigella sp • No H Antigens • Invasive • Shigatoxin Nicks 60S SU Neurotoxin Cytotoxin Enterotoxin • Enterocolitis • Bloody diarrhea • DOC: fluid and electrolytes FQ, Azithro

• Antigens: Vi, O, H • EMB/MacConkey • Predisposing factors High gastric pH Gastrectomy • Widal test (O, H ag) • Osteomyelitis in Sickle Cell disease • S. enterica subsp. typhi No animal res. No H2S produced Invasive (R-E) cells Rose spots • DOC: fluoroquinolones or cephalosporins • S. enterica subsp. enteritidis Poultry, reptiles Rx: Symptomatic • DOC for invasive: ampicillin, cephalosporins

Y. pestis • Coagulase (+) • V&W antigens • Safety-pin appearance (bipolar staining Wayson's stain) • Wild rodents • Flea bite • Southwest U.S. (Sylvatic) • Bubonic plague fever, buboes, conjunctivitis • Pneumonic plague • DOC: Aminoglycosides PLUS Quarantine (72 h) • Y. enterocolitica Cold growth • Heat-stable toxins

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APPENDICES │ F. Algorithms

►►Bacterial Algorithms (Cont’d.) Poorly Gram-Staining Organisms*

ACID FAST

SOME ATP

Mycobacteria

Rickettsias

M. tuberculosis

• Gram (+) wall but doesn't stain due to waxy CW • Acid fast, obligate aerobe • Respiratory transmission • Cord factor-trehalose mycolate-inhib. WBC migration mitoch. resp./ oxid. phosphor • Sulfatides-inhib. phagosomelysosome fusion • Niacin (+), catalase (+) at 37˚C, (–) at 68˚C • Slow growing • Drug resistance • Lowenstein-Jensen medium • DOC: isoniazid + rifampin + pyrazinimide (2 mo) then isoniazid + rifampin (4 mo)

M. avium-intracellulare

• Gram (+) wall but doesn't stain due to waxy CW • Acid fast • Obligate aerobe • Soil organism • Opportunist, non-contagious • Pulmonary → diss infections CA pts, late AIDS pts

M. leprae

• Obligate intracellular bacterium • Tuberculoid (CMI damage) • Lepromatous leprosy (poor CMI) • DOC: dapsone + rifampin + clofazimine

M. marinum

R. rickettsii

• Obligate intracellular bacteria • Gram-negative envelope but stain poorly • Rocky MT Spt'd Fever-rash on wrists/ankles → trunk, palms, soles • Vector: Dermacentor tick • Reservoirs: ticks, wild rodents • Dx: serol: 4x incr indir Fl. Ab + Weil-Felix DOC: Doxycycline

R. prowazekii

• Obligate intracellular bacteria • Epidemic typhus • Vector: Pediculus louse • Reservoir: humans, squirrel fleas, flying squirrels

Bartonella henselae

• Cat scratch fever • Bacillary angiomatosis in AIDS

Ehrlichia

• Ehrlichiosis • Morulae in WBC • DOC: doxycycline • E. chafeensis-monocytes + macrophages • E. phagocytophila - PMNs • Ixodes tick

NO ATP, mod. peptidoglycan Chlamydiaceae Chlamydia trachomatis

• Obligate intracellular bacteria • Gram-negative envelope but stain poorly; lack muramic acid • Elementary body-transmitted • Reticulate body-intracellular • Dx: serology or tissue culture growth confirmed by inclusion bodies (Fl Ab, Giemsa, iodine) Serotypes D-K • U.S.-Most common bacterial STD (HPV and HSV2 more common) • Neonatal/adult inclus. conjunct, neonatal. pneumo; urethritis cervicitis, PID, infertility Serotypes L1, 2, 3 • Lymphogranuloma venereum • STD in Africa, Asia, S. America Serotypes A, B, Ba, C • Trachoma-follic conjunctivitis → conj. scarring, entropion → corneal scarring • Leading infectious cause blindness • DOC: Doxycycline or azithromycin

NO CELL WALL Mycoplasmas M. pneumoniae

• Lack cell wall peptidoglycan → non-Gram-staining • Cholesterol (req'd) in membr. • Atypical pneumonia in youth and young adults • Free living (culturable, extracell.) • Slow growth, special media: Mycoplasma, Eaton's or Hayflick's media-sterols+pur/pyrimidines: mulberry colonies • Cold aggulutinins in 65% cases • No Penicillins nor Cephalosporins • DOC: erythromycin, azithromycin

Ureaplasma urealyticum

• Urethritis, prostatitis • Urease positive • No cell wall • DOC: erythromycin or tetracycline

Chlamydophila pneumoniae

• TWAR agent • Respiratory infections • Probably very common • Potential association with atherosclerosis • DOC: macrolides and tetracycline

Chlamydophila psittaci • Atypical pneumonia • Birds (parrots) • DOC: tetracycline

• Cutaneous lesions (fish tank granuloma) • DOC: isoniazid, rifampin, ethambutol *Also note that Legionella and the spirochetes (Treponema, Leptospira, and Borrelia)—all Gram-negative—do not show up reliably with Gram stain.

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APPENDICES │ F. Algorithms

Viral Algorithms RNA VIRUSES DOUBLE-STRANDED

SINGLE-STRANDED POSITIVE SENSE

NAKED

ENVELOPED

ICOSAHEDRAL REOVIRUS Reovirus Rotavirus Colorado tick fever virus

NEGATIVE SENSE

AMBISENSE AND NEGATIVE

ENVELOPED

ENVELOPED

NAKED

HELICAL

HELICAL

ICOSAHEDRAL

FLAVIVIRUS

CORONAVIRUS

CALICIVIRUS

PARAMYXOVIRUS

ARENAVIRUS

Yellow Fever Virus Dengue Virus St. Louis EV Hepatitis C

Coronavirus SARS-CoV

Norwalk Agent Noro-like

Mumps Virus Measles Virus RSV Parainfluenza Human metapneumovirus

(Segmented) Lassa Fever Virus Lymphocytic Choriomeningitis

ICOSAHEDRAL

HEPEVIRUS Hepatitis E

TOGAVIRUS

Rubella Virus Western Equine EV Eastern Equine EV Venezuelan EV

PICORNA

Polio Virus Enteroviruses Echovirus Coxsackie A & B Rhinoviruses Hepatitis A Virus

RETROVIRUS HIV HTLV

HELICAL

RHABDOVIRUS Rabies Virus Vesicular Stomatitis

BUNYAVIRUS (Segmented) California EV La Crosse Virus Hantavirus

FILOVIRUS Marburg Ebola

ORTHOMYXOVIRUS (Segmented) Influenza A & B

DNA VIRUSES DOUBLE-STRANDED ENVELOPED ICOSAHEDRAL CIRCULAR HEPADNAVIRUS Hepatitis B Virus

Herpes Simplex Virus Varicella-Zoster Virus Epstein-Barr Virus Cytomegalovirus Herpes virus 6 Herpes virus 8

NAKED

NAKED COMPLEX

LINEAR HERPESVIRUS

SINGLE-STRANDED

POXVIRUS Variola Vaccinia Molluscum Contagiosum

ICOSAHEDRAL

ICOSAHEDRAL CIRCULAR

LINEAR

PAPILLOMAVIRUS

ADENOVIRUS

Papilloma Viruses

Adenoviruses

PARVOVIRUS B19

POLYOMAVIRUS Polyoma Viruses

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Index A A band, 425 A Protein, 116 AA (afferent arteriole), 307, 316 Aβ amyloid, 220 Ab-Ag complexes, 95 Abciximab, 110, 464 Abdominal aorta, 338 Abdominal viscera, 337 Abducens nerve (VI), 205, 428 skeletal muscle innervated by, 430 Abducens nucleus, 209 Abductor digiti minimi, 436 Abductor pollicis brevis, 437 Abductor pollicis longus, 437 Abetalipoproteinemia, 353 abl oncogene, 160 Abruptio placentae, 329, 409 Abscess, pyogenic liver, 362 Absence seizure, 224 Absidia spp., 139 Absolute refractory periods, 152 Absorption, 352–354 Abstinence syndrome, 227 Abuse of drugs, 13–15 physical and psychological, 9 Acamprosate, 13 Acanthamoeba spp., 122, 123 Acanthosis nigricans, 451 Acarbose, 382 ACAT (acyl-cholesterol acyltransferase), 52 Accelerated rejection, 107 Acceleration, angular, 210 Accessory nerve (XI), 123, 434 skeletal muscle innervated by, 428 Accommodation, 208 Accommodation-convergence reaction, 208 Accuracy, in biostatistics, 34 ACE. See Angiotensin-converting enzyme ACE inhibitors. See under Angiotensin-converting enzyme Acebutolol, 193, 513 Acetaldehyde dehydrogenase, 13 Acetaminophen, 513 Acetaminophenoning, 172 Acetazolamide, 48, 207, 288, 326, 513 Acetic acid, 13 Acetoacetate, 52 Acetylcholine, 115, 186, 191, 207, 232, 252, 344 receptors, 169, 189 Acetylcholinesterase, 189 Acetylcholinesterase inhibitors, 190–191, 207, 220 antidote for, 172 poisoning by, 170 Acetyl-coenzyme A, 41, 50, 52 Acetyl-coenzyme A carboxylase, 50, 52 N-Acetylcysteine, 73 Acetylcysteine, as antidote, 172 N-Acetyl-glucosamine, 113 N-Acetylglutamate, 49 N-Acetyl-muramic acid, 113

ACh. See Acetylcholine ACh receptors. See under Acetylcholine Achalasia, 343, 355 AChE. See Acetylcholinesterase AChEI. See Acetylcholinesterase inhibitors Achilles tendon, 438 Achondroplasia, 442 Acid-base disorders, 323 diagnosis of, 323 Acid/base regulation, 319, 321 pH control mechanisms in, 322 Acinar cells, 350 ACL (anterior cruciate ligament), 440 Acne vulgaris, 453 Acquired diseases cystic, 327 hepatic, 361 Acquired immunodeficiency syndrome, 104 anti-HIV therapy in, 105 complications of, 105 opportunistic infections in, 104 Acromegaly, 371, 391 Acrosome, 400 Acrosome reaction, 407 ACTH (adrenocorticotropic hormone), 370 Actin, 81, 425 Acting out, 16 Actinic keratosis, 451 Actinomyces spp., 413, 454 Actinomyces israelii (lumpy jaw), 454 Actinomycosis, 454 Action potentials, 152 in cardiac phases, 238 in muscle, 424 Activated charcoal, 170, 172 Activation energy, 55 Active transport, 80, 149 Acute disseminated (postinfectious) encephalomyelitis, 199 Acute tubular necrosis, 329 Acyanotic congenital heart disease, 255 Acyclovir, 135, 419, 420, 454, 513 Acyl-cholesterol acyltransferase, 52 Adamantinoma, 199 Adaptive immunity, 88 ADCC (antibody-dependent cell-mediated cytotoxicity), 88 Addison disease, 376, 377 Adductor brevis, 439 Adductor longus, 439 Adductor magnus, 439 Adductor pollicis, 437 Adenine, 60 Adenocarcinoma, 296, 358 clear cell, 412 endometrial, 413 Adenoma, liver cell, 362 Adenomas adrenal, 377 cortical renal, 331 tubular, 358 villous, 358

Adenosine, 268 Adenosine deaminase deficiency, 62, 102 Adenosine diphosphate, 464, 465 antagonists, 464 Adenosine triphosphate, 38, 39 F0/F1 synthase, 40 synthesis of, mitochondria and, 79 Adenosis, sclerosing, 416 S-Adenosylhomocysteine, 47 S-Adenosylmethionine, 47 Adenoviruses, 132 40/41,539 Adenylyl cyclase, 169 ADH. See Antidiuretic hormone ADHD (attention deficit/hyperactivity disorder), 18 Adherens junctions (zonula adherens), 82 Adie pupil, 208 ADP. See Adenosine diphosphate Adrenal cortex hypofunctional, 376 neoplasms of, 377 Adrenal gland, 372–378 adenomas of, 377 congenital hyperplasia of, 375 neoplasms of, 377 Adrenal hormones, 372 Adrenal medulla, 377 disorders of, 377 Adrenergic (epinephrine) receptors, 85 Adrenergic neuron blockers, 194 Adrenergic pharmacology, 193–194 Adrenergic transmission, 192 Adrenocortical disease acute insufficiency, 376 treatment of, 377 Adrenocortical insufficiency, 376 Adrenocorticotropic hormone, 370 Adult polycystic kidney disease, 265 Adult respiratory distress syndrome, 295 Adult T-cell leukemia/lymphoma, 161, 474 Aerobic conditions, TCA cycle and, 39 Afferent arteriole, 306, 308, 316 Afferent limb, 202 Aflatoxin, 159 AFP (alpha-fetoprotein), 162, 362, 402 African trypanosomiasis (sleeping sickness), 126, 127 Afterload, cardiac, 242, 246 Agenesis, renal, 301 Agonists, 168 α-adrenergic, 85, 174, 207, 269, 270, 527, 530 β-adrenergic, 193, 294 cholinergic, 189 opioid, 226, 227 partial, 168 Agoraphobia, 24 Agranulocytes, 470 Agranulocytosis, 20 AICA (anterior inferior cerebellar artery), 222, 223 AIDS. See Acquired immunodeficiency syndrome AIDS dementia complex, 105 AII. See Angiotensin II

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INDEX

Airway resistance, 279, 483 Akathisia, 20 ALA. See δ-Aminolevulinic acid synthase Alanine, 41, 45 Alanine cycle, 44 Alar plate, 184 Albinism, 46 Albuminocytologic dissociation, 198 Albuterol, 193, 294, 513 Alcohol abuse, 13–14 Alcohol dehydrogenase, 13 Alcoholic cirrhosis, 361 Alcoholic hepatitis, 361 Alcoholic ketoacidosis, 52 and diuresis, 317 Alcoholic liver disease, 361 Alcoholics Anonymous, 13 ALD. See Aldosterone Aldesleukin,109 Aldolase B deficiency, 38 Aldosterone, 175, 312, 318, 372, 374 Aldosterone antagonists, 270 Aldosterone deficiency, 317 Aldosterone excess, 317 Alendronate, 385, 513 Alfentanil, 228 Aliphatic side chains, 45 Alkaptonuria, 47, 48 Alkylating agents, 176–177 as cancer risk, 159 ALL. See Lymphocytic leukemia, acute Allantois, 300, 334 Allele-specific oligonucleotide dot plot technique, 71 Allocortex, 218 Allograft, 107 Allopurinol, 61, 449, 513 Alpha exotoxin, 115 Alpha receptors in adrenergic transmission, 192 in cell signaling, 84 Alpha toxin, 115, 455 Alpha-1-antitrypsin deficiency, 293 α1,4-bond, 43 α1,6-bond, 43 α-adrenergic agonists, 193, 207, 269, 270 α-adrenergic antagonists, 193, 270 α-tocopherol, 57 Alpha-fetoprotein, 162, 362, 402 Alport syndrome, 328 Alprazolam, 25, 513 Alprostadil, 397 ALS (amyotrophic lateral sclerosis), 203 ALSO (antistreptolysin O), 328 Alanine, 38, 41, 44, 45, 49 Alanine cycle, 44 Aliskiren, 175, 269 Alteplase, 464, 513 Alternate pathway, in complement cascade, 99 Aluminum hydroxide, 349 Alveolar gas equation, 282, 482 Alveolar hypoxia, 285 Alveolar macrophages, 274 Alveolar ventilation equation, 278, 482 Alveoli, 274 Alzheimer disease, 220 treatment of, 220 Amantadine, 135, 216 Amastigotes, 122, 126, 456 Ambenonium, 190 Amebae, 122, 123 Amebiasis, 123, 127, 362 Amides, 227

Amiloride, 326, 513 Amines aromatic, as cancer risk, 159 tertiary and quaternary, 190 Amino acids, 44, 47, derivatives of, 46 genetic deficiencies and, 47 metabolism of, 47–48 as precursors, 46 structures of, 45 synthesis of, 39, 47–48 Aminocaproic acid, 465 Aminoglutethimide, 377 Aminoglycosides, 66, 117, 119 δ-Aminolevulinate dehydratase, 46 δ-Aminolevulinic acid synthase, 46, 56 Aminopterin, 61 Aminotransferases, 56 Amiodarone, 267, 268, 514 Amitriptyline, 22, 194, 514 AML (acute myelogenous leukemia), 474 Amlodipine, 269, 270, 514 Ammonia, tubular handling of, 320 Amnesia, anterograde, 217 Amniotic cavity, 143, 334 Amoxapine, 22 Amoxicillin, 118, 289, 291, 455, 514 Amphetamine, 14, 514 Amphipathic lipids, 80 Amphotericin B, 123, 139, 140, 292, 514 Ampicillin, 118, 514 Ampulla, uterine tube, 152, 407 Amygdala, 217, 219 Amylase, 342, 350, 352, 359 Amyloid Aβ, 220 types of, 158 Amyloid precursor protein gene, 220 Amyloidosis, 158, 328 Amyotrophic lateral sclerosis, 203 AN (anterior nuclear group), 214 ANA (antinuclear antibody), 106 Anabolic steroid, 362 Anaerobic conditions, 38, 41, 44 Anal canal, 345 Analgesic nephritis, 329 Analgesics, 226–227 Anaphase, in mitosis, 83 Anaphase-promoting complex, 83 Anaphylaxis, 97, 100 Anaplasia, 159 Anaplastic carcinoma, 389 Anastrozole, 411, 514 Anatomic dead space, 274 Anatomic snuffbox, 433 Ancylostoma spp., 127, 130, 456 hematologic changes caused by, 476 Andersen disease, 43 Androblastoma, 415 Androgen(s), 372 aromatization of, 403 binding protein, 401 receptor antagonist, 398 receptor gene, 394 receptor-positive prostate cancer, 398 Anemia, 284, 287, 467 hemolytic, 467 myelophthisic, 466 pernicious, 56, 354, 468 sideroblastic, 56 Anencephaly, 184, 185 Anesthetics, 227−228

dissociative, 228 local, 227 general, 228 inhalational, 228 intravenous, 228 Aneuploidy, 74 Aneurysm, 223, 251, 265 ANF (atrial natriuretic factor) receptors, 85 Angelman syndrome, 77 Angina pectoris, 256 Angiodysplasia, 358 Angioedema, hereditary, 99 Angiomyolipomas, renal, 331 Angiosarcoma, 266 Angiotensin I receptor antagonists, 175 Angiotensin II, 175, 253, 265, 308, 312, 316, 318, 321, 372, 374 receptor blockers, 146, 175, 269, 270 272 Angiotensin-converting enzyme, 175 inhibitors, 146, 175, 269, 270, 271 Angiotensinogen, 175 Angular acceleration, 210 Animal bites, 455 Anitschkow cells, 257 Ankle joint, movements at, 441 Ankylosing spondylitis, 446 Annular pancreas, 359 Anococcygeal ligament, 395 Anopheles mosquito, 124 Anorectal canal, 300 Anorexia nervosa, 23 Anorgasmia, 29 ANOVA one-way, 36 repeated measures, 36 ANP (atrial natriuretic peptide), 316, 378 ANS. See Autonomic nervous system Antabuse. See Disulfiram Antacids, 349 Antagonists, 173, 226 α-adrenergic, 193, 269, 270 β-adrenergic, 193, 269, 271, 294 competitive, 173 H1 and H2, 173 hormone, 177 Anterior cerebral artery, 222, 223 Anterior commissure, 218 Anterior communicating artery, 222, 223 Anterior cruciate ligament, 440 Anterior gray horn, 200 Anterior inferior cerebellar artery, 222, 223 Anterior interosseous nerve, 435, 436 Anterior mediastinum, 232 Anterior neuropore, 185 Anterior nucleus, 214 Anterior pituitary, 370–371 hyperfunction of, 371 Anterior spinal artery, 212, 223 occlusion of, 203 Anterograde amnesia, 217 Anterolateral pathway, 202, 203 Anthrax toxin, 115 Antiandrogens, 398 Antianginal drugs, 271 Antiarrhythmic drugs, 267–268 Antibiotics, 117, 177, 349 Antibody-dependent cell-mediated cytotoxicity, 88 Antibody(ies). See also Autoantibody(ies) anticentromere, 107 anti-DNA topoisomerase I, 107 anti-GBM, 328 antihistone, 60 antimicrosomal, 388

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insufficiency, 260 regurgitation of, 247 stenosis of, 247, 255, 260 Aortic vestibule, 230, 234 Aorticopulmonary septum, 231 AP endonuclease, 64 APC gene, 161 Ape hand, 432 APGAR score, 6 Aphasia, 219 Apicomplexa protozoans, 122, 127 Aplastic anemia, 120, 466 Apneustic center, 288 Apolipoprotein E gene, 220 Apomorphine, 346 Apoproteins, 53 Apoptosis, 155, 156 failure of, cancer risk and, 161 APP (amyloid precursor protein) gene, 220 Appendicitis, 358 Appendix, 358 of testes, 394 Appetite, 342 Apraclonidine, 207 Apyrimidination, 64 AR (androgen receptor) gene, 394 ara-C (cytarabine), 176 Arachidonic acid, 54 as inflammation mediator, 97 Arachnoid, 195 Arachnoid granulations, 196, 197 Arachnoid mater, 197 Arcuate nucleus, 214 ARDS (adult respiratory distress syndrome), 295 Area postrema, 174, 345 Area-velocity relationship, 249 Arenavirus, 132 Argatroban, 464 Arginase, 49 Arginine, 45, 46 Arginosuccinate lyase, 49 Argyll Robertson pupil, 208 Aripiprazole, 20, 23, 514 Arnold-Chiari malformation, 185 Aromatic “-amines,” 159 Aromatic D-amino acid decarboxylase. See DOPA decarboxylase Aromatic side chains, 45 Aromatization, of androgens, 403 Arrector pilus, 451 Arsenic, as cancer risk, 159 Arsenic poisoning, 171 antidotes for, 172 Arterial pressure, integrated control of, 253 Arteries. See individual arteries by name Arteriolosclerosis, 264 Arteritis, 263–265 Arthritis infectious, 447 reactive, 446 rheumatoid, 446 suppurative, 446 Arthroconidia, 136, 456 Arthus reaction, 106 Aryepiglotticus, 275 Aryl sulfatase A, 54 Aryl sulfatase A deficiency, 198 Arytenoids, 275 ASA. See Anterior spinal artery Asbestos exposure, 297 as cancer risk, 159 Ascariasis, 130 Ascaris spp., 127, 130

Ascending colon, 345 Ascending pathways, 202 Ascending thin loop of Henle, 306, 310, 314, 315 Aschoff bodies, 257 Ascorbate (vitamin C), 56, 68 ASDs (atrial septal defects), 230, 254 Aseptic meningitis, acute, 195 ASO (allele-specific oligonucleotide) dot blot technique, 71 Asparagine, 45 Aspartate, 45 Aspergillus spp., 195 in AIDS patients, 104 Aspergillus fumigatus, 139 Aspirin, 361, 448, 464, 514 AST cardiac enzyme, 257 Asteroid bodies, 293 Asthma, 237, 281, 293 extrinsic, 294 intrinsic, 294 Astrocytes, 198 Astrocytoma, 160 grade IV, 199 pilocystic, 199 AT1 (angiotensin I) receptor antagonists, 175 Ataxia, 213 Ataxia telangiectasia, 64 Atenolol, 193, 269, 271, 514 ATL. See Ascending thin loop of Henle ATN (acute tubular necrosis), 329 Atomoxetine, 18, 514 Atopic dermatitis (eczema), 451 Atorvastatin, 272, 514 Atovaquone, 127 Atovaquone-proguanil, 125 ATP. See Adenosine triphosphate Atracurium, 427 Atrial natriuretic peptide, 316, 378 receptors, 85 Atrial septal defects, 230, 254 Atrioventricular conduction block, types of, 240 Atrioventricular node, 236 Atrophy, 156 Atropine, 190 as antidote, 172 Atropine poisoning, 170 Attention deficit/hyperactivity disorder, 18 Attributable risk, 35, 479 Atypical antipsychotics, 19 Atypical hyperplasia, 159 Auditory pathways, 211 Auditory system (VIII), 211 Auditory tests, 211 Auditory tube, 429 Auer rods, 475 Auerbach plexus, 335 Augmented limb leads, 239 Auricle, 233 Auscultation Findings, 494–495 Autism, 17 Autoantibody(ies), 106–107 anti-dsDNA, 106 anti-Sm, 106 Autacoids, 173–175 Autografts, 107 Autoimmune diseases, 106–107 Autonomic ganglia, 189 Autonomic nervous system, 186, 187–188, 200 Autophagy, 79 Autoregulation, 252 of glomerular filtration rate, 308 of renal blood flow, 308 renin secretion, 307

INDEX

antimitochondrial, 361 antinuclear, 106 antiribonucleoprotein, 106 digoxin, as antidote, 172 excess, in Ab-Ag complexes, 95 monoclonal, 110 Anticholinergic poisoning, antidote for, 172 Anticipation in Huntington disease, 216 in single-gene disorders, 73 Anticlotting agents, 464 Anticoagulants, 464 poisoning by, antidote for, 172 Anticonvulsants, 224–225 Antidepressants, 22 Antidiarrheals, 226, 368 Antidiuresis, 314 Antidiuretic hormone, 214, 312, 313, 314, 378 See also Vasopressin absence and presence in countercurrent mechanism, 314, 315 antagonists, 326 disorders of, 378 inappropriate secretion of. See Syndrome of inappropriate ADH secretion plasma osmolarity regulated by, 316 regulating osmolarity and volume, 313, 378 secretion of, 371 Antidotes, for poisoning, 172 Antiemetics, 346 Antifibrinolytics, 465 Antifungal agents, 117, 140 Antigenic variation, 116 Antigen(s) binding sites, 94 in human major histocompatibility complex, 91 Antihypertensives, 269, 270 Anti-inflammatory drugs, 54, 448 Anti-influenza drugs, 135 Antimalarials, 125 adverse effects of, 125 Antimicrobials. See Antibiotics Antimuscarinics, 216 Antimycin, 40 Antineoplastic agents, 176–177 Antioxidants, 154 Antiparallel orientation, 60 Antiplatelets, 464 Antipsychotics, 19 atypical, 20 and basal ganglia diseases, 216 side effects of, 17–20 typical, 19 Antipyrine, 149, 302 Antisocial disorder, 26 Antistreptolysin O, 328 Antithrombin III (ATIII), 463 deficiency, 463 α-1-Antitrypsin deficiency, 361 Antitussives, 226 Antiviral agents, 135–136 Antimetabolites, 176 Antrum, 343 Anxiety disorders, 24 Aorta, 231 abdominal, 338 coarctation of, 255 dissection of, 265 stenosis, 247 Aortic pressure, 244 Aortic valve, 246 atresia, 255 bicuspid, 255

543

medEssentials_4E.indb 543

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INDEX

Autosomal dominant inheritance pattern, 72 Autosomal recessive inheritance pattern, 72 Aversive conditioning, 5 Avoidant disorder, 26 Axes, diagnostic, in psychopathology, 17 Axillary nerve, 236, 431, 432, 433, 434 Axon, 198 Axoneme structure, 81 8-Azaguanine, 62 Azathioprine, 109, 448 Azithromycin, 66, 120, 123, 167, 291, 367, 515 azlocillin, 118 “Azo-” dyes, as cancer risk, 159 Azole antifungal agents, 117, 140 AZT. See Zidovudine Aztreonam, 117, 119 Azurophilic granules, 469

