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FUNDAMENTALS OF

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PHARMACOLOGY

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FUNDAMENTALS OF

PHARMACOLOGY SHANE BULLOCK AND ELIZABETH MANIAS 7th EDITION

SHANE BULLOCK ELIZABETH MANIAS 7th EDITION

CVR_BULL3100_07_LT_CVR.indd 1

19/07/13 3:01 PM

FUNDAMENTALS OF

PHARMACOLOGY

FUNDAMENTALS OF

PHARMACOLOGY

SHANE BULLOCK AND ELIZABETH MANIAS 7th EDITION

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Copyright © Pearson Australia (a division of Pearson Australia Group Pty Ltd) 2014 Pearson Australia Unit 4, Level 3 14 Aquatic Drive Frenchs Forest NSW 2086 www.pearson.com.au The Copyright Act 1968 of Australia allows a maximum of one chapter or 10% of this book, whichever is the greater, to be copied by any educational institution for its educational purposes provided that that educational institution (or the body that administers it) has given a remuneration notice to Copyright Agency Limited (CAL) under the Act. For details of the CAL licence for educational institutions contact: Copyright Agency Limited, telephone: (02) 9394 7600, email: [email protected] All rights reserved. Except under the conditions described in the Copyright Act 1968 of Australia and subsequent amendments, no part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission of the copyright owner. Senior Acquisitions Editor: Mandy Shepherd Senior Project Editor: Rebecca Pomponio Development Editor: Katie Pittard Editorial Coordinator: Sophie Attwood Production Controller: Julie McArthur Copy Editor: Biotext Pty Ltd Proofreader: Jane Tyrrell Senior Copyright and Pictures Editor: Emma Gaulton Indexer: Garry Cousins Cover and internal design by Natalie Bowra Cover illustration © MEDI-MATION/Science Photo Library Typeset by Midland Typesetters, Australia Printed in China 1 2 3 4 5 18 17 16 15 14 National Library of Australia Cataloguing-in-Publication Data Author: Title: Edition: ISBN: ISBN: Notes: Subjects:

Bullock, Shane, author. Fundamentals of pharmacology / Shane Bullock, Elizabeth Manias. 7th edition. 9781442563100 (paperback). 9781442564411 (Vital Source) Includes index. Pharmacology—Study and teaching (Higher). Drugs—Study and teaching (Higher) Other Authors/Contributors: Manias, Elizabeth, author. Dewey Number: 615.1900711 Every effort has been made to trace and acknowledge copyright. However, should any infringement have occurred, the publishers tender their apologies and invite copyright owners to contact them. Due to copyright restrictions, we may have been unable to include material from the print edition of the book in this digital edition, although every effort has been made to minimise instances of missing content.

CONTENTS Preface Acknowledgments Features Teaching and learning package Figures and tables S EC T I O N I

S EC T I O N I I

PHARMACOLOGY WITHIN THE SOCIAL CONTEXT

viii x xi xv xvi

1

1 A historical perspective

2

2 Sociocultural aspects

8

PHARMACOLOGY WITHIN THE PROFESSIONAL CONTEXT

19

3 Health professionals and the law

21

4 Ethical issues

30

5 The roles and responsibilities of health professionals in medicine adherence, education and advocacy

39

6 The roles and responsibilities of health professionals in medicine management S EC T I O N I I I

MEDICINE ADMINISTRATION AND PROFESSIONAL RESPONSIBILITIES

S EC T I O N V

55

7 Medicine formulations, storage and routes of administration

56

8 The clinical decision-making process

76

9 Medicine administration strategies and documentation

S EC T I O N I V

44

82

10 Medication errors

92

11 Management of common adverse drug reactions

96

12 Risk communication: balancing the benefits and risks of drug treatment

113

GENERAL ASPECTS OF PHARMACOLOGY

125

13 Drug nomenclature

127

14 Pharmacokinetics: absorption and distribution

133

15 Pharmacokinetics: metabolism and excretion

142

16 Drug interactions

152

17 Pharmacodynamics

159

18 Drug development, evaluation and safety

171

19 Pharmacogenetics

182

20 Pharmacokinetic factors that modify drug action

190

21 Paediatric and geriatric pharmacology

195

TOXICOLOGY

209

22 Poisoning and envenomation

210

23 The management of acute clinical overdose

218

24 Contemporary drugs of abuse

227

25 Drug abuse in sport

239

vi

F U N D A M E N TA L S O F P H A R M A C O L O G Y

S EC T I O N V I

S EC T I O N V I I

AUTONOMIC PHARMACOLOGY

249

26 General aspects of neuropharmacology

250

27 Adrenergic pharmacology

258

28 Cholinergic pharmacology

286

CHEMICAL MEDIATORS

313

29 An introduction to chemical mediators

314

30 Histamine and antihistamines

318

31 Prostaglandins and serotonin

329

32 Nitric oxide and the endothelins

337

S EC T I O N V I I I T HE MODULATION OF BEHAVIOUR, COGNITION AND

S EC T I O N I X

S EC T I O N X

S EC T I O N X I

MOTOR ACTIVITY

345

33 General concepts of psychopharmacology

347

34 Antipsychotic agents

352

35 Anxiolytics and hypnotics

367

36 Antidepressants and mood stabilisers

380

37 Medicines used in neurodegenerative disorders

399

38 Antiseizure agents and muscle relaxants

418

39 Central nervous system stimulants

437

MEDICINES USED TO RELIEVE PAIN AND PRODUCE ANAESTHESIA

447

40 Narcotic analgesics

448

41 Non-steroidal anti-inflammatory, antipyretic and analgesic agents

466

42 Medicines used to treat migraine

488

43 General anaesthesia

498

44 Local anaesthesia

508

THE MODULATION OF OXYGENATION AND PERFUSION

521

45 Medicines used to lower blood lipids

522

46 Antihypertensive agents

534

47 Medicines used to promote tissue perfusion

556

48 Antithrombotic, fibrinolytic and haemostatic agents

572

49 Diuretics and other renal medicines

594

50 Medicines used to treat heart failure

606

51 Medicines used to treat cardiac dysrhythmia

626

52 Fluid and potassium imbalances

636

53 Antianaemic agents

651

54 Medicines used to maintain gas exchange

659

55 Medicines for upper respiratory tract conditions

681

THE MODULATION OF GASTROINTESTINAL FUNCTION

697

56 Upper gastrointestinal tract drugs

698

57 Lower gastrointestinal tract drugs

713

58 Antiemetic agents

734

CONTENTS

S EC T I O N X I I

S EC T I O N X I I I

S EC T I O N X I V

THE MODULATION OF BODY GROWTH, DEVELOPMENT AND METABOLISM

747

59 Medicines and the pituitary gland

749

60 Medicines and the thyroid

762

61 Medicines and the pancreas

770

62 Medicines and the adrenal cortex

791

63 Medicines and the gonads

801

64 Medicines and bone metabolism

822

65 Hyperuricaemia and gout

833

66 Obesity and its treatment

842

NUTRITIONAL AND NATURAL THERAPIES

855

67 Vitamins, minerals and amino acids

856

68 Enteral and parenteral nutrition

876

69 Herbal medicines

886

THE MODULATION OF CELLULAR GROWTH AND PROLIFERATION

907

70 Introduction to chemotherapy

909

71 Sulfonamides and trimethoprim

917

72 Antibacterial agents

923

73 Antituberculotics and antileprotic agents

947

74 Antiseptics and disinfectants

960

75 Antiparasitic agents

969

76 Antimalarial agents

981

77 Antiviral agents

S EC T I O N X V

APPENDIX

Glossary Index

991

78 Antifungal agents

1012

79 Immunomodulating agents

1025

80 Cytotoxic chemotherapeutic agents

1050

81 Gene therapies

1080

MEDICINES USED TOPICALLY

1089

82 Medicines used in diseases of the skin

1090

83 Medicines and the eye

1111

A Common prescription terminology

1135

B Common American generic drug names

1136

C SI units

1137

D Medicine calculations

1140

E Common symbols used in medication charts

1145

F Common word mix-ups

1146

G Drug–herbal interactions

1148

H Orphan drugs

1150 1153 1165

v ii

P R E FA C E Fundamentals of Pharmacology is primarily a text for undergraduate and postgraduate students in the health science disciplines, particularly those in nursing. Students of other health disciplines whose roles involve pharmacological therapy (such as pharmacy, podiatry, optometry, paramedic and physiotherapy), as well as those studying basic science, should find much of the material relevant to their studies. Qualified health professionals and pharmaceutical company sales representatives will also find the information useful in their daily roles. Unashamedly, we have written a pharmacology textbook for students of the health professions that does not compromise the scientific basis of the discipline. Many pharmacology texts previously published have been strong on clinical considerations, yet relatively weak in the science of pharmacology.

Our approach Philosophically, our goal is to empower health professionals through an understanding of the fundamental scientific principles of pharmacology. We believe that, to promote understanding, the effects of drugs on physiological and pathophysiological processes have to be clearly explained. We have included a small amount of chemistry and biochemistry where appropriate in order to facilitate this understanding. With a greater appreciation of the action of drugs and their target tissues, the reader should be able to deduce what adverse effects to expect, as well as the precautions and contraindications to consider. Furthermore, where possible we have tended to describe the important characteristics of medicine groupings rather than focusing on individual agents, and have used prototypes and common generics as examples. The rationale for this approach is that new medicines are regularly entering the market while older agents are removed. The average practitioner cannot possibly keep up with all these changes. However, if a student knows which grouping a new agent belongs to, the principal characteristics of the medicine can be easily deduced. This book is primarily designed to establish the foundations in pharmacology. We encourage students to refer to the electronic and hard copy references commonly found in the clinical setting and in hospital wards, such as the Australian Medicines Handbook, MIMS or Therapeutic Guidelines, for more detailed information regarding individual therapeutic agents (e.g. dosage, special precautions and toxicological information). We hope that you will find this textbook a valuable companion in your pursuit of a fundamental understanding in a most fascinating area of clinical knowledge—pharmacology.

Changes in the seventh edition This edition reflects the availability of medicines in Australia and New Zealand at the time of publication. Consistent with information currently available to us, we have updated new medicines that have entered the marketplace, as well as those that have been removed since the last edition. We use the word “medicine” rather than “drug” or “medication” where appropriate. This change was implemented in recognition of the increasing use of the word “medicine” as evidenced by a number of industry websites such as: • the National Prescribing Service (www.nps.org.au); • Australian Prescriber (www.australianprescriber.com); and • the Therapeutic Goods Administration (www.tga.gov.au/industry/pm.htm).

P R E FA C E

Where appropriate, the therapeutic approaches associated with the management of important clinical conditions, such as cardiovascular disease, diabetes mellitus and psychiatric illness have been brought up to date with current clinical guidelines.

FULL COLOUR FIGURES AND TABLES This edition is printed in full colour for the first time. Chapter figures are more dynamic, providing the representations of structures and processes with greater depth and vibrancy. Receptors are rendered more often in figures as G-protein-coupled or ion channels rather than basic geometric shapes. A number of new figures and tables have been included to assist students in visualising difficult pharmacological concepts, the sites of actions of drugs and the range of drug effects expected in a person when particular drug groups are administered.

END-OF-CHAPTER AND END-OF-SECTION FEATURES The book contains over 800 end-of-chapter questions to assist in the consolidation of learning— all of these have been reviewed. New and revised integrated case studies appear at the end of sections to assist with making links between theory and practice.

ix

ACKNOWLEDGMENTS We would like to thank a number of people who have contributed to the development of this textbook, and this edition in particular. Elizabeth wishes to thank her family for their patience and support, and for giving her an appreciation of things beyond the world of medicines. She would also like to thank her colleagues and students, who have provided her with helpful comments about the textbook and made suggestions for improvement. For Shane the writing of this edition was fuelled by the primary producers situated around his homebase in the Gippsland region of Victoria—yummy cheese, chutney, jam and wine. With respect to the latter indulgence, students are advised to do as I say (see Chapter 24) rather than as I do. He is grateful to the backyard chooks who proved to be a more receptive and attentive audience than other family members when workshopping new ideas for the book. We would like to thank the team at Pearson Australia for the preparation of this edition. Our thanks to Mandy Sheppard for her support, encouragement and good humour. We are also grateful for access to the expertise of Katie Pittard, Emma Gaulton and Rebecca Pomponio. It is always a pleasure working with you. We thank our copy editor, Anneliese Gillard, and proofreader, Jane Tyrrell, for their valuable advice on contemporary word usage and for picking up on our writing idiosyncrasies. Thanks also to the proposal reviewers: • Peter Athanasos, Flinders University • Dr Hemant Mehta, Australian Catholic University • Rebekkah Middleton, University of Wollongong • Dr Srinivas Nammi, University of Western Sydney • Dr Nicole Reinke, James Cook University • Dr Ross Richards, Charles Sturt University • Dr Scott Smid, The University of Adelaide • Dr Jenny Wilkinson, Charles Sturt University Shane Bullock and Elizabeth Manias July 2013

F E AT U R E S

Learning Objectives make clear what students will learn in each chapter.

C H A P T E R

1

A H I S TO R I C A L PERSPECTIVE

LEARNING OBJECTIVES

KEY TERMS

After completing this chapter, you should be able to:

Biotechnology

1

Define the term pharmacology.

Genetic engineering

2

Identify the roles of medicines in human society.

Natural products

3

Identify the three ages of pharmacology.

Pharmacology

4

Briefly describe the major characteristics of each of the three ages and their implications for society.

Recombinant DNA technology

Pharmacology is a branch of medical science that deals with the properties and characteristics of chemical agents used for medicinal or other purposes. The actions and effects of these chemical agents on physiological systems are of particular interest. The physiological systems in which these effects are observed may be organs or tissues isolated from the body and artificially maintained—in vitro situations—or within living whole organisms—in vivo situations. In an etymological sense, the word ‘pharmacology’ is derived from two Greek words: pharmakos, which means medicine or drug, and logos, which means study.

C H A P T E R

67

V I TA M I N S , M I N E R A L S AND AMINO ACIDS

Key Terms introduce students to new terminology and are helpful when revising for exams.

LEARNING OBJECTIVES

KEY TERMS

After completing this chapter, you should be able to:

Amino acids

1 List the functions, usage and dangers of vitamin A.

Disorders of metabolism

2 Name the functions and uses of members of the vitamin B group.

Elemental ions

3 Name the functions and use of ascorbic acid. 4 Describe the functions of vitamins E and K. 5 Describe the role of trace elements in human metabolism and disease. 6 Outline the role of fluoride in the prevention of tooth decay and

osteoporosis. 7 Describe the role of zinc salts in therapeutics. 8 Describe the difference between the D - and L -forms of amino acids. 9 Explain the significance of amino acids in disorders of metabolism. 10 Describe the treatment of metabolic disorders using the various amino-acid-

free preparations. 11 List the amino acids that can be used in therapeutics.

Fat-soluble vitamins Hepatic encephalopathy Macrominerals Maple-syrup-urine disease Microminerals Mineral supplementation Over-the-counter (OTC) medicines Phenylketonuria Vitamin supplementation Water-soluble vitamins

This chapter deals with vitamins, minerals and amino acids. All these substances work in complex ways to enable metabolic processes to occur efficiently in the body.

x ii

F U N D A M E N TA L S O F P H A R M A C O L O G Y

C H A P T E R 2 2 P O I S O N I N G A N D E N V E N O M AT I O N

2

What is a chelating agent?

3

Name the agent(s) used in the treatment of poisoning by each of the following substances: a

217

cyanide

Medicine Summary Tables provide a handy list of family names, generic names and trade names for specific medicines. Icons indicate medicines that are only available in Australia or New Zealand. Special considerations are listed where necessary.

b lead c

mercury

d pesticides 4

Define the term envenomation.

5

State the three aims of emergency care when someone is bitten or stung by a venomous animal.

6

Your neighbour visits you in an extremely distressed state. Joey, her three-year-old son, has just swallowed an unknown quantity of paracetamol tablets. What would you advise her to do? Why?

7

Mario Malodoro, a 60-year-old farmer, is brought into the emergency department with organophosphate poisoning. How would this form of poisoning be treated?

8

While clearing rubbish in his backyard, 28-year-old Jeffrey Abelcet is bitten on the hand by a redback spider. His partner bandages his hand and arm firmly. She then drives him to your clinic, which is only five minutes down the road. Comment on the suitability of this treatment. Describe the management of this type of envenomation.

22 MEDICINE SUMMARY TABLE FAMILY NAME

GENERIC NAME

Emetic

ipecacuanha

Adsorbent

activated charcoal + sorbitol

Carbosorb X Carbosorb XS

Iso-osmotic laxatives

electrolytes + polyethylene glycol + ascorbic acid

ColonLYTELY Glycoprep Glycoprep-C Klean Prep Movicol Movicol-Half Moviprep

Methanol intoxication

ethanol + glucose

Cyanide antidote

amyl nitrite dicobalt edetate sodium nitrite sodium thiosulfate

Organophosphate antidotes

atropine sulfate pralidoxime iodide

TRADE NAME(S)

PAM injection

Australia only New Zealand only

260

S E C T I O N V I A U TO N O M I C P H A R M A C O L O G Y

Figure 27.1 Adrenergic nerve action A The branching nerve terminal of a sympathetic postganglionic fibre shows a series of small swellings known as varicosities along the length of each branch. B A summary of events involved in adrenergic nerve stimulation. The action potential travels along the axon until it reaches the varicosities of the axon terminals (1). Depolarisation of the membrane of the varicosity causes the release of chemical transmitter, noradrenaline (NA), into the synaptic gap (2). NA diffuses across the gap and interacts with the adrenergic postsynaptic receptors, triggering an effector response via a G protein-coupledsecond messenger system (3). The transmitter is removed from the synaptic gap by the uptake-1 transporter (4) and is restored to the synaptic vesicles. Any excess transmitter within the terminal not restored to the vesicles is degraded by the mitochondrial enzyme, monoamine oxidase (MAO) (5). Any excess transmitter remaining within the synaptic gap is subject to extraneuronal reuptake (uptake-2). The release of transmitter from the varicosity is also subject to modulation by presynaptic adrenoceptors (enhancement of release by one type, inhibition by another) (6). Such control of transmitter release is known as autoregulation. A. Sympathetic postganglionic fibre

Figures illustrate and clarify complex processes, aiding student comprehension.

Presynaptic varicosity B. Synaptic vesicles containing noradrenaline (NA) 1 Action potential

5

6

Mitochondrion containing MAO 2

Presynaptic adrenoceptor Postsynaptic adrenoceptor CHAPTER 27 ADRENERGIC PHARMACOLOGY

4

Uptake-1

3

279

CLINICAL MANAGEMENT S Y M PAT H O M I M E T I C S Assessment ■■

■■

Obtain baseline vital signs for the person. Report any abnormal findings. These include blood pressure and rate, and rhythm of pulse. Assess colour and temperature of the person’s extremities (for drugs with α1 effects). Conscious state is assessed to determine cerebral perfusion (this is an important consideration if the medicine is administered intravenously for the purpose of maintaining blood pressure). Determine rate, rhythm and depth of respiration. Assess for wheezing if the medicine is used for asthma. Listen to the heart with a stethoscope for dysrhythmias and palpitations (for drugs with α1 or β1 effects). Compare the person’s apical beat with the radial rate. A difference indicates irregularity in rhythm. Determine urinary output and assess for bladder distension (for drugs with α1 effects). Assess whether the person has a history of the following: – glaucoma or prostatic hypertrophy (for drugs with α1 effects); – cardiovascular, cerebrovascular or circulatory disease, hyperthyroidism (for drugs with α1 or β1 effects); – diabetes mellitus (for drugs with α1 or β1 effects). The sympathomimetic agent may intensify the condition, therefore, leading to elevated blood glucose levels from increased glycogen breakdown. The situation would require further clarification with the prescriber.

■■

Determine whether the person is taking monoamine oxidase inhibitors, β-blockers or digoxin, as their effects can be either nullified or intensified by the administration of sympathomimetics.

■■

■■

■■

■■

■■

■■

■■

■■

The person’s vital signs will remain within an acceptable range for the person. The person will experience minimal or no adverse effects from the sympathomimetic.

■■

Implementation ■■

■■

Carefully and regularly monitor the person’s vital signs, conscious state and urinary output. Sympathomimetics administered intravenously can produce profound effects on vital organs at small

Report and record adverse effects of the sympathomimetic, including palpitations, tachycardia (pulse greater than 100 beats/min), tremors or increased glucose levels. Regularly monitor the person’s urinary output (for drugs with α1 effects). Prolonged use of a sympathomimetic may lead to a diminished clinical effect, which is caused by a regulatory decrease in receptor numbers.

Medicine education

Planning ■■

Response

dosages. Their haemodynamic effects should, therefore, be carefully monitored and recorded. Dosages are then titrated according to the person’s response. A large central vein should be used for the administration of intravenous sympathomimetics to prevent peripheral necrosis. The use of intravenous sympathomimetics is restricted generally to clinical settings in which close monitoring of venous and arterial pressures, electrocardiogram and urinary output can be performed, such as intensive care or coronary care units.

Drugs with β2 effects are usually given by inhalation or nebuliser. Check the methods for inhalation and nebulisation (refer to Chapter 7, Tables 7.17 and 7.18, for a description of methods). Instruct the person on the method of administering cold or flu preparations by nasal spray and drops (refer to Chapter 7, Tables 7.7 and 7.8, for description of methods). Instruct the person that nasal sprays used in excess could lead to a rebound nasal congestion. Directions for dosage should be carefully followed. Excessive use of bronchodilator inhalers could lead to adverse effects, such as tachycardia and skeletal muscle tremor. If asthma symptoms appear to be getting worse, the doctor should be consulted. Instruct the person to read all labels of over-thecounter preparations. Many of these preparations contain sympathomimetics and should not be taken if the person has a history of cardiac disease, diabetes, hypertension or cardiac dysrhythmias.

Evaluation ■■

Examine the person’s response to the sympathomimetic for expected and adverse effects. Continue to monitor

Clinical Management Tables highlight clinical applications of theory and utilise the clinical decision-making framework in a step-by-step process for care of the person.

F E AT U R E S

CHAPTER 27 ADRENERGIC PHARMACOLOGY

Figure 27.14  The effects of α antagonists Headache, drowsiness Nasal congestion

Pupil constriction Dry mouth

Vasodilation Decreased blood pressure

Reflex tachycardia

275

β-blockers were developed to reduce potentially lifethreatening reactions, such as bronchospasm, resulting from β2 receptor blockade. Acebutolol, oxprenolol and pindolol are partial agonists, and will induce sympathomimetic effects when there is low sympathetic tone. Uniquely, nebivolol produces a therapeutic mild vasodilating effect through an interaction with the nitric oxide synthesis pathway. Common adverse effects

Increased peristalsis

Promotes micturition Impotence

The effects of β-blockers are shown in Figures  27.15 and  27.16. Common adverse effects include dizziness, lethargy, insomnia and diarrhoea. Contraindications include known hypersensitivity, heart block, severe heart failure, cardiogenic shock and other severe circulatory disorders, bradycardia with a heart rate of less than 45–50 beats per minute, sick sinus syndrome, atrioventricular block, severe hypotension or uncontrolled heart failure. They should also not be used in people with a history of asthma or chronic obstructive pulmonary disease.

Human Models visually illustrate the effects, both positive and negative, of pharmacological agents on the human body. Male and female human models are used to illustrate the effects of pharmacological agents.

Clinical considerations

erectile dysfunction, but it must be used with papaverine or alprostadil to be effective. Selective α  antagonists are used for control of hypertension. All α1  antagonists may cause a rapid fall in blood pressure after the first dose. The patient should be advised to take the first dose at bedtime to reduce the consequences of this effect. The dose is then titrated slowly at two-weekly intervals. This hypotensive effect is likely to be more severe in the older person and in the individual who takes diuretics. It is recommended, therefore, that diuretics be withheld for a few days before commencing an α  antagonist. Postural hypotension and dizziness may occur and the person is advised to get up gradually from a lying or sitting position. Advise individuals to sit down if they become dizzy.

β A N TA G O N I S T A C T I O N Mechanism of action Acebutolol, carvedilol, nadolol, oxprenolol, pindolol, propranolol, sotalol and timolol are non-selective β antagonists or blockers. Atenolol, betaxolol, bisoprolol, esmolol, nebivolol and metoprolol are relatively β1selective (cardioselective) blocking drugs. Cardioselective

Applications for β1 antagonists are to be found in the control of cardiac disease, hypertension, migraine prophylaxis, situational anxiety and thyrotoxicosis. In a seemingly counter-intuitive way, metoprolol, bisoprolol and carvedilol have been used judiciously in the management of heart failure (for details see Chapter  50). There are no clinical applications for β2 antagonists. Abrupt withdrawal of β  antagonists may accentuate angina or produce rebound hypertension, myocardial infarction or ventricular dysrhythmias. It is, therefore, important that β  antagonists be slowly reduced when treatment is to cease. Cardioselective β antagonists may be preferred in conditions such as peripheral vascular disease, Raynaud’s syndrome or diabetes mellitus because of their decreased effect on altering glucose metabolism and causing peripheral vasoconstriction. In diabetes, non-selective β antagonists may mask important signs of hypoglycaemia, including tachycardia and tremor, therefore increasing the severity of the condition. However, β1 selectivity diminishes with higher doses of the medicine.

NON-SELECTIVE ADRENERGIC BLOCKING AGENTS Celiprolol and labetalol non-selectively block both α and β adrenoreceptors in the periphery.

Case Studies with Accompanying Questions immerse students in scenarios involving people taking medicines, family members and health professionals. Students are given the opportunity to apply knowledge, practise drug calculations and dosages, and convey their understanding of pharmacological principles and interactions in a variety of clinical settings.

18

SECTION I PHARMACOLOGY WITHIN THE SOCIAL CONTEXT

CHAPTER REVIEW ■■

Advertising of medicines can affect the medicine management activities of health professionals.

■■

Advertising can influence the medicinal activities of consumers.

■■

■■ ■■

■■ ■■

■■ ■■

CHAPTER 28 CHOLINERGIC PHARMACOLOGY

Mechanism of action

C A S E S T U DY 1

Questions

Mrs JH is a 62-year-old woman who has had rheumatoid arthritis in her hands, hips and knees for about eight years. She is receiving weekly assistance from her local district nursing service because of impaired mobility. For the arthritis, she is taking the non-steroidal anti-inflammatory drug ibuprofen daily and receives intermittent hydrocortisone therapy when the condition worsens.

1

Underlying Mr FT’s condition is a change in the level of activity of a division of the autonomic nervous system. Which division is affected and what is the nature of the change?

2

Which type or types of tissue receptor are involved in this condition?

3

Explain the mechanism by which the organophosphate insecticides induce this state.

4

Which clinical drug group do the organophosphate insecticides closely resemble in terms of their action? Why?

5

Which drug group can be used as an antidote to oppose the effects of the insecticide? Why?

You are caring for Mrs JH. She tells you that her eyes have ‘not been the best of late’ and she is finding it hard to see things out of the corners of her eyes. She is referred to her family doctor. He, in turn, refers her to the local eye clinic where a diagnosis of open-angle glaucoma is made. Mrs JH is prescribed eye drops containing a miotic agent. This medicine causes pupil constriction and facilitates the drainage of aqueous humour through the canal of Schlemm.

Questions 1

a Applying your knowledge of adrenergic and cholinergic pharmacology, which groups of drugs are well suited as miotics? b What receptor types are they acting on and how are they affecting the function of these receptors?

2

a State three common side-effects associated with each of these drug groups. b Would you expect to observe systemic side-effects associated with this therapy? Why?

3

Referring to Chapter 19, explain why Mrs JH may be predisposed to glaucoma.

C A S E S T U DY 3 Mr JJ, aged 68 years, visits the outpatient clinic for a checkup relating to his asthma condition. He has occasional bouts of acute asthma, which is adequately controlled using a salbutamol inhaler. Mr JJ indicates that he has just been diagnosed with open-angle glaucoma, which is being treated with timolol 0.25% eye drops. He inserts one drop in each eye twice daily. The outpatient nurse ascertains that he has used the eye drops for two days.

Questions 1

To which drug group does salbutamol belong and how does it act to relieve asthma? You may wish to refer to Chapter 27.

2

To which drug group does timolol belong, and how does it act to lower intraocular pressure? You may wish to refer to Chapters 27 and 83.

3

What is the potential problem for Mr JJ using salbutamol and timolol?

C A S E S T U DY 2 Mr FT is a 22-year-old man who has been admitted to your hospital emergency department. He has been working as a labourer at a nearby market garden that specialises in growing flowers. He was spraying the crops with the organophosphate insecticide malathion when he collapsed. He was not wearing the appropriate protective clothing. You observe that he is conscious and complains of gastrointestinal cramps and nausea. He vomited a couple of times in the ambulance as he was transported to hospital. You note the following manifestations: profuse sweating, drooling, lacrimation, bradycardia, agitation, muscle twitching and constricted pupils. Supportive treatment is implemented, which involves respiratory support and the administration of antidotes. His progress is carefully monitored during this critical period. His recovery is without complications. He is discharged from hospital several days later.

C A S E S T U DY 4 Ms RW is a 50-year-old woman who is suffering from sinus bradycardia (a slow heart rate). Recently, she has had some problems maintaining a normal blood pressure. She is given a medicine that acts on the autonomic innervation of the heart and returns her heart rate to normal.

Questions 1

State the divisions involved, the transmitters released, the receptors concerned and the effects associated with autonomic nervous system innervation of the heart.

2

Name the possible cholinergic and/or adrenergic drug groups that could be used to reverse Ms RW’s bradycardia.

Over-the-counter preparations are available to consumers without a prescription, and often without supervision of a health professional. The generic name of a medicine is the shortened, simplified version of the chemical name. The brand name is the trademark used by a pharmaceutical pharmaceutical company to identify the preparation of a particular drug. Generic prescribing means that a pharmacist can supply any formulation of a particular medicine. Generic substitution means that a pharmacist can supply any formulation of the medicine without referring back to the prescriber. Polypharmacy, which is a major problem for older people, involves the excessive or inappropriate use of medicines. The traditional beliefs and values of a particular culture influence an individual’s perceptions and expectations about drug therapy.

FURTHER READING Banning M, 2007, Medication Management in Care of Older People, Blackwell Publishing, Oxford. Carmody D & Mansfield PR, 2010, ‘What do medical students think about pharmaceutical promotion?’ Australian Medical Student Journal, 1(1), 54–7. DeLorme DE & Huh J, 2009, ‘Seniors’ uncertainty management of direct-to-consumer prescription drug advertising usefulness’, Health Communication, 24, 494–503. Hamilton HJ, Gallagher PF & O’Mahony D, 2009, ‘Inappropriate prescribing and adverse drug events in older people’, BMC Geriatrics, 9, 5, 28. Peiris DP, Patel AA, Cass A, Howard MP, Tchan ML, Brady JP, De Vries J, Rickards BA, Yarnold DJ, Hayman NE & Brown AD, 2009, ‘Cardiovascular disease risk management for Aboriginal and Torres Strait Islander peoples in primary health care settings: Findings from the Kanyini audit’, Medical Journal of Australia, 191, 304–9. Spurling GK, Mansfield PR, Montgomery BD, Lexchin J, Doust J, Othman N & Vitry AI, 2010, ‘Information from pharmaceutical companies and the quality, quantity, and cost of physicians’ prescribing: a systematic review’. Public Library of Science Medicine, 19,7(10), e1000352. Wessell AM, Nietert PJ, Jenkins RG, Nemeth LS & Ornstein SM, 2008, ‘Inappropriate medication use in the elderly’, American Journal of Geriatric Pharmacotherapy, 6, 21–7.

WEB RESOURCES A Brief History of Pharmacology pubs.acs.org/subscribe/journals/mdd/v04/i05/html/05timeline.html Australian Bureau of Statistics www.abs.gov.au/AUSSTATS What is Pharmacology? www.pharmacology.med.umn.edu/whatispharm.html Everybody (Health Consumer Information) www.everybody.co.nz Māori Health www.health.govt.nz/our-work/populations/maori-health New Zealand Deserves Better. Direct-to-Consumer Advertising (DTCA) of Prescription Medicines in New Zealand: for Health or Profit? journal.nzma.org.nz/journal/116-1180/556 Office for Aboriginal and Torres Strait Islander Health www.health.gov.au/oatsih

Chapter Review summarises the essential information in each chapter, providing a quick revision tool.

311

xiii

x iv

F U N D A M E N TA L S O F P H A R M A C O L O G Y

1106

S E C T I O N X V M E D I C I N E S U S E D T O P I C A L LY

REVIEW QUESTIONS 1 What are the major functions of skin? 2 Indicate the major characteristics of each of the following skin layers: a

Review Questions check that students remember and understand the clinical significance of key chapter content.

dermis

b stratum basale c

stratum corneum

3 Outline the major characteristics of each of the following skin preparations: a

lotion

b gel c

rubefacient

d keratolytic e 4

cream

For each of the following drug groups, indicate the skin condition(s) that they are used to treat: a

antimicrobial agents

b corticosteroids c

immunomodulators

d keratolytics 5 Outline the pathophysiology of the following two conditions: a

acne

b psoriasis 6 For each of the following agents used in the management of psoriasis, indicate whether it is directed towards

reducing the inflammation or the rate of cell proliferation: a

the corticosteroids

b methotrexate c

PUVA therapy

d cyclosporin 7 Ebony Tinselle is 17 years old and receiving treatment with the retinoid isotretinoin for severe acne. What

medicine education would you offer Ebony? 8 Mark Mitchell is a 35-year-old man about to commence methotrexate therapy for psoriasis. What baseline

examinations are required for this therapy? What advice should Mark receive regarding his therapy? 9 Two of the four primary school-aged children in Charlotte Austen’s family have head lice infestations. Charlotte

buys a shampoo containing piperonyl butoxide and a pyrethrin. Briefly outline the treatment approach to eradicate the infestation. 10 Judy Jones, a 35-year-old mother of two young children, is ordered a dithranol preparation to treat her psoriasis.

With what medicine education would you provide her for the application of dithranol? What extra care should she take when tending to her children? 11 Martha Bortiolis, a 15-year-old student, complains of pimples and blackheads on her face and back. As the health C H A P T E R 2 1 PA E D I A T R I C A N D G E R I A T R I C P H A R M A C O L O G Y

professional who examines Martha, you recommend a benzoyl peroxide cream to treat the acne. How would you advise Martha on the use of the cream? 12 Jack Brown, aged 55 years, begins a course of treatment with minoxidil liquid for the treatment of androgenic

F U R T H E R RE A DIN G

alopecia. What counselling would you offer Mr Brown about using this liquid?

Buxton IL, 2006, ‘Pharmacokinetics and pharmacodynamics: the dynamics of drug absorption, distribution and elimination’, in Brunton LL, Lazo JS & Parker KL (eds), Goodman and Gilman’s Pharmacological Basis of Therapeutics, 11th edn, McGraw-Hill, New York, pp. 1–39. Eshkoli T, Sheiner E, Ben-Zvi Z & Holcberg G, 2011, Drug transport across the placenta, Current Pharmaceutical Biotechnology, 12(5): 707–14. Hughes CM, Roughead E & Kerse N, 2008, ‘Improving use of medicines for older people in long-term care: contrasting the policy approach of four countries’, Healthcare Policy, 3(3): e154–e167. Jacqz-Aigrain E & Choonara I, eds, 2006, Paediatric Clinical Pharmacology, Informa HealthCare, London. Khojasteh SC, Wong H & Hop CECA, 2011, Drug Metabolism and Pharmacokinetics Quick Guide, Springer, New York. Koch S, Gloth MF, Nay R (eds), 2010, Medication Management In Older Adults: a Concise Guide For Clinicians. Springer Science and Business Media, New York. Le Couteur D, McLachlan A & de Cabo R, 2012, Aging, drugs, and drug metabolism. Journals of Gerontology. Series A: Biological Sciences & Medical Sciences, 67(2): 137–39.

Further Reading lists appear at the end of each section and provide information for students wishing to pursue a topic in further detail for assessment or interest.

McCance K & Huether SE, 2009, Pathophysiology, 6th edn, Elsevier Mosby, Sydney (for age-related and disease-related changes in body structure and function). Sissung TM, Troutman SM, Campbell TJ, Pressler HM, Sung H, Bates SE and Figg WD, 2012, Transporter pharmacogenetics: transporter polymorphisms affect normal physiology, diseases, and pharmacotherapy, Discovery Medicine, 13(68): 19–34. The Royal Australian College of General Practitioners, Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, Pharmaceutical Society of Australia, 2012, Australian Medicines Handbook, AMH Pty Ltd, Adelaide. Weier N, He SM, Li XT, Wang LL & Zhou SF, 2008, ‘Placental drug disposition and its clinical implications’, Current Drug Metabolism, 9, 106–21.

WE B RE S O U RCE S Australian Government Department of Health and Ageing www.health.gov.au Australian Statistics on Medicines www.tga.gov.au/hp/medicines-statistics-2010.htm Clinical Trials (US site) www.clinicaltrials.gov Health Insite www.healthinsite.gov.au/index.cfm Interactive Clinical Pharmacology www.icp.org.nz Medicines Australia (Pharmaceutical Industry Group) www.medicinesaustralia.com.au Medsafe www.medsafe.govt.nz NZ Ministry of Health www.moh.govt.nz/moh.nsf Pharmacokinetics: An Introduction (US site) www.4um.com/tutorial/science/pharmak.htm Therapeutic Goods Administration (TGA) www.tga.gov.au/index.htm Trials Central: online register of US clinical trials www.trialscentral.org

CHAPTER 58 ANTIEMETIC AGENTS

745

W EB R ESO UR C ES Better Health Channel: Haemorrhoids www.betterhealth.vic.gov.au/bhcv2/bhcarticles.nsf/pages/Haemorrhoids Centre for Digestive Diseases: Disease Information www.cdd.com.au Crohn’s and Colitis Australia www.acca.net.au Gastroenterological Society of Australia: Professional Information www.gesa.org.au Health Insite: Digestion and Stomach Disorders www.healthinsite.gov.au/topics/Digestion_and_Stomach_Disorders Medline Plus: Constipation (US site) www.nlm.nih.gov/medlineplus/constipation.html Medline Plus: Nausea and Vomiting (US site) www.nlm.nih.gov/medlineplus/nauseaandvomiting.html Nausea and Vomiting During Pregnancy (Canadian site) www.sogc.org/health/pregnancy-nausea_e.asp Primary Care Society for Gastroenterology (UK site) www.pcsg.org.uk

Web Resources lists appear at the end of each section and provide links to relevant websites for further study and online research.

207

TEACHING AND L E A R N I N G PA C K A G E

FOR STUDENTS

FOR INSTRUCTORS

MyHealthProfessionsKit is an online study tool that will help you understand, revise and master the concepts in the textbook.

Computerised TestBank

•

multiple-choice revision questions;

Create professional-looking customised printed or online exams in just minutes using Pearson’s TestGen software. Build tests from the database of over than 600 true–false and multiple-choice questions, edit questions or add questions of your own.

•

interactive ‘drag and drop’ revision activities;

PowerPoint Slides

•

animations demonstrating the mechanisms of action for various medicines;

•

glossary flashcards to test your knowledge of key pharmacology terms;

Lecture slides pair key points with images from each chapter to facilitate effective lectures and classroom discussions.

•

realistic drug calculation scenarios to give you practice;

•

searchable eBook (if you have purchased the MyLab with eBook option).

MyHealthProfessionsKit gives you access to these study resources:

Solutions Manual This manual provides the answers to the end-of-chapter exercises in the text. You have the option of making this manual available to your students.

Digital Media Library All figures and tables from the textbook are provided in jpeg format.

F I G U R E S A N D TA B L E S FIGURE

1.1

A time line highlighting some major pharmaceutical events

1.2

Medicinal plants commonly found in suburban gardens

2.1

Prescription indicating that brand substitution is permitted

13

7.1

Appropriate technique for administering eye drops

62

7.2

Appropriate technique for administering ear drops

62

7.3

Location of sublingual and buccal sites

63

7.4

Design of patches used for transdermal administration of medicines

65

7.5

Nebuliser unit with nebuliser, oxygen tubing and mask

72

7.6

Use of a metered-dose inhaler

72

7.7

Use of a spacer in a young child

72

9.1

Intravenous fluid chart

84

9.2

The national inpatient medication chart

86

9.3

Example of a completed medication chart

87

9.4

Request for cross-matching

88

9.5

4 6

Once-only medicines and health professional-initiated medications chart

89

9.6

Additive label

89

9.7

Additive label

89

9.8

Observation chart

90

9.9

Diabetic chart

91

10.1

Sequence of events and checking procedure for medicine administration

94

13.1

An example of drug nomenclature

129

13.2

Molecular structures of three tricyclic antidepressants

131

14.1

Drug absorption between body compartments

134

14.2

Factors influencing drug absorption

136

14.3

Protein-bound drug reservoir

137

14.4

Ion trapping

138

14.5

Apparent volume of distribution

139

15.1

Drug metabolism

143

15.2

Differences in spatial molecular arrangements of glucose and galactose

144

15.3

The enterohepatic cycle

145

15.4

Hepatic first-pass effects

146

15.5

Drug excretion

147

15.6

The development of a steady-state concentration

148

15.7

The effect of a loading dose on plasma concentration

149

15.8

Kinetics of drug metabolism

149

F I G U R E S A N D TA B L E S

FIGURE

16.1

Common sites of drug interactions

156

17.1

Competitive inhibition of enzyme–substrate reactions

162

17.2

Structures of 4-aminobenzoic acid and a sulfonamide, sulfamethoxazole

163

17.3

Non-competitive inhibition of enzyme-substrate reactions

164

17.4

Receptor sites of drug action

165

17.5

Agonist and antagonist action

166

17.6

Relative drug potency and efficacy

167

18.1

Time-line and costs for development and evaluation of new drugs

172

18.2

Graph of blood drug concentration showing the margin of safety

174

18.3

Type I hypersensitivity reaction

175

18.4

Type II hypersensitivity reaction

176

18.5

Type III hypersensitivity reaction

176

18.6

Type IV hypersensitivity reaction

177

19.1

Normally distributed drug responsiveness at the population level

183

19.2

Bimodal drug responsiveness at the population level

183

19.3

Tailoring drug treatment to the individual

184

19.4

Potential clinical consequences of genetic polymorphism

185

21.1

Administering medicine to a small child using a dropper

199

21.2

Example of a dose-administration aid

201

21.3

Sample morning and afternoon medicine clocks for use by an older person

202

22.1

Principles associated with the management of poisoning

211

22.2

Examples of terrestrial animals that pose a risk to humans

215

23.1

Principles associated with the management of an overdose

220

23.2

Gastric tubes that can be used for the rapid evacuation of gastric contents

221

23.3

Patient positioning during gastric lavage

221

23.4

Paracetamol treatment nomograph for Australia and New Zealand

222

25.1

Pharmacological effects of anabolic steroids

242

26.1

Divisions of the nervous system

251

26.2

Schematic representation of a typical autonomic nervous system pathway

253

26.3A

The characteristics of a sympathetic nerve pathway

254

26.3B

The characteristics of a parasympathetic nerve pathway

254

27.1

Adrenergic nerve action

260

27.2

Adrenergic agonist effects

261

27.3

Flowchart showing the effects of α1 agonists

263

27.4

The effects of α1 agonists

264

27.5

Flowchart showing the effects of β1 agonists

265

27.6

The effects of β1 agonists

266

27.7

Flowchart showing the effects of β2 agonists

267

27.8

The effects of β2 agonists

268

xv ii

xv iii

F U N D A M E N TA L S O F P H A R M A C O L O G Y

FIGURE

27.9

Intracellular events triggered by the action of a first messenger

269

27.10

Second messengers involved in adrenergic function

270

27.11

Direct- and indirect-acting sympathomimetics

271

27.12

Adrenergic antagonist effects

273

27.13

Flowchart showing the effects of α antagonists

274

27.14

The effects of α antagonists

275

27.15

Flowchart showing the effects of β antagonists

276

27.16

The effects of β antagonists

277

27.17

Flowchart showing the effects of dopamine agonists

278

28.1

Cholinergic nerve stimulation

287

28.2

Flowchart showing the effects of nicotinic receptor agonists

289

28.3

The effects of nicotinic receptor agonists

290

28.4A

Flowchart showing the effects of muscarinic receptor (M1 and M2)

28.4B

agonists

291

Flowchart showing the effects of muscarinic receptor (M3) agonists

292

28.5

The effects of muscarinic receptor agonists

293

28.6

Cholinergic agonist effects

294

28.7

Cholinergic antagonist effects

295

28.8

Flowchart showing the effects of nicotinic receptor antagonists

296

28.9

The effects of nicotinic receptor antagonists

297

28.10A Flowchart showing the effects of muscarinic (M1 and M2) antagonists

299

28.10B Flowchart showing the effects of muscarinic (M3) antagonists

300

28.11

The effects of muscarinic antagonists

301

30.1

The action of histamine and antihistamines at H1 receptors

322

30.2

The effects of the classic antihistamines

323

31.1

Pathway for prostaglandin synthesis and sites of drug action

330

32.1

The physiological effects of nitric oxide

339

32.2

The physiological effects of the endothelins

340

33.1

Principal parts of the human brain

348

34.1

Flowchart showing the effects of first-generation (typical) antipsychotics

34.2 35.1

357

Important adverse effects associated with the second-generation (atypical) antipsychotics

359

Mechanism of action of the benzodiazepines on GABA receptors

369

35.2

The effects of the benzodiazepines

370

35.3

Mechanism of action of the barbiturates on GABA receptors

373

36.1

Monoamine nerve function

382

36.2

Proposed synaptic sites of action of the antidepressant agents

383

36.3

The mechanism of action and adverse effects of the antidepressant drugs

37.1 37.2

384

Diagrammatic representation of (A) normal and (B) abnormal nigrostriatal pathway functioning

400

The effects of levodopa

402

F I G U R E S A N D TA B L E S

FIGURE

37.3

Anti-Parkinsonian agents and their common adverse effects

406

37.4

The effects of the acetylcholinesterase inhibitors

407

38.1

Sites of action of antiseizure agents

421

38.2

Sites of action of muscle relaxants

429

39.1

The effects of methylphenidate and dexamphetamine

439

40.1

The pain transmission pathway

451

40.2

Self-reporting measures for the intensity of pain

452

40.3

Analgesic chart for documenting pain assessment and management

453

40.4

World Health Organization ladder of analgesia

453

40.5

The effects of narcotics

455

40.6

Flowchart showing the effects of narcotic analgesics

456

41.1

Biosynthesis of prostaglandins and related mediators with the site of action of the NSAIDs

468

41.2

Flowchart showing the effects of NSAIDs

470

41.3

The effects of NSAIDs

471

42.1

Pathophysiological changes in cerebral blood flow underlying migraine headaches

489

43.1

The actions of general anaesthetics on membrane ion channels

500

44.1

The nerve action potential

509

44.2

States of activation in voltage-gated membrane channels

509

44.3

The physiology of nerve transmission

510

45.1

Cholesterol transport

524

45.2

The effects of the statins

528

46.1

Blood pressure control mechanisms

536

46.2

The sites of action of anti-hypertensive agents

539

46.3

Flowchart showing the effects of the angiotensin receptor antagonists

541

46.4

Flowchart showing the effects of the α1 antagonists

543

47.1

Pathophysiology and rationale of pharmacological therapy of an angina attack

557

47.2

Flowchart showing the effects of the organic nitrates

559

47.3

The effects of organic nitrates

560

47.4

Flowchart showing the effects of calcium channel antagonists

562

47.5

The effects of calcium channel blockers

563

47.6

Sites of action of drugs that produce smooth muscle relaxation

566

48.1

Normal coagulation and sites of anticoagulant action

574

48.2

Platelet adhesiveness and medicines that impair this process

580

49.1

Nephron physiology and the sites of action of renal medicines

596

49.2

The effects of the thiazides and related diuretics

598

50.1

Flowchart showing the pathophysiology of heart failure

609

50.2

Flowchart showing the effects of the angiotensin-converting enzyme inhibitors

611

50.3

The effects of angiotensin-converting enzyme inhibitors

612

50.4

Flowchart showing the effects of carvedilol

614

xix

xx

F U N D A M E N TA L S O F P H A R M A C O L O G Y

FIGURE

50.5

The neurophysiological actions of cardiac glycosides

50.6

Flowchart showing the effects of drugs on the pathophysiological

616

process of heart failure

620

51.1

Voltage-gated membrane channels with one gate

627

51.2

Voltage-gated membrane channels with two gates

628

51.3

The generalised myocardial action potential

628

52.1

Distribution of body compartments

637

52.2

Movement of fluid across the capillary

638

52.3

Schematic representation of changes in fluid pressure that lead to oedema

639

52.4

Effects of adding different fluids to the intravascular compartment

641

52.5

Effects of crystalloid, colloid and a combination of both fluids in the treatment of hypovolaemic shock

643

54.1

The pathophysiology of extrinsic asthma

661

54.2

The phases of an asthma attack

661

54.3

Flowchart showing the effects of β2 agonists

663

54.4

Flowchart showing the effects of antimuscarinic medicines

665

54.5

Flowchart showing the effects of methylxanthine bronchodilators

667

55.1

Flowchart showing the effects of α1 agonists

685

56.1

Gastric acid production and the sites of action of anti-ulcerant medicines

703

56.2

The effects of the histamine H2-receptor antagonists

704

56.3

The effects of the proton pump inhibitors

705

57.1

Mechanisms of action of laxatives

715

58.1

Pathophysiology of vomiting and the sites and mechanisms of action of antiemetic agents

735

58.2

The effects of the phenothiazine antiemetics and related agents

737

59.1

The effects of pituitary hormones and sites of action of medicines affecting pituitary function

751

61.1

Correct position for inserting an insulin injection

773

61.2

Sites of amino acid substitution in the insulin molecule required to make the short-acting insulin analogues

775

61.3

A chronic complication of diabetes mellitus

777

61.4

Flowchart showing the effects of the sulfonylureas

779

61.5

Flowchart showing the effects of the biguanides

780

61.6

Flowchart showing the effects of the thiazolidinediones

782

61.7

Sites of action of the hypoglycaemic agents

785

62.1

The effects of glucocorticoids

793

62.2

The mechanism of action of metyrapone

795

63.1

Sites of action of sex hormone antagonists

813

64.1

Cells involved in bone metabolism

823

64.2

Calcium homeostasis

824

64.3

Vitamin D metabolism

825

F I G U R E S A N D TA B L E S

FIGURE

65.1

Mechanism of action of uricosuric agents

836

65.2

Purine metabolism

837

66.1

The physiological regulation of food intake

844

66.2

The effects of the stimulant anorectics

846

67.1

The organs and body systems on which each vitamin has its major effect

857

67.2

Structural formulae of nicotine and nicotinic acid

860

67.3

The stereoisomers of serine

870

68.1

Percutaneous endoscopic gastrostomy (PEG) tube placement

877

68.2

Total parenteral nutrition through a central venous catheter in the right subclavian vein

881

69.1

The spiky leaves of the aloe vera plant

887

69.2

The chamomile daisy, matricaria recutita

888

69.3

Cranberry

888

69.4

The echinacea purpurea maxima flower

889

69.5

Evening primrose flower

890

69.6

The feverfew daisy

890

69.7

A basket of garlic bulbs

891

69.8

Ginger

892

69.9

Ginkgo

892

69.10

Ginseng

893

69.11

Flower of the red clover

894

69.12

St John’s wort (hypericum)

895

69.13

Saw palmetto

895

69.14

Valerian

896

70.1

Mechanisms of action of antimicrobial agents

910

70.2

Activity of time-dependent antimicrobial agents

914

70.3

Activity of concentration-dependent antimicrobial agents

914

71.1

The sites of action of the sulfonamides and trimethoprim in DNA/RNA synthesis

72.1

Mechanism of action of antibacterial medicines that inhibit cell wall  synthesis

72.2

928

Mechanism of action of the synthetic antibacterial medicines affecting  metabolism

72.4

924

Mechanism of action of antibacterial medicines that inhibit protein  synthesis

72.3

918

933

Mechanism of action of antibacterial medicines affecting plasma membrane permeability

933

73.1

Actions of the antituberculotic agents

949

74.1

Basic structure of a quaternary compound

963

74.2

The hexadecanyl group

963

75.1

Sites of action of the antiprotozoal agents

971

75.2

Sites of action of the anthelmintic medicines

974

xxi

x xii

F U N D A M E N TA L S O F P H A R M A C O L O G Y

FIGURE

76.1

Life cycle of Plasmodium

982

77.1

The process of viral infection in a human host cell

992

77.2

Common sites of action of antiviral agents

993

78.1

Cellular sites of action of antifungal agents

1014

79.1

The proliferation of immune cells in an immune response

1027

80.1

The cell cycle

1051

80.2

The folic acid pathway and sites of action of folic acid analogues

1056

81.1

Gene therapy techniques

1081

82.1

The structure of skin

1091

83.1

The parts of the eye

1112

83.2

The pathophysiology of glaucoma

1118

F I G U R E S A N D TA B L E S

TA B L E

2.1

Common features of polypharmacy

14

2.2

Consequences of polypharmacy

14

3.1

Control over medicine use in Australian state and territory legislation

22

3.2

Standard for the uniform scheduling of drugs and poisons in Australia

23

3.3

Grouping of medicines in New Zealand

24

3.4

Scheduling of controlled substances in New Zealand

24

3.5

Information required on a ward register for the administration of drugs of dependence

26

3.6

Steps required for telephone orders of prescription medicines

27

3.7

Steps required for standing orders of prescription medicines

27

4.1

Ethical principles and their meanings

31

4.2

Requirements for informed and valid consent

31

5.1

Factors affecting a person’s adherence to medicine regimens

40

5.2

Client teaching through the clinical decision-making process

41

7.1

Administering medicines by the oral route

59

7.2

Administering medicines by the nasogastric route

60

7.3

Administering medicines by the optic route

61

7.4

Administering medicines by the aural route

61

7.5

Administering medicines topically (on the skin)

62

7.6

Administering medicines by the sublingual/buccal route

63

7.7

Administering medicines by the nasal route: drops

64

7.8

Administering medicines by the nasal route: sprays

64

7.9

Examples of transdermal products

65

7.10

Administering medicines by the transdermal route

65

7.11

Administering medicines by the rectal route: suppositories

66

7.12

Administering medicines by the rectal route: enemas

67

7.13

Administering medicines by the vaginal route

68

7.14

Administering medicines by the subcutaneous route

69

7.15

Administering medicines by the intramuscular route

70

7.16

Administering medicines by the intravenous route

71

7.17

Administering medicines by the respiratory route: inhalers

73

7.18

Administering medicines by the respiratory route: nebulisers

73

7.19

Shelf life of preparations after opening

74

11.1

Respiratory depression

98

11.2

Anaphylactic shock

11.3

Dizziness

100

11.4

Constipation

101

11.5

Hypertension

101

11.6

Hypotension

102

11.7

Oral candidiasis (oral thrush)

103

11.8

Rash

103

11.9

Dry mouth

104

11.10

Nausea

105

99

xxiii

x xiv

F U N D A M E N TA L S O F P H A R M A C O L O G Y

TA B L E

11.11

Drowsiness/sedation

105

11.12

Fever

106

11.13

Photophobia

107

11.14

Stomatitis

107

11.15

Diarrhoea

108

11.16

Anogenital candidiasis

109

11.17

Vomiting

109

11.18

Blistering

110

11.19

Photosensitivity

110

11.20

Postural hypotension

111

12.1

Determination of relative risk

115

12.2

Determination of the population absolute risk

116

12.3

Determination of relative risk reduction and absolute risk reduction

116

12.4

Effect of increasing the incidence of events

117

12.5

Effect of increased duration on number needed to treat

118

13.1

Examples of differing forms of individual generic drugs used in clinical practice

128

13.2

Suffixes used to identify common drug groups

131

16.1

Interactions after absorption

154

16.2

Selected drug interactions associated with cytochrome P450

156

18.1

Categorisation of medicines in pregnancy

179

21.1

Reasons for non-adherence with treatment in older people

200

21.2

Improving adherence with drug treatments

201

21.3

Preparations that are not suitable for crushing

203

21.4

Medicines causing severe adverse drug reactions in the older person

203

22.1

Chelating agents

213

22.2

Antivenoms and their sources

216

25.1

World Anti-Doping Agency (WADA) list of banned substances

240

26.1

Effects of the parasympathetic and sympathetic divisions on various organs

26.2

252

Anatomical and physiological differences between the parasympathetic and sympathetic divisions

255

26.3

Examples of neuromodulators of the autonomic nervous system

256

27.1

Examples of autonomic second messenger systems

269

28.1

Pharmacokinetic profiles of some non-depolarising neuromuscular blocking agents

298

29.1

The classification of chemical mediators

315

29.2

Examples of peptide and protein mediators

316

30.1

Histamine receptor subtype locations and effects

319

31.1

General actions of prostaglandins

331

31.2

Some actions of serotonin at different receptor sites

333

33.1

Brain regions and chemical transmitters

350

34.1

Classification of dopamine receptor subtypes

353

F I G U R E S A N D TA B L E S

TA B L E

34.2

Tendency of antipsychotics to cause adverse effects

355

35.1

Types of common anxiety disorders

368

35.2

Half-lives and therapeutic uses of some benzodiazepines

371

36.1

Types of depression

381

36.2

Tyramine-containing foods

387

37.1

Treatment regimen for combined therapy in Parkinson’s disease

406

37.2

Medicines used in the symptomatic treatment of multiple sclerosis

410

38.1

Medicines that may produce seizure-like symptoms

419

38.2

Common seizure types and their major characteristics

420

38.3

Common medicines used to treat seizure types

422

40.1

Pain history

452

40.2

Endogenous opioid receptors

454

40.3

Equianalgesic agent table

457

41.1

Pharmacokinetic characteristics of NSAIDs and related medicines

472

43.1

The major contraindications of inhalation anaesthetics

501

44.1

Local anaesthetics comparative information

513

45.1

Desirable population blood lipid levels

524

46.1

Coexisting conditions and the antihypertensive agents

548

48.1

Some substances that promote or inhibit haemostasis

575

48.2

Some medicines that increase warfarin activity

579

48.3

Some medicines that decrease warfarin activity

579

50.1

New York Heart Association’s (NYHA) classification of heart failure

608

51.1

Classes of antidysrhythmic agents and their applications

630

52.1

Distribution of body fluids and fat at different ages

637

52.2

Definitions of pressures existing at the capillary level

638

52.3

Clinical indications for fluid therapy

641

52.4

Blood products

644

52.5

Colloid solutions

645

52.6

Examples of crystalloid solutions

646

52.7

Causes of hypokalaemia

647

52.8

Foods rich in potassium

647

52.9

Causes of hyperkalaemia

648

54.1

Signs of poor asthma control

671

54.2

How to help a person with asthma to achieve medicine adherence

671

54.3

Management of asthma according to severity of symptoms

671

54.4

First aid management of an asthma attack

672

54.5

Management of COPD according to severity of symptoms

672

56.1

Actions of prostaglandins on some digestive functions

705

57.1

Characteristics of laxative categories

716

57.2

Some common bulk-forming laxatives

719

59.1

Pituitary hormones and their effects

750

60.1

Major effects of thyroid hormone (T4 and T3) in the body

763

61.1

Insulin preparations and their pharmacokinetics

776

xxv

xx v i

F U N D A M E N TA L S O F P H A R M A C O L O G Y

TA B L E

61.2

Medicines that may raise or lower blood glucose concentration

776

62.1

Adrenocortical hormones and their effects

792

62.2

Some corticosteroid potencies compared with hydrocortisone

794

63.1

Summary of hormonal effects of oestrogens, progesterone and testosterone

802

63.2

Progestogen-only contraceptive preparations

806

63.3

Oral contraceptive preparations

808

63.4

Advice on a missed dose of an oestrogen–progestogen combined oral contraceptive pill

810

63.5

Advice on a missed dose of a progestogen-only contraceptive pill

810

63.6

Process for changing contraceptive pills

810

66.1

Suggestions for safe and effective weight loss

845

67.1

Amino acids used in therapy

871

68.1

Types of enteral feed

878

68.2

Management of enteral feed intolerance

879

68.3

Complications of enteral nutrition

880

68.4

Indications for parenteral nutrition

881

68.5

Complications of parenteral nutrition

882

70.1

Surgical and nonsurgical conditions requiring antimicrobial prophylactic therapy

915

72.1

Extended-spectrum β-lactamases

925

74.1

Examples of cationic detergents

963

78.1

Common forms of tinea and the affected body regions

1013

79.1

A selection of important cytokines

1028

79.2

Antisera preparations and their sources

1031

79.3

Vaccines

1031

79.4

Mixed vaccines

1033

80.1

Characteristics of protein kinase inhibitors

1066

80.2

Some common cytotoxic drug combinations

1071

81.1

Advantages and disadvantages of the viral vectors

1082

83.1

Autonomic nervous innervation of the eye

1113

S E C T I O N

I

PHARMACOLOGY WITHIN THE SOCIAL CONTEXT O, (abundant) is the powerful grace that lies In herbs, plants, stones … WILLIAM SHAKESPEARE—ROMEO AND JULIET

The quote from Shakespeare’s Romeo and Juliet alludes to two important points explored in this section. The first is that medicines can be obtained from a variety of sources within our environment. The other is that these substances produce a powerful effect on the body. The nature of the effect of medicines, both desired and unwanted, is the main theme of this book. Historical records show that medicine use has long been a part of human culture. A brief outline of the history of medicine use and the sources from which medicines are obtained is provided in Chapter 1. In Chapter  2, we move to the present with a discussion of the sociocultural aspects of pharmacology. Our society is coming to grips with a number of issues related to medicine use, and health professionals must be aware of these issues and implement effective strategies to deal with them. Some of the issues raised in Chapter 2 include the following: ■■

the use of generic substances versus proprietary medicines;

■■

medicine advertising;

■■

perspectives of medicine use in the older person;

■■

cultural differences;

■■

the use of over-the-counter (OTC) preparations.

The effect of these issues on health professionals, such as nurses, doctors and pharmacists, is also considered.

C H A P T E R

1

A H I S TO R I C A L PERSPECTIVE

LEARNING OBJECTIVES

KEY TERMS

After completing this chapter, you should be able to:

Biotechnology

1

Define the term pharmacology.

Genetic engineering

2

Identify the roles of medicines in human society.

Natural products

3

Identify the three ages of pharmacology.

Pharmacology

4

Briefly describe the major characteristics of each of the three ages and their implications for society.

Recombinant DNA technology

Pharmacology is a branch of medical science that deals with the properties and characteristics of chemical agents used for medicinal or other purposes. The actions and effects of these chemical agents on physiological systems are of particular interest. The physiological systems in which these effects are observed may be organs or tissues isolated from the body and artificially maintained—in vitro situations—or within living whole organisms—in vivo situations. In an etymological sense, the word ‘pharmacology’ is derived from two Greek words: pharmakos, which means medicine or drug, and logos, which means study.

C H A P T E R 1 A H I S TO R I C A L P E R S P E C T I V E

SUBSTANCE USE AND SOCIETY The use of chemical substances for medicinal and social purposes mirrors the course of human history itself. In fact, it probably even predates human history, as evidence of medicine use seems apparent among other animals (particularly chimpanzees, which have recently been shown to consume foods for their antibacterial, antifungal or antiworming properties). The methods used to identify useful pharmacological agents involve trial and error as well as careful observation. Indeed, many valuable therapeutic agents were discovered serendipitously during scientific investigations carried out for other purposes. A famous example of this is the discovery of penicillin by Sir Alexander Fleming. From the most primitive human communities to the most civilised, there exists a culture of using chemical agents for recreational, religious and medicinal purposes. The first recorded systematic register of medicines dates back to the ancient Greek and Egyptian civilisations. In all societies, it is apparent that the individuals who make and administer these agents possess power and influence over their fellows.

THE AGES OF PHARMACOLOGY The history of pharmacology is represented by the time line in Figure 1.1. It can be subdivided into three eras according to the characteristics of drug development: the first, in which the use of natural substances dominated; the next, in which products of laboratory chemistry emerged and became pre-eminent; and now, in the early 21st century, when biotechnological products are the focus of attention. While there is some overlap between the three eras, each era tended to dominate at certain time periods.

The age of natural substances Probably the earliest known natural substance used because of its profound effects on the human body is alcohol (ethanol). In fact, the process of fermentation is illustrated on pottery from Mesopotamia made around 4200  BCE. While the Mesopotamians would have been aware of the physiological effects of fermented beverages, it is a matter for conjecture whether or not alcohol was ascribed any medicinal properties. We had to wait a couple of millennia before its medicinal uses were documented. Alcohol has been used as a skin antiseptic, rubefacient, an appetite stimulant, a gastric acid stimulant, an analgesic, an anaesthetic and a tocolytic agent. One famous literary example of alcohol’s medicinal use is in the Bible in a letter from St Paul to Timothy: ‘… use a little wine for thy stomach’s sake and thine often infirmities’. Today, while the

social use of alcohol dominates any therapeutic applications that might remain, there is some evidence that St Paul’s words contain an element of truth (see Chapter 24). The period in which therapeutic agents were derived from plants is by far the longest: the first recorded use dates back to around 2700 BCE. Every culture throughout history has used plant derivatives—the leaves, fruit, bark, roots, flowers and sap—as a means to heal. Agents such as atropine, ergotamine, curare, morphine, reserpine, cocaine and marijuana were extracted from these sources. Indeed, the origins and uses of just a few of these substances broaden the view of pharmacology and remind us that there is more to this area of study than simply popping pills into sick people’s mouths.

ATROPINE: LEGENDS AND LADIES Atropine is derived from the fruits of various plants of the potato family, particularly the deadly nightshade, Atropa belladonna. As is obvious from the common name, the fruits of this plant have long been known to be poisonous. Throughout history, deadly nightshade has been used for nefarious purposes as an effective method of poisoning. Indeed, the scientific name for deadly nightshade does reflect atropine’s action. Atropos was one of the three Fates from Greek mythology. She, along with the other two Fates, decided individual destiny. It was her role to dispatch mortals by cutting the threads of life with a pair of shears. Belladonna means ‘beautiful lady’, and in the early part of the second millennium it was known that extracts from this plant would cause dilation of the pupils, an attribute that was considered desirable in women. This action, although for a non-cosmetic/medical purpose, is still one of the uses of atropine and its derivatives today.

ERGOTS: HEADACHES, HALLUCINATIONS AND HYSTERIA Ergotamine and its cousin ergometrine are derived from the fungus Claviceps purpurea, an important pathogen of the cereal, rye. These two medicines are used respectively to treat migraine and to induce uterine contractions in obstetrics, but in overdose can cause seizures and hallucinations (not surprisingly, as lysergic acid diethylamide, LSD, is a derivative of ergotamine). It has been suggested that many witches in the Middle Ages, and even up to the Salem witchcraft trials in America in the 17th century, could have been tried and burnt at the stake for having been intoxicated after ingesting infected cereals. How many migraine sufferers realise that an overdose of Cafergot (a brand name for an ergotamine preparation) could have had them burnt at the stake in previous eras?

3

4

SECTION I PHARMACOLOGY WITHIN THE SOCIAL CONTEXT

Figure 1.1 A time line highlighting some major pharmaceutical events A historical time line showing use of major pharmaceutical substances. The time line is divided into three distinct periods: the age of natural substances; the age of synthetic substances; and the age of biotechnology. CENTURIES

Prior to the 1st century

PHARMACOLOGICAL EVENT • Extracts of ephedrine, marijuana and opium used • Alcohol fermented • Camphor and cod liver oil used

1st century

Drug syrups first used

6th century

Colchicine used

14th century

Tinctures first used

16th century

Tobacco, coffee, cocoa and tea introduced into Europe

17th century

Extracts of ipecacuanha, strychnine and quinine first used in Europe. Nitrous oxide discovered

18th century

Extracts of digitalis and atropine first used in the Western world

19th century

Aspirin first used. Active constituents of plants isolated (morphine, strychnine, quinine, codeine, cocaine). Glyceryl trinitrate first used. Isolation of adrenaline from adrenal gland extracts

early 20th century

late 20th century early 21st century

Synthetic narcotics, insulin, antibiotics, anticonvulsants, psychotropic drugs, anticancer drugs developed ‘Human’ peptides extracted from microbial cultures Gene therapy THE AGE OF NATURAL SUBSTANCES THE AGE OF SYNTHETIC SUBSTANCES THE AGE OF BIOTECHNOLOGY

TUBOCURARINE: MACUSIS AND MUSCLES Tubocurarine has been used in surgery to paralyse skeletal muscle, a procedure that makes the surgeon’s task easier. (Nowadays, newer medicines have replaced it.) This medicine is derived from plants belonging to the genus Strychnos (some of which also provide strychnine). An impure preparation of the medicine is called curare, and has been used as an arrow poison by the Macusi Indians of Guyana. The interesting fact about this medicine is that

the Macusi, unwittingly, were making use of an important pharmacological property—the nature of medicine absorption. The majority of medicines are given by mouth—but some, if given by this route, are not absorbed. Tubocurarine is one of these. The Indians observed that death would soon come to the shot animal as curare was absorbed into the blood from the arrow wound. However, no harm came to the tribe as they consumed the meat of the animal that had been contaminated with curare.

C H A P T E R 1 A H I S TO R I C A L P E R S P E C T I V E

OPIUM AND COCA: ASSYRIA, ANALGESIA, THE ANDES AND ANAESTHESIA Morphine comes from opium, which is the dried exudate of the opium poppy, Papaver somniferum (meaning the sleepbearing poppy). The word morphine itself is derived from the Greek god of dreams, Morpheus. Opium was mentioned in one of the earliest and most influential pharmacology texts, that of Dioscorides, which was published in the first century AD. It is probable that opium was grown in Assyria, Greece and Mesopotamia long before this time. Many people think that opium came originally from China, but it probably did not reach there until at least the 6th century AD. Cocaine is obtained from the leaves of Erythroxylum coca, a shrub that grows wild in the Andes of Peru and Bolivia. It has been used for centuries as a stimulant by the Peruvian Indians of these areas. Its principal action is on the central nervous system but it has some peripheral effects; namely, that it reduces the desire for food and drink because of its local anaesthetic action. This action, much more than its stimulant properties, is the reason for its legitimate therapeutic value today. Today, cocaine is used as a local anaesthetic only occasionally, principally in nasal surgery. Like the Macusi Indians who used curare, the Peruvian Indians who used cocaine crudely applied some pharmacology. The leaves of this plant were mixed with lime prior to chewing. This prolonged the effect of the medicine by altering its rate of excretion from the body, and showed that medicine preparation has an important influence on therapeutic effect in the body. (Medicine preparations are discussed in detail in Chapter 7.)

RESERPINE: BRAIN IMBALANCE AND BLOOD PRESSURE Reserpine has an unusual place in the annals of historical pharmacology because its original use in treating mental illness is quite different from its modern use, which is to treat hypertension (although it has now been superseded by other, safer antihypertensive agents). Reserpine comes from the powdered root of Rauwolfia serpentine, and was used in India to treat the mentally disturbed. One of the undesirable effects of reserpine is that it can cause depressive illness. This adverse drug reaction helped to establish the theory that depression is not always due to reactions to life events but may well be related to changes in brain biochemistry (i.e.  that an imbalance in the level of brain neurotransmitters may underlie the behaviour).

MARIJUANA: MALINGERER OR MEDICINE? Marijuana is, in most countries, a substance of abuse; as (until recently) its effects have not been widely considered to be of clinical value. This substance comes from the plant

Cannabis sativa, and has been used intermittently since about 2700 BC as a sedative or analgesic. After World War  II particularly, it became a common recreational drug, and was outlawed by the World Health Organization as a drug of abuse with no therapeutic use. This may be inaccurate as the main active substance of marijuana, δ-9-tetrahydrocannabinol (THC), appears to have more potent antiemetic applications than most other antiemetics. Two related compounds, dronabinol and nabilone, have been approved in some countries for the treatment of the nausea and vomiting associated with the use of anticancer agents. Substances containing (or derived from) THC are called cannabinoids. There are clinical applications for the cannabinoids. An example is as appetite stimulants for people living with HIV/AIDS who experience significant weight loss.

ANTIBIOTICS: MEDICINAL MOULDS In the early part of the 20th century, we realised that there were other natural sources of therapeutic substances. Certain fungi and bacteria produce secretions that protect them from, or kill, other microbes. These secretions are known as antibiotics, and are among the most effective means available to combat the many infectious diseases that have plagued humankind (see Section  XIV). During the 1930s and 1940s penicillin was isolated and purified, and it became the precursor of other antibiotics, such as streptomycin for the treatment of tuberculosis. Interestingly, it was known in ancient times that the application of mouldy bread (presumably contaminated by fungus of the genus Penicillium) could help cure wound infections.

SOURCES OF NATURAL SUBSTANCES Natural substances with the potential to heal are all around us. You probably have some common clinical agents growing  in your gardens at home (see Figure  1.2)—a heart medicine from the purple foxglove (see Chapter 50), atropine from the deadly nightshade (see Chapter 28) and anticancer agents from the common periwinkle plant (see Chapter  80). Indeed, that we are surrounded by natural substances with medicinal properties is the reason for the use of herbal and alternative medicines. However, for many of these natural medicines, evidence of a therapeutic benefit, by the same methods used to authenticate conventional medicines, is less than convincing. There are many habitats and human cultures that remain relatively unexplored sources of natural medicines. The number of potential medicines that remain undiscovered

5

6

SECTION I PHARMACOLOGY WITHIN THE SOCIAL CONTEXT

Figure 1.2 Medicinal plants commonly found in

suburban gardens

A

amid the diversity of plants growing in the world’s rainforests has been put forward as an economic argument by conservationists for not destroying the remaining rainforests. Around the world, pharmacologists are busy examining traditional indigenous medicines, searching for substances that may prove to be potential clinical medicines in mainstream medical practice. Even today, the advantage of using products derived from living things is that the biologically active constituent has already been made by nature. It needs to be considered, however, that due to scarcity of the natural medicines or complexity of extraction, it is not always easy to obtain enough of the substance to use in the developed or developing areas of the world. There is an entire field of chemistry, called green chemistry, that focuses on recreating synthetically these medicines that occur naturally in plants. After varying degrees of extraction and testing (dependent on the technologies available in a particular society), a safe, relatively pure therapeutic preparation can be used.

The age of synthetic medicines

B

C A B C

Purple foxglove (Digitalis purpurea)—tubular flowers are characteristically purple. Deadly nightshade (Atropa belladonna)—a shrub with red or bluish-purple flowers and black berries. Periwinkle (Vinca rosea)—white or rose-tinted flowers.

Source: A © blondie/Shutterstock.com.  B Tom Oates at the English language Wikipedia. C  titanium22 at the English language Wikipedia.

The 20th century was characterised by the development of synthetic medicines, mass-produced relatively cheaply in pharmaceutical laboratories. The companies that run these laboratories are some of the most profitable businesses in the world today. Once the molecular structure of a natural medicine is identified, it may be more convenient to synthesise it wholly in the laboratory instead of extracting it, or else to modify it chemically for better absorption, greater effectiveness or fewer side-effects. One approach widely used by pharmaceutical companies is drug screening. Enormous resources (money, equipment and staff) are committed to the manufacture of novel synthetic compounds, which are then extensively screened for any potential pharmacological activity. The process of drug screening is also used on natural substances from microbial sources (e.g. fungal or bacterial secretions), plants (e.g. leaves, stems and roots) and animals (e.g. corals, venoms, frog skin secretions). Another approach that builds on information gathered from drug screening is structurebased drug design, where three-dimensional structures of protein targets, such as receptor or ion channels, are used to create medicines that have optimum inhibitory interactions with the targets. The dominance of technology and the realisation of the carcinogenic potential of synthetic chemicals have led some people in Western societies to reject mainstream therapies. Their search for alternative therapies often leads them back to methods of healing involving the use of more traditional

C H A P T E R 1 A H I S TO R I C A L P E R S P E C T I V E

natural substances. Chapter 69 addresses herbal medicines in more detail.