B B cells, 90, 470 antigen receptor, characteristics of, 90 receptor diversity, 90 B8, 91 B27, 91 Babesia spp., 122, 127 Babesiosis, 127 Bacillus anthracis, 115, 454 Bacillus cereus, 367 Back anatomy of, 431–438 muscles of, 434 Baclofen, 427, 515 Bacteria, 112 catalase-positive, 98 features of, 113 genetics of, 117 growth curve, 112 growth requirements, 116 pathogenic factors of, 116 toxins, 114, 115 Bacterial algorithms, appendix F, 533–538 Bacteriology, 112–117 Bacteroides spp., 114, 116, 291 bad gene, 161 BAL (dimercaprol), for heavy metal poisoning, 172 Baldness, male pattern, 398 Barbiturates, 14, 24, 228 Bare lymphocyte syndrome, 102 Baroreceptors, 253 Barr body, 74 Barrett esophagus, 355 Bartholin gland, 395, 396 Bartonella henselae, 455 Bartter syndrome, 375 Basal electric rhythm, 343 Basal ganglia, 184, 214, 215–216, 224 diseases of, 216 Basal lamina, 82 Basal plate, 184 Basement membrane, 82 Basilar artery, 222, 223 Basilar membrane, 211 Basophils, 97, 469 in chronic inflammation, 97 histamine and, 173 bax gene, 161 BBB (blood-brain barrier), 216 BC (Bowman capsule), 300, 306, 307 B-cell lymphoma, 161 bcl-1 oncogene, 160 bcl-2 oncogene, 156, 161 bcl-xS gene, 161

bcr-abl fusion protein, 160 Becker muscular dystrophy, 450 Beclomethasone, 294 Bedwetting, 11 Behavior therapy, 4–5 Benazepril, 175, 515 Bence-Jones proteins, 329, 475 Benign prostatic hyperplasia, 398 Benign prostatic hypertrophy, 398 Benign tumors, 355 of the kidney, 331 Benzene exposure, as cancer risk, 159 Benzocaine, 227 Benzodiazepines, 13, 14, 20, 24, 225, 228 poisoning by, antidote for, 172 Benztropine, 190, 216, 515 Berger disease, 328 Beriberi, 56 Bernard-Soulier syndrome, 460, 461 Berry aneurysms, 195, 224, 327 Beta agonists β1, 193, 272 β2, 193, 294 adrenergic, 193, 294 poisoning by, antidote for, 172 Beta blockers, 207, 267, 270, 271, 382, 389 poisoning by, antidote for, 172 Beta receptors in adrenergic transmission, 192 antagonists, 193, 207, 267, 269, 270, 271, 369, 382, 389 in cell signaling, 84 β-glucocerebrosidase, 54 β-hydroxybutyrate, 52 β-lactamases, 118 β-oxidation, 52 Betaxolol, 207 Bethanechol, 189 BG. See Basal ganglia Bias, statistical, 35 Bicarbonate, 350 tubular handling of, 320 Biceps brachii, 435 Biceps femoris, 439, 440 Biceps muscles, 431 Biceps short head, 434 Biceps tendon, 431 Bicuspid aortic valve, 255 bid gene, 161 Bifid scrotum, 394 Bifidobacterium spp., 114 Biguanides, 382 Bilaminar embryonic disk, 143 Bile, 351, 352 Bile acid sequestrants, 272 Biliary disease, 364 Bilirubin, 46, 352 Bioavailability, 166, 480 Biofeedback, 5 Biostatistics, 34–36 Biotin, 47, 56 Biotransformation, 167 Biperiden, 190, 216 Bipolar disorder, 20, 21, 22 Bisphosphonates, 385 Bites, Animal, 455 Human, 455 Bivalirudin, 464 Bladder congenital abnormalities of, 301 development of, 300 exstrophy of, 397 pathology of, 332

Blastoconidia, 136 Blastocyst, 142, 408 Blastomyces spp., 138 Blastomyces dermatitidis, 138, 292 Blastomycosis, 138 Blastula, 142 Bleomycin, 177, 515 Blockade, order of, 227 Blocking, 16 Blood flow control of, 252 pulmonary, 285 renal, 305 Blood gas, arterial, 321 Blood gas barrier, 274 Blood pressure. See also Hypertension; Hypotension integrated control, 321 long-term control, 374 Blood supply, to cortex, 222–224 Blood-brain barrier, 216 Blood-CSF barrier, 197 Blood-testis barrier, 400 “Blue bloaters,” 281 Body dysmorphic disorder, 25 Body fluid compartments, 302 Body fluid volume, normal values, 302 Body mass index (BMI), 23 Body osmolarity, 149 changes in, 150 Boerhaave, syndrome, 355 Bombesin, 158 Bone disorders, drug-induced, 385 Borderline tumor, 26, 414 Bordetella pertussis, 115 hematologic changes caused by, 476 Borrelia spp., 127 Borrelia burgdorferi, 122 Botulinum toxin, 115, 117, 191, 427, 515 Bounding pulse, 260 Bowen disease, 397 Bowman capsule, 300, 306, 307 BPH (benign prostatic hypertrophy), 398 Brachial plexus, lesions, 431–433 Brachialis muscle, 431, 435 Brachioradialis muscle, 431, 435 Bradykinin, 162, 175, 271, 285 as inflammation mediator, 96, 97, 99 Brain stem cranial nerves and, 204–205 lesions of, 212 Brain-growth spurt, 7 Branched-chain ketoacid dehydrogenase, 47, 48 Branching enzyme, 43 BRCA-1 gene, 161, 414, 417 BRCA-2 gene, 161, 417 Breast, pathology of, 416–418. See also Breast cancer Breast cancer, 417 fibrocystic disease versus, 418 risk factors for, 417 tumor suppresser genes in, 417. See also BRCA-1 gene; BRCA-2 gene types of, 418 Breathing cycle in, 280 mechanics of, 278–280 Brenner tumor, 414 Bretylium, 268 Bridging therapy, 448 Bridging veins, 195, 224 Brimonidine, 207, 515 Brinzolamide, 207

544

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C C3 nephritic factor, 327 CA (carbonic anhydrase), 350 Ca2+-ATPase, 80 CA19-9 tumor marker, 162 CA-125 tumor marker, 162 CAA (cerebral amyloid angiopathy), 220 Caffeine poisoning, antidote for, 172 CAI. See Carbonic anhydrase inhibitor CAIS (complete androgen insensitivity), 394 Calcarine sulcus, 218 Calcitonin, 162, 342, 383 Calcitonin gene-related polypeptide, 344 Calcitriol, 383 Calcium carbonate, 349 Calcium channel blockers, 268, 269, 270, 271 Calcium homeostasis, pathophysiology of, 385 Calcium pyrophosphate, 446 Calcium regulation, 384 disorders of, 384 endocrine, 383–385

Calcium stones, 330 Calicivirus, 133 Call-Exner bodies, 415 Calmodulin, 424 Caloric test, 210 Calves, pseudohypertrophy, 493 Calyces, 300 cAMP (cyclic adenosine monophosphate), 169, 397 Campylobacter, 66, 116, 120, 365, 537 Canal of Schlemm, 206 C-ANCA, 262, 263 Cancer. See Carcinoma Candesartan, 269, 272, 515 Candida spp., 114, 195, 412, 419 Candida albicans, 137, 139, 289, 290 in AIDS patients, 104 Candidiasis, 137, 412 in AIDS patients, 104 Cannabis, 15 Capacitation, 400, 407 Capillary(ies) filtration and reabsorption in, 250, 482 flow and pressure changes in, factors affecting, 251 hemangioma of, 451 hydrostatic pressure in, 250 oncotic pressure in, 250 peritubular, 306 pulmonary, 285 Capnocytophaga canimorsus, 455 Capsules, 116 Captopril, 175, 269, 271, 516 Caput medusa, 340, 361 Carbachol, 189, 207 Carbamazepine, 225, 516 Carbamoyl phosphate synthase I, 49 Carbapenems, 119 Carbenicillin, 118 Carbidopa, 216 Carbon dioxide transport, 285 Carbon monoxide, 40, 283 changes after heart failure, 243 Carbon monoxide poisoning, 170, 284, 287 antidote for, 172 Carbon tetrachloride (CCl4), 154, 159 Carbonic anh0ydrase, 350 Carbonic anhydrase inhibitor, 207, 317, 325, 326 electrolyte changes caused by, 326 Carbonic anhydrase reaction, 321 Carboplatin, 177 Carboxypeptidase, 350, 353 Carbuncles, 453 Carcinoembryonic antigen, 162 Carcinoembryonic antigen tumor, 358 Carcinogenesis, mechanisms, 160 Carcinoid, 296 Carcinoid syndrome, 46, 162, 296 Carcinoid tumor, 162 Carcinoma adrenal, 377 anaplastic, 389 basal cell, 451 bile duct, 362, 364 breast. See Breast cancer bronchogenic, 296 cervical, 161 colorectal, hereditary nonpolyposis, 64 defined, 159 embryonal, 402 esophageal, 355 follicular, 389 gallbladder, 364

hepatocellular, 161, 162, 360 large cell, 296 lung, 160 medullary. See Medullary carcinoma nasopharyngeal, 161 ovarian, 162 pancreatic, 162, 359 papillary, 389, 390 penile, 397 prostatic, 162, 398 renal cell, 161, 331 risk factors for, 159 small cell. See Small cell carcinoma squamous cell, 453 stomach, 356 transitional cell, of the bladder, 332 Carcinoma in situ, 159 penile, 397 Cardia, 343 Cardiac cycle, 244 Cardiac enzymes, after Cardiac output, 242, 481 changes after heart failure, 243 Fick method, 249, 481 integrated control, 321 integrated control of, 253 Cardiac performance definitions, 242 mechanical, 242 Cardiac pressure-volume loops, 245–246 Cardiac tamponade, 261 Cardiac valves, 246 disorders of, 247–253 Cardiogenic shock, 272 Cardiomyopathies, 260 Cardiovascular system. See also Cardiac entries; Heart anatomy of, 232–236 embryology of, 230–232 pathology of, 254–266 pharmacology of, 267–272 physiology of, 237–253 Carisoprodol, 427, 516 Carmustine, 176 Carnitine acyltransferases, 38, 50 Carnitine shuttle, 50 Carnitine transporter, 50 Carpal tunnel syndrome, 433 Carrier-mediated diffusion, 148 Carvedilol, 193, 516 Caseation, 155 Case-control studies, 35 Caseous necrosis, 155 Caseous pericarditis, 261 Caspofungin, 140 Castor oil, 368 CAT (carnitine acyltransferase), 38, 50 Cat scratches, 453, 455 CAT-1 (carnitine actyltransferase-1), 50 CAT-2 (carnitine actyltransferase-2), 50 Catalase, 116, 154, 453 Catecholamines, 46, 192 Catechol-O-methyltransferase, 192 inhibitors, 194, 216 Cats, as reservoir hosts, feces, 127 Cauda equina, 200 Caudate, 215 Caudate nucleus, 215 Cavernous sinus, 197 thrombosis of, 430 CCD (cortical collecting duct), 306 CCK. See Cholecystokinin CCR5 (chemokine receptor 5), 104 CCR5 antagonist, 105, 476

INDEX

Broca aphasia, 219 Brodie abscess, 443 Bromocriptine, 15, 174, 216, 371, 515 5-Bromodeoxyuridine, 61 Bronchial vessels, 276 Bronchiectasis, 293, 294 Bronchioloalveolar carcinoma, 296 Bronchitis, 281, 290 chronic, 293 Bronchogenic carcinoma, 296 Bronchopneumonia, 291 Bronchopulmonary dysplasia, 295 Bronchopulmonary nodes, 276 “Bronze diabetes,” 361 Brown tumors, 442 Brown-Séquard syndrome, 203 Brucella spp., 116, 122 Brugia spp., 127, 131 Brunner glands, 344 Bruton X-linked hypogammaglobulinemia, 102 Bruxism, 11 BuChE (butyrylcholinesterase), 220 Budd-Chiari syndrome, 361 Budesonide, 515 Buerger disease, 262 Bulbospongiosus muscle, 395, 396 Bulbourethral (Cowper) gland, 396 Bulb(s) penile, 396 vestibular, 396 Bulbus cordis, 230 Bulimia nervosa, 23 Bulk-forming laxatives, 368 Bullous pemphigoid, 82, 451 Bundle branches, 236 Bundle of His, 236 Bunyavirus, 134, 539 Bupivacaine, 227, 515 Buprenorphine, 14, 226 Bupropion, 22 Burkitt lymphoma, 161 undifferentiated, 473 Burns, 455 Buproprion 15, 22, 515 Buspirone, 24, 174, 515 Busulfan, 176 Butalbital, 515 Butorphanol, 226 Butyrylcholinesterase, 220

545

medEssentials_4E.indb 545

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INDEX

CD markers, 93 CD2, 93 CD3, 90. 93 CD4, 88, 89, 91, 93, 102, 104 CD8, 88, 90, 91, 93 CD10 (CALLA) surface marker, 474 CD14, 89. 92, 93 CD16, 88, 90, 93 CD18 absence, 98 CD19, 93 CD20, 93 CD21, 93 CD25, 93 CD28, 88, 93 CD40, 88, 93 CD40L, 88 CD56, 88, 90, 93 CDK4 oncogene, 160 cDNA, 69 CEA. See Carcinoembryonic antigen entries Cecum, 345 Cefazolin, 118 Cefepime, 118 Cefoperazone, 118 Cefotaxime, 420 Cefotetan, 118 Cefoxitin, 118 Ceftazidime, 118, 516 Ceftriaxone, 118, 289, 290, 419, 420, 421, 447, 457, 516 Cefuroxime, 118 Celecoxib, 448, 516 Celiac artery, 334, 335, 338 Celiac circulation, 338 Celiac sprue, 357 Cell adhesion, 82 Cell body, 198 Cell cycle, 83 proteins and, 160 Cell death, 155 programmed. See Apoptosis Cell injury causes of, 154 irreversible, 155 mechanisms of, 154 reversible, 155 Cell signaling, 84–85 Cell transport, 148 Cell wall, 112 Cell wall synthesis inhibitors, 118–119 carbapenems, 119 cephalosporins, 118 monobactams, 119 non-beta lactam, 119 penicillins, 118 Cell-cycle regulatory proteins, 160 Cells, 112 B cells, 90 chief, 336, 348 chromaffin, 377 of immune system, 89–90 natural killer, 88, 90 regeneration and repair, 157 response in acute inflammation, 100 T cells, 88 types, in nervous system, 198 Cellular membrane, 112 Cellularity, mixed, in Hodgkin disease, 472 Cellulitis, 454 Central artery, retinal, 223 Central canal, 196 Central nervous system, 184, 198 adult derivatives, 184

depressants, 14 stimulants of, 14 trauma to, 221 Central sulcus, 218, 219 Centriacinar (centrilobular) emphysema, 293 Centrilobular necrosis, 159 Cephalexin, 118 Cephalosporins, 113, 118, 119, 516 Cerebellar tonsillar herniation, 221 Cerebellum, 213 Cerebral amyloid angiopathy, 220 Cerebral aqueduct, 184, 196, 213, 218 Cerebral cortex, 218–221 Cerebral hemispheres, 184 Cerebral herniations, 221 Cerebral infarcts, 224 Cerebrospinal fluid, 196 parameters, in meningitis, 196 production of and barriers, 197 sinuses and, 197 Cerebrovascular disorders, 224 Ceruloplasmin, 361 Cervical intraepithelial neoplasia, 412 Cervical spondylosis, 431 Cervicitis, 419 Cervix, 394, 407 carcinoma, 161, 412 enlargement of, 200 Cestodes, 127, 129 Cetirizine, 173, 516 CFC. See Cardiac function curve CFTR protein, 359 CGD (chronic granulomatous disease), 98 cGMP, 84, 397 CGRP (calcitonin gene-related polypeptide), 344 Chagas disease, 126, 127, 355 Chancre, 421, 492 Chancroid, 421, 492 Chaperones, molecular, 67 Charcot-Marie-Tooth disease, 198 ChAT (choline acetyltransferase), 189 Chediak-Higashi syndrome, 81, 98 Chemical injury, 154 Chemokine, 96 Chemokine receptors, 104 Chemoreceptors, 288 trigger zone for, 345 Chenodeoxycholic acid, 351 Chenodiol, 368 Chest wall disorders of, 295 elastic properties of, 279 CHF (congestive heart failure), 258 Chief cells, 336, 348 Child abuse, 9 Child development, 6–9 milestones in, 7–8 Chinese liver fluke, 128 Chi-square, 36 Chlamydia spp., 412, 413, 419–420, 446 Chlamydia spp., infectious arthritis and, 447 Chlamydia trachomatis, 412, 413, 419, 420, 421 Chlamydiae, 122 Chlamydophilia psittaci, 292 Chloramphenicol, 66, 118, 120, 455 Chlordiazepoxide, 24 Chloroquine, 125, 476, 516 Chlorpheniramine, 173 Chlorpromazine, 19 Chlorpropamide, 382 Cholangiocarcinoma, 128, 361, 362, 364 Cholangitis, sclerosing, 361

Cholecalciferol. See Vitamin D Cholecystokinin, 342, 343, 346, 351 Cholelithiasis, 364 Cholera toxin, 115, 354 Cholestasis, 360 Cholesterol, 52, 53 synthesis of, 52 Cholesterol esters, 52 Cholesterol stones, 364 Cholestyramine, 53, 272, 516 Cholic acid, 351 Choline acetyltransferase, 189 Choline uptake, 189 Cholinergic agonists, 189 Cholinergic pharmacology, 189–191 Cholinergic transmission, 189 Cholinesterases, plasma, 227 Chondrocalcinosis, 446 Chondromatous tumors, 445 Chondromyxoid fibroma, 445 Chondrosarcoma, 445 Chordae tendineae, 233 Chordee, 397 Chordoma, 144 Choriocarcinoma, 162, 402, 415 Choriomeningitis, lymphocytic, 134 Chorion, 143 Chorionic plate, 408 Choroid plexus, 196, 197 Christmas disease, 463 Chromaffin cells, 377 Chromatin, 60 Chromium, as cancer risk, 159 Chromosomal abnormalities, 74–76 Chromosomal deletions, 77 Chromosomal inversions, 75 Chromosomal translocations, 75–76 Chronic granulomatous disease, 98 Chronic obstructive pulmonary disease, 280, 281, 293 Chronic passive congestion, 360 Churg-Strauss syndrome, 262 Chylomicrons, 50, 53, 353 Chyme, 343 Chymotrypsin, 350 Cigarette smoke, as cancer risk, 159 Cilastatin, 119 Ciliary body epithelium, 207 Ciliary ganglion, 186 Ciliary muscles, 186, 206, 207 Cilostazol, 464 Cimetidine, 173, 349, 517 CIN (cervical intraepithelial neoplasia), 412 Cingulate gyrus, 214, 218 Cingulum, 217 Ciprofloxacin, 121, 455, 517 Circadian rhythms, 214 Circle of Willis, 222 berry aneurysms of, 327 Circulation autonomic control, 252 celiac, 338 cerebrospinal fluid, ventricles and, 196 fetal, 232 hepatic portal, 340 parasympathetic regulation of, 252 pulmonary circulation, 249 sympathetic regulation of, 252 systemic, 249 Circumcision, 397 Circumflex artery, 233 Cirrhosis, 361 Cis (forming) face, Golgi apparatus, 79

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Codon, 64 Coelom, 334 Coenzyme Q, 40 Coenzyme Q10 (ubiquinone), 178 Cohort studies, 35 Colchicine, 81, 449, 517 Cold hemolytic anemia, 467 Colestipol, 53, 272 Colesevelam, 272 Colitis, ulcerative, 359 Collagen, 82 synthesis of, 68 type I, 442 types of, 157 Collagenase, 116 Collecting duct, 311, 313, 314, 315 Collecting tubule, 300 Colles fascia (superficial perineal fascia), 396 Colloid carcinoma, of the breast, 418 Colon. See Large intestine Colorectal cancer, hereditary nonpolyposis, 64 Coma, 14 Common coagulation pathway, 463 Common cold, 289 Common peroneal (fibular) nerve, 438 Common variable deficiency, 102 Communicating hydrocephalus, 197 Communicating rami, 200 Compensation, in acid/base regulation, 321 Competitive inhibitor, 55 Complement cascade, 98 Complementary DNA, 69 Complementation, 134 Complete androgen insensitivity, 394 Complete atrioventricular conduction block, 240 Complete endocardial cushion defect, 254 Complete mole, 415 partial mole versus, 415 Complex I (NADH dehydrogenase), 40 Complex II (succinate dehydrogenase), 40 Complex III (cytochrome b/c1), 40 Complex IV (chromosome a/a3), 40 Complex V, 40 Complex seizure, 224 Compliance, 248, 278, 279, 481 COMT. See Catechol-O-methyltransferase Concentrating segment, in loop of Henle, 310 Concentration, drug, 166 Concentration gradients, 148 Concussion, 221 Conditioning, 4, 5 Conducting zone, 274 Conduction, in heart, 236 Conduction blocks, atrioventricular, 240 Conduction deafness, 211 Condyloma acuminatum, 412, 420 Cone bug, 126 Confidence intervals, 36 Confluence of sinuses, 197 Confounding bias, 35 Congenital adrenal hyperplasia, 375, 377, 394 Congenital anomalies, 357 VACTERL, 144 VATER, 144 Congenital enzyme deficiency syndromes, 376 Congenital heart disease acyanotic, 254 cyanotic, 254–255 obstructive, 255 Congenital hepatic malformations, 360 Congenital malformations, of nervous system, 185 Congenital reproductive anomalies, 394

Congestive heart failure, 258 Congestive myopathy, 260 Congo red stain, 158 Conidia, 137 Conjugated bilirubin, 351 Conjugated hyperbilirubinemia, 360, 488 Conjugation, 117, 167 Conjugation phase, 72 Conn syndrome, 375, 377 Connective tissue diseases, 157 Connexon, 82 Constrictor pupillae, 206 Contact dermatitis, 106, 452 Contraception, 410 Contractility, cardiac, 242 Contraction, isovolumic, 245 Contralateral hemianopia, 219, 223 Contusion, 221 Conus arteriosus, 230 Conus medullaris, 200 Convergence, 208 Conversion disorder, 25 Cooper ligaments, 417 COPD. See Chronic obstructive pulmonary disease Copper poisoning, antidote for, 172 Coprophilia, 28 Cor pulmonale, 258 Cori cycle, 41 Cori disease, 43 Corona radiata, 404 Coronary arteries, 233 Coronaviruses, 133, 289, 539 Corpus albicans, 405 Corpus callosum, 215, 218 Corpus cavernosum, 395, 396 Corpus luteum, 404, 405, 406 Corpus spongiosum, 395, 396 Corpus striatum, 215 Cortex, 301 blood supply to, 222 Cortical adenomas, of kidney, 331 Cortical collecting duct, 306 Cortical reaction, 400, 407 Corticobulbar tract, 213 Corticospinal tract, 212, 213 Corticosteroids, 54, 109, 294, 448 Corticotropin-releasing hormone, 370 Cortisol, 372, 380 excess versus deficiency, 373 Corynebacterium spp., 114 Corynebacterium diphtheriae, 115, 289 Coumarin poisoning, antidote for, 172 Councilman body, 156 Countercurrent mechanism in absence of ADH, 315 in presence of ADH, 314 Cowper gland, 396 COX. See Cyclooxygenase(s) Coxsackie A virus, 289 Coxsackie B virus, 259, 409 CPM (progressive multifocal leukoencephalopathy), 198 Cranial nerves, 204 and brain stem, 204–205 skeletal muscle innervated by, 428 Craniopharyngioma, 199 Creatine, 46 Creatinine clearance, 305 Cremaster muscle and fascia, 399 Cremasteric reflex, 399 CREST syndrome, 107 Cretinism, 388

INDEX

Cisapride, 368 Cisatracurium, 427 Cisplatin, 177, 517 Citalopram, 22, 174, 517 Citrate, 39 Citrate shuttle, 39, 50 Citrate synthase, 39 Citric acid cycle, stoichiometry of, TCA, 39 Citrulline, 49 CJD. See Creutzfeldt-Jakob disease CK-MB cardiac enzyme, 257 c-kit oncogene, 160 Clarithromycin, 66, 120, 434, 517 Clarke’s nucleus, 200 Classical conditioning, 4, 5 Classical pathway, in complement cascade, 98 Clathrin-coated pits, 79 Clavicle, 433 Clavulanate, 291, 455 Claw hand, 432, 433 Clearance of drug, 166 renal, 305, 483 Cleavage, of zygote, 142 Cleft lip, 429 Cleft palate, 429 Climbing fibers, 213 Clindamycin, 66, 120 Clitoris, 394, 395 CLL (chronic lymphocytic leukemia), 474 Clomiphene, 411, 517 Clomipramine, 24, 517 Clonazepam, 24, 224, 517 Cloned DNA, 70 Clonidine, 13, 14, 193, 269, 517 Clonorchis spp., 127 Clonorchis sinensis, 128, 362 Clopidogrel, 464, 517 Clostridium botulinum, 115 Clostridium difficile, 119, 365 superinfection, 120 Clostridium perfringens, 115, 116, 366, 367, 455 Clotrimazole, 140 Clotting cascade, 463 pathologic dysregulation in, 462 physiologic regulation in, 462 Clozapine, 20, 517 CMI (cell-mediated immunity), 420 CML (chronic myelogenous leukemia), 76, 160, 474 CMV. See Cytomegalovirus CMV retinitis, 132, 135, 136 c-myc oncogene, 160, 161 CO. See Carbon monoxide CO2 transport, 285 CoA (coenzyme A), 41 Coagulase, 116, 453 Coagulation disseminated intravascular, 463 pathways of, 462. See also Clotting cascade tests of, 462 Coagulative necrosis, 155 Cocaine, 14, 194, 227 Coccidioides spp., 138 Coccidioides immitis, 97, 104, 136, 138, 292 in AIDS patients, 104 Coccidioidomycosis, 138 Coccygeus, 395 Cochlea, 211 Cochlear nucleus, 211 VIII fibers, 212 Codeine, 226, 517 Codman triangle, 445