The age of biotechnology The recent emergence of biotechnology as a means to produce medicines heralds a new age of drug development. It involves the production of endogenous proteins and peptides for therapeutic purposes using technologies that harness biological processes (biotechnology). Is this a hybrid of the two earlier ages, natural and synthetic? These proteins are highly complex compounds where the functional characteristics are determined by subtle chemical bonds and structural arrangements. At this time it is beyond our capacity to duplicate such structures in laboratories for use as therapeutic agents. Biotechnological techniques involve the manipulation of microbial and human genetic material. The discovery of deoxyribonucleic acid (DNA) heralded the start of extensive research on the application of biotechnological techniques for making innovative drug discoveries. In 1962, Maurice Wilkins, James Watson and Francis Crick jointly received the Nobel Prize in physiology or medicine for determining the structure of DNA in 1953. Wilkins was a New Zealand-born medical scientist who

undertook his important work with his colleagues in Cambridge. It was Wilkins’s idea to study DNA by X-ray crystallographic techniques, which helped in identifying its structure. His efforts in using X-ray crystallographic techniques supported subsequent work in refining biotechnological techniques. A human gene can be inserted into one bacterium or fungal cell, which in turn divides to produce a colony in which each microbe contains the gene. The colony subsequently produces large quantities of the natural human peptide, which can be extracted in an extremely pure form for clinical purposes. This process is referred to as recombinant DNA technology or ‘genetic engineering’. The best clinical examples of this process are substances used in hormone replacement therapy (e.g. insulin, growth hormone and erythropoietin) and the supplementation of plasma constituents (e.g.  clotting factors). Furthermore, receptor genes have been cloned, allowing the receptor proteins to be purified, leading to the development of new anticancer agents, such as tyrosine kinase inhibitors (see Chapter  80). Now, in the early stages of the 21st century, the focus of biotechnological development appears to be on gene therapy. The applications, procedures and implications of this technology are discussed in Chapter 81.

CHAPTER REVIEW ■■

Pharmacology is the study of the actions and effects of drugs on physiological systems.

■■

Drugs have been used for medicinal and social purposes throughout human history.

■■

The history of drug development and use can be divided broadly into three ages: – The age of natural substances is characterised by the use of plant derivatives. – The age of synthetic substances is characterised by the mass production of synthetic medicines and drug screening techniques. – The age of biotechnology is where endogenous signalling chemicals are isolated, characterised and manufactured in a laboratory for use as therapeutic agents. Genetic engineering techniques are being used to make and deliver drug treatments.

7

C H A P T E R

2

S O C I O C U LT U R A L ASPECTS

LEARNING OBJECTIVES

KEY TERMS

After completing this chapter, you should be able to:

Brand name preparation

1

Discuss factors affecting medicine advertising.

Generic preparation

2

Discuss the types of over-the-counter (OTC) preparations available and reasons for their use.

Generic prescribing

Describe the difference between generic and brand name preparations and understand the advantages and disadvantages associated with the prescription of each type.

Immigrant

Discuss relevant sociocultural factors influencing drug therapy in older individuals, immigrants and Indigenous people.

Older individual

3

4

Generic substitution Indigenous person Medicine advertising Over-the-counter (OTC) preparation

If a major focus of drug therapy is to promote adherence by the person to their prescribed regimen and self-care, then a wider view of health care that encompasses the sociocultural context must be considered. Health professionals, who are socialised through their educational and professional experiences, and influenced by their own demographic characteristics,tend to hold a particular view of health care. This tends to be especially influenced by the Anglo-Celtic health care system that dominates Australia and New Zealand. This set of beliefs is institutionalised in the large organisational structures evident in our health care settings and our legal systems, and is influenced by the advertising and marketing of medicines by the large multinational pharmaceutical companies. People have their own sociocultural context, which influences their view of health care. These factors include demographic characteristics, such as age and ethnicity. Their view of health is influenced also by medicine advertising and packaging, and is reinforced by the current emphasis

C H A P T E R 2 S O C I O C U LT U R A L A S P E C T S

on self-care conveyed through the media, ranging from lifestyle television programs to magazines and newspapers. This chapter highlights the interplay of these belief systems—in other words, the relationship between the health professional and the person receiving therapy. These issues have an effect on the health professionals’ choice of medicines, the medicines people wish to use, and the person’s adherence to a drug therapy regimen. Specifically, this chapter discusses medicine advertising, over-the-counter (OTC) preparations, generic versus brand name preparations, drug therapy in older people, and drug therapy for immigrants and Indigenous people of Australia and New Zealand, including Aboriginal and Torres Strait Islander peoples as well as Māoris.

MEDICINE ADVERTISING Two important institutions influence our decisions in Western society: the media and multinational corporations. These two institutions rely on advertising to maintain their viability and to promote particular preparations. Advertising targets health professionals and the consumers of medicinal preparations in different ways. Advertising of medicinal preparations has been a common feature of medical journals and some nursing journals since they were first produced. Other, more subtle, forms of advertising that have come into existence include the sponsorship of continuing education seminars and conferences by multinational pharmaceutical companies, the financial support of which is often needed for the very existence of these programs. Conference organisers and journal editors rely on promotional advertising to keep subscription and registration costs to an affordable level and to cover production costs. Other marketing methods include direct mail and visits from pharmaceutical company representatives. In situations where exposure of information involves health professionals as active participants, such as pharmaceutical company representatives’ visits, sponsored meetings, or sponsored trials, there have been consistent associations found with higher prescribing frequency than in situations where health professionals are passive participants, such as journal advertisements and mailed information. Health professionals would like to think that they are not swayed by pharmaceutical promotion. If pharmaceutical companies believed this view, however, they would not continue to spend large amounts of money on advertising. Research indicates that pharmaceutical promotion influences health care professionals. Media focus on certain medicines in mainstream circles has also been instrumental in promoting the use of certain medicines.

Cyclo-oxygenase-2 (COX-2) inhibitor medicines such as celecoxib and rofecoxib are an interesting illustration of this point. Doctors appear to have been swayed by media coverage about the musculoskeletal benefits of these medicines in osteoarthritis, which have subsequently led to increased prescribing levels. After rofecoxib was withdrawn worldwide in 2004 due to excessive risks of patients developing myocardial infarction and stroke, prescribing levels have subsequently decreased. However, despite warnings about the use of COX-2 inhibitors in people with cardiovascular, gastrointestinal or renal conditions, they are still commonly prescribed in clinical practice. The antibacterial product Augmentin, the combination of a penicillin (amoxycillin) and clavulanic acid, is another example where sales have improved through promotional claims. Doctors sometimes prescribe Augmentin for the treatment of otitis media and sinusitis in young children. Some research has suggested that Augmentin has no significant benefit over amoxycillin alone in treating children over two years of age with acute otitis media. The additional problem with Augmentin is that it can cause hepatotoxicity. Furthermore, the Australian Medicines Handbook recommends amoxycillin as the antibacterial agent of first choice for the treatment of otitis media if symptoms such as fever and vomiting occur.

Challenges for the health practitioner Nurses and pharmacists are not exempt from exposure to promotional activities. Pharmaceutical companies often provide generous grants to nurses wanting to research particular medicines produced by these pharmaceutical companies. Nurses and pharmacists are subjected to advertising in international journals for specialty areas such as operating room, medicine adherence and critical care. Pharmaceutical company representatives also visit health care agencies and provide educational sessions for nurses

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and pharmacists, which are sometimes a disguise for the promotion of their products. One of the major problems with drug promotion for the health professional is that advertisers can disguise promotional material as important information rather than advertising. Obviously, doctors, nurses and pharmacists continue to be influenced by the subtleties of drug promotion. There are various ways to tackle the problem. For instance, journal editors have a responsibility to protect their readers. Editors should ban the placement of a medicine advertisement next to an article about that medicine. Another way is to place all advertisements in a section separate from the articles. The Journal of the American Medical Association (JAMA) and Heart & Lung incorporate this layout style. Perhaps even more pertinent is the need for medical, nursing and pharmacy students to learn skills in the critical analysis of published advertising data. Continuing education sessions in the workplace for health professionals will also help here.

Restrictions on advertising to the general consumer In Australia, advertising of Scheduled medicines to the general consumer is restricted according to the Therapeutic Goods Act 1989 (refer to Chapter  3 for a full explanation of Scheduled medicines). The Medicines Australia Code of Conduct complements the legislative requirements for advertising in Australia. Apart from a few exceptions, medicines that are included in Schedule  3 (Pharmacistonly medicines), Schedule 4 (Prescription-only medicines) or Schedule 8 (Controlled drugs, where possession without authority is illegal) must not be advertised in the popular media, such as radio, television and general magazines. These Scheduled medicines can be advertised in trade and professional journals intended for circulation within the medical, nursing, veterinary, dental, pharmacy and pharmaceutical professions. Medicines in Schedule  3 that can be advertised in the popular media include inhaled corticosteroids, such as beclomethasone; vaginal antiinfective agents, such as miconazole; nicotine to treat smoking dependence; and topical corticosteroids such as hydrocortisone and mometasone. New Zealand and the United States are the only two countries in the Organisation for Economic Cooperation and Development (OECD) that allow direct-to-consumer advertising (or promotion of prescription medicines) to the general public. In New Zealand, a review of direct-to-consumer advertising found that it did not provide consumers with objective information about the risks, benefits and options for treatment, and effects on the sustainability of health systems.

Despite restrictions on direct-to-consumer advertising in Australia, pharmaceutical companies have become very creative in promoting restricted medicines in the popular media. De facto direct-to-consumer advertising occurs when pharmaceutical companies provide information about specific conditions that do not mention the name of a medicine. For example, orlistat has been extensively marketed in Australia for weight loss. Sildenafil, which is indicated for erectile problems, has also been the focus of extensive campaigns in Australia using celebrity endorsements in newspaper and television advertisements. These consumer campaigns did not mention the name of the medicines and, therefore, adhered to the current Medicines Australia Code of Conduct. However, the campaigns tended to rely on emotional appeals and promoted the medicalisation of normal health. Such campaigns may also instil false hopes in many people, and put doctors under increased pressure to prescribe even if the medicines are not appropriate clinically.

OVER-THE-COUNTER PREPARATIONS Health professionals must be aware that individuals are also making personal choices regarding medicines introduced into their therapy. OTC preparations are available to the general public at pharmacies and, depending on the restrictions imposed, in other places such as supermarkets. These products are available without a prescription, and often without restriction or supervision by a health professional. Complementary forms of therapy, such as chamomile, garlic, ginger, ginseng, St. John’s Wort and Echinacea can also be purchased from pharmacies, health food stores and supermarkets without a prescription. (Chapter 3 covers the legal controls placed on medicines, and Chapter 69 presents an overview of herbal and related medicines.) People often use these preparations to relieve a wide range of illnesses and minor complaints, including the common cold, mild pain, an upset stomach and constipation. In the Australian and New Zealand contexts, health is increasingly geared towards client self-care. This phenomenon is indicated by the shortened length of hospital stay following both acute illness and elective surgery and the increased emphasis on client health education (see also Chapter  5). Obviously, client self-care constitutes a significant factor that affects the cost of health care. People are also encouraged to practise self-care through media advertising, product literature found in their local pharmacy, discussions with friends and relatives about preparations they use, and articles located in popular magazines. The

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effects of packaging, pricing and other marketing ploys used by supermarkets also influence people’s decisions. Consequently, the self-medicating person is a day-to-day reality for most health professionals. The health promotion movement has identified the possibility of lifestyle change as an important factor in the battle to prevent disease. Through health promotion, health professionals redirect their efforts towards disease prevention rather than cure. Individuals and communities achieve this goal by setting up their own health agendas. People are now also more likely to buy an OTC preparation or a complementary therapy before visiting their local doctor for advice. Even if they then decide to consult their doctor, they may not tell the doctor about their use of these treatments. This is because people often do not consider OTC preparations or complementary therapies as proper medicines: these preparations do not require a prescription, so the belief is that they can be taken without concern or risk. However, if the person takes prescription medicines, OTC preparations or complementary therapies concurrently, drug interactions are more likely to occur (see also Chapter  16). In their role of patient advocate, health professionals should encourage self-care and health promotion, and advise on the appropriate use and possible problems with these non-prescription products. The person should also actively seek out information from doctors, pharmacists and other health professionals. Despite scepticism from health professionals about the possible benefits of complementary therapies, individuals are consuming them in increasing amounts to either supplement or replace traditional medical treatment. Doctors, pharmacists, nurses and other health professionals have struggled to access current knowledge about these therapies, which they need in order to help people make informed choices about their use and to separate legitimate claims from unproven claims or hype. While health professionals may not be in a position to answer questions about complementary therapies, people have often sought out this information for themselves from sources such as the Internet. The Internet also provides online stores whereby individuals can purchase complementary therapies without the need to speak to any health professional at all. A situation where health professionals do not have total knowledge of all medicine therapies consumed by the people they treat may present a challenge for the traditional health care establishment. Undoubtedly, individuals will continue to seek out complementary therapies independently to promote their state of health and wellbeing. It is up to health professionals to become cognisant of the types of therapies that may be sought to enable them to inform people about

the benefits as well as alert them to the potential risks and complications of complementary therapies. OTC preparations or complementary therapies used in the appropriate manner and according to the supplied directions may have a positive effect on health. Conversely, inappropriate use of these treatments can cause adverse effects. Self-diagnosis and prolonged treatment without advice from a health professional may delay the appropriate intervention and mask the symptoms of a serious condition. For example, a person with chronic obstructive pulmonary disease (COPD) should see a doctor and receive prescription medicine. This person with obstructed airways should not treat the condition with the inappropriate use of cough and cold preparations. Instead, the doctor will plan a specific regimen for the person to follow. Furthermore, a preparation that is perceived harmless by the person may produce serious effects. Tretinoin is marketed as a topical treatment of acne vulgaris and is available as a cream, liquid or gel. But the pharmaceutical companies also promoted tretinoin in the general media as an effective medicine for the prevention and treatment of wrinkles. Sales of the topical preparation grew. Birth defects were noted in babies born to women who used isotretinoin (an oral retinoid preparation used in severe cystic acne) during pregnancy. These defects included stillbirth, cleft lip, cataract, and hand and abdominal malformations. The popularity of topical preparations prompted the rescheduling of topical tretinoin from an OTC preparation to prescription status. Under Australian legislation, the manufacturer, packer or supplier is required to include strict warning instructions on the packaging of topical products. These warning statements are as follows: ‘Do not use if pregnant’, and ‘Warning—may cause birth defects’. Although absorption through the skin is minimal, in view of the teratogenicity of oral retinoids, topical preparations should not be used during pregnancy. Complementary therapies may also cause serious adverse effects in individuals. For instance, the use of chamomile oil in aromatherapy for an individual who has allergic tendencies may lead to anaphylactic shock.

Common characteristics of OTC preparations A major concern of manufacturers of OTC preparations is safety. A medicine’s toxicity and adverse effects are related to the unit dosage in a preparation. This risk is, therefore, theoretically minimised when the unit dosage is low. For example, Australian pharmacies supply codeine-containing products without a doctor’s prescription. For solid dose preparations, each dosage unit (e.g.  each tablet) must contain no more than 10  mg of codeine. These products

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are heavily advertised and typically promoted as providing ‘stronger’ pain relief. Clinical trials on codeine suggest, however, that codeine does not contribute effectively as an analgesic, cough suppressant or antidiarrhoeal medicine in the doses recommended in OTC products. Many OTC preparations contain a combination of several medicines. These are called fixed combination preparations because the dose of each medicine is fixed within the preparation. For example, if a person is taking a preparation containing 6 mg of one medicine and 60 mg of another medicine and wants to increase the dose, each medicine will be proportionally increased when administered. Each medicine has its own pharmacological activity, which increases the potential for adverse effects and drug interactions with other prescription preparations (see also Chapter 16). Several OTC products contain only one medicine as the active ingredient. These are often more advantageous for people, as complete control over medicine dosage is possible. It is also more appropriate for the person to receive specific single medicines for defined symptoms to decrease the incidence of adverse effects. For example, a dry cough warrants a cough suppressant, whereas nasal congestion would require a decongestant. Furthermore, single-drug preparations tend to be less expensive than combination products. (For further discussion on OTC respiratory preparations, see Chapter 55.) There has been extensive debate about the use of OTC preparations, in particular cough and cold formulations, in young children. In April  2008, Australia’s Therapeutic Goods Administration (TGA) announced that combination cough and cold preparations containing sedating and non-sedating antihistamines, antitussives, expectorants and decongestants were to be prescription only as of September  2008 for children under two years, due to concerns surrounding their use in this age group. Around the same time, the drug regulatory authorities in Canada, the United States, the United Kingdom, and New Zealand arrived at the same conclusion. There has been little conclusive evidence about the proven effectiveness in use of these medicines in this age group. They may also cause serious problems such as seizures or dysrhythmias.

GENERIC NAME VERSUS BRAND NAME PREPARATIONS The term generic name can be defined in different ways. The generic name of a medicine is the shortened, simplified version of the chemical name. Medicines that are bioequivalent, yet sold by different manufacturers, will

still have the same generic name, although they will have different brand names. The medicine’s brand name (also called the trade or proprietary name) is the registered trademark used by the pharmaceutical company to identify the preparation of a specific medicine (see also Chapter 13). An example of a generic name is paracetamol, which is sold under the brand names of Panadol and Panamax (as well as others). Prescribers can order medicines using ‘generic prescribing’, which means that the pharmacist can supply any formulation of the medicine. ‘Generic substitution’ means that the pharmacist can supply any formulation of the medicine without referring back to the prescriber. This process can occur even if the prescriber has written a prescription for a particular brand. The prescriber can endorse a prescription to make sure that a particular formulation is provided. More than one pharmaceutical company can assign its own specific brand name for a medicine, as long as one company does not hold the patent rights for the sale of that medicine. The medicine is patented for a time, during which no other pharmaceutical company may produce or sell that medicine without permission from the original patent holder. Much of the patent period protects the pharmaceutical company while it conducts clinical tests on the medicine. Once the pharmaceutical company puts the medicine on the market, the latter part of the patent period protects it from competition by other pharmaceutical companies. When the patent period expires, other companies are free to manufacture and sell the medicine. Once the patent has expired, pharmaceutical companies rely heavily on promotional advertising in an effort to encourage doctors to prescribe one specific brand name over another brand name. Price differences for alternative brands of medicines exist in Australia and New Zealand. Under current government policy, pharmaceutical companies can set their prices depending on market competition. Often the brand name originally protected by a patent agreement is more expensive than competitive brands because it had to bear the cost of the groundwork in research and development for the medicine. One of the major fears relating to the use of generic preparations of a specific medicine is that they may not be interchangeable or bioequivalent. In other words, it is feared that they may not be absorbed or act in the same way after medicine administration. But brand name preparations of the same generic medicine, however, do not create different clinical responses when administered. All medicines are now carefully evaluated for comparable effects on

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absorption and clinical response with the original patented medicine, so that all brand names of a particular generic medicine are equivalent to each other. Pharmaceutical companies submit supporting data regarding the absorption and clinical response of their medicines to central drug authorities, who ensure that different brands are bioequivalent. This information is readily available to the prescribing doctor and the pharmacist. As alternative brand names are considered bioequivalent, the person is entitled to discuss any cheaper options with the doctor and pharmacist. Nurses should also inform people of the possibility of choosing a cheaper brand if they experience difficulties covering the cost of their current brand. People receiving treatment can become confused if their doctor prescribes different brand names of the same generic medicine at different times. For example, in Australia the histamine H2-receptor antagonist ranitidine has several brand names available as tablet formulations. If the person is used to taking a ‘little blue pill’ and suddenly receives a ‘little white pill’, a great deal of time is often spent resolving the person’s confusion. In recent times, pharmaceutical companies have attempted to solve this problem by making their product look the same as another already on the market. Confusion may be reduced if pharmaceutical companies are required to make generic names of medicines more prominent on the label than the brand names. Problems may also arise in the institutional setting, where health practitioners have become familiar with the appearance and use of a particular brand of medicine. Students are taught pharmacology by reference to the generic names of medicines. Identifying medicines by their brand names in the institutional setting means there is a greater potential for making mistakes. It is important, therefore, for health professionals to refer to medicines by their generic names. Advocates of the prescription of specific brand names believe that it is the only way of ensuring high standards and well-tested products. The research and development required prior to the launch of a medicine is very expensive, and the ultimate success of a particular product often depends on the continued sales of that product. It is further believed that a person may favour one product over another because of flavour, appearance, packaging or past experience. The final choice of brand should arise from consultations between the person and their prescribing doctor. If more than one brand exists, the prescribing doctor can choose which is most appropriate for the person. Within the prescription, the doctor needs to indicate whether brand substitution is permitted (see Figure  2.1). Sometimes, however, company advertising will sway the doctor towards

Figure 2.1 Prescription indicating that brand

substitution is permitted Date: 1 January 2014

Dr Jack Muffler 123 Numbers Street Alphabetown 4321 Phone: 9876 5432 Prescriber no: 987876 Patient’s Name: Nancy Infectone Address: 123 Shapes Road Coloursville 4322 Brand Substitution not permitted (tick here)

❏

E-Mycin oral liquid 80 mg/mL, quantity: 100 mL Take 5 mls by metric measure every eight hours until finished. 1 repeat Signature of Doctor: Jack Muffler

one brand name over another. The doctor may, therefore, present a biased view of which brand name is more suitable for the person’s needs. It is important that doctors consider whether their prescribing habits may be influenced by pharmaceutical company advertising. Health professionals are responsible for promoting good treatment choices for people, communicating effectively with people about various preparations, and collaborating with other health professionals. While health professionals make the final decisions about appropriate therapeutic options, people should be included in the decision-making process. It should be apparent at this point in our discussion that an individual’s choice of medicine is not a clear-cut decision; these choices, made by both health professionals and people, are influenced by a number of external factors. These external factors include advertising in professional journals, the information placed on the packaging of medicines in supermarkets, and the confusion that may arise when people are presented with any number of medicines promising the same effect. Every person processes information differently, and the choices made are further complicated if we also consider issues such as the person’s age or background.

DRUG THERAPY IN THE OLDER PERSON The populations of Australia and New Zealand are growing older, as with all Western industrialised countries. Reasons

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for the ageing populations relate to sustained low levels of fertility, resulting in proportionally fewer children, and longer life expectancy. According to the Australian Bureau of Statistics, the median age of the Australian population has increased by 5.7  years in the past two decades, from 31.6  years in 1988 to 37.3  years in 2011. Approximately 80 per cent of the total Australian government expenditure on medicines relates to the concessional prescriptions of the ageing population. Statistics show a similar trend for New Zealand. These statistics have significant implications for medicine administration in older people. These individuals are also more prone to illnesses than other groups, which leads to the use of more medicines. (The practical aspects of medicine administration in the older person are discussed in Chapter 21.) One of the problems encountered with older people is the excessive or unnecessary use of medicines. This practice is known as polypharmacy.

Polypharmacy Polypharmacy may arise from actions taken by individuals, their families, doctors, nurses or other health professionals. As in aspects relating to the administration of OTC preparations, polypharmacy is affected by advertising. Thus, the reasons for this condition are complex. Table  2.1 lists common features of polypharmacy, which are discussed below.

USE OF MEDICINE WITH NO APPARENT INDICATION This process occurs when the person is taking drug therapy for a condition not diagnosed for the person. The practice may occur in residents newly admitted to nursing homes who continue with previous medicines without a reevaluation of their appropriateness.

USE OF DUPLICATE MEDICINES Sometimes drug therapy is duplicated, where the older person receives similar medicines with identical effects. This practice may increase the types of adverse effects and drug interactions that are likely to occur.

Table 2.1 Common features of polypharmacy Use of medicine with no apparent indication Use of duplicate medicines Concurrent use of interacting medicines Use of contraindicated medicines Use of inappropriate dosage Use of drug therapy to treat adverse drug reactions Improvement following discontinuation of medicines

CONCURRENT USE OF INTERACTING MEDICINES The older person may take medicines that have the potential to alter the effects of other medicines. Food may also produce interactions with medicines. (See Chapter 16 for a detailed discussion of drug interactions.)

USE OF CONTRAINDICATED MEDICINES The older person may take medicines that are not appropriate for a particular condition. For example, a doctor should not prescribe corticosteroid therapy to a person with both diabetes and asthma, as it enhances the blood glucose levels and may worsen their diabetes management. Contraindicated medicines also include medicines known to cause allergic or toxic reactions in the person.

USE OF INAPPROPRIATE DOSAGE The person may receive a dose that is too high or too low. Possible reasons include inappropriate adjustments for a person’s physical size, an incorrect frequency of administration and kidney or liver malfunction.

USE OF DRUG THERAPY TO TREAT ADVERSE DRUG REACTIONS Common in polypharmacy is the management of adverse drug reactions with the administration of yet more medicines. The medicine used to treat the adverse effects usually has its own adverse effects, which may lead to the administration of even more medicines. If this is allowed to continue, the older person may get on a merry-go-round of multiple medicine administration.

IMPROVEMENT AFTER DISCONTINUATION OF MEDICINES Sometimes it is difficult for the team of health professionals to determine whether medicines are helping or hindering the person’s condition. In this situation, the doctor may decide to discontinue all medicines. Specific medicines can be gradually introduced and their clinical effects assessed. Table  2.2 lists the possible consequences arising from polypharmacy. (These factors are further discussed in Chapter 21.)

Table 2.2 Consequences of polypharmacy Adverse drug reactions Drug interactions Financial expense Falling levels of orientation and alertness Diagnostic problems, with a medicine mimicking a disease state

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DRUG THERAPY IN INDIVIDUALS OF DIFFERENT CULTURAL AND LINGUISTIC BACKGROUNDS Australian and New Zealand societies comprise individuals of different cultural and linguistic backgrounds who have migrated from a variety of countries. Some individuals have come from English-speaking countries, but many are immigrants from countries with a first language other than English, or who do not speak English at all. The health care systems of Australia and New Zealand predominantly reflect the Anglo-Celtic structure. The majority of health care programs have been developed by white individuals with Anglo-Celtic roots, and these programs reflect their belief and value systems. Consequently, the more removed an immigrant’s original health care system is from the AngloCeltic/Western model, the greater their potential difficulty in acclimatising to the health care systems of Australia and New Zealand. Individuals of different sociocultural and linguistic backgrounds possess varying perceptions of illness and health. Ethnicity has been shown to be an enormous barrier to effective and safe medicine use, and immigrants—especially those of non-English-speaking backgrounds—are often most at risk of poor health, social and economic outcomes from medicine mismanagement. The traditional beliefs and values of a particular culture influence an immigrant’s perception and expectation of drug therapy. Conflicts may arise if these perceptions differ from those of the health professional, thus affecting the quality and effectiveness of care. The deeply rooted beliefs and values of immigrants may also affect their ability to comply with prescribed medicine regimens. For example, people of Chinese origin may use traditional medicines either simultaneously with or before seeking more conventional means of health care. These traditional medicines are influenced by the concept of the yin (cold air) energy forces and the yang (hot air) energy forces. The feminine energy force, yin, represents darkness, softness and cold, while the masculine energy force, yang, represents light, strength and heat. Excess of either energy force will lead to a lack of equilibrium and subsequent disease. Certain diseases are thought to occur through cold or hot aspects of substances present in medicines, food, air or the body itself. Treatment is by the application of a substance or food that is opposite to the cause. Disorders such as paralysis, pneumonia and earache are thought to arise from cold conditions. The Chinese often consume hot foods, such as

chocolate, cheese, alcohol, eggs and cereal grains, to treat a cold condition. Hot therapies include penicillin, tobacco, ginger root, garlic and castor oil. On the other hand, hot conditions, such as rashes, ulcers, fever, infections and liver problems, are treated with cold foods, such as dairy products, honey, tropical fruits and raisins. Bicarbonate of soda and herbs such as sage are also consumed as cold therapies. Traditional medicines can take the form of herbs or other plant extracts. As these preparations have their own pharmacological actions, they may interfere with the actions of more conventional therapy used in health care agencies. People may not perceive these naturally derived agents as medicines. Thus, in determining the person’s medicine history, the health professional should specifically ask whether herbs, plants or any other types of preparations are being used to treat a condition (see also Chapter 8). In some Asian cultures, a number of techniques for the cure of illnesses have evolved. ‘Coin rubbing’ is a technique commonly used to treat minor ailments of the forehead, nose, neck, chest and back. The coin, having been dipped in Tiger Balm, is forcefully rubbed over the body. If done properly, this procedure leaves long lines of dark bruises on the skin. In addition to traditional medicines, it is therefore important to determine what other kinds of home remedies are practised by ethnic groups. Besides the use of traditional medicines, some Asians often use conventional medicines concurrently. Selfmedication is a popular behaviour in Asian countries because many medicines do not require a prescription. This may partially explain the increasing resistance to bacteria in readily available antibiotics. More importantly, it may explain persons’ preferences for complex or drastic drug therapy. For example, they may consider that two tablets must be better than one tablet. Contrary to their feelings about medicines, some Asian people may be extremely uncomfortable about invasive procedures, such as surgery. Furthermore, certain ethnic groups equate operations and visits from the hospital clergy with a grave prognosis. These views may have evolved from the people’s hospital experiences in their countries of origin. In many cultural groups, kinship networks form strong social support systems that influence the person’s decision-making processes. For instance, for an older Greek female person to complete a course of cytotoxic therapy, approval may need to be obtained from an authoritative member of the family (e.g. her son or husband). To ensure rapport and promote cooperation, family members will need the opportunity to understand and appreciate the recommendations before the cytotoxic therapy program begins.

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Consequently, where ethnicity is likely to affect drug therapy, the health professional must assess the beliefs, values and other activities that could have an impact on each situation. In accepting, valuing and understanding people’s health practices, it is possible to determine appropriate methods of administering drug therapy without compromising their beliefs and values.

DRUG THERAPY IN INDIGENOUS PEOPLE The Māoris and the Aboriginal and Torres Strait Islander people were the original inhabitants of New Zealand and Australia respectively, before discovery and settlement by the Europeans. In contemporary society, the health of Māoris appears better than that of Aboriginal and Torres Strait Islander people. They do, however, still exhibit a higher incidence of rectal and colonic cancers, adolescent asthma, diabetes mellitus, tuberculosis, bronchitis, pneumonia and other diseases than their non-Māori counterparts. Life expectancy for Māoris compared with non-Māori individuals has dramatically improved, to the point where they are fairly similar. On the other hand, Aboriginal and Torres Strait Islander people experience extremely high death rates, where the life expectancy is about 15–20  years shorter than their non-Aboriginal counterparts. In addition, Aboriginal and Torres Strait Islander people have a higher incidence of hypertension, ischaemic heart disease, diabetes, alcoholism and venereal disease than the general population. Key policy differences in Australia include complexities relating to responsibilities for funding and service delivery between different levels of government, underexpenditure on Indigenous health care and essential services, and the lack of a treaty underpinning Indigenous rights. Conditions that are almost non-existent in the general population (e.g. leprosy and tuberculosis) are prevalent in Aboriginal and Torres Strait Islander populations. There is also a high prevalence of acute and chronic infections (e.g.  trachoma, a chronic conjunctivitis that causes blindness, and middle ear infections, which can lead to permanent hearing loss). Although the health situation for Māoris is better than that for Aboriginal and Torres Strait Islander people, the reasons for inequalities of health with their white counterparts remain the same. The problems of Indigenous people’s health resulted primarily from European contact, when traditional living patterns were disrupted and replaced with environmental and economic factors affecting health. These factors include unclean water, poor nutrition and inadequate housing. Before European

settlement, the traditional Indigenous society was healthier overall. The view of health maintained by Indigenous people has strong ties with spirituality, the land, plants and animals. On the other hand, most health professionals’ view of health is external to the environment. The conventional view maintains that the environment must be adapted to achieve health. Health professionals must develop ways of understanding how Indigenous people make decisions, valuing their cultural ways as being just as legitimate as those of the dominant Western culture. This improved awareness will assist in promoting effective means of medicine administration for these people. By acknowledging these cultural differences, health professionals will be better able to promote compliance, advocacy and education in areas of drug therapy. For Indigenous people, environmental and spiritual factors are central to their sense of wellbeing. Medicine administration must also take account of these factors. In Indigenous communities, many people would have an idea of time that relates to the movements of the sun and moon rather than the more conventional methods of time-keeping. Remote area health professionals on Aboriginal settlements in the Northern Territory prefer to provide medicines requiring once-a-day administration by Aboriginal and Torres Strait Islander people. Medicines requiring more frequent administration present a challenge for an Aboriginal or Torres Strait Islander person with no timepiece. The antibiotic doxycycline (Vibramycin) is extremely popular in these communities, as the Aboriginal and Torres Strait Islander people take it in a once-aday dose. Most other antibiotics require more frequent administration of therapy for optimal effectiveness. Problems with medicine compliance in the past have led to the increased use of the intramuscular contraceptive medroxyprogesterone acetate (Depo-Provera). Australian remote area nurses administer Depo-Provera at threemonthly intervals to Aboriginal and Torres Strait Islander women instead of providing these women with the opportunity to administer the more conventional oral contraceptive formulation. Depo-Provera is a reliable method of contraception with a prolonged activity, but it is associated with more adverse effects than its oral counterpart. Suggestions have been made that these Aboriginal and Torres Strait Islander women know nothing of this medicine’s effects except that it is a reliable form of birth control. As other methods of contraception were deemed unsuccessful, this is a difficult and ethical dilemma for remote area health professionals. On the one hand, Aboriginal and Torres Strait Islander women require an

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effective means of contraception. On the other hand, their culture may hinder compliance, which means that a more radical form of treatment is necessary (refer also to Chapter 4). In addition to the traditional languages of Indigenous people, most speak English. Health professionals may feel frustrated because Indigenous people appear reluctant or slow to answer questions about their medicines. The people may feel the question is not appropriate, or may lack understanding of certain ‘technical terms’ (e.g. cardiac tablets instead of heart tablets) or trust and rapport are lacking. Furthermore, Indigenous people do not often use the Western convention of asking questions. Instead, information is acquired by presenting the information to the health professional, who will either confirm or correct it. Tone is also important. A professional, officious, efficient approach is likely to be interpreted as ill-mannered and uncaring, further highlighting the Indigenous people’s stereotypes of non-Indigenous people. Similarly, attempting to establish rapport by asserting one’s role as a doctor, pharmacist or nurse is often insufficient. To establish rapport and trust, the health professional should identify a friend, family member or professional colleague, preferably of an Indigenous background, who is known to both parties. This individual can assist in laying the foundations for a good therapeutic relationship. Furthermore, health professionals should take account of problems relating to education, housing and employment in the delivery of health services, as these have implications

for subsequent drug therapy. For example, renal disease is rife in the Northern Territory among the Aboriginal and Torres Strait Islander population, where the prevalence is approximately 100 times that of the wider population. One of the causes of renal disease is infection by Streptococcus bacteria. About every four years a new strain of Streptococcus emerges, creating a new epidemic of renal disease in Aboriginal and Torres Strait Islander communities. Also endemic in these communities is scabies, a tick that moves under the skin and produces itching. The skin is broken through scratching the itch. This provides a portal of entry for Streptococcus into the bloodstream and to the kidneys. To treat the scabies and, therefore, the renal disease, a population and environmental approach rather than an individual approach is needed. Treatment of one individual with an antibiotic will not provide a blanket cure. In one particular Aboriginal community faced with an epidemic of renal disease, a program was started to eradicate it. The local council organised a clean-up day on which everyone and everything were cleaned up. Clean-up days are now held four times a year in this community. As a result, there is little incidence of scabies or renal disease. The issues outlined above provide only an overview of some factors affecting health and subsequent therapeutic agent regimens in Indigenous people. Obviously, for effective health promotion in medicine regimens in Indigenous people, health professionals must demonstrate empathy, tolerance and appreciation of the environmental, spiritual and community-oriented aspects of care.

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CHAPTER REVIEW ■■

Advertising of medicines can affect the medicine management activities of health professionals.

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Advertising can influence the medicinal activities of consumers.

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■■ ■■

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Over-the-counter preparations are available to consumers without a prescription, and often without supervision of a health professional. The generic name of a medicine is the shortened, simplified version of the chemical name. The brand name is the trademark used by a pharmaceutical pharmaceutical company to identify the preparation of a particular drug. Generic prescribing means that a pharmacist can supply any formulation of a particular medicine. Generic substitution means that a pharmacist can supply any formulation of the medicine without referring back to the prescriber. Polypharmacy, which is a major problem for older people, involves the excessive or inappropriate use of medicines. The traditional beliefs and values of a particular culture influence an individual’s perceptions and expectations about drug therapy.

FURTHER READING Banning M, 2007, Medication Management in Care of Older People, Blackwell Publishing, Oxford. Carmody D & Mansfield PR, 2010, ‘What do medical students think about pharmaceutical promotion?’ Australian Medical Student Journal, 1(1), 54–7. DeLorme DE & Huh J, 2009, ‘Seniors’ uncertainty management of direct-to-consumer prescription drug advertising usefulness’, Health Communication, 24, 494–503. Hamilton HJ, Gallagher PF & O’Mahony D, 2009, ‘Inappropriate prescribing and adverse drug events in older people’, BMC Geriatrics, 9, 5, 28. Peiris DP, Patel AA, Cass A, Howard MP, Tchan ML, Brady JP, De Vries J, Rickards BA, Yarnold DJ, Hayman NE & Brown AD, 2009, ‘Cardiovascular disease risk management for Aboriginal and Torres Strait Islander peoples in primary health care settings: Findings from the Kanyini audit’, Medical Journal of Australia, 191, 304–9. Spurling GK, Mansfield PR, Montgomery BD, Lexchin J, Doust J, Othman N & Vitry AI, 2010, ‘Information from pharmaceutical companies and the quality, quantity, and cost of physicians’ prescribing: a systematic review’. Public Library of Science Medicine, 19,7(10), e1000352. Wessell AM, Nietert PJ, Jenkins RG, Nemeth LS & Ornstein SM, 2008, ‘Inappropriate medication use in the elderly’, American Journal of Geriatric Pharmacotherapy, 6, 21–7.

WEB RESOURCES A Brief History of Pharmacology pubs.acs.org/subscribe/journals/mdd/v04/i05/html/05timeline.html Australian Bureau of Statistics www.abs.gov.au/AUSSTATS What is Pharmacology? www.pharmacology.med.umn.edu/whatispharm.html Everybody (Health Consumer Information) www.everybody.co.nz Māori Health www.health.govt.nz/our-work/populations/maori-health New Zealand Deserves Better. Direct-to-Consumer Advertising (DTCA) of Prescription Medicines in New Zealand: for Health or Profit? journal.nzma.org.nz/journal/116-1180/556 Office for Aboriginal and Torres Strait Islander Health www.health.gov.au/oatsih

S E C T I O N

II

PHARMACOLOGY WITHIN THE PROFESSIONAL CONTEXT Conciseness and decision are, above all things, necessary with the sick. Let your thought expressed to them be concisely and decidedly expressed. What doubt and hesitation there may be in your own mind must never be communicated to theirs, not even (I would rather say especially not) in little things. Let your doubt be to yourself, your decision to them. FLORENCE NIGHTINGALE—NOTES ON NURSING

During Florence Nightingale’s era, the caretaker of the sick was always held as being in the right. Paternalistic attitudes were prevalent, the person had little say in the choice of treatment, and the views of health professionals, especially doctors, were held in high esteem. This perspective differs somewhat from that of contemporary society, in which people are more likely to make decisions for themselves. This means that people must have access to adequate and easily understandable knowledge of medicines before they can agree to a proposed therapeutic regimen. The goals of independence, interdependence and self-care provide the major underpinning of the following chapters. Florence Nightingale also saw the need for precision and decisiveness in communicating and caring for people. Today, this situation is reflected in the way that health care professionals provide care for people in relation to therapeutic agent regimens. This care involves an understanding of medicine legislation, the ethical perspective, medicine education and advocacy, and the supplying, prescribing, administration and evaluation of drug therapy. The complex array of medicines available has created the need for legislative controls in the manufacture, sale, distribution, storage, labelling and administration of medicines. A discussion of controls over medicine use in Australia and New Zealand is covered in Chapter 3. Relevant aspects of common law with reference to unclear orders, telephone orders and standing orders are also considered. Specific areas of health care responsibility, including emergency situations, nurse practitioners, midwifery practice and remote area care, are briefly discussed.

SECTION II PHARMACOLOGY WITHIN THE PROFESSIONAL CONTEXT

In Chapter  4, ethical issues of pharmacology are discussed using the six principles of ethics. These principles are veracity, autonomy, non-maleficence, beneficence, justice and confidentiality. Ethical situations, however, often involve more than one principle, which may lead to conflicts regarding which principle should take precedence. The potential for conflict between ethical principles and the legal perspective underlying these principles are highlighted. The health professional’s role in pharmacology with reference to treatment adherence, medicine education, client advocacy and nursing research is discussed in Chapter  5. Principles that the health professional can use to promote client advocacy, compliance and learning are also considered. Chapter  6 covers the roles of the prescriber, nurse, pharmacist, physiotherapist, podiatrist, dietitian, paramedic and naturopath in relation to drug therapy, and how these health professionals collaborate with each other to ensure safe and effective medicine management for people. The roles of these health professionals are constantly changing in light of the increasing complexity of drug therapy, the value placed on non-drug therapy and the need for economic rationalism. These factors are also briefly considered.

C H A P T E R

3

H E A LT H P R O F E S S I O N A L S A N D T H E L AW

LEARNING OBJECTIVES

KEY TERMS

After completing this chapter, and with further reference to the legislation

Common law

pertaining to a jurisdiction, you should be able to:

Drug of dependence (controlled substance)

1

Describe the Acts and Regulations pertaining to the distribution, storage, labelling, recording and administration of medicines.

2

Describe the Schedules and the types of medicines allocated to each Schedule.

3

Describe the requirements for prescription, storage and administration of restricted substances (‘prescription medicines’ in New Zealand) and controlled drugs;

4

Discuss relevant aspects of common law pertaining to medicine administration; with reference to unclear orders, telephone orders and standing orders;

5

Develop an awareness of health care professionals’ responsibilities in medicine administration in emergency situations and remote area care;

6

Develop an awareness of the medicine administration responsibilities of nurse practitioners and midwives.

Legislation Midwife Nurse practitioner Remote area care Restricted substance (prescription medicine) Schedule Standing order Telephone order Unclear order

Medicines have the potential to produce adverse reactions, with possible fatal consequences. Furthermore, problems can arise associated with inappropriate use by the health care professional or the person taking the medicine. Consequently, legislative controls have been developed for the manufacture, sale, distribution, storage, labelling, recording and administration of medicines. The legislation is in place to protect people from harm arising from the inappropriate use of medicines, and to provide health professionals with a comprehensive framework for their clinical practice.

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SECTION II PHARMACOLOGY WITHIN THE PROFESSIONAL CONTEXT

CONTROLS OVER MEDICINE USE: AUSTRALIA Commonwealth laws of Australia control the quality, safety and efficacy of medicines, while state and territory laws detail more specific provisions for medicine regulation. Individuals, institutions and companies must comply with Commonwealth and state or territory laws. If a conflict arises between the Commonwealth and state/ territory legislation, the Commonwealth legislation takes precedence. Commonwealth legislation, however, does not provide directions for the prescription and administration of medicines. This information is located in the state/ territory legislative Acts and their Regulations.

State or territory laws Every state and territory has at least one Act and a set of Regulations that deals with the control of medicines, ranging from agricultural poisons and domestic pesticides to prescription medicines. In all states, these are known as the Poisons Act and the Poisons Regulations, or variations of such names. Table 3.1 shows this legislation. Information found within an Act includes the separation of available medicines into broad headings according to type, the issue of licences, general restrictions and conditions, and the documentation of registers and other records. The Regulations cover more specific information relating to the authority to prescribe, labelling, advertising, manufacture, packaging, storage, supply and administration of medicines. Medicines are divided into categories called Schedules. The Schedules indicate specific medicines by generic name according to their potency, therapeutic use, toxicity, addictive and abusive potential, safety and modes of action. Slight variations exist between states and territories relating to the number of Schedules, their content and their meaning. The National Drugs and Poisons Schedule Committee (NDPSC) of the Australian Government, Department of Health and Ageing, has produced the ‘Standard for the Uniform Scheduling of Drugs and Poisons’ in an attempt to promote uniformity of Schedules throughout Australia. Table 3.2 indicates the NDPSC’s classification of drugs into nine Schedules. Australian states and territories have adopted these uniform Schedules to a large degree.

Commonwealth laws The two Australian Commonwealth Acts affecting medicine manufacture and administration are the Therapeutic Goods Act 1989 and the Narcotic Drugs Act 1967.

Table 3.1 Control over medicine use in Australian state and territory legislation STATE/TERRITORY

ACT/REGULATIONS

Australian Capital Territory

Drugs of Dependence Act 1989 Drugs of Dependence Regulations Medicines, Poisons and Therapeutic Goods Act 2008 Poisons and Drugs Regulations Poisons Regulations

New South Wales

Poisons and Therapeutic Goods Act 1966 Poisons and Therapeutic Goods Regulation

Northern Territory

Poisons and Dangerous Drugs Act 1994 Poisons and Dangerous Drugs Regulations

Queensland

Health Act 1937 Health (Drugs and Poisons) Regulation

South Australia

Controlled Substances Act 1984 Controlled Substances (Poisons) Regulations

Tasmania

Poisons Act 1971 Poisons Regulations

Victoria

Drugs, Poisons and Controlled Substances Act 1981 Drugs, Poisons and Controlled Substances Regulations

Western Australia

Poisons Act 1964 Poisons Regulations

The Therapeutic Goods Act 1989 and its Regulations provide federal control over the standards, manufacture, supply, presentation, registration and availability of therapeutic goods. Therapeutic goods are those used in the prevention, diagnosis, cure or alleviation of a disease, defect or injury in people or animals. All goods must conform to internationally recognised standards, such as the British Pharmacopoeia or standards published by the Standards Australia. Therapeutic goods must be approved by the Therapeutic Goods Administration (TGA) before they are released on the market. Meanwhile, the Australian Drug Evaluation Committee (ADEC) of the TGA provides scientific evaluations of medicines and makes recommendations regarding their rejection or approval (see Chapter 18).

C H A P T E R 3 H E A LT H P R O F E S S I O N A L S A N D T H E L A W

Table 3.2 Standard for the uniform scheduling of drugs and poisons in Australia SCHEDULE

DESCRIPTION

Schedule 1 (Victoria)

Traditional Chinese herbs. Intentionally left blank in other states and territories.

Schedule 2

Pharmacy Medicine: Substances, the safe use of which requires professional advice from a pharmacist and which should be available from a pharmacy or, where a pharmacy service is not available, from a licensed person.

Schedule 3

Pharmacist Only Medicine: Substances, the safe use of which requires professional advice but which should be available to the public from a pharmacist without a prescription.

Schedule 4

Prescription Only Medicine, or Prescription Animal Remedy: Substances, the use or supply of which should be by or on the order of persons permitted by state or territory legislation to prescribe and should be available from a pharmacist on prescription.

Schedule 5

Caution: Household substances—substances with a low potential for causing harm, the extent of which can be reduced through the use of appropriate packaging with simple warnings and safety directions on the label.

Schedule 6

Poison: Agricultural, veterinary and industrial substances—substances with a moderate potential for causing harm, the extent of which can be reduced through the use of distinctive packaging with strong warnings and safety directions.

Schedule 7

Dangerous Poison: Substances with a high potential for causing harm at low exposure and which require special precautions during manufacture, handling or use. These poisons should be available only to specialised or authorised users who have the skills necessary to handle them safely. Special regulations restricting their availability, possession, storage or use may apply.

Schedule 8

Controlled Drug: Substances which should be available for use but require restriction of manufacture, supply, distribution, possession and use to reduce abuse, misuse and physical or psychological dependence.

Schedule 9

Prohibited Substance: Substances which may be abused or misused, the manufacture, possession, sale or use of which should be prohibited by law except when required for medical or scientific research, or for analytical teaching or training purposes with approval of Commonwealth and/or state or territory health authorities.

Source: Australian Health Ministers Advisory Council Standard for the Uniform Scheduling of Drugs and Poisons, Commonwealth of Australia, 2003. © Commonwealth of Australia 2012.

In the past, the TGA has received criticism for its delay in providing approval and therefore distribution of therapeutic goods. For example, although medicines recommended for the treatment of the human immunodeficiency virus (HIV) were already approved for human use by the United States Food and Drug Administration (FDA), the TGA originally denied access to these medicines to Australians living with HIV/AIDS. It was recognised, however, that to speed up marketing approval of therapeutic goods, greater recognition should be given to drug trials conducted overseas. The Therapeutic Goods Act now incorporates these changes. For example, in 2011, the TGA approved the inhaled dry powder mannitol (Bronchitol) for marketing in Australia for the treatment of cystic fibrosis in children aged over six years and in adults (see Chapter 54). The Narcotic Drugs Act 1967 was enacted to safeguard against the illegal manufacture, supply and use of narcotic medicines. Also, the manufacturers of narcotic medicines

for therapeutic use are licensed under this legislation. Licensed manufacturers must comply with specific requirements in areas of security, record keeping, handling, labelling and storage of narcotics. Failure to maintain these standards may lead to revocation of the manufacturer’s licence and criminal prosecution.

CONTROLS OVER MEDICINE USE: NEW ZEALAND Two sets of Acts and Regulations govern medicine control in New Zealand. The Misuse of Drugs Act 1975 and its accompanying Misuse of Drugs Regulations 1977 provide directions for any controlled drugs such as morphine, pethidine, amphetamines, barbiturates and cannabis. The Medicines Act 1981 and the Medicines Regulations 1984 control the use of other therapeutic agents.

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SECTION II PHARMACOLOGY WITHIN THE PROFESSIONAL CONTEXT

This legislation covers information such as the quality and standard of medicines; licence provisions for manufacturers, wholesalers and packers of medicines; advertising restrictions; the manufacture of medicines; the retail sale of medicines; and the enforcement of legislation. The Regulations govern more specific aspects regarding the control of medicines, such as requirements for prescriptions and the maintenance of records in New Zealand. Discussions between the drug scheduling bodies of New Zealand and Australia have led to the development of the trans-Tasman scheduling harmonisation agreement. This agreement has meant more compatible scheduling of medicines for the two countries. The medicine groupings are further described in Table 3.3.

The Misuse of Drugs Act 1975 specifies the Schedules for controlled drugs. Table 3.4 shows the four New Zealand Schedules for controlled substances, with descriptions and examples of drug groups in each Schedule.

LEGISLATION FOR THE PRESCRIPTION, STORAGE AND ADMINISTRATION OF MEDICINES The legislation controls the manner in which health care professionals conduct their practice of drug therapy. Besides the general principles pertaining to the administration and

Table 3.3 Grouping of medicines in New Zealand SCHEDULE

DESCRIPTION

Prescription Medicines

Medicines which require a prescription by a medical practitioner or veterinary surgeon.

Restricted Medicines

Medicines which may be sold by retail or supplied only by a pharmacist in a (pharmacist only) pharmacy or a hospital.

Pharmacy Only

Medicines which may be sold by retail or supplied only through pharmacies or hospitals, or through shops which are situated at least 10 km from the nearest pharmacy and which have been issued with a licence.

Source: Medicines Regulations 1984 (New Zealand), p. 5.

Table 3.4 Scheduling of controlled substances in New Zealand SCHEDULE, CLASS

DESCRIPTION

EXAMPLES

First Schedule, Class A

High potential for abuse

Hallucinogens (e.g. mescaline, lysergic acid diethylamide—LSD)

Drugs for experimental purposes

Thalidomide Opiate derivatives (e.g. etorphine, heroin) Second Schedule, Class B Part I, Part II, Part III

High potential for abuse Drugs for medical purposes

Narcotics (e.g. morphine, fentanyl, pethidine, methadone) Cannabis Central nervous system stimulants (e.g. amphetamines, methylphenidate)

Third Schedule, Class C, Drugs for Medical Purposes Part I, Part II, Part III, Part IV, Part V, Part VI, Part VII

Lower potential for abuse than above Schedules, but may lead to physical and/or psychological dependence

Narcotics (e.g. pholcodine, codeine)

Fourth Schedule, Part I, Part II

Have potential to cause harm, can be converted to other drugs with more abusive potential

Precursor substances, ergometrine, lysergic acid, pseudoephedrine

Source: Misuse of Drugs Act 1975 (New Zealand).

Industrial chemicals (e.g. diethyl ether, potential toluene, sulfuric acid)

C H A P T E R 3 H E A LT H P R O F E S S I O N A L S A N D T H E L A W

storage of medicines (see Chapters 7 and 9), there is specific legislation regarding restricted substances and controlled drugs. The universal regulations for restricted substances and drugs of dependence are summarised below.

Restricted substances (prescription medicines in NZ) Australian states and territories use various terms for medicines that require a prescription. These include ‘restricted substances’, ‘restricted drugs’, ‘prescription drugs’, ‘prescription only medicines’ and ‘poisons (medicinal)’. New Zealand uses the term ‘prescription medicines’. In the following section, the term ‘restricted substances’ is used to encompass all variations.

PRESCRIPTIONS Normally, doctors, dentists or veterinary surgeons are able to issue a prescription for a restricted substance. However, certain groups of nurses in New Zealand and Australia have been granted increased responsibility in prescribing restricted substances. In New Zealand, midwives can prescribe any quantity of restricted substances, up to a threemonth supply, for women under antenatal, intrapartum and postnatal care. They can also prescribe any medicine that is relevant to midwifery care from conception to the six-week postnatal check-up. New Zealand nurses working in the areas of child, family health or aged care have also obtained limited prescribing rights. Examples of the types of medicines these nurses are able to prescribe include systemic and topical antibacterials, systemic and topical nonsteroidal anti-inflammatory drugs, analgesics, antipyretics, cough and cold preparations, and antiasthma preparations. In Australia and New Zealand, prescribing rights have also been sought and obtained by other professional groups such as nurse practitioners and optometrists. In Australia, prescribing rights have also been obtained by podiatrists.

EMERGENCIES In an emergency, a doctor may order restricted substances verbally, including over the telephone. The doctor must document and sign the prescription or medication chart within a specific time, usually 24  hours. New Zealand legislation also allows midwives to order restricted substances verbally. As with doctors, the midwife must then document and sign the prescription or medication chart within a specified period, which is usually 24 hours.

NURSES Aside from nurse practitioners, normally nurses do not have the independent authority to administer restricted

substances without a medicine order in the doctor’s handwriting. When a new medicine chart is started for a person, the nurse should not transcribe the medicine details onto the new chart, and should await a doctor’s signature, as only doctors are legally entitled to complete these charts. (In New Zealand, midwives also have the independent authority to write up and sign these charts.) Individuals who have completed a year-long nursing qualification have been given special consideration to enable them to administer medicines. These nurses, who are known as enrolled nurses in some Australian states and territories, must have successfully completed additional educational preparation in the areas of medicine administration, legislation and drug nomenclature to enable them to participate in this administration activity.

PHARMACISTS In hospitals employing a pharmacist, this person is responsible for the storage and recording of restricted substances. These records are maintained for at least three years. In hospitals where no pharmacist is employed, the director of nursing is responsible for the storage and recording of restricted substances.

SECURITY All restricted substances are stored in a locked storage facility to prevent access by an unauthorised person. The nurse in charge of the shift or the nurse working directly under the supervision of the nurse in charge must carry the keys to the locked storage.

Controlled drugs Australian states and territories use various terms for controlled drugs or drugs of dependence. The terms used in Australia are ‘controlled drugs’, ‘prohibited substances’ and ‘drugs of dependence’. New Zealand uses the term ‘controlled drugs’. In the following section, the term ‘controlled drugs’ is used to encompass all variations.

PRESCRIPTIONS Generally, a doctor, dentist or veterinary surgeon can supply a prescription for controlled drugs. New Zealand midwives are also entitled to prescribe pethidine on up to two occasions for people in their care. In New Zealand, nurses working in the areas of child, family health or aged care have the authority to prescribe drugs of dependence such as morphine and pethidine. In Australia and New Zealand, some nurse practitioners have the authority to prescribe controlled drugs if these medicines are within their scope of practice.

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SECTION II PHARMACOLOGY WITHIN THE PROFESSIONAL CONTEXT

EMERGENCIES In an emergency situation, a nurse may administer a controlled drug when verbally instructed by the doctor. The doctor must subsequently document this instruction, usually within 24 hours. New Zealand midwives also have the authority to direct a pharmacist to supply pethidine as long as the pharmacist and the midwife have previously worked together professionally. In such cases, the midwife must supply a prescription to the pharmacist within two days of giving the authority to supply the drug.

RESTRICTIONS ON DOCTORS AND PHARMACISTS

Table 3.5 Information required on a ward register for the administration of drugs of dependence Person’s name Prescribed medicine and dose Prescribing doctor’s name Date and time of administration Balance of ampoules Signature of at least one nurse who has checked the preparation and administration Note: Any error should be ruled out in ink so that the entry is still legible.

In Australia, the legislation does not permit people with a drug dependence to be supplied with controlled drugs unless approval is obtained from the health department of the particular state or territory. In the state of Victoria, prescribers must obtain a permit if it is necessary to prescribe the medicine for more than eight weeks. They must also inform the Victorian Department of Health if they are treating a drug-dependent person, regardless of whether they prescribe the person with controlled drugs. Pharmacists in Victoria must also inform the Victorian Department of Health if they are asked to dispense more than an eightweek supply of a controlled drug. In the Australian Capital Territory, a prescriber is able to order a controlled drug for drug-dependent people if they are inpatients in a hospital and if the drug is to be used for a period not exceeding 14 days.

information noted in this register. The register is retained for a specific period from the date of the last entry. While in most Australian states and territories the register is held for three years, in New Zealand the register is kept for four years. At the change of each shift, it is good nursing practice to check the balance of each medicine against the number indicated in the register. In Australian legislation, there is a statutory requirement that the balance of ampoules, tablets and volume of liquid for controlled drugs should be checked periodically. For New Zealand, the Regulations state that nurses should check the register once every week. In practice, however, most New Zealand nurses check the register each shift.

PRESCRIPTION FOR THERAPEUTIC USE

DISPOSAL

In all Australian states and territories and in New Zealand, prescribers order controlled drugs for therapeutic use. Generally, a prescriber may administer or prescribe these drugs for two months. Permission must be obtained from the appropriate health department for drugs of dependence to be prescribed for longer periods. In New Zealand, controlled drugs may be supplied for a period not exceeding one month; however, this period may be extended to three months in some cases.

Only in New South Wales, Victoria and Western Australia do specific Regulations set out the procedure to be followed when controlled drugs are lost, destroyed or rendered unusable; however, there are procedures acknowledged as good practice that should be followed across the rest of Australia and in New Zealand. After reporting that a medicine is not usable, the nurse in charge of the shift should discard or destroy the medicine in the presence of another nurse. Both nurses should then sign the drug register as witnesses to the destruction. If nurses use only a portion of an ampoule, this information should be documented in the register. For example, if a person is ordered 7.5 mg morphine from a 10  mg ampoule, the register should indicate that the patient received 7.5 mg with the remaining 2.5 mg discarded or destroyed.

SECURITY Controlled drugs must be stored in a locked cupboard away from other medicines. The nurse in charge of the ward for a particular shift, or a nurse working directly under the supervision of the nurse in charge, is authorised to be in possession of and supply these medicines, and has full responsibility for the key to the cupboard.

REGISTERS Nursing staff must maintain a ward register for the administration of controlled drugs. Table  3.5 lists the

COMMON LAW Apart from having a sound knowledge of the relevant legislation concerning medicines, health professionals should take reasonable care in preventing harm to people

C H A P T E R 3 H E A LT H P R O F E S S I O N A L S A N D T H E L A W

from negligent handling and administration of medicines. The law recognises that health professionals show a reasonable standard and duty of care (see also Chapter 4). This duty of care is described under the areas of unclear orders, telephone orders and standing orders.

Unclear orders When a medicine order appears unclear, the nurse should question the prescribing doctor about what was intended. If this occurs during an emergency and the prescribing doctor is not available, the nurse should consult another doctor. The nurse should then ask the doctor to write the medicine order in a clearer way and to document his or her signature in the process. Nurses need to be familiar with the standard dosages, adverse reactions, contraindications and interactions of the medicines administered. This information may be checked through various sources and, if a discrepancy exists, the medicine order should be questioned. This issue is particularly important if nurses are asked to work in specialty areas in which they lack specialist knowledge and understanding (e.g.  paediatrics and intensive care). In these situations, nurses should preferably undertake activities that do not require the use of specialist knowledge. In reality, however, it may prove difficult for nurses to implement only general nursing measures, as they are often required in these areas because of staff shortages. In cases where relieving nurses are asked to undertake special procedures, they should be supervised by a specialist nurse and have access to up-to-date medicine information.

Telephone orders Most health care agencies have policies describing the procedure for taking telephone medicine orders. Table 3.6 indicates the steps that can be followed. Doctors must confirm verbal orders in writing as soon as is practicable. In any case, nurses must query any telephone order if they consider that the administration of the medicine is unreasonable.

Standing orders Standing orders are established procedures for the administration of certain restricted drugs, which can be given by nurses in special situations, such as emergencies and following routine treatment for a person, depending on the policies developed by a particular health care institution. An example of routine treatment given for a particular situation is the management of chest pain. Although standing orders have not yet been legally challenged, nurses will not be liable if their actions carefully follow established

Table 3.6 Steps required for telephone orders of prescription medicines 1 Obtain the person’s medical history, if possible, to check the medical diagnosis and condition. 2 Write the order as it is given, ensuring that the medicine’s name, dose, route and frequency of administration are provided. 3 Ask the doctor to repeat the order at least once, and on more occasions if it is unclear. 4 Read the order back to the doctor. 5 Get a second nurse to hear the order from the doctor and to repeat it back to the doctor as a second check. 6 Make an immediate entry on the medicine order chart. Note down the date, time, medicine, dose, route and frequency. Indicate that it is a telephone order. 7 Sign the order and have the second nurse countersign the entry. 8 Record in the person’s notes that the doctor needs to confirm the verbal order in writing.

Table 3.7 Steps required for standing orders of prescription medicines 1 Ensure the order is clearly written, with the medicine’s name, dosage, route and frequency of administration. 2 The order must clearly state the specific circumstances and conditions under which the medicine may be given. Do not accept conditions that are too non-specific (e.g. ‘If needed’, ‘If indicated’ or ‘As warranted’). Use standardised and approved abbreviations. 3 If relevant, ensure that the order notes the special observations and care required prior to, during and following administration. 4 Ensure that the order is signed with clear notation made of the prescribing doctor’s name. 5 The order should be clearly dated and current within the date frame. 6 If there is no legal time limit, a period of review should be met.

protocols. Table  3.7 indicates the general procedure to be followed.

EMERGENCIES Verbal orders are usually given only in emergency situations, such as a cardiac or respiratory arrest, or where the doctor is not able to be in attendance. In New South Wales and Tasmania, nurses may give analgesic medicines following a verbal order in the treatment

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SECTION II PHARMACOLOGY WITHIN THE PROFESSIONAL CONTEXT

of victims of major traumatic accidents, such as mining accidents, rail and plane crashes. Labels are then attached to these people, indicating to other health care professionals that a medicine has been administered. During a cardiac arrest where artificial ventilation and cardiac compressions are used, medicines are often administered on the verbal direction of the doctor. One nurse will act as ‘scribe’, noting down the name, time and dose of each medicine as it is given. The doctor will then be responsible for confirming these verbal orders as soon as possible.

MIDWIFERY PRACTICE In some instances, midwives are granted special privileges. For example, according to the Victorian regulations, a midwife who is employed in a hospital may, in an emergency and if a doctor is unavailable, administer a single dose of morphine or pethidine to a pregnant woman in labour. The administration is recorded in the ward register and the person’s treatment record, and the doctor is contacted as soon as is feasible. If a midwife is endorsed as a nurse practitioner in Victoria, that individual is also able to prescribe Schedule  8 medicines such as morphine and pethidine. According to the Misuse of Drugs Regulations, a New Zealand midwife may prescribe pethidine on up to two occasions at an interval specified by the midwife. The midwife is also able to direct a pharmacist, either verbally or by telephone, to supply pethidine for a pregnant woman, as long as the pharmacist and the midwife have previously worked together professionally. This information is documented by the midwife as a written prescription within two days of supply of the pethidine (refer also to the subsection on ‘Controlled drugs’).

The Medicines Regulations 1984 also allow a New Zealand midwife to prescribe for any person under antenatal, intrapartum and postnatal care a quantity of any prescription medicine that does not exceed a threemonth supply. It is considered appropriate for a midwife to prescribe medicines such as iron tablets, antifungal agents, oxytocin, vitamin K and antacids. New Zealand midwives are not able to prescribe medicines for the treatment of underlying conditions, such as hypertension, diabetes and asthma. New Zealand legislation also does not include the prescription of medicines such as antibiotics or oral contraceptives.

REMOTE AREA CARE Nurses in New Zealand (except for midwives) and Australia are not legally authorised to dispense or order prescription medicines. But in remote areas, where access to doctors is limited, nurses are often responsible for diagnosing illnesses and dispensing medicines. This situation is permitted for nurses working in isolated areas of the Northern Territory, Queensland, Tasmania and Western Australia. These extended rights over possession and administration of medicines are not automatic, and nurses must apply to the relevant health department for an authority to use these extended powers.

CONCLUSION Clearly, it is important for health professionals to possess a sound knowledge of the relevant legislation relating to medicines. It is equally important that they are aware of potential problem areas and of their need to maintain a duty of reasonable care to individuals.

C H A P T E R 3 H E A LT H P R O F E S S I O N A L S A N D T H E L A W

CHAPTER REVIEW ■■

■■

■■

■■

■■

■■

■■

■■

Commonwealth laws of Australia control the quality, safety and efficacy of medicines, while state and territory laws detail more specific provisions for medicine regulation. Medicines are divided into categories called Schedules. The nine Schedules indicate specific medicines by generic name according to particular characteristics. The Australian Therapeutic Goods Act 1989 and its Regulations provide control over the standard and availability of therapeutic goods. The Australian Narcotic Drugs Act 1967 safeguards against the illegal manufacture, supply and use of narcotic medicines. In New Zealand, the Misuse of Drugs Act 1975 and its Regulations provide directions for any controlled drugs, while the Medicines Act 1981 and its Regulations control the use of other therapeutic agents. An agreement between Australia and New Zealand has led to the trans-Tasman scheduling harmonisation agreement. This process enables compatible Schedules, labelling and packaging between the two countries. Normally only medical doctors, veterinary surgeons and dentists can write a prescription for a restricted or controlled substance. Other health care professionals, such as nurse practitioners, may have this responsibility for certain medicines. The law requires that all health care professionals show a reasonable standard and duty of care in medicine management.

REVIEW QUESTIONS 1

Indicate the Schedule to which the following medicines belong: a

morphine

b amoxycillin c

paracetamol

2

Differentiate the requirements for storage and administration of restricted substances and controlled drugs.

3

Explain the meaning of the following terms: a

telephone orders

b standing orders c

ward register

4

Explain the health professional’s responsibility for medicine administration in an emergency situation.

5

Explain the process a health professional should follow when confronted with an unclear medicine order.

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C H A P T E R

4

ETHICAL ISSUES

LEARNING OBJECTIVES

KEY TERMS

After completing this chapter, and with further clinical practice, you should be

Autonomy

able to:

Beneficence

1

Describe the six principles of ethics and provide examples of each principle.

Confidentiality

2

Describe the connection between the six principles of ethics with reference to the legal position.

Euthanasia

3

Explain the ways in which principles may conflict with one other.

Informed and valid consent Justice Non-maleficence Principles of ethics Veracity

Improved health, prolongation of life and recent advances in pharmacology have led to more emphasis on the ethical issues of clinical practice. There are six fundamental principles that are relevant and applicable to almost any ethical situation (see Table 4.1). These principles enable the health professional to follow a structured approach to ethical issues arising out of pharmacological situations. This chapter discusses these principles and relates them to common ethical situations pertaining to drug therapy. Discussion points are provided to illustrate some of the principles and form the basis for further discussion.

CHAPTER 4 ETHICAL ISSUES

Table 4.1 Ethical principles and their meanings PRINCIPLE

MEANING

Autonomy

Self-determination

Veracity

Trust through truth telling

Non-maleficence

Do no harm

Beneficence

Prevent harm, do good

Justice

Give to each person his/her right or due

Confidentiality

Not to divulge information without consent

AUTONOMY This principle asserts the person’s right to make decisions without interference from other people. It is important, however, that these decisions do not impinge on the moral interests of other people. The principle of autonomy comprises the two elements of informed and valid consent, and rights of refusal.

Informed and valid consent Health professionals and people in their care must share knowledge before people can agree to their proposed course of treatment. A person agrees to a particular treatment by means of an informed and valid consent. Table 4.2 indicates the requirements for an informed and valid consent, which will be discussed in turn.

APPROPRIATE DISCLOSURE OF INFORMATION Health professionals have a duty to inform people adequately of the effects, risks and complications arising from a proposed medicine regimen, but problems can arise to the amount and type of information to be disclosed to people. The courts of Australia and New Zealand commonly adhere to the ‘professional practice’ standard in determining this information. According to this standard, health professionals judge what information is Table 4.2 Requirements for informed and valid consent ELEMENTS THAT ENABLE INFORMED CONSENT 1 Appropriate disclosure of information 2 Understanding of information ELEMENTS THAT ENABLE VALID CONSENT 1 Free and voluntary consent 2 Competence

to be disclosed. They may withhold information if, in their opinion, disclosing such information is potentially harmful to the person. Problems may occur if the person wants to obtain more information about a medicine regimen than the health professional is prepared to offer. A less common standard of disclosure is the ‘reasonable person’ standard, which is based on the needs of a hypothetical person. The ‘reasonable person’ standard for disclosure of information is used in the United States and Canada. In this standard, the hypothetical person is an ideal representative of all reasonable people in society. In this instance, the health professional discloses the information a reasonable person would expect to receive. Unfortunately, as society is made up of people of different sociocultural backgrounds, it is difficult to determine what comprises a reasonable person (see also Chapter 2). Regardless of whether a standard is used or not, health professionals should offer simple but thorough information about the common effects and problems of a medicine regimen. Appropriate information should be given about the effects, benefits, risks and what is involved in taking a specific medicine. If the person asks a specific question, then the law requires that health professionals give an accurate answer. In the case of clinical trials for new medicines, people should attempt to obtain more thorough information due to the uncertain and experimental nature of these medicines. In addition, people who take complementary therapies should endeavour to obtain information about these preparations so that they are well informed about the therapeutic as well as unwanted effects. However, certain complementary therapies have untested properties that may not be known to the health professional or the person in their care. In such circumstances a health professional would not be held responsible if the person experienced D I S C U S S I O N P O I N T: W H AT W O U L D YO U D O ?

The following example reflects the dilemma concerning the amount of information the health professional should give the person about a drug treatment. A woman has a fatal reaction to the radio-opaque dye used during a myelogram. The radiologist and nurse indicate that they did not warn the person about a possible allergic reaction because she had never experienced an allergic drug reaction, and the chances of an allergic reaction were extremely remote.

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D I S C U S S I O N P O I N T: W H AT W O U L D YO U D O ?

The following example shows how a person’s cultural beliefs and values may affect acceptance of information about a proposed medicine regimen. An older Chinese woman is admitted to hospital following a fractured neck of her femur. Her hospital tests reveal the presence of breast cancer that is amenable to chemotherapy and surgery. The woman refuses to follow these options, preferring to use Chinese herbal remedies to treat the cancer. The woman continues to hold this view despite arguments to the contrary. an unexpected adverse drug reaction. Nevertheless, information about complementary therapies is growing all the time, and it is important that health professionals and people improve their knowledge about them.

UNDERSTANDING OF INFORMATION People must understand their drug therapy adequately; otherwise, their consent to the treatment will be uninformed. They may not understand information about their drug therapy for various reasons: they may be very young, older, suffering from a physical or psychiatric disorder, or there may be other reasons, such as the person may be of a cultural background that does not align with Anglo-Celtic views (see also Chapter 2). Problems may also occur when the health professional provides people with too much information to process. If the health professional provides insufficient information, people will not understand their medicine regimen. (Chapter 5 contains further information on effective teaching and learning strategies to facilitate understanding by people of their medicine regimens.) In addition, health professionals such as doctors, nurses and pharmacists may have an inadequate knowledge of complementary therapies, usually because the education of health professionals tends to focus on more traditional and conventional therapies. Alternatively, people may obtain information about complementary therapies from sources such as popular magazines, radio, television and the Internet. As a result, people may not have an adequate understanding of complementary therapies and of the ways these may interact with more conventional therapies. In addition, health professionals may not be able to communicate information to individuals about the risks and benefits of medicines in a simple and effective way (see Chapter  12). However, it is the health professional’s

responsibility to ensure that the person’s information is reliable and accurate, therefore enabling informed consent.

FREE AND VOLUNTARY CONSENT Free and voluntary consent means the ability to choose and act freely without the influence of others. If a person faces the decision whether or not to have drug therapy for a particular condition, the health professional should provide adequate and unbiased information about each option. The person can then make a free and voluntary decision. Sometimes people’s mental or physical functions are impaired to the point where they are unable to make voluntary decisions. If possible, health professionals should wait until the person can consent voluntarily before proceeding with treatment.

COMPETENCE The person must be competent for the consent to be valid. According to the law, all persons except minors and the mentally ill are competent to make their own decisions. Competence is the person’s ability to fully understand the D I S C U S S I O N P O I N T: W H AT W O U L D YO U D O ?

The following example demonstrates the problem confronting a health professional when a person is not fully informed about the beneficial as well as harmful effects of a herbal medicine. Refer to Chapter  69 for further information about herbal therapies. While herbal medicines are often freely available from pharmacies and health food stores, people do not always receive adequate information about their use. A 35-year-old woman who is 20  weeks’ pregnant comes into the health clinic for her prenatal checkup. She comments to the midwife that she has been able to sleep better now over recent months because she has started taking chamomile supplements. The woman adds that she read in one of the women’s magazines about the benefits of taking chamomile supplements to assist with insomnia, and bought the supplements from her local pharmacy. The midwife comments that although chamomile supplements may be normally beneficial, they should not be taken during pregnancy. Immediately the woman begins waving her arms around anxiously and states, ‘But they are supposed to be natural, so surely they should be okay?’

CHAPTER 4 ETHICAL ISSUES

consequence of their choices and actions. In the case of a minor (under 18 years of age in Australia and under 16 years of age in New Zealand), the doctor obtains consent from a parent or a legally appointed guardian. On the other hand, Australian and New Zealand common law does not fix any specific age below which a child is automatically presumed incapable of consenting to treatment. The child’s ability to consent mainly depends on whether the child is mature enough to understand and appreciate the implications of the treatment undertaken. Legislation also permits certain emergency treatments without parental consent. Furthermore, it allows health professionals to override the parental decision if it is in conflict with the child’s survival. An emergency situation here is one where the child will die or suffer serious damage if the treatment were not given. For people of different cultural and linguistic backgrounds, consent should be facilitated by involving health interpreters trained in the person’s own language. It has been common practice to ask untrained individuals who speak languages other than English to interpret for a non-English-speaking person. For a number of reasons, this practice is not acceptable. Untrained individuals may misinterpret the information to be communicated and may give their own assessment of a question being asked. They also do not have a professional relationship and are not bound by a code of professional ethics. As a result, they may not appreciate or understand their responsibility not to disclose the confidential information to which they have been exposed. In providing emergency procedures to adults, health professionals are forced to make difficult decisions, as people may not be able to decide for themselves. Examples include people who have a head injury following a motor car accident; who are under the influence of medicines or alcohol; or who have a massive myocardial infarction. In these situations, health professionals can perform procedures without seeking the person’s consent. Australia and New Zealand have legislation in place that deals with the care of the intellectually disabled. Disabled individuals who are able to function in the greater community and live independently are often considered competent to make their own decisions about health care. The legislation addresses the needs of severely disabled adults who possess the mental age of young children and may, therefore, not be able to protect themselves. The legislation is designed to prevent abuse, neglect and exploitation of these disabled adults. Parents or appointed guardians have the authority to consent to treatments that are necessary for the wellbeing of disabled adults.