547

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INDEX

Creutzfeldt-Jakob disease, 221 CRH (corticotropin-releasing hormone), 370 Cribriform plate, 205 Cricothyroid, 275 Cri-du-chat syndrome, 77 Crigler-Najjar syndrome, 46, 360 Crista terminalis, 233 Crohn disease, 359 Cromolyn, 294, 517 Crossbridge cycle, 425 Cross-sectional studies, 35 Croup, 290 Cruise ship agent (virus), 133 Crura of clitoris, 395 of penis, 396 Crus cerebri, 201 Cryotherapy, 456 Crypt abscesses, 359 Cryptococcus spp., 195 Cryptococcus neoformans, 139 in AIDS patients, 104 Cryptorchidism, 399 Cryptosporidiosis, 123 Cryptosporidium spp., 122, 123 Cryptosporidium parvum, 367 in AIDS patients, 104 CSF. See Cerebrospinal fluid Cumulus oophorus, 420 Cuneate fasciculus, 202 Cuneate nucleus, 202 Cuneus gyrus, 206, 218 Curling ulcers, 356 Currant jelly sputum, 291 Cushing disease, 371, 377 Cushing syndrome, 162, 177, 373, 377 Cushing ulcers, 356 Cutaneous larva migrans, 131 Cutaneous leishmaniasis, 126 CXCR4 (α-chemokine receptor), 104 Cyanide poisoning, 40 Cyanocobalamin (B12), 56 Cyanosis, 231, 488 Cyanotic congenital heart disease, 254–255, 442 Cyclin-dependent kinases, 83 Cyclins, 83 Cyclobenzaprine, 427, 517 Cyclooxygenase(s), 54, 448 COX-1 pathway, 448 COX-2 inhibitors, 448 COX-2 pathway, 448 as inflammation mediator, 97 inhibitors, 448, 464 Cyclopentolate, 190 Cyclophosphamide, 109, 176, 518 Cyclosporine, 109, 518 Cyclothymia, 20, 21 Cystadenocarcinoma, 414 Cystadenoma, 414 Cystathionine synthase, 47, 48 Cysteine, 45 Cystic disease, 416 renal, 327 Cystic fibrosis, 72, 73, 294 genetic testing in, 71 Cysticerci, 129 Cysticercosis, 129 Cystine, 48 Cystine stones, 330 Cystinuria, 48, 330 Cystitis hemorrhagic, 176, 332 infectious, 332, 419

Cystitis emphysematosa, 332 Cystosarcoma phyllodes, 416 Cytarabine, 176 Cytochrome a/a3, 40 Cytochrome b/c1, 40 Cytochrome c, 40 Cytochrome c oxidase, 116 Cytochrome P450 (CYP450), 79 Cytokeratin stain, 158 Cytokines, 88, 89, 94. See also Granulocyte colony-stimulating factor; Granulocytemacrophage colony-stimulating factor; Interferon entries; Interleukins; Tumor necrosis factor; individual cytokines in cell regeneration, 157 receptors, 169 recombinant, clinical uses of, 109 Cytomegalovirus, 131 in AIDS patients, 104 hematologic changes caused by, 476 Cytoplasmic pathway, 38 Cytosine, 60 Cytoskeleton, 81 Cytosol, 49, 50 Cytosolic enzymes, 44 Cytotoxic hypersensitivity reaction, 106 Cytotoxic T cells, 88, 90, 91 Cytotoxicity, antibody-dependent cell-mediated, 88 Cytotrophoblast, 142, 143, 145, 415

D D cells, 347 D receptors, in cell signaling, 84, 85 D-ala-D-ala-muramyl pentapeptide, 119 d4T (stavudine), 105 DA agonists, 216 DA antagonists, 346 Daclizumab, 110 Dalfopristin, 120 Dalton’s law of partial pressures, 282 Danazol, 411 Dandy-Walker malformation, 185 Dantrolene, 228, 427, 518 DAP (diaminopimelic acid), 40, 113 Dapsone, 455 Darbepoetin alpha, 468 Darrow-Yannet diagram, 150 Dartos fascia, 395 Davenport diagram, 322 DCC gene, 161 DCT (distal convoluted tubule), 270, 312 DDAVP (desmopressin), 465 ddC (zalcitabine), 105 ddl (didanosine), 105 de Quervain granulomatous subacute thyroiditis, 388 Dead space, 277–278, 286 Deafness, 211 Death, children’s conceptions of, 7 Death phase, bacterial, 112 Debranching enzyme, 43 Deceleration, 210 Decidua basalis, 145 Decidualization, 408 Deep cortical layers, and infarct, 224 Deep fascia, 395 Deep inguinal ring, 399 Deep perineal pouch, 396 Deep peroneal nerve, 439, 441 Deep tendon reflex, 202 Deep transverse perineal muscle, 396 Deep vein thrombosis, 265, 297

Defecation, 345 Defecation reflex, 345 Defense mechanisms, common Freudian, 16 Defensins, in phagocytosis, 98 Deferoxamine, for iron poisoning, 171, 172 Degenerative joint disease, 446 Dehydration, 317 Dehydroepiandrosterone (DHEA), 178 Delavirdine, 105 Delayed type hypersensitivity, 106, 420 Deletions, chromosomal, 75 Delirium, versus dementia, 27 Delirium tremens (DTs), 14 δ receptors, 226 Deltoid muscle, 432 clavicular part, 434 posterior fibers, 434 Demeclocycline, 326 Dementia as AIDS complication, 105 versus delirium, 27 Dendrites, 198 Dendritic cells, 89 Denial, 16 Dense deposit disease, 327 Deoxyribonuclease, 350 Deoxyribonucleotides, 61 Deoxyribose, 60 Dependence (use), 227 Depolarization action potential and, 152 membrane potential and, 151 Depolarizing blockers, 427 Depressants, 14 Depression, 21 Dermatitis, contact, 106, 452, 456, 525, 526 Dermatitis herpetiformis, 452 Dermatomyositis, 450 Dermis, 451 Dermoepidermal junction, 452 DES (diethylstilbestrol), 142, 146, 412 Descemet membrane, 361 Descending colon, 345 Descending pathways, 201 Descending thin loop of Henle, 306, 310, 314, 315 Descent, of testes, 398 Desflurane, 228 Desipramine, 22, 194 Desmin stain, 158 Desmoplasia, 159 Desmopressin, 371, 465, 518 Desmosome (macula adherens), 82 Dexamethasone, 373 Dexrazoxane, 177 Dextroamphetamine, 17, 518 Dextromethorphan, 226 DHFR (dihydrofolate reductase), 62 DHT (dihydrotestosterone), 398 DI. See Diabetes insipidus Di Guglielmo disease, 475 Diabetes acute metabolic complications, 381 late complications of, 381 treatment of, 382 Diabetes insipidus, 214, 317, 371, 378 Diabetes mellitus, 381 Diabetic gastroparesis, 344 Diabetic glomerulopathy, 328 Diabetic ketoacidosis, 52, 324, 381 and osmotic diuresis, 317 Diacylglycerol in adrenergic transmission, 192 in cholinergic transmission, 189

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DIT (diiodotyrosine), 386 Diuresis, water-induced, 315 Diuretics, 326 electrolyte changes caused by, 326 mechanisms of, 325 osmotic, 317 Diverticula, 355 of the bladder, 332 Diverticular disease, 358 DKA. See Diabetic ketoacidosis DMARDs (disease-modifying, slow-acting antirheumatic drugs), 448 DNA, 60 in cell synthesis, 83 cloned, 70 point mutations, 64 recombinant, 69–70 replication and transcription of, 63, 78 vectors, 70 DNA gyrase, 63, 121 DNA library, screening, 70 DNA polymerase, 63 DNA repair, 64 DNA replication inhibitors, 121 DNA telomerase, 63 DNA topoisomerase II and IV, 63, 121 DNA viruses, 132 2,4-DNP (dinitrophenol), 40 Docusate, 368 Dofetilide, 268 Dolasetron, 346 Donepezil, 190, 220, 518 DOPA decarboxylase, 46 inhibitor, 216 Dopamine, 46, 518 precursor to, 216 Dopamine β-hydroxylase, 46, 56 Dopamine receptors, 85 Dopamine 1 agonist, 269 Dorsal column-medial lemniscus pathway, 199, 202 Dorsal horn, 200 Dorsal interossei muscles, 436 Dorsal midbrain syndrome, 213 Dorsal pancreatic bud, 334 Dorsal root, 200 Dorsal root ganglia, 200, 202 Dorsal scapular nerve, 434 Dorsomedial nucleus, 214, 217 Dorzolamide, 207, 326 Dose-response curves, 168 Double ureters, 301, 331 Double-stranded RNA viruses, 133 Down syndrome, 74, 254, 255 Doxacurium, 427 Doxazosin, 193, 269, 518 Doxepin, 518 Doxorubicin, 40, 177, 518 Doxycycline, 66, 120, 291, 519 DPC4 gene, 161 2,3-DPG, 288 DQ2, 91 DQ8, 91 DR2, 91 DR3, 91 DR4, 91 Dracunculus spp., 127, 130, 131 DRG (dorsal root ganglia), 200, 202 Dronabinol, 15, 346 Droperidol, 228 Drug-induced disorders of bone, 385 of minerals, 385 neutropenia, 470

Drug development and testing, 179 Drug metabolism, 167 Drugs. See also individual drugs by name or class list, Appendix E, 513–532 of abuse, 14–15 pharmacodynamics of, 168–169 pharmacokinetics of, 166–167 volume distribution, 166 Dry eyes (keratoconjunctivitis sicca), 106 Dry mouth (xerostomia), 106 DTH (delayed type hypersensitivity), 106, 420 DTL. See Descending thin loop of Henle DTs (delirium tremens), 13 Dubin-Johnson syndrome, 360 Duchenne muscular dystrophy, 72, 450 Duct of Gartner, 394 Ductal cells, 350 Ductus arteriosus, 232 Ductus deferens, 394, 395, 399 artery to, 399 Duloxetine, 519 Duodenal atresia, 357 Duodenum, 336, 344 Dura, 195 Dura mater, 195 Duret hemorrhage, 221 Dwarfism, 391, 442 Dyes, as cancer risk, 159 Dynamic compression, 280 Dyneins, 81, 400 Dyscrasias, 475 Dysdiadochokinesia, 213 Dysentery, 365 Dysgerminoma, 414 Dyspareunia, 29 Dysplasia defined, 156, 159 tooth enamel, 120 Dysthymia, 20, 21 Dystonia, 20 Dystrophin, 450

INDEX

Diagnosis, immunology techniques in, 108 Diagnostic axes, in psychopathology, 17 Diagnostic enzymes, 116 Diaminopimelic acid, 40, 113 Diaphragm, 278 Diarrhea fluid and electrolyte abnormalities in, 303 inflammatory, 365 by intoxication, 367 noninflammatory, 366–367 Diastole, 244 Diazepam, 24, 224, 427, 518 Diazoxide, 269 DIC (disseminated intravascular coagulation), 463 Diclofenac, 448 Dicyclomine, 190 Didanosine, 105 Diencephalon, 184, 214, 215 Diethylcarbamazine, 131 Diethylstilbestrol, 142, 412 Diffuse axonal injury, 221 Diffuse cortical necrosis, 329 Diffuse non-Hodgkin lymphoma, 473 Diffuse nontoxic goiter, 388 Diffuse scleroderma, 107 Diffusion, 148, 282, 283 Diffusion coefficient, 149 Diffusion transport, 80 DiGeorge syndrome, 77, 102, 103, 255, 385, 429 Digestion, 352–354, 353 Digestive tract, layers of, 335 Digitalis, 268, 271 Digoxin, 268, 271, 518 poisoning by, antidote for ,172 Digoxin antibodies, as antidote, 172 Dihydrobiopterin reductase, 48 Dihydrofolate reductase, 62, 121 Dihydropteroate synthase, 121 Dihydrotestosterone, 394, 398 Dihydroxyacetone-P, 38 Diiodotyrosine, 386 Dilated heart failure, 251 Dilated myopathy, 260 Dilator pupillae, 206 Diltiazem, 268, 269, 270, 271, 518 Diluting segment, in loop of Henle, 311 Dimercaprol, for heavy metal poisoning, 171, 172 Dimorphic fungi, 137 Dinitrate, 271 2,4-Dinitrophenol (2,4-DNP), 40 Dinoprostone, 411 Dipeptidyl peptidase (DDP-4) inhibitor, 382 Diphenhydramine, 173, 518 Diphenoxylate, 226, 368, 518 Diphtheria toxin, 115, 118 Diphtheroids, 114 Diphyllobothrium spp., 127 Diphyllobothrium latum, 56, 129 hematologic changes caused by, 476 Dipivefrin, 207 Dipyridamole, 464 Diseases and Findings, Appendix D, 499–511 Disopyramide, 267 Displacement, 16 Disseminated intravascular coagulation, 4653 Dissociation, 16 Distal convoluted tubule, 300 Distal nephron, 300 Distal tubule, 311 diuretic action on, 317 Disulfiram, 13 Disulfiram-like reaction, 140

E EA (efferent arteriole), 306, 308 Ear infections, 289–290 Early distal tubule, 306 Eating disorders, 24 Ebola virus, 134 Ebstein anomaly, 146 EBV. See Epstein-Barr virus ECF (extracellular fluid) volume, 149 Echinacea, 178 Echinocandin, 140 Echinococcus granulosus, 129 Echothiophate, 195, 207 Eclampsia, 409 ECT (electroconvulsive therapy), 22 Ectasia, mammary duct, 418 Ectoderm, 144 derivatives, 144 neural, 184 Ectopic pregnancy, 142, 409, 412 Ectopic thyroid nests, 388 Edema, 266 pulmonary, 297 Edema factor, 115 Edetate calcium disodium, for lead poisoning, 171, 172 Edinger-Westphal nuclei, 207

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INDEX

Edrophonium, 190, 450, 519 EDT (early distal tubule), 306 EDTA (edetate calcium disodium), for lead poisoning, 171, 172 EDV (end diastolic volume), 242 Edwards syndrome, 74 EE (enteroendocrine) cells, 336 EF (edema factor), 115 EF (ejection fraction), 242, 481 Efavirenz, 105, 519 Efficacy, drug, 179 EGF. See Epidermal growth factor EHEC (enterohemorrhagic E. coli), 115 Ehlers-Danlos syndrome, 68, 157 Eicosanoids, 54 metabolism of, 54 Eikenella corrodens, 455 Einthoven’s triangle, 241 Eisenmenger complex, 254 Eisenmenger syndrome, 254 Ejaculation disorders, 29 Ejaculatory duct, 394, 395, 396 Ejection fraction, 242 Elasticity, 278 Elastin, 82 Elbow joint, movement at, 435 Elder abuse, 9 Electrocardiogram, principles of, 238–240 Electrochemical gradients, 148 Electroconvulsive therapy, 23 Electrogenic pump, 152 Electrolytes abnormalities of, 303 diuretic-induced changes in, 326 Electron transport chain, 39, 40 Elimination, drug, 166 ELISA. See Enzyme-linked immunosorbent assay Elongation, in protein translation, 66 Embolic cerebral infarcts, 224 Embryoblast, 142 Embryology early, 142 week 2, 143 weeks 3 through 8, 144 Embryonal carcinoma, 402 Embryonal rhabdomyosarcoma, 412, 450 Embryonic disk, bilaminar, 143 Emetics, 346 Emphysema, 278, 281, 283, 293 Empty sella syndrome, 371 Enalapril, 175, 269, 271, 519 Encainide, 267 Encephalitis amebic, 123 bacterial, 195 fungal, 195 viral, 196 Encephalopathy, 217 Enchondromatosis, 442, 445 End diastolic volume, 242 End systolic volume, 242 Endocarditis, 259 acute, 259 Libman-Sacks, 106, 259 Endocrine pancreas, 379–381 disorders of, 381 Endoderm, 144, 334 derivatives, 144 development of, 300 neural, 184 Endometrial adenocarcinoma, 413 Endometriosis, 413 Endometritis, 413

Endometrium, 407 Endomysium, 425 Endosomes, 79 Endospores, 136 Endotoxin, 92, 114 Enflurane, 228 Enfuvirtide, 105 Enoxaparin, 464, 519 Entacapone, 194, 216, 519 Entamoeba spp., 122 Entamoeba histolytica, 123, 365 Enterobacteriaceae, 455 Enterobius spp., 127, 130 Enterochromaffin cells, 346, 347 Enterococcus faecalis, 114 Enteroendocrine cells, 336 Enteroglucagon, 347 Enterohemorrhagic E. coli, 115, 366 Enteroinvasive E. coli, 365 Enterokinase, 350 Enteropathogenic E. coli, 366 Enterotoxic E. coli, 115 Enterotoxigenic E. coli, 366 Enuresis, 11 Enzyme-linked immunosorbent assay, 71 in AIDS diagnosis, 104 Enzyme-linked receptors, 84 Enzymes, 56. See also individually named enzymes deficiency syndromes of, 376 kinetics of, 55 ligand-regulated transmembrane, 169 Eosin stain, 158 Eosinophilic leukocytosis, 470 Eosinophils, 89, 469 in chronic inflammation, 100 Eotaxin, in chronic inflammation, 100 Ependymal cells, 197, 198 Ependymoma, 199 Ephedra (Ma Huang), 178 Ephedrine, 194 Epiblast, 143 Epidemic typhus, 457 Epidermal growth factor, 157 receptors, 85 Epidermis, 451 Epidermophyton spp., 137, 456 Epididymis, 394, 395, 396 Epidural hematoma, 195, 224 Epidural space, 195 Epiglottitis, 290 Epilepsy, myoclonic, 72 Epileptic seizures, 224, 225 Epimysium, 425 Epinephrine, 43, 46, 192, 207, 294, 380 Epispadias, 397 Epithalamus, 184, 214 Epithelial cells, 274 Epithelial foot processes, loss of, 327 Epithelium of digestive tract, 335 hyperplasia of, 416 tumors of, 414 Eplerenone, 326 EPO. See Erythropoietin Eponyms, disease, 487–491 EPS (extrapyramidal side effects), of antipsychotics, 19, 20 Epstein-Barr virus, 161, 289 hematologic changes caused by, 476 in non-Hodgkin lymphoma, 473 Eptifibatide, 464 Equations, Appendix A, 479–484

Equilibrium, 148 Equilibrium potential, 151 Equine encephalitis, viruses causing, 133 Equivalence zone, in Ab-Ag complexes, 95 Erb-Duchenne palsy, 488 erb oncogenes, 160 Erectile dysfunction, 29, 397 treatment of, 397 Erection, penile. See Penile erection Erector spinae muscle, 434 Ergonovine, 174 Ergosterol, 112 Ergot alkaloids, 174 Ergotamine, 174 Ergotism, 174 ERT (estrogen replacement therapy), 410 Erysipelas, 453 Erythema marginatum, 257 Erythema multiforme, 452 Erythema nodosum, 138, 452 Erythrocytes, abnormalties on peripheral smear, 512 Erythrocytic schizont, 124 Erythromycin, 66,120, 496, 497, 498, 519 Erythroplakia, 355 Erythropoiesis, 465 Erythropoietin, 109, 465 for anemia, 468 Escherichia spp., 114 Escherichia coli in bacterial meningitis, 195 enterohemorrhagic, 366 enteroinvasive, 365 enterotoxic, 115 enterotoxigenic, 366 Escitalopram, 22, 519 E-selectin, 96 Esmolol, 193 as antidote, 172 Esomeprazole, 349, 519 Esophageal hernias, 356 Esophageal strictures, 355 Esophageal varices, 265, 338, 340, 355, 361 Esophagitis, 356 Esophagus, 334, 336 carcinoma of, 355 pathology of, 355–356 Essential amino acids, 48 Essential thrombocythemia, 461 Esterases, 350 Esters, 227 Estradiol, 403 in feedback examples, 148 Estrogen replacement therapy, 410 Estrogens, 405, 406, 408, 410, 519 ESV (end systolic volume), 242 Eszopiclone, 11 Etanercept, 448, 519 ETC (electron transport chain), 39, 40 Ethacrynic acid, 326 Ethanol, 13,14, 146, 166, 170 as antidote, 172 Ethanol poisoning, 170 Ethical issues, 31–33 Ethinyl estradiol, 410 Ethosuximide, 225, 519 Ethylene glycol poisoning, antidote for, 172 Etidocaine, 227 Etidronate, 385 Etomidate, 228 Etoposide, 177 Euchromatin, 60 Eukaryotes, 63, 65, 112

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F F cells, 347 F- cells, 117 F+ cells, 117 F (filtered load), 304 F-1, 6-BP, 38 F-2, 6-BP, 38 FAb, in globulin structure, 94 F(Ab)2, in globulin structure, 94 Fabry disease, 54 Face, development of, 429 Facial nerve (VII), 205, 210 skeletal muscle innervated by, 428 Facial nucleus and fibers, 212 Facilitated diffusion, 80, 148, 149 Facioscapulohumeral muscular dystrophy, 450 Factitious, 25

Factor II, 462 Factor IIa, 462 Factor III, 462 Factor V, 116 Factor V Leiden, 463 Factor VII, 462 Factor VIIa, 462 Factor VIII deficiency. See Hemophilia A Factor VIIIa, 462 Factor IX, 462 Factor IX deficiency, 463 Factor IXa, 462 Factor X, 116, 462 Factor XII. See Hageman factor Facultative intracellular parasites, 122 FAD, 41 FADH, 403 FADH2, 39 Fading, 5 Falx cerebri, 197 Famciclovir, 135, 419, 420, 454, 458, 520 Familial hypercholesterolemia, 72 Familial polyposis coli, 159 Famotidine, 173, 349, 520 Fanconi syndrome, 488 Fas ligand, 156 Fasciculation, 427 Fasciculi, 200, 425 Fasciola spp., 127 Fasciolopsis spp., 127 Fat necrosis, 155 Fatty acids free, 53 metabolism of, 50 oxidation of, 50 synthesis of, 39, 41, 50, 56 Fatty acyl CoA synthetase, 56 Fatty change, cell injury and, 155 Fatty liver, 361 Fatty streak, 264 Fava beans, 42 FDP (fibrin degradation products), 462, 463 Feedback, negative and positive, 148 Feedback control, in differential diagnosis of cortisol excess, 373 Feeding center, 342 Felbamate, 224, 225 Felodipine, 270, 520 Felty syndrome, 446, 470 Female inhibited orgasm in, 29 sexual arousal disorder in, 29 Female reproductive system, 403–411 anatomy of, 395–396 congenital anomaly of, 394 development of, 394 pathology of, 412–415 pharmacology of, 410–411 physiology of, 403–408 Femoral nerve, 438, 439, 440 Fenofibrate, 272, 520 Fenoldopam, 269 Fentanyl, 226, 228, 520 Ferrochelatase, 46 Fertilization, 142, 400, 407 Fetal alcohol syndrome, 13, 146, 254 Fetal circulation, 232 Fetishism, 28 FEV1 (forced expiratory volume in 1 s), 237, 281 Fexofenadine, 173, 520 FGF (fibroblast growth factor), 157 Fibrates, 53, 272 Fibrin, 462

Fibrin degradation products, 463 Fibrinogen, 462 Fibrinoid necrosis, 155 Fibrinolysis, 462 Fibrinous pericarditis, 261 Fibroadenoma, 416 Fibroblast growth factor, 157 Fibrocystic disease, 416 versus breast cancer, 418 Fibroma chondromyxoid, 445 ovarian, 415 Fibronectin, 82 Fibrosis, 278, 281, 283, 416 Fibrous dysplasia, 442 Fibula, 440 Fibular collateral ligament, 440 Fick’s law of diffusion, 149, 283, 483 Filgrastim. See Granulocyte colony-stimulating factor Filovirus, 134 Filtered load, 304, 483 Filtration, in urine formation, 304, 307 Filtration fraction, 307, 484 Filum terminale, 200 Fimbria, 407 Finasteride, 398, 520 Finger, movement of, 436 Finger flexors, 432 First degree atrioventricular conduction block, 240 First-order elimination, 166 First-pass effect, 167 Fish tapeworm, 129 Fistulas, 359 Fitz-Hugh-Curtis syndrome, 412 Flagellates, 122 Flagellum, 400 Flat worms, 127 Flavivirus, 133 Flecainide, 267 Flexor carpi radialis muscles, 436 Flexor carpi ulnaris muscles, 436 Flexor digiti minimi muscles, 436 Flexor digitorum longus muscles, 441 Flexor digitorum profundus muscles, 436 Flexor digitorum superficialis muscles, 436 Flexor hallucis longus muscles, 441 Flexor pollicis brevis muscles, 437 Flexor pollicis longus muscles, 437 Flocculonodular lobe, 210 Flora, normal, 114 Flow cytometry, 108 Fluconazole, 140, 520 Flucytosine, 140 Fludrocortisone, 377, 520 Fluid abnormalities, 303 Fluid balance, estimation of fluid volumes, 302 Fluid volume changes in, 150 compartments and, 149 distribution and, 149 estimation and, 302 extra- and intracellular, 149 measurement of, 149 normal values of, 302 Flukes. See Trematodes Flumazenil,14, 520 as antidote, 172, 228 5-Fluorodeoxyuridine, 61 Fluoroquinolones, 118, 121 5-Fluorouracil, 61, 176 Fluoxetine, 22, 174, 520 Fluphenazine, 19

INDEX

Eukaryotic chromatin structure, 60 Eukaryotic elongation factor-2 (eEF-2), 66, 115, 289 Ewing sarcoma, 445 Excitation-contraction coupling, 424 Excretion, renal regulation of, 312 Excretion of X (EX), 304, 483 Exemestane, 411 Exenatide, 382 Exercise, cardiovascular response, 242 Exfoliatins, 453 Exhibitionism, 28 Exocrine pancreas,359 Exophthalmos, 388 Exotoxins, 114, 115, 453 Experimenter expectancy bias, 35 Expiration, 280 Expiratory reserve volume, 277 Exposure, classic conditioning and, 5 Exstrophy bladder, 332 of bladder, 397 Extensor carpi radialis brevis, 436 Extensor carpi radialis longus, 436 Extensor carpi ulnaris, 436 Extensor digitorum brevis, 441 Extensor digitorum longus, 441 Extensor hallucis longus, 441 Extensor pollicis brevis, 437 Extensor pollicis longus, 437 External anal sphincter, 395 External auditory meatus, 429 External intercostal muscles, 278 External oblique fascia, 399 External spermatic fascia, 399 Extinction, 5 Extracellular fluid volume, 149 Extracellular pathogens, 88 Extraembryonic mesoderm, 143 Extrahepatic biliary atresia, 360 Extramammary Paget disease, of the vulva, 412 Extraocular muscles, 209 Extrapyramidal nervous system, 215 Extrapyramidal side effects, of antipsychotics, 19, 20 Extremity findings on physical examination, 493 Extrinsic asthma, 294 Extrinsic coagulation pathway, 462 Eye anatomy of, 206 pharmacology of, 207 Eye movement, control of, 209 Eyeworm, 127 Ezetimibe, 272, 520

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INDEX

Flurazepam, 25 Flutamide, 398, 520 Fluticasone, 520 Fluvastatin, 272, 520 Fluvoxamine, 22, 174, 521 FO (foramen ovale), 230 Focal proliferative glomerulonephritis, 328 Focal segmental glomerulosclerosis, 327, 328 Folate, for anemia, 468 Folic acid, 56 Folic acid analogs, 61 Folic acid synthesis inhibitors, 121 Folinic acid, 121 Follicles, 394 antrum of, 404 carcinoma of, 389 development of, 404 Graafian, 404, 405 hyperplasia of, 471 Follicle-stimulating hormone, 370, 401, 403, 410, 411 Follicular lymphoma, 473 Follicular phase, in menstrual cycle, 406 Folliculitis, hot tub, 453 Folliculogenesis, and ovulation, 404 Fomepizole, as antidote, 172 Fondaparinux, 464 Food poisoning, 367 Foot, sensory innervation of, 439 Foramen lacerum, 205 Foramen magnum, 205 Foramen ovale, 205, 230, 254 Foramen rotundum, 205 Foramen spinosum, 205 Foramen/Foramina incisive, 429 jugular, 197, 205 of Luschka, 196 of Magendie, 196 of Monro, 196 Forced expiratory volume in 1 s, 281 Forced vital capacity, 281, 483 Foregut, 334, 335 Formoterol, 294 Formyl methionyl peptides, 97 Fornix, 217, 218 Forward motility factor, 400 Fosfomycin, 521 Fosinipril, 269, 521 Fosphenytoin, 224 Fourth ventricle, 196, 204, 218 Fracture(s) midshaft humeral, 433 vessel and nerve damage associated with, 236 Fragile X syndrome, 72 Frameshift point mutations, 64 Francisella spp., 116 Francisella tularensis, 122 Free energy, 55 Free fatty acids, 53 Free radicals, protection against, 154 Free water clearance, 305, 483 Freudian defense mechanisms, 16 Frontal eye field, 209, 219 Frontal lobe, 218, 219 Frontal lobe syndrome, 219 Frontonasal prominence, 429 Frotteurism, 28 Fructokinase deficiency, 39 Fructose-1,6-bisphosphatase, 44 Fructose-1-P aldolase B deficiency, 39 Fructosuria, 38 FSH. See Follicle-stimulating hormone