Other people suffering from mental illness, such as depression, are often legally capable of making their own decisions about treatment. During an acute stage of their illness, they may lack the legal capacity to consent to treatment. Sometimes it is up to health professionals to decide whether these people are competent enough to make decisions about treatment.

Rights of refusal Competent people can refuse drug treatment at any time. Continuing to give treatment when people have clearly refused consent constitutes trespass. Even if the treatment is life-saving, it should not be given to competent people without their consent. As nurses are the most likely health professionals to administer medicines, people who refuse their medicines usually direct their comments to the nurse. For many nurses, the person’s refusal of medicine means the unnecessary interruption of an already hectic administration schedule. It is important, however, that the nurse examine the reasons for the person’s refusal. It may be that the person has not been adequately informed about a newly prescribed medicine. The person may be experiencing adverse effects of the medicine, warranting a change in medicine or reassurance that the medicine is having the desired effect. Sometimes people are adamant that an error has been made in the medicine order, leading to their refusal of the medicine. People often become very familiar with their medicine regimen, so the nurse should determine the various potential sources of error (refer also to Chapter 10). D I S C U S S I O N P O I N T: W H AT W O U L D YO U D O ?

The following two situations illustrate differing capacities for competence and how consent may be waived depending on the urgency of treatment. A 20-year-old footballer is brought into the emergency department with a gash in the side of his face that has stopped bleeding. He refuses to have the area sutured as he does not like injections or pain. He also does not mind if a scar develops on the area. A 20-year-old man smelling of alcohol is brought into the emergency department after a fight outside the local pub. He sustains a deep stab wound to the abdomen and a cut on his hand. The man refuses treatment, even though his vital signs indicate that internal haemorrhage has occurred.

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If a confused person refuses medicine, a hurried and abrupt approach is hardly likely to produce a positive effect. Instead, the health professional should be reassuring and give the confused person some sense of control by offering a choice, such as whether the person would like water or lemonade with a tablet. Ultimately, the health professional should communicate in a pleasant and positive manner and never be forceful or intimidating. If the person still refuses the medicine, this should be documented on their medication chart. The health professional should also document in the person’s health history the reasons given for refusal, the attempts made to explain the situation to the person, and the actions taken.

Exceptions to veracity

VERACITY

The principle of non-maleficence involves the duty of not harming or injuring others. Examples of harm include the possibility of residual disability from an operation, or adverse effects from conventional and complementary therapies. According to law, the health professional should provide the person with information about the nature of the intended treatment and problems that may occur. Negligence, which is a failure to provide adequate care and to guard the person against harm or injury, involves conduct that falls below the professional standard set by law. The level of expertise and standard of care is that expected of an ordinary and competent practitioner.

Veracity relates to an obligation to tell the truth and not to lie or deceive others. It is closely associated with the principle of autonomy. A person cannot express autonomy unless the consent is informed and valid. The consent, therefore, depends on truthful communication in helping the person to make decisions about treatment. Due to the specialised knowledge of health professionals, health care sometimes takes a paternalistic approach, where individuals and their relatives are given just enough information to keep them content. This approach assumes that people do not expect to be told everything, as they lack specialised medical knowledge. But people often need more thorough explanations for information to make sense. The principle of veracity stresses the need for health professionals to honour the trust and confidence bestowed on them by people. Health professionals can do this by maximising the amount and kind of information they share with people. Furthermore, as society is becoming better educated about health care, fewer people are prepared to entrust themselves to the care of secretive and nondisclosing health professionals.

The law and therapeutic privilege A legal exception to the rule of veracity relates to therapeutic privilege, where a doctor may intentionally and validly withhold information based on ‘sound medical judgment’. In this instance the person may be depressed, emotionally drained or physically unstable. The disclosure of information is then potentially harmful. Health professionals often use therapeutic privilege in emergency and critical care situations. The provision of important information may be breached in favour of the more urgent need for life-saving treatment.

Occasionally there are situations where it is just not appropriate to divulge information to a person. These situations have been alluded to in the above section. In addition, failing to tell a person immediately after surgery that an inoperable cancer was found in theatre, or failing to tell a person that their family has been killed in the same accident that landed that person in hospital, are clearly exceptions to the principle. The intention is not to deceive but simply to convey the information at a more appropriate time.

NON-MALEFICENCE

D I S C U S S I O N P O I N T: W H AT W O U L D YO U D O ?

The following situation illustrates the conflict between meeting the obligation of veracity and trying to protect the person from needless suffering (beneficence). A 50-year-old man presents with a recent growth of a thyroid mass and a hoarse voice. Only partial removal of the tumour is possible during surgery. During discussions with the person’s spouse and children, the doctor and charge nurse inform them of the client’s poor prognosis. The family and health professionals decide to conceal the diagnosis and prognosis from the person, and to simply tell him that he needs ‘preventive’ treatment. The person receives irradiation and chemotherapy, but soon becomes quite concerned and upset that his condition is not improving. He is never offered the chance to talk about his impending death as everyone around him pretends that he will recover. He dies five months after the initial diagnosis.

CHAPTER 4 ETHICAL ISSUES

Thus, a graduate first-year trainee health professional is not expected to perform to the same standard as an experienced health professional. It is important that health professionals be constantly aware of their level of expertise and consistently aim to achieve a high standard of practice in all aspects of patient care (see also Chapter 8).

Euthanasia Health professionals continually face emotional issues of life and death in their working environments. Euthanasia is an example of such an issue. The literature commonly distinguishes between voluntary, involuntary and nonvoluntary euthanasia, and between active and passive euthanasia. With voluntary euthanasia, the person voluntarily and freely chooses death. With involuntary euthanasia, the health professionals carry out actions without the person’s consent. In non-voluntary euthanasia, the person is incapable of either giving or denying consent (i.e.  is permanently comatose or brain-injured). Active euthanasia is the intentional act that leads to the person’s death (e.g. the administration of a lethal injection). Passive euthanasia involves allowing the person to die by deliberately withholding or withdrawing life-supporting measures. Examples of passive euthanasia are the withholding or withdrawal of antibiotics, nutrition, respiratory mechanical support and cardiac medicines from a terminally or chronically ill person.

LEGAL PERSPECTIVE In Australia and New Zealand, active euthanasia is illegal. Currently, some forms of euthanasia are legal in Belgium, Luxemburg, The Netherlands, Switzerland, the Autonomous Community of Andalusia (part of Spain), Thailand, and Oregon and Washington in the United States. In Australia and New Zealand, when a health professional deliberately assists a person to die through (active euthanasia), the law considers it an act of homicide. Passive acts of euthanasia are common in Australian and New Zealand hospitals. Currently, people have the right to refuse treatment and treatment can be withheld, but they cannot legally receive assistance from health professionals to end their lives.

Withholding and withdrawing treatment Health professionals make and carry out euthanasia-type decisions every day in the health setting. These decisions relate to whether treatment should be withheld or withdrawn. Although it may not be the health professional’s intention to cause death in these situations, death may ultimately occur. Confusion often exists about the distinction between withholding (not starting) and withdrawing

(stopping) treatments. Many health professionals and family members appear more comfortable withholding treatments than withdrawing treatments that have already started. In withdrawing treatment, health professionals may feel more responsible for a person’s death than in not starting a treatment to sustain life. There is also the belief among health professionals that starting a treatment often creates an expectation that the treatment will continue. To avoid this situation, it is important for doctors and nurses to communicate to the family that they will act according to the person’s wishes and best interests. As far as the law is concerned, health professionals have no duty to continue treatment if it has proven ineffective. Instead, there should be a balancing of burdens and benefits to determine the overall effectiveness of treatment, and the person, in consultation with family members, ought to be the primary decision-maker. This distinction between ‘not starting’ and ‘stopping’ treatment may account for the relative ease with which health care workers accept a ‘not for resuscitation’ (NFR) order. This order means that if a person suffers a cardiac or respiratory arrest, the health professionals will not resuscitate. It is also often unclear whether NFR orders imply anything about other aspects of nursing and medical care. For instance, some people with NFR orders receive chemotherapy, surgery, admission to intensive care, respiratory support and full nursing care, while others do not. Decisions relating to NFR orders are also problematic, as they are often made without consultation with individuals or their families. Decisions relating to life and death situations can be extremely difficult and sensitive. As a result, the person and family are usually not involved, and naturally this affects the person’s right to autonomy. Health professionals must, therefore, confront these life and death situations more openly and involve the person and family in the decisionmaking process.

BENEFICENCE Beneficence is conduct aimed at the good and wellbeing of others. The main difference between non-maleficence and beneficence is that the former involves restraint, prevention and prohibition, whereas the latter involves positive action, intervention and provision of care. In cases of conflict between the two principles, the duty of non-maleficence usually has priority over beneficence.

Duty of beneficence The duty of beneficence involves the delivery of appropriate treatment and the assurance that the treatment will produce

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more good than harm. There are complex situations where it may be difficult to determine whether the treatment will be of ultimate benefit to the person. Some examples include considering the administration of an antianxiety agent to a suicidal person instead of improving support networks and counselling facilities; or the provision of expensive drug therapy to an extremely old and senile person. In assessing these decisions, the health professional needs to demonstrate a genuine responsibility for the person’s wellbeing. It involves consideration of the person’s desire not to have treatment, the long-term versus short-term benefits, the psychological and physical prognoses, and the presence of suffering accompanying the prolongation of life. From the legal perspective, health professionals should offer treatment and services deemed to be of benefit to the person.

D I S C U S S I O N P O I N T: W H AT W O U L D YO U D O ?

The following situation illustrates how a health professional’s duty of beneficence may lead to an infringement of a person’s autonomy. After receiving his preoperative medicine, a 20-year-old man scheduled for a knee reconstruction states to the nurse that he does not want the side rails up. He does not believe the hospital’s rules should apply to him as he is not drowsy from the medicine and he will not fall out of bed. After some discussion with the person, the nurse responsible for his care decides to put the side rails up. The nurse argues that she has restricted this person’s autonomy in order to protect him from harm.

Problems with paternalism Beneficence can lead to paternalism. This occurs when health professionals carry out a particular treatment deemed to be of benefit and then neglect to inform the person about this treatment. In some cases, the health professional may provide beneficent action when the person is not able to give informed consent, such as when a road accident victim sustains head trauma. In other cases, a health professional may provide beneficent action even if it opposes a competent person’s wishes, which is against the principle of autonomy.

Conflicts with other principles Sometimes the principle of beneficence conflicts with other principles. A health professional may be torn between beneficence and non-maleficence when considering the use of highly sophisticated or experimental treatment. The impulse towards beneficence can lead to excessive and unnecessary treatment, and increase client suffering. Beneficence can conflict with the principle of justice. A too-eager approach to beneficence may threaten the equitable allocation of resources, so those who are most in need of health care may not receive it. Beneficence may also affect veracity and confidentiality. With veracity, a doctor or nurse may believe it is best to withhold the news of a person’s poor prognosis as it may affect the psychological wellbeing of the person. A health professional may feel beneficence is served best by telling the person’s family about the person’s poor prognosis. Health professionals must obtain approval from the person before they can tell the family about the person’s condition, otherwise this action is contrary to the duty of confidentiality.

JUSTICE Justice means that people will be assured equal access to the benefits available. It aims to provide all people with reasonable, dignified health care based on the need for this care. Equal access to health care ensures that no-one is the subject of unreasonable discrimination. Unfortunately, not all sectors of the community have adequate access to this care, and subsequently their health suffers. The Indigenous people of Australia and New Zealand currently face this situation (see also Chapter 2).

Allocation of scarce resources The growing cost of treatment and the presence of limited health resources means that health services must be rationalised. The process of rationalisation is divided into two areas: macroallocation and microallocation.

MACROALLOCATION Macroallocation decisions determine the amount to be expended and the kinds of health services to be made available to the community. Government and health organisations carry out these decisions. Macroallocation decisions have become increasingly difficult to make for various reasons. There is concern that expensive technology is often employed unnecessarily and that the money is taken away from other less costly areas, such as health promotion and education. Furthermore, antagonism sometimes exists between hospitals and branches of the health sector (e.g. community health versus acute care) for a larger share of the limited resources.

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MICROALLOCATION Microallocation decisions determine who will obtain and use the available resources. Health professionals make these decisions for people based on need. The idea of microallocation can be applied to the triage situation of hospitals. The model of triage used in emergency and critical care departments involves sorting people to ensure that available resources are used as effectively and efficiently as possible. Triage decisions, which are generally made by a nurse, involve the determination of the greatest good for the greatest need. The nurse categorises people into those who would die without immediate help; those whose treatments can be delayed without immediate danger; and those with minor injuries. These decisions do not involve judgments about a person’s worth to society. Judgments about social worth, however, may need to be made in some situations. For example, in an outbreak of a contagious disease or following a serious earthquake, health professionals who are affected by the outbreak should (in some instances) be given priority of treatment. Once treated, these health professionals can care for other victims. Clearly, there are several approaches used in determining the allocation of health resources, and not everyone will have adequate access to health care. In developing an understanding of the complex factors impinging on the allocation of health resources, and of the sociocultural factors affecting people’s access to care, health professionals will be in a better position to help those most in need.

CONFIDENTIALITY Confidentiality occurs when one individual discloses information to another in the belief that the information will not be divulged without permission being given.

Difficulties in maintaining confidentiality The principle of confidentiality is often clouded by the need to protect the person and other individuals from harm. The following situations illustrate the difficulties that may occur. For example, if a person tests positive for exposure to the human immunodeficiency virus (HIV), health professionals must counsel these people to tell spouses and sexual partners themselves. If this fails, health professionals will consider informing the people at risk even if the person insists on maintaining confidentiality. The situation regarding a person living with HIV is very difficult, as the

disclosure of information regarding a person’s HIV status may have repercussions in several areas of the person’s life. Ultimately, therefore, the rights of the person may conflict with the rights of others. Conversely, health professionals may know of a person with severe coronary problems who wants to continue with dangerous and strenuous sporting activities. The family may know nothing about the situation. In this instance, issues of autonomy and confidentiality combine to make it difficult for health professionals to do anything else but give advice to the person. Furthermore, if a girl, regardless of age, wants to receive a prescription for the contraceptive pill, her doctor or community nurse should not inform her parents. If the girl has a family history of blood-clotting disease and she insists on continuing to take the contraceptive pill, the doctor or nurse should encourage her to tell her family. Without her consent, however, her family should not be told. In contemporary society, it is fairly difficult to maintain confidentiality in care relating to the older person, or those who are chronically or acutely ill. The delivery of care for these people often involves a number of specialists, who are all handling the person’s personal details. The increasing use of computers in the health care setting to store people’s data and progress notes adds to the possibility of accidental disclosure. The issue of confidentiality exposes a conflict between the obligation to preserve confidentiality and the duties relating to doing no harm and doing good. As shown, sometimes the respect for confidentiality must yield to the welfare of the person and of other people.

CONCLUSION The ‘principles approach’ towards ethical issues in pharmacology enables a systematic and structured approach to a particular situation. Health professionals will confront several situations in practice where there are conflicts between two or more principles. Equipped with a knowledge of these principles, the health professional can identify the conflicts that may arise, and either develop a set order of priority or choose a course of action that preserves the principles at stake. Ethical issues commonly abound in the area of pharmacology, and for health professionals to function effectively as moral practitioners, mediators and negotiators, they need to develop and maintain a responsible and accountable ethic of care.

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CHAPTER REVIEW There are six fundamental principles that are applicable to almost any ethical situation ■■

The principle of autonomy asserts the person’s right to make decisions without interference from other people.

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Veracity relates to an obligation to tell the truth and not to lie or deceive others.

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The principle of non-maleficence involves the duty of not harming or injuring others.

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Beneficence is conduct aimed at the good and wellbeing of others.

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Justice means providing all individuals with equal access, and reasonable, dignified health care based on the need for this care. Confidentiality is when one individual discloses information to another in the belief that this information will not be divulged without permission being given.

C H A P T E R

5

THE ROLES AND RESPONSIBILITIES O F H E A LT H P R O F E S S I O N A L S IN MEDICINE ADHERENCE, E D U C AT I O N A N D A D V O C A C Y LEARNING OBJECTIVES

KEY TERMS

After completing this chapter, you should be able to:

Client advocacy

1

Describe the health professional’s role in pharmacology with reference to medicine adherence, medicine education and client advocacy.

2

Describe factors affecting a person’s adherence to medicine regimens.

3

Discuss learning and teaching principles the health professional can use in developing and implementing a teaching plan.

4

Describe principles the health professional can use in promoting client advocacy.

Medicine adherence Medicine education

With the growing complexity of health care, health professionals have a dynamic, responsible and active role in managing medicines. Health professionals achieve these multifaceted roles with pharmacology by means of medicine adherence, medicine education and client advocacy. Increased understandings of these roles contribute to improving the quality of people’s experiences with managing their medicines.

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MEDICINE ADHERENCE Medicine adherence relates to compliance of a person to a prescribed medicine regimen, including dose, method of administration, frequency, specific recommendations and precautions for the medicine. Non-adherence refers to the deviation from a prescribed medicine regimen. Research indicates that many people fail to follow their prescriptions correctly in the home setting. Although attempts have been made to elucidate demographic characteristics affecting adherence, research indicates that factors such as gender, age, social class, education and mental status play only a small part in non-adherence. In fact, factors affecting nonadherence are more complex, relating to a lack of person– health professional interactions, disease consideration and medicine characteristics, as well as client characteristics. Table  5.1 summarises these factors. Health professionals play a vital role in minimising the level of non-adherence through individualised instruction according to the person’s particular circumstances. Written information in the form of consumer medicine information (CMI) is available to people to help them to become better informed about their medicines and to improve adherence. Currently, CMIs are available for prescription medicines and are distributed to people by pharmacists. Each CMI deals with a particular medicine, and should be used by health care professionals as a complementary aid to existing educational resources, rather than as a replacement for counselling. While the provision of a standard CMI is helpful, it does not provide an individualised approach to the supply of information. As shown in Table 5.1, several factors influence a person’s adherence to medicine regimens. With the aid of CMIs, health professionals can explain to people the particular ways in which medicines may affect their lifestyle. Through the increasing use and availability of CMIs as a medicine resource for people, together with counselling provided by health professionals, medicine adherence among people should be greatly enhanced.

MEDICINE EDUCATION Health professionals play an important role in the assessment, planning, implementation and evaluation of medicine education for drug therapy. Developing an awareness of learning and teaching principles will assist in the transmission of information and further facilitate a person’s adherence to medicines.

Table 5.1 Factors affecting a person’s adherence to medicine regimens PERSONAL CHARACTERISTICS • • • • • •

Age extremes Absence of family support (social isolation) Cost of medicines Personal/cultural beliefs Physical impairment (e.g. hearing, vision) Intellectual/mental impairment (e.g. congenital, acquired) • Motivation • Lack of cognitive skills PERSON–HEALTH PROFESSIONAL INTERACTIONS • Communication barriers (e.g. language, culture, anxiety) • Misunderstanding of directions • Absence of confidence in medicine regimen • Dissatisfaction with, or lack of confidence in, health professional • Lack of effective use of time DISEASE CONSIDERATIONS • Chronic long-term condition with no cure • Benefits of treatment not easily seen (e.g. hypertension) • Disease requiring a long treatment period before benefits apparent (e.g. depression) MEDICINE CONSIDERATIONS • • • • •

Multiple medicines (polypharmacy) Frequent doses Doses at inconvenient times Complex dosage regimen Adverse drug effects perceived as worse than condition treated • Route of administration not tolerated (e.g. unpleasant taste, vomiting, diarrhoea) • Inappropriate dosage form (e.g. tablets too big) • Extended duration of therapy

Learning principles With the help of a health professional, the person can apply certain learning principles to reinforce the knowledge gained about medicines. The following points cover important aspects that promote learning.

ACTIVE PARTICIPATION An effective way for the person to develop new skills or change a behavioural pattern is to play an active role in the educational process. For example, a person who is to administer subcutaneous insulin for diabetes will learn this skill more effectively by practising the procedure with the health professional. This method is useful in promoting

CHAPTER 5 THE ROLES AND RESPONSIBILITIES OF HEALTH PROFESSIONALS IN MEDICINE ADHERENCE, EDUCATION AND ADVOCACY

cognitive and psychomotor skills. In this example, cognitive skills relate to how much insulin to draw up depending on the blood glucose level. The psychomotor skills focus on how to draw up the insulin, as well as how and where to administer the injection.

about warfarin therapy and the person wants to focus on how daily activities will be affected, the health professional will incorporate these ideas in the session. This strategy promotes the feeling of security in the person.

MOTIVATION TO LEARN

Repetition provides the person with opportunities to practise psychomotor skills, observe improvement in the dexterity of these skills and allow for feedback between the person and health professional.

The health professional must be aware of the person’s motivation to learn. Without adequate motivation, the person will not retain or use the information. The health professional can attempt to boost a person’s motivational level by assessing the person’s perception of their medical condition and the social, cultural and environmental background, and incorporating this information in the learning process.

PRIOR EXPERIENCE AND KNOWLEDGE Knowledge is more effectively achieved if it builds on ideas and experiences already familiar to the person. Aspects of relevance to this area include the person’s educational level, occupation, cultural or ethnic beliefs, and familial predisposition to a particular medical condition. For instance, if after taking a medical history, it is identified that a person’s father has had an acute myocardial infarction, the health professional should ask the person what was learnt from the experience and build on it.

IMMEDIATE APPLICATION OF KNOWLEDGE Learning is enhanced if a particular skill is practised immediately. For example, when locating injection sites for the administration of insulin in a newly diagnosed diabetic, the health practitioner should demonstrate the procedure and then allow the person to indicate these sites. This process enables the health practitioner to provide immediate feedback.

PHYSICAL AND EMOTIONAL READINESS This principle focuses on the health professional’s awareness of the person’s physical, intellectual, emotional and spiritual traits so that adjustments can be made. For example, for a person recovering from a motor vehicle accident with head injuries and bone fractures, the health professional will assess characteristics that may interfere with learning, such as pain, confusion, drowsiness, anxiety and adverse reactions to medicines.

MEETING PEOPLE’S EXPECTATIONS AND GOALS Before beginning a teaching session, the health professional should assess the person’s expectations and goals for the prescribed medicines and adjust the plan accordingly. For instance, if the health professional is teaching the person

REINFORCEMENT OF LEARNING WITH REPETITION

Teaching principles Besides factors impinging on a person’s ability to learn, the health professional should be aware of principles influencing teaching strategies. The following points cover important strategies that facilitate effective teaching. Table 5.2 indicates the relevant aspects of client teaching with use of the clinical decision-making process (see also Chapter 8). Table 5.2 Client teaching through the clinical decision-making process CLIENT ASSESSMENT • Knowledge base • Physical abilities/disabilities (ability to perform motor functions) • Cognitive abilities/disabilities (thinking and intellectual processes) • Affective state (feelings, beliefs, values) • Barriers to communication (language, deafness, blindness) • Perceived needs • Attitudes towards health/disease state • Support networks (family and friends) • Self-esteem • Cultural, ethnic and religious beliefs CLINICAL DIAGNOSES • Relation of knowledge deficit to information identified in assessment PLANNING • Development of a teaching plan • Identification of person’s goals IMPLEMENTATION • Use of effective learning and teaching principles depending on people’s needs MEDICINE EVALUATION • Made at conclusion of teaching/learning process or occurring continuously throughout teaching/ learning process • Modification of steps to facilitate successful completion of goals

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HEALTH PROFESSIONAL—PERSON RAPPORT AND COMMUNICATION If the health professional and person have established effective rapport, the health professional is able to assess the person’s learning needs. Effective reciprocal rapport is achieved through communication, which has elements of friendliness, empathetic concern and a willingness to take the time to offer explanations. In examining responses and attitudes towards the person from the person’s perspective, the health professional assesses the person’s values, beliefs, vocabulary and ability to assimilate information. The health professional is responsible for respecting a person’s autonomy in decision-making about treatment (see Chapter 4), and is aware that there will always be people who fail to comply with the most logical and rational therapeutic recommendations. A mutually negotiated contract will assist in preserving the autonomy of and respect for the person.

ENVIRONMENTAL CONTROL Environmental factors such as noise, temperature, lighting and privacy can enhance or interfere with the effectiveness of a teaching session. Although the environment is not always amenable to change, the health professional should attempt to minimise distracting factors that may interfere with the person’s ability and willingness to participate in a teaching session.

MUTUALLY NEGOTIATED CONTRACT A mutually negotiated contract, outlining expected outcomes to be achieved, serves as a structured guideline for the person and the health professional. This contract can be verbal or written and provides meaningful goals for the person to ensure understanding about how to manage medications. Following the teaching session, the contract’s outcomes provide the means for evaluating the effectiveness of teaching and learning, and help the health professional and person identify areas that require further emphasis and attention.

VARIETY OF TEACHING STRATEGIES The health professional should use a variety of teaching strategies to enhance learning. Examples include smallgroup or one-to-one discussions, demonstrations, simulations, anatomical models and simple illustrations. The approach taken depends on information derived from the health professional’s assessment of the person.

CLIENT ADVOCACY Client advocacy is another important role performed by health professionals in relation to drug therapy. In their role as advocate, health professionals inform people about their rights in a particular situation, making sure they have all the information necessary to make informed decisions. The health professional supports them in their decisions, and protects and safeguards their interests. In their role as client advocate, health professionals are often confronted by adversaries that render the person powerless to make an informed decision. In this context, an adversary is something, or someone, that prevents the person from making an informed decision. Most commonly, these adversaries are members of the team of health care professionals, such as nurses, doctors, social workers, and family members. The adversaries may even include the rules, policies and protocols of the health care agency or sustained chronic illness, paraplegia, ageing, trauma or poverty in vulnerable people. Advocacy also relates to ideas of power and empowerment. The health professional advocate may experience this powerlessness and vulnerability when confronted by adversaries to the person’s autonomy. It may be difficult for health professionals to act as client advocates, as they may lack the self-esteem and professional identity required to stand up and represent the person. If the adversary is a confident person with a high professional status (such as a doctor), it may be particularly difficult for the health professional to represent the person’s wishes. Health professionals need to develop and implement strategies aimed at recognising, promoting and enhancing individuals’ abilities to determine their needs, and to help them to resolve their situations. Health professionals must present the information in a manner that promotes understanding. If health professionals impose their own feelings, this may lead to distortion of information. Another strategy is for health professionals to reassure people in the decisions they make and to convey to them that they have the right to make these decisions. Health professionals should also resist pressure from other individuals who attempt to undermine a person’s confidence in their decision-making. There are several indicators of the necessity for health professionals to address themselves as client advocates. Some of these indicators include the increase in the number of older, well-educated or demanding individuals, combined with the escalating costs of technology. Furthermore, client advocacy forms an important basis of nursing practice that is concomitant with the essence of caring. Advocacy is supported by ethical issues and ideas of informed consent, which are discussed in Chapter 4.

CHAPTER 5 THE ROLES AND RESPONSIBILITIES OF HEALTH PROFESSIONALS IN MEDICINE ADHERENCE, EDUCATION AND ADVOCACY

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Compliance relates to a person’s adherence to a prescribed medicine regimen, including dose, method of administration, frequency, specific recommendations and precautions for the medicine. Health professionals play an important role in the assessment, planning, implementation and evaluation of medicine education for drug therapy. In their role as advocate, health professionals inform people about their rights in a particular situation, making sure they have all the necessary information to make informed decisions.

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KEY TERMS

After completing this chapter, you should be able to:

Dietitian

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Describe the roles of the prescriber, nurse, pharmacist, physiotherapist, podiatrist, dietitian, paramedic and naturopath in relation to managing medicines.

Naturopath

Determine which health care professionals are able to perform the following duties: dispense medicines, prescribe medicines and administer medicines.

Pharmacist

Describe ways in which the roles of these health care professionals are changing in relation to drug therapy.

Podiatrist

Nurse Paramedic Physiotherapist Prescriber

There are several health professionals who assume responsibility for managing people’s medicines. These health professionals have important direct and indirect roles to play in the supply, distribution, prescription and administration of medicines to people. This chapter examines the roles of the prescriber, pharmacist, physiotherapist, podiatrist, dietitian, paramedic and naturopath in drug therapy and how these roles intertwine with those performed by various members of the health care team.

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THE PRESCRIBER According to medicine legislation, the prescriber may be a medical practitioner, dentist or veterinary surgeon, depending on the working environment. As nurses tend to associate with medical practitioners (doctors) in the health care setting, the term ‘prescriber’ will relate to this particular group. The medical practitioner is responsible for the diagnosis of illness and disease, and the initiation of therapy. According to legislation, doctors are authorised to have in their possession, use, sell or supply any medicine, as long as this occurs within the lawful practise of their profession. With some exceptions, a prescription or medicine order can be written only by a medical practitioner (see Chapter  3). These medicines must be ordered in the doctor’s handwriting and must include the dose, route and frequency of administration. If the order or prescription is unclear or ambiguous, the doctor must be contacted to obtain clear instructions. In an emergency situation, however, the doctor may verbally direct a registered nurse to administer a medicine to a person. The doctor should then document this order on the person’s medication chart within 24 hours. For example, the nurse may receive a verbal order for the intravenous administration of potassium chloride to a person with congestive cardiac failure and angina. This person would already be receiving a diuretic that may deplete serum potassium levels. If serum potassium levels are not maintained within normal limits, this person is predisposed to cardiac dysrhythmias. It is therefore important that the nurse treats a low serum potassium level promptly to prevent dysrhythmia problems. Doctors also play an important role in educating people about their drug therapy in the community and hospital contexts. As prescribers of drug therapy, they can provide people with the reasons for choosing one particular medicine over another. Doctors also determine the therapeutic and adverse effects of drug therapy on the person’s medical condition, and are responsible for any changes to the medicine regimen. As nurses are present at the person’s bedside more often than any other health care professional, doctors rely quite heavily on the assessment skills of nurses as a means of evaluating the effectiveness of the medicine regimen. Nurses may encounter doctors in a number of different contexts. On graduation, medical students are required to work as ‘interns’ in hospitals for one or two years, depending on registration requirements, before they can register as independent practitioners. Approximately half of these doctors will eventually work in general or community practice, while the other half will become specialists and

consultants within the hospital environment or in private practice. In the past, on successful completion of their internship, doctors have been able to register to practise medicine independently. It is now recognised that general practice is a specialty in its own right, requiring specific vocational training. Currently, all newly graduated doctors in Australia wanting to practise as general practitioners need to be ‘vocationally registered’. This process involves intensive general practice training following the internship year with supervision by an accredited supervisor. Advocates for the medical profession believe this program is an ideal way for new doctors to develop appropriate prescribing habits in the community context and will facilitate improved communication skills and client compliance. In addition, some medical courses are incorporating non-drug therapies in their syllabus, along with clinical pharmacology. With the importance of non-medicine therapies advocated by other health care professionals (e.g.  massage, therapeutic touch, relaxation), the goal is for less emphasis to be placed on the medicalisation of a person’s health problems.

THE NURSE Nurses contribute to the planning and modification of drug therapy from their assessment of client factors and evaluation of progress or problems occurring during drug therapy. Nurses share information with other health professionals to provide the most effective medicine regimen for the person. Furthermore, nurses have many opportunities in preparing people to participate as responsible contributors to their own care and to evaluate critically the existing therapeutic plans. The evolution of the nurse practitioner role has been instrumental in allowing nurses to take a more proactive approach in addressing the needs of people in a safe and effective manner. With the increasing complexity of health care, the demand for nurses to take on advanced clinical roles continues to gather momentum. The nurse practitioner is a registered nurse with appropriate accreditation to practise in the role. This nurse has developed expert clinical skills, knowledge and experience in a specific area of clinical practice, such as remote area nursing, midwifery, palliative care, wound care, women’s health or child health. In New Zealand and Australia, research has been undertaken to determine the benefits of the nurse practitioner role in a variety of health care settings. The role allows for autonomy in the workplace, and the freedom to make consistent decisions within the

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designated scope of practice. Expected standards of quality have also been demonstrated, which include exemplary professional behaviour, managerial capability and positive client reports. From studies already completed, the evidence suggests that nurse practitioners provide quality health care. In contrast to other types of nurses, nurse practitioners have some prescribing rights, are able to order context-specific pathology and radiology tests, and are able to make limited referrals. The accountability associated with this position adds another complex dimension to nurses’ interdependent and independent roles in client advocacy. It is important to note that nurse practitioners are expert nurses who are not meant to act as a substitute for medical practitioners. Various models of practice have been researched and subsequently advocated as suitable areas of work for nurse practitioners. These include the following: women’s health, primary health, emergency psychiatric liaison, community mental health, paediatric dermatology, wound care, neonatal nursing, perioperative nursing, intensive care nursing, emergency nursing, district nursing service within a homeless person’s program, diabetes care, family planning and sexual health. It is readily apparent that the nurse practitioner role varies in different contexts, and that nurses in this role require appropriate education in broad and context-specific aspects of their responsibilities. The educational preparation for a nurse practitioner is a Masters degree. Components of study undertaken in such a course include advanced health assessment, pathophysiology and pharmacology, as well as specific clinical elements that capture the context in which the nurse practitioner operates.

THE PHARMACIST The pharmacist is responsible for a number of duties, including the supply and distribution of medicines; educating people in the use of medicines and the treatment of medical conditions; educating health care professionals in all facets of medicine use; and the preparation of medicines. One of the most important roles of the pharmacist is the supply and distribution of medicines. Supply and distribution involve the all-encompassing term of dispensing. Dispensing a medicine means making it available from the central supply area of the pharmacy to people and other health care professionals. The role of pharmacists in dispensing differs depending on their area of employment. If employed in a community pharmacy, pharmacists supply medicines to the general public. The community pharmacist keeps a record of the prescription medicines supplied to the public, and retains these records for a period of time according to legislation.

Legislation also requires that community pharmacists keep medicines secure. Prescription medicines are stored in the dispensary area, where the pharmacist carries out the task of supplying medicines. The pharmacist personally supervises the dispensary area, ensuring that it is restricted to pharmacy employees only. The dispensary is separated from the rest of the premises, and access is not allowed to the general public. On the other hand, a hospital pharmacist is responsible for the issuing of medicines to health care professionals who are authorised to possess medicines, and to people who are receiving treatment in the hospital. In this instance, the whole pharmacy department is out of bounds to all individuals except pharmacists. Under normal circumstances, community pharmacists are unable to supply medicines requiring a prescription if one has not been presented. Pharmacists in New South Wales, Tasmania, Victoria, Western Australia, the Northern Territory and New Zealand may dispense certain medicines without a prescription if it is deemed an emergency. This situation may arise if it is impractical for a person to obtain a prescription in time to meet the need and the person is known to the pharmacist. The treatment must be an established medicine regimen for the person and the person must be aware of the appropriate dose. The medical practitioner then supplies a prescription within a specified period (see also Chapter 3). Hospital pharmacists are also responsible for checking and supplying imprest stocks of medicines. Imprest stocks of medicines are stored in wards as a matter of convenience. If these are prescription medicines, they are not administered until the doctor writes a medicine order. Imprest medicines, which are kept in a locked cupboard, include medicines given by different routes of administration and those that are commonly administered in the ward. Oral medicines for people are also checked and restocked. These are usually placed in a locked mobile medicine trolley for easy access. Alternatively, oral medicines may be placed in a locked drawer at the person’s bedside. Parenteral therapy, which is usually placed in a locked cupboard near the central ward station, is also checked and restocked. The hospital pharmacist also supplies medicines on receipt of a written requisition form from the nurse in charge of the shift. The nurse in charge over a weekend often completes these requisitions on weekend shifts to tide people over to the following week. Hospital pharmacists have the further responsibility of supplying controlled drugs such as morphine and oxycodone to the wards. Most controlled drugs are ordered from the hospital pharmacy by a written requisition from the nurse in charge. On supply to the ward, the pharmacist

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and a senior nurse will sign the requisition form and the balance in the administration book, indicating the stock on hand initially and the quantity of medicine supplied. To move controlled drugs (Schedule  8 medicines) from the pharmacy department to the ward, the pharmacist places them in a locked container and transports them to their destination. The container remains locked until the counting procedure is ready to begin between the pharmacist and nurse. Pharmacists also prepare a variety of medicinal products. These items include ointments; creams; powders; ear, nose and eye drops; lotions; mixtures; pessaries; suppositories; gels; antiseptic solutions; and syrups. Standard formulae (or recipes) used to prepare these items are located in such literature as the Australian Pharmaceutical Formulary (APF), the British Pharmacopoeia or the British Pharmaceutical Codex. As these formularies are legal standards, it is obligatory for the pharmacist to make a preparation conforming to these standards. For instance, if a doctor prescribes zinc and coal tar ointment (APF), then the pharmacist should prepare this item by following the formula documented in the APF. Hospital pharmacists also prepare intravenous infusions with additives. Total parenteral nutrition (see Chapter 68), which involves the incorporation of a number of amino acids, vitamins, electrolytes and trace elements in a highly concentrated glucose solution, is made up in hospital pharmacy departments under sterile conditions. The incorporation of cytotoxics, antibiotics or narcotics in intravenous fluids is also commonly done in hospital pharmacy departments. One of the most important tasks of the pharmacist is to ensure that medicines are taken or administered in a manner promoting the therapeutic efficacy (see Chapter 17) of the medicine. In a community pharmacy or in an outpatients area of a hospital pharmacy, the pharmacist performs an important counselling role with people. Studies have indicated that people often do not retain much of the information provided by a general practitioner during the medical consultation. Furthermore, this retention rate drops in proportion to the time spent with the doctor. Although the community pharmacist may counsel verbally, information is reinforced by attaching written instructions to the primary container of the medicine. These written instructions serve two major functions. First, they warn against undesirable effects, including drowsiness and interactions with other medicines or foods. An example of this function includes the use of benzodiazepines such as temazepam, which can cause drowsiness and increase the effects of alcohol. Second, these written instructions are

advisory in that they help improve the medicine’s efficacy. Examples of this function include the administration of a whole course of antibiotics to ensure that an infection is adequately treated, and the administration of oral erythromycin products one hour before food or two hours after meals for better absorption. In the ward setting, the pharmacist acts as a specialist consultant, attending to the needs of doctors, clinical nurses and allied health care professionals on a variety of aspects relating to medicine use. For this reason, pharmacists attend ward rounds and team meetings to familiarise themselves with individuals’ medical conditions and how these impinge on drug therapy. With drug technology becoming more complex, it may be anticipated that medicine information centres located within hospital pharmacy departments will play a more important and focal role in the dissemination of information to health care professionals. In the community sector, with the movement of items formerly available only on prescription to non-prescribed Schedules, there exists the opportunity for pharmacists to be more active in the management of common health problems and the promotion of personal communication with people. Pharmacists are also involved in producing comprehensive medicine regimen reviews for individuals in residential aged care facilities and in the home. The target group for a medicine review are those individuals who are at risk of medicine misuse due to age, social circumstances, complexity of their medicine regimen, health care status, and knowledge about their medicines. In conducting these reviews, pharmacists work in collaboration with an individual’s local medical officer to collate and evaluate medicine information. Reviews draw on information relating to all aspects of care for a particular individual. Some sources of information include the progress or case notes, treatment plans, laboratory tests, and nurses and other health care professionals who provide services within the aged care facility. Pharmacists and doctors work together to make recommendations concerning medicinerelated problems. They also document outcomes arising from these recommendations. Professional and educational pharmacy bodies have been instrumental in developing a framework that pharmacists can use in their interactions with people. This framework is termed the pharmaceutical care process. The basic components of the framework are similar to the clinical decision-making process discussed in Chapter  8, which contains the following components: interviewing the person; assessing drug therapy, formulating a plan, implementing the plan and evaluating outcomes. One of

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the major reasons for the creation of this framework is that major professional and educational bodies were concerned that the pharmacist’s role in the future should place greater emphasis on the particular needs of people. As a growing number of retail outlets and groups of health professionals obtained approval for the supply or dispensing of medicines, it was considered important that pharmacists re-establish their position in tending to people’s needs in drug therapy.

THE PHYSIOTHERAPIST Physiotherapists assess and treat people with a temporary or permanent physical disability, with the aim of achieving the highest degree of recovery. Treatment modalities include exercise, mobilisation and manipulation, massage, splinting, the application of hot and cold compresses, and electrical stimulation. Conditions treated include birth deformities, fractures, back strain, arthritis, spinal injuries, strokes and multiple sclerosis. Rehabilitation for preoperative and postoperative surgery, such as openheart, orthopaedic and abdominal surgery, is also an area of responsibility. Physiotherapists work in hospitals, private practice, rehabilitation centres, community health centres, sports medicine clinics, psychiatric hospitals, maternity hospitals and industrial clinics. Physiotherapists play an important role in drug therapy. In many cases, for treatment modalities to be thoroughly effective, medicines need to be administered for prophylactic and therapeutic reasons. For example, a person with asthma who is undertaking coughing and deep-breathing exercises under the supervision of the physiotherapist will benefit more from therapy if bronchodilators and corticosteroids are administered beforehand. Bronchodilators promote widening of constricted airways, while corticosteroids reduce the inflammation, improving lung expansion, the ability to cough up mucus and, ultimately, gas exchange. Similarly, open-heart, orthopaedic and abdominal surgery involves aggressive manipulation of bone and tissues, leading to intense pain in the immediate postoperative period. In this instance, the physiotherapist often requires pain relief to be administered before physical modalities can be successfully implemented. People with open-heart sternotomy wounds are unlikely to comply with coughing and deep-breathing exercises if they have not received narcotic analgesia beforehand. Women who have had a caesarean section procedure for the birthing process may need analgesic therapy prior to ambulatory activities. Cooperation with other health care professionals is obviously essential to the success of therapeutic regimens of people.

Physiotherapists play a vital role in the implementation of physical treatment modalities that the community views as important strategies for recovery. Meanwhile, with greater emphasis on non-drug therapies in the acute hospital setting, it is hoped that these will become established as integral modes rather than adjuncts to recovery.

THE PODIATRIST The podiatrist is involved with the prevention, diagnosis and treatment of foot disorders. These disorders may arise as a result of endocrine disease (e.g. diabetic neuropathy), biomechanical abnormalities (e.g.  flat feet), arthritis, neuromotor disease (e.g.  multiple sclerosis), vascular disease or skin conditions. Podiatrists work in hospitals, community health centres, private practice or as part of a general medical practice. Podiatrists use a range of skills, including surgical procedures, physical therapy and the manufacture of orthoses (foot supports). In implementing these skills, podiatrists are permitted to have in their possession, and administer, local anaesthetics and topical preparations. For instance, podiatrists commonly administer lignocaine intradermally or as a nerve block for a surgical procedure. Antiseptic lotions and antifungal creams are often used for skin disorders. Podiatrists play an important role in educating people about the correct use of drug therapy in relation to how medicines affect foot conditions. For example, a podiatrist would inform people with insulin-dependent diabetes that they must comply with their insulin therapy, otherwise they are more predisposed to leg ulcers and decreased circulation of the lower extremities. Podiatrists are in an ideal position to explain how noncompliance will create a deterioration in the status of foot disorders. In collaboration with doctors, podiatrists may also assist in deciding on the proper course of drug therapy for foot disorders. For example, if a person has a foot infection, the podiatrist can evaluate the effect of a particular antibiotic or antiseptic on the infection, and advise the doctor whether a change in therapy is warranted. In South Australia, podiatrists have limited prescribing rights to a number of prescription-only medicines, including antibiotics. Similar legislative changes have also been passed in Victoria and are currently being sought by podiatrists in other Australian states and territories. Podiatrists currently do not have prescribing rights in New Zealand.

THE DIETITIAN The dietitian (or nutritionist) possesses detailed knowledge of the principles of nutrition as these apply to health and

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disease states, the biochemical properties of food, the theory underlying food absorption, metabolism, digestion and elimination, and the indications for nutritional support. Dietitians work mainly in general hospitals, psychiatric hospitals and community health centres. Although dietitians are not directly or legally involved with medicine administration, they play an important role in the decision to introduce parenteral or enteral feeding, or other forms of nutrient supplementation for a person. People are susceptible to malnutrition in hospital while undergoing medical and surgical treatment, and disease states may alter the digestive process of nutrients. In collaboration with doctors, dietitians determine the requirements for energy, protein, vitamins, minerals, essential fatty acids, electrolytes and water. Enteral feeds are made in a diet kitchen within a hospital, the process of which is supervised by the dietitian. On the other hand, hospital pharmacists prepare parenteral nutrition using a sterile laminar flow environment. It is important that dietitians continue to monitor the effects of hospitalisation and illness on the nutritional needs of people. With greater participation of dietitians in teams of health care professionals, this process should be readily facilitated.

THE PARAMEDIC Paramedics attend to the general public in medical emergency situations and promptly transport these individuals to the nearest hospital. There are usually two levels of ambulance officers: these are the paramedics, and the mobile intensive care ambulance/unit (MICA) paramedics. Paramedics are able to administer medicines for chronic and potentially life-threatening conditions such as asthma and angina. They also carry defibrillator monitors for use in life-threatening cardiac dysrhythmias, conditions which may otherwise lead to cardiac arrest, respiratory arrest or unconsciousness. The MICA paramedic is qualified to administer a wide range of medicine therapies to treat a number of emergency conditions. MICA paramedics follow strict protocols to ensure accurate and prompt assessment and treatment. Some of the tasks performed by MICA paramedics include the insertion of intravenous lines, the insertion of chest drains for a tension pneumothorax, and intubation (the insertion of a breathing tube through the nose or mouth into the trachea). On arriving at the emergency scene, paramedics stabilise the person’s condition and prevent any further deterioration in health status. Consideration is primarily given to maintaining the person’s airway, breathing and circulation, as these factors are imperative to survival. For example, if

the person sustains a life-threatening cardiac dysrhythmia, such as ventricular fibrillation or ventricular tachycardia, the paramedic will administer treatment that will prevent a compromised circulatory or respiratory status. If the person experiences a non-life-threatening dysrhythmia, the paramedic is less likely to treat the condition unless clinical manifestations occur that compromise the person’s health status. Paramedics play an important role in collaborating with doctors and nurses in the hospital setting. They provide detailed assessment of the person’s condition before admission to hospital, the therapeutic effects observed from the medicine regimen and medical procedures administered to the person. Furthermore, the person’s therapeutic regimen before hospital admission often has a bearing on the therapeutic regimen used in hospital.

THE NATUROPATH Naturopaths treat medical conditions and implement preventive health measures by using nutrition, homeopathy, herbalism, iridology and other natural therapies. Naturopathy is a way of maintaining health and of helping in the removal of disease by stimulating the body to repair itself without the use of conventional medicines and surgery. Naturopaths tend to work in private practice, either alone or in association with other health care professionals, such as medical practitioners, osteopaths, chiropractors and physiotherapists. Some naturopaths work in large pharmacies, where they provide advice about therapies other than the traditional pharmaceutical formulations usually available in pharmacies. Naturopaths perform many roles that support the individual’s wellbeing. They examine the overall health of individuals and assess the foods they eat. Based on this information, they suggest specific diets, foods, minerals and vitamins to help improve general health. They may recommend and dispense substances made from herbal, mineral or animal sources (see Chapter 69). Naturopathic preparations can produce profound interactions with more conventional therapies. These preparations can have desired effects and unwanted effects, as do conventional therapies. Naturopaths thus have an important role to play in interdisciplinary collaboration with the aim of providing optimal medicine management for people.

CONCLUSION Often a team comprising several health care professionals plays an important role in relation to drug therapy. It is

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important for health professionals of different disciplines to develop and maintain an awareness of these roles to

enable better interdisciplinary collaboration and enhanced medicine efficacy.

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According to medicine legislation, the prescriber is a medical practitioner, dentist or veterinary surgeon.

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The nurse plays an important educational role in the assessment, planning, implementation and evaluation of medicine use. A nurse practitioner is a registered nurse in an advanced clinical role who has developed expert clinical skills, knowledge and experience in a specific area of clinical practice. The pharmacist is responsible for the supply and distribution of medicines, counselling people about the use of medicines and treatment of medical conditions, educating health care professionals and the preparation of medicines. Physiotherapists play an important role in drug therapy because, for their treatment modalities to be effective, medicines need to be administered. Podiatrists undertake a range of skills, including surgical procedures, physical therapy and the manufacture of orthoses. They administer local anaesthetics and topical preparations in performing these skills. Dietitians examine the parenteral or enteral feeding needs, and other forms of nutrient supplementation for people. Paramedics administer medicines for chronic and potentially life-threatening conditions, and also carry defibrillator monitors. The MICA (mobile intensive care ambulance) paramedics are qualified to administer a wider range of drug therapies for emergency conditions. Naturopaths recommend and dispense substances made from herbal, mineral or animal sources.

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C A S E S T U DY 1 Ms RK, a 68-year-old woman, was admitted to the intensive care unit after a diagnosis of pancreatic cancer. She had a very supportive family network, and prior to her hospitalisation she was actively involved with several community organisations. After admission to the intensive care unit, she received intravenous medicines for cardiac support, and was connected to a ventilator. Over a 10-day period, her condition progressively deteriorated to the point where she lost consciousness and required excessively high doses of cardiac medicines to sustain normal circulation. The doctor and primary nurse for the patient organised a family meeting to discuss Ms RK’s grim prognosis and deteriorating condition. After a prolonged discussion, the family members decided that they did not want Ms RK to continue to suffer unnecessarily, and requested that all cardiac medicines and ventilatory support be withdrawn. Over the next 24  hours, the primary nurse began to wind down Ms RK’s cardiac medicines and ventilatory support. She also provided Ms RK with adequate levels of pain relief and sedation to improve her level of comfort. The next day the doctor arrived in the unit and informed the nurse that he wanted Ms RK to have a CT scan to determine the possible reason for her sudden deterioration. He also requested all cardiac medicines and ventilatory support to be increased to previous levels. When the nurse protested that this decision went against what was decided at the family meeting, the doctor replied, ‘We need to find out what caused her sudden deterioration. Her family has the right to know that. We should also try and give her one last chance. I will explain it to them when they come in.’ The primary nurse sighed with frustration, and called on the nurse manager to discuss the situation.

which was confirmed by blood glucose levels and urinalysis. His doctor explained the condition and organised for Mr JB’s admission to the nearest public hospital for stabilisation of the diabetes. The team of health care professionals at the hospital arranged group sessions for Mr JB, where instruction was given on insulin administration, diet control and glucose assessment. Unfortunately, no-one at these group sessions was Italian, but the health care professionals believed Mr JB understood what was expected. After two weeks, he was discharged with the services of a district nurse. On her fourth visit, the district nurse found Mr JB lying down on the couch, breathing quite rapidly. On further examination he was nauseated and very weak, with acetonesmelling breath. A blood glucose test found him to be extremely hyperglycaemic, warranting hospital admission. In hospital, an Italian nurse who was looking after Mr JB informed the health care team that he had developed a cold soon after his initial discharge. His wife, Ms CB, put him to bed and gave him plenty of sweetened lemon drinks to promote recovery. Mr JB and Ms CB did not believe the insulin injections were required during this time. Mr JB also explained to the Italian nurse that he did not really understand his condition, but he did not want to upset people or take up their time by asking a lot of questions.

Questions 1

Did Mr JB have informed and valid consent for the insulin therapy required for his condition? Provide reasons to support your answer.

2

What are the barriers impeding Mr JB’s understanding of his diabetes?

3

What hospital and community resources could the nurse use to assist in promoting Mr JB’s understanding of his diabetes? What specific teaching and learning strategies could the nurse effectively employ in this situation?

Questions 1

Did the doctor provide the family with an informed and valid consent for his actions? Explain.

4

2

The doctor indicated that he wanted to provide detailed information to the family about Ms RK’s deteriorating condition. What ethical principle does this action uphold?

C A S E S T U DY 3

3

Explain how ethical principles may have conflicted with each other in Ms RK’s situation.

C A S E S T U DY 2 Mr JB is a 28-year-old Italian man who recently migrated from Italy. He is married with a 2-year-old child, and has only a minimal command of English. Over a three-week period, Mr JB experienced symptoms of lethargy, polyuria, polydipsia and polyphagia with increasing loss of weight. His wife recommended that he see the doctor to determine the problem. Mr JB was diagnosed with type 1 diabetes mellitus,

Nurse TS is the primary nurse caring for Mr RM, who is scheduled to have elective surgery for treatment of a kidney problem. When the nurse prepares Mr RM for theatre she notices that his consent form has not been signed. She reports the matter to the nursing unit manager, who contacts the surgical registrar about the need to obtain Mr RM’s signature on the consent form. On the surgical registrar’s arrival, Nurse TS comments that she has contacted the Greek interpreter because Mr RM’s understanding of English is very poor. The surgical registrar replies, ‘I know he has problems with English but I just can’t wait’. He sits down and attempts to explain to Mr RM about the anaesthetic and surgical procedure. The patient keeps shaking his head,

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saying ‘No understand’. The surgical registrar then seeks out the assistance of the ward cleaner, who is fluent in Greek and has some knowledge of English. As the cleaner tries to explain the procedure to the patient, Mr RM keeps shaking his head. The surgical registrar then points to the area of the consent form that requires Mr RM’s signature. Within minutes the orderly arrives to escort the patient to theatre. The nurse packs up all the patient’s files, including the completed consent form in his medical record, and accompanies him to theatre.

Questions 1

Explain what is meant by an informed and valid consent.

2

Has informed and valid consent been achieved in this case?

3

Was it appropriate to have the cleaner interpret details about the anaesthetic and surgical procedure to Mr RM? Explain your answer.

bedside. Nurse GK checks Mr MJ’s identification label with the label on the treatment chart before administering the morphine through the intravenous line. She discards the used needle and syringe in the sharps container but decides to keep the 5 mg of morphine remaining in the ampoule by the bedside. She reasons that if Mr MJ is in pain again within a few hours, she will be able to administer the remaining contents of the ampoule. There is no point in wasting it.

Questions 1

From a legal perspective of prescribing, checking and administering morphine, detail the tasks that were performed incorrectly.

2

Explain how you would perform these tasks if you were put in Nurse GK’s situation. Provide the rationale for your answer.

3

To which drug group does morphine belong? Why should it be stored in a locked cupboard?

4

To which Schedule does morphine belong? What Regulations and characteristics are associated with this Schedule? State the names of three other medicines that belong to this Schedule.

5

From an ethical perspective, state which principles have not been followed in this situation. Explain your answer.

C A S E S T U DY 4 Nurse GK is the primary nurse allocated to care for Mr MJ, a 51-year-old man who had abdominal surgery three days ago. Mr MJ had been on intravenous morphine for pain, but this order was ceased by the doctor. During the ward round, Nurse GK asks the doctor whether Mr MJ could have a morphine order written up as he is beginning to experience quite severe incisional pain. ‘Yes, that’s fine’, replies the doctor. ‘Just give him 5 mg of morphine through his IV drip and I’ll write it up later’, he adds. Wanting to give the morphine straightaway, Nurse GK seeks out Nurse AB to assist in the checking procedure of the morphine from the locked cupboard. ‘I’m a bit busy at the moment. Just check it out from the cupboard yourself and I’ll verify the amount after you’ve finished. I’ll only be a few minutes’, comments Nurse AB. Nurse GK obtains the keys for the locked cupboard from a hook on a nearby ledge. She checks out one ampoule containing 10 mg of morphine and documents the procedure in the drugs register. She signs her name in the register to verify that the procedure has taken place. She carefully locks the cupboard and places the key back on the hook. Within a few minutes, Nurse AB arrives to check that the number of morphine ampoules in the register corresponds to the number in the cupboard and countersigns her name in the register. She then walks to the medicine equipment trolley, where she finds Nurse GK assembling the syringe and needle and drawing up the required amount of morphine. ‘I’ve countersigned the drug register’, she states, before walking away. ‘Thanks, that’s great’, replies Nurse GK, as she continues with the task. As the ampoule contains 10 mg/mL of morphine, she draws up 0.5 mL and proceeds to Mr MJ’s

C A S E S T U DY 5 Mrs SS is a 70-year-old woman with hypertension, coronary artery disease and type  2 diabetes mellitus. She has lived alone since her husband died after a stroke last year. Her medicine regimen includes enalapril, atenolol, glibenclamide and glyceryl trinitrate. Her cardiologist decides to commence Mrs SS on atorvastatin, a cholesterol-lowering agent, to provide her with additional cardiovascular protection. She commences her atorvastatin, on a starting dose of 20 mg in the morning. You visit Mrs SS to see how she is going with her medicine regimen. She tells you that because she has begun to experience side-effects from the atorvastatin, including nausea, vomiting and severe headache, she has decided to stop her therapy completely. Mrs SS further adds: ‘My other medicines should help with most of my health problems. Stopping the new pills won’t hurt too much.’

QUESTIONS 1

Describe what is meant by medicine adherence.

2

State the reasons associated with Mrs SS’s lack of medicine adherence by referring to client and medicine considerations.

3

How would you advise Mrs SS about what to do?

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C A S E S T U DY 6 Mrs DM is 68-year old woman admitted to hospital with unstable angina. She also has severe osteoarthritis, which can cause extreme stiffness on movement and difficulties in opening medicine containers. The medical consultant, nurse manager and nurse caring for Mrs DM are at the bedside, discussing her condition and the possibility of whether Mrs  DM can go home. The consultant mentions that her angina has been stable and she has not had any episodes of chest pain since the day of her admission to the ward. The bedside nurse comments that her change in medicines has helped to improve her condition. Mrs DM’s medicine regimen comprises: a once-daily dose of isosorbide mononitrate (a controlled release tablet) for the prevention of angina, and sublingual glyceryl trinitrate tablets, for the treatment of angina. The consultant replies that on the basis

of this information, plans should be organised for Mrs DM’s discharge home. Mrs DM is happy that she is going home and asks whether her husband can be notified about her discharge, so that he can make plans to pick her up.

QUESTIONS 1

Describe the learning principles that can be applied in medicine education provided to Mrs DM to assist her in taking her medicines when she goes home.

2

Aside from the bedside nurse, what health professionals could be involved in this education process?

3

How can Mrs DM’s husband be included in education provided to Mrs DM about her medicines?

4

Comment on what types of community support could be organised that would assist Mrs DM in taking her medicines at home.

FU R T H ER RE A DI N G Adeponle AB, Thombs BD, Adelekan ML & Kirmayer LJ, 2009, ‘Family participation in treatment, post-discharge appointment and medication adherence at a Nigerian psychiatric hospital’, The British Journal of Psychiatry, 194, 86–7. Bolster D & Manias E, 2010, ‘Person-centred interactions between nurses and patients during medication activities in an acute hospital setting: qualitative observation and interview study’, International Journal of Nursing Studies, 47, 154–65. Brunton SA, 2011, ‘Improving medication adherence in chronic disease management,’ Journal of Family Practice, 60(4), S1–S8. Courtenay M, Carey N & Stenner K, 2011, ‘Non medical prescribing leads views on their role and the implementation of non medical prescribing from a multi-organisational perspective’, BMC Health Services Research, 11, 142 doi:10.1186/14726963-11-142. Falvo DR, 2011, ‘Effective Patient Education: A Guide to Increased Adherence’, 4th edn, Jones & Bartlett, Boston. Haslbeck JW & Schaeffer D, 2009, ‘Routines in medication management: the perspective of people with chronic conditions’, Chronic Illness, 5, 184–96. Johnstone MJ, 2008, Bioethics: A Nursing Perspective, 5th edn, WB Saunders, Sydney. Manias E, 2012, ‘Medication adherence in people of culturally and linguistically diverse backgrounds’, Journal for Patient Compliance, 2(2), 18–21. National Prescribing Service, 2012, Better Choices, Better Health. Competencies Required to Prescribe Medicines: Putting Quality Use of Medicines Into Practice. National Prescribing Service Limited, Sydney. Nuttall D & Rutt-Howard J, 2011, ‘The Textbook of Non-Medical Prescribing’, John Wiley, Chichester. Shakib S, Philpott H & Clark R, 2009, ‘What we have here is a failure to communicate! Improving communication between tertiary to primary care for chronic heart failure patients’, Internal Medicine Journal, 39, 595–9. Vervloet M, Linn AJ, van Weert JCM, de Bakker DH, Bouvy ML & van Dijk, 2012, ‘The effectiveness of interventions using electronic reminders to improve adherence to chronic medication: A systematic review of the literature’. Journal of the American Medical Informatics Association, doi:10.1136/amiajnl-2011-000748. Viktil KK & Blix HS, 2008, ‘The impact of clinical pharmacists on drug-related problems and clinical outcomes’, Basic & Clinical Pharmacology & Toxicology, 102, 275–80. Williams A, Manias E & Walker R, 2008, ‘Adherence to multiple, prescribed medications in diabetic kidney disease: A qualitative study of consumers’ and health professionals’ perspectives’, International Journal of Nursing Studies, 45, 1742–56. Williams A, Manias E & Walker R, 2009, ‘The role of irrational thought in medicine adherence: A qualitative study of people with diabetic kidney disease’, Journal of Advanced Nursing, 65, 2108–17.

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W E B R E S O UR C E S The Australasian Association of Bioethics and Health Law (AABHL) aabhl.org Australian Nursing and Midwifery Council: Code of Professional Conduct for Nurses in Australia www.nursingmidwiferyboard.gov.au/documents/default.aspx?record=WD10%2F1353&dbid= AP&chksum=Ac7KxRPDt289C5Bx%2Ff4q3Q%3D%3D Communicating with Patients: Advice for Medical Practitioners, NHMRC, 2004 www.nhmrc.gov.au/publications/synopses/e58syn.htm Ethical Dilemmas in Communicating and Decision-Making www.tg.org.au/etg_demo/tgc/pcg/1132.htm Ethical Issues in Terminal Health Care ennyman.com/ethics.html Guidelines for Pharmacist Counseling of Geriatric Patients, American Society of Consultant Pharmacists www.ascp.com/resources/policy/upload/Gui98-Counseling%20Ger%20Pat.pdf International Council of Nurses: Position Statements for Nurses and Midwives www.icn.ch/publications/position-statements/ New Zealand Nurses Organisation www.nzno.org.nz Therapeutic Goods Administation: Medication Information www.tga.gov.au/hp/information-medicines.htm

S E C T I O N

III

MEDICINE A D M I N I S T R AT I O N AND PROFESSIONAL RESPONSIBILITIES All drugs are poisons—what matters is the dose. PA R C E L S U S ( 1 4 9 3 – 1 5 4 1 )

All health care professionals play an important role in medicine management to ensure people’s safety. All substances, including synthetic medicines, vitamins, minerals, herbs and food, have beneficial or adverse effects on the body, and can interact with other substances. While Parcelsus advocated the importance of the correct dose, other aspects of medicine administration are important, such as the time, the individual, the route of administration and the medicine itself. This section, which covers medicine management responsibilities applicable to any medication and clinical situation, is divided into six chapters. Chapter 7 addresses medicine formulations, routes of administration and storage conditions. Chapter 8 examines two major areas of medicine management: one associated with macro-contextual policy and one associated with microcontextual issues. The first area relates to the National Medicines Policy or, more specifically, the concept of the ‘quality use of medicines’, which aims to improve the way in which medicines are used in society. The second complementary area is the clinical decision-making process in medicine management, which incorporates assessment, diagnosis, planning, implementation and evaluation. Chapter 9 looks at common examples of medicine administration strategies and documentation processes, while Chapter 10 examines how to avoid making medication errors. Chapter 11 gives an overview of common adverse drug reactions, the types of medicines that cause these reactions and strategies to deal with them. Finally, Chapter 12 considers the various ways in which medication risks and benefits are measured and how health professionals can communicate these risks and benefits to the individuals in their care.

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KEY TERMS

After completing this chapter, you should be able to:

Capsule

Storage of medicines Sustained-release preparation

1

Describe the basis for the formulation of common dosage forms of medicines.

Enteric-coated preparation

2

Explain all the common routes by which medicines can be administered.

Intranasal administration

Tablet

Parenteral administration

Transdermal administration

Rectal administration

Vaginal administration

3

Give the reasons for the use of each of these routes.

4

List the advantages and disadvantages of each route.

5

Understand the storage conditions required for particular medicines.

Topical preparation

Pharmaceutics is the branch of pharmacy that deals with the formulation of medicines. It is important that health professionals involved with the supply, prescription, preparation and administration of medicines have a good understanding of the ways in which medicines are formulated. They are, therefore, in a better position to instruct people about how to take medicines for maximum therapeutic effectiveness.

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TABLETS

CAPSULES

Solids are usually administered in tablet form, often erroneously described as pills. Note that the word ‘pill’ means a spheroid or ovoid body, usually coated with sugar or even silver or gold paint. Pills are, in fact, rarely manufactured today, and the ones that exist are usually homeopathic preparations. A tablet is a disc containing one or more drugs, prepared by compressing a granulated powder in the die of a suitable machine. As most drugs are administered in very small quantities, sometimes less than a milligram, other materials must be added to make them easy to handle and, in extreme cases, allow them to be seen. This problem is overcome by incorporating the appropriate amount of an inert filler. Tablets have to disintegrate in the gastrointestinal tract; to make this easier, a substance such as starch, which swells when in contact with fluids, is incorporated. These substances are termed excipients. Two other substances incorporated in tablets are a binding agent to help keep the tablet whole in the container and a lubricating material to help prevent the ingredients from sticking to the manufacturing machinery. Tablets may be sugar-coated or film-coated to disguise bad-tasting medicines. Some medicines that are unstable in solution can be administered as chewable tablets to patients who have difficulty in swallowing, and various flavourings can be added to disguise the taste of the medicine. When chewable tablets are sugar-coated they are called ‘dragees’—a name used for the coloured balls used as cake decorations.

Capsules come in two main forms, the hard and the soft gelatine types. Hard gelatine capsules contain the medicine as a solid. In soft gelatine capsules, the medicine is in a nonaqueous solution. If the medicine is a liquid, such as the oily form of vitamin E, it may be dissolved in another oil, usually soybean oil. Hard capsules have an advantage over tablets in that they can be opened up and the powdered contents sprinkled on jam or honey, whereas tablets need to be crushed, sometimes with difficulty. Capsules can come in many colours, which may make identification easier. This method of identification should not always be relied on as mistakes are easily made, but in cases of overdose emergencies it may be useful in determining how to treat the person. Soft gelatine capsules are completely sealed and contain a medicine in liquid or semiliquid form. They are useful not only for liquid medicines but also for medicines that are not easily dissolved in water. In the latter case, the medicine can be dissolved in a relatively non-toxic solvent such as propylene glycol, thus enabling the medicine to be more rapidly absorbed from the gastrointestinal tract. People with drug addiction problems have abused some preparations prepared in this way: for example, the liquidfilled capsule of the hypnotic temazepam has had its liquid aspirated with a needle and then injected. This practice is exceedingly dangerous. However, occasionally these liquidfilled capsules are useful if fast action is required. It is not unusual for nifedipine capsules (which are used in angina and hypertension) to be pricked and the contents dropped onto the tongue in the case of an acute attack of angina. Many people prefer capsules to tablets, as the former are good for camouflaging bad-tasting medicines. Antibiotics such as amoxycillin and clindamycin are formulated in capsules for this reason. Otherwise, capsules offer no other real advantages over tablets. One pharmaceutical manufacturer has coined the name caplet to describe a capsule-shaped tablet coated with a gelatine-like material.

ENTERIC-COATED PREPARATIONS Sometimes tablets are formulated so that disintegration takes place in the intestines rather than in the stomach. These tablets are coated with a material that does not disintegrate in the acidic conditions of the stomach but only in the alkaline conditions of the intestine. These tablets are known as enteric-coated preparations. This term may be abbreviated as EC on the medicine container. With people who have difficulty in swallowing tablets, it is imperative that such tablets not be crushed to enable easier swallowing. Many enteric-coated preparations now come in a form in which small portions of drug are enteric-coated into tiny balls and enclosed in a capsule. These capsules may be opened and the contents sprinkled on some suitable medium for swallowing.

SUSTAINED-RELEASE AND CONTROLLED-RELEASE PREPARATIONS With drugs that have a short half-life in the body, it is sometimes convenient to formulate the medicine in such a way that it is released slowly into the gastrointestinal tract. These preparations are termed sustained-release, slow-release or retard forms. Many medicines are being

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formulated in this way, as it increases patient adherence: it is easier to remember to take a medicine once or twice a day than three or four times a day. There are various ways in which slow release can be brought about. The active drug can be embedded in a matrix of relatively inert material, which disintegrates gradually in the gut, releasing the drug slowly. The drug can be prepared in a layered tablet, with layers of drug enclosed in successive layers of inert coating. As one layer of coating disintegrates, some drug is released and no further amount is released until the next inert layer is dissolved. Sometimes the drug is coated with an inert substance to produce many pellets, each pellet having a different thickness of coating. The thinner coating dissolves quickly to enable a rapid release of a drug, while the thicker coatings allow the release of the drug at later stages. These pellets can be presented as capsules, sometimes termed spansules, or compressed into tablets, sometimes called durules. At least one drug is presented bound to a resin, and is then released slowly from the resin in the basic surroundings of the small intestine, but not in the acid environment of the stomach. A more recent development in sustained-release preparations has been the controlled-release tablet. With sustained-release preparations there can be considerable variation in the disintegration, solubilisation or emulsification and absorption of the tablet or capsulated pellets. This variation could be due to various factors, such as rate of transit through the gastrointestinal tract. In addition, individual variations in the composition of the gastrointestinal fluids (e.g. pH differences, types of food consumed) can affect the rate of dissolution of the coatings protecting the medicine. The use of a controlledrelease tablet attempts to overcome this problem by a novel and ingenious method. The active drug is coated with a semipermeable membrane, through which a ‘hole’ is made using a laser. When ingested, water flows through the semipermeable membrane by an osmotic process, thus raising the pressure inside the tablet and forcing the contents out through the ‘hole’. As the ‘hole’ is minute, this process takes a considerable time, and the drug is released slowly into the lumen of the gut. This release is more or less constant between individuals because it is not pHdependent, and the presence of solutes in the gut fluids has minimal effects on this process. A medicine that is available using this delivery technique is nifedipine (under the trade name of Adalat Oros), an anti-hypertensive agent (see Chapter  46). The semipermeable membrane remains unscathed in its passage through the gut, and it appears in the faeces as tablet ghosts. Patients should be told of this

issue. Sustained-release or controlled-release formulations may be identifiable by the abbreviations SR or CR on the medicine container.

ORAL LIQUID PREPARATIONS Many people, especially children, find it difficult to swallow tablets, and for these people there are formulations made in liquid form. These preparations are usually made according to the characteristics of the medicine concerned. Flavourings, varying from raspberry to the more exotic tastes of coconut and passionfruit, are usually added to such preparations to make them more palatable. Sugar can be added to liquid preparations to form syrups, which enhance palatability, but it is common today to use sugar alcohols, such as sorbitol, as sweetening agents. Sorbitol is broken down to glucose more slowly and inefficiently than is sucrose, making it more suitable for people with diabetes. Sorbitol also has a lower calorific value than sucrose, and helps to prevent dental caries. Another advantage of sorbitol use in syrups is that, taken in excess, it can act as an osmotic laxative and will discourage abuse of potentially addictive preparations, such as codeine syrups. Saccharin or cyclamates can be used to make liquids completely free of kilojoules. A linctus is a syrup specifically formulated for coughs. It is a viscous liquid preparation that has demulcent, expectorant, cough-suppressing or sedative properties. A linctus is given in doses of small volume to be swallowed slowly without the addition of water. This preparation should be stored in a well-sealed container at temperatures below 25 °C. A common example is codeine linctus. In cases where a drug is insufficiently soluble in water, alcoholic solutions may be prepared. Such preparations are termed elixirs. Elixirs are aromatic liquid preparations that are a convenient way of administering potent or unpleasant-tasting medicines in a palatable formulation using a low-dose volume. The solvent often contains a high proportion of ethanol or syrup, but other solvents such as glycerol are also used. Tinctures, like elixirs, contain alcohol but are more concentrated. Most tinctures, such as tincture of iodine, are used mainly for topical treatment. In cases where relatively insoluble drugs are used without alcohol and the medicine is a solid, the resulting preparation is termed a suspension; if a liquid, the term emulsion is used. Even with the addition of stabilisers, these preparations have the tendency to separate into two or more layers. Therefore, thorough mixing before administration of such preparations is essential, as with all liquid medicines, because even in homogeneous mixtures there may be

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gradation in concentration due to the liquid being stored undisturbed for prolonged periods. Some drugs, such as penicillin, are relatively unstable in solution and are prepared as desiccated powders, water being added to the powder before use. Even after reconstitution, the resulting suspensions usually need refrigeration until the course is finished; the shelf life being only two weeks. Tables  7.1 and  7.2 provide information about medicines administered by the oral and nasogastric routes respectively.

TOPICAL PREPARATIONS The application of a medicine to an area of the body for direct treatment is termed topical application. This type of application is not restricted to the skin and hair: the mouth and the entire gastrointestinal tract can have medicines applied for topical treatment. Even body cavities can have topical applications applied, such as antibiotics during

surgery, or the lumen of varicose veins during sclerosing therapy.

Drops Eye and nose drops must be made isotonic to avoid pain or discomfort on application. Eye drops are aqueous or oily solutions or suspensions for instillation into the eye. Nose drops are liquid preparations used in the nasal passages. Oily solutions should not be used for nasal administration, as the oil hinders the ciliary action of the nasal mucosa. Oily solutions may cause additional problems by entering the trachea and causing aspiration pneumonitis. Ear drops are formulated as oily solutions to efficiently coat and adhere to the aural cavity.

Creams and ointments By far the most common topical preparations are those used for the treatment of skin conditions, ointments and creams being the most often used. Many medicines are available in both forms, especially corticosteroid preparations.

Table 7.1 Administering medicines by the oral route ACTION

RATIONALE

The person should be sitting upright (if not contraindicated).

To prevent aspiration of medicine into lungs. Aspiration causes dyspnoea and may lead to pneumonia.

Ensure the person has enough water to assist in swallowing medicines.

Medicines that lodge in the oesophagus can cause irritation and burning, leading to poor absorption. Water promotes dissolution and absorption of medicines.

Wash hands before preparing medicines. Without touching the medicines, place tablets or capsules in a medicine cup.

To prevent infection and cross-contamination.

Give medicines before, during or after meals, according to directions.

Food in the stomach generally slows down medicine absorption and decreases gastric irritation. The significance of each factor is weighed when determining whether a medicine is to be given with meals.

Shake the stock bottle of a suspension thoroughly before dispensing.

To ensure even distribution of ingredients.

Hold the medicine measure at eye level when pouring liquid. The base of the meniscus (lowest level) should be level with the required volume.

The meniscus is caused by surface tension against the walls of the measure.

Do not give medicines orally if the person is: (i) nil orally (ii) vomiting (iii) excessively sedated or unconscious.

(i)

Oral medicines can interfere with the visualisation of organs for diagnostic tests. During surgery, intubation requires the person to have an empty stomach to prevent aspiration pneumonia. (ii) Oral medicines increase the vomiting with further irritation to the gastrointestinal tract. Very little medicine will be absorbed through the tract. (iii) In these people oral medicines can lead to aspiration into the lungs due to an impaired gag reflex.