FTA-ABS test, 421 5-FU (5-fluorouracil), 176 Fulminant hepatitis, 362 Functional residual capacity, 277 Fundus, 336, 343, 395 Fungal infections, 137–139 nonsystemic, 137 opportunistic, 139 systemic, 138 treatment of, 140 Fungal meningoencephalitis, 195 Fungemia, systemic agents for, 140 Fungi, types of, 137 Funiculi, 200 Furazolidone, 127 Furosemide, 270, 317, 326, 521 Furuncles, 453 Fusion inhibitor, 105, 476 Fusobacterium spp., 114, 291 FVC (forced vital capacity), 237, 281

G G cells, 346, 348 G protein, 169 G protein–coupled receptor systems, 85 G6PD. See Glucose-6-phosphate dehydrogenase GABA. See γ-aminobutyric acid Gabapentin, 225, 521 GAE (granulomatous amebic encephalitis), 123 Gal-1-P uridyltransferase deficiency, 39 Galactokinase deficiency, 39 Galactosemia, 38 α-Galactosidase A, 54 inhibitors, 382 Galantamine, 190, 220 Gall bladder, 334, 351 Gallstones, 364 Gametocytes, 124 Gametogony, 124 γ-aminobutyric acid, 46 Ganciclovir, 133, 476, 521 Ganglionic blockers, 189, 269 predominant tone and effects of, 191 Ganglion cells, 358 Gangrenous necrosis, 155 Gap junctions, 82 Gardnerella spp., 413 Garlic, 178 Gartner, duct of, 394 Gas exchange, 282–288 diffusion-limited, 283 perfusion-limited, 283 Gastric H+ secretion, 348 Gastric inhibitory peptide, 346, 347, 379 Gastric reflux, 343 Gastric secretions, 348 mechanism of, 348 phases of, 349 Gastric veins, 340 Gastrin, 346, 347, 348, 349 Gastrinoma. See Zollinger-Ellison syndrome Gastrin-releasing peptide, 347 Gastritis acute, 356 chronic, 356 Gastrocnemius muscle, 440, 441 Gastrocolic reflex, 345 Gastroduodenal artery, 338 Gastroepiploic artery, 338 Gastroesophageal reflux disease, 343, 349 Gastroileal reflex, 344 Gastrointestinal system

cestodes in, 129 embryology of, 334–335 gross anatomy of, 337–340 histology of, 335–336 hormones in, 346–347 microbiology of, 365–367 pathology of, 355–364 pharmacology of, 368 physiology of, 342–344 Gastrointestinal tract cross-sectional anatomy of, 341 development of, 334 Gastroparesis, diabetic, 344 Gastroschisis, 357 Gastrulation, 144 Gatifloxacin, 521 Gaucher disease, 54 GBM (glomerular basement membrane), 328 GC (glomerular capillaries), 306, 307 G-CSF (granulocyte colony-stimulating factor), 94, 109 Gel electrophoresis, 71 Gemfibrozil, 53, 272, 521 Gender identity, 28 Gene disorders, 73 Gene flow, and equilibrium, 77 General anesthesia, 228 Generalized anxiety disorder, 24 Generalized seizure, 224 Genetic associations, 495–496 Genetic code, 66 Genetic drift, 134 and equilibrium, 77 Genetic reassortment (shift), 134 Genetic testing, 71 Genetics, population, 77 Genital warts, 412, 420 Genitofemoral nerve, 399 Genitourinary system disease, 419–420 Genomic imprinting, 216 Gentamicin, 66, 291, 521 GERD (gastroesophageal reflux disease), 343, 349 Germ cell tumors, 402, 414 Germ tube test, 137, 419 German measles. See Rubella Gerstmann syndrome, 219, 223 Gestational trophoblastic disease, 143, 415 GFAP (glial fibrillary acidic protein), 199 GFR. See Glomerular filtration rate GH. See Growth hormone Ghrelin, 342 Ghon complex, 293 GHRH (growth hormone-releasing hormone), 371 Giant cell tumor, 445 Giardia spp., 122 Giardia lamblia, 123, 367 in AIDS patients, 104 Giardiasis, 122, 127 Gigantism, 371, 391 Gilbert syndrome, 46, 360 Gingko, 178 Ginseng, 178 GIP. See Gastric inhibitory peptide Glanzmann thrombasthenia, 460, 461 Glatiramer, 521 Glaucoma and diuretics, 326 treatment of, 207 Glenohumeral joint, movement at, 434 Glia, 198 Gliadin, 357 Glial fibrillary acidic protein, 199

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GM-CSF (granulocyte-macrophage colonystimulating factor), 94, 109 GnRH. See Gonadotropin-releasing hormone Goblet cells, 336, 344 Gold compounds, 448 Golgi apparatus, 78, 79 Gonadotropin-releasing hormone, 370, 401, 403, 406 analog of, 398 in feedback examples, 148 Gonococci, 446 Gonorrhea, 401 Goodpasture syndrome, 106, 328 Gout, 62, 446 treatment of, 449 Gouty nephropathy, 329 Gp. See Glycoprotein IIb/IIIa gp41, in acquired deficiency syndrome, 104 Graafian follicle, 404, 405 Gracile fasciculus, 202 Gracile nucleus, 202 Gracilis muscle, 439, 440 Grade, of tumor, 163 Graded dose-response curve, 168 Gradients concentration, 148 electrochemical, 148 Graft versus host rejection, 107 Grafts rejection types and, 107 types of, 107 Gram characteristics, of bacteria, 113 Gram reaction, 113 Gram stain, 158 Granisetron, 174, 346, 521 Granules in acute inflammation, 96 azurophilic, 469 enzymes in, 469 Granulocyte colony-stimulating factor, 94, 109, 471 Granulocyte-macrophage colony-stimulating factor, 94, 104 Granulocytes, 469 Granulomatous diseases, 293 Granulopoiesis, 469 Granulosa cell tumor,415 Granulosa cells, 404 Granulovacuolar degeneration, 220 Graves disease, 387, 388, 389 Gravity, 210 Gray baby syndrome, 120 Gray communicating rami, 200 Gray matter, 200 Great vessels, transposition of, 231, 255 Greater peritoneal sac, 337 Greater vestibular gland, 396 Grief, 21 Griseofulvin, 140 Group transferases, 120 Growth curve, bacterial, 112 Growth factors in cell regeneration, 157 receptors, 169 Growth hormone, 371, 380, 390–391 biologic actions of, 390 control of, 390 disorders of, 391 receptors, 169 treatment options and, 391 Growth hormone-releasing hormone, 370 GRP (gastrin-releasing peptide), 347 Guanethidine, 194, 269 Guanine, 60

Guanylate cyclase, 84, 85 Gubernaculum, 398 Guillain-Barré syndrome, 198 Gummas, 401, 536 Gut tube, 334 GVD (granulovacuolar degeneration), 220 Gynecomastia,402, 418 Gyri, 218

INDEX

Glial fibrillary acidic protein stain, 158 Glimepiride, 382, 521 Glioblastoma multiforme, 199 Glipizide, 382, 521 Globus pallidus, 215 Glomerular capillaries, 306, 307 Glomerular diseases, 327–328 Glomerular filtration rate, 307, 483 autoregulation of, 308 filtration regulation and, 308 Glomeruli, hyalinized, 328 Glomerulonephritis chronic, 328 focal proliferative, 328 Glomus tumor, 266 Glossopharyngeal nerve (IX), 205, 428 Glottis, 343 Glucagon, 43, 347, 379, 380, 382 as antidote, 172 Glucagon receptors, 85 Glucocorticoids, 377 Glucogenic conversion, 47, 48 Glucokinase, 38, 44 Gluconeogenesis, 39, 41, 44 Glucosamine, 178 Glucose counter-regulation of, 380 integrated control, 380 Glucose transport, 38 Glucose-6-phosphatase, 43 Glucose-6-phosphate, 42 Glucose-6-phosphate dehydrogenase, 42, 46 Glucose-6-phosphate dehydrogenase deficiency, 42, 72, 467 Glucuronosyl transferase, 360 GLUT-1, 38 GLUT-2, 38 GLUT-2 transporter, 352 GLUT-4, 38, 84 GLUT-5 transporter, 352 Glutamate, 45, 46, 47 Glutamate decarboxylase, 46 Glutamine, 45 Glutathione peroxidase, 42, 154 Glutathione reductase, 42 Gluteus maximus, 395, 439, 440 Gluteus medius, 439 Gluteus minimus, 439 Glyburide, 382, 521 Glycerin, 368 Glycerol kinase, 51 Glycerol-3, 40 Glycerol-3-P, 44 Glycerol-3-P dehydrogenase, 51 α-Glycerol-3-P shuttle, 40 Glycine, 45, 46 Glycocalyx, 113 Glycogen formation of, 43 metabolism of, 43 Glycogen debranching enzyme, 43 Glycogen phosphorylase, 43 Glycogen storage diseases, 43 Glycogen synthase, 43 Glycogenolysis, 43 Glycolysis, 38 irreversible, 38 Glycoprotein IIb/IIIa inhibitors, 464 receptor, 464 Glycopyrrolate, 190 Glycosylation, N-linked, 78, 80

H H band, 425 H+ secretion, gastric, 348 H1 antagonists, 173 H1 receptor, 173 H2 antagonists, 173, 349 H2 receptor,173 H2O2 (hydrogen peroxide), 154 H3 receptor, 173 Haemophilus ducreyi, 421 Haemophilus influenzae, 114, 289, 290 in bacterial meningitis, 195 Hageman factor (factor XII) in coagulation, 462 as inflammation mediator, 97 Hair, 451 Hairy cell leukemia, 158, 474, 475 Hairy leukoplakia, 105, 355 as AIDS complication, 105 Half-life, of drugs, 166, 480 Hallucinogens, 15 Haloperidol,19, 521 Halothane, 228, 522 Hamate, 433 Hand innervation of, 433 muscles in, 432 Hand of benediction sign, 432 Hantavirus, 132, 292 Hardy-Weinberg equilibrium, 77, 480 Hartnup disease, 48, 353 Hashimoto thyroiditis, 388 Haustra, 345 Hay fever, 106 HBs (Hirano bodies), 220 HbeAg, 364 HbH disease, 466 Hb-O2 dissociation curve, 284 HBsAg, 363 HBV. See Hepatitis B virus hCG. See Human chorionic gonadotropin HCI, 348 HDL (high density lipoprotein), 53 Head and neck, embryology and anatomy, 428–430 Heart. See also Cardiac entries; Cardiovascular system autonomic control of, 252 borders of, 234 conduction in, 236 congenital abnormalities of, 254–255 mechanical performance of, 242 muscle of, 424 neoplasms of, 261 parasympathetic regulation of, 252 sympathetic regulation of, 252 valves of, 246. See also individually named valves valvular disorders of, 247 Heart disease congenital. See Congenital heart disease ischemic, 256 valvular, 260

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INDEX

Heart failure cardiac output changes after, 243 dilated, 251 drugs used in, 271–272 progressive, 246 Heart rate, 242 estimation of, 239 Heart rhythms, 240 Heart sounds, 244 Heart tube, 230 Heavy chain domains, in globulin structure, 94 Heavy metal poisoning, 171 Heinz bodies, 38, 467, 498 Helicobacter pylori, 349, 356 Heliotrope rash, 450 HELLP syndrome, 409 Helper T cells, 91 Hemangioblastoma, 266 Hemangioma, 266 capillary, 451 Hematoma, 195 epidural and subdural, 224 lens-shaped biconvex, 195 Hematopoiesis, 460 Hematopoietic growth factors. See Granulocyte colony-stimulating factor; Granulocytemacrophage colony-stimulating factor Hematoxylin stain, 158 Heme synthesis, 39, 56 Hemiballism, 189, 214, 216 Hemidesmosomes, 82 Hemisphere lesions, 213 Hemochromatosis, 361 Hemodynamics, 248-249 in acute inflammation, 96 Hemoflagellates, 122, 126 Hemoglobin. See Hb entries Hemolytic anemia, 135, 461, 467 Hemolytic crisis, 46 Hemophilia A, 72 463 treatment of, 465 Hemophilia B, 72, 463 Hemorrhage cerebrovascular, 224 Duret, 221 splinter, 259 subarachnoid, 185, 265, 474 Hemorrhagic cystitis, 332 Hemorrhagic pancreatitis, acute, 359 Hemorrhagic pericarditis, 261 Hemostasis, 460 Henderson-Hasselbalch equation, 321, 484 Henle, loop of. See Descending thin loop of Henle; Loop of Henle Henoch-Schönlein purpura, 262, 489, 493 Hepadnavirus, 132, 363, 539 Heparin, 464, 522 Heparin-induced thrombocytopenia, 464 Heparin poisoning, antidote for, 172 Heparinase, 116 Hepatic ducts, 351 Hepatic excretion, 351 Hepatic glycogen phosphorylase, 43 Hepatic portal circulation, 340 Hepatitis acute, 362 alcoholic, 361 chronic, 362 fulminant, 362 halothane, 228, 522 Hepatitis A, 133, 363, 539 Hepatitis B, 95, 109,132, 136,161, 363, 539 infectious arthritis and, 447 serology, 364

Hepatitis C, 109, 133, 136, 161, 361, 362, 363 Hepatitis D, 363 Hepatitis E virus, 133, 363, 539 Hepatoblastoma, 362 Hepatocellular carcinoma, 161, 162, 362 Hepatolenticular degeneration. See Wilson disease Hepevirus, 133, 539 Hereditary angioedema, 99 Hereditary nonpolyposis colorectal cancer, 64 Hereditary spherocytosis, 467 Hernias, 357 diaphragmatic, 357 femoral, 357 inguinal, 357 indirect, 357 direct, 357 Heroin, 14, 226 Herpes simplex virus, 131, 419, 420, 454 in AIDS patients, 104 Herpes viruses, 161, 266, 452 Hers disease, 43 Hesselbach’s triangle, 357 Heterochromatin, 60 Hexamethonium, 189, 269 Hexokinase, 38 Hexosaminidase A, 54 Hexose monophosphate shunt, 42 Hfr cells, 117 HGPRT (hypoxanthine guanine phosphoryl pyrophosphate transferase), 62 HHV8 (human herpesvirus type 8), 266, 446, 452 High altitude disease, 287, 288 High density lipoprotein, 53 High molecular weight kininogen, 97 Hilum, 301 Hindgut, 334, 335 Hinge region, in globulin structure, 94 Hip joint, movements at, 439 Hippocampus, 217, 219 Hirano bodies, 220 Hirschsprung disease, 358 Hirsutism, 373, 398 Hirudin, 464 Histamine, 46, 173, 347, 348 as inflammation mediator, 97, 99 Histamine receptors, 173 Histidine, 45, 46 Histidine decarboxylase, 46, 173 Histology, 274 Histones, 60 Histoplasma spp., 138 Histoplasma capsulatum, 122, 138, 292 in AIDS patients, 104 Histrionic disorder, 26 HIV. See Human immunodeficiency virus H+/K+-ATPase, 348, 349 HLA (human leukocyte antigen), 91, 446 HLA disease associations, 91 HMG (human menopausal gonadotrophin)-CoA reductase, 52 HMG-CoA reductase inhibitors, 52, 272 HMP (hexose monophosphate), 42 HMWK (high molecular weight kininogen), 97 HNPCC (hereditary nonpolyposis colorectal cancer), 64 Hodgkin disease, 472 Holoprosencephaly, 185 Homatropine, 190 Homeostasis, 214 Homocysteine methyltransferase, 56 Homocystinuria, 47, 48 Homogentisate oxidase, 47

Homogentisic acid, 48 Homosexuality, 28 Homovanillic acid, 377 Hookworms, 131, 456 Hormonal regulation of calcium and phosphate, 383 of spermatogenesis, 401 of steroidogenesis, 401 Hormone replacement therapy, 410 Hormones, 46, 177 adrenal, 372 characteristics of, 370 gastrointestinal, 346–347 lipase sensitivity to, 50, 51 Horner syndrome, 186, 203, 208, 296, 489, 492 Horseshoe kidney, 301 Hot tub folliculitis, 453 HPV (human papilloma virus), 101, 132, 161, 358, 397, 412, 420, 456, 539 HRT (hormone replacement therapy), 410 hst-1-int-2 oncogene, 160 HSV. See Herpes simplex virus 5HT. See Serotonin HTLV-1 (human T-cell leukemia virus), 161 HU. See Hydroxyurea Human chorionic gonadotropin, 143, 162, 404, 408 Human immunodeficiency virus, 133. See also Acquired immunodeficiency syndrome detection of, 71 hematologic changes caused by, 476 nephropathy in, 327 therapies, 105 Human leukocyte antigens, 94, 449 Human papilloma virus. See HPV Human T-cell leukemia virus, 153 Humerus, midshaft fracture, 432 Humor, 16 Humoral immunity, defects, 102 Hunter syndrome, 54 Huntington disease, 72, 215, 216 Hurler syndrome, 54 Hürthle cells, 388 HVA (homovanillic acid), 377 Hyaline membrane formation, 295 Hyalinized glomeruli, 328 Hyaluronidase, 116, 400 Hybridization, 71 Hydatid cyst disease, 129 Hydatidiform mole, 144, 415 hCG levels and, 143 Hydralazine, 60, 269, 270, 272, 522 Hydraulic resistance equation, 248, 481 Hydrocele, 398, 399 Hydrocephalus, 185, 197 Hydrocephalus ex vacuo, 197 Hydrochlorothiazide, 270, 326, 522 Hydrocodone, 226, 522 Hydrogen peroxide, 154 Hydronephrosis, 330, 331 Hydrophobic amino acids, 45 Hydropic swelling, cell injury and, 155 Hydrops fetalis, 466 Hydroureter, 331 Hydroxychloroquine, 125, 448 Hydroxyl radical, 154 Hydroxylase deficiency, 375 Hydroxylation phase, 79 Hydroxylysine, 68 Hydroxymethylbilane synthase, 46 Hydroxyproline, 68 Hydroxyurea, 61 for anemia, 468 Hydroxyzine, 173

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Hypothalamus-anterior pituitary system, 370–371 Hypothyroidism, 388 hypothalamic, 387 pituitary, 387 primary, 387 treatment of, 389 Hypoventilation, 287 Hypovolemic shock, 266 Hypoxanthine guanine phosphoryl pyrophosphate transferase, 62 Hypoxia, 154 alveolar, 285 Hypoxyphilia, 28

I I band, 425 I cells, 346 131I (radioactive iodine), 389 Ia sensory neuron, 202 Ibuprofen, 448, 522 Ibutilide, 268 I-cell disease, 67 ICAM-1, 289 ICF (intracellular fluid) volume, 149 ICP (inferior cerebellar peduncle), 212, 213 IDDM (insulin-dependent diabetes mellitus), 381 Idiopathic hypertrophic subaortic stenosis, 260 Idiopathic rapidly progressive glomerulonephritis, 328 Idiopathic thrombocytopenic purpura, 461 Idiotypes, 90 IDL, 53 L-Iduronate-2-sulfatase, 54 α-L-Iduronidase, 54 IFN. See Interferon entries Ig. See Immunoglobulin(s) IGF (insulin-like growth factor) receptors, 85 Ileocecal valve, 345 Ileum, 336 Iliacus muscle, 439 Iliocostalis muscle, 434 Ilioinguinal nerve, 399 Illness, children’s conceptions of, 7 ILs. See Interleukins Imipenem, 117, 119, 522 Imipenem/meropenem, 118 Imipramine, 22 194, 522 Imiquimod, 420 Immature teratoma, 414 Immediate hypersensitivity reaction, 106, 294 Immune complex hypersensitivity reaction, 106 Immune responses, 102 Immune system cells of, 89–90 innate versus adaptive, 88 response by, 88 Immunity, humoral, defects of, 102 Immunization, forms of, 101 Immunodeficiency(ies) acquired. See Acquired immunodeficiency syndrome diseases, 102, 103 Immunoglobulin(s) basic structure of, 94 chronic inflammation and, 100 IgA, 95 IgA deficiency, 102 IgA nephropathy, 328 gA proteases, 116 IgD, 95 IgE, 95 IgG, 95

IgM, 95 thyroid-stimulating, 387 Immunology, techniques in diagnosis, 108 Immunostaining, 71 Immunosuppressants, 109 Imperforate anus, 358 Implantation, and pregnancy, 408 Impotence, 29 Imprinting, in single-gene disorders, 73 In situ hybridization, 71 Incidence, in biostatistics, 34 Incisive foramen, 429 Indinavir, 105, 522 Indirect-acting sympathomimetics, 194 Indomethacin, 448, 449, 522 Infant development, 6 Infarction, evolution of, 240 Infections bacterial. See individual pathogens by name of ear, 289–290 fungal. See Fungal infections hepatic, 362 opportunistic, in AIDS patients, 104 parasitic, 362. See also individual parasites by name respiratory tract, 284–292 viral. See individually viruses by name Infectious arthritis, 447 Infectious cystitis, 332 Infectious diseases hematologic changes associated with, 476 of skin, mucosa, and underlying tissues, 453–456 Inferior cerebellar peduncle, 212, 213 Inferior colliculus, 204, 211 Inferior epigastric artery, 357 Inferior frontal gyrus, 218 Inferior gemellus muscle, 439 Inferior gluteal nerve, 438, 440 Inferior mediastinum, 232 Inferior mesenteric artery, 334, 335, 339 Inferior mesenteric vein, 340 Inferior oblique muscle, 204, 209 Inferior pancreaticoduodenal artery, 338 Inferior parathyroid gland, 429 Inferior parietal lobule, 218, 219 Inferior petrosal sinus, 197 Inferior rectus muscle, 204, 209 Inferior sagittal sinus, 197 Inferior temporal gyrus, 218 Inferior vena cava, 340 Infiltrating ductal carcinoma, 418 Inflammation acute, 96–99 chemical mediators of, 97 chronic, 100 transmural, 359 Inflammatory diarrhea, 365 Infliximab, 110, 448 Influenza, 134 Influenza virus, 292 Infraspinatus muscle, 434 Infraspinatus tendon, 435 Infundibulum, 233, 407 Inguinal canal, 399 Inhalants, 15 Inheritance patterns, 72 Inhibin, 403 Inhibited male orgasm, 29 Inhibitors, classes of, 55 Initiation, in protein translation, 66 Injuries, knee, 440 Innate immunity, 88

INDEX

Hymenolepis spp., 127 Hyperacute rejection, 107 Hyperaldosteronism, 375 Hypercalcemia, 162, 326, 384n, 385 Hypercholesterolemia familial, 72 type II, 53 Hypergammaglobulinemia, polyclonal, 475 Hyperglycemic agents, 382 Hyperkinetic movement disorders, 215 Hyperlipidemias, 43, 264 Hyperosmolar nonketotic coma, 381 Hyperosmotic volume, contraction and expansion, 150 Hyperostosis frontalis interna, 445 Hyperparathyroidism, 384 primary, 385 secondary, 385 Hyperplasia, 156 atypical, 159 congenital adrenal, 375 follicular, 471 paracortical, 471 Hyperpolarization, 151 Hyperprolactinemia, 371 antipsychotics and, 19 Hypersegmental neutrophils, anemia and, 446 Hypersensitivity reactions, 106 type I (immediate), 106, 294 type II (cytotoxic/noncytotoxic), 106 type III (immune complex), 106 type IV (delayed), 106, 420 Hypertension, 265 cerebral infarcts caused by, 224 concomitant disease states, 270 drugs for, 269, 270 pregnancy-induced, 409 prehypertension, 265 stage 1, 265 stage 2, 265 portal, 340, 355, 361 pulmonary, 231, 254, 258, 297 Hyperthermia, malignant, 518 Hyperthyroidism, 388 primary, 387 treatment of, 389 Hypertriglyceridemia, type I, 53 Hypertrophic cardiomyopathy, 260 Hypertrophic gastropathy, 356 Hypertrophic osteoarthropathy, 442 Hypertrophy, 156 Hyperuricemia, 446 Hypervitaminosis, 154 Hyphae, 137 Hypnozoites, 124, 125 Hypoactive sexual disorder, 29 Hypoaldosteronism, 376 Hypoblast, 143 Hypocalcemia, 384, 385, 429, 488 Hypochondriasis, 25 Hypogammaglobulinemia, Bruton X-linked, 102 Hypoglossal canal, 205 Hypoglossal nerve (XII), 205, 428 Hypokinetic movement disorders, 215 Hypoparathyroidism, 384, 385 Hypophosphatemic rickets, 72 Hypophysis, 218 Hyposmotic volume, contraction and expansion, 150 Hypospadias, 394, 397 Hypotension, cerebral infarcts and, 224 Hypothalamic hypothyroidism, 387 Hypothalamus, 184, 214, 218, 370–371 nuclei of, 214 supraoptic and paraventricular nuclei of, 378

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INDEX

Inner ear, 211 Inner mitochondrial membrane, 40 Innervation foot and leg, 439 hand and palm, 433 pelvic, 396 skeletal muscle, 428 sympathetic, 236 INO (internuclear ophthalmoplegia), 198, 209 Inorganic lead, antidote for, 172 Inositol triphosphate, 189, 192 Insomnia, 11 Inspiration, 280 Inspiratory capacity, 277 Inspiratory reserve volume, 277 Instrumental conditioning, 4 Insulin, 38, 41, 43, 50, 51, 52, 53, 346, 347, 372, 379, 380 in diabetes treatment, 382 pathophysiology associated with, 381 Insulin receptors, 84, 85, 169 Insulin-dependent diabetes mellitus, 91, 381 Insulin/glucagon ratio, 380 Insulin-like growth factor receptors, 85 Integral proteins, 80 Integrase inhibitor, 105 Integrins, 96, 98 Intellectualization, 16 Intention tremor, 213 Interferon-α, 94, 109, 522 Interferon-β, 94, 109, 522 Interferon-γ, 94, 109, 522 cell-mediated immunity and, 93 T-helper cells and, 92 Interleukins IL-1, 92, 94, 113, 114, 115, 157 IL-2, 92, 94, 109 IL-3, 94 IL-4, 92, 94 IL-5, 92, 94 IL-6, 92, 94, 114 IL-7, 94 IL-8, 94 IL-10, 92, 94 IL-11, 94, 109, 465 IL-12, 92 IL-17, 92, 94 Intermaxillary segment, 429 Intermediate filaments, 81 Intermediate gray horn, 200 Intermediate zone, 200 Intermittent porphyria, acute, 46 Internal arcuate fibers, 202 Internal auditory meatus, 205 Internal capsule, 201, 215 Internal carotid artery, 222, 430 Internal intercostal muscles, 278 Internal jugular veins, 197 Internal oblique muscle, 399 Internal spermatic fascia, 399 International normalized ratio (INR), 464 Internuclear ophthalmoplegia, 198, 209 Interossei muscles, 436 Interstitial (atypical) pneumonia, 291 Interstitial fluid, 149 Interval scale, 36 Interventricular foramen of Monro, 196, 218 Intestinal schistosomiasis, 128 Intoxication. See also Poisoning diarrhea by, 367 Intracellular fluid volume, 149 Intracellular pathogens, 88 Intracellular receptors, 169

Intracerebral hemorrhage, 224 Intraductal papilloma, 416 Intrahepatic biliary atresia, 360 Intrauterine devices, 410 Intrinsic asthma, 294 Intrinsic coagulation pathway, 462 Intrinsic factor, 348 Intrinsic sympathomimetic activity (ISA), 193, 271 Introjection, 16 Intussusception, 357 Inulin clearance, 305 Inversions, chromosomal, 75 Investigational new drug application (IND), 179 Involucrum, 443 IO (inferior oblique) muscle, 204, 209 IOC (intraocular pressure), 206 Iodides, 389 Iodination, 386 Iodoquinol, 123 Ionizing radiation, as cancer risk, 159 IP (inferior parathyroid gland), 429 IP3. See Inositol triphosphate Ipecac, 179, 346 Ipratropium, 190, 294, 522 Ipsilateral gaze, 209 IR (inferior rectus) muscle, 204, 209 IR (inferior rectus) nerve, 209 Irbesartan, 522 Iris, 206 Iron, for anemia, 468 Iron deficiency, Iron poisoning, 171 antidote for, 172 Ischemia, 154 myocardial, 155, 256 renal, 330 Ischemic acute tubular necrosis, 329 Ischemic bowel disease, 357 Ischemic heart disease, 256 Ischioanal fossa, 395 Ischiocavernosus muscle, 395, 396 Isethionate, 123 Islets of Langerhans, hormones of, 379 Isocarboxazid, 22 Isocitrate dehydrogenase, 39 Isoflurane, 228 Isograft, 107 Isolation of affect, 16 Isoleucine, 45 Isomaltase, 352 Isoniazid, 56, 523, 538 Isoproterenol, 193, 296, 523 Isosmotic volume, contraction and expansion of, 150 Isosorbide, 254, 523 Isosorbide dinitrate, 83, 255, 523 Isospora spp., 122 Isotretinoin, 523 Isovolumic contraction and relaxation, 242, 244, 245 ITP (idiopathic thrombocytopenic purpura), 461 Itraconazole, 139, 140, 523 IUD (intrauterine devices), 393 Ivermectin, 523 Ixodes tick, 127

J Janeway lesions, 259 Janus kinases, 169 Jaundice, 46 JC virus, 198 in AIDS patients, 104

Jejunum, 336, 344 JGA (juxtaglomerular apparatus), 306, 307 Joint space tumors, 449 Joints. See also individually named joints pathology of, 446 Jones criteria, 257 Jugular foramen, 197, 205 Juvenile rheumatoid arthritis, 446 Juxtaglomerular apparatus, 306, 307

K K+, 268 K+ channel blockers, 268 K+ excretion, 319 increased, 318 metabolic acidosis and, 319 metabolic alkalosis and, 319 K+ secretion volume contraction and, 318 volume expansion and, 318 K+ sparing diuretics electrolyte changes caused by, 326 mechanism of, 325 K cells, 346 Kala-azar, 126 Kallikrein, as inflammation mediator, 173 Kaposi sarcoma, 161, 251, 432 as AIDS complication, 105 κ receptors, 226 Kartagener syndrome,72, 81, 294, 400 Karyolysis, 155 Karyorrhexis, 155 Kawasaki disease, 262 Kayser-Fleischer rings, 216, 361 K3 (drug concentration), 168 Keloids, in wound healing, 157 Keratin, 81 Keratinocytes, 451 Keratitis, 123 Keratoconjunctivitis sicca, 106 Ketamine, 15, 228 Ketoacidosis. See Diabetic ketoacidosis Ketoconazole, 140, 292, 377, 398, 454, 523 Ketogenesis, 380 Ketogenic conversion, 47 α-Ketoglutarate, 39, 48 α-Ketoglutarate dehydrogenase, 39, 56 Ketolides, 120 Ketone body metabolism, 52 Ketoprofen, 448 Kf (ultrafiltration coefficient), 250 Kidney. See also Renal entries; Renal system cystic disease of, 327 development of, 300 function of, 302 gross anatomy of, 301 horseshoe, 301 pelvic, 301 relationship to abdominal wall, 301 tubular diseases and, 329 tubulointerstitial diseases of, 329 vascular diseases of, 330 Kimmelstiel-Wilson disease, 328 Kinases, cyclin-dependent, 83 Kinesins, 81 Kininogen, high molecular weight, 97 Ki-ras oncogene, 160 Kissing bug, 126 Klebsiella pneumoniae, 291 Klinefelter syndrome, 74, 418 Klumpke’s paralysis, 432 Klüver-Bucy syndrome, 217, 219

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L L cells, 347 LAAM, 14 Labetalol, 193 Labia majora, 394 Labia minora, 394 Labile cells, 157 Labile toxin, 115 Labioscrotal swelling, 394 Laboratory values, Appendix B, 485–486 Labyrinthine artery, 223 Lactase, 352 Lactase deficiency, 352 Lactate, in anaerobic conditions, 38, 44 Lactate dehydrogenase, 41 Lactation, 408 Lactic acid, 41 Lactic acidosis, 41 Lactobacillus, 114 Lactoferrin, in phagocytosis, 98 Lactulose, 368 LAD (left anterior descending artery), 233 Lag phase, bacterial, 112 Lambert-Eaton myasthenic syndrome, 162, 450 Lamina, basal and reticular, 82 Lamina propia, digestive tract, 335 Laminin, 82 Lamivudine, 105, 523 Lamotrigine, 224, 225, 523 Langerhans cells, 451 Lansoprazole, 349, 523 Laplace’s law, 251, 279, 482, 483 Large cell carcinoma, 296 Large intestine, 336. 342, 345, 358 Laryngopharynx, 275 Laryngotracheitis, 290 Laryngotracheobronchitis, 290 Larynx, 275 intrinsic muscles of, 275 Lassa fever, 134 Latanoprost, 195, 523 Late distal tubule, 306 Look bias, 35 Lateral condyle, 440 Lateral corticospinal tract, 201 Lateral cricoarytenoid muscle, 275 Lateral geniculate body, 206, 214 Lateral gray horn, 200 Lateral hypothalamic area, 342 Lateral hypothalamic nucleus, 214 Lateral lemniscus, 211 Lateral medullary syndrome, 212 Lateral meniscus, 440 Lateral nasal prominence, 429 Lateral pectoral nerve, 434 Lateral plantar nerve, 439, 441 Lateral pontine syndrome, 212 Lateral rectus, 209 Lateral spinothala,ic tract, 203 Lateral sulcus, 218

Lateral ventricle, 184, 215 body of, 196 Latissimus dorsi muscle, 432, 434 Laxatives, 368 LCAT (lecithin cholesterol acyltransferase), 53 LDH cardiac enzyme, 257 LDL (low density lipoprotein), 53 l-dopa, 216 LDT (late distal tubule), 306 Lead poisoning, 46, 171 antidotes for, 172 Lead time bias, 35 Learning, 4–5 Learning-based therapies, 5 Leber hereditary optic neuropathy, 72 Lecithin cholesterol acyltransferase, 53 Lecithinase, 115, 116, 455 Leflunomide, 448, 523 Left anterior descending artery, 233 Left atrium, 233 pressure in, 244 Left axis deviation, 241 Left coronary artery, 233 Left gastric artery, 338 Left testicular vein, 399 Left ventricle, 234 pressure in, 242, 244 Leg, sensory innervation of, 439 Legal issues, 31–33 Legionella spp., 116, 292 Legionella pneumophila, 122 Leiomyoma, 413 Leiomyosarcoma, 413 Leishmania spp., 122, 126, 456 Leishmania braziliensis, 126 Leishmania donovani, 126 Leishmaniasis, 126, 127 Lenticulostriate artery, 223 Lentiform nucleus, 215 Lentigo maligna melanoma, 452 Lepirudin, 464 Leprosy, 455 Leptin, 342 LES (lower esophageal sphincter), 343 Lesch-Nyhan syndrome, 62, 72, 446 Lesser peritoneal sac, 337 Lethal factor, 115 Leucine, 45 Leukemia(s), 160, 474 adult T-cell, 161, 474 classification of, 475 clues for, 475 hairy cell, 158, 474, 475 Leukocyte adhesion deficiency, 98 Leukocyte disorders, 472–475 neoplastic, 473 Leukocytoclastic angiitis, 262 Leukocytosis eosinophilic, 472 polymorphonuclear, 472 Leukodystrophies, 198 Leukoplakia, 355 Leukotrienes, 54, 97 antagonists, 294 Leuprolide, 398, 523 Levator ani muscle, 395, 396 Levator scapulae muscle, 434 Levetiracetam, 224, 225 Levodopa, 519, 523 Levofloxacin, 121, 523 Levorphanol, 226 Levothyroxine, 524

Lewy bodies, 216 Leydig cell, 401 LF (lethal factor), 115 LFT (liver function test), 448 LGB (lateral geniculate body), 206, 214 LH. See Luteinizing hormone Libman-Sacks endocarditis, 106, 259 Lichen planus, 355, 452 Lidocaine, 227, 267 Ligament(s) anococcygeal, 395 anterior cruciate, 440 Cooper, 417 fibular collateral, 440 median umbilical, 300 popliteus, 440 posterior cruciate, 440 suspensory, 395 tibial collateral, 440 transverse, 440 of Treitz, 338 Ligand-gated channels, 169 Ligand-regulated transmembrane enzymes, 169 Light chain domains, in globulin structure, 94 Limb leads, 239 Limb-girdle muscular dystrophy, 450 Limbic system, 217 Limited scleroderma, 107 Linear acceleration, 210 Lineweaver-Burk equation, 55 Lineweaver-Burk plot, 55 Linezolid, 66, 120 Lingual gyrus, 206, 218 Linitis plastica, 356 Linkage disequilibrium, 77 Lipase, 360 hormone-sensitive, 51 Lipids, 5. absorption of, 353 amphipathic, 80 derivatives of, 54 synthesis and metabolism of, 50–51 type A, 113 Lipid-soluble AChE inhibitors, 190 Lipid-soluble vitamins, 57 Lipoic acid, 41 Lipoid nephrosis, 327 Lipoma, 445 Lipopolysaccharide, 113, 114 Lipoprotein, 50 transport and metabolism, 53 Lipoprotein lipase, 50, 51, 53, 272, 379 Liposarcoma, 445 Lipoteichoic acid, 116 Lipoxygenase, 54 as inflammation mediator, 98 Lipoxygenase inhibitors, 294 Liquefactive necrosis, 155 Lisinopril, 269, 271, 524 Listeria monocytogenes, 122, 409 in bacterial meningitis, 195 Lithium, in bipolar disorder, 22, 326, 524 Liver. See also Hepatic and Hepato- entries failure of, 360 infections of, 362 nutmeg type, 258 pyogenic abscess of, 362 tumors of, 362 Liver cell adenoma, 362 Liver diseases acquired, 361 alcoholic, 361

INDEX

Knee injuries, 440 Knee joint, movements at, 440 Koilocytic cells, 412 Koilocytosis, 412 Koilocytotic atypia, 412 Koplik spots, 291 Korsakoff syndrome, 217 K-ras, 296 Krabbe disease, 54 Kübler-Ross stages of adjustment, 22 Kupffer cells, in chronic inflammation, 100

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INDEX

Liver fluke, Chinese, 128 Liver function test, 448 LMWH (low molecular weight heparin), 464 Loa loa, 130, 131 Loading dose, 167, 481 Lobar pneumonia, 291 Lobes, of brain atrophy of, 221 key features of, 219 Lobular carcinoma, of the breast, 418 Log phase, bacterial, 112 Lomustine, 176 Long thoracic nerve, 434 Longissimus muscle, 434 Loop diuretics, 270, 272, 317, 325, 326 electrolyte changes caused by, 326 Loop of Henle, 300, 310 ascending. See Ascending thin loop of Henle; Thick ascending loop of Henle and countercurrent mechanism, 314, 315 descending. See Descending thin loop of Henle Loperamide, 226, 368 Lopinavir, 105 Loratadine, 173, 524 Lorazepam, 14, 24, 25, 224, 524 Losartan, 175, 269, 272, 524 Lovastatin, 52, 272, 524 Low density lipoprotein, 53 Low molecular weight heparin, 464 Lower esophageal sphincter, 343 Lower extremities, musculoskeletal anatomy of, 439, 441 Lower medulla, 204 Lower motor neuron, 203 facial nerve lesions and, 210 Lower scapular nerve, 434 LPS (lipopolysaccharide), 113, 114 LSD (lysergic acid diethylamide), 15, 174 LT (labile toxin), 115 Lubricant, stool, 368 Lumbar enlargement, 200 Lumbar nodes, 402 Lumbar puncture, 195 Lumbar splanchnic nerves, 396 Lumbar ventral rami, 439 Lumbosacral plexus, lesions in, 438 Lumbricals, 436, 441 Lumpy jaw, 454 Lung capacity of, 277 changes in compliance, 278, 482 diseases of, 280, 298–295 elastic properties of, 278–279 small cell carcinoma of, 162 structure of, 276 tumors of, 296 vascular disorders of, 297 Lung disease, 281, 293–294, 295 Intrinsic, 295 Lung fluke, 128 Luteal phase, 403 in menstrual cycle, 406 Luteinizing hormone, 370, 401, 403, 406, 411 in feedback examples, 148 Lyme disease, 457 Lymph node disorders, nonneoplastic, 473 Lymphadenitis, nonspecific, 473 Lymphadenopathy, types, 473 Lymphatic vessels, 399 Lymphocyte depletion, in Hodgkin disease, 473 Lymphocyte predominance, in Hodgkin disease, 473 Lymphocytes, 88, 90, 470. See also B cells; Natural killer cells; T cells

B- and T-cell antigen receptors, characteristics of, 90 in chronic inflammation, 100 receptor diversity of, 90 Lymphocytic choriomeningitis, 134 Lymphocytic leukemia, acute, 160, 474 Lymphocytic leukemias, 474 acute, 160, 474 chronic, 474 Lymphocytosis, 473 Lymphogranuloma venereum, 421 Lymphoid cells, characteristics of, 90 Lymphoma, 357, 402 adult T-cell, 161, 474 B-cell, 161 Burkitt, 161, 473 cutaneous T-cell, 474 Lymphoplasmacytic, 475 non-Hodgkin. See Non-Hodgkin lymphoma Lymphotoxin, in chronic inflammation, 100 Lynch syndrome, 64, 413, 414 Lyon hypothesis, 74 Lysergic acid diethylamide, 15, 174 Lysine, 45, 68 Lysogeny, 117 Lysosomal storage diseases, 54 Lysosomal-α-1,4-glucosidase, 43 Lysosomes, 78, 79 Lysozyme, 469 in phagocytosis, 98 Lysyl hydroxylases, 56

M M cells, 336 M phase, in cell cycle, 83 M protein, 116 M receptors, in cell signaling, 83 MABs (monoclonal antibodies), 110 MAC (minimum alveolar anesthetic concentration), 228 mAChR (muscarinic cholinergic receptor), 207 Macroglobulinemia, 475 Macrolides, 66, 118, 120 Macrophages, 89, 472 alveolar, 274 in chronic inflammation, 100 mADhR. See Muscarinic cholinergic receptor Maffucci syndrome, 442 Magnesium hydroxide, 349 Magnesium-ammonium phosphate stones, 330 MAI. See Mycobacterium avium-intracellulare Maintenance dose, 167, 480 Major histocompatibility complex, 88 class I deficiency, 102 class II deficiency, 103 classes of, 91 Malaria, 125 Malassezia furfur, 137 Malate, 39, 40 Malate shuttle, 39, 40 Malathion, 191 Male erectile dysfunction in, 29, 397 inhibited orgasm in, 29 Male pattern baldness, 398 Male reproductive system, 396–403 anatomy of, 395–396 development of, 394 diseases of, 397–398, 402 physiology of, 396, 398–401 Malignant fibrous histiocytoma, 449 Malignant melanoma, 452

Malignant otitis externa, 290, 381 Malignant pustule, 454 Malignant tumors, 355, 358 renal, 331 Malingering, 25 Mallory bodies, 361 Mallory-Weiss tears, 356 Malonyl-CoA, 50 Maltase, 352 Maltase α-dextrinase, 352 MALToma, 357 Mamillary body, 204, 200, 203, 204 Mammary duct ectasia, 418 Mandibular nerve, 204 Manifesting heterozygote, 72 Mannitol, 207, 317, 326, 524 Mansonella spp., 130 Mantle cell lymphoma, 473 MAO (monoamine oxidase), 174, 192 MAOIs (monoamine oxidase inhibitors), 22, 174, 216 MAP (mean arterial pressure), 308 Maple syrup urine disease, 47, 48 Maprotiline, 22 Marcus Gunn pupil, 208 Marfan syndrome, 72, 73, 255, 260 Marijuana, 15 Masochism, 28 Mass balance, in renal evaluation, 304 Mass movement contractions, 345 Mast cell granule release, 95 Mast cells, 89, 469 in chronic inflammation, 100 histamine and, 173 Mastitis acute, 416, 418 plasma cell, 418 Matched pairs t-test, 36 Maternal rubella, 232, 254 Maxillary nerve (V2), 204, 420 Maxillary prominence, 429 MCAD (medium chain acyl-dehydrogenase deficiency), 50 McArdle disease, 43, 490 McCune-Albright syndrome, 442 MCP (middle cerebellar peduncle), 212, 213 MDMA (“ecstasy”), 15 MEA (mean electrical axis), 239 Mean arterial pressure, 308 Mean arterial pressure equation, 248, 481 Mean electrical axis, 239, 241 Measles. See Rubeola German. See Rubella Measurement bias, 35 Mebendazole, 131, 476, 524 Mecamylamine, 189, 269 Meclizine, 524 Meconium, 358 Meconium ileus, 359 Medial geniculate body, 211 Medial lemniscus, 202, 203 Medial longitudinal fasciculus, 209 Medial medullary syndrome, 212 Medial midbrain syndrome, 213 Medial nasal prominence, 429 Medial pectoral nerve, 434 Medial plantar nerve, 439, 441 Medial pontine syndrome, 212 Medial rectus muscle, 204, 209 Median nerve, 236, 431, 432, 433, 435, 436, 437 Median umbilical ligament, 300 Mediastinum, 233 Mediodorsal nucleus, 214

558

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Mesolimbic/mesocortical pathways, and antipsychotics, 18 Mesonephric ducts, 300, 394 Mesonephros, 300 Mesothelioma, 297 Messenger RNA, 65, 112 Mestranol, 410 Metabolic acidosis, 319, 323 chronic, 318 diagnosis of, 323 Metabolic alkalosis,318. 319, 323 diagnosis of, 323 Metabolic vasodilation, 252 Metachromatic leukodystrophy, 54, 198 Metanephric mass, 300 Metanephrine, 192 Metaphase, in mitosis, 83 Metaplasia, 156 Metaproterenol, 193, 294, 524 Metastasis, 159 osteoblastic, 398 in TNM staging, 159 Metastatic tumors, CNS and PNS, 199 Metaxolone, 427 Metazoans, 127 Metencephalon, 184 Metformin, 382, 525 Methacholine, 189 Methadone, 14, 226, 525 Methanol poisoning, antidote for, 172 Methemoglobin, 40 Methicillin, 118 Methimazole, 389 Methionine, 45, 46, 66 Methionine synthase, 48 Methohexital, 228 Methotrexate, 61, 176, 448, 525 Methoxamine, 193 Methoxyflurane, 228 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 216 Methylcellulose, 368 N-methyl-D-aspartate antagonist. See NMDA Methyldopa, 269, 270 Methyl-malonyl CoA mutase, 56 Methyl-malonyl CoA mutase deficiency, 47, 48 Methylphenidate, 18, 525 α-Methyltyrosine, 194 Methylxanthines, 294 Methysergide, 174 Metoclopramide, 344, 346, 368, 525 Metolazone, 270, 326 Metoprolol, 193, 267, 269, 271, 272, 525 Metronidazole, 121, 123, 127, 131, 349, 365, 367, 419, 420, 525 Metyrapone, 377 Metyrosine, 194 Mexiletine, 267 Meyer loop, 206, 219 Mezlocillin, 118 Mg2+, 268 MGB (medial geniculate body), 211 Mg[OH]2, 368 MGUS (monoclonal gammopathy of undetermined significance), 475 MHC. See Major histocompatibility complex Micelles, 351, 353 Michaelis-Menten equation, 55 Michaelis-Menten plot, 55 Miconazole, 123, 140, 289, 290, 420, 456, 525 Microbial diarrhea inflammatory, 365 noninflammatory, 366–367 Microcytic sideroblastic anemia, 46

Microfilaments, 81 Microglia, 196, 198 in chronic inflammation, 100 Microphallus, 394 Microscopic findings, 471 Microscopic polyangiitis, 262 Microsporum spp., 137, 456 Microtubules, 81 assembly of, 449 Midazolam, 24 228 Midbrain, 184, 204, 213, 215 Middle cerebellar peduncle, 212, 213 Middle cerebral artery, 222 ,223, 224 Middle ear cavity, 429 Middle frontal gyrus, 218 Middle mediastinum, 232 Middle meningeal artery, 195, 224 Middle respiratory tract infections, 290 Middle temporal gyrus, 218 Midgut, 334, 335 Midline/intralaminar nucleus, 214 Midshaft fracture of humerus, 433 Midsystolic click, 260 MIF (Müllerian-inhibiting factor), 394 Mifepristone, 410, 411, 525 Miglitol, 382 Migrating motor complexes, 343 Migratory polyarthritis, 257 Mikulicz syndrome, 106 Milk thistle, 178 Mineral disorders, drug-induced, 385 Mineral oil, 368 Mineralocorticoids, 377 Minimum alveolar anesthetic concentration (MAC), 228 Minocycline, 66, 120 Minoxidil, 269 Miosis, 14, 227 Mirtazapine, 22, 193, 525 Misoprostol, 349, 525 Missense point mutations, 64 MIT (monoiodotyrosine), 386 Mitochondria, 50, 78, 79 Mitochondrial encephalomyelopathy, lactic acidosis, and stroke-like episodes, 72 Mitochondrial enzymes, 44 Mitochondrial inheritance pattern, 72 Mitochondrial membrane, inner, 40 Mitochondrial pathway, 39 Mitosis in cell cycle, 83 phases of, 83 Mitral valve, 233, 246 prolapse of, 260 regurgitation of, 247 stenosis of, 247, 260 Mivacurium, 427 Mixed agonist-antagonist agents, 226 Mixed cellularity, in Hodgkin disease, 472 Mixed stones, 364 MLCK (myosin light chain kinase), 426 MLF (medial longitudinal fasciculus), 209 MMC (migrating motor complexes), 343 Mobitz I atrioventricular block, 240 Mobitz II atrioventricular block, 240 Moderate agonists, 226 Molar pregnancy, 415 Molecular chaperones, 67 Molluscum contagiosum, 456 Mönckeberg medial calcific sclerosis, 264 Monoamine oxidase, 174, 192 Monoamine oxidase inhibitors, 22, 174, 194, 216 Monobactams, 119

INDEX

Medium chain acyl-dehydrogenase deficiency, 50 Medroxyprogesterone, 411, 524 Medulla, 184, 212, 301 Medulla oblongata, 218 Medullary carcinoma, 437 of the breast, 437 of the thyroid, 158, 162, 381, 389 Medullary collecting duct, 306, 311, 312 Medullary sponge kidney, 327 Medulloblastoma, 199 Mefloquine, 125 Megaloblastic B12/folate anemia, 466 Meglitinides, 382 Meigs syndrome, 415 Meiosis, 400 nondisjunction during, 74 Meissner plexus, 335 Melanin, 46 Melanocytes, 451 Melanoma, 166 Melarsoprol, 126 MELAS, 72 Melasma, 452 Melatonin, 21, 46, 178 Memantine, 220, 524 Membrane, cellular, 112 Membrane potentials, 151 Membranoproliferative glomerulonephritis, 327 Membranous glomerulonephritis, 327 Membranous urethra, 300 Memory, 214 Memory B-cell antigen receptor, 95 MEN. See Multiple endocrine neoplasia Menetrier disease, 356 Ménière disease, 210 Meninges, 185, 195–197 Meningioma, 199 Meningitis, 195–196 acute aseptic, 195 acute purulent, 195 bacterial, 195 viral, 195 Meningococcemia, early, 457 Meningoencephalitis, fungal, 195 Meningomyelocele, 185 Menkes disease, 68 Menses, 406 Menstrual cycle, 406 follicular phase in, 406 luteal phase in, 406 menses in, 406 ovulatory phase in, 406 Mental retardation, 17 Meperidine, 226, 524 Mepivacaine, 227 6-Mercaptopurine, 61, 176 Mercury poisoning, 171 antidotes for, 172 Merkel diverticulum, 357 Meropenem, 117 Mesalamine, 524 Mesangial cells, in chronic inflammation, 100 Mescaline, 15 Mesencephalic nucleus (proprioception), 210 Mesencephalon,184 Mesenteric arteries, 339 Mesoderm, 334 derivatives, 144 development of, 300 extraembryonic, 143 in gastrulation, 144 neural, 184