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Table 7.2 Administering medicines by the nasogastric route ACTION

RATIONALE

Use dissolvable medicines or mixtures if available. Otherwise, finely crush medicines separately and administer with water.

To ensure complete passage of medicine to the stomach and prevent interaction between medicines in the tubing.

Check the position of the internal end of the tube using: (i) syringe with air, listen with stethoscope for gurgles (ii) aspiration of fluid from the tube, should have acidic pH.

Nasogastric tube should be in the stomach before medicines are administered.

Nasogastric tube should be flushed with water prior to administering medicine, between medicines and after all medicine is administered.

To ensure subsequent medicines do not precipitate with remains of earlier medicine and to maintain patency of tubing.

Slow-release and enteric-coated preparations should not be given through a nasogastric tube.

These preparations cannot be crushed.

Medicines should be either gently syringed down the nasogastric tube or allowed to run down the syringe barrel.

Forcing the medicine may cause damage to gastric mucosal membranes.

If the tube is on free drainage, the drainage bag must be elevated after administration of medicine.

To prevent the medicine from draining out.

Nasoenteric tubes are not suitable for medicine administration.

These contain a radio-opaque mercury tip which can break if medicines are forced through.

Creams have an aqueous base, the water evaporating fairly quickly, leaving the medicine on only the superficial layers of the skin. Very little of the medicine is absorbed through the skin, where it could have a systemic action. Ointments are lipid-based and accordingly have a greasy appearance and feel. The presence of water-repellent (hydrophobic) substances on the skin, such as Vaseline, acts like an occlusive dressing. An occlusive dressing completely shuts out the skin from the air, but sweating still occurs. The sweat is trapped under the dressing and the horny layer of the skin is softened, thus enabling the medicine to penetrate the tissues deeply. (Think how skin looks after being immersed in water for a considerable time; for example, after a long bath.) Absorption into the body can be significant. Ointments are better reserved for the treatment of dry or scaly skin conditions and should not normally be used on areas where skin is thinner, such as the face and genitals. Eye ointments are formulated to melt quickly on application so that vision is not seriously impaired. Tables 7.3 and 7.4 provide information about medicines administered by the optic route and aural route respectively. Figures  7.1 and 7.2 show the appropriate techniques for administering eye and ear drops. Ophthalmic pharmacology is covered in more detail in Chapter 83.

Pastes Pastes have a high powder content and are useful in protecting areas of skin from moisture, being waterrepellent. Clothes must be protected from pastes (although some pastes dry quickly) as well as ointments, as they can be messy. Nappy rash and other conditions of the perineal area in babies respond well to pastes.

Gels and lotions For hairy areas of the body, alcoholic gels or lotions are less messy than conventional ointments or creams but, as evaporation of the carrier is rapid, there is little penetration of the medicine. Gels are semisolid in consistency, whereas lotions are more liquid in character. Table  7.5 provides information about medicines administered topically through the skin.

SUBLINGUAL AND BUCCAL ADMINISTRATION The mucosa of the mouth is not really meant to be an absorptive surface, but a medicine that is active in very low concentrations in the blood can be administered by allowing absorption to take place here. Administration of medicines by this route avoids the mixing of the medicine with food and/or gastric juices, which may impede absorption. For some medicines, notably glyceryl trinitrate and isosorbide

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Table 7.3 Administering medicines by the optic route ACTION

RATIONALE

Only use preparations marked for ophthalmic use.

Ophthalmic preparations are made under sterile conditions and are usually isotonic to the eye’s contents.

Avoid touching the eyelid or other eye structures with dropper tip or ointment tube. Use medicine only for the affected eye if the problem relates to infection. Never allow a person to use another person’s preparation.

Risk of contamination of infection from one eye to the other is high.

All eye preparations should be discarded within 1–4 weeks after opening. Some deteriorate more rapidly and should not be used after 1 week from the date of opening (e.g. corticosteroids, particularly betamethasone and dexamethasone).

There is greater chance of contamination if the preparation is administered beyond this period.

If any crusts or discharge are present along eyelid margins, remove by applying a wool swab dampened with normal saline over the eye for a few minutes. Wipe the eye clean from the inner to outer canthus (inner to outer corner).

The presence of crusts and discharge promote microorganism growth. Cleaning from inner to outer canthus avoids entrance of microorganisms to the lacrimal duct.

To instil, gently pull lower lid down as person looks up. Place the eye drop or ointment in the lower conjunctival sac.

The cornea is rich with pain fibres and thus very sensitive.

Advise the person to close and not to rub the eyes. The person should also not blink for a short period of time.

Lack of movement of the eye following instillation allows for maximum absorption.

After administering eye drops, apply gentle pressure for a few minutes to the bridge of the nose.

This action prevents the medicine from being drained away from the eye.

After insertion of ointment, the person is instructed to wait until vision clears before attempting to drive vehicles or undertake hazardous activities.

Ointments usually cause blurring for about 15 minutes following insertion.

Do not use an eye drop preparation if it is discoloured or in some way changed since purchase.

This prevents possible damage to the eye.

Table 7.4 Administering medicines by the aural route ACTION

RATIONALE

If cerumen or drainage occludes the outer part of the ear canal, wipe it out gently with cotton-tipped buds. Never force wax inwards through the ear canal.

Occlusion of the ear impedes normal sound conduction, harbours microorganisms and blocks distribution of medicine.

Instil ear drops at room temperature.

Failure to instil drops at room temperature may cause vertigo and nausea.

In children under the age of 3 years, the auricle of the ear is pulled down and back. In children over the age of 3 years and adults, the auricle is pulled up and back.

In older children and adults, the ear canal is longer and composed of underlying bone. Straightening the ear canal provides access to the internal ear structures.

The person should lie with the affected ear facing up for about 10 minutes.

To allow the medicine to disperse and absorb.

dinitrate (see Chapter  47), sublingual administration avoids the hepatic first-pass effect (see Chapter 14). Some people have the idea that aspirin applied directly to the gum will relieve the pain from toothache. This may be the case,

but the analgesic effect will mainly be due to the absorption of the medicine into the bloodstream and the subsequent production of its normal systemic effect to relieve the pain. A high local concentration of the aspirin may contribute

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Figure 7.1 Appropriate technique for

administering eye drops

Figure 7.2 Appropriate technique for

administering ear drops

Source: © Alexander Raths | Dreamstime.com.

to its effect. This method of administration should be discouraged, as aspirin is an acid and can irritate the gum to such an extent that it causes quite severe ulceration. Oxytocin, a polypeptide hormone, is destroyed by gastrointestinal proteinases but is fairly efficiently absorbed from the oral mucosa. In many developing countries, where administration of this substance by continuous infusion is not practical, it is sometimes administered using a buccal (pertaining to the cheek) tablet. The tablets are too large to administer sublingually. The antiemetic prochlorperazine (see Chapter 58) is available as a buccal tablet in New Zealand. For obvious reasons, the swallowing of medicines to stop vomiting may not always be successful.

Source: Ton Kinsbergen/Science Photo Library.

Table 7.5 Administering medicines topically (on the skin) ACTION

RATIONALE

Disposable gloves should be worn for this procedure. If the person has an open wound, sterile gloves should be worn. If hands need to be placed in a large jar (e.g. silver sulfadiazine cream), use sterile gloves. Ensure gloves provide a snug fit.

Locally applied medicines can create local and systemic effects. Sterile gloves prevent cross-contamination with an open wound and ensure contents of jar remain sterile. Snug-fitting gloves promote ease of application.

Clean the skin thoroughly with soap and water before applying medicine.

Skin encrustations, dried exudate or remnants of medicine from previous applications can harbour microorganisms and block the passage of medicine to the tissue.

When applying preparation on the face, take care to avoid the eyes and lips.

Irritation may lead to tissue damage.

Spread the medicine evenly over the skin, covering the area well, without using a thick layer. Never rub the preparation in; use soft, gentle but firm strokes.

To ensure proper penetration and absorption and to minimise irritation.

A gauze or non-adhesive dressing may be applied over the area.

To prevent soiling of clothes and wiping away of the medicine.

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One medicine used in migraine is presented as a wafer for solubilisation and absorption through the tongue and oral mucosa. A more detailed discussion on the reasons for sublingual administration is given in Chapter  14. Table  7.6 provides information about medicines administered by the sublingual or buccal route, and Figure 7.3 shows the location for administering medicines by the sublingual and buccal routes.

INTRANASAL ADMINISTRATION Most medicines that are administered intranasally are solely for topical use. These topical applications are commonly used for the symptomatic relief of nasal congestion, such as that which can occur with hay fever and colds. These formulations are found as drops, sprays and metered sprays with a propellant to eject the medicine from its canister. The medicines used in nasal preparations can be absorbed systemically, especially with frequent use. Systemic

absorption of many of the decongestants can lead to adverse cardiac effects (see Chapter 55). There are only a few medicines that are administered intranasally for systemic action, the common examples being the posterior pituitary hormones, oxytocin (Syntocinon) and antidiuretic hormone (ADH). The latter is administered as vasopressin (Pitressin) or one of its analogues. Polypeptides of low molecular weight are quickly absorbed through the nasal epithelium. If taken by mouth, enzymic destruction would take place rapidly in the stomach, long before absorption could occur. An unusual method of intranasal administration is using the ADH analogue desmopressin (Minirin), in which the medicine in solution is poured into a flexible plastic tube termed a rhinyle. One end of the tube is placed in the nasal cavity through a nostril and the other into the mouth. The solution is then blown into the nasal area—a novel method of administration but rather complicated, and one wonders if this is really necessary. Insulin, being a much

Table 7.6 Administering medicines by the sublingual/buccal route ACTION

RATIONALE

Sublingual Instruct the person to allow the tablet to dissolve under the tongue. The person should not drink any fluid while the medicine is dissolving. Buccal The tablet is placed between the cheek and gum and allowed to dissolve. The person should alternate cheeks with each subsequent dose.

The tablet is absorbed into blood vessels surrounding the sublingual gland, bypassing the gastrointestinal tract where the medicine is destroyed by gastric secretions or by metabolism in the liver. The tablet is absorbed into blood vessels surrounding the buccal glands, bypassing the gastrointestinal tract, where the medicine is destroyed by gastric secretions. Alternating cheeks minimises mucosal irritation.

Figure 7.3 Location of sublingual and buccal sites

Sublingual route

Buccal route

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larger polypeptide, is not efficiently absorbed by this route, but tests incorporating it with a surfactant (which would render the mucosal cells more absorbent) have met with some success, and could in the future obviate the use of hypodermic needles by people with diabetes. Tables 7.7 and 7.8 provide information about medicines administered by nasal drops and nasal sprays respectively.

TRANSDERMAL ADMINISTRATION It is not surprising that, as the epithelial surfaces of the body are used to administer medicines, the skin can also be used for direct administration of medicines. The big difference between skin and the other epithelial areas of the body is the presence of keratin in the cells, which affords skin its toughness. Skin is, therefore, relatively more impermeable to medicines than other stratified epithelia, and only medicines that are very lipophilic and active in very small amounts can be successfully administered this way. The skin is useful to administer medicines that conform to these

properties and when low blood levels are required for long periods of time. Most of these medicines are administered as sticky discs called transdermal patches; a few medicines are applied using a quick-drying gel or spray (e.g. glyceryl trinitrate and oestradiol respectively). Examples of medicines commonly administered by this route are shown in Table  7.9. Figure  7.4 shows the design of patches used for transdermal administration of medicines. Table  7.10 provides information on medicines administered by the transdermal route.

RECTAL ADMINISTRATION Suppositories Suppositories are solid medicine formulations for rectal use. These formulations are usually inserted with the pointed end first in the rectum. However, there have been reports that discomfort is less if they are inserted blunt end first. The stated reason for this is that the external anal sphincter opens better when a larger surface area is pushed against it (i.e. faeces!). The converse is also true: if the blunt end is

Table 7.7 Administering medicines by the nasal route: drops ACTION

RATIONALE

Instruct person to blow nose before procedure (unless contraindicated).

Removes secretions that can impede distribution of medicine.

Have the person positioned lying down on back with head over the edge of the bed. Support person’s head with the non-dominant hand while head and neck are extended. Then turn person’s head to each side while head and neck are extended.

Position provides access to nasal passages. Ensures even distribution to all sinuses.

Hold dropper above nares (nostrils) during administration.

Avoids contamination of the dropper.

After administration of drops, the person is to remain in this position for about 5 minutes.

Prevents premature loss of medicine through nares.

The dropper should be used by one person only, and rinsed after each use.

Prevents infection.

The preparation should not be used more often than directed.

Overuse results in rebound congestion, which is often worse than the original manifestations.

Table 7.8 Administering medicines by the nasal route: sprays ACTION

RATIONALE

The person should be sitting upright with their head tilted slightly back. The spray is inhaled into one nostril while occluding the other.

Allows thorough inhalation to affected sinus area.

Apply strictly as directed.

Overuse results in rebound congestion, which is often worse than the original manifestations.

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Table 7.9 Examples of transdermal products MEDICINE

TRADE NAME

USE

CHAPTER(S)

glyceryl trinitrate

Transiderm-Nitro

Prophylaxis of angina

47

fentanyl citrate

Durogesic

Prevention of severe pain

40

hyoscine

Scopoderm TTS

Prophylaxis of motion sickness

58

nicotine

Habitrol , Nicabate Nicorette, QuitX

To aid persons to stop smoking

24, 28

oestradiol

Estraderm Femtran

Prevention of menopausal symptoms

63

oestradiol + norethisterone

Estracombi

Prevention of menopausal symptoms

63

, Nitroderm TTS

, Estradot

, Nicotrol , Climara,

,

Australia only New Zealand only

Figure 7.4 Design of patches used for transdermal administration of medicines Membrane enclosing drug solution

Peel off protective cover

Gel impregnated with drug

Table 7.10 Administering medicines by the transdermal route ACTION

RATIONALE

Apply disposable gloves or ensure hands are thoroughly washed immediately after the procedure.

To avoid coming into contact with the medicine and absorbing it systemically.

Apply the required amount of ointment/cream on the piece of ruled paper. Place paper against skin, secure with adhesive tape.

Ensures correct amount is administered.

If using discs, ensure area is free of hair.

The disc will not stick on a hairy surface; thus, affecting absorption.

facing down towards the internal sphincter, rejection can take place, whereas this is less likely to happen with the pointed end facing downwards. Many suppositories are now manufactured with both ends relatively blunt. Suppositories should not be halved, as the distribution of medicine in the matrix may be uneven. The administration of medicines

for systemic absorption through the rectal mucosa is more popular owing to certain advantages of this method, further described below. Unfortunately, many people are averse to this method of administration for aesthetic reasons and because of embarrassment if administered by another person.

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ADVANTAGES

DISADVANTAGES

The advantages of suppository administration are as follows. • If a patient is unconscious, oral administration is relatively difficult unless an enteral tube has been passed. The same goes for difficult or uncooperative patients and children. • Nauseous or vomiting people, for obvious reasons, may find oral administration less than effective. Thus, many antinauseants and antiemetics are available as suppositories. • People who have difficulty swallowing due to oesophageal strictures or other oral and oesophageal pathologies can be given suppositories. Medicines that are destroyed by gastric acid can be given this way. • The hepatic first-pass effect can be avoided as long as the suppository is not inserted into the upper third of the rectum, which is drained by the hepatic portal system. Thus, most suppositories that are not for topical use should be inserted only past the internal anal sphincter. • In cases where a vein is difficult to find for intravenous injection, rectal administration of lipid-soluble drugs can result in rapid action. • The opposite can also be true, particularly with acidic drugs, when absorption at a slower rate can be beneficial. This is the case with anti-inflammatory preparations, when long action is desired. Very often people with rheumatoid arthritis who take an oral preparation at night find they have difficulty in getting out of bed in the morning, as the effect of the medicine has worn off; a suppository used on retiring often avoids this consequence.

The disadvantages of suppository administration are as follows. • Insertion of suppositories can cause anal or rectal irritation. This can be a problem with haemorrhoidal preparations containing local anaesthetics, which will mask the irritation. Consideration to the privacy and modesty of the person should always be observed when rectal administration is performed. • Medicine education is required for suppository use. • If not self-administered, suppositories should be inserted with the person in the left lateral position, which lessens the risk of perforation of the rectum. (Think about the anatomy of the lower gastrointestinal tract.) • Suppositories are made to melt at body heat and are best kept refrigerated to maintain their shape. A drop of a lubricant jelly may help in their insertion. People must be told to remove the plastic or foil wrapping before use as well as exactly where to insert it. Many people are not aware of their own anatomy and have inserted suppositories with and without wrapping into a variety of different body orifices. Table  7.11 contains information about the administration of suppositories.

Enemas Enemas are liquid preparations for rectal administration. Enemas can be either for topical or systemic treatment, or to cause a bowel motion. When used for topical or systemic treatment they are termed retention enemas, and are hypotonic solutions. This ensures that the fluid will be

Table 7.11 Administering medicines by the rectal route: suppositories ACTION

RATIONALE

Assist the person in getting into the side-lying Sim’s position with knee and hip of upper leg flexed.

This position exposes the anus and helps to relax the anal sphincter.

Ask the person to relax the area.

Forcing a suppository through a constricted sphincter causes discomfort.

Apply disposable gloves. Lubricate the rounded end with water-soluble lubricant. With the index finger of the dominant hand insert suppository the entire length of the finger. The suppository must be pushed through the anus, past the internal sphincter and through to the mucosal rectal wall for absorption.

To allow absorption of suppository and prevent expulsion.

Impress on the person the need to retain the suppository for at least 20 minutes.

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taken up by the body and the active ingredient left in contact with both rectal and colonic mucosa. Some medicine will also, in all probability, be absorbed, and if appropriate can be administered by this method. Enemas are better than suppositories if the lower reaches of the colon are to be treated. When used as laxatives, enemas are hypertonic, to cause an outward flow of water from the body into the distal portion of the digestive system and thus promote defecation (see Chapter 57). In very rare instances, enemas have been reported to cause vagal inhibition, leading to cardiac arrest. Most abdominal and thoracic structures are innervated by the vagus nerve, including the rectum. The vagal supply to the heart consists of parasympathetic fibres, which cause bradycardia. When stimulated, the vagus nerve can cause a reflex increase in parasympathetic activity, which can lead to bradycardia or even cardiac arrest. Table 7.12 provides information about the administration of enemas.

VAGINAL ADMINISTRATION Suppository-shaped medicines for vaginal administration are usually termed pessaries. As vaginal administration of medicines is always for topical treatment, it is important that the medicine coat all the vaginal mucosa. To enable this to happen, the medicine should be inserted as high in the vagina as possible. Because of this, vaginal medicines, whether in pessary or cream form, come with applicators designed to reach the upper parts of the vaginal canal. Some manufacturers have modified the shapes of vaginal medicines and you will see terms like ovules (egg-shaped) and vaginal tablets being used. Creams for vaginal administration come with precalibrated applicators to facilitate insertion.

Vaginal douches containing antimicrobial substances are also available for thorough vaginal washouts. Vaginal preparations that are left in situ are best used at night. The vagina, unlike the anus, has no sphincters and so the medicine can leak out, lessening its effectiveness and causing possible embarrassment. This embarrassment could be considerable with iodine preparations. If women have to insert vaginal medicines during the day, they should be advised to wear some sort of protection, such as panty liners or sanitary pads. Tampons should not be used with vaginal medicines. Table 7.13 contains information about the administration of medicines by the vaginal route.

PARENTERAL MEDICINE ADMINISTRATION Any method of medicine administration that avoids the gastrointestinal tract is termed parenteral administration. Transdermal, lung and intranasal administration, discussed earlier, are parenteral methods. However, the use of this term is normally reserved for cases where invasive procedures are used, namely injections. Medicines can be administered to almost any part of the body by injection, some of these techniques being highly specialised, whereas others are routine. The routine methods are those discussed here. Injections, being invasive, require the use of aseptic procedures.

Intradermal administration In intradermal administration, a medicine or substance is injected into the dermis using a fine needle or needles (as is the case with an intradermal punch used in some vaccination procedures).

Table 7.12 Administering medicines by the rectal route: enemas ACTION

RATIONALE

Place the person in the side-lying Sim’s position, upper leg flexed.

Promotes access to the anal area, and relaxes the anal sphincter.

Wear disposable gloves. Lubricate tip of catheter with water-soluble lubricant. Administer medicine slowly.

Prevents contamination and friction to anal walls. A slow rate of administration prevents expulsion.

Use appropriate-sized tubing depending on the person (adults: 14–30 French gauge), and insert tube to a specific length (adults: 7.5–10 cm).

To prevent damage to the rectal wall.

Following insertion of enema, ask the person to gently hold the buttocks together.

This allows the immediate urge to defecate to subside.

The person should be instructed to hold the medicine for as long as is instructed by the medicine’s directions.

This process allows adequate time for the enema to perform its action prior to defecation.

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Table 7.13 Administering medicines by the vaginal route ACTION

RATIONALE

The woman should be lying down with legs flexed and extended apart.

This position promotes ease of application and facilitates relaxation.

If the woman prefers and is able, provide supplies for self-administration.

Some women may be embarrassed and prefer selfadministration.

Tip of applicator should be moistened with water-soluble lubricant.

Prevents friction against the vaginal wall during insertion.

If the woman is using one dose a day, it is inserted just before sleep, and after urination. If the dose is ordered on a more frequent basis, the woman should lie down for about 20–30 minutes after administration.

To ensure medicine does not drain out or become expelled.

Medicines are rarely administered by this route as absorption is slow and only very small quantities can be given. Local anaesthetics are occasionally given by this method to stop pain during superficial suturing procedures. Immunity tests are commonly carried out using this method when only a localised response is wanted or a systemic response could prove dangerous. Likewise, antigen tests for allergies are performed using this procedure.

Subcutaneous injections The blood supply to the subcutaneous tissue is poor, so absorption of an injected medicine will be relatively slow. This is often an advantage with medicines that cannot be given by mouth. An example is the protein insulin, which would be digested if given orally; when injected intravenously, the resultant fast action is not always desirable. Absorption rate of medicines given by subcutaneous injection can be slowed down further by incorporating adrenaline in the injection. Adrenaline promotes vasoconstriction, which slows the distribution of the injected material. This vasoconstriction will also decrease bleeding when adrenaline is injected with a local anaesthetic for minor surgical procedures. Conversely, if the enzyme hyaluronidase is added to a subcutaneous injection, the tissue cement hyaluronic acid (which helps cells to adhere to each other) is destroyed, enabling the other medicine to diffuse into the tissues. Sustained effects can be achieved, using subcutaneous injections, by dissolving the medicine in a slowly dispersible oil or by implanting a pellet containing the medicine in the tissues. Steroid hormones used for contraception or for treating menopausal symptoms are sometimes given this way. Subcutaneous injections are useful when other routes may be hazardous, as is the case with heparin. When injected into a muscle, heparin (being an anticoagulant)

could lead to intramuscular haemorrhage, producing a painful haematoma. Tablets can be implanted into subcutaneous tissues for prolonged action; this is used as a means of contraceptive delivery for some of the sex hormones, for example, progestin analogues. Table 7.14 contains information about the subcutaneous administration of medicines.

Intramuscular injections Skeletal muscle is highly vascular, and its capillaries contain small pores that enable substances of small molecular weight to pass through into the bloodstream. Lipid-soluble drugs are taken up rapidly by direct diffusion through the capillary walls. Substances of large molecular size, which are lipophobic, can be slowly absorbed into the lymphatic system. Several muscles of the body have considerable mass and are able to be injected with quantities of up to several millilitres of fluid, generally without undue discomfort to the person. The gluteus medius of the buttocks is the best muscle to use in this respect. The deltoid muscle of the upper arm has a richer blood supply than the gluteus muscle so is good for rapid absorption of many medicines, but its size limits the injectable amount to about 1 mL. Intramuscular injections are not always given for quick action; if the medicine is mixed with an oil such as peanut oil, the oil is not absorbed rapidly from the injection site. The medicine diffuses slowly from the oily solution into the muscle’s capillaries. This can take a few weeks to occur. This type of injection is known as a depot injection. Exercise, which causes an increase in skeletal muscle blood flow, improves absorption of a medicine after intramuscular injection. The main danger from intramuscular injection is damage to nerves, especially in the case of gluteal injections, as the large sciatic nerve passes through this region. Knowledge of anatomical positions of major nerves and blood vessels is

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Table 7.14 Administering medicines by the subcutaneous route ACTION

RATIONALE

Inspect skin surface; palpate for masses or tenderness. Site should be free from infection, skin lesions, scars and bony prominences.

Site should be free from abnormalities that interfere with absorption.

In long-term therapy, such as with insulin, rotate the injection sites.

A site used repeatedly can become hardened due to hypertrophy (thickening of skin) and lipodystrophy (atrophy of tissue).

If giving at a 45° angle, palm up and bevel of needle down. If giving at a 90° angle (e.g. insulin in an insulin syringe, or heparin), hold syringe as a dart, palm down.

Good manipulation of syringe allows for a quick, smooth injection.

Grasp the skin with thumb and forefinger of nondominant hand and lift up. Ensure the person relaxes arm, leg or abdomen.

Needle penetrates tight skin more easily than loose skin. Relaxation of site reduces discomfort.

Only small doses (0.5–1 mL) of water-soluble drugs should be given.

Subcutaneous tissue is sensitive to lipid-soluble drugs and large volumes. Collection of medicines in the tissue can cause abscesses.

For a thin, cachectic person, the abdominal site is best. For an obese person, pinch skin at site and inject below the fold.

Thin people have insufficient tissue for subcutaneous injections. Obese people have a fatty layer of tissue above the subcutaneous layer.

necessary in order to avoid irreparable damage or injection into these structures. Apart from pain and irritation to tissues, sterile abscesses can occur with intramuscular injections. Not all intramuscular injections act faster than using enteral routes; for example, diazepam (see Chapter  35) is faster-acting when given rectally or orally. Table 7.15 contains information about the intramuscular administration of medicines.

Intravenous injections The administration of medicines intravenously avoids the process of absorption, resulting in most cases in very fast action. The action of a medicine given by this route may take only seconds, as is the case with the injectable general anaesthetics, such as propofol (see Chapter  43). When extreme speed is required, as in an emergency, this is often the method of choice. Another reason for intravenous administration occurs when using extremely irritant medicines, such as the cytotoxic drugs used in cancer chemotherapy (see Chapter 80). These medicines, which are given intravenously at high concentrations, have been known to leak into the surrounding tissues, either from needle dislodgment or from vein damage caused by faulty insertion of the cannula. If this happens, severe necrosis of the tissue can result. This has, on occasion, necessitated the affected limb being amputated. (Imagine the result if these medicines were injected directly into the tissues.) When introduced into the

bloodstream they are diluted within seconds into the total blood volume, this diluting effect preventing any direct damage to the formed elements in the blood. Another possible advantage of intravenous injections is that, in case of rapid development of adverse reactions, injection may be stopped before a critical blood level occurs. The use of aseptic technique is of extreme importance with intravenous injections, as is the avoidance of intraarterial injection, which can cause arterial spasm, leading to gangrene in the tissues supplied by the artery. Intravenous medicines should be examined for particulate material before administration. If such material is found, the medicine should be discarded. Table 7.16 contains information about the intravenous administration of medicines.

Some other modes of injection •

•

Intra-arterial injections can be used to infuse an organ directly with a medicine while more or less avoiding other parts of the body. This may be of use in cancer chemotherapy. Intrathecal injections are made into the cerebrospinal fluid (CSF), usually at the level of the third or fourth lumbar vertebra in order to avoid the spinal cord. (You may remember that the spinal cord terminates here at the conus medullaris to become the cauda equina.) These injections are given to place medicines directly into the central nervous system (CNS) by avoiding the blood–brain barrier (see Chapter 14).

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Table 7.15 Administering medicines by the intramuscular route ACTION

RATIONALE

Avoid areas with lumps, bruises and other lesions. Note integrity and size of muscle and palpate for tenderness.

Insertion site must be free of abnormalities that may impede medicine absorption. Rotate site if frequent injections are given.

Position non-dominant hand against skin, spreading it tightly. Hold syringe as a dart, palm down.

Insertion will be quick and smooth, reducing discomfort.

If muscle mass is small, grasp the centre of muscle between thumb and other fingers of non-dominant hand.

Ensures injection reaches muscle mass.

Have the person lie flat, on the side, prone or sit, depending on the chosen site. Slightly flex knee.

These positions reduce strain on muscle, minimising discomfort and movement during injection.

3 mL of medicine can be safely tolerated in larger muscles (vastus lateralis or dorsogluteus). Young children, elderly and frail people tolerate no more than 2 mL.

Small muscles can tolerate only small amounts of fluid before causing discomfort.

Aspirate for blood prior to giving the injection.

Aspirating for blood determines whether a blood vessel has been entered.

•

Epidural injections are given at the same position as intrathecal injections, but the medicine is deposited outside the dura mater and not into the CSF. Local anaesthetics are often given this way during surgical procedures, especially for procedures involving the pelvic and inferior regions, to block pain transmission to higher centres of the CNS.

•

Intra-articular injections are made into articular joints to obtain high concentrations of, for example, anti-inflammatory corticosteroids in the treatment of inflammatory conditions of a joint.

These are just a few of the more common routes for giving injections, but almost any part of the body can be injected under appropriate circumstances.

NEBULISER AND INHALER ADMINISTRATION Nebulisers and inhalers are used to administer medicines into the lower respiratory passages of the body (refer to Figures  7.5 and 7.6). Metered-dose inhalers (MDIs) deliver medicines in an inert propellant gas and require good hand–breath coordination. They are, therefore, not suitable for children under 5 years. Spacers are devices used in conjunction with MDIs and are suitable for individuals who lack hand–breath coordination (see Figure  7.7). Dry powder inhalers deliver medicines in a dry powder form and are activated by a breath. As dry powder devices require a higher inspiratory flow than MDIs, they may not be

effective in situations of acute exacerbation of asthma. They may be used in children older than 5–7 years. Nebulisers produce an aerosol by using an air compressor or jet and are able to deliver large doses of medicine over a long period. Due to the warmth and moisture associated with using such devices, nebulisers carry the risk of microbial contamination. Nebulisers can be used for lifethreatening asthma, when high doses of β2 agonists can be delivered through high-flow oxygen. Tables  7.17 and  7.18 provide information on the administration of medicines by inhalers and nebulisers respectively. Figure 7.5 shows a nebuliser attached to oxygen tubing.

STORAGE OF MEDICINES Health professionals must be extremely aware of storage conditions of medicines. Generally, medicines should not be exposed to sunlight, bright light, moisture or extremes in temperature. Some medicines are particularly sensitive and will rapidly deteriorate or become ineffective if subjected to these conditions. The standard storage instructions for labelling pharmacotherapeutical medicines in Australia are as follows. • Store below –18 °C • Store below 8 °C • Store below –5 °C • Store below 25 °C • Store at 2–8 °C • Store below 30 °C The temperature conditions of various medicines are often critical. Many medicines, especially those of a biological origin, need to be stored between 0 °C and 4 °C. Common examples are insulin and vaccine preparations. Amoxycillin, in a reconstituted form with water, is extremely

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Table 7.16 Administering medicines by the intravenous route ACTION

RATIONALE

Observe the person for the following systemic complications: (i) Excess fluid volume caused by a too fast flow rate. Treatment: diuretic, oxygen, sit up. (ii) Decreased fluid volume caused by a too slow flow rate. Treatment: fluids. (iii) Air embolism caused by air in line. Treatment: oxygen, heparin, +/– mechanical ventilation. (iv) Infection and febrile reaction caused by contamination of intravenous line or insertion site. Treatment: blood cultures, antibiotics.

Potentially lifethreatening situations require prompt recognition of manifestations, early intervention and knowledge of preventive measures.

Observe the person for the following local complications: the person is not receiving the prescribed amount through the vein, and the effect is very uncomfortable. (i) Phlebitis: where a vein is inflamed, manifesting as a red, swollen and painful area. (ii) Thrombophlebitis: where vein is inflamed and has clotted, manifesting as a red, swollen, warm and hard area. (iii) Infiltration: where the cannula has come out of the vein, manifesting as an oedematous and painful area. Treatment: turn line off, check site with another health professional, remove cannula, set up for reinsertion of line by health professional.

The solution must be flowing freely for accurate medicine administration.

Care of site: (i) Cover with a transparent adhesive film over area, redress only if necessary. (ii) Ensure no dried blood is located under the dressing. (iii) Splint area if located over a joint. (iv) Place a plastic bag over arm for shower. (v) Change line and cannula every 48 hours or depending on hospital policy.

This route is susceptible to infection because of the break in skin integrity and direct access to bloodstream. Thus, strict asepsis is imperative.

Flow rate: (i) Check half-hourly. (ii) Fill to the required amount for the hour. Ensures the person does not become underhydrated or overhydrated. Never overfill burette if it is attached.

Allows the health professional to maintain accountability for actions.

Documentation and medicine-checking: (i) If an additive is placed in the flask, an additive label needs to be filled in and signed by two health professionals. If an additive is placed in the burette, an additive label needs to be filled in and placed against the burette for the duration of the medicine’s administration. (ii) Fluid balance chart needs to be kept up to date, indicating when flasks start and finish, and hourly measures for burettes and volumetric pumps. (iii) Intravenous order chart: orders need to be up to date and signed by a health professional. The order also needs to be signed by a health professional at the start and completion of infusion. (iv) The patient notes need to be documented with the type of fluid, additive, duration, volume and dose per hour.

Documentation provides a permanent record of intravenous administration.

If the intravenous drip stops or slows down: (i) Check the roller clamp and reposition if necessary. (ii) Check insertion site for infiltration etc. (iii) Check tubing for kinking and reposition if necessary. (iv) If site is over a joint, check limb joint for obstruction. Place a splint against the limb. (v) Raise the flask on the pole.

The correct flow rate must be maintained to ensure the person obtains the prescribed dose.

unstable and needs to be refrigerated. Amoxycillin in a powder form must be stored at a temperature below 25 °C, although when reconstituted the mixture must be stored at 2–8 °C. Most biological products, such as insulin, vaccine preparations, total parenteral nutrition and blood products

are easily denatured, causing a loss in effectiveness. Denaturation is usually found to be minimal at 4 °C, and consequently this is the temperature selected for biological preparations. Preparations must not be frozen, as this may result in crystal formation with concomitant loss of

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Figure 7.5 Nebuliser unit with nebuliser, oxygen

tubing and mask

Figure 7.7 Use of a spacer in a young child

Source: © Danijel Micka | Dreamstime.com .

Source: © Leonidikan | Dreamstime.com.

Figure 7.6 Use of a metered-dose inhaler

Source: © Jirsa | Dreamstime.com.

activity. It is also important not to store preparations in the refrigerator when optimal conditions are considered to be at temperatures greater than 4 °C. For example, crystal growth and separation occurs when phenoxymethylpenicillin suspension is stored at 4 °C. Furthermore, many refrigerated preparations (e.g.  total parenteral nutrition and insulin) need to be kept at room temperature before administration to acclimatise to body temperature. Naturally produced and semisynthetic penicillins possess certain common properties regarding temperature. Except for ampicillin, all penicillins will retain at least 90  per  cent of their initial potency for a few days when stored at 4 °C in solutions for injections. Chemical reactions, however, do occur when penicillins are in aqueous solution. As the chemical reactions of penicillins may lead to allergic effects, it is recommended that solutions for injections be administered within 24 hours. Excess supplies should not be kept for a prolonged period in the refrigerator. When ampicillin powder is reconstituted with water for injection, it undergoes rapid hydrolysis; such solutions should be used immediately. Expiry dates should be carefully checked before a medicine is administered. This information is documented on the container of the product. Certain preparations have a very short shelf life due to chemical instability or the possibility of bacterial contamination. Ophthalmic preparations (see Chapter 83) carry the risk of contamination  once the sterile container is opened. The volume of solution placed in eye drop preparations is often limited to 5–10  mL in order to discourage prolonged storage. Breakdown or loss of preservative, together with an incorrect technique of administration, can result in contaminated preparations. Table 7.19 shows the suggested

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Table 7.17 Administering medicines by the respiratory route: inhalers ACTION

RATIONALE

Shake canister vigorously prior to use.

Allows dispersion of contents.

With lips open, instruct the person to place inhaler in the mouth and direct towards the back of the throat. The mouthpiece is gripped with teeth. Instruct person to exhale fully, then inhale, breathing deeply through mouth and depressing the canister fully. Hold breath for 10 seconds.

Medicine is directed towards the respiratory airways and not allowed to escape through the mouth.

Wait 5–10 minutes between inhalations.

The first inhalation dilates airways, and the second inhalation penetrates more deeply.

Drink, eat, brush teeth or rinse mouth immediately after use.

Prevents oropharyngeal candidiasis, hoarseness and an irritated sore throat.

Table 7.18 Administering medicines by the respiratory route: nebulisers ACTION

RATIONALE

Place the required amount of medicine and diluent in the nebuliser device.

To ensure the right proportions of medicine and diluent are used.

Connect tubing, nebuliser and mask to an oxygen or air source. Ensure all connections are tight. Turn the flow rate to the required level (e.g. 10 L per minute).

Allows for continuous mist from the mouthpiece.

Instruct the person to sit up as straight as possible. Tell the person to hold the nebuliser upright, and to breathe slowly and deeply until the medicine mist stops. Turn off oxygen or air source.

Allows for maximal chest expansion and efficient use of the nebuliser.

For cleaning, dismantle the nebuliser unit and disconnect the tubing. Rinse the nebuliser unit and mask in warm water. Shake and allow to drain dry.

Cleaning is important to prevent microbial growth from moisture accumulation.

Do not wipe nebuliser parts with a towel or tissue.

A towel or tissue should not be used to dry the nebuliser unit as particles may block the nebuliser jet, leading to poor or no misting.

time intervals for various preparations. Some eye drops are presented in individual plastic containers, containing only enough medicine for one application to both eyes. This packaging prolongs the shelf life and prevents wastage but is more costly. The package insert should always be consulted for concise information regarding expiry dates. Besides observing expiry dates of medicines, the health professional should ensure that tablets of different generic names are never put in the one container. Despite the obvious risk of the wrong medicine or dose being taken, the medicines may interact and alter their chemical composition. Furthermore, medicines of the same generic name (e.g.  digoxin or glyceryl trinitrate) must never be removed from their individual containers and placed in the one container. Different batches of tablets usually indicate a different expiry date. Out-of-date tablets may chemically

interact with other tablets, altering their composition and rendering them ineffective. Sensitivity to light may also cause changes in chemical composition. Manufactured preparations will be presented in dark protective containers if light is an important factor. These containers should be stored away from sunlight (e.g. in a cupboard or on an enclosed trolley) and situated away from the bright lights often present in hospital wards and community health centres. Light-sensitive medicines that need to be made up in infusion fluids should have black plastic bags placed over the fluid flasks to provide protection during administration. Examples include amphotericin, total parenteral nutrition, amiodarone and sodium nitroprusside infusions. Care must also be taken to avoid moisture coming in contact with preparations. Several medicines are broken

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Table 7.19 Shelf life of preparations

after opening

PREPARATION

SHELF LIFE AFTER OPENING

Penicillin syrups (when reconstituted)

7 days

Eye preparations (general)

28 days

Ear preparations

28 days

Corticosteroid eye drops and ointments 7 days Insulin preparations

30 days

Total parenteral nutrition

2 days

Glyceryl trinitrate tablets

90 days

Aspirin mixture

7 days

Magnesium trisilicate and belladonna mixture

7 days

Australia only

down by hydrolysis, often rendering them ineffective. Common examples are aspirin and glyceryl trinitrate tablets. The degradation of aspirin is easily determined by the presence of a vinegary smell. In preparations such as paints, pastes, pessaries, suppositories, inhalations and ointments, contact with water makes application or insertion fairly difficult and their therapeutic activity is often nullified. On hospital discharge, patients should be advised to store medicines in a cool, dry place and to ensure that containers are always kept airtight. The bathroom and kitchen should be avoided as storage areas, because of their propensity for continuous and excessive humidity and warmth. Due to the possibility of perspiration and sweating, containers should not be carried close to the body. Attention is given to issues surrounding the correct storage of medicines so that they maintain their effectiveness, including the specific needs of more sensitive agents. Furthermore, we have provided an overview of the common techniques employed for various routes of administration. To deliver medicines using the correct technique, the health professional must possess an understanding of human anatomy and physiology as well as a familiarity with the required equipment.

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CHAPTER REVIEW ■■

Medicines can be formulated in many different forms, from tablets to capsules and powders to liquids.

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Medicines can be administered to the body by routes involving the gastrointestinal tract.

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Medicines administered avoiding the gastrointestinal tract are termed parenteral medicines.

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Almost any part of the body can be used to administer medicines parenterally.

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Medicines are very often unstable, and cannot be stored indefinitely.

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All medicines have an expiry date on the package.

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Storage of medicines must be according to the manufacturer’s directions.

REVIEW QUESTIONS 1 Why should suppositories be inserted with the person in the left lateral position? 2 Can you think why cocoa butter is sometimes used in the formulation of suppositories? 3 Suggest two reasons why suppositories should not always be inserted high into the rectum. 4 Ibuprofen (an anti-inflammatory analgesic) can be obtained as a solution in gelatine capsules for the treatment

of acute, painful conditions. In the treatment of rheumatoid arthritis it is usually given in the form of an entericcoated tablet. Why is there a difference in the two formulations? 5 Why is indomethacin, an acidic drug, absorbed from the rectum at a slower rate than prochlorperazine, a basic

drug? 6 What advice should be given to women concerning the administration of pessaries or vaginal creams? 7 Can you think of any reasons why medicines are not normally administered vaginally except for topical treatment?

(Think about the gross and microscopic anatomy of the vagina.) 8 The person in your care has been ordered enteric-coated aspirin tablets. How do these tablets work to prevent

gastric irritation? 9 Bupivacaine is available with adrenaline for use as an epidural anaesthetic. What advantages does adrenaline

provide in this preparation? 10 How would you administer an intramuscular injection into the gluteal muscles to prevent damage to the sciatic

nerve? 11 The person in your care has been ordered aminophylline suppositories for asthma. What advantages has this

formulation over theophylline (Nuelin) tablets? 12 How would you prepare the skin for a transdermal patch? 13 You, as the administering nurse, are confronted with the following order for your patient: enoxaparin (Clexane)

20 mg IM daily. What is wrong with this order? Why? 14 Morris Jones, a 50-year-old executive, takes glyceryl trinitrate tablets when he has an attack of angina, and applies

a glyceryl trinitrate transdermal pad every morning as a preventive measure against angina. With reference to the formulations (tablet versus transdermal pad), describe how they act to either treat angina or prevent an attack of angina. 15 While caring for a person with an intravenous infusion, you notice the infusion stops dripping. What action will

you take?

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THE CLINICAL DECISION-MAKING PROCESS

LEARNING OBJECTIVES

KEY TERMS

After completing this chapter, you should be able to:

Assessment

1

Describe the principles of the National Medicines Policy of Australia.

Care planning

2

Describe the concept of ‘quality use of medicines’.

3

Apply the clinical decision-making process to principles of medicine administration.

Clinical decision-making process

4

Describe the aspects that are considered in assessment.

5

Describe the aspects that are considered under diagnosis.

6

Describe the aspects that are considered under care planning.

7

Describe the aspects that are considered under implementation.

8

Describe the aspects that are considered under evaluation.

Diagnosis Evaluation Implementation Quality use of medicines

There are certain principles of management that health professionals must apply to every facet of medicine administration. This chapter examines two major areas of medication management. The first area relates to Australia’s National Medicines Policy or, more specifically, the concept of the ‘quality use of medicines’, which aims to improve the way in which medicines are used in society. The second complementary area is clinical decision-making in medication management. The principles outlined in detail in this chapter have, as their primary focus, the safe and effective administration of medicines and a high standard of health care.

CHAPTER 8 THE CLINICAL DECISION-MAKING PROCESS

THE QUALITY USE OF MEDICINES During the 1950s the World Health Organization encouraged countries to implement national medicinal policies. By December 1999 a formal document had been launched in Australia, entitled Australia’s National Medicines Policy. Despite a number of innovative policies, New Zealand has yet to develop a coherent national medicines plan or quality use of medicines strategy. Australia is the only country worldwide that has such a comprehensive medicinal policy implemented at Commonwealth level. The purpose of the policy is to ensure the availability of essential affordable medicines of acceptable quality, safety and efficacy. The National Medicines Policy aims to meet the medicine and all related service needs of patients, so that optimal health outcomes and economic objectives are achieved. It  has four central objectives, which are interdependent and overlapping: 1 timely access to the medicines that Australians need, at a cost individuals and the community can afford; 2 medicines that meet appropriate standards of quality, safety and efficacy; 3 quality use of medicines; 4 maintenance of a responsible and viable medicines (pharmaceutical) industry. The third objective of the National Medicines Policy, the quality use of medicines, has been further expanded and delineated to support the development of innovative educational and professional strategies to achieve highquality management of medicines. The initiative has a participatory focus, involving all stakeholders who influence medicine use, including doctors, nurses, allied health professionals and consumers. There are three major principles associated with the quality use of medicines: 1 selecting management options wisely—drug versus non-drug treatment; 2 choosing suitable medicines if a medicine is considered necessary—appropriate selection of a medicine; 3 using medicines safely and effectively. In these three major considerations, it is first important to determine whether a person needs a medicine. Second, once the decision is made to administer a medicine, the health professional considers which medicine is appropriate, taking into account what is known about the person. Finally, the medicine is used in a safe and effective manner, taking into account the other medicines ordered and the wider sociocultural conditions surrounding the person.

The purpose of the quality use of medicines initiative is to try to understand how people live, how they think about illness, health and medicines, how people learn, how health professionals teach, what people regard as barriers and facilitators for effective use of medicines, and what are the motivations for effective management. While the National Medicines Policy and the quality use of medicines initiative help us to think about medicine management from a macro-contextual perspective, the clinical decisionmaking process is a useful and complementary way of considering medicine management from the individual’s perspective. Increasing access and assistance for medicine use through a coordinated and systematic approach lays the foundation for culturally sensitive interventions to achieve optimal health outcomes. With this goal in mind, the Quality Use of Medicines Maximised for Aboriginal and Torres Strait Islander Peoples (QUMAX) program was established in 2008. The QUMAX program, funded by the Australian Government Department of Health and Ageing and organised by the Pharmacy Guild of Australia, in collaboration with the National Aboriginal Community Controlled Health Organisation (NACCHO), seeks to trial service-level work plans developed by Aboriginal health services with assistance from community pharmacists in rural and urban areas.

THE CLINICAL DECISIONMAKING PROCESS The clinical decision-making process, as it applies to drug therapy, is an effective means of enabling health professionals to provide individualised care that takes into account all aspects of the person’s condition. The clinical decisionmaking process is a means of gathering and organising information, and using this information to plan, administer and evaluate nursing care. Knowledge and skill in the use of the clinical decision-making process are needed for medicine administration as in other areas of individualised care. The process follows five steps: assessment; diagnosis; planning; implementation; and evaluation.

Assessment The first step involves the collection of information about the person that is likely to affect drug therapy. This information forms the basis for an individualised medicine regimen. The health professional obtains data by interviewing the person and family members, collaborating with other health care professionals, performing a physical assessment, and reviewing diagnostic and laboratory test results. Objective

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data are information concerning the person’s condition. These data provide unbiased factual information about the person. Subjective data obtained during the person’s interview include the person’s feelings, thoughts, values and expectations, which cannot be directly observed and can be obtained only by questioning the person. On admission, the health professional assesses the person for age, weight, height, acute or chronic disease processes with their associated clinical manifestations, and current health status (particularly concerning cardiovascular, renal and hepatic functions). At this stage, a preliminary determination of developmental level, particularly in children and older people, is essential in planning their care. The health professional also considers the family history and personal disease history to determine the person’s risk for various medical conditions. Next, a medicine history is taken of past and current use of prescription, nonprescription and recreational (e.g. alcohol, caffeine, tobacco) preparations. Questions that the health professional would consider include the following. • What are the current medicine orders? • What medicines has the person taken before? Include prescription medicines used for chronic conditions such as diabetes mellitus, arthritis and hypertension. Non-prescription (over-the-counter) medicine preparations commonly used for headaches, nasal congestion, indigestion or constipation should also be considered, as people often do not view these preparations as medicines (see also Chapter 2). For the same reason, the health professional should ask about the person’s use of homeopathic and naturopathic medicines, such as tea-tree oil, comfrey, royal jelly, aloe vera, garlic, special teas and liniments. Homeopathic and naturopathic medicines produce their own therapeutic effects that may ultimately impinge on the current medicine regimen. • Does the person know about the actions, adverse reactions and other specific aspects of the medicine regimen? These may include the effect of giving the medicine with food (e.g. whether the medicine is taken with food or on an empty stomach); the regularity of the dose (same time each day); the storage conditions and the need to avoid alcohol or other medicines. • Has the person had an allergic reaction to a medicine? What clinical manifestations occurred and on what date did they occur? This information will prevent the administration of medicine that can produce severe, life-threatening reactions (e.g. anaphylaxis with penicillins). Conversely, some

•

• •

•

•

•

people describe certain effects as allergies when, in fact, these are mild adverse reactions to the medicines. One common example is the side-effects of nausea and vomiting associated with morphine use, which are not allergic reactions. Does the person follow a special diet? For example, low-salt, low-protein, low-fat, low sugar. The health professional should also determine whether the person is following a particular fluid regimen, such as fluid restriction. What immunisations has the person received? When did the person last receive a tetanus injection? What is the person’s attitude to medicines? Does the person think the medicine is doing what it was originally prescribed to do? What are the person’s concerns about the medicines? Concerns could relate to the safety, therapeutic and adverse effects, and the appropriateness for the medical condition being treated. What is the person’s level of willingness to take all prescribed medicines according to the required dosage, time, route and formulation? This willingness contributes to whether the person is complying with the medicine regimen, taking the medicines reluctantly or abusing the designated orders (see Chapter 5 for further discussion about adherence). Many medicines rely on regular, continuous dosage to maintain a steady response in the person. Treatments for hypertension, diabetes and epilepsy are only a few examples where missed doses can cause severe problems. Can the person communicate his or her needs freely regarding medicine administration? This may involve a lack of command of the English language, sensory problems (e.g. a loss of vision or hearing) or loss of voice (e.g. postlaryngectomy). It may also involve cognitive deficits, such as confusion or dementia. If several tablets are involved, is the person able to swallow oral medicines? Does the person possess a sensory or motor deficit, impeding self-administration of medicines (e.g. rheumatoid arthritis, loss of sight)? What sources of objective data are available? Include the person’s health history, progress notes, laboratory reports and diagnostic tests in formulating data concerning the person’s response to medicine. These, together with baseline and ongoing vital sign measurements and physical assessments, form the basis of monitoring the therapeutic or adverse effects of drugs. Laboratory tests of liver function (e.g. serum bilirubin, alkaline phosphatase and gamma-glutamyl transferase levels) and kidney function (e.g. serum

CHAPTER 8 THE CLINICAL DECISION-MAKING PROCESS

potassium, urea and creatinine levels) are very helpful because certain medicines can damage these organs. Furthermore, liver and kidney damage can lead to altered drug excretion and metabolism, thus requiring a decrease in dosage (see Chapter 15). Other important and common laboratory tests include the analysis of microbiology and culture specimens before antibiotic administration, the monitoring of serum potassium levels before digoxin therapy (see Chapter 50) and the monitoring of clotting tests before and during anticoagulant therapy (see Chapter 48).

Diagnosis The assessment statements describe the person’s actual or potential needs, and are based on the analysis and interpretation of assessment data. A diagnosis statement comprises the identification of an actual or a potential problem, the cause of the problem and the clinical manifestations of an actual problem. The following diagnoses are applicable to medicine administration. • Non-adherence related to: – individual or family misunderstanding of directions; – poor vision or hearing of the person; – the lack of affordability of the medicine; – the person’s inability to get the prescription dispensed at a pharmacy due to immobility; – the person’s confusion with medicines leading to administration in incorrect amounts or at the wrong times; – the person’s inability to manage a new route of administration (e.g. self-injection with insulin); – intolerable adverse reactions (e.g. postural hypotension with antihypertensives); – the person’s inability to accept a particular medical diagnosis (e.g. adolescent with asthma); – lack of control of the problem in the doses designated by the doctor’s order (e.g. person experiencing severe pain following a surgical procedure). • Knowledge deficit—drug therapy regimen related to: – misunderstanding of the benefits and adverse effects of drug therapy; – lack of availability of medicine information explained in a simple and thorough manner. • Knowledge deficit—safe and effective selfadministration related to: – the person’s fear of implementing the task associated with self-administration (e.g. selfinjection with insulin);

•

– lack of explanation involved in practising the task required for self-administration before and leading up to the time for discharge. Potential for injury—adverse drug reactions related to: – central nervous system depressant effects leading to altered level of consciousness; – damage caused to specific organs (e.g. altered levels of magnesium, calcium and potassium causing cardiac damage, nephrotoxic medicines such as vancomycin causing kidney damage, or ototoxic medicines such as gentamicin causing ear damage).

Planning/goals This step involves stating the expected outcomes of drug therapy. These goals are expressed in terms of the person’s behaviour rather than the health professional’s behaviour. Goals may be either short term or long term. A short-term goal can be achieved very quickly, often during a period of hospitalisation or a home visit. A long-term goal is one that may be achieved in the future. Long-term goals usually focus on health promotion, rehabilitation and health education (see Chapter  5 for further information about teaching and learning strategies for drug therapy). Relevant aspects pertaining to the planning phase of drug therapy include the following goals. • The person will receive and understand relevant education about the medicine regimen, and will: – receive all medicines as prescribed; – tend to self-administration of medicines in an accurate and safe manner (if applicable); – display a good knowledge of essential medicine information; – maintain appointments for monitoring and follow-up. • The person will receive the safe administration of the medicines, and will: – display the therapeutic benefits of medicines; – avoid the occurrence of adverse drug reactions. In planning the safe administration of medicines, the health professional will carefully analyse the person’s subjective and objective data. For instance, if the radial pulse is 50  beats per minute, the person will not receive cardiotoxic medicines such as digoxin, or if the person’s INR (international normalised ratio) is 4, a warfarin dose will be withheld. An appropriate plan incorporates the five rights of medicine administration, which are discussed in detail in Chapter 9.

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It is also important to ensure that the correct techniques and equipment are used for medicine preparation (e.g. syringes, needles, sterile water, alcohol swab, additive label for intravenous antibiotics).

Implementation This step involves putting the plan of care into action. Interventions may be dependent, independent or interdependent. A dependent intervention is a nursing activity requiring a prescriber’s order. An independent intervention is one that does not require consultation or collaboration with other health care professionals. An interdependent intervention is one that is implemented in collaboration with the health care team. Relevant aspects pertaining to the implementation phase of drug therapy include the following: • The health professional will administer the medicines as prescribed, in the manner required by the agency’s policies and procedures. • Several non-medicine interventions can be employed to improve the therapeutic effects or to nullify the adverse effects of medicines. These interventions include: – hand-washing between people, maintaining a meticulous aseptic dressing technique to prevent infection; – maintaining body alignment of people when positioning in a bed or chair, turning bed-bound people at least two-hourly for pressure area care; – assisting to cough and deep-breathe, especially in bed-bound or postoperative people; – assisting and encouraging ambulation; – applying heat or cold treatments (e.g. tepid sponge, hot or cold compresses) to relieve pain or itchiness, or to alter body temperature; – changing the level of sensory stimulation; – scheduling nursing activities to allow for adequate periods of rest and sleep. • The health professional should provide accurate records and interpretations of the effects of medicines on vital signs, fluid intake, urine output and other assessment data. The drug order should be promptly documented immediately after administration.

Evaluation This step involves assessing the person’s status in relation to stated goals and the expected outcomes. The person’s progress towards goal achievement governs future directions for reassessment, prioritisation, new goal setting, anticipated outcomes and revision of the care plan.

Relevant aspects pertaining to the evaluation phase include the following. • The health professional shall determine whether the therapeutic benefits of the medicines are apparent. The health professional should therefore know the expected effects of the medicines administered and when to expect these effects. • Adverse or unwanted reactions should also be observed. These effects are more likely in people with severe liver or renal disease, the very young or the older person, those receiving large doses of a medicine and those receiving several medicines. • The health professional will observe whether the person is experiencing any difficulties in compliance. • The person is observed for ability to undertake self-administration of the medicine. • The health professional must also be aware of the common drug–food and drug–drug interactions that may occur (see Chapter 16). As most people often receive two or more medicines, a drug interaction may be the cause of an unexpected response. • Some medicines are potentially quite toxic or possess a therapeutic range that is close to the toxic dose range (i.e. have a narrow margin of safety). For some antimicrobial agents, their antibacterial activity is also dependent on a relatively high peak level in the blood. The blood levels of these medicines are routinely checked to ensure the required dose is within the therapeutic range. Common examples include quinolones (e.g. norfloxacin, ciprofloxacin) and aminoglycosides (e.g. gentamicin, tobramycin) (see Chapter 72). • A person should be observed for an allergic response to medicines. Typically this reaction does not occur on the primary exposure to the medicine, as time is needed to create antibodies required for an allergic reaction (see Chapter 18). Once the person exhibits an allergic reaction, the health professional documents this information on the person’s identity label, history and medication chart. • The potential for drug tolerance should also be considered, particularly in people receiving longterm analgesic cover. Tolerance is the situation where repeated use of the medicine creates a lesser response unless the dose is raised. A person receiving a narcotic analgesic for acute pain is unlikely to become tolerant, because when the pain starts to decrease, so too does the desire for the medicine. As the pain continues to subside, the person should be gradually weaned off

CHAPTER 8 THE CLINICAL DECISION-MAKING PROCESS

•

the narcotic and placed on other types of analgesics. Note, however, that people with severe chronic pain associated with terminal cancer are an exception to this consideration. In determining the required dose for a specific person, much consideration is placed on assessment data so that the potential for toxic effects is low. However,

certain people have a greater potential for developing toxic effects and should therefore be closely monitored. For instance, people admitted into emergency departments following a drug overdose would almost certainly exhibit toxic effects. Similarly, administration of medicines with a narrow margin of safety may lead to toxicity if drug levels are not regularly monitored.

CHAPTER REVIEW ■■

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■■ ■■

■■

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■■

There are three major principles associated with the ‘quality use of medicines’: selecting management options wisely in deciding between drug versus non-drug treatment, choosing suitable medicines if a medicine is considered necessary and using medicines safely and effectively. The clinical decision-making process follows five steps: assessment, diagnosis, planning, implementation and evaluation. Assessment involves the collection of information that is likely to affect the person’s drug therapy. Diagnosis involves identifying an actual or a potential problem, the cause of the problem and the clinical manifestations of an actual problem. Planning concerns involve stating the expected outcomes or goals of drug therapy, which are expressed in terms of the person’s behaviour. Goals may be either short term or long term. Implementation involves putting the plan of care into action through interventions. Interventions may be dependent, independent or interdependent. Evaluation involves assessing the person’s status in relation to expected outcomes.

REVIEW QUESTIONS 1

State the principles of the National Medicines Policy.

2

Describe the concept associated with the ‘quality use of medicines’.

3

Identify the important components of the clinical decision-making process.

4

Maria Bombardi, a person who has developed a severe chest infection, is commenced on vancomycin therapy. What aspects will you evaluate while the person is on this therapy?

5

Jane Black has commenced a course of warfarin therapy following a heart value replacement. What aspects will you evaluate while the person is on this therapy?

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M E D I C I N E A D M I N I S T R AT I O N S T R AT E G I E S A N D D O C U M E N TAT I O N LEARNING OBJECTIVES

KEY TERMS

After completing this chapter, you should be able to:

Agency policy and procedure

Five ‘rights’ of administration

Checking procedure

Right person

Documentation procedure

Right dose

1

Describe the five ‘rights’ of medicine administration.

2

Describe the checking procedures for medicine administration.

3

Describe the documentation procedures for various types of medicines.

Right medicine Right route Right time

The principles that ensure a high standard of clinical practice in medicine administration are covered in this chapter. These principles include the five ‘rights’ of medicine administration, agency policies and procedures as well as checking and documenting strategies.

C H A P T E R 9 M E D I C I N E A D M I N I S T R AT I O N S T R AT E G I E S A N D D O C U M E N TAT I O N

FIVE ‘RIGHTS’ OF MEDICINE ADMINISTRATION Accurate medicine administration centres on the five ‘rights’: giving the right medicine, to the right person, in the right dose, by the right route, at the right time. Although on the surface it may appear that these five rights should be relatively easy to achieve, each right requires considerable knowledge, skill and concentration.

serious problems may develop if other routes are used. For example, sympathomimetic medicines such as adrenaline and noradrenaline, which are commonly used in critical care areas, cannot be given through a peripheral vein as they can cause necrosis of extremities. Furthermore, the health professional must use appropriate anatomical landmarks in identifying areas for intramuscular injections. If the sciatic nerve is damaged on injection, paralysis of the limb may occur.

Right medicine

Right time

In providing the right medicine, the health professional should interpret the doctor’s order accurately. If the medicine appears to be unfamiliar, the information is checked from an authoritative source, such as independent pharmaceutical references (e.g.  Australian Prescriber and the Australian Medicines Handbook) rather than from nonindependent sources (e.g. Australian Prescription Products Guide, New Ethicals Compendium, and MIMS Annual), or with other health care professionals. To understand whether a particular medicine is suitable for a specific person, the health professional must know and understand the person’s health problems, and the way in which the medicine will assist in providing therapeutic benefit. Careful attention is paid to the labels of medicine containers, ensuring that they match up with the medicine orders. The prescribing health professional should be questioned about the order if the name of the medicine is unclear or if the medicine appears inappropriate for the person’s health condition.

Right dose Providing the right dose is extremely important. Here, the health professional should interpret measurements and abbreviations accurately. Medicine calculations should be carefully made and then rechecked for correctness before administration. The health professional must also determine whether the dose is an appropriate one for the size, age and condition of the person.

Right person In identifying the right person, the health professional should check the identification bands of institutionalised people and verify the identity of other people. This checking procedure must be undertaken every time a medicine is administered.

Right route In ensuring the right route, the health professional must use the correct technique for medicine administration. Some medicines can be given only by a specific route, and

Providing the person with the dose at the right time may be difficult to accomplish, particularly in a busy ward where a health professional is responsible for a number of people. If this is the case, it is important that the health professional concentrate on providing parenteral medicines at the recommended schedule, as time plays a critical role in their therapeutic effects (e.g. subcutaneous insulin and intravenous antibiotics).

AGENCY POLICIES AND PROCEDURES A health professional must practise within the policies and procedures of the health care agency, as well as follow the legal framework of government legislation. Policies relate to general principles by which an agency manages its affairs. A health professional employed by an agency is required to know these policies and to follow the procedures that lead from them. Generally, policies and procedures are developed to complement and integrate with legal guidelines. Although policies and procedures may differ between agencies, most have fairly strict and detailed guidelines on medicine administration. Policies and procedures of health care agencies should be regularly re-examined to ensure that the most current policies and procedures are followed. Students and clinical teachers who supervise students’ clinical experiences are not usually employed by a health care agency, and are, therefore, not covered by the agency’s insurance policy in liability cases. The lack of familiarity with agency routines, which often ensues from casual contact with the environment, creates a necessary obligation for students and clinical teachers to become fully conversant with an agency’s policies and procedures. Policies associated with checking and documentation procedures are very closely linked to the five ‘rights’ of medicine administration. As checking and documentation procedures are extremely important areas of policy development, general aspects of each area are considered.

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The main area of focus is on the hospital setting. It should be noted, however, that variations will exist between agencies.

CHECKING PROCEDURES While many health professionals are involved in checking medicines before they are administered to people, nurses are the final link in the chain before medicines are given to people. In relation to parenteral therapy (e.g. subcutaneous, intramuscular and intravenous preparations), two registered nurses are usually required to check the medicine administered. Until nursing students start receiving instruction in the area of pharmacology, no contact with medicines is allowed or expected. Once provided with this instruction, nursing students with appropriate knowledge of the medicines to be administered should check the medicine orders with a registered nurse who is employed by the institution. The nursing student and registered nurse then take the medicine to the person’s bedside, checking the identification of the person against that on the medicine order. Nursing students who administer these medicines to the person should be under the direct supervision of the registered nurse to ensure the correct administration technique. According to hospital policy, certain groups of medicines are usually checked by two registered nurses because they are potent, potentially dangerous or addictive. The administration of blood transfusions requires the

following specific information to be checked: blood ABO group, Rhesus factor group, type of blood product (e.g. whole blood or packed cells), specific number of the donor unit, doctor’s signature on the tag attached to the unit of blood as well as the doctor’s signature on the intravenous fluid order and cross-matching charts, expiry date and the person’s unit record identity number. Information on the  request for cross-matching form should match up with the documentation on the slip attached to the blood, on the intravenous fluid order chart (see Figure 9.1), as well as on the blood bag itself. If any information is inconsistent, the nurse returns the blood to the serology department. Again, if a nursing student is involved in the checking procedure of blood products, this should be done with the accompaniment of two registered nurses. Narcotic analgesics are also often checked by two registered nurses (or by two registered nurses and a nursing student). However, this practice is also dependent on the policy procedures of a particular hospital. Chapter 3 details the checking protocol followed for controlled drugs. Digoxin and warfarin are usually tagged as ‘special’ oral preparations. These tablets are also often checked by two registered nurses because, if an error is made in dosage, there may be dire consequences. The checking procedure for other oral medicines usually involves at least one registered nurse. Nursing students should check oral medicines with one other registered nurse. It may be considered preferable

Figure 9.1  Intravenous fluid chart This intravenous fluid chart indicates the orders for two units of whole blood documented on the request for cross-matching form. The order needs to be signed by two registered nurses on the request for cross-matching form and by one registered nurse on the intravenous fluid chart. The two units of blood were followed through by a normal saline flush to clear blood from the intravenous line. A Hartmann’s flask is currently in progress, which needs to be documented once the whole amount has gone through.

KNOWN OR SUSPECTED ADVERSE DRUG REACTION TO:

Penicillin ——> skin rash

INTRAVENOUS FLUID

U.R. Number: Surname: Given Names: Address: Date of Birth:

Date of Nature of fluid Rate Additive Doctor’s order and volume signature

987654 BLOGGS Joseph Paul 1 Smith Street Smithsville 9123 1.1.1950 male

Date of Time Time Vol given Nurse’s admin started finished (mL) signature

1.1.15 Whole Blood 10 3/24

S. Medico

1.1.15

0100

0400

400

R. Naber

1.1.15 Whole Blood 10 3/24

S. Medico

1.1.15

0400

0700

400

R. Naber

S. Medico

1.1.15

0700

0730

100

R. Naber

S. Medico

1.1.15

0730

1.1.15 1.1.15

Normal Saline flush 100 mL Hartmann’s 1000 mL 12/24

R. Naber

C H A P T E R 9 M E D I C I N E A D M I N I S T R AT I O N S T R AT E G I E S A N D D O C U M E N TAT I O N

to use a registered nurse who is employed permanently on the ward, as this individual is usually extremely familiar with the person’s diagnoses, characteristics, habits and idiosyncrasies. This situation may, however, not always be practicable.

DOCUMENTATION PROCEDURES An important aspect of medicine administration involves careful and accurate documentation. The National Inpatient Medication Chart was developed by the Australian Commission on Safety and Quality in Health Care as a means of providing a standardised approach to documenting the management of medicines in hospital settings (see Figure 9.2). In terms of managing medicines for specific purposes, such as diabetes, palliative care and pain relief, it is recommended that additional specific forms of documentation are used. A Paediatric National Inpatient Medication Chart has also been developed. Although some medicines may require two health care professionals to check the information, the documentation usually has space for only one set of initials or a signature. Intravenous fluids need one registered nurse’s signature (see Figure 9.1). Orally administered and intermittent intravenous medicines usually require one set of initials (see Figure 9.3). Nursing students must always ensure that anything they have administered is countersigned by a registered nurse (see Figure  9.3). This nurse should preferably be a permanent employee of the ward, so that if any problems arise from the procedure it will not be difficult to contact the nurse at a later stage. Narcotic analgesics need two registered nurses’ signatures on the controlled drugs register (see Chapter 3). Blood transfusions also require the signatures of two registered nurses documented on the request for crossmatching form (see Figure 9.4), while once-only or nurse-

initiated medicines require only one registered nurse’s signature (see Figure  9.5). The administration of a blood transfusion carries the requirement of noting the vital signs for the duration of therapy, to allow early detection of fluid overload, underload or allergic reactions. The additive labels placed on burettes for the administration of an intermittent intravenous medicine have the signatures of two registered nurses (see Figure 9.6). Likewise, the additive label on intravenous flasks will have two registered nurses’ signatures (see Figure 9.7). It is important to document the therapeutic and adverse effects of a medicine on the observation chart, especially if the reaction is of significance or intended to resolve a specific problem. Common examples include pain relief, blood pressure control, and alleviation of nausea and vomiting (see Figure  9.8). As anaesthetics affect the cardiovascular, respiratory and neurological systems, the nurse should conduct routine post-anaesthetic observations for a time after the person’s return to the ward setting (see Figure 9.8). Diabetic charts are provided for people with a medical diagnosis of type  1 or type  2 diabetes mellitus. Following the administration of insulin or oral hypoglycaemic agents, the nurse notes the effect on the person’s blood glucose level, urinalysis or clinical manifestations (see Figure 9.9).

CONCLUSION Although several health care professionals are involved in people’s medicine regimens, nurses possess a major share of the responsibility, especially in relation to medicine administration. In the sequence of events progressing from medicine supply leading to people receiving their medicines, nurses are the linchpin. Nurses’ duties also involve direct care, more so than any other health care professional. They are, therefore, in an ideal position to ensure a high standard of care in relation to drug therapy. This chapter has explained the medicine administration strategies and documentation that contribute to realising this standard.

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Figure 9.2 The national inpatient medication chart The National Inpatient Medication Chart is divided into four pages. The first page includes details about once-only and nurse-initiated medications, premedications and telephone orders. The second and third pages include details about regular medications and the fourth page includes information about ‘as required’ medications. AFFIX PATIENT IDENTIFICATION LABEL HERE AND OVERLEAF

Medication Chart Page 1 of 4

URN:

ALLERGIES & ADVERSE DRUG REACTIONS (ADR) Nil known Unknown (tick appropriate box or complete details below) Drug (or other) Reaction/Type/Date Initials

Family name:

NOT A VALID PRESCRIPTION UNLESS IDENTIFIERS PRESENT

Given names: Address:

Date of birth:

Sex:

First Prescriber to Print Patient Name and Check Label Correct: Weight(kg): Sign

Print

ADDITIONAL CHARTS IV Fluid BGL/Insulin Palliative Care Chemotherapy

Ward/Unit: Medication (Print Generic Name)

Route

Dose

£F

of Acute Pain IV Heparin

ONCE ONLY, PRE-MEDICATION & NURSE INITIATED MEDICINES

Date Prescribed

£M Height(cm):

MEDICATION Chart No.

Date

Facility/Service:

Prescriber/Nurse Initiator (NI) Date/Time of Given By Dose Signature Print Your Name

Time Given

Other

Pharmacy

TELEPHONE ORDERS (To be signed within 24 hours of order) Date Time

Medication (Print Generic Name)

Route

Dose

Frequency

Nurse Initials NR1/NR2

Medicines Taken Prior to Presentation to Hospital (Prescribed, over the counter, complementary)

Medication

GP: Documented by:

Own medications brought in?

Dose & frequency

Duration

Dr Sign.

Dr Name

Y

N

Medication

Date

RECORD OF ADMINISTRATION Time / Time / Time / Time / Given by Given by Given by Given by

MEDICATION CHART

DO NOT WRITE IN THIS BINDING MARGIN

86

Administration Aid (specify) .......................... Dose & frequency

Duration

Community Pharmacy: (Sign)

(Date)

Medicines usually administered by:

Source: Australian Commission on Safety and Quality in Health Care www.safetyandquality.gov.au/wp-content/uploads/2012/05/NationalInpatient-Medication-Chart-four-A4-page-version.pdf. © Copyright 2011 The Australian Commission on Safety and Quality in Health Care (ACSQHC) .

1.1.15 1.1.15 1.1.15 1.1.15 1.1.15

JS

EM

FU

JS

FU

24.12.13

24.12.13

24.12.13

24.12.13

24.12.13

Date C’menced

1.1.15

Dose Route Freq

10-20 mg

– O

node S. Medico for sleep

Doctor’s Signature Indication

Time Dose Initial Time Dose Initial Time Dose Initial Time Dose Initial Time Dose Initial

2200 10 IN

Date 1.1.14 Time 2 4 6 8 10 12 2 am JK SR pm JK am SR pm am EM SR pm am JK pm SR IN am IN pm DB JK am pm am pm am pm

Henrietta 1 Brown Street Brownsville 9123 1.1.1930 female

654321

Doctor’s Date Signature Ceased

Date of Birth:

U.R. Number: Surname: JONES Given Names: Address:

Transiderm NITRO 1 patch skin daily S. Medico – digoxin 250 mg O BD S. Medico – frusemide 40 mg O BD S. Medico – slow K. Ti O BD S. Medico – naproxen 250 mg O TDS S. Medico

Name of Drug

24.12.13 temazepam

P.R.N. ADMINISTRATION

Date

Pharmacy Use only

Nil known

KNOWN OR SUSPECTED ADVERSE DRUG REACTION TO:

DRUG ADMINISTRATION SHEET

4

2.1.14 6 8 10 12 2

C H A P T E R 9 M E D I C I N E A D M I N I S T R AT I O N S T R AT E G I E S A N D D O C U M E N TAT I O N

Figure 9.3 Example of a completed medication chart

The medication chart indicates the oral and prn (as required) medicines for the person, with the accompanying nurse’s initials. Note the countersigning that has occurred with naproxen given at 1400 hours. The person with the initials DB is a nursing student.

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Figure 9.4 Request for cross-matching The blood group, Rhesus factor, type of blood, expiry date, patient unit record number, person’s name and donor unit identifying number must be checked on the request for cross-matching form, and matched up with information on the tag attached to the blood and the information contained on the blood bag. REQUEST FOR CROSS-MATCHING

U.R. Number: Surname: Given Names: Address:

TO BE COMPLETED BY THE MEDICAL OFFICER Ward 1 West Date 1.1.15 Senior M. O. Dr S. Medico

Date of Birth:

Patient Details Previous transfusions yes/no Pregnancies, miscarriages yes/no Hb 8.2 g/dL Pulse 110 /min BP 110/60 mmHg

987654 BLOGGS Joseph Paul 1 Smith Street Smithsville 9123 1.1.1950 Male

Note: This section must be completed in the medical officer’s handwriting Blood group and antibody screen only Blood group, antibody screen and hold ✓ serum

Operation Oversewing of duodenal ulcer, laparotomy Clinical Notes Postoperative bleeding

units packed cells units whole blood

2

TO BE COMPLETED BY PERSON DRAWING BLOOD

Required at 1 a.m./pm. Date: 1.1.15 If blood is needed urgently (in less than four hours), the laboratory must be telephoned and this box ticked. ✓ Dr S. Medico M.O. Signature Surname (print) MEDICO

I certify that the blood specimen accompanying this order is as indicated by direct enquiry and inspection of wrist band.

D. Smith R.N. Signature Surname (print) Smith Date 1.1.14

TO BE COMPLETED BY BLOOD TRANSFUSION SEROLOGIST Blood Group

O

+ve

I certify that the blood group of the blood specimen supplied to me, and labelled with the identity of the patient whose details heads this form, is as recorded in the adjacent panel.

ABO Rh Atypical Antibodies present yes/no

Date 1.1.15 Signature Dr B. Serologist

Record checked ✓

REPORT OF CROSS-MATCH AND/OR ANTIBODY SCREEN Blood Group of Donor Unit

Number of Donor Unit

Date

From

To

Signature 1

Signature 2

1.