559

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INDEX

Monocistronic RNA, 112 Monoclonal antibodies, 109 Monoclonal gammopathy of undetermined significance, 475 Monocytes, 89, 476 in chronic inflammation, 100 Monocytosis, 470 Monodeiodinase, 387 Monoiodotyrosine, 386 Monometasone, 525 Mononuclear phagocyte system, 198 Mononucleosis, 470 Monosodium urate, 446 Monospot test, 289 Montelukast, 294, 525 Mood disorders, 20–22 Moraxella catarrhalis, 289 Morphine, 14, 226, 228, 526 Mortality rates, 34 Mosaicism, 74 Mossy fibers, 213 Motilin, 396 Motor neuron lesions, upper versus lower, 201 Movement disorders, 215 moxifloxacin, 121 6-MP (6-mercaptopurine), 62 M-phase/maturation promoting factor, 83 M-protein spike, 475 MPSI. See Hurler syndrome MPSII. See Hunter syndrome MPTP (1-methyl-4-phenyl-1,2,3,6tetrahydropyridine), 216 MR (medial rectus) muscle, 204, 209 mRNA, 65, 112 MRSA (methicillin-resistant S. aureus), 453 MS (multiple sclerosis), 198 MSSA (methicillin-sensitive S. aureus), 453 Mucocutaneous leishmaniasis, 126 Mucor spp., 139, 195 Mucormycosis, 139 sinus, 381 Mucosa, digestive tract, 335 Mucosal protective agents, 349 Mucous cells, 336, 348 Mucous membrane, infectious diseases of, 453–454 Mucus, 344, 348 Müllerian-inhibiting factor, 394 Multidrug exporters, 120 Multifidus muscle, 434 Multiple endocrine neoplasia, 160 type I, 381 type IIa, 381 type IIb/III, 381 Multiple myeloma, 329, 475 classic clues for, 475 Multiple sclerosis, 198 μ receptors, 226 Mumps, 134, 401 Mupirocin, 526 Murmurs, 234 Muromonab, 110 Muscarinic acetylcholine receptors, 85 Muscarinic antagonists, 190, 294 Muscarinic blocker poisoning, 170 Muscarinic cholinergic receptor, 207 Muscle glycogen phosphorylase, 43 Muscle relaxants, 427 Muscle spindle receptor, 202 Muscle stretch reflexes, 202 Muscles of breathing, 278 characteristics of, 424–426

disorders of, 450 fiber types I and II, 425 laryngeal, 275 pharyngeal, 275 Muscular dystrophies, 450 Muscularis externa, digestive tract, 334 Muscularis mucosa, digestive tract, 334 Musculocutaneous nerve, 431, 432, 434, 435 Musculoskeletal system disorders of, 442–450 head and neck, 428–430 lower extremities, 438–441 muscle structure and function in, 424–427 skin in, 451–458 tumors of, 445 upper extremities and back, 431–437 Myasthenia gravis, 450 Myasthenic syndrome, 162 myc oncogenes l-myc, 160, 296 N-myc, 160, 377 Mycobacteria, nontuberculous, 122 Mycobacterial meningoencephalitis, 195 Mycobacterium avium-intracellulare, 195 in AIDS patients, 104 Mycobacterium leprae, 122, 455 Mycobacterium marinum, 454 Mycobacterium tuberculosis, 122, 195, 292 in AIDS patients, 104 infectious arthritis and, 447 in osteomyelitis, 443 Mycolic acids, 113 Mycology, 136–140 Mycophenolate, 109, 526 Mycoplasma pneumoniae, 290, 291 Mycosis fungoides, 474 Myelencephalon, 184 Myelin, 198 Myelination, disorders of, 198–199 Myelodysplastic syndromes, 474 Myelofibrosis, myeloid metaplasia with, 466 Myelogenous leukemias, 474 acute, 474 chronic, 75, 160, 474 classification of, 475 Myeloid metaplasia with myelofibrosis, 466 Myeloma, multiple. See Multiple myeloma Myeloperoxidase, in phagocytosis, 98 Myelophthisic anemia, 466 Myenteric plexus, 335 Myocardial infarction, 233, 240, 256 myocardium appearance after, 257 Myocardial ischemia, 155, 256 Myocarditis, viral, 259 Myoclonic epilepsy, 72 Myoclonic seizure, 224 Myofilaments, 425 Myogenic response, 308 Myometrium, 408, 409 Myopathic CAT/CPT deficiency, 50 Myophosphorylase, 43 Myosin, 425 Myosin light chain kinase, 426 Myositis, 450 Myositis ossificans, 450 Myotatic reflex, 202 Myotonic dystrophy, 450 N-Myristoylation, 80 Myxedema, 388 Myxoma, 261

N Na+ channel blockers, 267 Na+-dependent coporter, 352 Na+-K+ pump, 80, 152 Na+/glucose symporter, 80 NADH dehydrogenase, 40 NAD/NADH, 38, 39, 41 Nadolol, 193, 389 NADPH, 38, 39, 41, 42 NADPH oxidase, in phagocytosis, 98 NADPH oxidase deficiency, 98 NAE (net acid excretion), 319, 484 Naegleria spp., 122, 123 Nafcillin, 118, 444, 453, 457, 526 Nagler reaction, 366, 455 Nalbuphine, 226, 526 Nalmefene, 226 Naloxone, 226, 526 as antidote, 172 Naltrexone, 13, 226, 526 Naphthylamine, as cancer risk, 159 Naproxen, 448, 526 Naratriptan, 174 Narcissistic disorder, 26 Narcolepsy, 11 Narrow-angle glaucoma, 206 Nasopharynx, 275, 430 carcinoma of, 161 Natalizumab, 198 Nateglinide, 382 Natural killer cells, 88, 90, 93, 470 Natural selection, and equilibrium, 77 Necator spp., 127, 130 hematologic changes caused by, 476 Neck. See Head and neck Necrophilia, 28 Necrosis, 155 acute tubular, 329 Necrotizing enterocolitis, 357 Nedocromil, 294, 526 Nefazodone, 22, 526 Negative feedback, 148 Negative predictive value, 34, 479 Negative-sense RNA viruses, 132 Negri bodies, 196 Neisseria gonorrhoeae, 412, 419, 420 infectious arthritis and, 447 pathogenic factors, 116 Neisseria meningitidis in bacterial meningitis, 195 in early meningococcemia, 457 Nelfinavir, 105, 526 Nemathelminthes, 127 Nematodes. See Roundworms Neocortex, 218 Neomycin, 66, 120 Neonatal respiratory distress syndrome, 295 Neoplasia, 159 Neoplasms adrenal, 377 cardiac, 261 testicular, 402 thyroid, 389 Neostigmine, 190, 526 Neostriatum, 216 Nephroblastoma, 331 Nephrons, 300 blood vessels associated with, 306 structure of, 306 Nephropathy, 328, 329 Nephrotic syndrome, 327 Nephrotoxic acute tubular necrosis, 329

560

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Nitroglycerin, 85, 256, 271, 272, 527 Nitroprusside, 85, 269, 272 Nitrosamines, as cancer risk, 159 Nitrosoureas, 176 Nizatidine, 173, 349 NK (natural killer) cells, 88, 90, 104 NMDA antagonist, 220 NMDA receptor, 169 NNRTIs (nonnucleoside reverse transcriptase inhibitors), 105 NO. See Nitric oxide Nocardia spp., 122, 454 Nodular hyperplasia, 362 Nodular melanoma, 452 Nodular non-Hodgkin lymphoma, 473 Nodular sclerosis, in Hodgkin disease, 472 Nominal scale, 36 Nonbacterial chronic prostatitis, 398 Nonbacterial thrombotic endocarditis, 259 Nonbacterial verrucous endocarditis, 259 Noncommunicating hydrocephalus, 197 Noncompetitive antagonist, 168 Noncompetitive inhibitor, 55 Noncytotoxic hypersensitivity reaction, 106 Nondepolarizing blockers, 427 Nondisjunction, during meiosis, 74 Nonessential amino acids, precursors, 48 Non-germ cell tumors, 402 Non-Hodgkin lymphoma, 357, 473 as AIDS complication, 105 Noninfiltrating intraductal carcinoma, 418 Noninflammatory diarrhea, 365–366 Noninsulin-dependent diabetes mellitus, 381 Nonnucleoside reverse transcriptase inhibitors, 105 Nonpolar aliphatic side chains, 45 Non-selective β agonists, 294 Nonsense point mutations, 64 Nonsteroidal antiinflammatory drugs, 448, 449 Norepinephrine, 192 Norethindrone, 410 Norgestrel, 410 Normal pressure hydrocephalus, 197 Normetanephrine, 192 Nortriptyline, 22, 194 Norwalk virus, 366 Nose, infection of, 289 Notochord, 184 NPH (neutral protein Hagedorn) insulin, 382 NRDS (neonatal respiratory distress syndrome), 295 NRTIs (nucleoside reverse transcriptase inhibitors), 105 NSAIDs, 57, 449, 450 Nucleic acids, 60 structure of, 60 synthesis and salvage of, 61–62 Nucleoside reverse transcriptase inhibitors, 105 Nucleosides, 60 Nucleosomes, 60 N-Nucleotide addition, 90 Nucleotides, 60, 62 synthesis of, 42 Nucleus, 78 Nucleus ambiguus, 212 Null Hypothesis, 35 Nutmeg liver, 258, 360 Nutrasweet®, 48 Nystatin, 140, 289, 290, 419

O O2, 154 O2 capacity, 284 O2 content, 284 Oat cell carcinoma. See small cell carcinoma Obligate intracellular parasites, 122 Oblique and transverse arytenoids, 275 Observational studies, 35 Obsessive-compulsive disorder, 23, 26 Obstruction, ureteral, 331 Obstructive congenital heart disease, 254 Obstructive lung disease, 280, 281, 293–294 Obstructive uropathy, 330 Obturator externus muscle, 439 Obturator internus muscle, 439 Obturator nerve, 438, 439, 440 Occipital lobe, 218, 219 Octreotide, 391 Oculomotor nerve (III), 204, 430 skeletal muscle innervated by, 428 Oculomotor nucleus, 209 Oddi, sphincter of, 351 Odds ratio, 35, 36, 479 Ofloxacin, 121 OH (hydroxyl) radical, 154 1,25-(OH)2-vitamin D3, 383 Okazaki fragments, 63 Olanzapine, 20, 527 in bipolar disorder, 22 Olfactory bulb, 219 Olfactory nerve (I), 204 Olfactory tract, 219 Oligoclonal bands, 198 Oligodendrocytes, 198 Oligodendroglia, 199 Oligohydramnios, 409 Oligomycin, 40 Ollier disease, 442, 445 Omental bursa, 338 Omeprazole, 527 Omphalocele, 357 Onchocerca spp., 127, 130, 131 Oncogenes, 160 Oncogenic viruses, 161 Ondansetron, 174, 346, 527 One-way ANOVA, 36 Oocyte, 405 Open-angle glaucoma, 206 Opening snap, 260 Operant conditioning, 4, 5 Operculated eggs, 128 Ophthalmic artery, 223 Ophthalmic nerve (V1), 204, 430 Opioid poisoning, 170 antidote for, 172 Opioid receptors, 226 Opioids, 14, 226–227 characteristics, 227 Opponens digiti minimi muscles, 436 Opponens pollicis muscles, 14, 437 Opportunistic infections in AIDS patients, 104 fungal, 139 Oprelvekin, 465 Opsonization, 98 Optic canal, 205 Optic chiasm, 206, 218, 430 Optic nerve (II), 204 Optic tract, 206 Oral cavitary disease, 289 Oral contraceptives, 362 Ordinal scale, 36

INDEX

Nernst equation, 151, 480 Nerve damage, associated with fractures, 236 Nerves. See individual nerves by name Nervous system and cell types, 198 cell types of, 198 congenital malformations of, 185 development of, 184–185 Net acid excretion, 319 Neural crest, 144, 184, 231, 428 Neural folds, 184 Neural tube, 184 defects, 146, 225, 362 Neuroectoderm, 144, 184 Neurofibrillary tangles, 220 Neurofibromatosis, 72 type 1, 73 type 2, 73 Neurofilament, 81 Neurohistology, and pathology correlates, 198–199 Neuroleptanesthesia, 228 Neuroleptic malignant syndrome, 368 Neuromuscular blockers, 427 Neuron, 198 Neuron specific enolase stain, 150 Neurosyphilis, 208 Neurotoxicity, anesthetics, 227 Neurotransmitters, 46 Neurulation, 184 Neutral lipids, 53 Neutropenia, 470 Neutrophils, 89, 469 hypersegmental, anemia and, 466 margination and extravasation, 96 migration/chemotaxis of, 97 Nevirapine, 105, 526 Nevocellular nevus, 452 Nevus flammeus, 452 New drug application (NDA), 179 Newborn, diseases in, 295 NF. See Neurofibromatosis NF-1 gene, 161 NF-2 gene, 161 NFT (neurofibrillary tangles), 220 NHL. See Non-Hodgkin lymphoma Niacin, 41, 56, 272, 526 Nickel, as cancer risk, 159 Niclosamide, 476 Nicotinamide adenine dinucleotide. See NADPH entries Nicotine, 15, 189 Nicotinic AChR, 450 Nicotinic acid, 53 Nicotinic agonists/antagonists, 189 Nicotinic receptors, 189 Nicotinamide-adenine dinucleotide phosphate, 98 NIDDM (noninsulin-dependent diabetes mellitus), 381 Niemann-Pick disease, 54, 490 Nifedipine, 269, 271, 526 Nifurtimox in Chagas disease, 127 Night terrors, 11 Nightmares, 11 Nigrostriatal pathway, and antipsychotics, 19 Nitazoxanide, 123, 367 Nitrates, 85, 271 Nitric oxide, 46, 84, 114, 187, 272, 344, 396 drugs acting via, 269, 272 Nitric oxide receptors, 85 Nitric oxide synthase, 46, 85 Nitrofurantoin, 526 Nitrous oxide, 228

561

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INDEX

Organ blood flow, control of, 252 Organ of Corti, 211 Organ systems, autonomic effects on, 187–188 Organ transplantation, immunology of, 107 Organelles, subcellular, 59 Organophosphate, 191 Orgasm disorders, 29 Orlistat, 368, 527 Ornithine,49 Ornithine transcarbamoylase deficiency, 401 Oropharynx, 275 Orotic acid, 49 Orthomyxovirus, 134 Oseltamivir, 135, 292 Osmotic diuresis, 317 Osmotic diuretics, 317, 325, 317 Osmotic laxatives, 368 Osteitis fibrosa cystica, 385, 442 Osteoarthritis, 446 Osteoarthropathy, hypertrophic, 442 Osteoblastic metastases, 398 Osteoblastic tumors, 445 Osteoblastoma, 445 Osteochondromatosis, 442, 445 Osteoclasts, in chronic inflammation, 100 Osteogenesis imperfecta, 68, 157, 442 Osteoid osteoma, 445 Osteomalacia, 354, 442, 445 Osteomyelitis, 443 microbiology of, 444 Salmonella, 468 Osteopetrosis, 443 Osteoporosis, 443 Osteosarcoma, 161, 445 Osler nodes, 259 Ostium primum defects, 254 Ostium secundum defects, 254 Otic ganglion, 186 Otitis externa, 290 malignant, 381 Outer cortical artery, 223 Outer membrane, 113 Ovary, 384 cancer of, 175 diseases of, 414 fibroma of, 415 Overdose. See also Poisoning of opioid analgesics, 227 Oviduct, 395 Ovulation, and folliculogenesis, 404 Ovulatory phase, in menstrual cycle, 406 Oxacillin, 118, 457 Oxaloacetate, 39, 41 Oxazepam, 24, 527 Oxazolidinones, 120 Oxidative phosphorylation, 40 Oxybutynin, 527 Oxycodone, 14, 226, 527 Oxygen, as antidote, 172 Oxygen transport, 284 Oxygen-dependent killing, in phagocytosis, 112 Oxygen-independent killing, in phagocytosis, 112 Oxytocin, 408

P P wave, 238 p16 gene, 161 p24 antigen, 104 p53, 83 p53 gene, 156, 161, 296 PA (protective antigen), 115 Paclitaxel, 177

PAG (plasma anion gap), 324, 484 Paget disease, 443 of the breast, 418 extramammary, of the vulva, 412 PAH (para-aminohippuric acid), 305 Paired helical filaments, 220 Palate, development of, 429 Palatine tonsil, 429 Palatoglossus muscle, 275 Palatopharyngeus muscle, 275 Pale infarct, 224 Palivizumab, 110 Palm, innervation of, 433 Palmar interossei muscles, 436 Palmitoylation, 80 Palmitoyl-CoA, 50 2-PAM (pralidoxime), 172 PAM (primary amebic meningoencephalitis), 123 Pamidronate, 385 Pampiniform plexus, 399 Panacinar emphysema, 293 P-ANCA, 262, 263 Pancoast tumor, 296, 490 Pancreas, 379–382 annular, 360 carcinoma of, 174 secretions of, 350 Pancreatic amylase, 352 Pancreatic duct, 350 Pancreatic enzymes, 350 Pancreatic polypeptide, 347 Pancreatic proteases, 353 Pancreatic secretions, 350 Pancreatitis acute hemorrhagic, 360 chronic, 360 Pancrelipase, 368 Pancuronium, 427 Paneth cells, 336 Panic disorder, 517 PANS (parasympathetic autonomic nervous system), 186, 187, 207 Pantoprazole, 349, 527 Pantothenic acid, 56 Papanicolaou (Pap) smear, 412 Papez circuit, 214, 217 Papillary carcinoma, 390 Papillary hidradenoma, 412 Papillary muscles, 233, 234 Papilloma, 539 intraductal, 416 Papilloma viruses, 358 Papovavirus, 132 Para-aminohippuric acid, 305 Paracentral lobule, 218 Paracortical hyperplasia, 471 Paragonimus spp., 127 Paragonimus westermani, 128 Parainfluenza, 134 Parainfluenza virus, 290 Parallel circuits, 248, 481 Paralytic ileus, 344 Paramedial pontine reticular formation, 209 Paramesonephric ducts, 300, 394 Paramyxovirus, 132 Paraneoplastic syndromes, 162 Paranoid disorder, 26 Paraphilias, 28 Paraphimosis, 397 Parasites facultative intracellular, 122 obligate intracellular, 122 protozoan, 122. See also Protozoal infections

Parasitic infections, 362 Parasympathetic autonomic nervous system, 187, 200, 201, 207, 236 Parasympathetic neurons, 200 Parasympathetic outflow, 201 Parasympathetic stimulation, for penile erection, 396 Parathion, 205 Parathyroid gland, 383 Parathyroid hormone, 312, 383 Paraumbilical veins, 340 Paraventricular nuclei, hypothalamic, 378 Paraventricular nucleus, 214 Parietal cells, 336, 348 Parietal lobe, 218, 219 Parietooccipital sulcus, 218 Parinaud syndrome, 213 Parkinson disease, 215, 216 treatment of, 216 Parkinsonism, 20 Parotid salivary glands, 342 Paroxetine, 22, 174, 527 Paroxysmal hemolytic anemia, 461 Partial agonist, 168 Partial mole, 415 versus complete mole, 415 Partial seizure, 224 Partial thromboplastin time, 462 Parvovirus, 132 B19, 409 infectious arthritis and, 447 PAS (periodic acid-Schiff) stain, 158 Passive-aggressive, 16 Pasteurella spp., 116 Pasteurella multocida, 455 Patellar tendon, 438 Patent ductus arteriosus, 232, 254 Patent foramen ovale, 254 Patent urachus, 301, 332 Paternity testing, 71 Pathogens extracellular and intracellular, 88 factors and diagnostic enzymes for, 116 unusual growth requirements of, 116 Pavlovian conditioning, 4 PBPs (penicillin binding proteins), 113, 118 Pcap (capillary hydrostatic pressure), 250 PCL (posterior cruciate ligament), 440 PCP (“angel dust”), 15 PCR (polymerase chain reaction), 69, 71, 104 PDA (patent ductus arteriosus), 232, 254 PDE (phosphodiesterase) inhibitors, 85, 397, 530, 531 PDE/adenosine uptake inhibitors, 464 PDGF. See Platelet-derived growth factor Pearson correlation, 36 Pectineus muscle, 439 Pectoral girdle, movements of, 434 Pectoralis major muscle, 432, 434 Pectoralis minor muscle, 434 Pedophilia, 28 Peduncle(s) cerebellar, 204, 213 cerebral, 204 inferior cerebellar, 212 middle cerebellar, 212 Pellagra, 56 Pelvic diaphragm, 396 Pelvic floor, and perineum, 396 Pelvic inflammatory disease, 142, 412, 420 Pelvic innervation, 396 Pelvic kidney, 301 Pelvic splanchnic nerves, 187, 335, 396

562

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Phenotypic mixing, 134 Phenoxybenzamine, 193, 527 Phentolamine, 193 Phenylalanine, 45, 48 Phenylalanine hydroxylase, 47 Phenylephrine, 193 Phenylethanolamine-N-methyl transferase, 46 Phenylketonuria, 47, 48, 72 Phenytoin, 528 Pheochromocytoma, 377, 381 PHF (paired helical filaments), 220 Philtrum, 429 Phimosis, 397 Phobias, 23 Phocomelia, 146 Phosphate regulation, 384 disorders of, 384 endocrine, 383–385 Phosphofructokinase, 38 6-Phosphogluconate, 42 Phospholipases A2, 54 A and B, 350 C, 169 Phospholipids, 54 Phyllodes tumor, 416 Physical injury, 154 Physician-patient relationships, 30–31 Physiologic dead space, 278, 482 Physiologic jaundice, of newborn, 46 Physostigmine, 190, 207, 528 as antidote, 172 Pia mater, 195, 197 PICA (posterior inferior cerebellar artery), 212, 222, 223 Pick disease, 221 Picornavirus, 133 PID (pelvic inflammatory disease), 142, 412 Pigment stones, 364 Pigmented villonodular synovitis, 449 PIH (prolactin-inhibiting factor), 370 Pili, 116 Pilocarpine, 207, 528 Pilocystic astrocytoma, 199 Pilosebaceous units, 451 Pindolol, 193, 528 Pineal body, 204, 214, 218 Pineal gland, 184 Pineal region tumor, 213 “Pink puffers,” 281 Pinworms, 130 Pioglitazone, 382, 528 Piperacillin, 118 Piriformis muscle, 439 Piriformis syndrome, 438 Piroxicam, 528 Pityriasis rosea, 452 Pituitary gland, 370–371, 430 anterior, hyperfunction of, 371 characteristics of, 370 hypofunction, 371 in hypothalamus-anterior pituitary system, 370–371 Pituitary hyperthyroidism, 387 Pituitary hypothyroidism, 387 Pityriasis, 137 PKU (phenylketonuria), 72 Placenta, 142, 145, 404, 408 abnormalities, 409, 415 infectious agents that cross, 409 Placenta accreta, 409 Placenta previa, 409 Placental transport, 95

Plant alkaloids, 177 Plaques complicated, 264 mature, 264 senile, 220 Plasma, 149 Plasma anion gap, 324 Plasma cell dyscrasias, 475 Plasma cell mastitis, 418 Plasma cells, 90 Plasma flow, renal, 305 Plasma membrane, 80 Plasma osmolarity, regulation by ADH, 316 Plasminogen, 462 Plasminogen activator, 462 Plasmodium spp., 122 125 hematologic changes caused by, 476 life cycle of, 124 Plasmodium falciparum, 125 Plasmodium malariae, 125 Plasmodium ovale, 125 Plasmodium vivax, 125 Platelet-derived growth factor, 157 Platelets, 460 disorders of, 461 Platyhelminthes, 127 Pleura, 276 diseases of, 297 tumors of, 296 Pleural effusion, 297 Plummer-Vinson syndrome, 356, 490 PMN (polymorphonuclear leukocyte), 420 PNET (primitive neuroectodermal tumor), 199 Pneumocystis jiroveci (formerly carinii), 127, 139, 292 in AIDS patients, 104 Pneumocystosis, 127 Pneumonia, 291–292 Pneumotaxic center, 288 Pneumothorax, 297 PNMT (phenylethanolamine-N-methyltransferase), 46 Podagra, 446 Podocytes, 307 Podophyllin, 420 Poiseuille’s equation, 248 Poisoning. See also Intoxication antidotes for, 172 common toxic syndromes, 170 food, 367 heavy metal, 171 management of the poisoned patient, 170–172 Polio, 203 Polio virus, 133, 409 Poliomyositis, 450 Polyarteritis nodosa, 262 Polycistronic mRNA, 112 Polyclonal hypergammaglobulinemia, 475 Polycystic disease in adults, 327 in childhood, 327 ovarian, 414 Polycythemia, 162, 284, 465 Polycythemia vera, 465 Poly-D-glutamate, 113, 454, 535 Polydipsia, 317 primary, 378 Polyene antifungal agents, 118 Polyhydramnios, 274, 409 Polymerase chain reaction, 69 Polymorphonuclear leukocytes, 420 Polymorphonuclear leukocytosis, 470 Polyoma, 132

INDEX

Pemphigus vulgaris, 452 Penciclovir, 135 Penicillamine, 216 for heavy metal poisoning, 171, 172 Penicillin G, 118 Penicillin V, 118 Penicillin-binding proteins, 113, 118 Penicillins, 113, 118, 289, 421, 449, 454–455, 457, 527 Penile erection dysfunctional, 29, 397 physiology of, 396 Penis, 394, 395 bulb of, 396 carcinoma, 397 diseases of, 397 Pentamidine, 127, 139, 456 Pentazocine, 226 Pentose phosphate shunt, 42 Pepsin, 348, 353 Pepsinogen, 348 Peptic ulcer disease, treatment of, 349 Peptic ulcers, 356 Peptidoglycan, 113, 118 Peptostreptococcus spp., 413 Perforin, 93 Pergolide, 174, 216 Pericardial disease, 261 Pericardial effusion, 261 Pericarditis, 261 Perimetrium, 407 Perimysium, 425 Perineal pouches, 396 Perineum, 395–396 and pelvic floor, 396 Periodic acid-Schiff stain, 158 Peripheral nervous system, 184 Peripheral proteins, 80 Periplasmic space, 113 Peristalsis, 343–344 Peritoneal organs, 337 Peritoneum, 395 Peritubular capillaries, 306 Permanent cells, 157 Permeability, selective, 151 Pernicious anemia, 56, 354, 356, 468 Peroneus brevis muscle, 441 Peroneus longus muscle, 441 Peroxisomes, 78, 79 Peroxisome proliferator-activated receptor (PPAR), 53, 272, 382 Persistent truncus arteriosus, 231, 255 Personality disorders, 26 Pertussis toxin, 115 Petechiae, 457, 460 Petit mal seizure, 224 Peyer patches, 336 Peyronie disease, 397 PFK-1 (phosphofructokinase), 38 PGs. See Prostaglandins pH control mechanisms, 322 Phagocytosis, 98 Phallus, 394 Pharmacodynamics, 168 Pharmacokinetics, 166 Pharyngeal arch, muscles derived from, 428 Pharyngeal pouches, 334, 429 Pharynx, 275 Phencyclidine, 15 Phenelzine, 22, 174, 193, 527 Phenobarbital, 24, 225, 527 Phenothiazine, 346 Phenotypic masking, 134

563

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INDEX

Polyps, 358 Polysaccharidase, 350 Polysome, 66, 78 POMC (proopiomelanocortin), 372 Pompe disease, 43 Pons, 184, 201, 204 212, 218 Popliteus ligament, 440 Popliteus muscle, 440 Population genetics, 77 Pork tapeworm, 129 Porphobilinogen deaminase, 46 Porphyria, acute intermittent, 46 Porphyria cutanea tarda, 46 Port wine stain, 263, 452 Portacaval anastomoses, 340 Portal hypertension, 340, 361 Portal vein, 337 Positive feedback, 148 Positive predictive value, 34, 479 Positive-sense RNA viruses, 133 Postcentral gyrus, 218 Postcoital contraceptives, 410 Postductal coarctation, 255 Posterior cerebral arteries, 222, 223 Posterior communicating artery, 223 Posterior cricoarytenoid, 275 Posterior cruciate ligament, 440 Posterior fornix, 395 Posterior funiculus, 200 Posterior inferior cerebellar artery, 222, 223 Posterior interventricular artery, 233 Posterior mediastinum, 232 Posterior nucleus, 214 Posterior pituitary, 370–371 Postganglionic sympathetic terminal blockers, 194, 269 Poststreptococcal glomerulonephritis, 327 Postsynthetic gap phase, in cell cycle, 83 Post-translational modifications, 67 Potassium. See K+ entries Potassium iodide, 389 Potency, drug, 168 Pott disease, 443 Potter sequence, 301 Pouch of Douglas, 395 Poxvirus, 131 PP (pulse pressure), 248 PPRF (paramedial pontine reticular formation), 209 PR interval, 239 Prader-Willi syndrome, 77 Pralidoxime, 172 Pramipexole, 216 Pramlintide, 382 Pravastatin, 52, 272, 528 Praziquantel, 131 Prazosin, 193, 269 Precentral gyrus, 218 Prechordal plate, 143 Predictive value, 34 Prednisolone, 294 Prednisone, 294, 528 Preductal coarctation, 255 Preeclampsia, 409 Prefrontal cortex, 219 Pregabalin, 528 Pregnancy diseases of, 409 ectopic, 142 and implantation, 408 molar, 415 Prekallikrein, 97 Preload, cardiac, 242

Premature ejaculation, 29 Premature infants, and jaundice, 46 Premature ventricular contraction, 240 Premenstrual phase, in uterine cycle, 405 Premenstruation, 405 Premotor cortex, 219 Prenylation, 80 Preoptic nucleus, 214, 403 Pressure gradient equation, 248, 481 Presynthetic gap phase, in cell cycle, 83 Pretectal nuclei, 207 Prevalence, 34 Prevotella spp., 114 Priapism, 397 Primary active transport, 148 Primary adrenocortical insufficiency, 376 Primary amebic meningoencephalitis, 123 Primary amyloidosis, 158 Primary auditory cortex, 219 Primary bile acids, 351 Primary biliary cirrhosis, 361 Primary cell type variable, acute myelogenous leukemia and, 474 Primary follicle, 404 Primary hyperaldosteronism, 375 Primary hyperparathyroidism, 384, 385 Primary hypoparathyroidism, 384 Primary hypothyroidism, 387 Primary motor cortex, 219 Primary palate, 429 Primary polydipsia, 378 Primary premotor cortex, 219 Primary sclerosing cholangitis, 362 Primary somatosensory cortex, 219 Primary spermatocyte, 400 Primary tumors, CNS and PNS, 199 Primary union, in wound healing, 157 Primary visual cortex, 206, 219 Primary yolk sac, 143 Primitive atrium, 230 Primitive gut tube, 334, 335 Primitive neuroectodermal tumor, 199 Primitive streak, 144 Primitive ventricle, 230 Primordial follicle, 404 Prinzmetal angina, 256 Prion protein, 221 Probenecid, 449 Procainamide, 60, 267, 528 Procaine, 227 Processus vaginalis, 398 Prochlorperazine, 19, 528 Progesterone, 405, 406, 408 Progestins, 410 Proglottid, 129 Progressive multifocal leukoencephalopathy, 198 Progressive systemic sclerosis. See Scleroderma Projection, 16 Prokaryotic cells, 112 Prokaryotic chromosomes, 63 Prolactin, 370, 408 Prolactin-inhibiting factor, 370 Proliferative phase, in uterine cycle, 405 Proline, 45, 68 Prolonyl CoA carboxylase deficiency, 47 Promethazine, 173 Pronator quadratus muscles, 435 Pronator teres muscle, 435 Pronator teres syndrome, 433 Proopiomelanocortin, 372 Propafenone, 267 Propamidine, 123 Prophase, in mitosis, 83

Propionibacterium acnes, 453 Propionyl-CoA carboxylase, 47, 56 Propionyl-CoA carboxylase deficiency, 48 Propofol, 228 Propranolol, 24, 193, 267, 269, 389, 528 Propylthiouracil, 528 Prostaglandins, 54, 448 PGE1, 397 PGE2, 54 PGF2α, 54 PGI2, 54 Prostate, 395, 396 cancer of, 162, 398 diseases of, 398 Prostate-specific antigen, 158, 162 Prostatic acid phosphatase, 162 Prostatic urethra, 300 Prostatitis, 398 acute, 398, 418 chronic, 398 Protamine, 464 as antidote, 172 Protease inhibitors in AIDS treatment, 104 as anti-HIV therapy, 105, 476 Proteases, IgA, 116 Proteasome, 78 Protein translation, 66 modifications after, 67 Protein(s), 67 apoproteins, 53 C type, 462, 463 cell cycle and, 160 CFTR, 360 chronic inflammation and, 100 digestion of, 353 integral, 80 M type, 116 in plasma membrane, 80 post-translational modifications to, 67 S type, 462, 463 structure of, 67 synthesis inhibition, 120 tau, 220 A type, 116 Proteins, peripheral, 80 Proteoglycans, 82 Proteosomes, 67 Proteus spp., 290 in urolithiasis, 330 Prothrombin (factor II), 462 Prothrombin gene mutation, 463 Prothrombin time, 462 Proto-oncogenes, 160 Protozoal infections, 122, 127, 126 major, 127 Proximal convoluted tubule, 300 Proximal nephron, 300 Proximal penile urethra, 300 Proximal tubule, 300, 309–310 Prozone phenomenon, 95 PRPP aminotransferase, 62 Prussian blue stain, 158 PSA (prostate specific antigen) stain, 162 Psammoma bodies, 199, P-selectin, 97 Pseudoephedrine, 194 Pseudogout, 446 Pseudohyperparathyroidism, 385 Pseudohypertrophy, of the calves, 493 Pseudointersexuality female, 394 male, 394

564

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Q 22q11 syndromes, 77, 255 Q waves, 240 QRS complex, 238

QRS duration, 239 QT interval, 239 Quadratus femoris muscle, 439, 440 Quadratus plantae muscles, 441 Quantal does-response curve, 168 Quaternary amines, 190 Quetiapine, 20, 528 Quinidine, 267, 529 Quinine, 125

R R Groups, 45 R (reabsorption), 304 p-value, 35 using for decision-making, 35 Rabeprazole, 349, 529 Rabies, 196 Radial dilator muscles, 207 Radial nerve, 236, 431, 432, 433, 435, 436, 437 Radiation, ionizing, as cancer risk, 159 Radioactive iodine, 389 Radioulnar joints, movement at, 435 Raloxifene, 411, 529 Ramipril, 269, 529 Ranitidine, 173, 349, 529 Rapidly progressive glomerulonephritis, idiopathic, 328 Rasagiline, 194, 216 Rashes, 457–458 Rathke pouch, 199 Ratio scale, 36 Rationalization, 16 Raynaud disease, 264 Raynaud phenomenon, 85 Rb gene, 161 RBC (red blood cell), 38 RBF. See Renal blood flow Reabsorption, 304 Reaction formation, 16 Recall bias, 35 Receptive relaxation, 343 Receptors. See also individual receptor types by name in cell signaling, 85 in cholinergic transmission, 189 diversity of, 90 enzyme-linked, 85 within ion channels, 169 in parasympathetic autonomic nervous system, 187–188 in sympathetic autonomic nervous system, 187–188 T cell, 88 transmembrane, tyrokinase activation and, 169 Reciprocal translocations, chromosomal, 75 Recombinant cytokines, clinical uses, 109 Recombinant DNA, 69–70 Recombination homologous, 117 site-specific, 117 Rectouterine pouch, 395 Rectovesical pouch, 395 Rectum, 345 Rectus femoris muscle, 439, 440 Recurrent laryngeal branch, 275 Recurrent laryngeal nerve, 296 Red blood cells, 38 disorders of, 465–468 Red man syndrome, 119 Red muscle fibers, 425 Red nucleus, 213 5α-Reductase 2 deficiency, 394

5α-Reductase 2 gene, 394 5α-Reductase inhibitor, 398 Reduviid bug, 126 Reed-Sternberg cells, 472 Reflex tests brachial plexus, 432 lumbosacral plexus, 438 Reflex(es) cremasteric, 399 deep tendon, 202 defecation, 345 gastrocolic, 345 gastroileac, 344 muscle stretch, 202 myotatic, 202 pupillary light, 207 Reflexes, vestibuloocular, 210 Reflux nephropathy, 329 Refractory periods, 238 absolute and relative, 152 Regression, 16 Regular insulin, 382 Reinforcement, 4 Reiter syndrome, 446 Rejection acute, 107 chronic, 107 Relative afferent pupil, 208 Relative polycythemia, 465 Relative refractory periods, 152, 238 Relative risk, 35, 479 Relaxation isovolumic, 245 receptive, 343 Remelteon, 24 Remifentanil, 228 Renal agenesis, 301 Renal blood flow, 305, 483 autoregulation of, 308 filtration regulation and, 308 Renal caliculi, 301 Renal cell carcinoma, 331 Renal failure, 263, 327–330 Renal pelvis, 300 Renal plasma flow, 305 Renal sympathetic nerves, 316 Renal system acid/base regulation and, 319 embryology and anatomy of, 300–301 pathology of, 309–332 pharmacology of, 325–326 physiology of, 302–325 water and solutes regulation in, 312 Renal vein, 340 thrombosis of, 330 Renin, 175, 374 Renin inhibitor, 175 Renin secretion, autoregulation of, 307 Renin-angiotensin-aldosterone, 316 blood pressure control by, 374 Reovirus, 133 Repaglinide, 382 Repeated measures ANOVA, 36 Replication fork, 63 Repolarization, 152 Repression, 16 Reproductive system female. See Female reproductive system male. See Male reproductive system RER (rough endoplasmic reticulum), 78 Reserpine, 194, 269, 270 Residual volume, 277

INDEX

Pseudomonas spp., 290, 291 in osteomyelitis, 443 Pseudomonas aeruginosa, 115, 290, 359, 453, 454, 455 Pseudomyxoma peritonei, 414 Pseudopolyps, 359 Psilocybin, 15 Psoriasis, and antimalarial drugs, 452 Psoriatic arthritis, 446 Psychopathology, 17–27 Psyllium, 368 PT (prothrombin time), 462 PT (proximal tubule), 306, 309–310 PTH (parathyroid hormone), 312, 383 PTT (partial thromboplastin time), 462 PTU (propylthiouracil), 389 Pudendal nerve, 345, 396 Pulmonary arteries, 276 Pulmonary blood flow, 285 Pulmonary capillary, 283 Pulmonary circulation, 249 Pulmonary edema, 297 Pulmonary emboli, 297 Pulmonary hypertension, 297 Pulmonary trunk, 231 Pulmonary veins, 276 Pulmonic valve, 246 stenosis or atresia of, 255 Pulse pressure, 248 Pulvinar nucleus, 214 Pupillary light reflex pathway, 207 Pupillary light-near dissociation, 208 Pupillary sphincter, 207 Pupils abnormalities of, 208 constriction of, 14, 208 Purine, 60 analogs of, 61 synthesis of, 61–62 Puromycin, 367 Purkinje cells, 213 Purpura, 461 Purulent meningitis, acute, 195 Pustule, malignant, 454 Putamen, 215 PV loops (cardiac pressure-volume loops), 245–246 PVC (premature ventricular contraction), 240 Pyelonephritis, 329, 419 Pyknosis, 155 Pylorus, 336, 343 stenosis of, 356 Pyogenic liver abscesses, 362 Pyramidal decussation, 201 Pyramids, 201, 212 Pyrantel pamoate, 131 Pyridostigmine, 190 Pyridoxine, 56 Pyrimethamine, 61, 118, 121, 127 Pyrimidine, 60 analogs of, 61, 63 synthesis of, 60 Pyruvate carboxylase, 41, 44, 56 Pyruvate dehydrogenase, 41, 56 Pyruvate kinase, 38, 44 Pyruvate kinase deficiency, 39 Pyruvate metabolism, 41

565

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INDEX

Resistance, 248, 481 Respiratory acidosis, 323 Respiratory alkalosis, 323 Respiratory bronchioles, 274 Respiratory depression, 13 Respiratory distress syndromes, 278, 295 Respiratory syncytial virus, 132, 290 Respiratory system anatomy of, 275–276 embryology of, 274 histology of, 274 pathology of, 289–297 physiology of, 277–288 Respiratory zone, 274 Respondent conditioning, 4 Responses, cellular (adaptive), 156 Resting membrane potential, 151 Restless legs syndrome, 216 Restriction endonucleases, 69, 70 Restriction fragment length polymorphisms, 71 Restrictive (infiltrative) myopathy, 260 Restrictive lung disease, 281, 295 ret oncogene, 160 Retarded ejaculation, 29 Rete ovarii, 394 Rete testes, 394 Reteplase, 464 Reticular lamina, 82 Reticulin stain, 158 Retinoblastoma, 83, 159, 161, 199 Retinoblastoma susceptibility protein, 83 Retrolental fibroplasia, 295 Retroperitoneal organs, 337 Retrovirus, 133 Reuptake, adrenergic transmission and, 192 Reuptake inhibitors, 194 Reverse transcriptase inhibitors in AIDS treatment, 104 as anti-HIV therapy, 105, 476 Reye syndrome, 361 RFLP (restriction fragment length polymorphisms), 71 Rh disease, of newborn, 46 Rhabdomyoma, 261 Rhabdomyosarcoma, 412, 450 embryonal, 412, 450 Rhabdovirus, 132 RhD immune globulin, 109 Rheumatic fever, 106 acute, 257 Rheumatic heart disease, 257 Rheumatoid arthritis, 446 treatment of, 448 Rheumatoid factor, 446 Rhinoviruses, 289 Rhizopus spp., 139 RhoGAM™, 109 Rhomboid major muscle, 434 Rhomboid minor muscle, 434 Ribavirin, 133, 290, 292 Riboflavin (B2), 56 Ribonuclease, 334 Ribonucleic acid, 60, 112 Ribonucleotidase, 61 Ribonucleotide reductase, 61 Ribonucleotides, 61 Ribose, 60 Ribose-5-phosphate, 61 Ribosomal RNA, 65 Ribosomes, 66 Ribosylation, 115 Ribulose-5-P, 42 Rickets, 57, 354, 442 hypophosphatemic, 72

Rickettsia spp., 122 Rickettsia prowazekii, 457 Rickettsia rickettsii, 457 Riedel thyroiditis, 388 Rifampin, 529 Right and left bundle branches, 236 Right atrium, 233 Right axis deviation, 241 Right coronary artery, 233 Right testicular vein, 399 Right ventricle, 233 Ring-enhancing lesions, 127 Ringworm, 456 Rinne test, 211 Risedronate, 385, 529 Risperidone, 20, 529 Ritonavir, 105 Rituximab, 110 Rivastigmine, 190 RM (resting membrane) potential, 151 RNA, 60, 112 processing and transcription of, 65 types of, 65 RNA viruses double-stranded, 133 negative-sense, 134 positive-sense, 133 RNA-dependent DNA polymerase, 133 Robertsonian translocations, 76 formation and consequences of, 76 Robin sequence, 428 Rocky Mountain spotted fever, 457 Rocuronium, 427 Rolando sulcus, 219 Romaña sign, 126 Romberg sign, 202 Ropinirole, 216, 529 Ropivacaine, 227 Rose gardener’s disease, 137 Rosenthal fibers, 199 Rosiglitazone, 382, 529 Rosuvastatin, 529 Rotator cuff, 435 Rotatores muscle, 434 Rotaviruses, 133, 366 Roth spots, 259 Rotor syndrome, 360 Rough endoplasmic reticulum, 78 Roundworms, 127 transmitted by eggs, 130 transmitted by larvae, 131 RPF (renal plasma flow), 305 RPGN (rapidly progressive glomerulonephritis), idiopathic, 328 rRNA, 65 RS (Reed-Sternberg) cells, 472 RSV (respiratory syncytial virus), 290 RT-PCR (reverse transcriptase PCR), 69, 104 RU-486 (mifepristone), 410, 411 Rubella, 133 infectious arthritis and, 447 Rubeola, 458 Rugae, 336 Russell bodies, 475

S S cells, 346 S phase, in cell cycle, 83 S-100, 162 S-100 stain, 158 Saccule, 210 Sacrococcygeal teratoma, 144

SAD (seasonal affective disorder), 21 Saddle nose, 442 Sadism, 28 Salicylates, 40, 448, 514 poisoning by, 170 Saliva, 342 amylase in, 352 Salivary glands, 342 Salmeterol, 193, 294, 529 Salmonella spp., 365 in osteomyelitis, 443 Salmonella osteomyelitis, 468 Salmonella typhi, 122 Salvage pathways, 61–62 SAM (S-adenosylhomocysteine), 47 SAM (S-adenosylmethionine), 47 San Joaquin Valley fever, 138 Sandfly, and leishmaniasis transmission, 126 SANS (sympathetic autonomic nervous system),186–187, 189, 207 Saphenous nerve, 439 Saquinavir, 105 Sarcoidosis, 293 Sarcoma defined, 159 Kaposi. See Kaposi sarcoma Sarcoma botryoides, 412, 450 Sarcomeres, 425 Sarcoplasmic reticulum, 79 Sargramostim. See Granulocyte-macrophage colony-stimulating factor Sarin, 191 SARS virus, 133, 292 Sartorius muscle, 439, 440 Satiety center, 342 Saturday night palsy, 432 Saw palmetto, 178 Scalded skin disease, 457 Scales, statistical, 36 Scarlatina, 457 Scarlet fever, 457 Scarpa fascia, 396 Schatzki rings, 356 Schaumann bodies, 293 Schistosoma spp., 127 Schistosoma haematobium, 128 Schistosoma japonicum, 128 Schistosoma mansoni, 128 Schistosomiasis, 128, 362 Schizogony, 124 Schizoid disorder, 26 Schizophrenia, 18 Schizotypal disorder, 26 Schwann cells, 198 Schwannoma, 199 bilateral acoustic, 199 Sci-70 (anti-DNA topoisomerase I antibodies), 107 Sciatic nerve, 438, 439, 440 Scleroderma, 107 diffuse, 107 limited, 107 Sclerosing adenosis, 416 Sclerosing cholangitis, 361 Sclerosis amyotrophic lateral, 203 Mönckeberg medial calcific, 250 multiple, 198 nodular, in Hodgkin disease, 451 tuberous, 261 Scolex, 129 SCP (superior cerebellar peduncle), 213 Scrotum, 394 Scurvy, 56, 68, 157

566

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Sexual arousal disorders, 29 Sexual aversion, 29 Sexual desire disorders, 29 Sexual disorders, 28–29 Sexual pain disorders, 29 Sexually transmitted diseases, 419–420 Sézary syndrome, 474 SGLUT 1 (Na+ -dependent coporter), 352 Shaping, 5 Sheehan syndrome, 371 Shiga toxin, 115 Shigella spp., 365 Shigella dysenteriae, 115 Shock, 258, 266 Short-acting AChE inhibitor, 190 Short tandem repeats (STRs), 71 Shoulder movement effect on trunk, 434 glenohumeral joint, 434 Shunt, 286 SIADH. See Syndrome of inappropriate ADH secretion Sickle cell anemia, 62, 72, 444 Sickle cell crisis, 46 Sickle cell disease, 443, 468, 512 genetic testing in, 71 “Sickle prep,” 468 Sideroblastic anemia, 46, 56 SIDS (sudden infant death syndrome), 11 Sigmoid colon, 335 Sigmoid sinus, 197 Signal transduction, 169 Sildenafil, 85, 397, 530 Silent point mutations, 64 Simple cysts, of the kidney, 327 Simple diffusion, 80, 148 Simple seizure, 224 Simvastatin, 272, 524, 530 Single-gene disorders, 73 Sinoatrial node, 236 Sinus histiocytosis, 471 Sinus mucormycosis, 381 Sinus rhythm, 240 Sinus venarum, 230, 233 Sinus venosus, 230, 254 Sinusitis, 289 Sirenomelia, 144 Sirolimus, 109 sis oncogene, 160 Sitagliptin, 382 SITS (subscapularis) tendons, 435 Sjögren syndrome, 106 Skeletal disorders, 442 Skeletal muscle, 424 cholinergic transmission and, 189 cranial nerves innervated by, 428 morphology and function of, 425 Skeletal muscle relaxants, 427 Skin, 451–458 infectious diseases of, 453–456 pathology of, 505 rashes on, 457–458 Skull base, anatomy of, 205 SLE (systemic lupus erythematosus), 106 Sleep deprivation, 11 disorders of, 11, 12 physiology of, 10 Sleep apnea syndromes, 11 Sleeping sickness, 126, 127 Sleepwalking, 11 Slime, capsular, 113 Small cell carcinoma, 296 of lung, 162

Small intestine, 336, 344, 353 Small nuclear RNA, 65 Smooth endoplasmic reticulum, 78, 79 Smooth muscle characteristics of, 424 contraction of, 426 function of, 426 snRNA, 65 Social phobia, 24 Sodium. See Na+ entries Soleus muscle, 441 Solubility, 228 Solute balance, 315 Solute regulation disorders of, 317 renal, 312 Somatic hypermutation, 90 Somatic nervous system, 186 Somatization, 16 Somatoform disorders, 25 Somatoform pain disorder, 25 Somatomedins, 390 Somatosensory association cortex, 210 Somatostatin, 347, 370, 379 Somatrem, 391 Somatropin, 391 Somnambulism, 11 Sore throat, 289 Sotalol, 268 Southern blot technique, 71 SP (septum primum), 230 SP (superior parathyroid gland), 429 Spare receptors, 168 Sparganosis, 129 Sparganum, 129 Spasmolytics, 427 Specific phobias, 23 Specificity, biostatistical, 34, 479 Spermatic cord, 399 Spermatic fascia, 399 Spermatids, 400 Spermatocele, 399 Spermatogenesis, 400 hormonal control of, 401 Spermatogonium, 400 Spermatozoa, 396, 400 Spermiogenesis, 401 S-phase promoting factor, 83 Sphenoidal sinus, 430 Spherocytosis, hereditary, 467 Spherules, 136 Sphincter of Oddi, 346, 351 Sphincter urethrae muscle, 396 Sphingomyelinase, 54 Spider angiomata, 361 Spina bifida, 184, 185 Spinal cord, 185, 200–203 lesions of, 203 Spinal cord tracts, 200 Spinal nerve, 200 in lateral medullary syndrome, 212 Spinal trigeminal nucleus/tract, 212 Spinalis muscle, 434 Spinothalamic tract, 202, 203, 212 Spiral artery, 405 Spiral ganglion, 211 Spironolactone, 270, 326, 398, 530 Splenic artery, 338 Splenium, 218 Splenius capitis muscle, 434 Splenius cervicis muscle, 434 Splinter hemorrhage, 259

INDEX

Seasonal affective disorder, 21 Seborrheic keratosis, 452 Second messengers, 84 Secondary active transport, 148 Secondary amyloidosis, 158 Secondary bile acids, 351 Secondary biliary cirrhosis, 361 Secondary hyperaldosteronism, 375 Secondary hyperparathyroidism, 384, 385 Secondary oocyte, 404 Secondary palate, 429 Secondary (pituitary) adrenocortical insufficiency, 376 Secondary polycythemia, 465 Secondary spermatocyte, 400 Secondary syphilis, 458 Secondary union, in wound healing, 157 Secretin, 346, 350, 352 Secretion, in urine formation, 304 Secretory phase, in uterine cycle, 405 Secundum-type atrial septal defects, 230 Sedative-hypnotics, 24 poisoning by, 170 Segmentation contractions, 344, 345 Seizures, 224 anticonvulsants and, 224–225 Selectins, 96 Selection bias, 35 Selective estrogen receptor modulator (SERM), 177, 411 Selective permeability, 151 Selective serotonin reuptake inhibitors (SSRI), 22, 174 poisoning by, 170 Selegiline, 194, 216, 529 Sella turcica, 197 Semicircular ducts, 210 Semimembranosus muscle, 439, 440 Seminal vesicles, 394, 395, 396 Seminiferous tubules, 394 Seminoma, 402 Semispinalis muscle, 434 Semitendinosus muscle, 439, 440 Senna, 368 Sensitivity, statistical, 34, 479 Sensorineural deafness, 211 Separation anxiety, 7 Septal nuclei, 217 Septic shock, 266 Septum pellucidum, 218 Septum primum, 230 Septum secundum, 230 Sequestrum, 443 SER (smooth endoplasmic reticulum), 78, 79 Stercobilins, 352 Series circuits, 248, 481 Serine, 45 SERM (selective estrogen receptor modulator), 177, 411 Serosal layer, digestive tract, 335 Serotonin, 46, 174 as inflammation mediator, 97 receptors, 174 Serotonin syndrome, 174 Serous pericarditis, 261 Serratus anterior, 432 Serratus anterior muscle, 434 Sertoli cell, 400, 401, 402 Sertoli-Leydig cell tumor, 415 Sertraline, 22, 174, 529 Serum sickness, 106 Severe combined deficiencies, 102 Sevoflurane, 228

567

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INDEX

Spongiform change, 221 Spores, 137 Sporogony, 124 Sporothrix schenckii, 137, 140, 454 Sporotrichosis, 137 Sporozoites, 124 Spousal abuse, 9 Squamous cell carcinoma, 296, 355, 358, 453 penile, 397 “Squamous pearls,” 296 SR (superior rectus) muscle, 204, 209 SS (septum secundum), 230 SSRIs. See Selective serotonin reuptake inhibitors St. John’s wort, 167, 174, 178 ST elevation, 256 ST segment, 238 depression of, 256 Stable angina pectoris, 256 Stable cells, 157 Stage, of tumor, 163 Staining methods, 158 Standard limb leads, 239 Staphylococci, coagulase-negative, infectious arthritis and, 447 Staphylococcus spp., 446 Staphylococcus aureus, 114, 115, 116, 290, 418, 455, 457 infectious arthritis and, 447 methicillin-resistant, 453 in osteomyelitis, 443 Staphylococcus epidermidis, 114 Staphylococcus saprophyticus, 332, 362, 419 “Starry sky” pattern, in non-Hodgkin lymphoma, 473 Starvation, and osmotic diuresis, 317 Statins, and cholesterol synthesis, 52 Stationary phase, bacterial, 112 Statistical scales and tests, 36 Statistical power, 35 Status epilepticus seizure, 224 Stavudine, 105, 530 STDs (sexually transmitted diseases), 419–421 Steady state, 148, 166 Stein-Leventhal syndrome, 414 Steroid receptors, 169 Steroidogenesis, hormonal control of, 401 female, 403 Stibogluconate, 126 Still disease, 446 Stimulant laxatives, 368 Stimulants, CNS, 14 Stimulus control, 5 Stomach, 334, 343, 353 body and fundus of, 336 Stool-softener, 368 Straight sinus, 197 Stranger anxiety, 7 Stratum basale, 451 Stratum corneum, 431 Stratum granulosum, 451 Stratum lucidum, 451 Stratum spinosum, 451 Streptobacillus moniliformis, 455 Streptococcus spp., 418, 446 group A, 116 group B, 195, 413 Streptococcus mutans, 114 Streptococcus pneumoniae, 289, 291 in bacterial meningitis, 195 Streptococcus pyogenes, 115, 289, 453. 457 erythrogenic toxin of, 118 Streptococcus viridans, 114, 259 Streptogramins, 118