O +ve

1234567

1.1.15

0100

0400

R. Naber

S. Jones

2.

O +ve

8910123

1.1.15

0400

0700

R. Naber

S. Jones

3. 4. 5. 6. 7. 8. 9. 10. Ab. Screen NOTE: COMPATIBILITY IS VALID FOR 3 DAYS FROM DATE OF ISSUE (SEE LABEL)

C H A P T E R 9 M E D I C I N E A D M I N I S T R AT I O N S T R AT E G I E S A N D D O C U M E N TAT I O N

Figure 9.5 Once-only medicines and health professional-initiated medications chart This chart indicates once-only and health professional-initiated medicines. Warfarin is checked by two registered nurses, although only one signature is needed on the chart. Nurse-initiated medicines are those that do not require a doctor’s order.

ONCE-ONLY DRUGS Drug

Date

Dose

Route

– O

1.1.15

warfarin

2 mg

2.1.15

warfarin

2.5 mg

3.1.15

warfarin

3 mg

– O – O

Date to Time to be given be given

Doctor’s Signature

Time given

Given by

1.1.15

2000

S. Medico 2000 J. Kennedy

2.1.15

2000

S. Medico 2000 J. Kennedy

3.1.15

2000

S. Medico 2000 J. Kennedy

NURSE-INITIATED DRUGS Drug

Date

1.1.15

Panadol

Dose

Route

500 mg

– O

Date to Time to be given be given

1.1.15

1600

Nurse’s Signature

Time given

Given by

J. Kennedy 1600 J. Kennedy

Figure 9.6 Additive label

Figure 9.7 Additive label

This additive label documents information relating to an intermittent antibiotic the person will receive through the burette of an intravenous line. This label is attached to the side of the burette.

This additive label documents information relating to an intravenous Actrapid (a fast-acting insulin preparation) infusion. The label is attached to the flask of Normal Saline. ADDITIVE LABEL

ADDITIVE LABEL

Jane BLOGGS Name U.R. Number 876543 Ward 1 South Fluid Additive vancomycin 2.4.15 Date

Volume Time Prepared Time Administered

Signature of Person Preparing D. Smith Signature of Person Preparing R. James

500 mg

Name U.R. Number Ward Fluid Additive Date

Jane BLOGGS 876543 1 South Normal Saline Volume Actrapid 100 units 2.4.15 Time Prepared

Time Administered Signature of Person Preparing D. Smith Signature of Person Checking R. James

100 mL

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Figure 9.8 Observation chart Routine post-anaesthetic observations taken on a person post-appendicectomy. Note that morphine and metoclopramide (Maxolon) were given for pain and nausea, respectively, with reference made to dosage, route and time of administration. Effects on vital signs and other clinical manifestations are indicated.

OBSERVATION CHART

U.R. Number: Surname: Given Names: Address:

Routine Post-Anaesthetic Observations (RPAO) Date

Time

T

P

6 15.3.15 0700 36 PO 70

R

BP

18

110⁄70

Date of Birth:

Pupils Limb Consc. Site React move. state R L R L

equal

S

N

1/2 hourly obs — 4 hrs 2 36 PO

106 16

100⁄60

1100

110

18

1130 1200

1030

765432 BLOGGS Cindy Jane 1 Smith Street Smithsville 9123 5.6.1970 Female

Nursing Comments

Pre-operative obs. (appendicectomy)

N/S

D

Dressing dry and intact

140⁄80

S

D

Dressing dry and intact

120 22

140⁄90

S

D/N

c/o abdo. pain & nausea

108 18

136⁄84

S

D/N

4 1230 36 PA 100 16

130⁄80

S

D/N

morphine 10 mg IV Maxolon 10 mg IV @ 1140 Pain and nausea relieved

1300

90 18

120⁄76

S

D/N

Dressing dry and intact

1330

76

18

114⁄72

S

D/N

Dressing dry and intact

1400

72

18

110⁄70

S

N

Dressing dry and intact

70

18

110⁄65

S

N

Dressing dry and intact

1430

8 36 PA

equal

obs. — 4/24 1830

Abbreviations: Limb movements S – Spontaneous

NS – Not spontaneous, in response to command State of consciousness N – Normal D – Drowsy but rousable, will speak and respond to command

P/S – In response to painful stimuli

N/R – No response to painful stimuli

SC – Unconscious, responds to painful stimuli only

C – Comatosed, not responding to painful stimuli

C H A P T E R 9 M E D I C I N E A D M I N I S T R AT I O N S T R AT E G I E S A N D D O C U M E N TAT I O N

Figure 9.9 Diabetic chart This diabetic chart indicates the profile of a person with unstable diabetes who is on a sliding scale of Actrapid if the blood glucose level goes above 10 mmol/L. Note that the insulin type, amount and time are documented, together with subsequent changes in blood glucose and urinalysis.

DIABETIC CHART Diet: Diabetic

Weight:

U.R. Number: Surname: Given Names: Address:

50 kg

Date of Birth: Date

Time

Insulin Dose

Urine Glucose 1 1 — – 1 – 10 4 2 1 2 % % % % % %

(mmol/L) 0 2.4.15 0700 0730

18.2 Actrapid s/c

Nursing Comments Protein Ketone

Type

Blood glucose

876543 BLOGGS Jane 1 Smith Street Smithsville 9123 4.8.1950 Female

+ – Feeling sweaty and nauseated

12u

0830

9.2

1100

8.4

1500

4.5

1900

8.5

Refused morning tea – – Given cheese & biscuits – –

CHAPTER REVIEW ■■

■■

■■

■■ ■■

Accurate medicine administration centres on the five ‘rights’: giving the right medicine, in the right dose, to the right person, by the right route and at the right time. A health professional must practise within the policies and procedures of the health care institution, as well as follow the legal framework of government legislation. With parenteral therapy, two nurses are usually required to check the medicine administered. Certain groups of medicines may also need to be checked by two nurses because they are potent, potentially dangerous or addictive. Nurses need to document that they have administered a medicine immediately on completion of the task. Health professionals should also document the therapeutic and adverse effects of medicines on the observation chart or medical history.

REVIEW QUESTIONS 1

You are asked to assist in the checking procedure of a morphine ampoule from the locked controlled drugs cupboard. Outline what is involved in this procedure.

2

Describe the checking procedure involved in administering one unit of packed cells to a person.

3

Describe the checking procedure involved in administering warfarin to a person.

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M E D I C AT I O N E R R O R S

LEARNING OBJECTIVES

KEY TERMS

After completing this chapter, you should be able to:

Checking procedure

1

Define the term ‘medication error’.

Drug calculation

2

Describe how failure to follow the five ‘rights’ of medicine administration can lead to a medication error.

Medication error

3

Describe strategies that could be implemented to avoid medication errors.

The management of medicines is one of the most common duties undertaken by a health professional. As some health professionals may consider this task a routine procedure, complacency may take over from meticulous and safe practice. Conversely, some health professionals may feel overwhelmed and have trouble in keeping up with the sheer number of medicines available. Others may experience extreme pressure in having to handle several important responsibilities with little time to spare.

C H A P T E R 1 0 M E D I C AT I O N E R R O R S

TYPES OF MEDICATION ERRORS A medication error is an error that occurs during the process of choosing, prescribing, transcribing, dispensing, administering and monitoring a medicine for a person. There are several causes of medication errors, but they all fundamentally stem from the five ‘rights’ of medicine administration (see Chapter  9). The five rights involve giving the right medicine to the right person, at the right dose, by the right route and at the right time. Some examples of medication errors that are potentially dangerous or that lead to ineffective medicine use are listed here. • The wrong medicine is given, as it is mistaken for another medicine of a similar name. • The wrong dose is ordered on the medication chart. • An error is made calculating the mass or volume, so the person receives the wrong dose. • The medicine is given by an incorrect route. • The right dose is ordered, but because of illegible writing an incorrect dose is administered. • The person’s identity is not checked and subsequently the wrong medicine is administered. • The medicine is administered to a person who is experiencing an adverse reaction that warrants discontinuation of the medicine. • The person takes the medicine by the correct route but consumes the medicine in an incorrect way (e.g. enteric-coated tablets). • The person takes the medicine at the wrong time. • The person takes the medicine concurrently with another medicine that is contraindicated. • The person takes two tablets simultaneously that are very similar in action and use, thus leading to a medicine overdose.

HOW TO AVOID MEDICATION ERRORS Although medicine management is one of the most problematic areas of professional responsibility, the use of guidelines based on evidence and common sense will be most helpful in preventing errors. Each medicine order should be carefully read, noting whether the particular medicine is applicable for the person at the specific dose. Never assume that just because the medicine has been dispensed on a previous occasion, it must be correct. If there is any doubt about the information noted down in

the medicine order, consult one of the health professionals, a nursing colleague or a medicine reference book. If the writing itself is unclear, seek clarification from the doctor who wrote the order. The checking procedure for medicines involves reading the container on three occasions: the first is when the medicine is obtained from the medicine trolley; the second, just before it is prepared and administered; the third, just before the container is returned to the medicine trolley. Always check the person’s identity carefully, even for oral medicines. The health professional should check that the person’s name and unit record number match up with those noted on the medicine order. This process may seem rather time-consuming, especially if several medicines need to be given out to a large number of people; however, employing this strategy as standard practice before administering any medicine is the best way of preventing the medicine from being given to the wrong person. As two people may possess the same name, it is also important to check the unit record number against the medicine order. It is a good strategy to have two patients with the same name positioned next to each other. In this way, all health professionals will be more aware of the issue. The medication chart and patient wrist labels may even be documented with this information to further alert individuals. If a person takes oral medicine regularly, be sure to gauge the technique carefully. For instance, ensure that the person takes enough water to swallow the tablets properly. Tablets and capsules may lodge in the oesophagus if little or no water is used, leading to tissue trauma. Other people make the mistake of chewing or breaking enteric-coated or delayed-action (slow-release) tablets. Breaking an  entericcoated tablet allows exposure of the medicine to the stomach lining and may cause gastric irritation. Similarly, crushing a delayed-release tablet allows too much medicine to be absorbed at once, which could lead to a toxic medicine level. Always take note if people question their medicines, as they tend to become very familiar with their medicine regimen, especially if it has remained unchanged for a period of time. Examples include: ‘What happened to the white pill I usually take in the morning?’ or ‘I don’t normally have this tablet at this time of the day’. If the person is not present, never leave the medicines at the bedside, as you run the risk not only of the individual not taking the medicine but also of the wrong person taking it. Visitors who are young children may also accidentally consume medicines that are left lying around. Ensure that medicine calculations are carefully checked. Where two nurses are required to check a dose (e.g.  for parenteral administration of medicines), each nurse should

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Figure 10.1 Sequence of events and checking procedure for medicine administration Flow chart indicating the components of events and sequence for medicine administration. The checking procedure involves the five rights of medicine administration (right medicine, right dose, right person, right route and right time). Note, in particular, the number of times the medicine is checked, and the signing of the medicine order following medicine administration. Read the drug order. Is the writing unclear?

Seek clarification from the doctor.

Yes

No

No

Is it the right time for the medication to be given? Yes Are you aware of the medication’s actions, adverse effects, contraindications, normal dose range and drug interactions?

No

Consult the pharmacological literature.

Wait until it is the right time for the medication to be given.

Yes Is the information on the drug order appropriate for the person’s diagnosis and past health history (e.g. known allergies)? Is the dose appropriate for the person’s age and size?

No

Consult the doctor.

Yes Check the label of the container following removal from the drug trolley. Does the label match up with the drug order? Is the correct form of the medication used (e.g. tablet, injection)?

No

Obtain the correct container from the drug trolley. Obtain correct form of medication.

Yes Perform calculation of the amount of medication required. Recheck the calculation. Do you obtain the same result? Is the result obtained reasonable and according to what would be expected? Are you confident about the calculation?

No

Recheck calculations. Check with a colleague if unsure.

No

Obtain the correct container from the drug trolley.

No

Obtain the correct container from the drug trolley.

Yes Check the label of the container prior to removal of the medication. Does the label match up with the drug order? Yes After removing the medication, check the label of the container again before returning it to the drug trolley. Does the label match up with the drug order? Yes Check the person’s identity label against the drug order. Check the person’s full name and the unit record number. Do you have the right person?

No

Find the right person.

Yes Administer the medication. Document the drug order following administration. Observe for therapeutic effects, adverse effects and allergies. Are there any problems?

Yes

Consult with the doctor, pharmacist and nursing colleagues.

No Document the effects of therapy and measures used to address any problems in the person’s health history.

Implement measures that address these problems.

C H A P T E R 1 0 M E D I C AT I O N E R R O R S

calculate the result separately, and then compare it with the other’s result. The use of calculators is acceptable, although it is better practice to get into the habit of doing calculations manually. Calculators are not infallible, nor are they always readily available, and manual competence improves mathematical ability for logic. If calculators are used, you need also to be able to estimate the correct amount manually as a further check of the result. Always be very wary of amounts that appear unbelievably large or small (e.g. 1000 drops per minute or 10 tablets per dose). Remember, always recheck your calculations. A set of drug calculation exercises is provided in the Appendices for you to practise this important skill. If the doctor orders the medicine to be given at particular time intervals, the nurse should aim to never deviate from this time by more than half an hour. For instance, if the doctor orders erythromycin every six hours, this can be translated to mean 6 am, 12 noon, 6 pm and 12 midnight (or 8  am, 2 pm, 8 pm and 2 am). Either way, the person would have to be given a dose late in the evening. Attempting to change the 12  midnight dose to 10  pm is an unsafe practice: it means therapeutic agent levels will not be maintained as the administration times are no longer regular and consistent.

On administration of the medicine, ensure that this is followed up with documentation of the medicine order, which is completed after the person has been observed taking the medicine. It is also important to document whether a medicine has been withheld or omitted. This issue is particularly important for ‘as required’ (‘prn’ medicines), which are administered depending on individual need. The person’s response to the medicine should also be documented, especially if a problem develops. In this case, the nurse should clearly document the actions taken to rectify the problem. Figure 10.1 shows the sequence of events and checking procedure for medicine administration. It incorporates the five rights of medicine administration and identifies strategies that the nurse should use to avoid medication errors.

CONCLUSION Due to the sophistication of current medicine regimens and the demands of the health care setting, it is possible that medication errors will occur. However, by using a systematic approach to medicine management, problems relating to medication error can be largely avoided.

CHAPTER REVIEW ■■

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■■ ■■

■■ ■■

Each medicine order should be carefully read, noting whether the particular medicine is applicable for the person at the specific dose, using the specified route and indicated time. The checking procedure involves reading the container on three occasions. The first is when the medicine is obtained from the medicine trolley, the second is just before it is prepared and administered and the third is just before the container is returned to the medicine trolley. If a person takes oral medicine regularly, be sure to observe the technique carefully. Always take note if people question their medicines, as they tend to become very familiar with their medicine regimen. Ensure that drug calculations are checked carefully. If the doctor orders a medicine to be given at particular time intervals, the nurse should never deviate from this time by more than half an hour.

REVIEW QUESTIONS 1

The graduate nurse Clara Tsen has been assigned to care for four patients, two of whom are named Mr Smith. What strategies can Clara implement to avoid medication errors relating to these two patients?

2

State the five ‘rights’ of medicine administration, and give examples of errors relating to each right.

3

You notice that medicines for Jack Peterson have been placed on the over-bed table. The patient has left the ward to have an X-ray taken. Is this good practice to have medicines placed on the table? Why or why not?

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MANAGEMENT OF COMMON ADVERSE DRUG REACTIONS LEARNING OBJECTIVES

KEY TERMS

After completing this chapter, you should be able to:

Adverse drug reaction

1

Define what is meant by an adverse drug reaction.

Predictable reaction

2

Identify the two broad classifications of adverse drug reactions.

Unpredictable reaction

3

Describe the management of common adverse drug reactions.

Although the principal aim of drug therapy is to provide maximal therapeutic benefits while minimising adverse effects, adverse reactions continue to be a problem. With some medicines, adverse drug reactions are very common. It is important to consider the undesirable effects as well as the therapeutic effects following medicine administration and what action to take if an individual experiences an adverse drug reaction. In some cases, the dose may need to be reduced or the medicine may need to be stopped altogether. The symptoms experienced by the individual also need to be managed in an appropriate manner. Depending on the severity of the disease being treated, the risk associated with an adverse drug reaction may be considered reasonable—as with, for example, medicines used in the treatment of cancer and life-threatening dysrhythmias.

CHAPTER 11 MANAGEMENT OF COMMON ADVERSE DRUG REACTIONS

DEFINITION AND CLASSIFICATION Adverse drug reactions are undesirable effects that occur with the administration of medicines at normal doses. They can occur as a part of the normal pharmacological profile of the particular medicine (type  A reactions) or they may be unrelated to the medicine (type B reactions). When an adverse drug reaction occurs as a result of the pharmacological profile of the medicine, it is known as a predictable effect. Predictable effects take place soon after the medicine is initiated or when a medicine dose is increased. Examples of medicines that exhibit predictable adverse effects include anticoagulants, which produce bleeding, cardiac glycosides, which produce cardiac dysrhythmias, and insulin, which produces hypoglycaemic coma. In most situations, adverse reactions arising from predictable effects are reversible by decreasing the dose or by changing to another medicine. In other situations, however, the effect can be fatal. Adverse drug reactions that are unrelated to the pharmacological action of the medicine are classified as unpredictable reactions. These reactions include those that are immunologically mediated, involve genetic differences in drug metabolism and whose underlying mechanism is not known. In this case, the onset of the adverse drug reaction is not related to the initiation of the medicine or the dose administered, and is often delayed. Examples of medicines that exhibit unpredictable effects include the sulfonamides, which are associated with generalised erythema multiforme (Stevens–Johnson syndrome), and chloramphenicol, which is associated with aplastic anaemia. As the adverse drug reactions arising from unpredictable effects are not directly related to a particular medicine, these reactions are more difficult to manage. Drug hypersensitivity reactions, which are immunologically mediated adverse effects, are described in Chapter 18. Medicine-related problems account for a large proportion of hospital admissions. Medicine-related problems account for as many as 3.6 per cent of all admissions to Australian hospitals. Furthermore, for older people the proportion is higher, constituting 15–21  per  cent of all admissions. Patients over the age of 65 years account for approximately 50  per  cent of all those admitted for medicine-related

causes. More specifically, studies have shown that adverse drug reactions occur in up to 30  per  cent of hospitalised patients. Clearly, the incidence of adverse drug reactions is a major concern for all health care professionals, and great care must be exercised to determine who is at risk of having an adverse drug reaction, the types of medicines that cause particular adverse drug reactions, and their management.

COMMON ADVERSE EFFECTS OF MEDICINES The following tables (11.1–11.20) identify the most common adverse reactions caused by medicines, with associated actions and rationales for management. The actions indicated are of a collaborative nature, which means they are performed in conjunction with all members of the health care team. Common drug groups causing adverse reactions are also indicated.

Respiratory depression Respiratory depression is a pattern of regular respirations with a rate of less than 12 breaths per minute in an adult. The respiratory centre regulates breathing, which functions as a coordinated unit in the medulla and pons. A decrease in respiration occurs when there is insufficient cerebral perfusion to activate the neurones of the respiratory centre, when changes in arterial carbon dioxide levels affect chemoreceptor responsiveness, or when neurone responsiveness to changes in arterial carbon dioxide levels is reduced. Medicines that commonly affect respiration are the central nervous system depressants.

Anaphylactic shock Anaphylactic shock is a dramatic acute reaction, characterised by respiratory distress, angio-oedema, cardiovascular collapse, vomiting and urticaria. It culminates as systemic shock and may lead to death (see Chapter  18 for a description of the pathophysiology). The cause of anaphylactic shock is administration of a sensitising medicine. The most common cause of anaphylaxis is penicillin, which affects approximately 4 in every 10 000 individuals. Penicillin allergy is more likely to occur in people with a familial history of atopic allergy.

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Table 11.1 Respiratory depression Common causes: narcotic analgesics, barbiturates, phenothiazines, general anaesthetics; any of these medicines when given with alcohol will compound the problem. ACTION

RATIONALE

(i)

(i)

Assess the rate of respiration (attempt to maintain above 12 breaths/minute for an adult). (ii) Auscultate the chest bilaterally for strength of respiration. (iii) Auscultate abnormal breath sounds (wheezing, crackles). (iv) Assess respiratory status regularly. Be prepared to provide respiratory support in mechanical ventilation and intubation if required. Position: (i) If person is conscious, place in a semi-Fowler’s position. (ii) If person is unconscious, place to one side, keep suction source connected and close at hand.

To determine effectiveness of intervening measures and to provide an evaluation of the current problem. (ii) To determine equal air entry on both sides. Central nervous system depression may lead to decreased strength of respiration. (iii) Wheezing is associated with decreased diameter of respiratory airways, while crackles occur with fluid in airways. Both conditions may accompany respiratory depression. (iv) Frequent observations are required to determine whether depression leads to apnoea. To prevent hypoxia and respiratory failure.

(i)

To facilitate manual chest expansion and ease of movement of lung muscle. (ii) To prevent aspiration of secretions.

If person is drowsy, assess neurological status by checking pupil size and reactivity, ability to obey commands, verbal response and orientation.

Allows evaluation of the degree of central nervous system depression.

Do not leave the person unattended. Keep the bed in the lowest position, with bed rails up.

A decreased level of consciousness can lead to physical injury.

If the cause is a suspected overdose from medicine misuse, attempt to determine the medicine(s) taken, how much, when and by what route. Check the person’s arms for track marks. Take blood and urine samples for drug identification.

Allows determination of the drug misuse and the best means of intervention.

If a narcotic analgesic is the cause, administer naloxone 0.4–2 mg IV, IM or SC to a max. of 10 mg (for narcotic overdose); or 0.1–0.2 mg IV at 2–3 minute intervals (for postoperative narcotic depression). Assess return of normal respiration and the onset of withdrawal symptoms in people with addiction problems.

Naloxone is a specific narcotic antagonist which reverses the toxic effects within a few minutes.

Obtain arterial blood gases and electrolyte levels as ordered.

Respiratory depression can manifest as a fall in blood oxygen and a rise in blood carbon dioxide. Allows monitoring of the effectiveness of therapy.

Oxygen by face mask/nasal prongs as ordered. If person has a past history of chronic obstructive pulmonary disease (COPD) (e.g. emphysema or chronic bronchitis), ensure inspired oxygen level does not exceed 24%.

To provide supplemental oxygen. A healthy person’s stimulus to breathe is elevated blood carbon dioxide levels, while the stimulus to breathe for a person with COPD is decreased blood oxygen levels.

CHAPTER 11 MANAGEMENT OF COMMON ADVERSE DRUG REACTIONS

Table 11.2 Anaphylactic shock Common causes: antibiotics, aspirin and other non-steroidal anti-inflammatory drugs, angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors, barbiturates, contrast media, transfused blood or blood products, snake/ spider antivenom, immunoglobulins. ACTION

RATIONALE

Identify the cause and if possible discontinue therapy.

Limits extent of anaphylactic reaction.

If response occurs during blood administration, discontinue the transfusion and replace with normal saline. Return the unused portion to the blood bank, take a blood sample from person’s other arm and send specimen to pathology.

Intravenous access can remain open and is readily available for emergency medicine administration. Blood specimen allows determination of a hypersensitivity reaction to a specific allergen.

Secure intravenous access as soon as possible.

Allows for rapid absorption of medicines that may need to be administered.

In cases where the cause cannot be removed (e.g. injection or ingestion of a medicine), measures are needed to reverse the effects of the mediator substances. (i) Mainstay of treatment, adrenaline, 10 μg/kg using 1:1000 solution IM, repeat every 5 minutes. Or adrenaline, 5 μg/kg using 1:1000 solution IV, repeat every 5 minutes. (ii) Antihistamine: promethazine, 25–50 mg IV. (vasodilation, bronchospasm). (iii) In severe cases, hydrocortisone, 5 mg/kg IV stat., 200 mg max.

(iv) Aerosol or nebulised short-acting β agonist.

(i)

To restore vascular tone and raise blood pressure.

(ii) To reverse the adverse effects of histamine. (iii) To reverse the effects of immune mediator substances and decrease capillary permeability and, hence, decrease shift from blood vessel to interstitial space. Note that antihistamines and corticosteroids have a delayed effect. They may help to reduce the duration of reaction and prevent relapse but they are supportive agents in the management of anaphylaxis and should not be used instead of adrenaline. (iv) To relieve bronchospasm.

Assess temperature, pulse (rate, rhythm, depth), respiration (rate and depth) and BP. Observe for drop in BP, rising and irregular pulse, increasing rate and depth of respiration and falling temperature.

Antibody–antigen reaction causes release of vasoactive substances, leading to massive vasodilation and decreased cardiac output and decreased peripheral vascular resistance. Histamine causes bronchoconstriction, leading to difficulty in and rapid breathing. Release of vasoactive substances also causes increased capillary permeability and subsequent shift of fluid from blood vessel into interstitial space. Pulse may be irregular from cardiac ischaemia.

Assess for chest pain (onset, intensity, duration).

Decreased peripheral vascular resistance leads to lowered diastolic BP and hence lowered coronary artery perfusion.

Assess peripheries for colour, warmth, pulses, oedema, moistness. Observe for pale or flushed, moist, cool skin. Take note of any macular or papular rashes.

Sympathetic nervous system causes blood to be shunted away from skin to vital organs. Increased sweat gland activity causes moistness and clamminess. Decreased cardiac output leads to lowered tissue perfusion. Shift of fluid from blood vessel to interstitial space causes oedema.

Auscultate chest: listen for equal air entry, wheezes, crackles. Check for manifestations of respiratory distress: flaring nares, downward movement of trachea, use of accessory muscles, orthopnoea.

Due to bronchoconstriction from histamine release. Progressive respiratory changes lead to interstitial oedema. continues

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Table 11.2 Anaphylactic shock (continued) ACTION

RATIONALE

Establish a patent airway: suction secretions, postural drainage, oral airway.

Assists in establishing access of air to respiratory passages.

Ensure adequate breathing: encourage coughing and deep breathing regularly. If respiratory muscles are fatigued and person hypoventilates, mechanical ventilation and intubation are indicated.

To ensure adequate ventilation and gaseous exchange.

Administer intravenous fluids as ordered: crystalloids (normal saline); colloids (Haemaccel, human albumin).

To replace volume lost in intravascular area (blood vessels).

Administer positive inotropic agents as ordered (e.g. adrenaline).

Contractility is usually decreased due to inadequate ventricular filling. The positive inotropic effect of adrenaline increases stroke volume and cardiac output.

Assess renal function. Insert an indwelling catheter for accurate urine measurement; accept levels of 30 mL/h or 0.5 mL/kg.

Decreased cardiac output leads to lowered perfusion of kidneys and decreased urine output.

Dizziness Dizziness is a sensation of imbalance or faintness, which is also associated with weakness, confusion and blurred or double vision. Episodes of dizziness are usually short,

with an abrupt or gradual onset. It is often aggravated by standing up quickly, and is improved by lying or sitting down. Dizziness results from an inadequate or irregular blood flow to the brain and spinal cord.

Table 11.3 Dizziness Common causes: central nervous system depressants, narcotic analgesics, decongestants, antihistamines, antihypertensives, hypertensives, vasodilators. ACTION

RATIONALE

Assess frequency, intensity, onset and duration of dizziness. Assess associated manifestations: headache, vertigo, drowsiness, blurred vision; aggravating factors: stooping over, standing up quickly; and alleviating factors: lying down, rest.

To determine the severity of condition and effectiveness of interventions.

Assess vital signs, especially an elevated or a lowered BP. Take lying, standing and sitting BP.

Excessive vasoconstriction leads to an increase in peripheral vascular resistance and thus dizziness. A drop in systolic or diastolic pressure of >10–20 mm Hg between position changes suggests postural hypotension.

Assess level of consciousness, motor sensory functions, reflexes, pupil size and reactivity.

Dizziness may be associated with a decreased blood supply to the brain.

Assess level of emotional stress, irritability, anxiety, insomnia and inability to concentrate.

Anxiety can produce continuous dizziness, which may result from inadequate blood flow and oxygen supply to the brain and spinal cord.

Institute measures that help the person cope with stress and anxiety (e.g. relaxation and distraction therapy).

Assists in maintaining blood flow to the brain.

If dizziness is experienced in an upright position, advise the person to lie down, rest for a while, and then to rise very slowly.

This allows opportunity for the baroreceptors and chemoreceptors to become accustomed to changes in position.

Ensure the person wears clothes that are not constricting around the neck. Encourage the person to turn the head and body together, rather than just the head alone.

This prevents compression of the carotid arteries and promotes central blood flow.

Accompany the person during ambulation. Provide with a walking aid if needed.

To prevent physical injury.

CHAPTER 11 MANAGEMENT OF COMMON ADVERSE DRUG REACTIONS

Constipation

Hypertension

Constipation involves infrequent and difficult bowel movements. Normal bowel movements vary quite widely between individuals. It is, therefore, important to determine the problem in relation to the individual’s particular pattern. The autonomic nervous system is responsible for controlling bowel movements by sensing rectal distension from the presence of faeces, and by relaxing the external rectal sphincters. If untreated, constipation may lead to a lack of appetite and abdominal discomfort.

Blood pressure relates to the force exerted on the blood vessels, and is affected by cardiac output, peripheral vascular resistance and blood volume. Raised blood pressure generally involves a sustained increase above 140/90  mm  Hg. With sustained hypertension, arterial walls become thickened, less elastic and resistant to adequate blood flow. Individuals with hypertension may be asymptomatic or experience headaches (especially on awakening), tinnitus, lightheadedness, fatigue and palpitations.

Table 11.4 Constipation Common causes: narcotic analgesics, antacids containing aluminium or calcium, antimuscarinics, tricyclic antidepressants, excessive use of laxatives. ACTION

RATIONALE

Assess the size, consistency and frequency of bowel motions. Inspect the abdomen for distension and auscultate for bowel sounds. Percuss all four quadrants and gently palpate for abdominal tenderness.

To determine the extent of bowel activity and severity of the problem.

Assess the person’s level of mobility and stress. Encourage graded activities and introduce regimens aimed at promoting relaxation. If the person is bed-bound, reposition at least every two hours and encourage active and passive exercises.

Acute emotional stress creates a sympathetic response, leading to decreased intestinal mobility. Infrequent activity leads to decreased peristalsis.

Ensure the diet contains a lot of high-fibre foods (e.g. fresh vegetables and fruit) and an adequate fluid intake.

High-fibre foods and fluids will shorten intestinal transit time and promote ease of defecation.

Caution the person not to strain during defecation.

To prevent injury to recto-anal tissue.

If the person has not opened bowels for a number of days, the health professional should perform a per rectal (pr) examination using a disposable glove and lubricant. Laxatives or enemas may be required, as ordered.

This will remove impacted faecal contents and determine the extent of the problem. Laxatives and enemas mobilise faecal contents, allowing greater ease of defecation.

Table 11.5 Hypertension Common causes: sympathomimetics, corticosteroids, oral contraceptives, monoamine oxidase inhibitors, central nervous system stimulants. ACTION

RATIONALE

Monitor BP regularly and assess for changes in HR/pulse (usually tachycardia >100 beats/min).

To determine the effectiveness of therapy. If BP is consistently above 140/90 mm Hg, further therapy may be required.

Monitor for associated clinical manifestations: headache, epistaxis, visual disturbances, neck vein distension, peripheral oedema.

Inappropriate vasoconstriction leads to signs of increased peripheral vascular resistance.

If BP remains consistently high, appropriate forms of treatment should be administered (e.g. α-adrenoreceptor antagonists, calcium antagonists, angiotensin-converting enzyme inhibitors).

BP reading consistently below 140/90 mm Hg demonstrates effectiveness of treatment.

continues

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Table 11.5 Hypertension (continued) ACTION

RATIONALE

Encourage the person not to drink large amounts of fluid (e.g. not >1.5 L/day) and to avoid added salt in food.

Fluid and salt raise blood volume and potentiate any rise in BP.

Encourage stress-alleviating measures: relaxation exercises, massage.

Stress stimulates the sympathetic nervous system, aggravating rises in BP.

Encourage adequate bedrest. Elevate head of bed.

Promotes drainage of fluid via gravity away from the brain.

Over-the-counter preparations, such as cough and cold medicines, must be approved by the person’s doctor prior to use.

Several of these preparations contain sympathomimetics, which may raise BP.

Hypotension Low blood pressure means inadequate blood pressure to oxygenate the body tissues. Although low blood pressure varies among individuals, a reading below 90/60  mm  Hg or a drop of 30 mm Hg from the baseline level is classified

as low blood pressure. Low blood pressure can occur from an expanded intravascular area within blood vessels, such as vasodilation; reduced intravascular volume, such as dehydration and severe bleeding; or decreased cardiac output, such as cardiac failure and dysrhythmias.

Table 11.6 Hypotension Common causes: calcium channel blockers, diuretics, antihypertensives, general anaesthetics, narcotic analgesics, monoamine oxidase inhibitors, benzodiazepines, antipsychotic agents, antidysrhythmics, contrast media. ACTION

RATIONALE

Assess vital signs regularly: BP for hypotension, HR (pulse) for tachycardia, respirations for tachypnoea. If dizziness or fainting occurs when person stands suddenly, compare readings when person is lying, sitting and standing.

These manifestations may relate to myocardial shock created by low cardiac output and require immediate intervention. A drop in systolic or diastolic pressure of at least 10–20 mm Hg between position changes suggests postural hypotension.

Check person’s BP regularly. If BP drop is constant and 38.5 °C.

Prevent the hypothalamus from synthesising prostaglandin E, inhibiting the set point of temperature from rising further.

Keep room temperature at 18 °C–20 °C unless shivering develops. Aim to provide cool, circulating air. Maintain light clothing and bedclothes. Ensure not to induce chills.

Assists in stabilising body temperature through conduction and radiation.

Provide dry clothes and bed linen. Change as often as required.

To increase heat loss through conduction and convection.

Provide at least 3000 mL fluids daily. Input must exceed output. Measure input/output on a fluid balance chart.

To replace fluids lost through insensible water loss and sweating, and to ensure a positive balance is maintained.

Maintain strict oral hygiene every 2 hours (e.g. mouth rinse, clean teeth/dentures).

Oral mucosal membranes are easily dried through dehydration.

Encourage well-balanced meals (e.g. high complex carbohydrate and high energy).

To meet the increased metabolic needs that occur with fever.

Use of thermo-regulating blanket underneath bottom bed sheet.

This device provides continuous circulating cool water through conduction and radiation.

CHAPTER 11 MANAGEMENT OF COMMON ADVERSE DRUG REACTIONS

Photophobia

Stomatitis

Photophobia is an abnormal sensitivity to light. Many medicines produce photophobia via ocular dilation and reduction in aqueous humour drainage.

Stomatitis is characterised by recurrent, painful ulcerations of the oral mucosa, often involving the gingiva, hard palate and top of tongue. Medicines can cause this effect by direct activity on the mucosa or by an allergic reaction.

Table 11.13 Photophobia Common causes: mydriatics, ophthalmic viral medicines. ACTION

RATIONALE

Ask person whether eye pain is present, and to describe its location, duration and intensity. Discontinue medicine if eye pain occurs.

Mydriatics reduce aqueous humour drainage and are contraindicated in people with glaucoma as they may cause an abrupt rise in intraocular pressure.

Examine pupils regularly following administration into eye. Assess other changes such as blurred vision and tearing. Examine the conjunctiva and sclera, noting their colour. Characterise the amount and consistency of discharge.

To evaluate the effectiveness and duration of drug therapy. Mydriatics typically accommodate for distant vision.

Darken the room and avoid individual contact with bright lights. If discomfort continues, encourage person to close eyes or to wear dark glasses. Discourage television and reading after administration of mydriatics.

Dilated pupils are unable to constrict in response to light, leading to eye discomfort.

Table 11.14 Stomatitis Common causes: anticancer medicines, radiation therapy, penicillins, sulfonamides, quinine, streptomycin, phenytoin, aspirin, gold salts, barbiturates. ACTION

RATIONALE

Assess the lesion: determine onset, pain, odour, discharge. Note the lesion site and character. Examine the tongue, buccal mucosa, gums and upper/lower lips for colour, texture and contour. Inspect teeth and gums, recording missing, broken and discoloured teeth, and debris. Note also bleeding, inflamed, swollen and discoloured gums. Assess also for signs of infection: inflammation, pain and discharge.

Determines effectiveness of measures implemented. Oral impairment provides a portal of entry for microorganisms.

Maintain a strict oral hygiene regimen after every meal (e.g. saline rinses, dilute hydrogen peroxide rinses, use of a soft toothbrush or mouth swab). Avoid mouth rinses that contain alcohol.

These prophylactic measures prevent infection. Alcoholcontaining mouth rinses dry out the mouth and may cause pain on contact with lesions.

Encourage a bland diet. Instruct the person to avoid spicy foods, citrus fruits and alcohol.

These can irritate the condition, leading to pain and loss of appetite.

Assist the person in avoiding stress and anxiety through relaxation, distraction therapy and quiet environment.

Stress- and anxiety-provoking situations can aggravate the condition and delay healing.

Topical anaesthetics such as lignocaine or benzocaine preparations can be massaged into the affected areas, as ordered.

These local anaesthetics provide temporary pain relief.

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Diarrhoea

Anogenital candidiasis

Diarrhoea is an increase in the frequency and fluidity of bowel motions compared with the individual’s normal bowel habits. Given the fluid and electrolyte imbalances that occur with severe diarrhoea, it is important to protect against life-threatening dysrhythmias and hypovolaemic shock. Diarrhoea may result from ingestion of poorly absorbed material, such as bulk-forming laxatives; local lymphatic or venous obstruction; stimulation of mucosal, intracellular enzymes; decreased integrity of the small intestinal mucosal wall or increased intestinal motility.

Anogenital candidiasis is a mild, superficial fungal infection caused by Candida species, affecting the vaginal, anal or penile areas. The infection is caused by an overgrowth of the fungus, which can lead to a white or yellow discharge, pruritus, excoriation and inflammation.

Vomiting Vomiting is the expulsion of gastric contents by the mouth, and results from the coordinated contraction of abdominal muscles and reverse oesophageal peristalsis. Medicines can cause vomiting by irritating the gastric intestinal mucosa or by stimulating the vomiting centre in the medulla oblongata.

Table 11.15 Diarrhoea Common causes: several antibiotics; antacids containing magnesium; colchicine; allopurinol, lactulose, laxative overuse, ethacrynic acid, digoxin (high dose), methotrexate, nasogastric/enteric feeds. ACTION

RATIONALE

Assess hydration status: check skin turgor, mucous membranes, urine output, BP (lying, standing, sitting). Assess abdomen: inspect for distension, palpate for tenderness, auscultate bowel sounds. Characterise the onset, frequency, amount and intensity of diarrhoea. Submit a faecal specimen for microbiology and culture. Explore any associated complaints such as nausea, vomiting, abdominal pain, anorexia, weight loss, excessive belching and bloating.

To determine severity of the condition, to diagnose the causative agent and prevent the onset of hypovolaemic shock.

Ensure the person’s privacy during defecation. Empty pans promptly.

To maintain people’s dignity and avoid embarrassment.

Advise the person to avoid spicy and high-fibre foods (e.g. fruit and vegetables), caffeine and fat products (e.g. milk and butter). Organise smaller, more frequent meals.

To promote ease of digestion and to prevent incidence of excess osmotic load in the small intestine.

Cleanse the perineum thoroughly and promptly. Offer pans regularly. Avoid the use of a rectal tube unless the diarrhoea is extremely severe despite conservative measures.

To prevent the breakdown of skin. A rectal tube is extremely uncomfortable for a conscious person and may cause recto-anal trauma if inserted incorrectly.

Maintain an accurate input/output record on a fluid balance chart. Ensure person remains in a positive or at least even balance. Encourage oral fluids (at least 2 L/day) and administer intravenous fluids as ordered.

To monitor the effects of dehydration and prevent the person becoming dehydrated.

Antidiarrhoeal medicines such as loperamide may be required, as ordered.

To slow gut peristalsis.

If the person is receiving nasogastric/enteric feeds, slow down the rate. Monitor nasogastric aspirate every 4 hours.

Slowing the rate of feed will facilitate a more acceptable absorption.

CHAPTER 11 MANAGEMENT OF COMMON ADVERSE DRUG REACTIONS

Table 11.16 Anogenital candidiasis Common causes: see Table 11.7, also oral contraceptives, other oestrogen-containing preparations. ACTION

RATIONALE

(i) Female person: Identify the onset, colour, consistency, odour, and the texture of vaginal discharge. Determine how the discharge differs from the usual vaginal secretions and whether onset relates to the menstrual cycle. Ask about associated manifestations such as dysuria, perineal pruritus and burning. Examine the external genitalia, observe the vulvar and vaginal tissues for redness, oedema and excoriation. (ii) Male person: Examine the anogenital area for erythematous, weepy, round lesions. These are often present under the prepuce. Note the location, size, colour and pattern of the lesions. Ask about associated manifestations such as dysuria, perineal pruritus and burning.

Observations determine the course of infection and the effectiveness of interventions.

Instruct the person to wear loose-fitting clothes, cotton underwear, and to avoid nylon underwear and tight clothes.

Moist, warm environments created by tight clothes and nylon underwear encourage the growth of Candida albicans.

Instruct the person on the use of antifungal vaginal pessaries/cream (for women) and cream (for men). Preparations are usually applied/inserted at bedtime. Sexual partners would also need to be treated. Advise the person to take prescribed medicine even if the symptoms clear or, in the case of a woman, menstruation occurs. Advise the person to avoid intercourse until the symptoms clear, and thereafter to have the male partner use condoms until the course of medicine is completed.

These measures prevent the chance of reinfection.

Advise salt baths twice daily.

To relieve itchiness.

Table 11.17 Vomiting Common causes: as described for nausea in Table 11.10. ACTION

RATIONALE

Characterise the onset, frequency and intensity of vomiting. Collect and measure resultant vomitus. Explore any associated complaints such as nausea, abdominal pain, anorexia, weight loss, changes in bowel habits, excessive belching and bloating.

To determine the severity of the condition. It is important to diagnose the underlying cause, as antiemetics will provide only symptomatic relief.

Monitor vital signs, input/output, and clinical manifestations of dehydration (e.g. decreased skin turgor, dry mucous membranes, decreased urine output, cool skin).

To determine the onset of dehydration, which can occur with severe vomiting.

Ensure the person maintains an adequate intake of fluids; aim to maintain an even or slightly positive fluid balance.

To prevent onset of dehydration.

If vomiting continues, obtain blood tests as ordered to determine fluid, electrolyte and acid–base balance.

Prolonged vomiting can lead to dehydration, electrolyte imbalance and metabolic acidosis.

If vomiting is caused by: (i) Theophylline or digoxin, take a blood specimen to determine blood levels. (ii) Narcotic analgesics, this will generally subside with continuous administration.

(i) Toxic levels of theophylline or digoxin can lead to vomiting. (ii) Stimulation of the chemoreceptor trigger zone to produce nausea and vomiting is only a transient effect.

Elevate the person’s head or position on the left side.

To prevent aspiration of vomitus.

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Blistering

Photosensitivity

A blister is a small, thin-walled raised vesicle containing clear, serous, purulent or bloody fluid. Medicines may produce this effect as a result of an allergic or immunosuppressant reaction.

Photosensitivity is an increased reactivity to sunlight. Brief exposure to sunlight or an ultraviolet lamp may lead to urticaria, oedema, papules or burns.

Table 11.18 Blistering Common causes: antibiotics, allopurinol, aspirin, barbiturates, anticancer agents, hypoglycaemic agents, gold salts, phenytoin, phenolphthalein. ACTION

RATIONALE

Inspect the distribution of blisters, noting their exact location, colour, shape and size. Observe for the presence of crusts, scales, macules, papules, weals and scars.

Determines the severity and nature of the condition, and allows evaluation of the effectiveness of measures implemented.

Ensure fluid status is well maintained. If necessary, commence intravenous administration.

Blisters that cover a large area can cause substantial fluid and electrolyte loss through weeping lesions.

Keep the environment warm. Cover the person with blankets as necessary.

Warmth may be lost through breaks in the skin barrier caused by the blisters.

Obtain swabs for microbiology and culture as ordered, if the temperature is >38.5 °C or if purulent exudate and swelling are present. Report the presence of a secondary infection to the health professional.

Infection occurs easily due to loss of the protective skin barrier. Increased inflammation and the immune response lead to hyperthermia.

Instruct the person to wash hands regularly and not to touch the lesions.

Burst blisters are predisposed to infection through the exposure of denuded skin.

Cover blistered area with occlusive dressing or non-adhesive covering (e.g. Melonin, Op-site).

Provides artificial barrier to area, protecting it against infection.

Apply antimicrobial cream to the area (e.g. silver sulfadiazine cream) prophylactically and therapeutically. Give systemic antibiotics according to the results of skin cultures.

To prevent and treat infection. Silver sulfadiazine acts as a bactericidal against several Gram-positive and Gram-negative organisms.

Table 11.19 Photosensitivity Common causes: antineoplastic agents, phenothiazines, nalidixic acid, griseofulvin, quinine, chloroquine, tetracyclines, tricyclic antidepressants, antihistamines, thiazide diuretics, loop diuretics, carbonic anhydrase inhibitors, sulfonamides, oral contraceptives, dantrolene, vitamin A derivatives, clofibrate, carbamazepine, non-steroidal anti-inflammatory drugs. ACTION

RATIONALE

Assess sunburn that develops after sun exposure, such as blisters, red skin, pain, or discomfort over the skin surface.

Determines severity and nature of reaction to the sun, and allows for evaluation of effectiveness of measures implemented.

Limit outdoor activities during peak ultraviolet exposure between about 10 am and 3 pm.

This is the warmest part of the day and has the potential to cause the severest effects.

When outside, advise the person to wear a wide-brimmed hat, also a long-sleeved shirt or jacket and long pants. Ensure feet remain covered.

It is important that the person wears clothes and shoes that will maintain maximum protection from the sun. A hat also protects the face from exposure.

Advise the person to wear a sunblock with maximum protection (sun protection factor 30+). Ensure sunblock is applied to exposed skin surfaces and the application is repeated every 1–2 hours.

Sunblock provides protection against the sun’s ultraviolet rays. Regular application is required to maintain effectiveness of sunblock.

CHAPTER 11 MANAGEMENT OF COMMON ADVERSE DRUG REACTIONS

Postural hypotension Postural hypotension is an abnormally low blood pressure that occurs when an individual takes a standing position.

It is often associated with medicines that block the α adrenoreceptors.

Table 11.20 Postural hypotension Common causes: sympatholytics (α-blockers, β-blockers), phenothiazines, antihypertensives, diuretics, insulin, monoamine oxidase inhibitors, narcotic analgesics, nitrates, sildenafil, vasodilators, vincristine. ACTION

RATIONALE

Assess for dizziness, light-headedness, weakness and fainting. Postural hypotension occurs with a fall of systolic BP between 10–20 mm Hg within three minutes of standing.

Determines severity of problem and allows evaluation of the effectiveness of measures implemented.

Advise the person to tighten calf muscles regularly while standing or to walk on the spot.

This promotes blood circulation around the body and facilitates brain perfusion.

Instruct the person to consider sitting rather than standing, if possible.

Standing requires greater effort for the body to pump blood to the head.

Advise the person to move slowly from a lying to sitting or standing position, also to hold onto something while moving from a lying to sitting or standing position.

Allows body to bring regulatory mechanisms into play in adjusting to changes in blood pressure. Holding onto an object while moving provides support and prevents falls.

Advise the person to avoid the use of alcohol.

Alcohol causes dehydration and therefore may lower blood volume.

Encourage the person to maintain an adequate fluid intake, especially if sweating profusely.

To avoid dehydration, which may decrease blood volume.

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CHAPTER REVIEW ■■ ■■

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Adverse drug reactions are undesirable effects that occur with the administration of medicines at normal doses. Adverse drug reactions can occur as a part of the normal pharmacological profile of the particular medicine (type A reactions) or they may be unrelated to the medicine (type B reactions). When a reaction is part of the pharmacological profile of the medicine, it is known as a predictable effect. Predictable effects take place soon after the medicine is initiated or when a medicine dose is increased. Adverse drug reactions that are unrelated to the pharmacological action of the medicine are classified as unpredictable reactions. Unpredictable reactions include those that are immunologically mediated effects, involve genetic differences in drug metabolism or whose underlying mechanism is not known.

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Unpredictable reactions are more difficult to manage than predictable reactions.

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Drug-related problems account for a large proportion of hospital admissions.

REVIEW QUESTIONS 1

Chui Yuit Ming, a 60-year-old woman with severe peripheral vascular disease, returns from theatre following a femoro-popliteal bypass operation. She has been placed on an epidural infusion containing bupivacaine for analgesic relief. On performing her vital signs, her respiration rate has dropped from 16 to 10 breaths per minute over one hour. What would you suspect? What would you do?

2

Marissa Bombaso, a person admitted for severe anaemia, is cross-matched for two units of packed cells. During the first hour of the blood transfusion, you notice her oral temperature rises to 38 °C. What would you do?

3

After one week of receiving digoxin therapy for advanced chronic heart failure and atrial fibrillation, Madga Borishev complains of diarrhoea and feeling very nauseated. What would you suspect? What would you do?

4

Jane Blake, who has asthma, is ordered timolol eye drops to treat acute closed-angle glaucoma. What is the problem associated with this order?

5

John Hall, a 45-year-old man, has been ordered sulfamethoxazole and trimethoprim (co-trimoxazole) tablets over a 21-day period to treat a mild Pneumocystis jiroveci pneumonia infection. What counselling would you offer Mr Hall in reducing the risk of photosensitivity?

6

Joe Bombardario, a 75-year-old man with a past history of hypertension, has been ordered irbesartan (an angiotensin II antagonist) 150 mg each morning and perindopril (an angiotensin-converting enzyme inhibitor) 4 mg each morning. He complains to the doctor of experiencing dizziness and visual disturbances after standing up from a lying position. What problem is the patient experiencing? Explain the mechanism of this problem. (See Chapter 46 for further assistance.)

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KEY TERMS

After completing this chapter, you should be able to:

Absolute risk

1

Describe the difference between relative and absolute risk.

2

Describe how to perform calculations for relative risk, absolute risk and number needed to treat.

3

Describe strategies for communicating risks and benefits about medicines to individuals.

Absolute risk reduction Benefit Informed decisionmaking Number needed to treat

Population absolute risk Relative risk Relative risk reduction Risk communication Risk difference

All medicines have risks and benefits. When health professionals make clinical decisions involving medicines, the issue arises of whether the benefits exceed the risks. There has been a substantial growth in the knowledge about risk factors associated with ill health. However, the full benefits of medicines can be gained only if health professionals can communicate this knowledge effectively and individuals are willing and able to use it in their medicine decisions. For example, aspirin can prevent serious vascular events, such as myocardial infarction, embolic stroke or vascular death. However, aspirin may also cause major extracranial bleeding or haemorrhagic stroke. It is contraindicated in people with a history of intracranial haemorrhage, recent or active peptic ulcer disease, allergy to aspirin or a bleeding disorder. Health professionals need to consider the benefits and risks of treatment, coupled with the person’s demographic background, when making an informed decision about whether to prescribe aspirin. People need to be able to evaluate the information conveyed about aspirin and to decide how to incorporate it in their medicine regimen. When individuals follow a particular course of drug therapy, they are influenced by their social context. For example, the social context affects the relevance of the information and the extent

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to which individuals trust the source of information. The social context is defined as the environmental aspects that affect the person, which include family and community support systems, and collaboration between these support systems, language difficulties, cultural traditions, individual values, access to information resources and the impact of media reports. Consequently, health professionals need to consider the social context when talking to people about risks and benefits associated with their medicines. Risk communication is defined as the ability to talk effectively about risks and benefits of medicines between consumers and health professionals. In practice, risk communication involves a wide array of terms that may confuse not only the person to whom it is directed but also the health professionals trying to convey this information. It is important that health professionals have a good understanding of the various ways in which medicine risks and benefits are measured. They then will be in a better position to convey these reasons more clearly to people. It will also ensure that an evidence-based approach is applied to the prescribing process. Health professionals need to be able to understand and interpret a number of measurements relating to risks and benefits. These measurements include: relative risk, absolute risk (or risk difference), population absolute risk, risk reduction or increase in terms of absolute and relative risk, and the number needed to treat. These terms are defined and explained with reference to drug examples.

RISK In relation to drug therapy, the basic measure of risk is the incidence of an adverse event. For example, the medicines of interest could be the angiotensin converting enzyme (ACE) inhibitors captopril and enalapril, and the adverse event measured is the incidence of elevated bilirubin levels after one year of treatment. If it is found that the incidence of elevated bilirubin levels is 35  patients out of a total of 1000 patients receiving captopril after one year of treatment, then the risk is 3.5  per  cent. If the incidence of elevated bilirubin levels is 20 patients out of a total of 1000 patients receiving enalapril, then the risk is 2 per cent. By definition, therefore, risk is the incidence of an adverse event in a defined population over a specific period of time divided by the population at risk for the adverse event over a specific period of time. The population at risk is the total number of people who take the medicine. Some of these people will develop the adverse event, while others will not.

RELATIVE RISK Risk is associated with the incidence of an adverse event in one population group for one medicine. Relative risk is an extension of risk, in that it compares the risk of an adverse event in one group of individuals for a particular

medicine to the risk of an adverse event for another group of individuals not receiving the medicine. We can then answer the question: how many times are people who take a particular medicine more likely to have the adverse event than those who do not take this particular medicine? The relative risk is defined as the ratio of the incidence of the adverse event in those individuals who take the medicine to the incidence of the adverse event in those who do not take the medicine. As one example, the medicine of interest to determine relative risk could be aspirin. If, when aspirin is taken, the incidence of the adverse event relating to gastrointestinal bleeding is found to be 50 out of a total of 1000  patients in one year, then the risk is 5  per  cent. In another group where aspirin is not taken, the incidence of the adverse event relating to gastrointestinal bleeding is 25 out of a total of 1000 patients in one year, and the risk is therefore 2.5 per cent. The relative risk is the ratio of the incidence of adverse events between the group of individuals who take aspirin compared with the group of individuals who do not take aspirin—that is, 5% ÷ 2.5% = 2. We can also look at clopidogrel as another example to explore relative risk. This is an antiplatelet agent used to prevent vascular ischaemic events. If a research study shows that when clopidogrel is taken, the incidence of adverse events relating to intracranial bleeding is 4  out of a total

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of 1000 patients in one year, the risk is 0.4 per cent. If the same research study shows that in another group of patients where clopidogrel is not taken, the incidence of adverse events relating to intracranial bleeding is 2 out of a total of 1000 patients in one year, then the risk is 0.2 per cent. The relative risk is the ratio of the incidence of adverse events between the group of individuals who take clopidogrel compared with the group of individuals who do not take clopidogrel—that is, 0.4% ÷ 0.2% = 2. A value of 1 means there is no difference in the relative risk between the two groups. It is important to be aware that the relative risk does not tell us anything about the absolute risk or the incidence of adverse events in either group. The idea of relative risk can be further illustrated by using two hypothetical examples (see Table 12.1). The population absolute risk is calculated by multiplying the absolute risk for the incidence of an adverse event by the prevalence of use of the medicine in the population. It gives an indication of how common the adverse event will be in the whole population. Thus, there are 0.15 additional adverse events of postural hypotension per 1000 patients in individuals taking medicine B compared with medicine A (Table 12.2). While this difference may not seem very great, it becomes significant when it is considered within the context of the total population. For example, in Australia, with a population of about 23 000 000, there would be an extra 3300  additional adverse events of postural hypotension per year in patients using medicine  B rather than medicine A.

Table 12.1 Determination of relative risk EXAMPLE 1 Medication A (medication taken) incidence of adverse event relating to postural hypotension = 50 per 1000 patients per year (5%). Medication A (medication not taken) incidence of adverse event relating to postural hypotension = 20 per 1000 patients per year (2%). ⇒ Relative risk = 5%/2% = 2.5. EXAMPLE 2 Medication B (medication taken) incidence of adverse event relating to postural hypotension = 25 per 1000 patients per year (2.5%). Medication B (medication not taken) incidence of adverse event relating to postural hypotension = 10 per 1000 patients per year (1%). ⇒ Relative risk = 2.5%/1% = 2.5.

ABSOLUTE RISK (RISK DIFFERENCE) In the two hypothetical examples presented in Table 12.1, the relative risk is the same for medicine A and medicine B. However, the absolute risk profile for each medicine is different. For medicine  A, there will be an additional 30  adverse events of postural hypotension for every 1000 patients who are treated with medicine A compared with those not treated with this medicine. For medicine B, there will be only an additional 15  adverse events of postural hypotension for 1000  patients who are treated with medicine B compared with those not treated with this medicine. Due to the problems associated with relative risk, a more useful measurement to employ is the absolute risk. This measurement is also known as the risk difference. The incidence of the event may lead to an absolute risk reduction or an absolute risk increase, depending on whether the medicine decreases or increases the risk of an event occurring. Absolute risk answers the question: what is the additional risk of adverse events in individuals taking a specific medicine over and above the risk experienced by individuals who are not taking that specific medicine? The absolute risk is, therefore, defined as the difference between the incidence of the adverse event for those individuals who take the medicine and the incidence of the adverse event for those individuals who do not take the medicine. By referring to the hypothetical examples in Table  12.1, the absolute risk for medicine  A is 30  adverse events of postural hypotension per 1000  patients for one year, while for medicine  B the absolute risk is 15  adverse events per 1000 patients each year.

POPULATION ABSOLUTE RISK For decision-makers who are responsible for making health care policies at the government level, such as managers of the Australian Pharmaceutical Benefits Scheme, the population absolute risk is an important measurement to consider. This parameter takes into account the risk of the medicine as well as the prevalence of the medicine’s use in the population. It answers the question: how much does a specific medicine contribute to the overall risk of an adverse event in the total population rather than just in individuals? The parameter, therefore, addresses the percentage of the population that is taking the medicine. The way in which population absolute risk is determined can be illustrated by considering the two hypothetical examples in Table 12.1 again. For medicine A the absolute

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risk is 30  adverse events per 1000  patients per year, and for medicine  B the absolute risk is 15  adverse events per 1000  patients per year. If the prevalence of use for medicine A is 2 per cent and for medicine B is 5 per cent, we can calculate the population absolute risk (see Table 12.2). The population absolute risk becomes an important issue if the prevalence of use for a medicine is increased. For example, the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors or statins are currently available in Australia as a restricted item on the Pharmaceutical Benefits Scheme. If this group of medicines becomes available over the counter, an absolute risk that is quite small, such as myopathy, could develop into a significant population absolute risk. For instance, if the absolute risk of the incidence of myopathy was found to be 5 adverse events per 1000 patients per year and the prevalence rate for use was 2  per  cent (0.02), then the number of adverse events would be 0.1 adverse events per 1000 patients per year (e.g. 5 × 0.02). However, if the statins became available over the counter and the prevalence rate for use rose to 50 per cent (0.5), then the number of adverse events for myopathy would rise to 2.5  adverse events per 1000  patients per year (e.g.  5  ×  0.5), which is quite a significant result. Table 12.2 Determination of the population

absolute risk

Medication A Absolute risk of 30 adverse events of postural hypotension per 1000 patients per year × 2% (0.02) = 0.6 adverse events per 1000 patients per year. Medication B Absolute risk of 15 adverse events of postural hypotension per 1000 patients per year × 5% (0.05) = 0.75 adverse events per 1000 patients per year.

RELATIVE RISK REDUCTION VERSUS ABSOLUTE RISK REDUCTION In determining the benefits of treatment using a specific medicine, pharmacologists and epidemiologists tend to consider the incidence of a particular outcome event rather than the risk of an adverse event caused by a medicine. An outcome event is, therefore, defined as a disease process. Pharmacologists and epidemiologists want to find out about the benefits of particular medicines in preventing a disease process from happening. Common examples of outcome events are myocardial infarction, colorectal cancer, stroke, an osteoporotic fracture or death. Two measurements are used to determine the clinical benefits of drug therapy—relative risk reduction and absolute risk reduction. Relative risk reduction is the reduction in the incidence of outcome events achieved by a medicine in individuals who take the medicine, expressed as a proportion of the incidence in individuals who do not take the medicine. The absolute risk reduction is the difference in the incidence of outcome events between individuals who take the medicine and individuals who do not take the medicine. For example, a clinical trial conducted by a team of pharmacologists and epidemiologists has 1000  patients each in the treatment group (individuals who take the medicine) and the control group (individuals who do not take the medicine). The research team finds there are 25 and 50 outcome events in each group respectively at the end of a one-year study. It is possible, therefore, to determine the event incidence and the level of benefit for each group (see Table 12.3). The figure obtained by calculating relative risk reduction obviously seems more impressive than that

Table 12.3 Determination of relative risk reduction and absolute risk reduction If there were 25 outcome events in the treatment group and 50 outcome events in the control group, then the event incidence is 2.5 per cent for the treatment group and 5 per cent for the control group. The benefit to patients could be expressed as a relative risk reduction or an absolute risk reduction. To calculate the relative risk reduction, the result will be: (No. of outcome events in patients who take the medication – No. of outcome events in patients who do not take the medication) ÷ (No. of outcome events in patients who do not take the medication) Thus, in the example here, the relative risk reduction is (25 – 50) ÷ 50 = –25 ÷ 50 = 0.5. This ratio expressed as a percentage is therefore 50%. The absolute risk reduction is the difference between the outcome event incidences of both groups—that is: 5% – 2.5% = 2.5%.

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obtained by calculating the absolute risk reduction. It is important to note, however, that the absolute risk reduction is the more accurate figure because it is more dependent on the incidence of the outcome event. On the other hand, the relative risk reduction will either overestimate or underestimate the absolute impact of medicine when the outcome event is very rare or very common respectively. As tight legal regulations, and ethical and standardised research guidelines, direct human testing of medicines, we often deal with outcome events that are quite rare. We tend to see the relative risk reduction overestimate the absolute impact of a medicine. It is always better, therefore, to consider the absolute risk reduction calculation when making decisions about a medicine’s benefits. We can then make predictions about how many patients are likely to benefit using a particular medicine. Consider the data again: of the 1000 untreated patients, 50  will have outcome events, and of the 1000  treated patients, 25 will have outcome events. Hence, treating the patients with the medicine has saved 25  outcome events. This number equates to 2.5 events for every 100 patients or, alternatively, 1  patient in every 40  patients. The question that needs to be asked at this point is: should we be treating 40 patients to benefit 1 patient?

NUMBER NEEDED TO TREAT The number needed to treat helps us determine how many patients need to receive the medicine to enable one patient to benefit over a given time period. This measurement is calculated by taking the reciprocal (or inverse) of the absolute risk reduction for one patient. Thus, if a medicine has an absolute risk reduction of 2.5 events for 100 patients, this figure equates to 0.025 events for 1 patient. To calculate the number needed to treat, note that the absolute risk reduction figure must be expressed as the actual number, not as a percentage. If the percentage is used, an incorrect figure for the number needed to treat will result. You can easily convert the actual number from the percentage by moving the decimal point two places to the left. The number needed to treat is therefore 1 ÷ 0.025 = 40 patients. It is important to note that the number needed to treat will be different for different patient populations, depending on their baseline risk for developing the outcome of interest. The number needed to treat for those at a higher risk will be smaller than for those at lower absolute risk. We can illustrate how to calculate the number needed to treat by using examples from an actual research study. The landmark Heart Protection Study published in The Lancet in 2002 involved 20 536 patients at high cardiovascular risk.

These patients who had a history of angina or myocardial infarction were treated with either the statin, simvastatin, at a dose of 40 mg daily, or with a placebo medicine over a five-year period. Compared with placebo, the absolute risk reduction obtained for prevention of any death by simvastatin was 1.8 per cent. Thus, the number needed to treat was 1 ÷ 0.018 = 56. This figure means that 56 patients needed to be treated with simvastatin for five years to prevent one death. Compared with placebo, the absolute risk reduction obtained for the prevention of myocardial infarction, stroke or any revascularisation by simvastatin was 5.4  per  cent. Thus, the number needed to treat was 1 ÷ 0.054 = 19. This figure means that 19 patients needed to be treated with simvastatin for five years to prevent one patient from getting myocardial infarction, stroke or revascularisation. Patients who had ischaemic heart disease showed an absolute risk reduction of 5.7  per  cent for serious vascular events. The number needed to treat was 1 ÷ 0.057 = 18. This figure means that 18 patients who had ischaemic heart disease needed to be treated for five years with simvastatin to prevent one patient from developing a serious vascular event. All these benefits associated with the statin medicine simvastatin were in addition to those of aspirin, β-blockers and ACE inhibitors, and were not dependent on baseline cholesterol levels. The issue relating to the number of patients likely to benefit from treatment becomes more crucial when the incidence of disease rises (see Table 12.4). It is interesting to note that in this situation the medicine’s efficacy remains the same—that is, the medicine will cut the number of events in half. What has changed is the incidence of disease. The number needed to treat is, therefore, highly dependent on the incidence of disease, if the relative risk reduction (or risk profile of the medicine) stays the same. When trying to work out the benefits of new therapy, it is always best to first determine the incidence of disease. This information will provide some idea of the number of patients who will need to be treated in order to benefit one patient. Table 12.4 Effect of increasing the

incidence of events

If we assume there are five times as many events (disease) in each group, there will be 125 events in the medication group and 250 events in the control group. The relative risk reduction remains the same as before: 125 – 250/250 = 0.5, which equates to 50%. The absolute risk reduction changes: 25 – 12.5 = 12.5%. The number needed to benefit one patient also changes to 1/0.125 = 8 patients.

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A further caution is needed when considering treatment data. In the example discussed in Table 12.3, the study was conducted over a one-year period. What would happen if the results were obtained over a two-year period? It is then important to reflect on the effect of increased duration on the number needed to treat (see Table  12.5). Assuming that the efficacy or risk profile of the medicine remains the same and the benefits are spread equally over the two years, 80 patients will need to be treated to benefit one patient over a one-year period. This information relating to duration of treatment in order to obtain benefit must be examined carefully when making clinical decisions about whether a patient should be given a particular medicine. Table 12.5 Effect of increased duration on

number needed to treat

For the study, 40 patients will need to be treated over a two-year period to benefit one patient over a two-year period. The relative risk reduction remains at 50 per cent and the annual event rate will be one-half of the original. The annual absolute risk reduction will change to one-half of the original (1.25 per cent). Assuming that the benefit will be spread equally over two years, then only half a patient out of 40 will benefit in the first year. Thus, 80 patients will need to be treated to benefit one patient over a one-year period.

APPLYING RISK–BENEFIT ANALYSIS TO EXAMPLES IN PRACTICE The medical literature has many examples of studies that measure risks and benefits of medicines. Health professionals should examine these studies with a critical view, and make rational decisions based on sound reasoning. The Women’s Health Initiative (WHI) study initially published in 2002 is an example of a study that focused on defining both risks and benefits of hormone replacement therapy (HRT) that sought to reduce the incidence of heart disease, breast cancer, colorectal cancer and fractures in postmenopausal women (see Chapter 63). The primary WHI study involved the enrolment of 16 608 postmenopausal women and followed them for 5.2  years. The women in the study were largely healthy, although 7.7  per  cent of the women had existing cardiovascular disease. Women were randomised to receive a tablet containing a standard dose of an oestrogen and progestin combination or a placebo tablet. One of the areas of interest was the probability of

women in the HRT group experiencing osteoporotic fractures compared with those in the control group. The incidence rate for osteoporotic fractures in the HRT group was 1.47  per  cent, while the incidence rate in the control group was 1.91  per  cent. The relative risk reduction was, therefore, found to be (1.47 – 1.91 ÷ 1.91) = 0.23, or 23%. As mentioned previously, the relative risk reduction tells us little about how many women were affected by the change in risk because the measurement of relative risk reduction is isolated from the underlying prevalence of the event. If we calculate the absolute risk reduction, which is the difference between the event rate in the treatment group versus the control group, we get a result of 1.47% –1.91% = –0.44%. Thus, HRT reduced the absolute risk of postmenopausal women developing osteoporotic fractures by 0.44 per cent, or 0.0044 in one year. The number needed to treat to determine HRT’s efficacy is calculated by the reciprocal of the absolute risk reduction, or 1 ÷ 0.0044 = 227. In total, around 227 women needed to use HRT for one year to prevent one woman from experiencing an osteoporotic fracture. Should we be impressed with a number needed to treat of 227? We can get an idea of its value by comparing the number needed to treat for the development of postmenopausal osteoporotic fractures in HRT with other interventions, such as the bisphosphonate group of medicines (see Chapter 64). The smaller the number needed to treat result, the more impressive it is. The value of the number needed to treat will also depend on the duration of therapy, tempered by the clinician’s own experience and expertise with the therapy. Cost of the intervention will also affect the importance of the result obtained. The result will further need to be considered in relation to the incidence of harmful events after use of HRT; for example, the incidence of a cardiovascular event. For the WHI research group, a controversial area of interest was to determine the outcome of a cardiovascular event. For the HRT group the incidence rate for a cardiovascular event was 1.57  per  cent, whereas the incidence rate for the placebo group was 1.32  per  cent. The relative risk increase was (1.57 – 1.32) ÷ 1.32 = 0.189, or 18.9%. The absolute risk increase in this case was 1.57%  –  1.32%  =  0.25%, or 0.0025. In this instance, the HRT was not beneficial but actually caused harm. The number needed to treat is now more appropriately called the number needed to cause harm, and is worked out in the following way: 1 ÷ 0.0025 = 400. A number of 400 means that around 400 women need to use HRT for one year for one woman to experience a cardiovascular event. So what does all this information mean? When the results of the WHI study were initially announced in the

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media, the reporting was alarmist. While the incidence of myocardial infarction, stroke and breast cancer rose, the magnitude of the rise was small and generally not significant statistically. The conclusion from this trial was that HRT has no benefit in reducing cardiovascular events in postmenopausal women. Unfortunately, popular media coverage at the time the results were reported implied that HRT should not be used in postmenopausal women because it significantly increased the number of deaths from cardiovascular disease or breast cancer. However, the more rational view is that there is no point taking an ineffective treatment that may cause harm. Media reports conveyed the incidence of disease, such as a cardiovascular event, in terms of changes in relative risk, which persuaded many women in the community to stop their HRT. As already mentioned, aside from risks and benefits, the cost of a medicine influences whether it is prescribed or not. For example, the bisphosphonate group of medicines is very expensive. Alendronate, a medicine of this group, is available on the Pharmaceutical Benefits Scheme as an authority script for individuals with established osteoporosis who have had a fracture due to minimal trauma. An authority script is one where the patient pays a subsidised rate and the Commonwealth government takes up the remaining cost only when the specified criteria are met by patients. If patients without the specified criteria were to start a course of therapy with alendronate, the doctor would need to write them a private script and the patients would have to bear the full cost of the medicine.

HOW TO COMMUNICATE RISKS AND BENEFITS TO INDIVIDUALS Effective risk communication is the basis of informed consent for drug treatment. Health professionals must be able to read and interpret information about medicines in a systematic way. They also need to be able to communicate this information effectively and simply to individuals. Examples of health professionals who might be in a position to read and interpret information about medicines include doctors, pharmacists who undertake home medicine reviews, optometrists who have prescribing rights, nurse practitioners, nurses employed in specialty practice settings such as intensive care, diabetes nurse educators who counsel patients about their diabetes control, and maternal and child health nurses who provide childhood immunisation. Several simple techniques can be used to improve the way health professionals communicate.

Avoid using descriptive terms for risk It is important to avoid explaining risks in purely descriptive terms, such as ‘low risk’ or ‘high risk’. Elaborate by using numbers. Descriptive terms often reflect the health professional’s perspective, with the patient often understanding risks to be a different degree of magnitude.

Use a consistent denominator for risk For consistency, the odds of possible risk outcomes should be expressed with a common denominator—for example, 50 out of 1000 and 5 out of 1000, rather than 1 in 20 and 1  in 200. By using different denominators, people can misinterpret which is the greater risk. Some individuals may mistakenly believe that 1 in 200 is a greater risk than 1 in 20 because the number is larger.

Offer information about positive and negative outcomes It is important to present a balanced perspective and offer information about medicines in both positive and negative ways—for example, the chance of side-effects and  the chance of remaining free from side-effects. Honestly presenting outcomes in positive and negative forms is more likely to facilitate open and collaborative discussion about the merits of particular treatments.

Use absolute, not relative risks Whenever possible, absolute numbers should be used—not relative risks. Individuals can easily misinterpret statements such as medicine A has a 20 per cent greater risk of causing a heart attack as compared with medicine B. Figures about absolute and relative risks are available in journal articles that describe the results of clinical trials on the risks and benefits of medicines (e.g.  the Heart Protection Study and the Women’s Health Initiative study). Summaries of absolute and relative risks of medicines from a number of clinical trials can be obtained from the Cochrane Reviews and other systematic reviews.

Use visual aids for probabilities In society, many individuals have difficulty understanding the meaning of numbers. For these people visual aids can help, by showing the numbers in diagrammatic form. Several tools are available in the literature and through consumer support groups to explain the risks of different orders of likelihood (e.g. see journal and website references at the end of this section). Alternatively, health professionals can draw diagrams freehand. In summary, all medicines have concomitant risks and benefits. Risk communication is an important facet

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of the relationship between health professionals and individuals. While an abundance of research has been conducted on medicines, health professionals need to be able to understand and interpret the data in a rational and clinically justifiable way. The full advantages of knowledge gained from this research can be achieved only if health professionals can communicate this knowledge effectively to help patients make informed decisions about their health.

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SUMMARY OF CALCULATIONS OF RISK

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Risk = Incidence of an adverse event in a defined population over a specific period of time ÷ Population at risk of the adverse event over a specific period of time. Relative risk = Incidence of adverse events between individuals who take the medicine over a specified time ÷ Incidence of adverse events in individuals who do not take the medicine over a specified time.

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Absolute risk = Incidence of adverse events for those individuals who take the medicine – Incidence of adverse events for those individuals who do not take the medicine. Relative risk reduction = (Incidence of outcome events in individuals who take the medicine – Incidence of outcome events in individuals who do not take the medicine) ÷ Incidence of outcome events in individuals who do not take the medicine. Absolute risk reduction = Incidence of outcome events in individuals who take the medicine – Incidence of outcome events in individuals who do not take the medicine. Number needed to treat = 1 ÷ Absolute risk reduction for one individual.

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Risk communication is the ability to talk effectively about risks and benefits of medicines between consumers and health professionals. Risk is the incidence of an adverse event. Relative risk is the ratio of how often an adverse event occurs in individuals who take a medicine compared with individuals who do not take a medicine. Absolute risk is the difference between the incidence of the adverse event for those individuals who take the medicine and the incidence of the adverse event for those individuals who do not take the medicine. The relative risk reduction is the reduction of outcome event incidence achieved by a medicine, and expressed as a percentage of the outcome incidence of individuals who do not take the medicine. The absolute risk reduction is the actual difference between how often an outcome event occurs in individuals who take a medicine compared with the individuals who do not take the medicine. This term is also referred to as the risk difference or absolute risk. A medicine may cause an increased risk of incidence of a particular outcome event. The terms used are relative risk increase or absolute risk increase. A medicine may cause a decreased risk of incidence of a particular outcome event. The terms used are relative risk decrease or absolute risk decrease. It is more accurate to consider figures that relate to absolute risk reduction than those that relate to relative risk reduction. The number needed to treat is the number of people you will need to treat with a specific medicine over a given time period for one person to benefit in the outcome event of interest.

REVIEW QUESTIONS 1

Is it more accurate to explain the risk profile of a particular medicine using relative risk reduction or absolute risk reduction? State why.