Streptokinase, 453, 462, 464 Streptomycin, 66, 120 Stretch reflex, 202 Striatum, 215 String sign, 359 Stroke volume, 242, 481 Stroke work, 245 Strong agonists, 226 Strongyloides spp., 127, 130 Sturge Weber syndrome, 263 Subacute bacterial endocarditis, 259 Subacute combined degeneration, 203 Subarachnoid hemorrhage, 195, 224 Subarachnoid space, 195, 196 Subcellular organelles, 42–43 Subcutaneous granulomas, 454 Subcutaneous nodules, 257 Subcutaneous tissue, infectious diseases of, 454 Subdural hematoma, 195, 224 Subdural space, 195 Subendothelial deposits, 327 Subepithelial humps and spikes, 327 Subfalcine herniation, 221 Sublimation, 16 Sublingual salivary glands, 342 Submandibular salivary glands, 342 Submandibular VI ganglion, 186 Submucosal layer, digestive tract, 335 Submucosal plexus, 335 Subscapularis muscle, 434 Subscapularis tendons, 435 Substance abuse, 13–16, 33 Substantia nigra, 213, 215 Subtalar joint, movements at, 441 Subthalamus, 184, 214 Succimer, for heavy metal poisoning, 171, 172 Succinyl CoA, 39 Succinylcholine, 228, 427, 530 Sucralfate, 349 Sucrase, 352 Sudden acute respiratory syndromes, 292 Sudden infant death syndrome, 11 Sulci, 218 Sulcus limitans, 184 Sulfasalazine, 448, 530 Sulfinpyrazone, 449 Sulfonamides, 121, 449, 454 Sulfonylureas, 382 Sumatriptan, 174, 530 Superantigens, 92, 115, 289, 457 Superficial inguinal nodes, 402 Superficial inguinal ring, 399 Superficial perineal (Colles) fascia, 396 Superficial perineal pouch, 396 Superficial peroneal nerve, 439, 441 Superficial transverse perineal muscle, 395 Superior cerebellar artery, 223 Superior cerebellar peduncle, 213 Superior cerebral artery, 222 Superior colliculus/pretectal area, 213 Superior frontal gyrus, 218 Superior gluteal nerve, 438, 439 Superior mediastinum, 232 Superior mesenteric artery, 357 Superior mesenteric veins, 340 Superior oblique muscle, 209 Superior olivary nucleus, 211 Superior orbital fissure, 205 Superior parathyroid gland, 429 Superior parietal lobule, 218, 219 Superior petrosal sinus, 197 Superior rectal veins, 340

Superior rectus muscle, 204, 209 Superior sagittal sinus, 197 Superior temporal gyrus, 211, 218 Superior vena cava syndrome, 296 Supinator muscle, 435 Suppression, 16 Suppurative arthritis, 446 Suppurative pericarditis, 261 Suprachiasmatic nucleus, 214 Supramarginal gyrus, 218 Supraoptic nuclei, hypothalamic, 378 Supraoptic nucleus, 214 Suprascapular nerve, 432, 434 Supraspinatus tendon, 435 Sural nerve, 439 Suramin, 126, 127 Surface tension, 279 Surfactant, 274, 279 deficiency of, 295 Suspensory ligament, 395 SV (stroke volume), 242 Swallowing, 343 Swarming motility, 290, 419, 537 Sweat glands, 451 Sweating, fluid and electrolyte abnormalities in, 303 Swelling hydropic, cell injury and, 155 labioscrotal, 394 Sydenham chorea, 257 Sylvius, aqueduct of. See Cerebral aqueduct Sympathetic autonomic nervous system, 186, 187–188, 207 Sympathetic chain, 186 Sympathetic innervation, 335 Sympathetic neurons, 186 Sympathetic regulation, of heart and circulation, 252 Sympathetic (thoracolumbar) outflow, 187 Sympathomimetics, indirect-acting, 194 Syncytiotrophoblast, 142, 143, 145, 408, 415 Syndrome of inappropriate ADH secretion (SIADH), 150, 162, 317, 378 Synoviosarcoma, 449 Syphilis, 401 primary, 421 secondary, 421 tertiary, 421 Syringomyelia, 185, 203 Syrup of ipecac, 170, 346 Systematic desensitization, 5 Systemic circulation, 249 Systemic lupus erythematosus, 106 Systole, 244

T T cells, 88, 460 antigen receptor, characteristics of, 90 cytotoxic (CD8+), 91 defects, 102 receptor diversity, 90 receptors, 88 T tubules, 424 T wave, 238 T3. See Triiodothyronine T4 (thyroxine), 46, 386 Tabes dorsalis, 203 Tachycardia, ventricular, 381 Tacrine, 190, 220 Tacrolimus, 109 Tadalafil, 397, 530 Taenia spp., 127

568

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Theca interna, 404 T-helper cells, 92–94 Theophylline, 294, 531 poisoning by, antidote for, 172 Therapeutic index, 168, 481 Thiamine, 41, 56 Thiamine pyrophosphate, 41 Thiazide diuretics, 270, 311, 317, 325, 326 electrolyte changes caused by, 326 Thiazolidinediones, 382 Thick ascending loop of Henle, 306, 310, 311 Thioamides, 389 6-thioguanine, 61 Thiopental, 24, 228 Thioridazine, 19 Third degree atrioventricular conduction block, 240 Third ventricle, 184, 196, 215, 218 cerebral aqueduct of, 196 Thoracic splanchnic nerves, 187 Thoracodorsalis nerve, 434 Thorax, cross-sectional anatomy of, 235 Threadworm, 131 Threonine, 45 Threshold, 152 Throat, infection of, 289 Thrombasthenia, Glanzmann, 460 Thrombin (factor IIa), 462 Thrombin time, 462 Thromboangiitis obliterans, 262 Thrombocythemia, essential, 461 Thrombocytopenia, 461 Thrombocytosis, 461 Thrombolytics, 464 Thrombophlebitis, migratory, 359 Thrombopoietin, 109 Thrombosis cavernous sinus, 430 renal vein, 330 Thrombotic cerebral infarcts, 224 Thrombotic thrombocytopenic purpura, 461 Thromboxanes, 54 Thumb, movements of, 437 Thymidine kinase, 133 Thymidylate synthase, 56 Thymoma, 450 Thymus, 429 abnormalities of, 450 Thyroarytenoid, 275 Thyroepiglotticus, 275 Thyroglobulin, 386 Thyroglossal duct, 429 Thyroglossal duct cyst, 388 Thyroid gland, 366–369, 429 activity regulation in, 387 disorders of, 387–388 medullary carcinoma of, 158, 381 neoplasms of, 389 treatment options and, 389 Thyroid hormones, 380. See also Thyroxine; Triiodothyronine control, 386 physiologic actions of, 386 secretion of, 387 synthesis and storage of, 386 Thyroid receptors, 169 Thyroiditis de Quervain granulomatous subacute, 388 Hashimoto, 388 Thyroid-stimulating hormone, 370, 386 Thyroid-stimulating immunoglobulins, 387 Thyrotropin-releasing hormone, 370, 386 Thyroxine, 386 TI (therapeutic index), 161, 431

Tiagabine, 225 Tibial collateral ligament, 440 Tibial nerves, 438, 439, 440, 441 Tibial tuberosity, 440 Tibialis anterior muscle, 441 Tibialis posterior muscle, 441 Ticarcillin, 118 Ticlopidine, 464 Tidal volume, 277 Tight junction (zonula occludens), 82 Timolol, 193, 207, 531 Tinea barbae, 137 Tinea capitis, 137 Tinea corporis, 137 Tinea cruris, 137 Tinea pedis, 137 Tinea versicolor, 137 Tiotropium, 294 Tirofiban, 464 Tissue hydrostatic pressure, 250 Tissue oncotic pressure, 250 Tissue plasminogen activator, 462 inhibitor, 464 Tizanidine, 427 Tmax. See Transport maximum TMP-SMX (trimethoprim-sulfamethoxazole), 127 TNF. See Tumor necrosis factor TNM staging, 163 Tobramycin, 120 Tocainide, 267 Toes, movements of, 441 Togavirus, 133 Tolbutamide, 382 Tolcapone, 194 Tolterodine, 531 Tonic-clonic seizure, 224 Tooth enamel dysplasia, 120 Topiramate, 224, 225, 531 Topoisomerase, 60 TORCH syndrome, 409 Torsemide, 326 Torsion, 399 Total body water, 149 Total lung capacity, 277 Total peripheral resistance, 248, 481 Tourette syndrome, 216 Toxic epidermal necrolysis, 453 Toxic shock syndrome, 457 Toxic syndromes, common, 170 Toxicity, cardiovascular, 227 Toxicology, 170–172 Toxins, bacterial, 114, 115 Toxocara spp., 127 Toxocara canis, 130 Toxocara cati, 130 Toxoplasma spp., 122 Toxoplasma gondii, 122, 127 in AIDS patients, 104 Toxoplasmosis, 127 t-PA. See Tissue plasminogen activator TPP (thiamine pyrophosphate), 41 TPR (total peripheral resistance), 248, 481 Trabeculae carneae, 233, 234 Tracheobronchial nodes, 276 Tracheoesophageal fistula, 274, 356 Tracheoesophageal septum, 274 Traction diverticula, 355 Tracts, spinal cord, 200 Tramadol, 531 Tranexamic acid, 465 Trans (maturing) face, Golgi apparatus, 79 Transaminase, 41

INDEX

Taenia solium, 129 Takayasu arteritis, 263 TAL. See Thick ascending loop of Henle Tamoxifen, 177, 411, 530 Tamsulosin, 193, 530 Tanner stages of development, 9 Tapeworms, 127, 129 Tarasoff case, 33 Tardive dyskinesia, 20 Tarsal joints, movements at, 441 Tartrate-resistant acid phosphatase, 158, 474, 475 tau protein, 220 Taxol, 81 Tay-Sachs disease, 54 Tazobactam, 118 TB (tuberculosis), 448 TBW (total body water), 149 3TC (lamivudine), 105 TCA (tricarboxylic acid), 39 T-cell leukemia / lymphoma, 161, 474 TCR (T cell receptor), 88 TD (tardive dyskinesia), 20 Tectorial membrane, 211 Teeth grinding, 11 Teichoic acids, 113 Telencephalon,184 Telithromycin, 120 Telophase, in mitosis, 83 Temazepam, 24, 530 Temporal arteritis, 263 Temporal lobe, 218, 219 Teniae coli muscle bands, 345 Tensor fasciae latae muscle, 439 Tentorium cerebelli, 197 Teratogens, 146 Teratoma, 402 immature, 414 sacrococcygeal, 144 Terazosin, 193, 269, 530 Terbinafine, 140, 530 Terbutaline, 193, 294, 411 Teres major muscle, 434 Teres minor muscle, 434 Teres minor tendon, 435 Terminal bronchioles, 274 Termination, in protein translation, 66 Tertiary amines, 190 Testes, 394 inflammatory lesions of, 401 neoplasms of, 402 Testicle, 395 Testicular artery, 399 Testicular feminization syndrome, 394 Testosterone, 375, 394, 397, 398, 401, 403 Tetanus toxin, 115 Tetracaine, 227 Tetracycline, 292, 530 Tetracyclines, 66, 120, 118, 146, 419, 420, 421 Tetraiodothyronine, 386 Tetralogy of Fallot, 231, 254, 255, 287 Tetrodotoxin, 152 TGF-α (transforming growth factor α), 157 TH1 cells, 88, 92, 94, 106, 476 TH2 cells, 88, 92, 94 TH17 cells, 92, 94 Thalamus, 184, 214, 215, 217, 218 Thalassemia-α, 466 Thalassemia-β, 466 Thalidomide, 146 Thayer-Martin agar, 419 Theca cell, 403 Theca externa, 404

569

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INDEX

Transamination, of amino groups, 47–48 Transcription, and RNA processing, 65 Transfer RNA, 65, 66 Transforming growth factor α, 157 Transitional cell carcinoma, of the bladder, 332 Transitional cell carcinoma, of the kidney, 331 Transketolase, 56 Translation, of protein. See Protein translation Translocations chromosomal, 75 Robertsonian. See Robertsonian translocations Transmembrane receptors, tyrosine kinase activation and, 169 Transplantation immunology, 107 Transport, 148, 304 types of, 80 Transport maximum (Tmax), 308 estimation of, 309 Transposition of the great vessels, 231, 255 Transtentorial (uncal) herniation, 208, 221 Transversalis fascia, 399 Transverse colon, 345 Transverse sinuses, 197 Transversospinalis muscle, 434 Transvestite fetishism, 28 Tranylcypromine, 22, 174, 193, 194 TRAP (tartrate-resistant acid phosphatase), 158, 474, 475 Trapezius muscle, 434 Trapezoid body, 211 Trastuzumab, 110 Trauma, to central nervous system, 221 Trazodone, 22, 531 Treacher-Collins syndrome, 428 Treg cells, 92 Trematodes, 127 diseases caused by, 128 Treponema pallidum, 421, 458 Tretinoin, 531 TRH (thyroid-releasing hormone), 370, 386 Triacylglycerol lipases, 350 Triacylglycerols, 50, 53 Triamterene, 326, 531 Triazolam, 24 Tricarboxylic acid cycle, 39 Triceps muscle, 431 Triceps tendon, 431 Trichinella spp., 127, 130 Trichinosis, 131 Trichomonas vaginalis, 123, 420 Trichomoniasis, 123, 127 Trichophyton spp., 137 Trichrome stain, 158 Trichuris spp., 127, 130 hematologic changes caused by, 476 Tricuspid valve, 233, 246 Tricyclic antidepressants, 22, 190, 194 poisoning by, 170 Trigeminal nerves (V), 204, 210 skeletal muscle innervated by, 428 Triglyceride metabolism and regulation, 50 Trihexyphenidyl, 190, 216, 531 Triiodothyronine, 386 reversal, 387 Trimethoprim, 61, 121 Trimethoprim-sulfamethoxazole, 127, 292, 531 Trinucleotide repeat, 450 Trisomy 13 (Patau syndrome), 74 Trisomy 18 (Edwards syndrome), 74 Trisomy 21 (Down syndrome), 74, 254, 255 tRNA, 65, 66 Trochlear nerve (IV), 204, 430 skeletal muscle innervated by, 428

Tropheryma whippelii, 357 Trophoblast, 142 Trophoblastic tumors, 162 Trophozoite, 123 Tropical sprue, 357 Tropicamide, 190 Troponins, 257, 424 Trousseau syndrome, 359 Truncoconal septum, 255 Truncus arteriosus, 230 Trypanosoma spp., 122 Trypanosoma b. rhodesiense, 126 Trypanosoma brucei gambiense, 126 Trypanosoma cruzi, 122, 126, 355 Trypanosomiasis, 127 Trypomastigotes, 126 Trypsin, 350 Tryptophan, 45, 46 Tryptophan hydroxylase, 46, 174 Tsetse fly, 126 TSH (thyroid stimulating hormone), 370, 386 TSI (thyroid-stimulating immunoglobulin), 387 TSST-1, 115 TT (thrombin time), 462 t-test, 36 TTP (thrombotic thrombocytopenic purpura), 461 Tuber cinereum, 218 Tuberculin test, 106 Tuberculosis, 293, 401, 448 Tuberoinfundibular pathways, and antipsychotics, 19 Tuberous sclerosis, 261 Tubocurarine, 427 Tubular adenoma, 358 Tubulin, 81 Tubuloglomerular feedback, 308 Tubulointerstitial diseases, renal, 329 Tubulovillous adenomas, 358 Tumor markers, 162 Tumor necrosis factor, 156, 448 TNF-α, 92, 114, 157 TNF-β, 92, 93 Tumor suppressor genes, 161 breast cancer and, 417 Tumors benign, 355 borderline, 414 of breast, 416 of CNS and PNS, 199 epithelial, 414 germ cell, 402, 414 giant cell, 445 grade and stage of, 163 hepatic, 362 of joint space, 449 of lung and pleura, 296 malignant. See Malignant tumors metastatic, 199 musculoskeletal, 443, 445 non-germ cell, 402 osteoblastic, 445 Pancoast, 296 in paraneoplastic syndromes, 162 pineal region, 213 renal, 331 suppressor genes, 161 trophoblastic, 162 vascular, 266 Tunica vaginalis, 398 Turner syndrome, 74, 255 T-wave inversion, 256 Twinning, 145 TX (thromboxanes), 54, 61, 460

Tympanic membrane, 211, 429 Type I error, 35 Type II error, 35 Typhus, epidemic, 457 Tyramine, 174 Tyrosine, 45, 46 Tyrosine hydroxylase, 46 Tyrosine kinase, 169 receptor, 84 transmembrane receptors activating, 169 Tyrosine transporter, 45, 46 Tzanck smear, 419

U UAG (urinary anion gap), 324, 484 UB (ultimobranchial body), 429 Ubiquitin, 67 UDP-glucose, 43 UDP-glucuronyl transferase, 46 UDP-glucuronyl transferase deficiency, 46 UES (upper esophageal sphincter), 343 Ulceration, 454 Ulcers, 349, 356, 454 curling, 356 Cushing, 356 esophageal, 385 peptic, 349, 356 Ulnar artery, 236 Ulnar nerve, 236, 431, 432, 433, 436, 437 Ultimobranchial body, 429 Ultrafiltration coefficient, 250 Ultraviolet exposure, as cancer risk, 159 Umbilical artery, 145, 408 Umbilical cord, 145 Umbilical vein, 145, 232, 408 UMN. See Upper motor neuron Uncal herniation, 208, 221 Unconjugated hyperbilirubinemia, 360 Undoing (defense mechanism), 16 Union, in wound healing, 157 Unipolar depression, 21 Unithiol, for heavy metal poisoning, 172 Unstable angina, 256 Upper esophageal sphincter, 343 Upper extremities, musculoskeletal anatomy, 432–438 Upper medulla, 201, 204 Upper motor neuron, 201 facial nerve lesion and, 210 Upper respiratory system infections, 289–290 Urachus, 145, 300 patent, 301, 332 Uracil, 49, 60, 64 Urate nephropathy, acute, 329 Urea cycle, 49 Ureaplasma spp., 413 Ureaplasma urealyticum, 419 Urease, 116 Ureteric bud, 300 Ureters, 395 anomalies of, 331 development of, 300 double, 301, 331 obstruction of, 331 Urethra, 395 congenital abnormalities of, 301 development of, 300 Urethritis, 419 Uric acid, 61 Uric acid stones, 330 Uricosuric agents, 449 Uridine diphosphate. See UDP entries

570

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V V receptors, in cell signaling, 85 VA (ventral anterior nucleus), 214 Vaccines bacterial, 101 viral, 101 Vaccinia, 132 VACTERL congenital anomalies, 144 Vagina, 394, 395, 407 diseases of, 412 Vaginal adenosis, 146, 412 Vaginal clear cell adenocarcinoma, 146, 412 Vaginismus, 29 Vaginosis, bacterial, 420 Vagus nerve (X), 205 skeletal muscle innervated by, 428 Valacyclovir, 135, 419, 420, 454, 458, 531 Valine, 45 Valproic acid, 531 Valsalva maneuver, 345 Valsartan, 175, 269, 531 Valvular disorders, 247–253 Valvular heart disease, 260 Vancomycin, 117, 119, 444, 447, 453, 454, 455, 457, 531 Vancomycin-resistant enterococcus (VRE), 66, 119 Vancomycin-resistant Staphylococcus aureus (VRSA), 66, 119 Vanillylmandelic acid, 178, 377 Vardenafil, 397 Varenicline, 15 Variant CJD, 221 Varicella-zoster virus, 132 Varicocele, 399 Varicose veins, 265 Variola, 131 Vas deferens, 396 Vasa recta, 306, 314, 315 Vascular diseases, renal, 330 Vascular disorders, pulmonary, 297 Vascular function curve, 242 examples of, 243 Vascular tumors, 266 Vasculitides, 262–264 Vasoactive inhibitory peptide, 343 Vasodilation, metabolic, 252

Vasodilators, 269, 272 Vasopressin, 378. See also Antidiuretic hormone receptors, 85 Vastus intermedius muscle, 440 Vastus lateralis muscle, 440 Vastus medialis muscle, 440 VATER congenital anomalies, 144 VA/VL thalamic nuclei, 215 VDJ recombination, 90 VDRL test, 421 Vector cardiogram, 241 Vectors DNA, 69 viral, 132 Veillonella, 114, 534 Veins. See individual veins by name Velocardial facial syndrome, 255 Venlafaxine, 22, 532 Venous disease, 266 Venous drainage, 195–197 of lungs, 276 ventricular system and, 195–197 Ventilation, 277–278 control of, 288 Ventilation-perfusion relationships, 286 Ventral anterior nucleus, 214 Ventral gray horn, 200 Ventral horn synapse, 201 Ventral lateral nucleus, 213, 214 Ventral pancreatic bud, 334 Ventral root, 200 Ventral white commissure, 203 Ventricular fibrillation, 240 Ventricular septal defect, 231, 254 Ventricular septum, 231 Ventricular system, 195–197 and CSF circulation, 196 and venous drainage, 196–197 ventricles in, 184, 233 Ventricular tachycardia, 240 Ventromedial nucleus, 214, 342 Ventroposterolateral nucleus, 202, 203, 214 Ventroposteromedial nucleus, 210, 214 Verapamil, 268, 269, 270, 271, 532 Vermis, 213 lesions of, 213 Verotoxin, 115, 366 Vertebrae, 185 Vertebral arteries, 222, 223 Vertigo, 210 Very low density lipoprotein, 50, 53 Vesamicol, 191 Vecuronium, 427 Vesicouterine pouch, 395 Vesicular lesions, 454 Vesicular stomatitis virus, 134 Vessel damage, associated with fractures, 236 Vestibular bulb, 395, 396 Vestibular nuclei, 210, 212 Vestibular system, 210, 240 Vestibulocochlear nerve (VIII), 205 Vestibulo-ocular reflex, 210 VFC. See Vascular function curve VHL gene, 161 Vibrio cholerae, 115, 366 Vibrio parahaemolyticus, 366 Vibrio vulnificus, 454 Vigabatrin, 225 Villous adenoma, 358 Villus/Villi, 336, 344, 408 Vimentin, 81 Vimentin stain, 158

Vinblastine, 81, 177, 532 Vincristine, 81, 177, 532 Vinyl chloride, as cancer risk, 159 VIP (vasoactive inhibitory peptide), 343, 344, 347 VIPoma, 347 V/Q mismatch, 287 Viral algorithms, Appendix F, 539 Viral encephalitis, 196 Viral genetics, 134 Viral myocarditis, 259 Viral vectors, 134 Virchow node, 356 Viridans streptococci, 114, 259 Virology, 132–136 Viruses, 132. See also individually named viruses DNA, 132 oncogenic, 161 RNA, 133, 134 structure and morphology, 132 Visceral larva migrans, 130 Visceral leishmaniasis, 126 Visual association cortex, 219 Visual field defects, 206, 225 Visual system, 209 lesions of, 206 Vital capacity, 277, 279 Vitamin A, 57 Vitamin B1, 41, 56 Vitamin B2, 56 Vitamin B3, 41, 56 Vitamin B6, 56 Vitamin B12, 56, 468 Vitamin C, 56, 68, 354 Vitamin D, 57, 354 in regulation of calcium and phosphate, 383 Vitamin D deficiency, 384, 443 Vitamin D excess, 384 Vitamin D3, 383 Vitamin E, 57 Vitamin K, 57, 354 as antidote, 172 coagulation and, 462, 464, 465 Vitamin K deficiency, 463 Vitamins. See also individually named vitamins deficiencies in, 154 lipid soluble, 57 water-soluble, 56 Vitelline duct, 334 Vitelline fistula, 357 Vitiligo, 453 VL (ventral lateral nucleus), 214 VLDL (very low density lipoprotein), 50, 53 VMA (vanillylmandelic acid), 192, 377 Voltage-gated channels, Na+, 152 Volume drug distribution, 166, 480 fluid distribution, 149, 480 Voluntary contralateral horizontal gaze, 219 Voluntary motor system, 201 Vomiting, 345 von Gierke disease, 43, 44 von Hippel-Lindau disease, 72, 73, 161, 331 von Recklinghausen disease, 73 of bone, 385 von Willebrand disease, 460, 461 treatment of, 465 von Willebrand factor, 460 Voriconazole, 140 Voyeurism, 28 VPL (ventroposterolateral nucleus), 202, 214 VPM (ventroposteromedial nucleus), 210, 214 VSD (ventricular septal defect), 231, 254

INDEX

Urinary anion gap, 324 Urinary bladder, 395 Urine extravasation of, 396 formation processes, 304 Urine flow, 313 Urine osmolarity, 313, 316 Urobilinogens, 352 Urodilatin, 316 Urogenital diaphragm, 395, 396 Urogenital folds, 394 Urogenital sinus, 300 Urokinase, 462, 464 Urolithiasis, 330 Uroporphyrinogen decarboxylase deficiency, 46 Urorectal septum, 300 Urothelia, 28 Ursodiol, 368 Urticaria, 453 Uterine cycle, 405 Uterine tubes, 394 fertilization in, 142 Uterus, 394, 395, 407 diseases of, 413 Utricle, 210

571

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INDEX

VSV (vesicular stomatitis virus), 134 Vulva, diseases of, 412 Vulvovaginitis, 420 Candida, 412 vWF (von Willebrand factor), 460 VZV (varicella-zoster virus), 132

W Waiter’s tip sign 432 Waldenström macroglobulinemia, 475 “Walking pneumonia,” 291 Wall tension, 251 Wallenberg syndrome, 212 Warfarin, 464, 532 poisoning by, antidote for,172 Warm hemolytic anemia, 467 Warts, 456 genital, 412, 420 Water deprivation, 317 Water regulation disorders of, 317 renal, 312 Waterhouse-Friderichsen syndrome, 376 Water-induced diuresis, 315 Watershed areas, 224 Water-soluble vitamins, 56. See also individually named vitamins Weak agonists, 226 Weber syndrome, 213 Weber test, 211 Wegener granulomatosis, 262 Wernicke encephalopathy, 217 Wernicke-Korsakoff syndrome, 13, 214 Wernicke aphasia, 219 Wernicke area, 219 West Nile virus, 133

Western blot technique, 71 in AIDS diagnosis, 104 Whipple disease, 357 Whipworm, 130 White blood cell disorders, 470 nonneoplastic, 470 White blood cells, 469 White matter, 200 White muscle fibers, 425 Wigger’s diagram, 244 Wilms tumor, 77, 161 Wilson disease, 216, 361 antidote for, 172 Window period, in Ab-Ag complexes, 95 Winged scapula, 433 Withdrawal, 13, 227 Worms. See individual types of worm Wound healing, 157 Wrist extensor muscles of, 432 flexor muscles of, 432 movement at, 436 WT-1 gene, 161 WT-2 gene, 161 Wuchereria spp., 127, 130, 131

X Xanthine oxidase, 62, 449 Xenografts, 107 Xeroderma pigmentosum, 64 Xerostomia, 106 XII nucleus, 212 X-linked hyper-IgM syndrome, 102 X-linked inheritance patterns, 72 XYY syndrome, 74

Y Yeasts, 136 Yersinia enterocolitica, 365 Yersinia pestis, 122 Yohimbine, 193 Yolk sac, 334 primary, 143 tumor of, 402 Yolk stalk, 334

Z Z lines, 425 Zafirlukast, 294, 532 Zalcitabine, 105 Zaleplon, 24 Zanamivir, 135, 292 ZDV (zidovudine), 105 Zenker diverticula, 355 Zero-order elimination, 166 Zidovudine, 105, 532 Zileuton, 54, 294, 532 Ziprasidone, 20 Zollinger-Ellison syndrome, 173, 347, 349, 356, 381 Zolmitriptan, 532 Zolpidem, 24, 532 poisoning by, antidote for, 172 Zona fasciculata, 372 Zona glomerulosa, 372 Zona pellucida, 404, 407 Zona reticularis, 372 Zonal reaction, 400 Zoophilia, 28 Zygote, 142

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