2

A randomised controlled clinical trial was conducted to determine whether treatment with the statin, pravastatin, reduces the rate of recurrent cardiovascular events in older adults over a two-year period. The event incidences in the placebo group (n = 643) and in the pravastatin group (n = 640) were 10.8 per cent and 17.3 per cent respectively. Calculate the event incidences for 1000 patients in each group.

3

For the study described in question 2, calculate the relative risk of recurrent cardiovascular events. Calculate the relative risk reduction.

4

For the study described in question 2, calculate the absolute risk reduction or increase.

5

For the study described in question 2, calculate the number needed to treat to prevent one patient from experiencing a recurrent cardiovascular event.

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C A S E S T U DY 1

C A S E S T U DY 3

Ms JT accompanies her three-year-old son, Master M, to the doctor. Over the past week, Master M has suffered an upper respiratory tract infection with symptoms including a runny nose, sore throat and coughing. Over the past 24 hours, the symptoms have become progressively worse. Master M has developed laboured breathing, with pronounced wheezing and increased coughing. The child also has difficulties in speaking due to his symptoms.

Ms LT, aged 72  years, is admitted to the emergency department with chest pain. After her heart condition is stabilised, the emergency department doctor attempts to work out the cause of the problem. According to her medical history, Ms LT has been taking sublingual glyceryl trinitrate tablets for four months to treat ischaemic heart disease. Ms  LT indicates to the doctor that she stores the bottle of tablets on the window sill of her bathroom, and that she initially opened the bottle about four months ago.

The local doctor diagnoses that Master M is experiencing an episodic asthma attack caused by the respiratory tract infection, and promptly prescribes the bronchodilator salbutamol, to be administered as a metered-dose inhaler, using a mask and spacer device. Antibiotic treatment is not required as the infection is of viral origin. The doctor asks Ms JT to return with Master M within 24 hours to check that his respiratory symptoms have improved. He also indicates to Ms JT that the child could possibly experience similar symptoms again with future respiratory tract infections, and to administer salbutamol prophylactically at the first sign of an infection. The next day Ms JT visits the doctor with Master M, whose symptoms are considerably improved.

Questions 1

Why was the spacer device together with the mask recommended for Master M rather than a metered-dose inhaler on its own?

2

What instructions would be provided by the doctor and pharmacist to Ms JT in administering salbutamol using a spacer device?

3

Using the clinical decision-making process, what aspects would be evaluated to determine that the child’s respiratory symptoms had improved?

C A S E S T U DY 2 Ms HD is a 19-year-old physiotherapy student who visits her doctor after developing a sticky and red left eye, with a yellow discharge. The doctor diagnoses bacterial conjunctivitis, and prescribes a week’s course of chloramphenicol eye drops. He also asks her to return to see him if the symptoms do not improve in 48 hours. Ms HD is relieved that her symptoms have begun to improve after one day, and she continues to administer the eye drops for the remainder of the week.

Questions 1

How should the eye drops be administered to ensure maximum benefit from the antibiotic therapy?

2

Where should the eye drops be stored?

3

When should the eye drops be discarded, and why?

Questions 1

How should glyceryl trinitrate be stored to ensure maximum effectiveness of therapy?

2

When should a bottle of glyceryl trinitrate be discarded after opening?

3

What would be the recommended practice for Ms LT in administering the sublingual dose of glyceryl trinitrate?

C A S E S T U DY 4 Ms AA, aged 85  years, has a history of hypertension. She has been on lisinopril (an angiotensin-converting enzyme inhibitor) 20  mg orally daily for over six months. After a routine visit to the doctor her blood pressure is still relatively high (150/90  mm  Hg) and the doctor commences her on eprosartan (an angiotensin II antagonist) 400 mg orally daily in addition to the lisinopril. One week later she returns to her doctor because of experiencing severe dizziness after getting up from a lying or sitting position.

Questions 1

What adverse effect is the person experiencing?

2

How are the medicines causing the adverse effect?

3

How do you think the adverse effect could be resolved?

C A S E S T U DY 5 A randomised controlled trial has been conducted to determine the effectiveness of an experimental medication, compared to the corticosteroid, dexamethasone, in reducing mortality after an acute traumatic brain injury. The patients in one group have received dexamethasone therapy, while the patients in the second group have received the experimental medicine. The table below summarises the final results obtained. Exposure Yes (dexamethasone) No (experimental medicine) Total

Outcome (mortality) Yes (dead) No (alive) Total 28 52 80

178 152 330

206 204 410

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Questions 1 2

Calculate the risk of mortality in the dexamethasone group. Calculate the risk of mortality in the experimental medicine group.

3

Calculate the relative risk between the two groups in relation to producing mortality.

4

Calculate the number needed to treat to prevent one bad outcome of mortality.

FU R T H ER RE A DI N G Callréus T, 2008, ‘On pharmaceutical risk minimization’, Drug Safety, 31, 737–42. Fialova D & Onder G, 2009, ‘Medication errors in elderly people: contributing factors and future perspectives’, British Journal of Clinical Pharmacology, 67, 6, 641–5. Heart Protection Study Collaborative Group, 2005, ‘Cost-effectiveness of simvastatin in people at different levels of vascular disease risk: economic analysis of a randomised trial in 20 536 individuals’, The Lancet, 365, 9473, 1779–85. Keller KB & Lemberg L, 2005, ‘Estrogen plus progestin, benefits and risks: the “Women’s Health Initiative” trials’, American Journal of Critical Care, 14, 157–60. Loke Y K, 2012, ‘Adverse drug reactions’, British Journal of Clinical Pharmacology, 73, 908–11. Manias E, Gerdtz MF, Weiland TJ & Collins M, 2009, ‘Medication use across transition points from the emergency department: identifying factors associated with medication discrepancies’, The Annals of Pharmacotherapy, 43, 11, 1755–64. Manias E, Williams A & Liew D, 2012, ‘Interventions to reduce medication errors in adult intensive care: a systematic review’ British Journal of Clinical Pharmacology, 74, 3, 411–23, Parsons C, Johnston S, Mathie E, Baron N, Machen I, Amador S & Goodman C, 2012, ‘Potentially inappropriate prescribing in older people with dementia in care homes: a retrospective analysis’, Drugs and Aging, 29, 143–55. Roughead L & Semple S, 2008, ‘Literature Review: Medication Safety in Acute Care in Australia’, Australian Commission on Safety and Quality in Health Care, Sydney. Seligman PJ & Osborne SF, 2009, ‘Perspectives on early communication of drug risks to the public’, Clinical Pharmacology & Therapeutics, 85, 335–9. Therapeutic Guidelines Ltd, 2005, Therapeutic Guidelines: People with Developmental and Intellectual Disabilities, Version 2, Therapeutic Guidelines, Melbourne. van Doormaal JE, van den Bemt PMLA, Mol PGM, Zaal RJ, Egberts ACG, Haaijer-Ruskamp FM & Kosterink JGW, 2009, ‘Medication errors: the impact of prescribing and transcribing errors on preventable harm in hospitalised patients’, Quality and Safety in Health Care, 18, 22–7. Walsh KE, Dodd KS, Seetharaman K, Roblin DW, Herrinton LJ, Von Worley A, Usmani GN, Baer D & Gurwitz JH, 2009, ‘Medication errors among adults and children with cancer in the outpatient setting’, Journal of Clinical Oncology, 27, 891–6. Writing Group for the Women’s Health Initiative Investigators, 2002, ‘Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial’, Journal of the American Medical Association, 288, 321–33.

W E B R E S O UR C E S Australian Commission on Safety and Quality in Health Care, Medication Charts www.safetyandquality.gov.au/our-work/medication-safety/medication-chart Australian Commission on Safety and Quality in Health Care, National Recommendations for User-applied Labelling of Injectable Medicines, Fluids and Lines www.safetyandquality.gov.au/wp-content/uploads/2012/03/LabellingRecommendations-2nd-edition-February-2012.pdf Cochrane Reviews www.cochrane.org/cochrane-reviews New Zealand Medicines and Medical Devices Safety Authority www.medsafe.govt.nz

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IV

GENERAL ASPECTS OF PHARMACOLOGY In order to insure that a potion is effective, it must be ingested through the mouth and from there into the digestive system. Applications on the skin may also yield results, but this method is more laborious and its fruits weaker and more ephemerous … In certain cases, it may be possible to inhale the potion in the form of vapors and thereby distribute its particles through the lungs into the blood … F E D E R I CO A N D A H A Z I — T H E A N AT O M I S T

In this quote the author has elegantly considered some key aspects of pharmacology. Importance is placed on deciding the route of administration that will maximise the absorption and distribution of a drug, thus guaranteeing its effectiveness. In Section  IV you will be introduced to the general pharmacological principles and concepts that underlie clinical practice. The system by which drugs are named is explained in Chapter 13. After  a  drug is given to a person, a number of events occur before any observable effect is produced. This branch of pharmacology is divided into two areas: pharmacokinetics (Chapters 14 and 15) and pharmacodynamics (Chapter 17). These topics are of the utmost importance to all who deal with medications. An understanding of these basic concepts enables you to grasp more easily many seemingly complicated aspects of drug therapy. Before proceeding too much further, the distinction between the terms drug and medicine as used in this book should be made. A drug is considered to be a substance that when introduced into the body will produce an effect. The term is mostly used in a pharmacological context to describe the mechanism by which the substance acts to produce that effect and how it is handled physiologically within the body. A medicine is a term mostly used in a clinical context to refer to a drug taken to relieve a symptom of disease, to cure an illness or to prevent a condition from developing. A medicine is a preparation that may contain one or more drugs. In some instances in the book the terms drug and medicine have been used interchangeably.

SECTION IV GENERAL ASPECTS OF PHARMACOLOGY

Moreover, a number of factors can influence treatment outcomes. Factors such as genetic makeup (Chapter 19), pregnancy, lifestyle, occupation (Chapter 20) and age (Chapter 21) can all alter the magnitude of the observed effects of medications. Many of these changes are predictable if you learn to appreciate these factors. Medicines can also interact with one another when taken concurrently or within the environment in which they are placed, both before and after administration (Chapter 16). These issues, as well as some other important considerations concerning drug development and safety (Chapter 18), are dealt with in appropriate detail.

C H A P T E R

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DRUG N O M E N C L AT U R E

LEARNING OBJECTIVES

KEY TERMS

After completing this chapter, you should be able to:

Brand names

1 2

Distinguish between the chemical, generic and proprietary names of medications.

Chemical names

Differentiate between the following three drug classifications: therapeutic; mode of action; molecular structure.

Generic names

Drug classes Nomenclature Proprietary names Trade names

Drug nomenclature refers to the classification system or taxonomy associated with the naming of drugs. As this system forms an important part of the language of pharmacology, you will be introduced to the principles of classification in this chapter. The focus of drug classifications is on groups or classes of medicines, but you will also be introduced to a number of important individual medicines.

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NAMING OF MEDICINES Most medicines have at least three different names by which they can be recognised. These are their chemical, generic (or non-proprietary) and trade (or proprietary) names. Chemical names of drugs can be extremely cumbersome and they are almost never used in the clinical setting, except for the simplest of compounds. Imagine telling a person that the medicine he or she is receiving is 7-chloro-1,3dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one or, worse still, (5Z,13E)-(9S,11R,15R)-9,11,15-trihydroxy16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor5,13-prostadienoic acid, isopropyl ester. A simplified naming system exists whereby the original makers of the drug, in conjunction with the appropriate drug authorities, derive a simplified chemical name. This name does not usually reflect the chemical structure of the molecule, and is usually derived from the chemical name to make a supposedly easier-to-recall name. This simplified name is the generic or non-proprietary name. The generic name is the preferred drug name that will be generally used throughout this book. The generic names of the above-mentioned compounds are diazepam (an important antianxiety agent, see Chapter  35) and travoprost (a prostaglandin analogue used in the treatment of increased intraocular pressure, see Chapter 83) respectively. There are other methods whereby the generic names are derived. For example, aspirin (the anti-inflammatory medicine, see Chapter 41) is a derivative of a chemical found naturally in a plant with the Latinised name Spirea, and the name morphine (the narcotic analgesic, see Chapter  40) is derived from the Greek god of sleep, Morpheus. What about the antiplatelet agent abciximab? How many words do you know that start with ABC? Actually, this name is not completely artificial: ‘ab’ is an accepted abbreviation for antibody, so ‘mab’ stands for monoclonal antibody and has become the suffix for all the generic names of monoclonal antibodies used in therapeutics (see Chapters 48, 79 and 80). Unfortunately, generic names are not standardised across the world, and this can become confusing when using foreign textbooks, especially those from the United States. For example, the diuretic agent known as frusemide in our region (see Chapter  49), is called furosemide in North America. A list of medicine names and their North American equivalents is given in Appendix B. Some medicines are not easy to pronounce—for example, the generic names moroctocog, fondaparinux and ezetimibe. Another trend that is becoming apparent is the frequent use of the initial letter ‘Z’ in proprietary names. You may notice that many generic names of drugs

have another substance attached to them: for example, morphine is rarely used as such because of its insolubility in water for injection. Instead, it is used as a salt, such as morphine sulfate. The type of salt used may alter morphine’s pharmacokinetics, but generally the salt names are not used in medicine descriptions in this book. Some manufacturers use complex organic acids to form salts or esters with drugs and give these acids their own generic name, which is often used with the actual medicine’s generic name. An example of this is found in the drug sometimes termed mycophenolate mofetil (see Chapter 79, where the medicine is discussed as simply mycophenolate); mofetil is a generic form of ‘morpholino methyl ester’. Examples of the differing forms of individual generic medicines are provided in Table 13.1. In this text, these salt or ester names shall not be used in either the full or simplified form unless there is a particular reason to do so, but you may come across them in other books or references. The reason for using these unusual derivatives is generally to improve the medicine’s bioavailability (see Chapter  15). For example, betamethasone dipropionate is much more potent than the valerate ester when applied topically, as skin penetration is accelerated. Sometimes the chemical name for a drug is so simple that it would be of no advantage to create a generic name. Common examples are lithium carbonate (used in the treatment of bipolar disorder, see Chapter 36), potassium chloride (see Chapter  52) and glyceryl trinitrate (used in the treatment of angina, see Chapter  47). Usually chemical names are obvious because they do not seem to be contrived, unlike the generic names. Occasionally, creating an abbreviation shortens the chemical name; for example, glyceryl trinitrate is often abbreviated to GTN. Table 13.1 Examples of differing forms

of individual generic drugs used in clinical practice

CHAPTER REFERENCE

DRUG

FORMS AVAILABLE

morphine

hydrochloride, sulfate, tartrate

40

aluminium

acetate, chloride, hydroxide, sulfate

57

iron (ferrous)

sucrose, polymaltose, phosphate, gluconate

53

naphazoline

hydrochloride, nitrate

55

testosterone

decanoate, enathate, isocaproate, propionate

63

C H A P T E R 1 3 D R U G N O M E N C L AT U R E

Once a generic name has been given, the manufacturer gives the medicine a name by which to sell it. This is the proprietary name (otherwise known as the trade or brand name) which, like a trademark, is the property of the company manufacturing the medicine and can be used only by that company. When a manufacturer and discoverer first markets a medicine, it is usually sold under patent; hence, only the company holding the patent can sell it. When the patent expires, other companies may want to market the medicine, but if they do they must use a different proprietary name. Widely sold unpatented medicines may have several different proprietary names. These names can change rapidly, and vary greatly between countries. This makes the use of proprietary names cumbersome, and health professionals are encouraged to use generic names

wherever possible. For these reasons we tend to focus in this book on the generic name, because each medicine has only one such name; at the end of relevant chapters the medicines mentioned are listed with the proprietary names used in Australia and New Zealand. In this book, trade names are always written with a capital first letter, while generic names are printed in lower case. Another consideration is that proprietary names beginning with the same letter can look and sound similar, particularly when the names are short, leading to medication errors (e.g.  in Australia three medicines with quite different therapeutic uses, Ziagel, Ziagen and Zentel, could easily be confused on a badly written prescription) (see Appendix F: Common word mix-ups). Figure  13.1 shows the application of the drug

Figure 13.1 An example of drug nomenclature The chemical name for the generic drug morphine sulfate is provided with examples of trade (non-proprietary) named products available in Australia and New Zealand.

CH 2 H

N

CH 2

H

• H 2 SO 4 • 5H 2 O CH 2

HO

C

OH 2

7,8-didehydro-4,5α- epoxy-17-methylmorphinan- 3,6α-diol sulfate Chemical name

Morphine sulfate

Kapanol Australia only

Source: © Mundipharma Pty Ltd.

(50 mg)

MS Contin

(15 mg)

MS Mono

30

MS OD

Generic name

(50 mg)

Sevredol (20 mg)

129

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SECTION IV GENERAL ASPECTS OF PHARMACOLOGY

nomenclature to a common and important medicine, morphine. In some instances, trade names suggest their therapeutic use. As examples, Serenace is a trade name for an antipsychotic agent that suggests serenity, and Lopressor is a trade name for an anti-hypertensive agent that induces low(er) blood pressure. In recent years, a plethora of generic medicines have been released that bear the name of pharmacy chains plus the generic names. When a doctor prescribes generically and the prescription is filled in a pharmacy belonging to one of these chains, the pharmacy will automatically dispense its brand of that generic drug. The label on the prescribed medicine will name the drug generically, with the pharmacy name at the bottom or top. The label does not say ‘Joe Bloggs paracetamol’ but ‘paracetamol dispensed by Joe Bloggs’. In Australia, the pharmacy chains and pharmaceutical manufacturers that dispense their own branded generics are Chem  Mart, Chemists’ Own, DBL (David Bull Laboratories), GenRx, Healthsense and Terry White Chemists. In New Zealand, the prefix ‘Apo-’ before a generic name is often seen, representing the first three letters of the manufacturing company Apotex. Some of these labels may be seen only in hospitals. In order to spare you cumbersome lists of trade names, we have decided not to include trade names that incorporate the generic name in chapter medicine summary tables.

DRUG CLASSES AND GROUPINGS Individual medicines can be grouped into drug classes or families according to shared characteristics. Such groupings can be by therapeutic use, mode of action or molecular structure. For example, in considering what type of antidepressant (therapeutic use) to prescribe, the doctor may consider giving a monoamine oxidase inhibitor (mode of action) or a tricyclic antidepressant (molecular structure). The therapeutic use of a medicine is determined by the conditions the prescriber wants to treat. Medicines used to treat cancers are called anticancer or antineoplastic agents. Medicines used to treat asthma are antiasthma

agents. However, this can lead to confusion, as many medicines have a number of therapeutic uses. For example, propranolol can be used to treat high blood pressure (see Chapter  46), migraine (see Chapter  42), angina pectoris (Chapter 47) or to relieve some of the symptoms associated with hyperthyroid states (see Chapter 60). Thus, propranolol has at least four different therapeutic uses. The mode of action describes how the drug exerts its effect on the body. Fortunately, for most medicines there is only one mode of action; propranolol, no matter what its therapeutic action, acts by blocking beta-adrenergic receptors on body tissues (see Chapter  27). A few medicines act by differing mechanisms (see amantadine in Chapters 37 and 77), but this is unusual. The molecular structure of a drug often shows great similarity to other drugs, usually those with similar action. Chemists and pharmacologists tend to group drugs according to their basic structure, creating new drugs by making slight alterations and substitutions to the basic structure. This could be analogous to changing the chimney shape on one of two identical houses or by having different numbers of chimneys present on each house. Figure  13.2 shows three tricyclic antidepressant drugs. If you examine each structure you should be able to see the slight differences in overall structure, with the basic tricyclic (three-ringed) structure being similar in all cases. These relatively minor changes can lead to huge changes in therapeutic effects, to the point of completely negating them in some circumstances. It has long been a convention that for certain drug classes the generic name incorporates a common suffix to indicate their shared properties. An important group of cardiovascular agents are the β-blockers (a classification by mode of action). Most generics in the group share the suffix -olol (e.g. metoprolol, atenolol and propranolol). If you note this suffix, you will generally conclude that this individual medicine is a β-blocker. Table 13.2 lists some examples of suffixes that are used to identify common drug groups. Such common terminology is of enormous benefit to students as you try to connect drug groups or families with the large number of individual medicines that you are exposed to in the classroom or in the clinic.

C H A P T E R 1 3 D R U G N O M E N C L AT U R E

Figure 13.2 Molecular structures of three tricyclic antidepressants Imipramine

Amitriptyline

N

C

CH 2 CH 2 CH 2 N(CH 3 ) 2

CHCH 2 CH 2 N(CH 3 ) 2

Doxepin

O

C CHCH 2 CH 2 N(CH 3 ) 2

Table 13.2  Suffixes used to identify common drug groups CHAPTER REFERENCE

DRUG GROUP

THERAPEUTIC USE

SUFFIX

EXAMPLES

β-blockers

sympatholytics

-olol

timolol pindolol

27

Benzodiazepines

anxiety, insomnia

-azepam -azolam

diazepam triazolam

35

HMG-CoA reductase inhibitors

cholesterol-lowering medicines

-statin

simvastatin pravastatin

45

Serotonin (5-HT3) receptor antagonists

antiemetics

-setron

ondansetron tropisetron

58

Angiotensin-converting enzyme inhibitors

anti-hypertensive agents

-pril

quinalapril captopril

46

Monoclonal antibodies

immunomodulators

-mab

basiliximab abciximab

79

-caine

lignocaine bupivacaine

44

-azole

ketoconazole miconazole

78

Local anaesthetics Azoles

antifungal agents

131

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CHAPTER REVIEW ■■

Drug nomenclature is the classification system associated with naming these substances.

■■

Most medicines have at least three names: chemical, generic and proprietary.

■■

The chemical name represents the molecular structure of the drug.

■■

The generic name is a simplified name that is usually based on the chemical name. It is also known as the nonproprietary name.

■■

The trade, or proprietary, name is given to the medicine by the manufacturer, and may often be trademarked.

■■

Drug groups can also be classified by molecular structure, mode of action and/or therapeutic use.

REVIEW QUESTIONS 1

For the following medicines, indicate whether they are generic, chemical or trade names: a

lithium chloride

b Zoloft c

codeine phosphate

d frusemide

2

e

infliximab

f

Lopressor

For the following drug classes, indicate whether they are classified by therapeutic use, molecular structure or mode of action (you may need to use the index to look up these drug families): a

anti-inflammatory drug

b β2 agonist c

phenothiazines

3

There is a common suffix for β-blockers. What is it?

4

Indicate the specific uses for the following pairs of medicines. While the medicine pairs may sound similar, they work in different ways and are in different drug groups. You may need to check the index to find out more about them: a

amiloride and amlodipine

b prochlorperazine and procarbazine c

thiamine and thyroxine

d thioridazine and thyroxine e

vitamin K and potassium (K+) supplement

f

clozapine and clonazepam

C H A P T E R

14

PHARMACOKINETICS: ABSORPTION AND DISTRIBUTION

LEARNING OBJECTIVES

KEY TERMS

After completing this chapter, you should be able to:

Absorption

1

Explain the principles of pharmacokinetics.

Blood–brain barrier

2

Define drug absorption and outline the factors that can affect this process.

Distribution

3

Define drug distribution and describe the factors that can affect this process.

Lipophilic

4

Define the volume of distribution and identify its clinical applications.

Lipophobic Protein binding Volume of distribution

Pharmacokinetics literally means the movement of drugs inside the body. It describes the physiological processes that act on a drug once it enters the body or, put another way, how the  body handles the drug. Pharmacokinetics encompasses the absorption, distribution, metabolism and excretion of drugs, and is often referred to by the abbreviation ADME. The absorption of a drug and its distribution within the body take place first, and are dealt with in this chapter. As  metabolism and excretion follow, and are closely related, they are dealt with in Chapter 15. The two processes of drug absorption and distribution are of great importance in pharmacology, and their study can be extremely complicated. This is because there are so many factors that can affect these processes and, ultimately, the action of a drug.

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SECTION IV GENERAL ASPECTS OF PHARMACOLOGY

DRUG ABSORPTION Usually, when a medicine is administered, absorption has to take place before the drug gains access to, and moves between, the interior compartments of the body; the most important of these is the blood (see Figure 14.1). Usually, a drug has to cross a membrane or membranes to gain access. In the case of a swallowed medicine, there are layers of protective mucus in many parts of the gastrointestinal tract that must be traversed before the drug reaches the cell membranes of the epithelial cells lining the tract. Several membranes may have to be penetrated before the drug eventually reaches the bloodstream. Cell membranes form the dividing walls separating body compartments, such as the gastrointestinal tract and blood.

Factors influencing absorption The chemical nature of the drug determines just how this absorptive process takes place. With the majority of drugs, the process is simple diffusion. The molecular size of the drug is important, as small molecules diffuse more rapidly than large molecules. Furthermore, the drug must be present in a state that enables it to penetrate the cell membranes. As cell membranes consist mainly of lipid materials, only lipid-like or lipophilic substances cross through easily and rapidly. Therefore, drug solubility is another important factor determining the time taken to cross the membrane and the degree to which this is possible. By way of explanation, lipophilic means ‘fat-loving’. For example, when olive oil is mixed with sunflower oil, the two oils are completely miscible. This process is true for all oils Figure 14.1 Drug absorption between body compartments The movement of drugs between body compartments is shown here. The most important is the movement of a drug from its site of administration to the blood. Gastrointestinal tract (an example of a site of drug administration)

Blood

Kidney filtrate

or lipids, and substances that can be mixed with oils are termed lipophilic. Lipids, when mixed with aqueous media, produce two phases: the lipid phase and the aqueous phase. In other words, they are immiscible. (This is easily seen when one tries to wash greasy dishes in water without the addition of a detergent.) As lipids ‘do not like’ water, they are termed hydrophobic. The terms lipophilic and hydrophobic are more or less synonymous. The word used is determined by the context. For example, you would say that safflower oil was lipophilic when it proved to be completely miscible with palm kernel oil, but hydrophobic when it proved to be immiscible with water. Thus, to be absorbed effectively, drugs should preferably be lipophilic or lipid-soluble. Generally, drugs are weak acids or weak bases. They tend to dissociate in body fluids, which are largely water, and form ionised particles. These particles tend to be lipophobic, or relatively insoluble in lipid, and are poorly absorbed. Generally speaking, a weak acid tends to form a negatively charged particle, and a weak base tends to form a positively charged particle. Under certain conditions, the dissociation reaction moves towards the ionised (polar) state and under different conditions it moves towards the un-ionised (non-polar) state. Indeed, the pH of body fluids influences the direction of this reaction and consequently the proportion of drug molecules in the ionised or un-ionised state. As a rule of thumb, the higher the number of un-ionised drug molecules in solution, the more lipophilic the drug and the greater the degree of drug absorption that occurs. The gastrointestinal tract is a major site of drug absorption. It has a variable pH, and this variability is especially great between the stomach and duodenum; the pH gradient is steep, from about pH 3 to about pH 8. Generally, weakly acidic drugs are lipophilic when present in acid surroundings (a low pH), whereas weakly basic drugs are lipophilic when in basic or alkaline surroundings (a high pH). Under these conditions, the reaction moves predominately in favour of the un-ionised state. When a weak acid is placed in an alkaline environment, or a weak base is placed in an acid environment, the reaction moves predominately in the direction of the ionised state—the lipophobic state. Theoretically, this will mean that acidic drugs such as aspirin will be absorbed best in the stomach, whereas basic drugs such as morphine will be better absorbed in the small intestine. This would be accurate if it were not for the fact that the time a drug spends in the stomach is limited. The surface area of the stomach is also small compared with the intestinal surface area. This area is sometimes said to be equivalent to a singles tennis court. So, even though aspirin

CHAPTER 14 PHARMACOKINETICS: ABSORPTION AND DISTRIBUTION

will cross through a square centimetre of stomach wall much faster than through a similar area of small intestine, there are many more square centimetres of small intestine. Thus, for most drugs, absorption takes place mainly in the intestines. So, another factor influencing drug absorption is the surface area of the absorptive site. A large surface area can lead to greater, and more rapid, absorption. In fact, for a number of drugs, the large surface area of the lungs also represents a site of rapid and effective absorption. That absorption takes place mainly in the intestines can be a problem if a basic drug is taken for fast action and is given orally after a meal. Depending on the nature of the meal, it may take quite some time for the drug to reach an absorptive surface. If an acidic drug is taken after a meal, a therapeutic effect may be noticed much more quickly, owing to gastric absorption. Gastric absorption has another advantage: acidic drugs are often gastric irritants, and the presence of food will lessen the irritation to the gastric mucosa. For a drug, even though lipophilic, to be absorbed in the intestine, some portion of it needs to be dissolved in the intestinal juices, which are primarily aqueous. There are few substances that are completely insoluble in water, and if only a small portion is soluble at one point in time, this amount will be absorbed. An equivalent amount will then be dissolved from the undissolved portion. Thus, the process will continue until complete absorption takes place. The presence of bile salts in the intestine will, of course, also aid in the dissolution of drugs and their resultant absorption. Some drugs may be amphipathic; that is, they have both lipophilic and hydrophilic properties. Absorption of this type of compound poses no problem, a common example being ethanol (drinking alcohol). A few drugs are so hydrophobic that absorption is very difficult. They are present in the gastrointestinal juices like globules of oil floating in dirty kitchen-sink water. The bile salts present in the small intestines can emulsify these drugs, rendering them into small enough particles for absorption to take place. The fat-soluble vitamins are examples of this type of compound. Interestingly, there are some drugs that have comparatively low molecular weights but are lipophobic in nature (i.e.  highly ionised) and will not diffuse through the gastrointestinal wall. An example of this was known to the South American Indians, who knew that animals killed with the arrow poison curare could be safely eaten. Curare is a highly ionised molecule, which causes death by paralysis when injected into the bloodstream, but can be safely ingested. Similar compounds to curare, known

as neuromuscular blocking drugs, are still used today to paralyse patients during surgery and in intensive care (see Chapter 27). Some medicines are naturally occurring substances and can be absorbed by active transport. l-Thyroxine, one of the thyroid gland hormones used in the treatment of hypothyroidism, is formed from an iodinated amino acid. Amino acids are absorbed across membranes by active transport. This is also true for l-Dopa, used in Parkinson’s disease (see Chapter 37), a naturally occurring compound in humans absorbed by active transport. When medicines are given by injection into muscle or subcutaneous tissue, absorption still has to take place. This time the chemical nature of the drug is not so important because absorption is by entry to the circulation through small pores in the capillary walls. Another factor that affects absorption is the nature of the blood supply to the site of absorption. High blood flow can facilitate the absorptive process, whereas poor blood flow can impede it. Medicines administered into highly vascular tissues, such as muscle, or directly into the circulation are readily absorbed. Whereas those medicines administered into less vascularised tissues, such as the subcutaneous layer, represent sites that are absorbed relatively slowly. Circulatory disorders, such as shock, can greatly diminish the effectiveness of the absorptive process. Within the gastrointestinal tract, other factors that can influence absorption include the rate of gastric emptying, peristaltic activity and the presence of digestive enzymes. As the small intestine is the major region of gastrointestinal absorption, the rate-limiting step is the delay in moving the contents of the stomach into the duodenum. A relatively rapid gastric emptying rate will make for faster absorption. Regarding peristaltic activity, slow peristalsis allows drugs in the gut to be absorbed more completely. Finally, a number of digestive enzymes can act on drug molecules, transforming them into inactive metabolites before they can be absorbed. Peptide drugs such as insulin or vasopressin are good examples of this, as the action of proteolytic enzymes is so complete that the drugs are rendered useless. The most important factors influencing the rate and degree of drug absorption from one compartment to another are summarised in Figure 14.2.

DRUG DISTRIBUTION After absorption the drug enters the blood, which is itself an aqueous medium, and travels to its site of action. As the drug has to be lipophilic for absorption to take place, the plasma solubility of some drugs may be limited. This

135

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SECTION IV GENERAL ASPECTS OF PHARMACOLOGY

Figure 14.2  Factors influencing drug absorption A number of factors generally influence the absorption of drugs from their sites of administration to the bloodstream. (GI = gastrointestinal tract.) Drug molecule

Blood supply

Food particle

Rate of gastric emptying, GI motility, presence of food, digestive enzymes

Absorptive surface

Drug molecular size and solubility

Active drug transport system

is normally of no consequence. Some drugs become associated with plasma transport systems, binding to plasma proteins such as albumin. Protein binding also acts as a type of drug reservoir, prolonging a drug’s presence in the body. An additional drug reservoir of some importance is body fat tissue. Another significant distributive issue is that many drugs are prevented from entering particular body compartments due to the presence of natural barriers. All of these elements are discussed below.

Protein binding The bloodstream has the ability to transport relatively insoluble substances. Many naturally occurring substances, such as the sex hormones, are lipophilic and yet are

transported efficiently in the blood. They are transported attached to blood proteins (i.e. they are said to be ‘proteinbound’). The most important of the blood proteins associated with drug binding are albumin and the globulins. Protein binding is usually reversible and, as there is always some free drug present in the plasma, the proteinbound drug component is in equilibrium with that of the free drug. The proportion of bound drug in the plasma is expressed as a percentage (see Figure 14.3). Acidic drugs are usually bound to albumin, and basic drugs to some of the globulins. As globulin levels increase with age, this factor has to be taken into account when using highly protein-bound drugs in the older person. Proteins, under normal circumstances, do not leave the bloodstream

CHAPTER 14 PHARMACOKINETICS: ABSORPTION AND DISTRIBUTION

Figure 14.3 Protein-bound drug reservoir Drug binding to plasma proteins is represented in this diagram. The proportion of bound drug molecules is in equilibrium with free molecules. In this example, the drug is 40% protein-bound. Blood vessel

Plasma protein particle

Drug molecule

and enter the tissues. For drugs to act on the body, entry to the tissues is usually required. This means that protein-bound drugs will not leave the bloodstream—but the free drug can. So only the free drug is able to induce pharmacological effects. As the bound drug component cannot leave the blood, it cannot be metabolised or eliminated. Importantly, this will prolong the time that a drug remains in the plasma. As this system is in equilibrium, if the free drug leaves the bloodstream, more drug will be released from the protein to maintain the equilibrium. The stronger the protein binding, the lower the proportion of free drug present in the plasma. Protein binding can have another important clinical implication. Binding to plasma proteins is generally nonselective, and there are only a limited number of binding sites available on the plasma protein surface. Drugs administered concurrently may compete with each other for access to these binding sites. This could lead to greater amounts of free drug in the bloodstream. For drugs with low margins of safe dosage, toxicity may develop. When blood proteins are deficient, as can occur in kwashiorkor (dietary protein insufficiency) or any other cause of hypoproteinaemia, there may be insufficient protein to provide for normal transportation. This deficiency in blood proteins can lead to an increase in the amount of free drug, leading to an enhanced effect of the drug. This type of reaction is often seen in patients with chronic liver diseases or with severe burns. Chronic liver disease can lead to a decrease in protein synthesis; and in the tissue damage caused by burns, proteins can be lost by exudation through the damaged tissues. The converse of this process is also true. There are various types of tumour that secrete excessive amounts of plasma proteins. An example is multiple myeloma, in

which there is rapid synthesis of an immunoglobulin. This protein can bind to some drugs and necessitate an increase in dosage, as less free drug is available.

Other drug reservoirs Other tissues can be involved in drug binding. Fat tissue is an important reservoir for lipophilic drugs. These drugs can be taken up into fat deposits to be slowly released into the circulation over time, greatly prolonging their presence in the body. The active ingredient in marijuana, δ-9tetrahydrocannabinol (THC), is lipophilic and is readily taken up into body fat. After a single use, THC may still be detectable in the blood weeks later. Tissue binding can also be very important for drugs that show selectivity. This property can greatly affect drug distribution. The selectivity of iodine uptake into the thyroid can be put to therapeutic advantage when using radioactive iodide in the management of hyperthyroid states (see Chapter 60). The radioactive isotope concentrates in the thyroid, minimising irradiation of other body structures.

The blood–brain barrier The capillaries of most of the cerebral circulation are structurally different from those of the rest of the body. The endothelium of most blood capillaries has small pores present at intervals between the cells. These pores help materials cross to and fro between the tissues and the blood. They are not big enough to let through larger molecules such as proteins. The set-up in the cerebral circulation is rather different: the endothelial cells are closer together, and some of the connective tissue cells of the central nervous system (CNS) create a barrier between the capillaries and the brain tissue. This effectively prevents many molecules from traversing from the blood to the brain tissue. Only substances that are very lipophilic or are actively transported across this barrier can pass from the bloodstream into the CNS. This barrier, referred to as the blood–brain barrier, protects the CNS. It prevents harmful substances that may be present in the blood from entering the brain. Not all of the brain is protected by this barrier: the chemoreceptor trigger zone (CTZ) present in the fourth ventricle is an example. (See Chapter  58 for further explanation and the function of the CTZ.) This barrier is sometimes useful in drug therapy, as it can prevent some drugs from crossing into the CNS and causing a deleterious effect. The neuromuscular blocking agents (see Chapter  28) are examples of this effect. These substances completely block the action of acetylcholine at neuromuscular synapses. If they were to block the action of acetylcholine completely in the CNS, death could ensue.

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On the other hand, drugs such as penicillin do not cross the blood–brain barrier, and in CNS infections this may be problematic. The penicillin in these cases has to be given by intrathecal injection (into the cerebrospinal fluid). In cases of meningitis, the blood–brain barrier, being in the meninges, is often damaged, allowing some antibiotics to cross over to treat the infection. Since the blood–brain barrier is incomplete in neonates, penicillins can be used to treat such babies for meningitis. Very often the blood–brain barrier allows the passage of drugs, resulting in unwanted effects. A good example of this occurs with many of the antihistamines. The administration of most antihistamines invariably results in a certain amount of drowsiness, an effect not usually required when treating cases of allergy-induced runny nose or itching. Second-generation antihistamines that are not as lipophilic may not as easily cross the blood–brain barrier, and so the incidence of drowsiness is reduced (see Chapter 30).

Figure 14.4 Ion trapping The pH of the environment influences drug solubility. Drugs that are weak acids are predominantly un-ionised in acidic environments and are relatively lipidsoluble. In this form they readily cross between body compartments. When the pH of the environment is alkaline, the drug is predominantly ionised and shows poor lipid solubility. The drug cannot diffuse back to the compartment from which it came and becomes ‘trapped’ in the body compartment. Stomach pH ~3

Blood pH ~7.4

Drug is a weak acid

Drug is a weak acid – – –

Other barriers Other barriers to drugs in the body are the placental and the testicular barriers. The placental barrier is not very efficient, and most drugs cross over into the fetus and, thus, may cause congenital malformations. In general, most drugs should be withheld during pregnancy unless they are needed for life-saving purposes. Drug reference books usually identify drugs that are known to harm the fetus, and categorise them according to their safety. Placental drug transfer is further explored in Chapter 18. The testicular barrier, which protects spermatogenesis from some blood-borne chemicals, is little understood. Not much is known about the adverse effects that may occur when drugs cross this barrier.

Drug ionisation and distribution Adjacent body compartments can have markedly different pH environments. As discussed in the drug absorption section above, the pH of the environment can have a significant effect on the degree of ionisation of drugs—and, consequently, their solubility. While the pH of one body compartment allows the passage of a drug into another, the pH environment of the new compartment may cause most of the drug particles to become ionised and unable to readily move back to the first compartment. Thus, there is a net shift of the drug from the first to the second compartment. This is a phenomenon called ion trapping (see Figure 14.4). A good example of ion trapping is when the weak acid aspirin is absorbed from the stomach (a pH of around 3) into the blood (a pH of 7.45). In the blood it is predominately ionised and therefore lipophobic. Weak

acids will tend to unilaterally shift from acidic environments to alkaline ones, while weak bases will shift from alkaline environments to acidic ones. In clinical situations we may deliberately manipulate the pH of a particular compartment to prolong the presence of a drug in that part of the body or, alternatively, promote its removal from that region. Urinary alkalinisation will promote the excretion of a weak acid like aspirin, whereas it will prolong the duration of action of a weak base like the antimuscarinic agent atropine.

VOLUME OF DISTRIBUTION When a medicine is administered and its concentration measured in the plasma (i.e. intravascular compartment), the figure obtained usually does not correlate with the amount given. This lack of correlation is not unexpected, as drugs can diffuse from the blood into other compartments. It is useful to know just how much of a drug does get distributed into these other compartments. To do this a known amount of a drug can be injected intravenously and then its concentration measured. If the drug stayed wholly in the plasma, the concentration would be equivalent to the amount dissolved in litres of liquid. The approximate volume of plasma in a 70 kg adult is 3 L, so the apparent volume of distribution, or simply Vd , would be around 3 L (or 0.04 L/kg). The word ‘apparent’ is used as the drug seems to be distributed only in this volume. Heparin, an anticoagulant, has a Vd of ~0.07  L/kg, signifying that this drug is totally contained in the bloodstream. If the drug

CHAPTER 14 PHARMACOKINETICS: ABSORPTION AND DISTRIBUTION

were evenly distributed in the body, the concentration would be equivalent to the drug being dissolved in 0.57 L/kg (the total body fluid volume)—a Vd of 0.57 L/kg. If the drug is concentrated in certain tissues (as is iodine by the thyroid gland) by being tightly bound to receptors in the nervous system or, by being highly lipophilic, is concentrated in the adipose tissue, then the concentration could be equivalent to the drug being dissolved in a greater

volume than the total body volume (i.e. much greater than 0.57  L/kg). For some drugs the Vd has what is seemingly astronomical values: nortriptyline, an antidepressant, has a Vd of ~14 L/kg and chloroquine, an antimalarial and antiinflammatory agent, has a Vd of ~185 L/kg. In both cases these very high figures are due to extensive tissue binding of the drug. Figure 14.5 illustrates the concept of apparent volume of distribution for drugs with differing properties.

Figure 14.5 Apparent volume of distribution A When a drug remains wholly in the blood plasma, its volume of distribution, Vd, is equal to the volume of plasma in the body, approximately 3 L in a 70 kg person (0.04 L/kg). B When a drug is evenly distributed throughout the extracellular fluid compartment, the Vd is equal to that volume, approximately 0.57 L/kg. C If the drug is concentrated in one tissue the Vd is very high. A.

Drug molecules

Intravascular compartment B.

C.

Tissue cells

Interstitial compartment

Drug molecules

Drug molecules

Tissue cells

Tissue cells

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Apart from giving an idea of the amount of distribution of a drug in the body, the Vd of a drug, if low, is helpful in determining whether in cases of poisoning the drug can be cleared from the body by haemodialysis. If the Vd is

low, this procedure will usually be successful. The volume of distribution can also be used to calculate an initial, or loading, dose that produces therapeutic effects quickly (see Chapter 15).

CHAPTER REVIEW ■■

■■ ■■

■■

■■

■■

■■

With most methods of delivery to the body, drugs must be absorbed into the internal environment, usually the blood, in order for them to exert their pharmacological effect. After delivery to the internal environment, the drug has to be distributed to its site/s of action. Factors affecting the rate and efficiency of absorption include drug solubility, drug molecular size, surface area and blood supply of the absorptive site, and the presence of active transport systems. Factors affecting drug distribution include strong binding to plasma proteins, the presence of natural drug barriers and the degree of drug ionisation. For drugs that bind to plasma proteins, only the free drug molecules can exert a pharmacological effect. The bound drug portion remains pharmacologically inert, but cannot be metabolised. Protein binding provides both a drug reservoir and a means to transport relatively hypdrophobic drugs in plasma. Ionised drugs are relatively lipophobic, while un-ionised drugs are lipophilic. Generally, a weak acid in an acidic environment is relatively lipophilic and well-absorbed. A weak acid in an alkaline environment is relatively lipophobic and poorly absorbed. A weak base in an acidic environment is relatively lipophobic and poorly absorbed. A weak base in an alkaline environment is relatively lipophilic and well-absorbed. The apparent volume of distribution indicates whether a drug is distributed predominately in the bloodstream, throughout body water or is concentrated in tissue. It can be used clinically to calculate a loading dose or indicate whether haemodialysis could be used effectively in case of poisoning.

REVIEW QUESTIONS 1 Explain the following terms and derive a sentence for each word: a

lipophobic

b lipophilic c

hydrophobic

d hydrophilic 2 Theoretically, aspirin is better absorbed in the stomach. In actual fact, most is absorbed in the small intestine.

Why? 3 Insulin is a protein that cannot be given orally. Why is this so? 4 Indicate whether you think the absorption of the following medicines would be relatively poor or good based on

the information provided: a

Medicine A is a weak base in an acidic environment.

b Medicine B has a small molecular weight. c

Medicine C is injected into a body site with a poor blood flow.

5 What is the function of the blood–brain barrier? 6 Why may a person suffering from severe burns respond badly to some medicines?

CHAPTER 14 PHARMACOKINETICS: ABSORPTION AND DISTRIBUTION

7 Medicine A is known to prolong gastric emptying time. In the presence of medicine A, would the oral absorption

of another medicine, medicine B, be faster or slower than usual? 8 Medicine Z has a protein binding of 90%. Would you expect protein binding to greatly influence its magnitude

and effect? Explain why. 9 You are supplied with estimates of the volume of distribution values for the following medicines. Which one(s)

would be most likely to be predominately tissue-bound? In the case of poisoning, which one(s) would be likely to be effectively treated with haemodialysis? a

phenytoin, Vd = 0.7 L/kg

b metoprolol, Vd = 4 L/kg c

fluoxetine, Vd = 35 L/kg

d chloroquine, Vd = 185 L/kg 10 Normally, the blood–brain barrier provides a protective covering for the central nervous system. Explain why

penicillin can be used to treat meningitis in neonates.

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LEARNING OBJECTIVES

KEY TERMS

After completing this chapter, you should be able to:

Bioavailability

1

Identify the sites of drug metabolism.

2

Describe the mechanisms of metabolism and the factors that can affect this process.

3

Identify the sites of excretion of drugs and their metabolites.

4

Define the bioavailability of a drug and describe the factors that affect the degree of its bioavailability.

5

Define drug half-life and outline its effects on dose regimens.

Cytochrome P450 enzymes Drug clearance Drug excretion Drug half-life Drug metabolism Drug steady-state concentration Hepatic first-pass effects Loading dose Phase I metabolism Phase II metabolism

Humans ingest chemicals for which there are no physiological uses. To counteract this, we have developed various ways to deal with these chemicals so that they can be removed from the body. Drugs are chemicals and are dealt with in the same way as unwanted chemicals in food. It is reasonable to think that the body will simply excrete unwanted chemicals via either the bile or urine in an analogous fashion to the removal of natural wastes such as bile pigments or urea. However, with many chemicals, this may not be as simple as it sounds.

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DRUG METABOLISM Remember from Chapter 14 that in order for a drug to be efficiently absorbed from the gut, it is better for it to be in a lipophilic (fat-soluble) state. If the drug remains in a lipophilic state and is either filtered at the glomerulus or excreted via the bile, most will be reabsorbed and, thus, remain in the body for prolonged periods. This is why processes are available in the body to metabolise drugs: not so much to detoxify them but to make them less lipophilic (or more hydrophilic) in order that they will not be reabsorbed during the excretory process (see Figure 15.1). In some instances, one of the breakdown products of metabolism, a metabolite, is the pharmacologically active substance. In this situation, the adminstered medicine is really a pro-drug. A group of cardiovascular agents called angiotensin-converting enzyme (ACE) inhibitors are a case in point (see Chapters  46 and 50). Alternatively, the metabolites can be more active than the administered medicine, thus prolonging its effects. This is true of many of the anxiolytic benzodiazepines (see Chapter 35). Drugs can be metabolised in most cells of the body, but the principal site of drug metabolism is the liver. Inside the liver cells are organelles/vesicles known as microsomes, which contain the relevant enzymes for metabolism. Why is it that, in the majority of instances, a new chemical never before met by the human body can be metabolised by enzymes? Enzymes have, after all, specificity for certain substrates. In many instances this specificity is absolute, which means only one compound out of an infinite variety of compounds can be acted on by a given enzyme. Take glucose dehydrogenase, for instance: this enzyme will act only on glucose and not galactose, but both have a more or less identical structure when represented on paper. Spatially, however, the arrangement of one hydroxyl (-OH) group is different for the two molecules (see Figure 15.2). This slight variation in structure makes all the difference to the action of the enzyme. The enzyme pepsin, which is found in the stomach, does not have this absolute specificity. Pepsin will act on most soluble proteins and break them down into polypeptides and perhaps some amino acids. It does not matter whether the protein is muscle protein from a piece of steak or the globin part of porcine haemoglobin found in black pudding—the breakdown is similar. The reason for this is that amino acids are joined together by bonds, which are called peptide bonds. The peptide bond formed when most amino acids combine with each other is identical, and it

Figure 15.1 Drug metabolism The purpose of metabolism is to alter the chemical properties of drugs to make them less lipophilic and more readily excreted. The liver is an important site of drug metabolism. See Chapter 14 for more information on drug solubility and pH. Stomach pH ~3 weak acid un-ionised (relatively lipophilic)

Blood pH ~7.4 weak acid ionised (less lipophilic)

Liver converts drug into a weak base

Blood pH ~7.4 weak base un-ionised (relatively lipophilic)

Kidney filtrate pH ~5 weak base ionised (less lipophilic)

Drug excreted

is these bonds that pepsin and other proteolytic enzymes break down, rather than the individual amino acids. On our planet there exists an astronomical number of different compounds, but all these compounds are put together using similar bonds and groupings. For example, many compounds and drugs have amino groups (-NH2) and only one enzyme may be needed to react with this group; therefore, one enzyme can alter the structure of

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Figure 15.2 Differences in spatial molecular

arrangements of glucose and galactose

Glucose and galactose are isomers. They have the same molecular formula but there is a difference in the arrangement of one hydrogen atom and one hydroxyl group (shown in orange). This minor change affects the activity of the glucose dehydrogenase enzyme. CH2OH H C HO

CH2OH

C

O

H

H OH

H

C

C

H

OH

OH

C

C OH

glucose

H

C

O

H

H OH

H

C

C

H

OH

C OH

galactose

many different drugs. This means that there need only be a limited number of enzymes present in the body to be capable of metabolising a large number of compounds.

Phases of metabolism There are two phases involved in metabolism—phases I and II. Phase I metabolism is where enzymes modify the drug chemically by processes such as oxidation (adding oxygen atoms to the molecule), reduction (adding hydrogen atoms) and hydrolysis (adding water molecules), or by removal or addition of an active group. In adding to or taking away molecules from the drug’s structure, the properties of the drug are altered—in particular, its solubility and its pharmacological activity. Phase  I metabolism is of tremendous importance in drug use, and is dealt with more fully in Chapter 16 under liver actions and drug interactions. The cytochrome P450 enzyme family plays a critical role in phase I metabolism. Cytochromes are haem proteins that catalyse important physiological reactions involved in phase  I drug metabolism and energy production. The cytochrome P450 enzyme family consists of several hundred isoforms. An isoform is simply the same enzyme that is encoded by the same gene but with some variations in the amino acid coding, resulting in a protein that is structurally slightly different and has a different range of substrate specificity. The cytochrome P450 enzymes are responsible for the oxidation of a number of important clinical medicines. The ‘P450’ represents the wavelength of the colour, a ‘pink’ colour near 450 nanometres, which characterises the chemical properties of this family. The cytochrome P450 family is encoded by between 20 and 200 different genes. The current naming system (nomenclature)

for the family members is CYP, and there are three main groups of this family involved in drug metabolism in the liver: CYP1 (cytochrome P450  1), CYP2 and CYP3. Each specific enzyme, or isoform, in these groups is then represented by a further letter and numeral, which is its unique identification. For example, cytochrome P450 1A1 would be CYP1A1. In order to indicate the importance of the cytochrome P450 enzymes in metabolism, two isoforms, CYP2D6 and CYP2C9, together account for around 24  per  cent of the total human liver cytochrome P450 content. CYP2D6 is involved in the breakdown of more than 100  drugs used in psychiatric, neurological and cardiovascular diseases. CYP2C9 is necessary for the breakdown of at least 60 drugs, including the benzodiazepine diazepam (see Chapter 35), the aspirin-like anti-inflammatory drug ibuprofen (see Chapter  41), and the anticoagulant warfarin (see Chapter  48). The cytochrome P450 enzymes are further discussed in the context of drug interactions and the genetic basis of drug variability in Chapters 16 and 19 respectively. In phase  II metabolism, a drug or phase  I metabolite is conjugated (joined) with a polar molecule to render the product soluble for excretion. Some drugs that are readily water-soluble are often excreted largely unchanged. Substances that are commonly used in conjugation reactions are sulfates and glucuronides. Glucuronides are derived from an acidic compound made from glucose, called glucuronic acid. These conjugation reactions are used not only in the removal of drugs and unwanted chemicals from the body but also in the removal of natural substances, such as steroid hormones and the bile pigments. The antibiotic chloramphenicol (see Chapter  72) is conjugated before removal from the body, and in newborn babies this conjugation process is often ineffective. If chloramphenicol is administered to young babies, death can result from chloramphenicol toxicity, as blood levels continue to rise with each administration. In the early days of antibiotic therapy, many babies died of circulatory collapse resulting from the use of this drug. This phenomenon is called ‘grey baby syndrome’. A less serious problem involving conjugation can occur with the common laxative phenolphthalein, found in some gastrointestinal preparations. Phenolphthalein is conjugated in the liver and is partly excreted, via the bile duct, into the duodenum. Bacterial enzymes in the small intestine can deconjugate the hydrophilic, conjugated phenolphthalein, converting it back into the lipophilic base. The base is therapeutically active and causes another laxative effect on the bowels, maybe when it is not wanted. If large doses are taken, the laxative effect continues for

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several days. Reabsorption from the gastrointestinal tract of compounds that have been excreted via the bile can occur naturally. This reabsorption happens with the bile salts, used in fat emulsification, and allows them to be reutilised. This process is known as the enterohepatic cycle (see Figure 15.3). The disruption of drug conjugates (deconjugation) by bacterial enzymes in the gut can sometimes lead, indirectly, to unforeseen circumstances. The hormones in the contraceptive pill are partially metabolised by conjugation and it is expected that there will be significant enterohepatic recycling. This recycling means that less of the hormones should be given to maintain adequate blood levels. A problem sometimes arises when women on oral contraceptives take certain types of antibiotics concurrently. Such use leads to lack of bacterial deconjugation and, hence, lower blood levels of the hormones. Obviously, this lack of deconjugation can lead to failure of the drug, and unwanted pregnancies have occurred during concurrent antibiotic therapy. Once a drug has been metabolised to render it hydrophilic, under normal conditions it can then easily be excreted by the bile or urine without significant reabsorption. Factors that can affect metabolic processes involving drugs are the basis for many drug–drug interactions. These can cause problems during drug therapy, although occasionally the alteration of metabolic processes can be used to beneficial effect. The nature of drug interactions is dealt with in Chapter 16.

Hepatic first-pass effects After a drug is absorbed from the gastrointestinal tract, it is taken up by the part of the bloodstream called the hepatic portal system. This is true for most substances that are absorbed from the gastrointestinal tract. The exceptions are lipids, which normally enter the lymphatic system and are eventually deposited in the blood via the thoracic duct into the superior vena cava. The hepatic portal system is designed to take digested foodstuffs to the liver, where they can be processed. In some cases, they are stored before being distributed to the rest of the body. As the liver is a major site of metabolism, some drugs may be extensively metabolised before reaching the rest of the body. This extensive metabolism means that an analgesic taken for a headache might, in theory, never reach the structures in the head, the drug not making it past the liver. Such a drug is said to have ‘a high hepatic first-pass effect’ (see Figure 15.4). This phenomenon can be illustrated by comparing orally administered drugs with those given by a parenteral method. The narcotic morphine (see Chapter  40), for example, when given parenterally, may need an injection of only 5  mg to produce an analgesic effect equivalent to 15 mg taken orally. Some drugs are metabolised so completely during their hepatic first pass that they cannot be given orally to produce a therapeutic effect. An example is glyceryl trinitrate, used to treat angina pectoris (see Chapter  47). Once absorbed by the oral mucosa (i.e.  sublingually), glyceryl trinitrate will not be carried to the liver via the hepatic portal system

Figure 15.3 The enterohepatic cycle Enterohepatic recycling occurs when a substance, such as bile salts, is secreted into the intestinal environment and, instead of being excreted with the faeces, it is reabsorbed back into the portal blood. Bile enters duodenum to emulsify fats

Bile salts are reabsorbed into blood

Bile salts resecreted into newly released bile

Bile salts returned to liver via hepatic portal vein

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Figure 15.4  Hepatic first-pass effects A A drug is administered orally at a dose of 100 mg. B There may be some loss of dose in the gastrointestinal tract, resulting in the absorption of 90 mg of the drug. C As the drug is absorbed from the gastrointestinal tract, it enters the hepatic portal veins and passes through the liver. D Due to metabolism in the liver, only 10 mg of the original dose enters the systemic circulation. The drug has been subject to significant first-pass effects. (Hepatic first pass effect has led to the manufacture of many drug dosage forms that are dealt with in Chapter 7.)

Drug molecule 100 mg

A.

90 mg

B.

but will reach the other areas of the body long before the liver, where drug metabolism usually takes place. Almost 96  per  cent of glyceryl trinitrate is destroyed by the liver on its first journey through; that is, glyceryl trinitrate has a high hepatic first pass. Medicines that have a high hepatic first pass are better given by a route other than oral in order to obtain therapeutic blood levels.

Bioavailability The bioavailability of a particular drug is perhaps the most important aspect of pharmacokinetics, and is quite easily defined. It describes the amount of drug that is available to the body to produce a therapeutic effect. There are two parameters in pharmacokinetics that determine this— absorption and hepatic first pass. Bioavailability is expressed as the percentage of the dose administered that is available therapeutically, and can vary from 0 per cent to 100 per cent. As you would expect, the route of administration with the greatest variability in bioavailability is the gastrointestinal tract. The example provided in Figure  15.4 represents a bioavailability of only 10 per cent. The only way to ensure 100 per cent bioavailability is to give a drug intravenously. The majority of other methods used to deliver drugs still involve absorption, although the hepatic first pass can be avoided. It is important to know the bioavailability of a drug so that the dosage can be calculated. An extreme example of this is with the drug etidronate, used in the management of osteoporosis (see Chapter 64), which has a bioavailability

90 mg

10 mg

C.

D.

of 0.5 per cent (due to poor absorption). Importantly, this is sufficient to induce the desired effect As the formulation of a drug (mainly the excipients) can affect its absorption, any variation in the manufacturing of this drug could result in a large change in bioavailability, with the consequence of either over- or underdosing. Therefore, two manufacturers could produce two formulations of the same drug at the same dose but with differing bioavailability. Indeed, the term ‘bioequivalence’ has been coined to reflect an equal bioavailability of different formulations of a specific drug.

DRUG EXCRETION The principal sites of drug excretion are the kidneys and the gastrointestinal tract. The majority of drugs are excreted either unchanged or as metabolites in bile or urine (see Figure 15.5). Some drugs, such as penicillin, can be actively secreted from the peritubular capillaries of the nephron in an unchanged state, directly into the lumen of the nephron. This phenomenon can be used therapeutically. To maintain higher blood levels of penicillin, this process can be inhibited by the antigout drug probenecid, which inhibits tubular secretion (see Chapter 65). These are not the only routes by which drugs may be excreted: they can leave the body by any other natural route, including saliva, sweat, tears and breath. Indeed, most of the dose of the halogenated general anaesthetics isoflurane or sevoflurane (see Chapter 43) is eliminated unchanged via

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Figure 15.5 Drug excretion The principal sites of drug excretion are the gastrointestinal tract via the bile or the kidneys. There are a number of possibilities as to how the drug will be eliminated from the body: A the drug is transported from the bloodstream to the liver, where it may or may not be chemically altered; B the drug or its metabolites are incorporated into bile and secreted into the gastrointestinal tract, where it is excreted with the faeces; C the drug may be metabolised in the liver and transported to the kidneys via the blood, where it is excreted in the urine; D the drug may be transported to the kidneys unchanged and excreted in the urine.

A.

D.

C.

B.

the lungs. A small amount of alcohol (ethanol) is excreted unchanged by the lungs and in sweat (although most of the metabolism is completed in the liver). Indeed, as the level of ethanol present in breath is in equilibrium with the blood drug concentration, the random breath test for alcohol remains a convenient and non-invasive method for detecting drunk drivers. Another example is less clinically related, but is certainly a common experience with which you may identify. After eating a meal rich in garlic, the next day is characterised by a stale, garlicky breath and body odour as we eliminate some of the more volatile constituents through our lungs and sweat glands. In a clinical sense we often speak about drug elimination from the body in terms of drug clearance. Clearance takes into account both the metabolism and excretion of a drug, and is seen as a sum of the clearances through each body site—liver, kidneys, gastrointestinal tract, lungs and so on. It indicates a volume of blood cleared of a drug per period of time and is represented by the unit L/h (litres/hour). As the majority of drugs are largely excreted in the bile and urine, individuals with liver and kidney problems need special consideration during drug therapy and often

Drug excreted

require reduced dosages. Hepatic disorders can cause extra problems by reducing the rate of drug metabolism. This leads to the concept of blood levels and drug action. In order for a therapeutic effect from a drug to be achieved, a certain blood level has to be obtained. Drugs are generally poisonous, and at higher blood concentrations these poisonous effects are more apparent and can cause serious consequences, even death. It is important to keep blood concentrations as near to the non-toxic level as possible. This crucial aspect of pharmacology is concerned with drug dose and when and how often medicines should be administered.

Drug dosage and blood levels The faster the metabolism and/or excretion of a drug, the less time it will remain in the circulation and so, as a consequence, less drug will be available to the tissues. This type of medicine will thus have to be given more often than one that stays in the circulation for a longer period. It is not appropriate to state the time that a drug lasts in the circulation, as this figure is almost impossible to arrive at, for reasons that will become apparent. It is much more

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useful to talk about a drug’s elimination half-life—that is, the time for the concentration of a drug to decrease by onehalf or, put another way, the time taken for half the drug concentration to be eliminated from the body. For example, if the blood concentration of a drug is 1000 mg/L at a certain time and this level drops to 500 mg/L after four hours, the drug’s half-life is four hours. After another four hours the concentration would be 250 mg/L, and so on. The elimination half-life of a drug (t1/2) is related to the apparent volume of distribution (Vd) and its clearance (Cl), according to this expression: t1/2 =

0.693 × Vd Cl

However, it is unlikely that you will ever be required to calculate a drug half-life in practice. This information can be readily obtained from a clinical reference like the Australian Medicines Handbook. Half-lives are useful for calculating when repeat doses of a drug should be given. Look at Figure 15.6, which shows the progression in blood levels, giving a drug at an interval of every half-life. If this dosing schedule is to be maintained for a long interval, at some point the rate of administration of the drug will equal its rate of elimination. The peak and trough blood concentrations will become set (see Figure 15.6). In other words, a steady plasma drug level, or steady-state concentration, will develop. This state will arise after five half-lives have passed. Invariably, the intention is to attain steady-state concentrations of a drug during therapy. For drugs with long

half-lives of, say, 48 hours, this would take around 10 days to achieve, whereas drugs with short half-lives of, say, two hours, would need less than a day. This can create problems, as drugs with long half-lives may take considerable time to reach therapeutic concentrations in the blood. With drugs that must be given to attain therapeutic levels quickly, long half-lives can be problematic. A way around this is to give what is known as a ‘loading dose’ or ‘priming dose’ (see Figure  15.7). This dose is normally twice the usual dose. Many of you will have been told, at some time, to take two tablets of a drug initially, and follow this dose with one tablet at half-life intervals. A similar dose of the drug may be given by injection and given initially in place of the tablets. In a clinical setting, the loading dose can be calculated if you know the drug’s volume of distribution and the plasma drug concentration you desire. The relationship is expressed as follows: loading dose (mg/kg) = Vd (L/kg) × plasma drug concentration (mg/L) As an example, the antiseizure drug phenytoin (see Chapter  38) has a volume of distribution of 0.7  L/kg. An optimal therapeutic serum concentration would be 15 mg/L. The loading dose of phenytoin needed to produce this is 10.5 mg/kg. (However, as the drug is manufactured as phenytoin sodium, a slightly larger dose of 11.5 mg/kg would be required to equal 10.5 mg/kg phenytoin.) Look at Figure 15.7 to see what happens with a loading dose. A loading dose cannot be administered with all drugs,

Figure 15.6 The development of a steady-state concentration The MEC represents the minimum effective concentration of a drug that is therapeutically beneficial. 2000 1750 Plasma concentration ( µg/L)

148

1500 1250 MEC

1000 750 500 250 0 0

4

8

12

16

20

24

28

Time (hours)

32

36

40

44

48

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Figure 15.7 The effect of a loading dose on plasma concentration

Plasma concentration ( µg/L)

In this example, a loading dose produces a plasma concentration well above the minimum effective concentration (MEC). 2000 1500 1000

MEC

500 0 0

1

2

3

4

5

Time (hours)

Kinetics of drug metabolism Drugs that are metabolised in such a way that a fixed half-life (which is more or less a constant figure) can be measured are said to undergo first-order reactions or to follow first-order kinetics (see Figure  15.8A). Most drugs used at therapeutic dosages tend to follow this pattern and thus fit into the preceding section on drug metabolism. However, a few drugs do not follow first-order kinetics. Instead, these drugs undergo what is termed zero-order kinetics (see Figure  15.8B). In this case, metabolism takes place at a constant rate, and the metabolic process is measured in the amount of drug metabolised per unit time. For example, ethanol is metabolised at a rate of approximately 10  mL/h. Therefore, this is quite different from dealing with half-lives. This type of kinetic process

Figure 15.8 Kinetics of drug metabolism A In first-order kinetics the drug is metabolised by a fixed amount proportional to its half-life. B In zero-order kinetics the drug is metabolised in a more linear fashion, at a constant rate per time interval. 1.0

Concentration

0.8 0.6 0.4 0.2 0

0

1

0

1

2 Time

3

4

2

3

4

A 1.0 0.8 Concentration

as adverse effects can occur more often with such doses than with normal dosages. One reason why there are many drugs in a therapeutic group is because of differences in their half-lives. For example, a hypnotic agent with a short half-life will be better for people with difficulty in falling asleep, whereas one with a longer half-life will be more suitable for those with insomnia due to early-morning awakening. (The failings of this last statement are discussed in Chapter 35.) Another reason is that drugs with longer half-lives are taken less often. Some people prefer this but, as pointed out above, steady state is not achieved quickly. Manufacturers today artificially increase half-lives by using sustained-release preparations (see Chapter  7), partly in order to improve compliance. When looking at values given for half-lives, a range is usually given. This is because the half-life of a drug varies from individual to individual with factors such as age and weight, which are discussed fully in Chapters 20 and 21.

0.6 0.4 0.2 0

Time B

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is due to the body having a limited amount of enzymes for metabolic processes, which can consequently quickly become saturated with excess quantities of substrate. Ethanol does follow first-order kinetics if consumed at a rate of less than 8 g/h (about half a glass of wine) by an averagesized man or 4  g/h by an average-sized woman (about a quarter of a glass). Drug kinetics explains why a person can still be over the legal limit of blood alcohol concentration on the morning after a night’s heavy drinking. As ethanol is rarely used therapeutically (see Chapter  24), what, therefore, is the relevance of zeroorder kinetics in clinical pharmacology? Because of enzyme saturation, several drugs, if taken in excess (either intentionally or accidentally) may change their rate of metabolism from first-order to zero-order kinetics. This

makes them considerably more toxic, and often delays recovery from the overdose. Two common examples of such drugs are aspirin and phenytoin (an antiseizure drug). The blood concentration at which first-order kinetics changes to zero-order kinetics can change due to enzyme induction (see Chapter  16), where continued exposure to the drug induces increased levels of the enzyme involved in metabolism. This is common with ethanol, where regular heavy drinkers can stay apparently sober after an evening’s drinking. The same amount consumed by light or nondrinkers would place them in an extremely inebriated state. Note that other factors can affect this: for example, genetics and sex are important determinants of the kinetics of ethanol’s metabolism (see Chapter 24).

C H A P T E R 1 5 P H A R M A C O K I N E T I C S : M E TA B O L I S M A N D E X C R E T I O N

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Drugs are metabolised in the body by various organs but principally by the liver. Drugs are metabolised to assist in their excretion by converting a lipophilic substance into one that is hydrophilic. There are two phases of drug metabolism: phase I reactions, where molecules are added to or taken away from the drug; and phase II reactions, which are characterised by conjugation. Drugs are excreted by numerous routes from the body, but principally by the liver via the bile and the kidneys via the urine. After gastrointestinal absorption, some drugs are subject to significant metabolism as they pass through the hepatic portal system. This is known as the hepatic first-pass effect. Drug dosage and/or route of administration may have to be altered to take this phenomenon into account. Bioavailability is the amount of drug available to produce a therapeutic effect. It is largely determined by the degree of absorption and first-pass effect. Drug elimination half-life is the time taken for half the amount of drug in the body to be removed. It is used to determine the dosing frequency and when the steady-state blood drug concentration develops. First-order kinetics describes the metabolism of most drugs. It states that a constant amount of drug is removed over time in proportion to the drug half-life. Zero-order kinetics is when a constant rate of drug is removed over time.

REVIEW QUESTIONS 1 Explain the significance of the enterohepatic cycle. 2 What is the purpose of drug metabolism? What is the principal site of metabolism in the body? 3 Name the major sites of drug excretion. 4 Compare and contrast phase I and phase II metabolism. Can a drug be subjected to both phases of metabolism? 5 Why are cytochrome P450 enzymes important in drug metabolism? 6 Medicines A and B are administered orally. Medicine A is administered at a dose of 600 mg, while Medicine B is

taken at a dose of 10 mg. Both medicines are absorbed rapidly and completely from the gastrointestinal tract. Shortly after administration, there is 200 mg of medicine A and 8 mg of medicine B in the circulation. a

Compare the bioavailability of the two drugs.

b What factor(s) has/have influenced the bioavailability of these drugs? c

In what ways could bioavailability of the drug with the lower bioavailability be improved?

7 Medicine C has a half-life of 6 hours. If 400 mg of medicine C is administered intravenously, how much will remain

in the body after 24 hours? 8 The half-life of a particular drug is five hours. It is administered as a single dose. If the blood concentration present

at a certain time is 500 µg/L, what will be the blood concentration after a further 10 hours? 9 The half-life of a particular drug is eight hours. If the blood concentration present 16 hours after administration is

250 µg/L, what will the blood concentration have been after eight hours? 10 Medicine X has a half-life of five hours. If 500 mg of medicine X is given to a patient intramuscularly every six

hours, how long will it take to reach the steady-state blood concentration?

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DRUG INTERACTIONS

LEARNING OBJECTIVES

KEY TERMS

After completing this chapter, you should be able to:

Cytochrome P450 enzymes

1

Identify the common types of drug interactions.

2

Outline the common forms of drug–environment interactions and the clinical consequences of such interactions.

3

State examples of drug–food interactions and how they affect drug absorption.

4

Differentiate between a pharmacokinetic and pharmacodynamic drug–drug interaction.

5

Define the terms drug synergism, summation and potentiation.

6

Outline the consequences of altering hepatic enzyme activity on drug metabolism.

Drug–drug interactions Drug–environment interactions Drug–food interactions Enzyme induction Enzyme inhibition Potentiation Summation Synergism

Drugs are chemicals, and as such can be reactive with their environment or with other chemicals. When this happens, the effects of a drug may be different from what is expected. The effects may be diminished or enhanced, or the drug may be rendered completely inactive. Such chemical interactions with the environment occur even before a drug is administered. In the presence of another chemical, a drug’s action, or its metabolism, may be altered. Multiple drug therapy, or polypharmacy (see Chapters  2 and 21), is commonplace in our health care system, so this type of reaction can occur often. Most clinical pharmacology references contain information about known drug interactions, and these handbooks should be consulted before drug mixtures are given, multiple drug therapies instituted, or drugs added to existing pharmacological treatments. With so many drugs available, no-one can know all the potential interactions, but it is of great importance that, when multiple drug therapy is used, any new

CHAPTER 16 DRUG INTERACTIONS

adverse drug interactions be reported to the appropriate authorities for publication in bulletins such as the Medicines Safety Update produced by the Therapeutic Goods Administration. In this chapter we explore the nature of common drug–environment interactions outside the body, drug–food interactions in the gastrointestinal tract, and drug–drug interactions in the general circulation.

INTERACTIONS OUTSIDE THE BODY The most common of these environmental interactions is due to storage conditions, in which the drug can decompose due to the action of light, oxygen or moisture (see Chapter 7). Shelf-life, expiry date and appropriate storage of medicines are discussed in detail in Chapter 7. Once the expiry date has been reached, medicines should be discarded as their potency will no longer be guaranteed and, with some drugs, toxic degradation products can be formed. The latter can happen with the tetracycline antibiotics. Medicines can also interact with their containers. The antiseizure agent phenytoin (see Chapter 38) can, in dilute solution, react with glass. Thus, when phenytoin is added to glass infusion bottles, much of the drug remains stuck to the glass and is not part of the dose administered. This is not a problem with phenytoin in glass vials, as the surface area is small and the concentration of the drug is high. Another example of a drug reacting with containers is that of the hypnotic paraldehyde (see Chapter 35). This liquid dissolves plastics, so it must be administered parenterally using a glass syringe. Mixing two drugs in the same syringe for injection can precipitate an adverse chemical reaction. These reactions are known as drug incompatibilities. For example, the neuromuscular blocking agent suxamethonium (see Chapter  28) reacts with thiopentone (an intravenous anaesthetic used in Australia and New Zealand, see Chapter  43) and forms an insoluble derivative, which it would be inadvisable to inject. As these two drugs can be given together during anaesthesia, they must be injected separately. A number of clinical references include comprehensive tables of drug incompatibilities. In practice, we would recommend that drugs not be mixed before injection in case there is any reaction between them, resulting in inactivation of one or more of the drugs. Another reaction that can occur is between the rapid-acting insulins and the slower-acting forms (see Chapter 61). Slow-acting insulins consist of insulin bound

to various compounds, such as protamine, which slows down the insulin’s absorption rate from the injection site. Rapid-acting insulins consist of relatively pure insulin. If the two are mixed, some of the rapid-acting insulin can combine with the protamine, rendering it slow-acting. If a person with diabetes mellitus injects this, most of the benefit of the rapid-acting insulin will be lost, which could have serious consequences. Fortunately, this reaction is slow, and in practice both can be mixed for immediate injection.

INTERACTIONS IN THE GASTROINTESTINAL TRACT The amount of drug that is absorbed from the gastrointestinal tract into the bloodstream determines the subsequent plasma levels of the drug and, hence, its therapeutic action. The amount absorbed is termed the drug’s bioavailability (see Chapter 15). The pharmaceutical formulation can influence the bioavailability of a drug. For example, slow-release tablets are specially formulated to prolong a drug’s duration of action but may consequently decrease its bioavailability. However, many other factors can lead to a decrease in the bioavailability of the drug and can interfere with the absorption of the drug. This leads to a decrease in blood levels, with the effective blood drug concentration not being reached and the medicine unable to act as intended. Food consists of innumerable chemicals, so it should not surprise you that some of them react with the medicines we take. It is even more surprising that there are not many of these reactions. Calcium is present in many foods, especially dairy products, and swallowing a bisphosphonate such as clodronate, etidronate or risedronate with calcium products will reduce the therapeutic activity of the bisphosphonate. Ideally, bisphosphonates should be taken each morning with a full glass of plain water before food, drink or other oral medicines such as antacids, calcium, iron and mineral supplements. Calcium supplements, which are often prescribed with bisphosphonates, should be taken one hour before or two hours afterwards. For similar reasons, tetracycline should be taken one hour before or two

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hours after a meal, and iron, calcium and zinc supplements, and antacids, with the exception of sodium bicarbonate, should be avoided with all types of tetracyclines. Iron is best absorbed in the ferrous (Fe2+) state. Ferrous iron is easily oxidised to the ferric (Fe3+) state by oxidants in food, and ferric iron is not absorbed well. This suggests that iron tablets ought to be given on an empty stomach to ensure reliable absorption. However, as iron salts can be irritant to the gastrointestinal tract it is better to take iron tablets with food, perhaps in combination with an antioxidant such as vitamin C (see Chapter 67), which will make more of the ferrous iron available for absorption. A problem with some medicines in the gastrointestinal tract is their ability to prevent absorption of some of the fat-soluble vitamins. This can happen during treatment with either liquid paraffin or the antihypercholesterolaemic agent cholestyramine (see Chapter 45). Another indirect reaction with medicines and vitamins involves some of the broader-spectrum antibiotics, which can kill off some of the natural flora of the intestine. Some of this flora makes vitamin K (important in the manufacture of key clotting factors), and deficiencies of this vitamin have occurred with antibiotic therapy. Tannin, which is present in tea, can bind to many medicines after oral administration. It is recommended that people be instructed not to swallow medicines with tea. An important drug–food interaction has been noted to occur with the antihypertensive felodipine (see Chapter 46). When consumed with grapefruit juice, its bioavailability is increased by a factor of about 250  per  cent. This does not happen with other citrus fruit juices, except with bitter Seville oranges. The suggested mechanism for this interaction is that substances present in grapefruit, namely some flavonoids, suppress intestinal cytochrome P450 enzymes (see below) but not the hepatic isoform. Since this chance finding, grapefruit juice has been shown to adversely affect many other drugs, and these effects are shown in Table 16.1. It should be noted that this effect of grapefruit on drug metabolism could last for up to three days. Table 16.1 Interactions after absorption Examples of drugs affected by grapefruit juice/ grapefruits. amlodipine benzodiazepines nifedipine cyclosporin felodipine

nimodipine oestrogens terfenadine verapamil warfarin

INTERACTIONS AFTER ABSORPTION After absorption is when most of the known drug interactions take place, and usually happens when two or more medicines are administered concurrently. Sometimes interactions occur between medicines and compounds absorbed from food. These compounds can be vitamins, as is the case with vitamin K and its interference with the action of warfarin (see Chapter  48), and isoniazid with vitamin B6 (pyridoxine) (see Chapter 73). A potentially fatal reaction can occur between a group of medicines used in the treatment of depression and amines found in some foodstuffs. These medicines are called monoamine oxidase inhibitors (MAOIs) and act by inhibiting the metabolism of the catecholamines noradrenaline, serotonin and dopamine in the central nervous system. Similar enzymes to those involved in normal catecholamine metabolism are found in the gut and liver, which metabolise amines in food such as tyramine to biologically inactive compounds. MAOIs may be either selective or non-selective in their activity against these enzymes. Non-selective MAOI agents prevent these enzymes from working in the gut and liver, so that bioactive amines like tyramine get into the general circulation and can cause a hypertensive crisis by potentiating or mimicking the effect of noradrenaline. This reaction can also be induced in people taking MAOIs concurrently with other medicines that mimic the effects of noradrenaline on tissues, such as some nasal decongestants. People taking non-selective MAOIs are warned not to eat foods high in monoamines, such as yeast products (including Vegemite), red wines and broad bean skins. (See Chapter 36 for more details on these medicines.) As mentioned previously, drug–drug interactions are numerous, making vigilance a necessity when new combinations of drugs are used in treatment. Many of these effects are due to interactions between drugs and enzymes in the liver, which can alter the length of time that a drug remains active in the body. Some drugs interfere with the excretion of other drugs, which, like metabolic effects, can alter the length of time that a drug remains active in the body. (Both of these effects are dealt with in Chapter 15.) Such drug interactions are called pharmacokinetic interactions. Pharmacodynamic drug interactions occur when the action of one drug interferes with that of another. This interaction may result in a significant reduction of the effects of one or both drugs, or an enhancement of one or both drugs. Sometimes enhancing-type pharmacodynamic drug interactions can be put to good use, in that a combination

CHAPTER 16 DRUG INTERACTIONS

of two or more drugs may lead to an increased beneficial therapeutic effect. The most important example of this type of interaction is synergism, which can be subdivided into two kinds: namely, those of addition or summation, and potentiation. Summation occurs when two types of drugs work by altering different physiological or biochemical activities to produce an additive effect: that is, analogous to 1  +  1  =  2. There are many examples of this type of effect in therapeutics, a common example being in the treatment of hypertension (high blood pressure), where two or more medicines are given concurrently to produce a larger drop in blood pressure than that which could be obtained by using one medicine alone (see Chapter 46). Potentiation occurs when two medicines act, again on different physiological or biochemical activities, to produce an effect that is more than additive: that is, as if 1 + 1 = 3. Again there are many examples of this, which can usually be explained by examining the drugs’ modes of action. For example, two antibacterial medicines, trimethoprim and sulfamethoxazole, can be combined in one preparation— this combination being so commonly used that it has its own generic name of co-trimoxazole—(see Chapter 71) and the antibacterial activity of the mixture is much better than that which can be simply explained by an additive effect.

Liver enzymes and drug interactions Many drug–drug interactions result from enzymic interference, and an awareness of these is important when more than one drug is prescribed. The inhibition, or induction, of enzyme activity by one drug on another can have serious ramifications on the magnitude of drug effects observed. This phenomenon is discussed below with some classic examples.

ENZYME INDUCTION Under normal circumstances, the enzymes involved in drug metabolism are present only in small quantities. When a drug is present in the body, especially for prolonged periods, the amount of enzyme can increase and speed up the metabolism of that drug. This is very noticeable with the metabolism of ethanol: habitual drinkers metabolise it at a faster rate than light or non-drinkers, and therefore ethanol appears to have less effect on the habitual drinker. Ethanol stimulates the production of several hepatic enzymes—not only those involved in its metabolism per se, but enzymes that can be involved in the metabolism of other drugs. In cases where one medicine taken with another (or others) causes a decrease in half-life of the second medicine(s), the likelihood is that there has been an enzyme

induction. This process of enzyme induction obviously will lessen the therapeutic effect of the second medicines with normal dosing schedules. Examples of well known enzymeinducing medicines include the barbiturate phenobarbitone, the antiseizure agents phenytoin and carbamazepine, and the antituberculosis medicine rifampicin. It is not only standard drugs that can act as enzyme inducers: other substances, including tobacco smoke, barbecued and smoked foods, and even Brussels sprouts, can act similarly. Enzyme induction may require an increase in drug dosage with long-term therapy to maintain its therapeutic effect. This is one explanation for the development of tolerance with some drugs. With drugs such as warfarin, an anticoagulant (see Chapter 48) whose blood levels must be strictly controlled, an awareness of drug enzyme induction is of extreme importance.

ENZYME INHIBITION As mentioned in Chapter  17, drugs that are enzyme inhibitors are used therapeutically to moderate enzyme activity and slow down body processes. Some drugs that are not specifically used for their enzyme inhibitory properties, nevertheless, can cause enzyme inhibition, which may lead to accumulation of other drugs, and possible toxicity, in the body. The H2-receptor antagonist, antiulcer drug cimetidine (see Chapter  56) inhibits some liver enzymes involved in the metabolism of other drugs. When, for example, the antihypertensive β-blocker propranolol (see Chapter 46) is used with cimetidine, propranolol’s metabolism is slowed down and higher than usual blood levels are attained. The antiseizure drug phenytoin (see Chapter  38) inhibits its own metabolism, and after prolonged therapy the dose may have to be reduced to avoid toxicity. This type of drug action is the converse of enzyme induction, and is another example of a drug–drug interaction.

CYTOCHROME P450 ENZYMES Most of the known drug–drug interactions occur in phase I drug metabolism. The cytochrome P450 (CYP) family of enzymes, discussed in Chapter 15, plays an important role in phase I metabolism. These enzymes have been implicated in numerous important clinical drug–drug interactions. Several hundred CYP isoforms have been identified. Their substrate specificity is low so that they have the ability to metabolise literally millions of different chemicals, including drugs and toxins. During multiple drug therapy, some drugs may either induce or inhibit CYP activity, affecting the metabolism of other drugs used as a part of the therapy. The consequences are that the magnitude of the

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therapeutic effects is either very much higher or lower than expected. Some examples of common drug interactions based on altered CYP activity are provided in Table 16.2. As there are so many possible drug–drug combinations, it is useful to remember those that affect liver enzymes

and to be wary about prescribing them together. When in doubt, drug reference books listing these interactions should be consulted. Figure 16.1 summarises the common sites of drug interactions.

Table 16.2 Selected drug interactions associated with cytochrome P450 CYP ISOFORM

DRUG/DRUG GROUP

CYP INHIBITORS

CYP INDUCERS

CYP3A

calcium channel blockers protease inhibitors carbamazepine dexamethasone

azole antifungals SSRIs (fluoxetine, sertraline, paroxetine)† cimetidine

phenytoin carbamazepine dexamethasone rifampicin

CYP2D6

many antipsychotics many beta blockers codeine

SSRIs (fluoxetine, sertraline, fluvoxamine) cimetidine

CYP2C9

NSAIDs* phenytoin warfarin

azole antifungals

rifampicin

A. Drug interactions outside the body

*NSAIDS = non-steroidal anti-inflammatory drugs. †SSRIs = selective serotonin reuptake inhibitors.

B. Drug interactions in the gastrointestinal tract Gut microbe

Figure 16.1 Common sites of drug interactions

Food particle

Drug interactions can occur outside the body prior to administration, inside the gastrointestinal tract, and after gastrointestinal absorption. A Prior to administration, drugs may interact with the walls of the vessels in which they are contained or with another drug in the vessel. B While in the gastrointestinal tract, the absorption of the drug may be affected by interactions with the gut flora, food particles or other drugs. These interactions may reduce or enhance the drug’s absorption rate. C Drug actions may be altered by interactions with other drugs that act on the same cellular mechanisms, such as a surface receptor or ion channel. Drugs can also interact with liver enzyme systems to enhance or inhibit the metabolism of other drugs. A. Drug interactions outside the body

C. Drug interactions after absorption Ion channel

Cell

B. Drug interactions in the gastrointestinal tract Gut microbe

Food particle

Drug molecule Other chemical

C. Drug interactions after absorption Ion channel

Cell

CHAPTER 16 DRUG INTERACTIONS

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Drugs can interact with the environment before administration. Exposure to light, moisture, oxygen and to the walls of the vessels containing the drugs can trigger chemical changes. Drugs can be affected by the presence of certain foods in the gastrointestinal tract, which alters their absorption. Drug–drug interactions can be related to pharmacokinetic parameters, such as one drug altering the metabolism of another. Within the liver, enzymes can be induced or inhibited. Drugs can alter the activity of an important family of liver enzymes, called the cytochrome P450 enzymes. Some drug–drug interactions are pharmacodynamic, where the actions of drugs interact to either reduce or enhance the effects of each other. Synergism is where treatment with two or more drugs concurrently leads to increased therapeutic effects. Summation produces combined effects that are additive, whereas in potentiation the combined effects are more than additive.

REVIEW QUESTIONS 1 Why should thiopentone and suxamethonium, two medicines that can be administered at the same time, not be

given in the one injection? 2 What happens when a rapid-acting insulin is mixed with slower-acting insulin containing protamine? How could

this effect be avoided? 3 Why should a person on a non-selective MAO inhibitor avoid preparations such as nasal decongestants for the

common cold? 4 What is the effect of grapefruit juice on the antihypertensive agent felodipine? Explain why this occurs. 5 Two medicines are administered to a person. One of these medicines, medicine A, is acted on by a cytochrome

P450 enzyme isoform and the other, medicine B, inhibits the activity of this specific enzyme isoform. a

What is the clinical consequence of this interaction?

b Is this a pharmacokinetic or pharmacodynamic drug–drug interaction? 6 Patty Smyth is 60 years old, and has been taking the tetracycline antibiotic minocycline. She has told you the

medicine upsets her stomach and that a friend suggested she take it with a big glass of milk. You check the packaging and observe that the medicine is two weeks past its expiry date. Outline your concerns about the information that Mrs Smyth has volunteered. 7 Fred Zentell is 50 years old and is receiving treatment for his hypertension. He has been taking 10 mg mane

of medicine X, which dropped his systolic blood pressure by 10 mm Hg. He was then swapped to 250 mg of medicine Y mane, which dropped his systolic blood pressure by 15 mm Hg. His doctor has decided to get Fred to take a combination 10 mg of medicine X and 250 mg of medicine Y mane. The combination has dropped his systolic blood pressure by 25 mm Hg. a

What form of drug synergism has been described here?

b Is this an example of a pharmacokinetic or pharmacodynamic drug–drug interaction? 8 Nancy Nobel, aged 55 years, is stabilised on carbamazepine for treatment of her epilepsy. She is experiencing

severe depression following difficulties in her family situation, and the doctor considers prescribing her a course of fluoxetine, an antidepressant from the selective serotonin reuptake inhibitor group. In reading information about fluoxetine in his medication reference file, he finds that fluoxetine inhibits CYP2D6, and its active metabolite norfluoxetine inhibits CYP3A4, therefore affecting the metabolism of carbamazepine. What would be the likely effect of fluoxetine on carbamazepine blood levels if the two medicines were administered together?

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9 Orlistat, a medicine used to assist with weight loss, inhibits gastrointestinal lipases and prevents the absorption of

dietary fat. a

The absorption of what type of vitamins could be affected by orlistat?

b Would absorption of the combined oral contraceptive pill be affected if it were administered with orlistat?

Explain your answer. (Refer to Chapters 63 and 66.) 10 Missy Langer, aged 62 years, has been prescribed a course of etidronate and calcium to treat postmenopausal

osteoporosis. What would you recommend that she does in relation to taking her medicines?

C H A P T E R

17

PHARMACODYNAMICS

LEARNING OBJECTIVES

KEY TERMS

After completing this chapter, you should be able to:

Affinity

1

Define the term pharmacodynamics.

Agonism

2

Describe how some medicines act by chemical or physical modes of action.

Antagonism

3

Explain the nature of competitive and non-competitive inhibitors of enzymes.

Chemical action

4

Describe the use of competitive inhibitors of enzymes in therapeutics.

5

Describe the concept of receptors and their significance.

Competitive and noncompetitive enzyme inhibition

6

Differentiate between agonists and antagonists and their action on receptors.

Efficacy

7

List the uses that enzymes can have in therapeutics.

Pharmacodynamics Physical action Potency Receptors Specificity

Pharmacodynamics is the mechanism whereby drugs exert their effect on the body; that is, what the drugs do to the body in order for a therapeutic action to occur. To exert their therapeutic effects, drugs usually act on physiological processes. Disease is, after all, usually an alteration in the normal functioning of the body. The aim of drug therapy is to reverse any changes so that the body returns to the homeostatic state. Bear in mind that a drug does not confer absolute changes on physiological processes, but rather it modifies those processes. This modification can be either an increase or a decrease in a specific process, shifting the pathophysiological state towards normal. To illustrate this, in hypertension, the condition is characterised by excessively elevated blood pressure. Anti-hypertensive agents act to suppress one or more of the contributing processes that give rise to the higher than normal blood pressure. In bradycardia, characterised

SECTION IV GENERAL ASPECTS OF PHARMACOLOGY

by a slowing of the heart rate, drug therapy is intended to increase or enhance the activity of the heart. All bodily functions are a result of interactions of various chemicals; drugs act by interfering with these processes. Most medicines act on receptors, cellular ‘locks’ into which specific chemical ‘keys’ fit. As a result of this interaction, the medicines either mimic the normal response or block it. Some medicines act on enzyme systems, which use the same ‘lockand-key’ principle. Such interactions are, in most cases, only temporary and reversible. In a few instances, the drug–receptor or drug–enzyme interaction is permanent. Medicines that do not act on receptors or enzymes tend to act on chemical or physical processes in the body. The different mechanisms of action are now described in some detail.

DRUGS THAT WORK BY SIMPLE CHEMICAL ACTION Although almost all drugs work by a chemical process, the agents considered here are those that act on simple chemical processes in the body. These chemical processes involve basic inorganic compounds or non-complex organic compounds. A few commonly used medicines have what can be termed a direct chemical action on the body. If we consider a drug such as magnesium hydroxide (Mg(OH)2, a component of some antacid preparations), the action is simple chemistry. All this drug is required to do is to neutralise stomach acid (HCl) in the treatment of indigestion and other gastrointestinal conditions. The product of this reaction is a salt, magnesium chloride (MgCl2). This type of action can be represented by using a simple chemical equation: Mg(OH)2 + 2HCl ↔ MgCl2 + 2H2O Other examples of medicines that exert their effects through chemical action and that are described elsewhere in this book are as follows: • the chelating agents used to remove heavy metal ions from the body in cases of poisoning or in disorders of heavy metal ion handling by the body (see Chapter 22); • acetylcysteine, used both in paracetamol poisoning (see Chapters 23 and 41) and as a mucolytic (a medicine that breaks down mucus) in cystic fibrosis (see Chapter 54).

DRUGS THAT WORK BY PHYSICAL ACTION Not many medicines act by a physical mechanism, principally because not many purely physical processes

occur in the body. One of these physical activities, which is very common, is osmosis. Osmosis results when two differing concentrations of molecules are separated by a selectively permeable membrane. When a solution of high molecular concentration is separated from one of low concentration, water from the more dilute solution (with respect to solute) will pass through the membrane into the strong solution until the concentrations on both sides of the membrane are equal (see also Chapter 52). In this example, the more dilute solution actually has a higher concentration of water molecules (the solvent). In other words, water will flow from regions with a higher water concentration to those of a lower water concentration. Solutions that are at a relatively higher solute concentration or osmolarity than others are termed hypertonic, and those at lower concentration hypotonic. Those at the same concentration are isotonic. A common example of an isotonic solution is ‘normal’ saline, a 0.9 per cent solution of sodium chloride used for irrigations and formulating injections. You will probably have experienced water from a swimming pool (fresh water) entering your nasal cavity, where it causes considerable pain. This is because the water is hypotonic and causes fluid to move into mucosal nerve endings by osmosis. This movement causes swelling of these nerve endings, which results in pain. Nose drops do not cause pain, as they are isotonic to body fluids. This shows that altering osmotic pressures in body compartments causes an upset in fluid balance. Osmosis is an important factor in preserving fluid balance between body compartments. Any upset in osmolarity in these compartments will result in an imbalance. Changes in osmolarities can be brought about by using medicines to correct imbalances or cause a change in normal osmotic balances to produce a therapeutic effect. Examples of this type of medicine can be found with the

CHAPTER 17 PHARMACODYNAMICS

osmotic laxatives discussed in Chapter 57 and the osmotic diuretics discussed in Chapter 49. Another example of a physical mechanism of action is with medicines that lower the surface tension of gastrointestinal fluids to relieve conditions in which excess gastrointestinal gases are causing problems. (The medicine used in such conditions, simethicone, is dealt with in Chapter 57.) The last example of a physical action is with activated charcoal, which is used to relieve flatulence (see Chapter 56) and in cases of poisoning (see Chapters 22 and 23). Its action is as an adsorbent in both cases. The charcoal has a large surface area, which can physically bind to many materials, including gases, facilitating their removal from the body.

DRUGS THAT ACT ON ENZYMES Enzymes are biological catalysts and carry out countless reactions in the body. A catalyst is a substance that is involved in a reaction but remains unchanged itself at the conclusion of the reaction. An enzyme reacts with a substrate, and the generalised reaction is shown in the following equation: E + S ↔ [ES] ↔ E + P where E stands for the enzyme, S for the substrate and P for the product or products; ES is an enzyme–substrate complex. The arrow going both ways signifies that enzyme reactions are reversible and the direction of action is determined by the conditions under which the reaction occurs. The arrows also show that enzyme reactions are equilibrium reactions. Under constant conditions the rate of the forward reaction is constant, as is the rate of the backward reaction. An important aspect of equilibrium reactions in pharmacology is that if the product is removed or consumed by physiological processes, more enzymes will combine with the substrate to form more product. Another important concept to consider with enzymes is that they are relatively, or sometimes completely, specific for a certain substrate. Pepsin is an enzyme found in the stomach. It is classed as a protease as it breaks down proteins into polypeptides and amino acids by hydrolysing peptide bonds associated with certain amino acids. While pepsin is specific for proteins compared to fats and carbohydrates, it can break down a globulin in a similar fashion to a muscle protein. Some enzymes are much more specific than this, as they act on only one compound and are completely specific to that compound. An example is glucose dehydrogenase,

which acts only on glucose and not on the closely related sugar mannose. The specificity of enzymes in biological reactions is often likened to that of a lock-and-key mechanism. Generally, only one shape of key will unlock a door and, likewise, only one substrate will fit into the binding site of an enzyme.

Competitive inhibition Everybody has experienced the situation in which the wrong key fits into a lock, starts to turn and then sticks. The key then has to be withdrawn. If you have a bunch of keys and only one fits a given lock, it takes time to find the correct key. Consider the case where an enzyme meets a look-alike substrate, they interact at the enzymic binding site, but, because the enzyme cannot do anything with the look-alike, it is discarded unchanged. Another look-alike may then be taken up by the enzyme, and so the process is repeated until the correct substrate is met. Like searching through a bunch of keys, this process takes time and thus the rate of the normal enzyme reaction is slowed down. This slowing is even greater than with a person with a bunch of keys, who has the advantage of knowing which keys he/she has previously tried. An enzyme has no memory and may continually bind with the same look-alike. These look-alikes can be medicines used to slow down enzyme reactions. This type of action is known as competitive inhibition, as the medicine is competing with the natural substrate for access to the binding site of the enzyme (see Figure 17.1). From this, it should be clear that if the inhibitor is present in excess, the enzyme will meet it more often than the normal substrate and the normal reaction that should occur will be slowed down greatly or, in some cases, even completely inhibited. Medicines that act this way can be counteracted by increasing the substrate concentration, and this process is the basis of some antidotes. (See Chapter 48 for a description of the treatment of warfarin overdose.) There are many medicines that work like this. A good example occurs in the class of antimicrobial drugs known as sulfonamides (see Chapter  71). Sulfonamides are very similar in structure to a compound called 4-aminobenzoic acid, which is an essential component in the synthesis of folic acid, one of the B  group of vitamins. The structures of 4-aminobenzoic acid and a sulfonamide are shown in Figure 17.2. Bacteria cannot use ready-made folic acid; they must synthesise it intracellularly for their own use. Humans, on the other hand, can use only preformed folic acid. Sulfonamides are competitive inhibitors of the enzyme that uses the 4-aminobenzoic acid in the synthesis of folic acid, and thus the bacteria are starved of folic acid. Consequently,

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Figure 17.1 Competitive inhibition of enzyme–substrate reactions A The enzyme converts the substrate into a product or products without interference. B A drug that is a competitive inhibitor of the enzyme is present and competes with the substrate for the binding site of the enzyme. If the drug binds to the enzyme site, it prevents binding of the normal substrate. Enzyme action is still occurring but at a much slower rate. C The drug can be displaced from the binding site by increasing the substrate level, increasing the rate of product formation. A. Substrate reacts with enzyme

Substrate

Enzyme

Product formed from reaction

Product

B. Access to enzyme binding sites by substrate reduced by enzyme inhibitor

Less product formed

Competitive enzyme inhibitor

C. Enzyme inhibitor can be displaced by adding more substrate, restoring access to more enzyme binding sites for substrate

More product formed from reaction

CHAPTER 17 PHARMACODYNAMICS

Figure 17.2 Structures of 4-aminobenzoic

acid and a sulfonamide, sulfamethoxazole H2N

Enzyme + Non-competitive inhibitor →  [Enzyme – Non-competitive complex]

CO O H

4-aminobenzoic acid

H2N Sulfamethoxazole

The action of a non-competitive inhibitor can be represented by the following equation:

SO 2 NH N O

CH3

when they are exposed to these antimicrobial agents, they will die. Other examples of competitive inhibitors include the acetylcholinesterase inhibitors used in the treatment of myasthenia gravis (see Chapter  28), the monoamine oxidase inhibitor moclobemide, which is an antidepressant agent (see Chapter 36), and the alpha-glucosidase inhibitor acarbose, used in the management of type  2 diabetes mellitus (see Chapter 61).

Non-competitive inhibition Think back to the lock-and-key description given earlier. Sometimes when a key is inserted in a lock it turns and then sticks, and you have to get a locksmith to extract the key. A similar thing can happen with enzymes, but there are no ‘enzyme locksmiths’! Therefore, the enzyme is effectively rendered non-functional. When this happens, a stop is put to all competition; this type of inhibition is called noncompetitive and is usually irreversible (see Figure  17.3). Note that in non-competitive inhibition the inhibitor binds to a part of the enzyme’s structure that is distinct and often remote from the binding site. This causes a conformational change in the tertiary structure of the enzyme, rendering it inactive. Non-competitive inhibitors bear no resemblance to the normal substrate but are substances that combine with the enzyme in a permanent fashion. In fact, many noncompetitive inhibitors are simple metal ions such as arsenic or mercury. Arsenic compounds were used as some of the first antimicrobial agents against Treponema pallidum, the causative agent of syphilis, but are now only of historic interest. Mercury is still used occasionally in the treatment of superficial skin infections, usually in an organic form such as mercurochrome, which is less toxic to us than the inorganic forms but still fairly toxic to some microbes. It is, of course, too toxic to be used internally.

When this happens, the enzyme is inactivated and, under most circumstances, will never again carry out an enzymic reaction: that is, the reaction is not normally reversible, hence the unidirectional arrow. There are not many examples of medicines that act like this, as compounds that act as non-competitive inhibitors are not usually selective in their action, will destroy all enzymes and thus be very toxic to life in general. The socalled ‘nerve gases’ and garden insecticides are examples of fairly specific non-competitive enzyme inhibitors, which inactivate the enzyme acetylcholinesterase, which is essential at cholinergic synapses (see Chapter 28). Important medicines that do act as non-competitive enzyme inhibitors are aspirin, when used as an antiplatelet agent (see Chapter 48), and the first generation monoamine oxidase inhibitors (MAOIs) used in the treatment of severe endogenous depression (see Chapter 36). The use of the first generation MAOIs can have severe consequences, in some cases even after the medicine has been withdrawn from treatment, owing to inactivation of enzymes that the body needs time to remanufacture. This problem was overcome by the development of a more specific and reversible MAOI called moclobemide. It is relatively specific for a subtype of MAO found in the brain. These aspects are discussed in more detail in Chapter 36.

DRUGS ACTING ON RECEPTORS By now you may be aware that many processes in the body are controlled by chemicals, such as hormones or neurotransmitters. These chemicals carry out their actions usually by binding to receptors externally on the cell membrane’s surface, or internally in cytoplasm or within the nucleus. This action is, in many ways, analogous to the lock-and-key mechanism discussed above. When receptors are bound to a certain chemical, this directs a change to occur in the cell, which then alters an activity of the cell. In a way, it can be considered analogous to a key opening a lock, in a similar way to enzyme action. The lock will not open by itself, as it needs the key. Receptors are like locks needing a specific key to be opened in that they need a specific chemical in order to be activated. Substances that stimulate receptors can be termed, generally, first messengers, as they are often one element of many in the process of causing an effect. This stimulation

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Figure 17.3 Non-competitive inhibition of enzyme-substrate reactions A The enzyme converts the substrate into a product or products without interference. B A drug that is a non-competitive inhibitor of the enzyme is present and interacts with the enzyme binding site. Its binding may alter the configuration of the binding site. The substrate is prevented from interacting with the binding site, so no product is produced. C The noncompetitive enzyme inhibitor cannot be displaced from the binding site when substrate levels are increased. The enzyme may become permanently incapacitated by this drug. Enzyme activity will be restored when the incapacitated molecule is replaced by a new enzyme molecule. A. Substrate reacts with enzyme

Substrate

Product formed from reaction

Enzyme

Product

B. Access to enzyme binding site by substrate prevented by non-competitive enzyme inhibitor. Binding site may change configuration.

No product formed

Non-competitive enzyme inhibitor C. Non-competitive enzyme inhibitor cannot be displaced by adding more substrate.

cannot really be likened exactly to a switching on or off mechanism, but receptor stimulation produces conformational structural change in the receptor, which then initiates sequences of other biochemical changes. There are at least four types of receptors for first messengers (see Figure 17.4): • those linked to ion channels; • those linked to G-proteins; • those linked to tyrosine kinases; • those linked to DNA interactions (steroid receptors). For receptors that are linked directly to ion channels, the change in receptor structure allows ions to flow through the synaptic membrane to initiate the neural response. This

Enzyme remains inhibited until it is replaced by new functional one.

happens in milliseconds. For example, when acetylcholine stimulates the nicotinic receptor in motor nerve synapses, there is an immediate influx of sodium ions across the skeletal muscle membrane. When a first messenger acts on a receptor, it sometimes acts on what are known as transducer substances called G proteins. The sequence of events that takes place in the cell depends on which G  protein is activated. A common action of a G  protein is to stimulate (or in some cases inhibit) the enzyme adenylate cyclase. Adenylate cyclase, in turn, converts adenosine triphosphate (ATP) to 3´,5´-cyclic adenosine monophosphate (cAMP). In turn, cAMP can then activate many cellular functions, including the

CHAPTER 17 PHARMACODYNAMICS

Figure 17.4 Receptor sites of drug action A Receptor on ion channel. B G-protein-coupled receptor. C Tyrosine kinase receptor. D Cytoplasmic receptor for highly lipid-soluble drug that facilitates action on gene(s) within nucleus to increase/decrease gene expression. (ATP = adenosine triphosphate.) A.

B. Drug molecule binds to receptor

Drug molecule binds to ion channel

Membrane-bound enzyme

Cell membrane

Cell membrane

ATP 2nd messenger formation

G-protein complex

D.

C.

Drug molecule crosses cell membrane

Drug molecules bind to tyrosine kinase receptor

Cell membrane

Cell membrane Drug binds to cytoplasmic receptor then interacts with gene(s) within nucleus

Nuclear membrane DNA

activation of enzymes involved in energy regulation, cell division, cell differentiation and ion channel function. As cAMP causes the effect, it is known as a second messenger (see Chapter 27 for a detailed discussion). There are several different types of G  proteins, each of which can interact with different receptors and control different effectors. Thus, G proteins can also be involved in ion channels, but the response here is generally slower than that described above, where receptors are directly linked to ion channels. The series of actions with the G proteins

amplifies the response to receptor stimulation, not unlike that associated with the blood clotting or complement cascades. Some medicines can act through a direct effect on the second messenger system: an example is aminophylline, a medicine that may used in the treatment of severe asthma attacks (see Chapter 54), which inhibits cAMP metabolism. G  protein-associated receptors generally produce a moderately quick response, whereas those linked to DNA interactions are quite slow, from seconds to hours respectively.

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Tyrosine kinase-linked receptors are involved in growth and differentiation; the biochemical response time is measured in minutes, but the observable response may be much slower. For example, the growth hormone receptor initiates the signal transduction rapidly, but the observable response in cellular growth can take hours. As tyrosine kinase receptors are involved in cellular proliferation, there is great interest in the development of tyrosine kinase inhibitors as potential anticancer agents. Imatinib, gefitinib and dasatinib are examples of tyrosine kinase inhibitors available in Australia and New Zealand for the management of chronic myeloid leukaemia, non-small cell lung carcinoma and some forms of chronic and acute leukaemias respectively (see Chapter 80). Many other hormones, for example thyroxine, steroids and even some vitamins, interact with DNA. There are two processes that slow down this type of receptor action. The interacting molecule must first enter the cell and then be transported to the nucleus. When in the nucleus, the binding of the molecule to DNA results in gene expression and, as a consequence, secondary transduction can result in a decrease or increase in protein synthesis, which then can ultimately cause physiological changes. This takes hours. For example, in anaphylaxis, prompt treatment to cause an immediate reversal of bronchoconstriction and hypotension is essential. Adrenaline can achieve this by being mediated through the G proteins; however, (cortico)steroids are also usually given concurrently and, even though the response takes several hours, can prevent secondary sequelae from developing. Substances that bind to receptors can be referred to as ligands. Many drugs are similar to—or have similar chemical groups to—the naturally occurring chemical and have the ability to bind to a receptor where one of two things can happen: either the receptor will respond or it will be blocked (i.e. the drug will bind to the receptor but nothing will happen). When a drug stimulates a receptor, it is known as an agonist and therefore mimics the endogenous transmitter. Where it blocks a receptor, it is an antagonist and therefore blocks the action of an endogenous transmitter. As a result, the effects observed are often the opposite to stimulation of a receptor. When a drug acts as an antagonist, it will prevent the natural chemical from acting on the receptor. Receptor agonism and antagonism are illustrated in Figure 17.5. If the drug, an antagonist, leaves the receptor soon after binding, the action will be similar to competitive inhibition that is observed with enzymes. The drug and the natural stimulus will compete for access to the receptor. The more drug that is present, the smaller the chance of the natural

Figure 17.5 Agonist and antagonist action A The natural chemical messenger interacts with its receptor on a gated ion channel, resulting in the influx of ions into the effector cell. B An agonist drug mimics the natural response when it interacts with the receptor on the ion channel stimulating ion influx. C An antagonist drug prevents access of the natural chemical messenger with its receptor on the ion channel, so normal ion influx cannot occur. A. Natural chemical messenger stimulates receptor

Ions pass through channel as it opens

Extracellular fluid

Cell membrane

Cytoplasm

B. Agonist drug molecules stimulate receptor

Ions pass through channel as it opens

Extracellular fluid

Cell membrane

Cytoplasm

C.

Antagonist drug blocks access of chemical messenger to receptor

Extracellular fluid

Cell membrane

Cytoplasm

Ions cannot pass through channel as it remains closed

CHAPTER 17 PHARMACODYNAMICS

Figure 17.6  Relative drug potency and efficacy The graphs represent the relative responses of Drugs X and Y at a range of concentrations. A Drug X induces a set response at a lower concentration than that of Drug Y. The maximal responses of both drugs, however, are the same, indicating equal efficacy. B The maximal responses of Drug X and Y are not equal, indicating that Drug Y has lower efficacy. It is also less potent. Drug Y Greater efficacy

Drug X

Greater potency 0

Drug concentration

A

Drug X Drug Y

Greater potency 0

B

Greater efficacy

Some words often used to describe a drug’s action at a receptor site are affinity, specificity, efficacy and potency. • Affinity is defined as the extent of binding of a drug to a receptor: in other words, how good the fit is of the drug into the receptor. An analogy for drug affinity is the fit of a foot into a shoe. When your foot is bigger than the shoe, your foot juts out. When the shoe is too big, your foot sits too loosely. In both cases the affinity is not equal to 100 per cent. • Specificity relates to a degree of selectivity. One drug tends to interact with one subtype of receptors rather than another, or produces an effect at one site but not another. • Efficacy is the ability of a drug to produce an effect at a receptor. It is sometimes termed the drug’s intrinsic activity or power. When comparing efficacy between drugs, the one with the higher maximum effect is more

Students (and some clinicians) often confuse efficacy and potency, but they are certainly not the same property. Figure  17.6 is a classic pharmacological representation of the relationship between dose and response of a drug interaction with its receptor: Figure  17.6A shows how two drugs can have differing potency without differing efficacies because the maximum responses that can be induced are the same for both drugs; in Figure 17.6B, not only is one drug more potent than the other, but it is clearly more efficacious.

Drug response

Affinity, specificity, efficacy and  potency

•

efficacious. Importantly, an agonist has an affinity for a receptor and has efficacy; an antagonist has affinity but cannot have efficacy. Potency is the relative amount of drug that has to be present to produce a desired effect. It is sometimes referred to as the strength of the drug. For a more potent drug, a lower dose should to be administered to produce the desired clinical effect.

Drug response

stimulus having an action. As with competitive inhibition in enzymes, this type of antagonism can be reversed by increasing the amount of natural stimulatory chemical at the receptor sites. Drugs that displace other chemicals from receptor sites can be used as antidotes in some cases of poisoning or drug overdose. Competitive receptor antagonism can be illustrated using a simple analogy. Imagine you have a board with thousands of holes (receptors) into which round balls can be fitted, and you have both black (a chemical transmitter) and white (an antagonist drug) balls. When you pour the balls onto the board, both colours will fill the holes, and the colour that is in excess will fill more of the holes. If the chemical transmitter is in excess (black balls), the normal cellular response will occur. If the antagonist drug is in excess (white balls), the response induced by the transmitter is lessened. Occasionally drugs bind firmly and irreversibly to receptors; in these instances, antagonism will continue until the drug is destroyed. This represents a non-competitive action. There can be no antidote to this type of antagonism. Non-competitive antagonism can occur when a drug binds irreversibly to the receptor, blocking the response of the endogenous substance that interacts with this receptor. The non-competitive antagonist can bind to the same binding site as the endogenous substance or it can bind to a different site on the receptor, which consequently changes receptor conformation and alters the access of the endogenous chemical to its binding site.

Drug concentration

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Partial agonists Sometimes drugs act like the natural stimulus but to a lesser extent than the natural agonist. When a transmitter binds to a receptor, bonding occurs between the drug and the receptor. For normal action to proceed there has to be a complete match between the drug and the receptor in this bond formation. Some drugs do not fit exactly on the receptor site but still form some of these bonds: this binding is therefore not a 100 per cent fit or affinity, but is enough to initiate some response. Drugs with lower affinity are termed partial agonists (they could also be referred to as partial antagonists). As their action is less than the natural stimulus, a decrease in receptor response is achieved but not to the same extent as when using an antagonist.

Receptor modulators Another type of drug that acts at receptors is the so-called receptor modulator. This drug group is thought to have mixed activity and can work either as an antagonist or as an agonist, depending on the receptor subtype involved. At one receptor subtype they alter receptor configuration such that they antagonise the normal response. At another receptor subtype the alteration in configuration produces agonism. A group of medicines known as the selective (o)estrogen receptor modulators, or SERMS, act on oestrogen receptors around the body. These medicines are antagonistic at oestrogen receptors on breast tissue and endometrium but are agonistic for oestrogen receptors associated with bone, lipid metabolism and blood coagulation (see Chapter 63).

Inverse agonists The concept of inverse agonism or negative efficacy is relatively novel in pharmacology, and so only a brief statement regarding it is given here. The concept is that some drugs, instead of actually blocking a receptor, stimulate the receptor in such a way that the opposite effect to the normal agonistic effect is seen. This type of action may apply to many existing so-called antagonists. Much research is at present being undertaken to develop drugs that theoretically will be more efficacious than plain antagonists. Put simply, if an inverse agonist is used to control high blood pressure, the drug will actually cause a direct fall in the blood pressure rather than just block intrinsic mechanisms that cause a rise in blood pressure.

Drugs that act on ion channels Drugs that interact with receptors on ion channels are important in pharmacology. These receptors are associated with the transport of ions to and from cells. Ions such as

calcium, sodium and potassium are transported into or from cells in order to cause various physiological events. Opening or closing these channels is known as gating, and drugs can affect this gating mechanism. The initiation of these transport mechanisms often involves enzymes, as is the case with sodium–potassium transport or, in the case of calcium, stimuli associated with neurotransmission. If enzymes are directly involved, an enzyme inhibitor can block the transport. The cardiac glycoside digoxin (see Chapter  50) acts by inhibiting enzymes involved with the ATPase enzyme, which is involved in the interchange of sodium and potassium ions. In other cases, drugs that react with the receptors in the channels can prevent the transport of the ions. Like other receptors, these ion channel receptors vary in different parts of the body. This enables drugs to be made that have selectivity for specific channels. For example, the calcium channel blocker nifedipine has an action on arterioles but little action on the myocardium, whereas another calcium channel blocker, verapamil, has exactly the opposite effect (see Chapters 46, 47 and 50). Interestingly, neither of these drugs has an affinity for calcium channels in skeletal muscle. Clinical benefit may also be brought about by using drugs to open ion channels. The antianginal agent nicorandil (see Chapter  47) acts to open potassium channels in the cell membranes of arterial smooth muscle. This hyperpolarises the membrane and is thought to prevent calcium channels from opening. As a consequence, arterial vasodilation is induced. This is a particularly novel physiological approach—to open one set of ion channels so another set cannot open.

ENZYMES AS DRUGS Many enzymes are themselves used as medicines, their action being biochemical rather than chemical. There are several different uses of enzymes in therapeutics, of which the following are representative examples. Others are dealt with in subsequent chapters. In some conditions there may be a deficiency of a natural enzyme, particularly digestive enzymes. These enzymes can be replaced orally and are usually taken with food. An example is pancreatin, which is a mixture of pancreatic enzymes (see Chapter 61). Enzymes can also be used to increase the speed of absorption of injected medicines. An example of this is the enzyme hyaluronidase, which acts on hyaluronic acid, a component of tissue cement. It helps to keep cells glued together. If a medicine is injected together with this enzyme, especially by a subcutaneous injection, the medicine will be

CHAPTER 17 PHARMACODYNAMICS

absorbed faster and with less discomfort to the person than when large volumes are injected. Enzymes are sometimes used to destroy unwanted materials in the body. An ancient example of this is the application of leeches to bruises. When a leech bites, it injects some of its saliva, containing a mixture of proteins and enzymes, which prevents blood clotting. Enzymes can also destroy preformed blood clots, such as those found in bruised tissue. Many of these substances have now been identified, and will probably be used to treat blood coagulation disorders in the future. Examples are hirudin, which inactivates thrombin; destabilase, which depolymerises fibrin; and haementin, which cleaves aggregated platelets. Finally, an enzyme can be used to destroy a substrate within the body. One example of this is the enzyme asparaginase (or colaspase) used in the treatment of some types of cancer (see Chapter 80).

Note that the action of a medicine is its effect at the cellular or biochemical level, whereas therapeutic action is the end result of a drug action. For example, the action of aspirin is as an enzyme inhibitor but its therapeutic action is in the production of analgesia.

DOSAGE AND ACTION In general, a medicine that acts by chemical or physical means can be identified by its dose, which is considerably higher than that required by medicines that act by interacting with a receptor or enzyme system. Antacids are usually given in gram quantities, and anaesthetics in large volumes for considerable periods of time, whereas many medicines that act on receptors often act with a total administered dose of micrograms or, more often, milligrams. This type of categorisation cannot always be relied on, as there are exceptions to this rule: for example, the normal dose of paracetamol for an adult is 1 g.

CHAPTER REVIEW ■■

The general term for the mechanism of action of drugs on the body is pharmacodynamics.

■■

Pharmacodynamics can, in a few instances, be due to physical or chemical changes induced by drugs.

■■

Most pharmacodynamic activity is due to the action of drugs on enzymes or receptors within the body.

■■

■■ ■■

■■

■■ ■■

■■

Drugs can inhibit enzymic activity irreversibly, but most drugs that act on enzymes reversibly inhibit enzyme activity. Irreversible inhibition is termed non-competitive and reversible inhibition, competitive. Drugs that act on receptors can either stimulate the receptor or inhibit (block) receptor activity. Drugs that stimulate receptors are termed agonists and those that block receptors are antagonists. Affinity is the tendency for the drug to bind to the receptor. Specificity relates to the ability of a drug to produce an effect at one site but not another. Efficacy is the ability of the drug to activate a receptor. Potency is the relative amount of drug required to produce an effect. Agonists have both efficacy and potency, but an antagonist cannot have efficacy. Receptor stimulation is usually the first step in a cascade of events at the cellular level. For this reason, the interaction between drug and receptor may be called the first messenger. A second messenger may facilitate the change in cellular activity that leads to the effect. An important second messenger involved in drug responses is cyclic adenosine monophosphate (cAMP).

REVIEW QUESTIONS 1 Differentiate between the terms pharmacodynamics and pharmacokinetics. 2 Define the following terms: a

affinity

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b efficacy c

potency

3 Drug A is administered to a person and acts on a particular receptor. Unfortunately, it is given in overdose. Drug B

is then administered, which blocks that receptor. The effects of drug B result in a reduction in the effect of drug A. Is drug A acting competitively or non-competitively? 4 For each of the following examples, indicate whether the drug is acting on a physical process, chemical process or

enzyme system. a

Drug is used as an antidote in lead poisoning and acts by binding to lead particles in body.

b Drug acts as a diuretic (increases urine production) by loading the kidney filtrate with an increased number of

large particles. c

Drug competes with alpha-glucosidases in intestines to reduce glucose conversion from disaccharides.

d Drug acts to reduce flatulence by reducing the surface tension of intestinal gases. 5 State the appropriate pharmacodynamic term to match the description relating to drugs that act on receptors. a

The capacity to produce the desired effect at a lower dose than another drug.

b The capacity to bind with a receptor. c

The capacity to activate a receptor. At the same dose, one drug produces a stronger effect than another.

d A drug that prevents a receptor from being stimulated. e

The structure which, when activated, triggers its characteristic effects.

f

The ability to produce an effect on a particular target tissue.

g A drug that activates a receptor. 6 The natural response of stimulating a receptor on the heart muscle is to slow the heart rate. A drug is given that

acts on this receptor, resulting in a raised heart rate. a

Is this drug an agonist or an antagonist?

b Would you expect this drug to have affinity and efficacy? 7 What is the difference between a partial agonist and a receptor modulator? 8 State the relative time course of the effects observed when the response of a first messenger is linked to each of

the following receptor systems: a

DNA interactions

b ion channels c

a G protein linked to an ion channel

9 Agnes Mooranda, aged 66 years, is experiencing elevated blood pressure and her doctor wants to commence

her on a calcium channel blocker. Which one of the following two calcium channel blockers is likely to assist with her condition—nifedipine or verapamil? Explain your answer by referring to their effects on the transport of ions to and from cells in various areas of the body. 10 Mirando Minto, aged 72 years, has been taking buprenorphine patches to treat her chronic back pain.

Buprenorphine is a partial agonist. Explain what is meant by the term partial agonist, and give an example of an analgesic medicine that is a full agonist.

C H A P T E R

18

D R U G D E V E L O P M E N T, E VA L U AT I O N A N D S A F E T Y

LEARNING OBJECTIVES

KEY TERMS

After completing this chapter, you should be able to:

Adverse drug reactions

Briefly outline the process of evaluation and approval of new drugs in Australia and New Zealand.

Drug development

2

Define the terms margin of safety and therapeutic index.

Drug teratogenicity

3

Briefly outline how unwanted drug effects arise and differentiate between predictable and unpredictable reactions.

Drugs in pregnancy

4

Describe the underlying pathophysiology of drug allergy and state examples of differing degrees of allergic severity.

Lactation and drugs

5

Describe the pharmacological properties that influence drug transfer both across the placenta and into breast milk.

Placental drug transfer

6

Describe the factors that determine the teratogenic potential of drugs once they enter the embryonic/fetal circulation.

1

Drug safety

Hypersensitivity Margin of safety Therapeutic index

In this chapter, an overview of the process of new drug testing and evaluation is presented. The drug development process not only involves a determination of the effectiveness of a new drug but also includes an assessment of its toxicity. A potential clinical drug must be judged not only on its clinical benefit but also on the harm it might do. The discussion of aspects of drug safety involves the nature of adverse drug reactions, drug hypersensitivity, as well as placental and breast milk transfer. For many drugs there is a wide margin between a therapeutically effective dose of a drug and one that is toxic. For others, there is a fine line between safe and unsafe dosage; these medicines are considered highly toxic. In such instances, the costs of crossing this line have to be weighed against the benefits to the person receiving treatment. One example is in the cytotoxic therapy of cancer sufferers (see Chapter 80); another is the use of certain antimicrobial agents in the treatment of serious infection (see Section XIV).

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NEW DRUG EVALUATION AND APPROVAL Drug manufacturers commit significant amounts of time, money and other resources to the development of  new therapeutic agents. In Chapter  1, the nature of screening chemicals isolated from plants, animals and other sources for therapeutic effects was outlined. Once a potential medicine is identified, it is subjected to a battery of assays and other tests in living biological systems. A time line of the drug evaluation process is represented in Figure 18.1. It is worth noting that there is considerable controversy regarding the process of drug discovery and evaluation. From the pharmaceutical industry’s point of view, the commercial risks are substantial. The time taken and the costs involved in drug development have dramatically risen, while the number of new drug approvals by government authorities has decreased. The cost of drug development increases substantially at each stage, and can reach billions of dollars by the time the drug has been launched on to the market. On the other hand, consumer advocacy groups have argued that the pharmaceutical industry has falsely inflated the actual development costs in order to justify long periods of exclusive patent protection and high pricing of new medicines. Before any human testing can commence, potential drugs are tested on cells in tissue culture and on a variety of animal species in order to establish a chemical and pharmacological profile. The agent is described in terms of its chemistry, its probable physiological mechanism of action (and whether it is antagonistic or stimulatory on its physiological system), its therapeutic uses, its potency and efficacy, as well as its toxicity. The safety tests determine a drug’s acute toxicity

(indicating tissue targets for damage resulting from high single doses), subacute toxicity (repeated doses given over a prolonged period of days in order to reveal tissue targets for damage and the potential for toxicity resulting from drug accumulation) and chronic toxicity (repeated doses for a period of months to assess the safe therapeutic and toxic dose ranges). These tests should also assess its carcinogenic potential and its reproductive toxicity (affecting fertility, implantation, embryonic and fetal development, as well as its effects on the breastfed infant). The drug is then ready for testing on humans. Approval for human clinical trials is granted by a government authority after a thorough examination of all the known data about the drug. The government drug regulatory agencies that oversee the evaluation of new drugs in Australia and New Zealand are the Therapeutic Goods Administration (TGA) and the Medicines and Medical Devices Safety Authority (MedSafe) respectively. A new regulatory agency, called the Australia New Zealand Therapeutic Products Agency, may eventually replace both these organisations with the aim of providing a more coordinated approach. There are four phases of clinical trial testing when drugs are ready to be tested in humans. Phase  I clinical trials involve investigating the pharmacodynamics and pharmacokinetics of a small number of healthy volunteers in open label or single blind trials. In this phase, the maximum tolerated dose is determined, which is the lowest dose that cannot be tolerated before acute toxicity occurs. Phase  II clinical trials are dose-ranging studies to find therapeutically effective and safe dosages that can be administered. They are usually conducted in patients who are at risk of adverse effects. These clinical trials are single or double blind, or parallel or crossover in design. Phase III

Figure 18.1 Time-line and costs for development and evaluation of new drugs 0 yrs

Drug screening phase Identification of potential therapeutic agent.

Costs

10 yrs

Pre-clinical testing Drug chemistry, mechanism of action, therapeutic use, potency, efficacy described. Acute, subacute, chronic and reproductive toxicity tested. Carcinogenic potential identified.

Human clinical trials Safety, potency and efficacy in humans described.

Pharmacovigilance Post-marketing monitoring for safety and effectiveness.

$billions

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clinical trials are double blind, randomised and controlled studies that include people who have clinical manifestations of a particular disease. Phases I to III are the pre-marketing phases of clinical trials. Phase  IV clinical trials relate to post-marketing surveillance (‘pharmacovigilance’) of treated patients, which rely on data from spontaneous adverse reactions reports. Pharmacovigilance refers to the ongoing monitoring of safety and usage, not only of newly introduced drugs but of all drugs available on the market. In many clinical trials, a currently licensed medicine is used instead of a placebo because the participant is a sick person who ethically cannot be denied drug treatment for his/her illness (or if drug therapy was withheld the participant might self-medicate, which could invalidate the trial results). After the clinical trial is completed a final report is submitted to the government therapeutic goods authority for approval to market the drug. In Australia and New Zealand, it is the ministerial council of the ministers responsible for health that makes this decision on the recommendations of its drug regulatory authority. In order to get approval, the pharmaceutical company must demonstrate that the new agent is quantitatively better (usually in terms of the quality, safety and efficacy) than drugs currently available. As human clinical trials comprise only a few thousand participants, serious adverse effects may go undetected, not manifesting until the drug is used by tens of thousands or millions of people, or after a prolonged period of community use. A case in point is the worldwide withdrawal in 2004 of the COX-2 inhibitor refecoxib (Vioxx), a drug used in the treatment of arthritis (see Chapter  41). Refecoxib was shown to significantly increase the risk of myocardial infarction, but the adverse effect was not widely reported until after the drug was released into the market. With the growth in community use of complementary medicines in Western countries, the drug regulatory authorities also oversee the evaluation and regulation of complementary health care products. The lawful supply of medicines in Australia requires that they are approved in the Australian Register of Therapeutic Goods (ARTG). Products may be registered and have an AUST R number on their label, or they may be listed and have an AUST  L number. Medicines that are registered include all prescription medicines, vaccines, over-thecounter medicines, and a small number of complementary medicines. Approval of AUST  R preparations is based on an examination of their quality, safety and efficacy. AUST L preparations, on the other hand, comprise complementary medicines, including herbal medicines, vitamin and mineral supplements, other nutritional supplements, traditional Chinese medicines and aromatherapy oils. To be listed as

an AUST L preparation, it must not contain substances that are prohibited imports or come from endangered species. An AUST  L preparation must be supplied with a list of permitted ingredients on its container. If there is evidence to support the efficacy of an AUST L medicine in treating serious illness, the manufacturer can apply for registration as an AUST R product.

DRUG EFFECTIVENESS AND SAFETY The aim of therapeutics is to maintain the plasma drug concentration within its known effective range and thus avoid the extremes—ineffective at one end and toxic at the other. The dose range that places the plasma concentration within this effective level (between the minimum effective concentration and the maximum safe concentration) is called the margin of safety (see Figure 18.2). For all drugs there is a minimum effective concentration, below which there will be no therapeutic effect. This is often termed the MEC. Likewise, there is usually a concentration of drug in plasma which, if exceeded, will result in the development of toxicity. This is the maximum safe concentration (MSC). With many drugs it is important that the concentration of the drug in the blood not fall below the MEC; therefore, the drug must be given at regular intervals once steady-state conditions have been attained. The further apart the MEC is from the MSC, the safer a drug will be. The safety of drugs can be expressed in another way, by extrapolating their effects on animals, such as mice. This is done by giving a large number of mice a drug, then finding out at what dosage 50 per cent of the mice show an effective therapeutic response. This dose is termed the effective dose 50, or ED50. The dose that is toxic to 50 per cent of the animals is then obtained experimentally, and this is the toxic dose  50, or TD50. The ratio of these two parameters is the therapeutic index (TI), and the larger this figure, the safer the drug (with improved experimental procedures during drug trials, humans can be used to obtain these figures, which are of much greater value). It can be calculated as follows: TI =

TD50 ED50

For a number of drugs, the margin of safety can be so narrow (or, put another way, the TI so low) that individual variations in pharmacokinetics can be enough to push the drug towards the toxic extreme. Examples of medicines in this category are digoxin, the cardiac glycoside used in the treatment of congestive cardiac failure and dysrhythmia (see Chapters 50 and 51), the mood stabiliser

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Figure 18.2 Graph of blood drug concentration showing the margin of safety The graph shows the range of blood concentrations that are considered therapeutic for any drug. Concentrations above the toxic threshold (maximum safe concentration) would cause serious harm, while concentrations below the subtherapeutic (minimum effective concentration) threshold would be inefficacious. Blood concentrations between these thresholds would be the most effective therapeutically. The range of doses that would produce blood concentrations lower than the toxic threshold but above the subtherapeutic threshold represents a drug’s margin of safety. Toxic threshold Drug blood concentration (units)

174

Therapeutic range

Margin of safety

Subtherapeutic threshold

Time (days) Dose administered

lithium (Chapter  36), and the aminoglycoside antibiotics gentamicin and tobramycin (see Section XIV). For these drugs, plasma levels must be monitored during therapy in order that toxic levels are not reached. For other drugs, such as the penicillins, the margin of safety is very broad (the TI is high), offering the clinician a choice of a wide range of doses considered both safe and therapeutic.

Missed doses A common question asked regarding drug dosages is what to do when a dose is missed? There is no single answer to this question, as it depends on the drug and what the drug is being administered for. A general rule is that a drug with a long half-life should be taken at the normal dose when next due; or, in the case of short half-life drugs, double the dose should be given at the next dosage time. The second option should normally be used only with drugs with a high margin of safety. If in doubt, and if the situation seems to warrant it, a pharmacist should be consulted or the manufacturer contacted. Most large pharmaceutical companies have hotline numbers to deal with such queries. Any deviation from the norm should be recorded.

ADVERSE DRUG REACTIONS Another consideration is the frequency and nature of the adverse reactions or unwanted effects observed after the

administration of drugs. Drug side-effects usually arise out of an alteration of similar physiological processes at sites distant from the primary site of action. Consider the instance where a medicine is administered for the purpose of altering the heart rate. It does this by stimulating a population of receptors on the myocardium. However, it also induces an undesirable alteration in gut motility, because that type of receptor is located on this tissue as well. The Scottish physician and textbook author Sir Derrick Dunlop, renowned for his work on drug safety in the United Kingdom during the 1960s, once said, ‘Show me a drug with no side-effects, and I’ll show you a drug with no actions’. Unwanted effects can manifest as either side-effects or idiosyncratic effects. In this book, a clear distinction is made between these types of adverse reactions. A side-effect is an unwanted effect of the medicine related to its action at other sites in the body. It is predictable (a type A reaction), and its intensity often relates to dosage. Obviously, side-effects are context-specific. For a person with bradycardia taking an antimuscarinic agent such as atropine (see Chapter 28), urinary retention is a side-effect. However, for an incontinent person on the same drug, the urinary retention is therapeutic. More unpredictable and variable are allergic reactions and idiosyncratic drug effects (type  B reactions). These reactions do not occur in every patient who receives the

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drug, and the seriousness of the reaction is sometimes unrelated to the dose administered. An example of such a reaction is the potentially fatal allergic reaction called anaphylaxis. (This is discussed below.) Idiosyncratic drug effects occur infrequently, affect a very small proportion of people and are related to the individual’s genetic make-up. (Such reactions are discussed in detail in Chapter 19.)

Figure 18.3 Type I hypersensitivity reaction 1 Antigens enter body

2 Differentiated B cell secretes IgE antibodies

3 Antigen–antibody interaction neutralises antigen

4 Excess IgE antibodies bind to tissue mast cells and blood-borne basophils

5 Antigen re-enters body (may be years later)

6 Antigen–antibody interaction triggers mast cell/basophil degranulation and release of chemical mediators. Mediators induce clinical manifestations

DRUG HYPERSENSITIVITY Hypersensitivity reactions to drugs are characterised by inappropriate immune responses of an allergic type to the administered therapeutic agent. There are four types of drug hypersensitivity reaction: type I (anaphylaxis), type II (cytotoxic), type III (serum sickness) and type IV (delayed). Known hypersensitivity to a particular medicine is always a contraindication for its use. Therefore, simply asking a person whether he/she is allergic to the medicine you are about to administer is an important part of the general role of the health professional in regard to drug therapy.

Type I hypersensitivity The most severe form of type  I hypersensitivity is a lifethreatening reaction called anaphylactic shock. On entering the body the drug, alone or in combination with an endogenous protein such as a hapten, acts as an antigen. An immune response is triggered by its interaction with specific IgE antibodies. Excess IgE antibodies bind to basophils and tissue mast cells. Subsequent re-exposure to the antigen causes the rupture of the membranes of mast cells and basophils, resulting in the systemic release of chemical mediators from these cells (see Figure 18.3). This induces a widespread vasodilator response, which consequently produces a state of circulatory shock. The mediators also trigger spasms of bronchial and gastrointestinal smooth muscle, resulting in severe respiratory distress and abdominal cramping. The treatment of anaphylaxis involves ice packs over the injection site to reduce systemic absorption, and administration of the adrenergic agonist adrenaline, which produces vasoconstriction, bronchodilation and relaxes the gut muscle (see Chapter 27). The intensity of the reaction varies from individual to individual and often depends on the access of the antigen to the bloodstream. If the antigen remains confined to one region, it will produce only a localised anaphylactoid reaction, simply called an allergy. Hay fever is an example of a localised allergic reaction of the upper respiratory tract. A localised anaphylactic reaction of the skin usually manifests as an urticarial skin rash.

Type II hypersensitivity Type II hypersensitivity reactions occur when an absorbed drug binds to the surface of blood cells and consequently induces antibody production. On subsequent exposure to the drug, the antibody–drug combination triggers blood cell lysis through complement fixation (see Figure  18.4). Depending on the blood cell type involved, this reaction leaves the affected individual in a state of anaemia, thrombocytopenia or agranulocytosis. Antimicrobial drugs such as the penicillins and sulfonamides (see Section  XIV) have been reported to produce type  II hypersensitivity.

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Figure 18.4 Type II hypersensitivity reaction 3 Complement activation leads to cell lysis

Figure 18.5 Type III hypersensitivity reaction A.

Antibodies bind to antigens in blood. Complex leaves bloodstream

2 Antibodies facilitate activation of complement

Antibody–antigen complexes enter tissue and bind to basement membrane

1 Antibodies bind to cell antigens

Type III hypersensitivity Type  III hypersensitivity involves an interaction between circulating antibodies to the therapeutic agent while it is present in the plasma. The antigen–antibody interaction leads to the formation of an insoluble complex that precipitates out of the blood and into the tissues. Within the tissues, the complex elicits an inflammatory reaction that severely damages the surrounding tissue (see Figure 18.5). Common sites of deposition include the skin, kidneys and joints. The manifestations usually include fever, skin rash, protein in the urine and swollen lymph nodes. Immunostimulants such as antivenoms (see Chapter  22), antitoxins and other antisera raised in non-humans (see Chapter  79) are usually associated with this form of hypersensitivity.

B.

Antibody–antigen complexes attract immune cells (such as polymorphs) that damage tissues

Type IV hypersensitivity Type  IV hypersensitivity reactions depend on an interaction between the drug and T  lymphocytes (see Figure 18.6). The underlying response is delayed at least 12 hours after exposure to the drug, and is characterised by an inflammatory skin reaction. Manifestations of delayed hypersensitivity can include redness, induration, blistering and scaly skin. Drug-related contact dermatitis and eczema are examples of this form of hypersensitivity. Another type of delayed hypersensitivity reaction is photosensitivity. In this condition, ultraviolet light from the sun enhances the antigenic quality of the drug. This is of particular importance to people living in this region of the world, who are not only exposed to the sun for much of the year but actively pursue an outdoor lifestyle. Medicines that induce photosensitivity include some antibiotics (see Section XIV) and the phenothiazine antipsychotic drugs (see Chapter 34).

PLACENTAL TRANSFER INTO THE FETAL CIRCULATION The transfer of drugs from the maternal circulation across the semipermeable placental barrier into the embryonic/ fetal circulation is dependent on three factors: the physicochemical properties of the drug itself, transplacental transport systems and the dose of the drug. The capacity of the placenta for limiting access to the fetal circulation through metabolic processes is also an important factor influencing placental drug transfer, and is considered here.

Physicochemical drug properties The physicochemical properties of the drug determine the nature of the interaction at the placental interface. Molecular size, solubility, degree of ionisation and affinity for plasma

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Figure 18.6 Type IV hypersensitivity reaction

1 Th cell becomes sensitised to cell antigens

2 Th cell presents to resting macrophage. Activates macrophage through release of cytokines

3 Activated macrophage attacks cell bearing antigens

proteins influence the rate and extent of absorption into the embryonic/fetal circulation. (To some degree, this has already been discussed in Chapters 14 and 15, which cover pharmacokinetics.) The size of the drug is determined by its molecular weight. Drugs with molecular weights under 500 daltons cross into the fetal circulation with ease. Drugs with molecular weights between 500 and 1000 daltons can still cross the placenta, but more slowly. Drugs with higher molecular weights are restricted to the maternal circulation. Lipid-soluble drugs readily cross the placenta and exert their effects on the developing conceptus. However, their effects may be short-lived as they rapidly move back into the maternal circulation. The amounts of lipid-soluble drug in the embryonic/fetal circulation are largely determined by placental blood flow. Water-soluble drugs cross the placenta less easily because they readily form ions. Water-soluble drugs cross membranes most efficiently when they are in a non-ionised form. For acidic drugs the greatest proportion of un-ionised drug occurs at acidic pH values; for basic drugs this occurs at alkaline pH values (see Chapter 14). That is not to say that the ionised portion cannot transfer across the placenta, but, relative to that of the un-ionised portion, the transfer rate is slow and the extent is marginal. In this instance, placental permeability to ionised drugs is largely determined by the magnitude of the concentration gradient across this barrier. Furthermore, drugs that are highly ionised at physiological pH tend to bind to maternal plasma proteins. This further impedes placental transfer,

as only the unbound fraction, a relatively small portion of the total blood drug concentration, is free to cross into the embryonic/fetal circulation.

Transplacental transport The movement of drugs across the placenta is also dependent on exchange systems. Passive diffusion down a chemical concentration gradient is by far the most common transplacental drug transport mechanism. However, a growing number of drugs have been found to gain access to the fetal circulation via active, energy-dependent transport systems within the placenta that move these substances out of the cytoplasm against their concentration gradients. These drugs become substrates because they are structurally similar to the natural substances that use these pumps. For example, the transplacental transfer of the amphetamines is achieved via serotonin, noradrenaline or monoamine transporter proteins. Interestingly, some drug molecules can bind to placental tissue irrespective of their solubility, which reduces the amount of drug entering the fetal circulation. As an example, the local anaesthetic bupivacaine is far more lipid-soluble than lignocaine, but relatively less of the former enters the fetal circulation as a consequence of placental tissue binding. The adenosine triphosphate (ATP)-dependent membrane pumps are also very important in the removal of potentially toxic medicines from the fetal circulation. They are known as the permeability-glycoprotein (P-gp) transporters, multidrug resistance proteins or ATP-binding cassette proteins (see Chapter 19). A wide range of medicines from key drug classes are recognised as substrates to these pumps including anticancer agents, immunosuppressants, corticosteroids, antiviral agents used in the management of HIV/AIDS, cardiac drugs, antibiotics, antipsychotic agents, narcotics, and the statins used to lower blood lipid levels.

The effect of drug dose Another contributing factor to placental transfer is the drug dose. Obviously, the higher the plasma drug levels in the maternal circulation, the greater the magnitude of the concentration gradient across the placenta. Therefore, under these circumstances one would expect higher drug concentrations within the embryonic/fetal circulation.

Placental drug metabolism The placenta has some capability as a site of drug metabolism, but these processes are not considered a major impediment to drug transfer. A number of cytochrome P450 (CYP) isoforms are present in the placenta to carry out phase I metabolism. It appears that these enzymes are

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more abundant during the first trimester, at a time when the developing human is most susceptible to birth defects, compared with late pregnancy. Glutathione, sulfate and glucuronide conjugation comprise the placental phase  II reactions. As in the liver, the process of conjugation makes drugs and other chemicals more water-soluble in order to facilitate their elimination.

DRUG TERATOGENICITY Having discussed the rate and extent of placental transfer, in terms of drug safety the most important consideration, once a drug has entered the circulation of the developing conceptus, is whether it will cause harm in the form of birth defects. Medicines that cause morphological defects in the developing human in utero are called teratogens. Tissue growth and development is dependent on the rate at which cell division occurs. Therefore, drugs that affect cellular proliferation are most likely to cause major morphological abnormalities in the developing human if they can cross the placenta. Examples of drugs to avoid during pregnancy because they impair cell division are most antimicrobial agents and the drugs used in cancer therapy. Not all organ systems and structures develop at the same time. The nervous system and heart develop first, followed later by sense organs, digestive system, then limbs. Irrespective of which structure develops first, all tissues are most susceptible when they are undergoing optimal rates of proliferation. It follows, therefore, that the timing of drug exposure determines the extent of damage. The conceptus is most susceptible as an embryo during the first trimester (i.e.  the first three months of pregnancy), when body structures are forming. After this time all structures undergo further development but no new ones form. Some drugs need to be avoided only during one trimester (usually the first), while others are so toxic they are contraindicated throughout pregnancy. Many studies have been conducted on both animals and humans to determine the risk of drug teratogenicity. In Australia and New Zealand, drugs are categorised from no evidence of increased teratogenicity to demonstrable teratogenicity (see Table   8.1). This information is now included for specific medicines in clinical references such as the Australian Medicines Handbook (AMH), MIMS Annual and New Ethicals Compendium.

DRUGS AND LACTATION As most drugs administered during lactation pass into the breast milk, there may be clinical implications for newborn babies from such exposure. The problem is that

for many drugs, the effects on breastfeeding infants are not yet known. As a consequence, negative attitudes to drugs and breastfeeding prevail. Maternal compliance with drug therapy during breastfeeding is relatively poor, even when the medicines, such as the penicillins, are considered safe. Clearly, there is a need to understand more about the nature of drug transfer into breast milk and the clinical consequences of this phenomenon. The factors that determine placental transfer also contribute to entry into breast milk—drug molecular size and solubility, ionisation, as well as affinity for plasma protein. As a general rule, small lipophilic molecules that are positively charged (cations) and have poor plasma protein binding are more likely to be deposited into and accumulate within breast milk. As is the case for the placenta, there is also evidence emerging of carrier-mediated transport across the mammary glands for some drugs. The effects on the breastfeeding infant vary greatly from drug to drug. Narcotic analgesics, antianxiety agents and hypnotics can have profound effects on the breastfeeding infant, causing central nervous system depression, whereas the effects of many antibiotics are relatively insignificant at this time of life (although the exposure may sensitise the child for drug hypersensitivity reactions later in life). In the literature, there are reports of toxic reactions in breastfeeding infants to a number of drugs, including the β-blocker atenolol, caffeine, the antidepressant fluoxetine and the salicylates (the group to which aspirin belongs). In order to better predict the degree of drug transfer into breast milk, research has focused on developing improved methods of measurement. Much has been made of the milk to plasma concentration (M/P) ratio. This involves measuring the concentration of a drug in the milk and plasma and then extrapolating to other doses or human subjects. This method provides a good measure of drug excretion and accumulation in breast milk. However, final drug concentrations in the infant’s blood are also influenced by the maternal dose, amount of milk consumed, the composition of the milk (this changes over several weeks postpartum and can change during a feeding period), and the time interval between maternal absorption and when the infant was fed. Thus, an infant’s exposure to the drug over a time period is considered a more useful measure. The ‘exposure index’ is a relatively new concept that takes into account the M/P ratio and these other factors, as well as the ability of the infant to clear the drug from its body. The kidneys and liver are relatively immature at birth, but do undergo significant development over the first few months of life, so exposure to drugs via the breast milk is going to be more significant in early infancy than at a later

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Table 18.1 Categorisation of medicines in pregnancy CATEGORY

DESCRIPTION

EXAMPLES

A Drugs taken by large numbers of pregnant women and women of childbearing age

No proven increase in occurrence of fetal damage or other proven harmful effects on the fetus.

penicillin G or V (Ch. 72) erythromycin (Ch. 72) paracetamol (Ch. 41)

B Drugs taken by limited number of pregnant women and women of childbearing age

No proven increase in occurrence of fetal damage or other harmful effects on the fetus.

B1 subcategory

Animal studies have not produced evidence of increased incidence of fetal damage.

oestrogens (Ch. 63) ipratropium (Ch. 54)

B2 subcategory

Animal studies may be inadequate but available data have not produced evidence of an increased incidence of fetal damage.

mefloquine (Ch. 76) aciclovir (Ch. 77)

B3 subcategory

Animal studies have shown evidence of fetal damage but the significance to humans is unclear.

carbamazepine (Ch. 38) dopamine (Ch. 27)

C

Drugs that have caused or are suspected of causing fetal harm without causing malformations. Harmful effects may be reversible.

antipsychotics (Ch. 34) benzodiazepines (Ch. 35)

D

Drugs that have caused or are suspected of causing higher occurrences of fetal malformations or irreversible damage.

aminoglycosides (Ch. 72) cytotoxic antibiotics (Ch. 80) antiseizure drugs (Ch. 38)

X

Drugs with a high risk of causing irreversible damage. They should not be used during pregnancy or when there is a possibility of pregnancy.

isotretinoin (Ch. 82)

stage. The exposure index is simply defined as 100 × M/P ratio × (milk intake/infant drug clearance) and is expressed in units of mg/kg/min. Clinical references, such as the AMH, the MIMS Annual and New Ethicals Compendium, advise that in the absence

of clinical data, the potential risk to the child must be carefully weighed against the benefits of taking the drug. Nowadays, these clinical references include a section with available data on the potential risks of specific medicines to an infant during breastfeeding.

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CHAPTER REVIEW ■■ ■■

■■

■■

■■

■■

■■

■■

■■

New drugs are submitted to an evaluation and approval process by an appropriate government body. Any new drug is submitted to an evaluative process that describes its chemistry, physiological effects, therapeutic uses and toxicity. The new drug is then subjected to human clinical trials. Even if the new drug is approved for marketing, it is still subjected to ongoing monitoring of safety and effectiveness. The margin of safety defines the plasma drug concentrations that are therapeutically effective and safe and those that are considered toxic. A narrow margin of safety indicates a potentially toxic drug. Another measure of drug safety is the therapeutic index. A low therapeutic index indicates a potentially toxic drug. Adverse drug reactions are unwanted drug effects that may derive from the drug’s action in other body tissues (side-effects), allergic reactions, and those which are idiosyncratic (derive from differences in genetic make-up). Drug hypersensitivity reactions are characterised by inappropriate immune responses to the presence of a drug. There are four distinct types: type I (anaphylaxis), type II (cytotoxic), type III (serum sickness) and type IV (delayed). Placental transfer of drugs into the fetal circulation is largely determined by the drug’s physicochemical properties and the drug dose. Some drugs may damage the developing human in the womb. This property is called teratogenicity. The risk of damage is represented as an alphabetical category (A, B, C, D, X). However, different tissues and organs are more susceptible at certain times during pregnancy. Therefore, some drugs are contraindicated only during certain periods in pregnancy. Most drugs administered during lactation will pass into breast milk. The effect on the infant varies from drug to drug. For a significant number of drugs, the effects on an infant are unknown.

REVIEW QUESTIONS 1 Name the government drug regulatory agencies that oversee the evaluation of new drugs in Australia and

New Zealand. 2 What is the difference between acute, subacute and chronic toxicity? 3 In order to get approval, what must a pharmaceutical company be able to demonstrate regarding a new drug? 4 Explain why a double-blind experimental design is appropriate in human clinical drug trials. 5 Briefly describe two ways in which drug safety can be expressed. 6 What are the options regarding missed drug doses? 7 Determine whether the following drug effects should be generally regarded as predictable or unpredictable

effects: a

drug allergy

b pupil dilation c

dry mouth.

8 For each of the following reactions, indicate the type (or types) of hypersensitivity to which it belongs: a

photosensitivity

b joint pain and swollen lymph nodes c

bronchoconstriction, abdominal cramping and circulatory collapse

d thrombocytopenia e

blistered, red and scaly skin.

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9 Comment on the expected degree of drug transfer across the placenta (or into breast milk) for a medicine that is a

water-soluble drug that is 90 per cent bound to plasma proteins and has a molecular weight of 5000 daltons. 10 Classify the following drugs into an appropriate risk category for use during pregnancy: a

aciclovir

b erythromycin c

dopamine

d antiseizure drugs. 11 Jan Wallace, aged 33 years, is 32 weeks’ pregnant. She develops an acute bacterial sinusitis infection caused by

Streptococcus pneumoniae. After visiting her doctor, Ms Wallace is prescribed a 14-day course of oral amoxycillin. In view of her advanced stage of pregnancy she is rather concerned about having to take an antibiotic. Using a suitable clinical drug reference, determine the drug category in pregnancy to which amoxycillin belongs. Should Ms Wallace be worried about taking the amoxycillin preparation? 12 Give two examples of the types of medicines that are registered with an AUST R number and two that are listed

with an AUST L number. 13 Identify the phase of clinical trial testing relating to the following situations: a

Investigating a small number of healthy volunteers in open label or single blind trials.

b Double blind, randomised and controlled studies that include people with the disease. c

Dose-ranging studies to find therapeutically effective and safe dosages in patients who are at risk of adverse effects.

d Post-marketing surveillance or pharmacovigilance of treated patients.

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LEARNING OBJECTIVES

KEY TERMS

After completing this chapter, you should be able to: 1

Define the terms pharmacogenetics and genetic polymorphism.

Cytochrome P450 enzymes

2

Describe how genetic polymorphism can affect drug responsiveness at the population level.

Fast metabolisers

3

Outline how genetic polymorphism can be tested for diagnostically.

4

In terms of the effects on drug treatment, compare responders and nonresponders.

5

Outline the relationship between genetic polymorphism and ethnicity.

6

Outline the ethical considerations and the factors that determine costeffectiveness associated with pharmacogenetics.

Drug stratification Genetic polymorphism Pharmacogenetics Pharmacogenomics Slow metabolisers

There can be significant variation in individual responsiveness to drug therapy. For some people, standard medicine regimens induce inappropriate drug concentrations at the site of action (due to pharmacokinetic variability) or unsuitable effects at appropriate drug concentrations (due to pharmacodynamic variability). The clinical consequences of such variability can range from poor effectiveness of treatment to serious injury, or possibly death, caused by adverse drug reactions. At the population level, responsiveness to a particular medicine is considered to be normally distributed. That is, drug responsiveness can be represented as a bell-shaped curve, where the most frequent level of response corresponds to the mean or average (see Figure 19.1). The level of responsiveness decreases as you move to the left or right of this average value. The differences in drug responsiveness can be due, at least in part, to a person’s genetic make-up. Pharmacogenetics is a branch of pharmacology established to investigate how genetic variation contributes to variable drug responsiveness. It is defined as the use of biological markers

CHAPTER 19 PHARMACOGENETICS

(such  as  DNA, RNA or proteins) to predict drug responsiveness. Pharmacogenomics is another term used to describe the study of all the genes that determine drug behaviour. However, the two terms, pharmacogenomics and pharmacogenetics, are now frequently used interchangeably. In this chapter we provide an overview of pharmacogenetics and some clinical considerations associated with this field of study.

AN OVERVIEW OF PHARMACOGENETICS Our genes are responsible for the coding of enzymes, receptors, ion channels, drug transporter molecules and other physiological systems involved in observable drug responses. Some of these proteins are located at the drug’s site of action, while others are involved in the metabolism of drugs. Within the human population, genetic variation causes individuals to express different forms of these proteins. This phenomenon is known as genetic polymorphism. Genetic polymorphism occurs when a genetic trait (e.g.  coding for the synthesis of a particular enzyme) can be expressed within the population in two (or more) different forms, or phenotypes. These phenotypes may be the consequence of either gene deletions or duplications. It is this type of polymorphism that can lead to differential responses to medicines.

Responders and non-responders In pharmacogenetics, gene sequences are examined and differences in DNA, RNA or proteins are noted. These are markers that can be used to predict the probability of a particular drug response. Broadly speaking, a person will be likely either to respond (i.e. be a responder) or not respond (i.e. be a non-responder) to the therapy. At the population Figure 19.1 Normally distributed drug responsiveness at the population level

40% 60% Measured drug response

Diagnostic testing A relatively sophisticated example of pharmacogenetic screening has been adopted in clinical practice and is seen to be the way of the future with regard to drug stratification. In cases of primary breast cancer, 25–30 per cent of patients overexpress a cancer-related gene called HER2, the product

Response frequency

Response frequency

15

20%

Clinically, the presence of these genetic markers can be tested for using a suitable diagnostic procedure and then individualised drug treatment can commence. This is not so new a concept, as diagnostic testing for specific genetic markers is routinely done when a person requires a blood transfusion. In this case, the genetic markers are the different blood groups, and it is this that determines the type of blood the person receives. An individualised pharmacogeneticbased therapeutic approach is known as drug stratification, where the dose and/or choice of medicine is determined by a person’s genetic status. The goal of such an approach is to tailor the safest and most appropriate drug treatment to the needs of an individual (see Figure 19.3).

45

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0

Tailor-made drug therapy

Figure 19.2 Bimodal drug responsiveness at the population level

mean drug responsiveness

45

level, responsiveness of this kind fits a bimodal distribution, where there are two peak frequencies of responsiveness (see Figure  19.2). This is in contrast to a normal distribution, where there is only one peak.

80%

non-responders

responders

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15

0

20%

40% 60% Measured drug response

80%

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Figure 19.3 Tailoring drug treatment to the individual Drug stratification is achieved by tailoring the safest and most appropriate treatment to the needs of the individual.

LITHIUM CARBONATE/LITHICARB

50mg/400m (Sapadex) CAPSULE 10x20) Take ONE capsules every TWO hours when required Maximum of 12 capsules daily.

John BROWN

SP

09/07/14 - 007:KS 1/2 The Noosa Hospital, phone (07) 54559317

TRIMIPRAMINE/MELIPRAMINE/TCA 32.5mg/325m (capadex) CAPSULE 9x20) Take TWO capsules every four to six hours when required Maximum of 8 capsules daily.

Susan SMITH

SU

09/07/14 - 006:KS 1/1 The Noosa Hospital, phone (07) 54559317

SERTRALINE/ZOLOFT/SSRI

32.5mg/325m (capadex) CAPSULE 9x20) Take TWO capsules every four to six hours when required Maximum of 8 capsules daily.

John BROWN

SU

09/07/14 - 006:KS 1/1

The Noosa Hospital, ph ne (07) 54559317 o

Appropriate medicines for this illness. Drugs A, B and C respectively.

LITHIUM CARBONATE/LITHICARB

50mg/400m (Sapadex) CAPSULE 10x20) Take ONE capsules every TWO hours when required Maximum of 12 capsules daily. John BROWN

SU

09/07/14 - 007:KS 1/2

The Noosa Hospital, phone (07) 54559317

For person 1: select therapy with Drug A

Person 1

Body cells collected for testing

Identification of genetic markers

TRIMIPRAMINE/MELIPRAMINE/TCA

32.5mg/325m (capadex) CAPSULE 9x20) Take TWO capsules every four to six hours when required Maximum of 8 capsules daily. Susan SMITH

SU

09/07/01 - 006:KS 1/1 The Noosa Hospital, phone (07) 54559317

For person 2: select therapy with Drug B Person 2

CHAPTER 19 PHARMACOGENETICS

POLYMORPHISM AND DRUG METABOLISM In pharmacogenetics, genetic polymorphism is most widely studied in relation to drug metabolism. More than 20 human enzymes associated with drug metabolism have polymorphisms. In addition, ethnicity plays a role in the frequency of these polymorphisms. A number of important enzymes are involved in drug metabolism—N-acetyltransferase and some of the cytochrome P450 family of oxidative enzymes. For these enzymes, human populations can be divided into two groups based on their ability to metabolise particular medicines—responders (extensive metabolisers) and nonresponders (poor metabolisers). In this section, some welldocumented examples of this bimodal distribution of drug responsiveness are outlined. From a clinical perspective, non-responders are of great importance. If, during therapy, plasma drug concentrations remain high because of an inability to degrade the active drug, non-responders are at risk of developing serious adverse drug reactions. Such individuals may require a reassessment of the dose regimen or choice of medicine in order to avoid toxicity. For the responders, the worst scenario is that the medicine will be less effective because the plasma concentration is subtherapeutic. This again could be redressed by altering the choice of medicine or dosage (see Figure 19.4).

Figure 19.4 Potential clinical consequences of genetic polymorphism Blood drug concentration

of which forms an HER2 receptor on the cancerous cells. These tumours tend to grow aggressively. The HER2 receptor represents a genetic marker whose overexpression can be tested for. If the marker is overexpressed, the choice of medicine is a monoclonal antibody against the HER2 receptor, called trastuzumab (see Chapter  80). In this way, the test result determines the appropriateness of drug treatment. Pharmacogenetic testing is not widely used. It is limited to some hospitals and specialist centres. ‘Phenotyping’ high-risk individuals prior to or during therapy has been the main way of assessing pharmacogenetic factors. This involved the administration of a test substance, collection of samples (e.g. from urine or breath tests) and laboratory analysis of the ratio of active drug to inactive metabolites. Simpler and more convenient diagnostic techniques to detect genetic markers will ensure more widespread testing of the population in clinics and hospitals. DNA tests using small amounts of tissue (such as hair follicles or buccal cells) could rapidly provide the information about a person’s genetic status required for drug stratification.

30

drug toxicity maximum safe concentration

20

minimum effective concentration

10

drug ineffectiveness

non-responders

responders

Fast (effective) and slow (poor) acetylators The process of metabolic acetylation is where inactive metabolites are created in the liver by the attachment of a two-carbon acetyl group donated by acetyl coenzyme A, a component of the citric acid cycle. The hepatic enzyme N-acetyltransferase is involved in the acetylation of drugs such as the sulfonamide antibiotics, the antituberculotic agent isoniazid, the hydrazines (such as the peripheral vasodilator hydralazine and the antidepressant phenelzine) and caffeine. A slow acetylator is a non-responder who inactivates the medicine more slowly than the general population, leading to an accumulation of the drug in the blood and possible toxicity. As a consequence, a reassessment of dosage or medication may be required. A fast acetylator is a responder who degrades the active drug into its acetylated metabolite effectively. Some individuals, however, can achieve this too effectively, ending up with lower than normal blood concentrations of the active drug. Such individuals may require a change in the standard dose regimen for these medicines (i.e.  more frequent or higher dosage) in order to compensate. In terms of ethnicity, recent studies indicate that for N-acetyltransferase, 60 per cent of Caucasians and 20 per cent of Asians are poor metabolisers. This suggests that, as a significant proportion of our community is at risk of toxic adverse reactions, testing genetic status would be worthwhile. The underlying problem is related not to a defect in the enzyme responsible for acetylation but rather to the amount of enzyme present in the liver. The pattern of inheritance is that fast acetylators are either homozygous or heterozygous for the autosomal dominant gene (R), which

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programs for higher enzyme levels, while slow acetylators are homozygous for the recessive gene (r). Caffeine has been used as a safe phenotyping probe to determine fast and slow acetylators. As indicated above, the ratio of caffeine to its metabolites in the urine indicates to which group a person belongs. High levels of caffeine metabolites indicate fast acetylation.

Polymorphism involving cytochrome P450 enzymes Genetic polymorphism is associated with a number of cytochrome P450 (CYP) enzymes. The focus of the research in this area has been on CYP2D6 and CYP2C9, which together account for around 24 per cent of the total human liver cytochrome P450 content. Another isoenzyme, CYP2C19, also accounts for significant variability in observed medicine effects. For each of these enzymes the population is distributed into responders and nonresponders. Interestingly, the polymorphic states of one isoenzyme have no bearing on that of the other. CYP2D6 is involved in the breakdown of more than 100 medicines used in psychiatric, neurological and cardiovascular diseases. CYP2C9 is necessary for the breakdown of a similar number, including the benzodiazepine diazepam and the aspirin-like anti-inflammatory drug ibuprofen. A narrow margin of safety is associated with some of the medicines affected by this polymorphism (e.g.  the anticoagulant warfarin) so the consequences of being a non-responder may be serious toxicity. On the other hand, for CYP2D6, a subgroup of responders is ultra-extensive metabolisers. For them, the CYP2D6 gene is amplified, so they metabolise the enzymedependent drugs very rapidly. The consequence is that it may be difficult to produce a therapeutic effect at standard doses of such drugs in these individuals. Some interesting data have been published with respect to CYP activity and ethnicity. In Caucasians, poor metabolisers of CYP2D6 represent 5–10  per  cent of the population and poor metabolisers of CYP2C9 represent 1–5  per  cent. In Asian populations, poor metabolisers of CYP2C9 represent up to 18 per cent of the population and of CYP2D6, 1 per cent. For CYP2C9 this fits well with the observation that doctors working in Hong Kong routinely prescribe lower than standard doses of diazepam for Chinese patients. As to the amplification of the CYP2C9 gene, 20 per cent of Ethiopians are so affected. The possibility of having to produce different clinical medicine regimens for different subgroups within the population is posing some interesting problems for multinational pharmaceutical companies. Over recent

times, these companies have become more interested in exploring the genetic status of participants in clinical trials in order to account for variation in drug responsiveness. These data are then used to inform decisions related to the development of new drugs. New drugs that have a high dependence on one of these polymorphic CYP enzymes for their metabolism pose too high a safety risk for further development, unless the structure of the drugs can be modified to avoid this. As a consequence of this approach, problematic drugs can be eliminated from the development process during an early stage, at substantial savings in terms of time and money to the company involved.

Poor suxamethonium metabolism The role of acetylcholinesterase as the highly specific degradative enzyme responsible for the inactivation of the neurotransmitter acetylcholine is covered in Chapter  28. The relatively non-specific cholinesterases, the pseudocholinesterases, are present in blood and other tissues. They appear to be involved in the local modulation of the response to acetylcholine. Pseudocholinesterases are important in the breakdown of the neuromuscular blocking agent suxamethonium. About 1 in 2000 of the population shows phenotypic variation for pseudocholinesterase synthesis. Non-responders break down suxamethonium more slowly, and in these individuals such treatment leads to prolonged paralysis of about 24 hours. There is no antidote to suxamethonium. Paralysis, when it occurs, requires that the person be mechanically ventilated and maintained in deep sedation for the duration of the facilitated respiration. When this idiosyncrasy is known, suxamethonium should be avoided.

Erythrocyte reactions Individuals who have an inheritable defect in the stability of erythrocytes may be more susceptible to either haemolysis or structural changes in haemoglobin during therapy with a number of common clinical medicines. Drugs such as the sulfonamides, antimalarial agents, some non-steroidal anti-inflammatory drugs and the antimicrobial drug chloramphenicol are known to induce these changes. Another condition that can manifest during drug therapy is porphyria, a disorder of haem synthesis. A haem group is formed in either the liver or bone marrow from the combination of a ferrous ion with a pigment called a porphyrin. In porphyria, haem synthesis is abnormal, resulting in the deposition of porphyrins into body tissues such as the skin. There is evidence of a genetic predisposition to porphyria that can be precipitated by drug treatment.

CHAPTER 19 PHARMACOGENETICS

In these individuals, the hepatic level of the enzyme, ALA-synthetase, which converts the precursor substance aminolaevulinic acid (ALA) into a porphyrin, is high. Certain drugs induce more ALA-synthetase, producing porphyria. These drugs include ethanol, the sulfonamides, oestrogen and the barbiturates.

Polymorphism and membrane transporters There is a great deal of interest in polymorphism associated with a number of membrane transporter systems involved in the movement of drugs into (influx) and out of (efflux) cells. Such polymorphism may contribute to altered drug distribution, clearance and variable effects. Attention has focused on the permeability-glycoprotein (P-gp) transporters—ATP-dependent efflux pumps that appear to be involved in the removal of a number of molecules from cells, such as anticancer agents, the cardiac glycoside digoxin, antigout medicines and immunosuppressants. These are also known as multidrug resistance proteins (MDRs) or ATP-binding cassette (ABC) proteins. The most studied of these transporters is ABCB1, also known as MDR1. Thus, these transporters limit the intracellular accumulation of such potentially toxic medicines and other chemicals from structures such as the heart, brain, testes, placenta and bone marrow cells. Some of the medicines mentioned above have a narrow therapeutic index, and are associated with serious adverse effects. The polymorphic forms of these pumps appear to have variable efficiency. It is hoped that the application of pharmacogenetic screening for polymorphic P-gp transporters prior to medicine administration will reduce the incidence of toxicity.

PHARMACOGENETICS AND DRUG PHARMACODYNAMICS It appears that genetic variation in drug metabolism is not the only inheritable factor to affect drug responsiveness. Genetic variation in the mechanisms by which medicines act has also been found to affect the observed responses.

Variations in receptor structure Recent studies have shown genetic variation in the programming of receptor structures, which, therefore, affects the observed responses to medicines. An example of this is the β2 receptor. Molecular variants of this receptor show normal binding of agonist drugs but a three- to fivefold reduction in the response to agonist activation. The clinical consequence is that the bronchodilator effect associated with β2 agonist therapy will be reduced.

There is also some evidence that central dopamine receptor variation may play a role in altered responsiveness to the antipsychotic drugs used in the management of schizophrenia.

Reactions to mydriatics It is also interesting to note that certain drug effects are enhanced in individuals with a particular family background. Medicines that dilate the pupil (i.e. mydriatics) produce stronger effects in people with blue eyes than in those with a more deeply pigmented iris. This must be a genetic predisposition because eye colour is an inheritable trait.

Reactions to corticosteroids Another example involving the eye relates to the use of topical corticosteroid therapy (see Chapter  83). Some individuals with a family history of glaucoma have shown raised intraocular pressure in response to eye drops/ ointments containing corticosteroids. Individuals with such a background should be monitored for this during corticosteroid-based eye therapy.

ETHICAL CONSIDERATIONS ASSOCIATED WITH PHARMACOGENETICS The use of this treatment approach raises some ethical issues that are worth considering. First, once the pharmacogenetic data are collected, there are questions of who is entitled to access the information and how confidentiality is protected. These issues need to be worked out by the individual and the health professionals associated with that person’s care before the data are collected. Another issue relates to the insurance risk associated with the genetic data. For some people, screening prior to treatment may actually reduce the risk because there will be a lower incidence of serious adverse reactions associated with individualised therapy. However, for those shown to be poor metabolisers, the risk may increase. Will these individuals be refused insurance or pay a significantly higher premium if there is no alternative treatment available?

PRESENT LIMITATIONS ASSOCIATED WITH PHARMACOGENETIC TESTING While there is tremendous potential in pharmacogenetics to individualise drug therapy for maximal effectiveness and

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negligible toxicity, this approach has not yet been widely adopted in clinical practice. Even though there has been, and will be, some uptake of pre-prescription testing for particular treatments, widespread routine pharmacogenetic screening seems unlikely. In essence, usage is determined by the costeffectiveness of such testing. The testing must have a significant effect on the treatment outcomes and be

relatively inexpensive. In order to address the question of pharmacogenetic testing on treatment outcomes, rigorous evaluations in randomised controlled clinical trials are required. Up until now this has not been done. In such trials, doctors will need to consider genotypes when making decisions about drug therapy for one group of participants, while in another group, empirical drug treatment is used.

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Pharmacogenetics is the study of how genetic variation contributes to differences in drug responsiveness. Differences in DNA, RNA and protein products can be identified as biological markers for the purposes of pharmacogenetic testing. Genetic variation contributes to differences in the structure and function of proteins involved in drug metabolism, receptors and other physiological systems involved in drug responsiveness. This represents genetic polymorphism. Where genetic polymorphism exists, drug responsiveness at the population level is broadly divided into responder and non-responder groups. In terms of drug metabolism, this is expressed as extensive and poor metabolisers respectively. Biological markers can be screened for in diagnostic tests to determine whether a person is a responder or nonresponder. Examples of genetic polymorphism have been determined for a number of enzymes involved in drug metabolism, such as N-acetyltransferase, the cytochrome P450 family, membrane transporters and pseudocholinesterases. Genetic polymorphism also exists in the structure of receptors and the responses to certain clinical medicines. There are ethical considerations associated with pharmacokinetics as to who has access to a person’s genetic data and how this information might be used to assess insurance risk. At this time, widespread routine pre-prescription pharmacogenetic testing appears unlikely. The costeffectiveness of such testing depends on the prevalence of the polymorphism being considered, the sensitivity and specificity of the testing, the likelihood that, if left untreated, the condition will result in significant mortality or morbidity, and that acting on the pharmacogenetic data leads to significant treatment outcomes and/or a reduction in costs.

REVIEW QUESTIONS 1 Define the following terms: a

pharmacogenetics

b polymorphism c

drug stratification

2 Name specific examples of polymorphism that may lead to significant pharmacokinetic variability. 3 Name specific examples of polymorphism that may lead to significant pharmacodynamic variability. 4 What are the consequences of being an ultra-extensive metaboliser in regard to drug effects?

CHAPTER 19 PHARMACOGENETICS

5 For the following medicines, indicate an idiosyncratic reaction that can occur as a result of an unusual genotype: a

β2 agonists

b oestrogens c

mydriatics

d sulfonamides 6 Halle Zingiber has been granted refugee status in this country. He has had to leave his wife and two children

in Ethiopia. He is severely depressed, and is receiving treatment with the tricyclic antidepressant nortriptyline. No effects were reported when standard doses of the drug (25 mg tds) were used. His doctor has increased the dose manyfold to 200 mg/day, a dose that is inducing effects. Can you account for Halle’s unusual response to therapy? 7 Marvin Chung Au has a form of tuberculosis that responds well to isoniazid therapy. Marvin is found to be a slow

acetylator. What alterations to therapy should be considered by Marvin’s doctor? 8 Jack Smith has a genetic make-up that involves a deficiency of pseudocholinesterases. How would this affect the

metabolism of the neuromuscular blocking agent suxamethonium? 9 Betty Blackwell is 56 years old and has breast cancer. Her doctor is considering trastuzumab therapy. Which

biological marker is screened for, and is it the underexpression or overexpression of this marker that is used to determine the appropriateness of this therapy? 10 Jason Silver, aged 14 years, sustains a dislocated shoulder during a football match. After relocating and stabilising

the shoulder in the emergency department of the children’s hospital, the doctor writes up an analgesic order of ibuprofen for Jason. In the medical history it is noted that Jason is a poor metaboliser with respect to CYP2C9. In what way, if any, will this situation affect the dose of ibuprofen ordered for Jason? 11 With respect to metabolism of a particular drug, what does it mean when a person has a high ratio of active to

inactive metabolites present in a urine sample? 12 Jack Rundle, who has been diagnosed with depression, has been placed on a course of the antidepressant

venlaflaxine. Jack is an ultra-extensive metaboliser of the CYP2D6 gene and venlaflaxine is a major substrate of the CYP2D6 gene. What does this situation mean in terms of the metabolic breakdown of venlaflaxine?

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LEARNING OBJECTIVES

KEY TERMS

After completing this chapter, you should be able to:

Drug absorption

1 2 3 4

Describe the ways in which drug absorption is altered by disease, diet, exercise and pregnancy, and the consequent effects on drug action.

Drug distribution

Name the ways in which drug distribution is altered by disease and pregnancy, and the consequent effects on drug action.

Drug excretion

List the ways in which drug metabolism is altered by disease, occupation and diet, and the consequent effects on drug action.

Occupational effects

Describe the ways in which drug excretion is altered by disease, and the consequent effects on drug action.

Pregnancy

Drug effects Drug metabolism Pharmokinetics

In Chapters 14 and 15 you were introduced to pharmacokinetics, the study of how the human body processes a drug once it has been administered. There are four stages of pharmacokinetics: drug absorption, distribution, metabolism and excretion. During drug development (see Chapter 18), the appropriate formulation, dosage and route of administration for humans are determined, taking into account the medicine’s pharmacokinetics. In this way, if the dispensing instructions are followed, the drug should reach the site of action in an appropriate concentration that is both safe and therapeutically effective. Unfortunately, a number of factors can affect the drug concentration at the site of action. If the concentration is higher than expected, the drug may exert a stronger, and possibly toxic, effect. If the concentration is lower than expected, the medicine may not be therapeutically effective. In Chapter  19 we saw an example of this, where genetic variability can affect the process of drug metabolism. Disease, diet, occupation and pregnancy are other states that can affect the efficiency of pharmacokinetic processes and ultimately induce stronger or weaker than expected drug effects. The nature of these influences is discussed in this chapter. The effects of age on pharmacokinetics are discussed in Chapter 21.

C H A P T E R 2 0 P H A R M A C O K I N E T I C FA C T O R S T H A T M O D I F Y D R U G A C T I O N

ABSORPTION AND DRUG ACTION The rate and degree of drug absorption into the blood (bioavailability) is obviously dependent on the route of administration. Effective absorption from the oral route depends on both the chemical properties of the drug and the functional efficiency of the gastrointestinal tract. Parenteral absorption depends on the extent of the blood supply through the tissue where the medicine is injected.

Effects of disease Gastrointestinal illness can affect the rate and degree of oral absorption. Conditions affecting gastrointestinal peristalsis, such as severe vomiting, diarrhoea or constipation, or the rate of gastric emptying, may significantly alter the degree to which drugs are absorbed. Inflammatory conditions that cause changes to the structure and function of the gut wall may also impede drug transit into the blood, but this is dependent on the region of the tract affected and the usual site of drug absorption. Fortunately, the problem of poor oral absorption under these circumstances can be overcome by administering the drug parenterally. The pharmacokinetic behaviour of drugs can also be affected indirectly by gastrointestinal illness. A number of nutrients are essential for normal liver function. Nutritional imbalances brought about by gastrointestinal diseases can affect normal drug metabolism, resulting in unexpected drug effects. The effects of diet on drug metabolism are discussed in detail below. The rate of drug absorption from a parenteral site can also be greatly affected by disease. As stated earlier, absorption here is determined by the vascularity of the tissue. Diseases such as circulatory shock, congestive cardiac failure and peripheral vascular disease often profoundly reduce the perfusion of tissues with blood. As a result, the blood levels may be lower than expected, while the drug concentration at the injection site remains high. In effect, the injection site becomes a drug reservoir. If, under these circumstances, tissue perfusion were to suddenly increase, the levels of circulating drug might rise accordingly, leading to increased drug activity and possible toxicity.

injection site. An example of this is when a person receives an intramuscular drug injection and participates in vigorous exercise shortly afterwards. Increased blood flow to the muscle will enhance drug absorption. This may result in faster drug absorption and higher circulating drug than expected.

Effects of diet The presence of food in the gut around the time of medicine administration can greatly affect the degree of absorption. Nutrient molecules compete with drugs for sites of absorption. As a result, peak plasma concentrations are lower than expected and the drug action is more prolonged. However, drug solubility has a significant influence on the degree of absorption. Lipid-soluble drugs are less affected by this competition than are water-soluble drugs. For some drugs it is not just a matter of competition for binding sites that impedes absorption. Medicines such as the more water-soluble tetracycline antibiotics are chelated by calcium salts, predominantly found in milk products but also present in some antacid preparations. Drug bioavailability is then greatly lowered, as the conjugated antibiotic is mostly excreted with the faeces. As a rule, unless it is explicitly stated that a medicine can, or should, be given with food, medicines must be administered either one hour before or two hours after food.

Effects of pregnancy The function of the gastrointestinal tract may be greatly altered by hormonal action during pregnancy. Peristalsis and gastric emptying may be slowed to such a degree as to affect the amount of drug absorbed from the gut. Gastric acid secretion is also more erratic, which can affect the degree of absorption of acidic drugs. However, because of individual differences in the effects of pregnancy, the observed effects on absorption can vary greatly and are difficult to predict. Nevertheless, an awareness of the kinds of pharmacokinetic effects to expect during pregnancy is valuable, even if these effects don’t occur every time.

Effects of exercise

DISTRIBUTION AND DRUG ACTION

Tissue vascularity greatly affects the rate of drug absorption. This can be illustrated by comparing the rates of absorption from skeletal muscle with those from the subcutaneous layer of the skin. Circumstances that result in tissue blood flow changes can certainly influence the absorption of a drug from an

The factors that determine distribution include plasma protein concentration and affinity for the drug, body fluid levels, drug solubility, degree of drug ionisation, body fat content and the tissue blood flow. Some of these characteristics are intrinsic properties of the drug; however, conditions that influence body fluids, fat content, tissue

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perfusion/permeability or plasma proteins can also affect drug distribution.

Effects of disease Any condition that decreases the concentration of plasma proteins (e.g. kidney disease, severe burns or malnutrition) will affect the activity of drugs that bind strongly to these proteins. While the plasma drug levels may be within the normal therapeutic range, the proportion of unbound drug will be higher. As a result, the drug effects will be greater in these individuals. Examples of medicines that bind strongly to plasma proteins are the benzodiazepine diazepam (see Chapter 35), the antiseizure drug phenytoin (see Chapter  38), the sulfonylureas (see Chapter  61), the sulfonamides (see Chapter  71) and the anticoagulant warfarin (see Chapter 48). The margins of safety of some of these medicines are narrow under normal physiological conditions; therefore, the consequences of such a change would be expected to be toxic. Diminished synthesis of plasma proteins can occur in severe liver disease. For drugs that bind strongly to plasma proteins, there will subsequently be a higher proportion of unbound drug in the blood. As a result, the drug effects will be stronger and potentially more toxic. These effects are compounded by the fact that, in severe liver disease, hepatic drug clearance is greatly reduced. Another physiological imbalance affecting the plasma protein binding of drugs is a sudden and dramatic rise in plasma bilirubin levels. Plasma bilirubin levels will rise as a result of haemolytic anaemia or serious internal haemorrhage. Bilirubin is transported to the liver attached to the plasma protein albumin. Drugs that bind to plasma proteins can be displaced by the competing bilirubin molecule, leading to a higher concentration of unbound drug. Again the consequences are greater drug effects and increased toxicity. Drugs are distributed to their sites of action via the body fluids, particularly extracellular fluids. Indeed, body fluid levels ultimately determine the concentration of a drug at its receptor sites. Oedematous states reduce the drug concentration around its receptors, diminishing the magnitude of the effect. Conversely, dehydration concentrates the drug at this location, causing stronger and potentially more toxic effects.

Effects of pregnancy There is little evidence of altered drug effects as a result of changes in drug distribution. However, with the expanded plasma volume that occurs during pregnancy, one would expect some drugs to be distributed to their receptors

differently. Subsequently, the concentration of drug at the receptor site would be presumed to be lower than normal.

METABOLISM AND DRUG ACTION The major site of metabolism in the body is the liver. Therefore, any condition that affects hepatic function will alter the rate and/or degree of drug metabolism. More specifically, drug metabolism is determined by the activity of microsomal oxidative enzymes, such as the CYP enzymes, and the liver’s capacity for conjugation (see Chapter 15).

Effects of disease Diseases of the liver can lead either to the accumulation of pharmacologically active drugs to toxic levels or to prolonged drug effects, or both. The consequences vary between drugs and depend on the pharmacokinetic characteristics of the drug itself. The impact is definitely greatest for those drugs that must be mostly metabolised before excretion. Examples of specific drugs in this category are the narcotic morphine (see Chapter 40), and the non-specific β-blocker propranolol (see Chapter  27). Drugs excreted unchanged from the administered form are handled normally under these circumstances. Health professionals are advised to consult a clinical reference, such as the MIMS Annual, Australian Medicines Handbook or New Ethicals Compendium, for the relevant pharmacokinetic information pertaining to specific medicine ordered for people with hepatic disease. Metabolic processes can also be influenced indirectly by other diseases, even when liver function is normal. Congestive cardiac failure significantly reduces hepatic blood flow. As a result, drug clearance through the liver is diminished, prolonging the drug action. Conditions characterised by deficient levels of plasma proteins produce a higher proportion of unbound drug. Only this component is susceptible to metabolic degradation so, even though drug effects are stronger under these conditions, the duration of action will be shorter than normal.

Effects of occupation A number of chemical agents, such as insecticides and pesticides, are known to induce microsomal enzymes in the liver. Occupational exposure to these chemicals in agriculture and chemical manufacturing industries would be expected to result in altered drug metabolism in these workers. The inactivation of drugs dependent on the action of microsomal enzymes would be faster than expected in these individuals.

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Furthermore, chronic exposure to such chemicals has been linked to the onset of a number of diseases, such as cancer and pulmonary disease, which would be expected to affect drug pharmacokinetics (refer to the specific sections on the effects of disease on drug action in this chapter).

Effects of diet The most important consideration in regard to the influence of nutrition on metabolism is that microsomal enzyme activity is dependent on the presence of certain vitamins and minerals. Deficiencies in the levels of vitamins A, B1 and B2, essential fatty acids, protein or the minerals copper, zinc or calcium will result in ineffective metabolism. Blood drug levels will be higher than expected for those drugs metabolised by microsomal enzymes.

EXCRETION AND DRUG ACTION The principal site of drug excretion is the kidneys. Conditions that affect kidney function, either directly or indirectly, will alter drug concentrations in the body and the observed clinical effects.

Effects of disease Renal diseases will affect the blood concentrations of most medicines. The extent to which this changes the drug’s effects depends on whether the drug is mostly metabolised in the liver, producing inactive metabolites which are eliminated via the kidneys, or whether the drug is excreted mostly unchanged from its administered form. Obviously, the latter drug will be the one that produces stronger and potentially more toxic effects under these conditions. Examples of drugs in this group are the penicillins, the aminoglycosides (both antimicrobial drug groups; see Chapter  72) and digoxin (see Chapter  50). Renal drug clearance can also be affected indirectly by diseases that impede blood flow through the kidneys. This can occur in conditions such as congestive cardiac failure. Health professionals are advised to consult an appropriate clinical reference for pharmacokinetic information on specific medicines when required. Tables of the drug dosage adjustments recommended in renal disease are included in the appendices and general information section of the MIMS Annual and New Ethicals Compendium, respectively.

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Factors that affect pharmacokinetic processes can alter drug concentrations at the site of action. This may result in unexpected drug effects. Drug absorption may be altered in gastrointestinal and cardiovascular diseases, or by the presence of food or exercise. Drug distribution may be altered by conditions that affect the availability of plasma proteins (e.g. kidney disease, malnutrition or severe burns), body fluid balance or pregnancy. Drug metabolism may be altered in liver disease, hepatic blood flow, conditions that affect hepatic enzyme levels or diet. Drug excretion may be altered by kidney disease or renal blood flow.

REVIEW QUESTIONS 1 For each of the following situations, indicate whether you would expect the drug effects to be increased or

decreased: a

warfarin treatment when the levels of plasma protein are decreased

b morphine treatment in a person with liver disease c

an intramuscular drug injection just prior to a person running a footrace

d penicillin therapy in a person with renal disease 2 Name a circumstance that would tend to increase the rate of drug metabolism.

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3 Given the physiological changes that occur during pregnancy, list the expected effects on absorption, distribution,

metabolism and excretion. If all of these effects did occur, what would you expect the net change in drug action to be (increased or decreased action)? 4 Mary Wolstencort is suffering from acute renal failure following a very severe bleeding episode. How would this

condition be expected to alter the effects of any medicines she might take during this time? How would her drug treatment have to be modified to minimise these effects? 5 Peter Josshaus is a small property owner in north Queensland. To protect his crops from locust attack, he has been

periodically spraying insecticides around the property. He is in hospital receiving treatment for an ongoing heart condition. The drug Peter is receiving is not as effective as expected at the standard dose range and his dosage has been increased. The drug is subject to significant liver metabolism. How do you account for Peter’s poor responsiveness to his drug therapy? 6 Your next-door neighbour, who is pregnant, complains to you that in the past week she has been experiencing

severe heartburn. How would you explain the reason underlying this condition? 7 Richard Kriochek suffers from severe end-stage liver failure. How would the dosage of his medicines be

modified? Why? 8 Cecil Lu is 45 years old and has been prescribed tetracycline for an infection. Cecil is also taking an antacid

preparation containing calcium carbonate for the relief of indigestion. What would be the consequences of taking these medicines concurrently? What is your advice to Mr Lu? 9 Despina Stamatopoulous is a 65-year-old widow with congestive cardiac failure. She is taking the ACE inhibitor

enalapril for her cardiac failure and the penicillin ampicillin for a respiratory infection. How would her condition affect the excretion of ampicillin? 10 Sinead O’Donald, an 18-year-old student, is brought to your community hospital. Her mother is concerned

that she does not eat a balanced diet. Ms O’Donald is on amoxycillin for a respiratory infection. How would Ms O’Donald’s diet affect the metabolism of amoxycillin? 11 Julie McGee, aged 44 years, sustains a full-thickness burn to 30 per cent of her body following an occupational

accident. Ms McGee also has type 2 diabetes mellitus, which is being treated with the sulfonylurea glibenclamide. How would the burn affect the plasma protein binding of glibenclamide? 12 Abdul Mohomhadah, aged 33, migrates to Australia as a refugee. When assessed by the health authorities he is

found to have severe malnutrition. How would microsomal enzyme activity be affected in this situation? 13 Ralph Mezenanov, aged 58 years, has severe liver disease. He is prescribed diazepam by his doctor in effort to

alleviate the anxiety he sustained after finding out a friend was involved in a serious car accident. How would diazepam be affected by protein binding in Mr Mezenanov?

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LEARNING OBJECTIVES

KEY TERMS

After completing this chapter, you should be able to:

Clinical decision-making process

1

List the ways in which drug absorption, distribution, metabolism and excretion are altered by age, and the consequent effects on drug action.

2

Describe the means by which adult doses must be adjusted for paediatric administration.

Geriatric care

3

Describe the principles involved in paediatric and geriatric clinical management.

Paediatric care

4

Discuss the issue of non-adherence with drug treatment and older people.

Drug actions Non-adherence Paediatric dosage calculation Pharmacokinetics and age

The efficiency and effectiveness of the physiological processes involved in drug absorption, distribution, metabolism and elimination change across the lifespan. Since the body systems of young children are still developing and maturing, the manner in which their bodies handle medicines can be quite different from that of adults. The effects of these medicines may be either stronger or weaker than those observed in adults given the same treatment. At the other end of the lifespan, older people experience age-related changes in body structure and function that alter the behaviour of medicines after administration. The effect of these altered pharmacokinetic processes on drug action is examined in this chapter. The principles involved in the clinical management of paediatric and older patients are also outlined, as is the issue of non-adherence with drug treatment and older people. The lifespan can be arbitrarily divided into a number of developmental periods, and these designated periods are used in this chapter. Neonates are babies from birth to 28 days, young infants are aged from 1  month to 3  months, infants are aged from 3  months to 2  years, and

SECTION IV GENERAL ASPECTS OF PHARMACOLOGY

children are individuals aged from 2  to 12  years, while adolescents are aged from 13  to 19 years. Adults are aged from 20 to 64 years, and older people are those aged 65 years and over. These developmental periods are subjective, and do not necessarily mean that all individuals of a particular age will demonstrate specific pharmacokinetic characteristics. Nevertheless, the developmental periods do help health professionals to develop an awareness of how drug absorption, distribution, metabolism and elimination change across the lifespan.

ABSORPTION AND DRUG ACTION The function of the gastrointestinal tract is quite different in the very young and the very old from that of a young adult. Common problems in both age extremes are slowed peristalsis and gastric emptying. Both can lead to a greater degree of drug absorption than normal and, subsequently, higher plasma drug levels than expected. The activity and concentration of digestive secretions is lower in the newborn infant; low levels of bile may lead to impaired absorption of some fat-soluble drugs. Another problem in early infancy is that gastric acid secretion is erratic; this may result in reduced bioavailability of acidic substances best absorbed in the stomach. In this case, parenteral administration may be indicated. However, for some medicines, lower stomach acid levels can be turned to clinical advantage. In the adult, penicillin is poorly absorbed from the gut because it is degraded by stomach acid. In an infant, because of lower gastric acid levels to neutral, absorption is significantly better and produces effective plasma drug levels. This improved absorption enables the administration of penicillin G orally to young infants. At birth, gastric pH is between 6 and 8, which gradually falls to adult levels by the age of 2–3 years. Parenteral absorption is also influenced by age. Both the very young and older people have poor peripheral tissue perfusion and reduced skeletal muscle mass compared with adults. These differences may influence the rate of drug absorption from the injection site. There is also a consideration regarding the topical administration of medicines to the very young. Young infants are, quite literally, thin-skinned. In particular, preterm neonates have a thinner stratum corneum than neonates. In neonates and infants, drug absorption through the skin is enhanced because the surface area to body weight is greater than that of adults. The absorption of some topically applied medicines may, therefore, be greater than expected. For example, infants may be more susceptible to hypothalamic–pituitary–adrenal suppression than

adults after the application of corticosteroid creams and ointments. There has been concern about the application of EMLA cream (a lignocaine and prilocaine anaesthetic preparation) in neonates and young infants because it may cause methaemoglobinaemia. In this condition the structure of haemoglobin is altered such that it can no longer carry oxygen. As a result, EMLA cream is not recommended for children under 6 months of age.

DISTRIBUTION AND DRUG ACTION The concentration of plasma proteins is lower in the very young and the very old, leading to a higher proportion of unbound drug in the blood. Drug activity and potential toxicity is thus increased, even though total drug concentration in the plasma is within the expected range. Compounding this problem is the fact that the capacity of plasma proteins to bind with medicines is well below adult levels for the first two years of life. In neonates, plasma protein binding is decreased as a result of low levels of albumin and globulins, decreased binding affinity and increased competition for binding sites. As it is the free medicine amount that brings about therapeutic and unwanted effects, dosing of high-protein-bound drugs needs to be carefully adjusted in this age group. Bilirubin can be displaced from albumin by drugs that bind strongly to plasma proteins. This displacement is of particular concern during the neonatal period, when the blood–brain barrier is neither fully developed nor functionally complete. At this time bilirubin can enter the developing brain and cause a profound degree of damage, resulting in severe mental retardation. This condition is known as kernicterus. It is interesting to compare the levels of body fluid and fat tissue across the lifespan and the consequences of these differences on drug effects. The levels of body fluid fall as we age, while the amount of fatty tissue increases. Such variation has an impact on the behaviour of drugs. For a given plasma drug concentration, the amount of drug actually present at

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the receptors, and the magnitude of the subsequent drug effect, depend on the level of extracellular fluid. Therefore, in neonates there will be a lower concentration of drug around its specific receptors and a diminished response, while in older people there will be a higher than expected drug concentration with greater effects. Some fat-soluble drugs are distributed into adipose tissue, which acts as a reservoir, reducing the amount of free drug readily available to its receptors and prolonging the duration of action. Altered adipose tissue levels can cause unexpected drug effects. Young children, having less adipose tissue, may have stronger but more short-lived responses to fat-soluble drugs, whereas drug effects in older people may be reduced in magnitude but more prolonged. Drugs that are hydrophilic (β-lactams, such as amoxycillin, and aminoglycosides, such as gentamicin) have a larger volume of distribution (see Chapter  14) in neonates and young infants, and, therefore, require a larger dose on a milligram per kilogram (mg/kg) basis to reach therapeutic levels.

METABOLISM AND DRUG ACTION The activity of microsomal enzymes and conjugative ability do not reach adult levels until approximately 3 years of age. Prior to this time, the capacity of neonates and young children to metabolise medicines is poor. Hepatic clearance of drugs is slowed and, as a consequence, drug half-lives are prolonged. However, some medications have the ability to induce higher cytochrome P450 levels, which enhance the activity of microsomal enzymes. Antiseizure medications, barbiturates, glucocorticoids and some antibiotics are examples of enzyme inducers. Moreover, if in late pregnancy a woman received treatment with these medicines, enzyme induction could occur in the fetus. This induction would result in a greater capacity to metabolise certain medications as a neonate. In children aged between one and nine years, the size of the liver is proportionally larger than that of adults, and this size difference partially explains the increased clearance of many medicines in this age group, including antiseizure agents. Metabolic processes alter with age. In older people, the ability to metabolise certain drugs deteriorates. It appears that drugs that depend on the action of microsomal enzymes are most affected (e.g. barbiturates, some benzodiazepines, the methylxanthines and some tricyclic antidepressants), whereas drugs inactivated by conjugation are relatively spared.

EXCRETION AND DRUG ACTION The rate of glomerular filtration and the extent of renal blood flow are substantially lower in the neonate than in adults. Therefore, the clearance of drugs dependent on renal means is completed more slowly during this time. Thus, extended dosage intervals may be required in the neonate and infant. Fortunately, this is a concern only for a relatively short period, because renal function usually reaches adult levels within the first year of life. A significant proportion of the older population shows deterioration in the renal clearance of drugs. The glomerular filtration rate decreases by 1 per cent each year over the age of 40. Clearly, the action of drugs that are primarily excreted by the kidneys (e.g. digoxin, penicillin) will be prolonged under these circumstances and may accumulate to toxic levels if no adjustment of dosage is considered.

PAEDIATRIC DOSAGE CONSIDERATIONS In young children, many organ systems—kidneys, liver and circulation—are yet to reach maturity. Muscle mass is lower than in adults, but the body water percentage is higher. As discussed, these factors can affect the absorption, distribution, metabolism and elimination of drugs. The physiological differences between adults and children suggest that the pharmacokinetic behaviour of some medicines will vary greatly across age. Indeed, the dose of medicine administered to a child is never equivalent to that given to an adult. However, one cannot regard a young child as merely a small adult and scale down the dose accordingly. Scaled-down doses do not take into account the maturation development of organs involved in drug deposition. It is important to stress that the relationship between a paediatric and adult dose is not linear. Although for many clinical agents the recommended paediatric dose has been calculated by the manufacturer, this is not always the case. Age and bodyweight have been used to calculate paediatric dosage, but it is generally agreed that body surface area is the more reliable indicator. Using the body surface area method is most accurate because it takes into account cardiac output, fluid requirements and renal function better than bodyweight-based dosing. Most medicines used in paediatric practice follow the ‘mass per kilogram bodyweight’ method of dosage calculation. Several paediatric hospitals have their own lists of tables, indicating the appropriate level in amount per kilogram. With knowledge of the child’s weight, this unit dose is multiplied by the number of kilograms to determine the

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amount that needs to be given. For example, a unit dose of 10 mg/kg for a 20-kg child would result in a dose of 200 mg being administered. Other formulae using the variables of age, weight and surface area are as follows: AGE: Young’s rule Child’s age (Child’s age + 12)

× Adult dose = Paediatric dose

BODYWEIGHT: Clarke’s bodyweight rule Child’s weight (kg) 68

× Adult dose = Paediatric dose

BODY SURFACE AREA: Clarke’s surface area rule Surface area of child (m2) 1.73*

× Adult dose = Paediatric dose

*Average value of adult surface area in square metres.

PAEDIATRIC CLINICAL MANAGEMENT Drug therapy in children requires special consideration because of their constantly changing size, body composition, developmental level and organ functions. The principles relating to medicine administration are covered below with regard to the use of the clinical decision-making process.

Assessment The height (or length) and weight of the child are documented to assist in the calculation of accurate doses of medicines. For a child whose weight varies greatly from the ‘ideal’ weight for a particular age group, it is appropriate to calculate the required dose using the actual bodyweight rather than ideal bodyweight. However, if the calculated dose using the mg/kg method is higher than the adult dose, the recommended adult dose should be used instead. When examining medicine information to determine dosage requirements, take care to interpret whether the dosage is expressed as mg/kg/dose or mg/kg/24 hours. The child’s physical development, motor activity, social interactions with other children, vocabulary and ability to conceptualise are all assessed. These aspects are very important, as they determine to what extent the child can be included in the medicine administration process. Furthermore, as the family plays a major supportive role in a child’s experiences, it is important to determine the family’s response to illness and treatment, and their knowledge of the child’s drug therapy.

Planning The child should be provided with information appropriate to age and level of development. Written instructions should also be given to all parents. Interpreters should be used where possible for those families of non-Englishspeaking background. Most children’s hospitals have a Poisons Information Centre that provides information about child and adult poisoning to the general public and health professionals. Families should be encouraged to visit the centre to obtain current information regarding the first aid measures and safety precautions for child poisoning, as well as the safe use, handling and storage of medicines. Parents should be encouraged to keep a medicine diary for their child, which includes information on the medicines used, dosage, anticipated effects and adverse reactions. If possible, parents should plan for the medication of schoolaged children to be administered out of school hours to minimise non-adherence and possible embarrassment to the child.

Implementation It is important to include the child in the medicine administration process as much as possible. As already explained, this depends on the child’s age and developmental level. Including the child will promote a sense of independence and achievement. The oral route of medicine administration is used where possible. Many young children need to have the medicine placed directly into their mouths. This can be accomplished with a syringe, dropper, calibrated spoon or medicine cup. Regular kitchen teaspoons should not be used because the amount administered may not be accurate. The child should be held in an upright position with the hands kept away from the medicine container. The tip of the dropper or syringe is placed midway along the side of the mouth, rather than towards the back of the throat. In this position, the child is less likely to gag or aspirate when the medicine is administered (see Figure 21.1). If medicines are available in a tablet or capsule form, it is important to assess the child’s ability to swallow these preparations. If the medicine does not have an enteric coating and is not in a delayed-release form, the child may chew or the health professional may crush or dissolve the medicine. Crushed medicines and the contents of capsules can be mixed with a small amount of soft food, such as custard, fruit puree, jam, yoghurt or syrup, using the smallest possible amount of food or fluid to ensure that the child takes the entire dose. No medicine should be added to milk or formula, because the change in taste could lead

C H A P T E R 2 1 PA E D I A T R I C A N D G E R I A T R I C P H A R M A C O L O G Y

Figure 21.1 Administering medicine to a small child using a dropper

blurred vision for a few minutes. Psychological preparation will promote the child’s confidence in you and facilitate cooperation. When giving an injection, one practitioner should administer the injection while another holds the child still to immobilise the injection site. For an intramuscular injection, the vastus lateralis is the preferred site. Because of underdevelopment of the gluteal muscles, they are not recommended as an injection site in children under three years of age. Likewise, the deltoid muscle is not well developed in children, so it is also not a preferred site. Parents or carers should be involved as much as possible in the administration of injections to help pacify the child. Safety is an extremely important issue in paediatrics. Medicines should never be left on bedside lockers. Medicine trolleys, cupboards and fridges should be locked when not in use, and the keys should always be in the nurse’s possession. Adherence is a significant concern in children, especially those with a chronic illness or those entering adolescence. Demanding or complex schedules may contribute to nonadherence. Where possible, it is desirable to maintain onceor twice-daily schedules. In children with chronic illness, it is also important to adjust doses for when there are significant increases or decreases in weight.

Evaluation Source: © Blend Images / Fotolia 2004-2010. All rights reserved.

to the child developing a disliking for milk. Furthermore, if the child does not drink the whole bottle or cup of milk, he/she will not get the prescribed dose. Identification of the right child is essential. As young children may not be verbally competent or reliable, the identification label must be checked and verification from the parent or carer present obtained. A firm and confident approach should be used where the medicine is administered promptly. Distraction methods (e.g.  toys) are often effective during the procedure. After administration, reassurance and positive reinforcement should be offered. Medicines should be prepared out of the child’s sight to avoid added anxiety and distress. Be honest about the purpose of and necessity for medicine (e.g.  the medicine will reduce pain or stop infection). The sensations that will be felt should be explained. For instance, the child should never be told an injection will be painless but rather that the duration of discomfort is short. Likewise, the child must be informed if a medicine will leave a bitter taste in the mouth or cause

The therapeutic and adverse effects of the medicine should be monitored, as well as any drug interactions. The effect of therapy is also gauged on the child’s emotions and behaviour. The ultimate aim is to establish a trusting relationship, build self-esteem, instil acceptance and receive cooperation.

GERIATRIC CLINICAL MANAGEMENT A number of important issues related to the use of medicines by older people must be emphasised. People over the age of 65 years represent approximately 13 per cent of the population, but account for nearly half of the prescriptions written and about 30  per  cent of the total hospital admissions. In Chapter 2, the sociocultural aspects of drug therapy in older people, including polypharmacy, were examined. In this section, issues related to noncompliance with drug treatment and the principles relating to medicine administration, with regard to the use of the clinical decision-making process, are covered.

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Non-adherence to drug treatment and the older person

intolerable. The reasons for non-adherence with therapy are summarised in Table 21.1.

The issue of non-adherence to drug therapy, addressed in general terms in Chapter 8, has the potential to arise in any person. In older people, the likelihood of non-adherence with drug treatment is probably greater. The reasons for this relate to the biological effects of ageing, the social circumstances of older people, the perceptions of older people about their medicines and health professionalrelated issues.

CONSEQUENCES OF NON-ADHERENCE AND POSSIBLE

THE BIOLOGICAL EFFECTS OF AGEING As we age, we are more prone to develop disease. A disease may affect a person’s ability to process information and instructions related to prescribed medicines, leading to poor adherence. Disease states and ageing can affect cognitive processing, which may result in confusion, memory loss or even dementia. Forgetting when to take medicines or remembering whether the medicine was taken at the correct time are common problems for older people. There may also be deterioration in eyesight and hearing that affect the reading of medicine labels and listening to information about medicines. Some older people develop depression, which may further affect their capacity to comply with therapy.

SOCIAL CIRCUMSTANCES OF OLDER PEOPLE In terms of social circumstances, some older people live alone and lack social support from neighbours, family or friends. Older people may have depleted finances and poor access to transport. These factors can affect a person’s ability to buy medicines or to travel to their local pharmacy or hospital to pick up their medicines. Other social issues are literacy level and whether a person comes from a nonEnglish-speaking background. These factors can affect a person’s capacity to read medicine labels or comprehend any educative material received while in hospital.

SOLUTIONS Non-adherence with drug treatment usually leads to consequences including increases in the number and magnitude of adverse effects induced, prolonged illnesses and hospital stays, readmissions to hospital, decreased therapeutic effectiveness of treatment, increased wastage of medicines and growing costs to the health care system. There are a number of ways that adherence to drug therapy by older people can be improved. Wherever possible, the medicine regimen should be simplified in order to minimise error (e.g. if possible, fewer medicines per day given at common times). Client assessments should be comprehensive and include learning ability, manual dexterity, cognition, eyesight, hearing and social circumstances. The use of dose medication aids should be discussed with people. Client assessment means the gathering of information about the person’s physical and emotional status. Those who would benefit from using a dose administration aid include peoplewho have multiple medicines, who experience difficulty in managing their medicines, and who have to manage the medicines of others. Individuals demonstrating Table 21.1 Reasons for non-adherence with

treatment in older people CATEGORY

DESCRIPTION

Biological effects of ageing

More prone to disease Altered cognition (confusion, memory loss, dementia) Altered special senses (poor hearing, poor eyesight, depression)

Social circumstances

Living alone Lack of social support Depleted finances Poor access to transportation Low literacy Non-English-speaking background

Health teamrelated

Complicated medicine regimens Overprescribing Multiple prescribing Poorly prepared for selfadministration of medicines Insufficient communication between team members

Perceptions about medicines

Medicines not seen to be helpful Intolerable adverse effects

PROBLEMS CAUSED BY THE HEALTH TEAM Compliance problems caused by the team of health professionals caring for their older people include prescribing complicated medicine regimens (where a number of medicines need to be taken often or at various times during the day), overprescribing or multiple prescribing of medicines, poor preparation of people for self-administration of medicines, and insufficient communication between health professionals about the management of therapy. Some older people may have the perception that the medicine they have been prescribed will not help their condition and/or that the adverse effects are

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problems with managing medicines through previous hospitalisation or worsening of their medical condition should also consider using a dose administration aid (Figure 21.2). The medicine education provided to people should be individualised, recognising what the person wants to know about their medicines. The knowledge retained by people after information sessions should be evaluated. In addition, there should be better communication between members of the health team (doctors, nurses, pharmacists and other health professionals) about what information has been given, and will be given, to people regarding their drug therapy. Ways of improving adherence to therapy are summarised in Table 21.2.

Principles of medicine administration and older people

Table 21.2 Improving adherence with

drug treatments SUGGESTION

EXAMPLES

Simple medicine regimens

Fewer medicines per day Medicines given at common times during the day

Comprehensive client assessment

Includes learning ability, cognitive function, hearing, eyesight, social circumstances

Use of medication aids

Dose administration aid or medicine diary

Individualised medicine education

What do people want to know about their medicines? Determine person’s knowledge about their medicine

Improved communication between health professionals

Noting what people have been told and what further information they need

ASSESSMENT The person’s distribution of fat, muscle and condition of skin should be assessed. Neurological status and parameters relating to renal, liver, cardiac and respiratory function should be noted. The person’s level of knowledge about the disease process, current medicines, sensory problems (hearing, vision, touch), memory, mobilisation and level of independence should also be considered. It is important to have detailed information about these issues to determine how they may be influenced by medicines. For instance, several medicines can increase the incidence of falls and fractures (e.g.  antiemetics, antipsychotics and benzodiazepines), thus further debilitating a person’s mobility. Acute illnesses, such as myocardial infarction and urinary tract infection, can lead to a rapid decline in renal function, and affect the older person’s ability to eliminate Figure 21.2 Example of a dose-administration aid

medicines. Health professionals should regularly assess the renal function of older people with an acute illness and make adjustments to chronic drug treatments based on the findings. It is also important to determine the number of medicines taken by the older person and their indications. Some of these medicines may be self-prescribed and others may be taken for forgotten reasons. With the growing number of medicines in the therapy, adverse drug reactions are much more likely to occur. Furthermore, the person may be under the care of a number of doctors who each prescribe medicines for various reasons and who may not communicate effectively with each other. Also, it is important to acknowledge that presenting symptoms may be a result of existing medicines rather than the result of advancing age.

PLANNING

Source: © Scruggelgreen | Dreamstime.com.

Encourage the person to learn about medicines while in hospital, so that this will not pose a significant problem at discharge. Medicine cards can be made out for each medicine, indicating the name, strength, dose, time to be taken, and the purpose of administration (e.g.  ‘blood pressure’, ‘heart’ or ‘infection’). Ensure that the person also practises self-administration of medicines before discharge (e.g.  subcutaneous insulin or inhaled bronchodilator administration). If necessary, a district or community nurse may be organised for home visits to enable the older

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person to practise under supervision before safe selfadministration is possible. A medicine clock may also be a useful mechanism for helping older people to take their medicines. In making the clocks, two large clock faces can be drawn, with each one being a different colour. One is marked ‘am’ and the other is marked ‘pm’. The names of the person’s medicines are then placed beside the appropriate times (see Figure 21.3). Be sure that the person can open medicine containers. Child-proof containers are difficult to open for an older person with arthritic hands and should, therefore, be avoided. An older person who has taken several medicines over the years may have developed a specific routine for medicine administration. This may involve the time of day or the sequence in which medicines are taken. When introducing to or removing medicines from the regimen, attempts should be made to maintain the same or a similar routine. It is also advisable to keep the regimen as simple as possible at all times.

IMPLEMENTATION The person should be sitting upright when taking tablets to prevent oesophageal erosion or aspiration of tablets into the lungs. Generally, medicines should be taken one-by-one with water. Tablets are not to be crushed if they are entericcoated or delayed-release. This information is noted on the

container. As these tablets are usually somewhat larger than the normal scored tablets, the person may have trouble in swallowing them. In this instance, effervescent tablets or mixtures may be more palatable alternatives. Table  21.3 contains information about the types of tablets and other preparations that should not be crushed. Capsules can be opened and the contents given to the person, as long as the release properties are built into the small pellets and not part of the capsule casing. It is, however, important that the pellets not be crushed. When tablets and capsules are to be given together, crush the tablets first. Then add the pellets or the powder contents of the capsules to the crushed tablets. In this way, it is possible to maintain the integrity of the sustained-release or entericcoated contents of the capsules. Film-coated, uncoated and sugar-coated tablets can be crushed without a problem. It is important to check whether people can open and properly use the preparations being taken. It is useful to have them demonstrate that they can open containers rather than just asking, ‘Can you open the container?’ Older people may experience difficulties in reading and understanding the directions on containers. Health professionals should check whether older people can read the directions on the container and understand their intent. It may be necessary to write the instructions in big letters on a medicine record.

Figure 21.3 Sample morning and afternoon medicine clocks for use by an older person Morning medication clock midnight 1 am

11 am

Afternoon medication clock—small scale 2 am

10 am

noon brimonidine drops— 1 drop each eye

morning clock

9 am

3 am

frusemide tab 40 mg (before captopril tab food) 50 mg (before food)

8 am

2 pm

10 pm

afternoon clock

9 pm

3 pm

8 pm

4 am

brimonidine drops— 1 drop each eye

7 am

1 pm

11 pm

Serevent inhaler 2 puffs

6 am

5 am

captopril tab 50 mg (2 hrs after food)

4 pm 7 pm

5 pm 6 pm Serevent inhaler 2 puffs

brimonidine drops— 1 drop each eye

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Table 21.3 Preparations that are not

suitable for crushing TYPE OF PREPARATION

EXPLANATION

CD

Controlled-dissolution

CR

Controlled-release

EC

Enteric-coated

ER, XR

Extended-release

HBS

Hydrodynamically based system (floating capsules that gradually release medicine)

LA

Long-acting

MR

Modified-release

OROS

Osmotic release oral system (two-layered tablet with drilled hole in casing, water enters to allow gradual release of medicine)

Repetabs

Two-stage release (immediate and delayed-release)

Retard

Delayed-release

SA

Sustained-action

SR

Slow-release

In some cases, non-drug measures can be used to decrease the need for or dependence on medicines. For an older person who experiences sleep disturbance, avoiding caffeine and daytime naps, and taking up light exercise may

decrease the need for sedatives. All medicines should be given for the shortest possible time, and using the smallest number of doses. Typically, an older person would require less than half of the adult dose of a preparation. These adjustments allow for less disruption of normal activities and promote medicine compliance. The deltoid or vastus lateralis muscles should be avoided as intramuscular injection sites in a person with muscle wasting. The dorsogluteal muscle is a more suitable option. If repeated doses are required, consider alternative routes of administration (e.g. intravenous or rectal route). The health care team should also review regularly the effectiveness and need for long-term drug therapy. It may be possible to stop the medicines or to reduce the dose if renal or liver function declines.

EVALUATION Evaluate the therapeutic effects, adverse reactions and drug interactions of the medicine. If new or unusual clinical manifestations occur, they may be medicinerelated. Sometimes such manifestations are attributed to the ageing process. Consequently, they may be ignored or dealt with by prescribing a new medicine, where stopping the original medicine would have been the correct intervention. Changes to body systems, especially to renal and liver functions, should also be noted. Some medicines are particularly problematic for older people and should be avoided altogether. Table 21.4 lists the types of preparations to be avoided and their adverse effects.

Table 21.4 Medicines causing severe adverse drug reactions in the older person DRUGE OR DRUG GROUP

ADVERSE REACTION

Antimuscarinic agents (e.g. atropine)

Confusion, delirium, dry mouth, blurred vision, constipation, impaired thermoregulation, urinary retention

Antiemetics (e.g. metoclopramide, prochlorperazine)

Drowsiness, confusion, postural hypotension (prochlorperazine), dizziness (metoclopramide), extrapyramidal manifestations

Antipsychotic agents (phenothiazine group)

Postural hypotension, confusion, oversedation, extrapyramidal manifestations, blurred vision, urinary retention, permanent tardive dyskinesia

Benzodiazepines

Confusion, oversedation, memory impairment, poor muscle coordination

Digoxin

Nausea, vomiting, confusion, loss of appetite

Flucloxacillin

Hepatotoxicity

Histamine H2-receptor antagonists (especially cimetidine)

Confusion, dizziness, tiredness, multiple drug interactions

Non-steroidal anti-inflammatory drugs (especially non-selective agents)

Sodium and water retention, renal dysfunction, peptic ulceration

Sulfamethoxazole and trimethoprim

Blood dyscrasias, severe skin reactions (e.g. Stevens–Johnson syndrome)

Theophylline

Confusion, dysrhythmia, tremor

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SECTION IV GENERAL ASPECTS OF PHARMACOLOGY

CHAPTER REVIEW ■■

■■

■■

■■ ■■

■■

■■

The efficiency of pharmacokinetic processes varies across the lifespan. The manner in which the bodies of the very young and the very old handle medicines can be quite different from that of young adults. The differences in pharmacokinetics can lead to stronger or weaker medicine effects in children and older people than those in young adults. The physiological processes that influence pharmacokinetics in children and older people include gastrointestinal function, tissue blood flow, body fluid levels, plasma protein concentrations, liver function and renal function. Paediatric doses can be based on body surface area, age and bodyweight. Children should be included in the planning and implementation of drug treatment as much as possible. The explanations and degree of involvement depend on their age and level of development. Parents provide important verification of drug treatment and can participate in the monitoring of medicine effects. Non-adherence to drug therapy in older people is a significant problem. The reasons for this relate to the ageing process, the person’s social circumstances, prescribing patterns and the level of communication between health professionals. The problem of non-adherence can be addressed by an appropriate assessment of the person, simplified medicine regimens, medicine education and improved communication between health professionals.

REVIEW QUESTIONS 1 Outline all the possible pharmacokinetic effects on the actions of medicines in the very young. 2 Outline all the possible pharmacokinetic effects on the actions of medicines in older people. 3 A 20-kg child is to receive a dose of 12.5 mg/kg paracetamol. Your stock solution of paracetamol is 120 mg/5 mL.

How many millilitres of paracetamol are required? 4 Calculate the appropriate paediatric dose of allopurinol if the adult dose is 600 mg per day, given the following

information: a

the age of the child is 6 years

b the weight of the child is 16 kg c

the child’s body surface area is 0.44 m2

5 Summarise the key aspects of paediatric clinical management with respect to each part of the clinical

decision-making process. 6 State one reason for non-adherence to drug treatment for each of the following categories, and indicate how

the effect of each reason on adherence could be minimised: a

social circumstances

b biological effects of ageing c

health-team-related problem

7 Summarise the key aspects of geriatric clinical management with respect to each part of the clinical

decision-making process. 8 Name five types of medicine formulation that are not suitable for crushing prior to administration. 9 Aaron Skelad is two years old and is being hospitalised for a respiratory condition. His father is present at the

bedside. Aaron requires an intramuscular injection of a medicine. Outline the procedure you would take in managing the administration of this medicine.

C H A P T E R 2 1 PA E D I A T R I C A N D G E R I A T R I C P H A R M A C O L O G Y

10 Aldo Tagliatelli is 71 years old and migrated to this country from Italy with his wife ten years ago. He is in hospital

having treatment for a minor stroke. The stroke has affected his speech, as well as the movement of his right arm and hand (he is right-handed). He is recovering well and it is expected that he will be discharged home where his 68-year-old wife, Mary, will care for him. He is taking, and will continue to take, the diuretic hydrochlorothiazide and the β-blocker atenolol for hypertension. Added to this will be the anticoagulant warfarin. Discuss the factors, both positive and negative, affecting Aldo’s adherence to his drug therapy. 11 State whether dosing based on bodyweight or dosing based on body surface area is the more accurate method

to use. Explain your answer. 12 Gelia Angelle, aged two years and weighing 15 kg, is prescribed 9 mL of paracetamol elixir. Outline the process

that should be followed in administering the medicine.

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C A S E S T U DY 1 Ms HH is a 28-year-old pregnant woman who visits her midwife for her antenatal check-up. She is eight months’ pregnant and speaks to her midwife about clotrimazole 2 per cent vaginal cream prescribed by her local doctor for vulvovaginal candidiasis. Clotrimazole cream is a topical antifungal preparation. Her symptoms, which include vulval irritation, itching and a yellow discharge, have been very uncomfortable for Ms HH, but she is very concerned about the possible harm of the medicine to her baby. She is also unsure about how to use the vaginal cream. Clotrimazole is in category A of the Australian categorisation of medicines in pregnancy.

of 60 mg/kg daily. Jason weighs 16 kg and normally dislikes the taste of medicines.

Questions 1

What dose (in mg) can be safely administered to Jason before receiving his vaccination?

2

What is the maximum total amount (in mg) that can be administered in a 24-hour period?

3

What techniques can Jason’s mother use to help him take his medicine?

4

Jason’s mother is extremely concerned about safety surrounding medicine use. What safety measures would you recommend to her in storing the paracetamol preparation?

Questions 1

Is clotrimazole likely to cause any harm to the fetus? Explain your answer.

2

When are medicines likely to cause more harm during pregnancy—during the early or late stages? Explain your answer.

3

Describe how Ms HH should administer the vaginal cream.

C A S E S T U DY 2 Mr JM, aged 42 years, visits the community health centre to obtain manipulation therapy from the physiotherapist. He sometimes experiences flare-ups from a chronic back problem, which is greatly relieved by physical manipulation. After the therapy session, the physiotherapist asks Mr JM if he is doing anything else to help with his back problem. Mr  JM replies that he has started taking soluble aspirin, which decreases the pain he experiences. From Mr JM’s medical history, the physiotherapist discovers that Mr JM also suffers from epilepsy, which is treated with sodium valproate. The physiotherapist knows that both aspirin and sodium valproate are highly bound to plasma proteins.

Questions 1

What is the drug interaction that may occur here?

2

What is the potential end result?

3

What alternative to aspirin could the physiotherapist recommend?

C A S E S T U DY 3 Jason Forbes, aged six years, is due for his routine vaccination at the local doctor’s office. His mother is concerned that, on the previous occasion, Jason became extremely anxious about having the vaccinations and cried for nearly an hour after the event. On this occasion she wants to give him some paracetamol before and after the vaccination. The dose for paracetamol is 15 mg/kg every 4–6 hours up to a maximum

C A S E S T U DY 4 Millie Right, aged 90  years, has come to visit you at the community health centre. Ms Right is very concerned about the large number of tablets she is required to consume every day. She comments to you that her swallowing ability has declined over recent years, and that she finds it a real chore to take so many tablets. Ms Right also says that she worries she might accidentally forget to take some of her prescribed medicines.

Questions 1

What advice can you offer Ms Right to help her to swallow her medicines?

2

What potential problems can you envisage with any strategies you might offer Ms Right to help her to consume her medicines?

3

What advice can you offer Ms Right about helping her to remember to take her medicines?

C A S E S T U DY 5 Henry Chinn, aged 19 years, has recently moved to Australia to begin his university engineering course. He is diagnosed with generalised tonic-clonic seizures after experiencing a number of fits soon after his arrival and is placed on phenytoin to treat his condition. Following concentration monitoring of Mr Chinn’s phenytoin levels, his general practitioner surmises that he must be a poor metaboliser of the cytochrome P450 enzyme, CYP2C9.

Questions 1

What does the term ‘genetic polymorphism’ mean?

2

Phenytoin is a substrate of the cytochrome P450 enzyme, CYP2C9. What does this mean?

3

Since Mr Chinn is a poor metaboliser of CYP2C9, what is a possible outcome of this situation?

C H A P T E R 2 1 PA E D I A T R I C A N D G E R I A T R I C P H A R M A C O L O G Y

FU R T H ER RE A DI N G Buxton IL, 2006, ‘Pharmacokinetics and pharmacodynamics: the dynamics of drug absorption, distribution and elimination’, in Brunton LL, Lazo JS & Parker KL (eds), Goodman and Gilman’s Pharmacological Basis of Therapeutics, 11th edn, McGraw-Hill, New York, pp. 1–39. Eshkoli T, Sheiner E, Ben-Zvi Z & Holcberg G, 2011, Drug transport across the placenta, Current Pharmaceutical Biotechnology, 12(5): 707–14. Hughes CM, Roughead E & Kerse N, 2008, ‘Improving use of medicines for older people in long-term care: contrasting the policy approach of four countries’, Healthcare Policy, 3(3): e154–e167. Jacqz-Aigrain E & Choonara I, eds, 2006, Paediatric Clinical Pharmacology, Informa HealthCare, London. Khojasteh SC, Wong H & Hop CECA, 2011, Drug Metabolism and Pharmacokinetics Quick Guide, Springer, New York. Koch S, Gloth MF, Nay R (eds), 2010, Medication Management In Older Adults: a Concise Guide For Clinicians. Springer Science and Business Media, New York. Le Couteur D, McLachlan A & de Cabo R, 2012, Aging, drugs, and drug metabolism. Journals of Gerontology. Series A: Biological Sciences & Medical Sciences, 67(2): 137–39. McCance K & Huether SE, 2009, Pathophysiology, 6th edn, Elsevier Mosby, Sydney (for age-related and disease-related changes in body structure and function). Sissung TM, Troutman SM, Campbell TJ, Pressler HM, Sung H, Bates SE and Figg WD, 2012, Transporter pharmacogenetics: transporter polymorphisms affect normal physiology, diseases, and pharmacotherapy, Discovery Medicine, 13(68): 19–34. The Royal Australian College of General Practitioners, Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, Pharmaceutical Society of Australia, 2012, Australian Medicines Handbook, AMH Pty Ltd, Adelaide. Weier N, He SM, Li XT, Wang LL & Zhou SF, 2008, ‘Placental drug disposition and its clinical implications’, Current Drug Metabolism, 9, 106–21.

W E B R E S O UR C E S Australian Government Department of Health and Ageing www.health.gov.au Australian Statistics on Medicines www.tga.gov.au/hp/medicines-statistics-2010.htm Clinical Trials (US site) www.clinicaltrials.gov Health Insite www.healthinsite.gov.au/index.cfm Interactive Clinical Pharmacology www.icp.org.nz Medicines Australia (Pharmaceutical Industry Group) www.medicinesaustralia.com.au Medsafe www.medsafe.govt.nz NZ Ministry of Health www.moh.govt.nz/moh.nsf Pharmacokinetics: An Introduction (US site) www.4um.com/tutorial/science/pharmak.htm Therapeutic Goods Administration (TGA) www.tga.gov.au/index.htm Trials Central: online register of US clinical trials www.trialscentral.org

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V

TO X I C O L O G Y A dram of poison, such soon-speeding gear As will disperse itself through all the veins, That the life-weary taker may fall dead And that the trunk may be discharged of breath As violently as hasty powder fired … WILLIAM SHAKESPEARE—ROMEO AND JULIET

The consequences of ingesting a poison can be fatal, as the unfortunate Romeo discovered. However, it is often the case that we have sufficient time to neutralise, or at least attenuate, the effects of many toxic substances if we act promptly. In this section, the effective management of poisoning and envenomation is the primary objective. Chapter 22 covers the general management of poisoning by non-therapeutic substances, such as household and environmental agents, as well as the management of envenomation by a venomous animal. Specific antidotes are discussed when applicable. Chapter 23 examines the management of poisoning due to overdosage of therapeutic substances. As you will see, there is some overlap between strategies across the two chapters. Chapters  24 and 25 examine drugs used mainly for social rather than therapeutic purposes. In some instances, these drugs are taken to gain an unfair competitive advantage in sport. Drugs including tobacco, alcohol, marijuana, hallucinogenic agents, anabolic–androgenic agents, stimulants and hormones are covered. In many cases, their use is better described as abuse. We have included them in this section because their effects can be toxic to the body.

C H A P T E R

22

POISONING AND E N V E N O M AT I O N

LEARNING OBJECTIVES

KEY TERMS

After completing this chapter, you should be able to:

Clinical assessment

Outline the mechanisms of action of medicines used in the treatment of poisoning.

Cyanide poisoning

2

Identify contraindications for use of specific antidotes.

Envenomation

3

Outline how the effectiveness of emetics and adsorbents is influenced by the manner in which the substance is administered.

Life support

4

Define envenomation and outline the management of this condition.

Methanol poisoning

5

Define an antivenom.

6

Outline the common adverse effects of antivenoms.

1

Decontamination

Metal poisoning Neutralisation Organophosphate poisoning Venomous animals

This chapter explores poisoning as a result of the ingestion, usually accidental, of nontherapeutic chemicals, such as heavy metals, pesticides and domestic agents (e.g.  household cleaners, disinfectants). In some cases of poisoning, specific antidotes are available. However, it is common for a more general approach to be adopted, especially when the identity of the poison is unknown (see Figure 22.1). The management of an overdose of medicines is covered in Chapter 23. A number of venomous animals live in this region, particularly in Australia. These include species of snakes, spiders, jellyfish, molluscs and octopus. Some of these are considered to be the most toxic of their kind in the world. Envenomation is the injection of a biological toxin from a venomous animal by biting or stinging. The emergency management of envenomation in humans is briefly discussed here.

C H A P T E R 2 2 P O I S O N I N G A N D E N V E N O M AT I O N

MANAGEMENT OF POISONING

Life support

The main principles associated with the emergency management of poisoning are: • life support • clinical assessment • decontamination and detoxification • neutralisation and elimination of the poison (see Figure 22.1).

Clinical assessment

In this way you can see that the priority is on the treatment of the poisoned person rather than on identifying the chemical poison.

Life support is concerned with ensuring a clear airway, maintaining an effective respiration and circulation, and addressing any fluid or metabolic imbalances. A thorough clinical assessment is vital. The principles of clinical assessment have already been described in Chapter 8. In order to implement an appropriate treatment you need to gather as much information as possible about the poisoning episode. Important data include the time of poisoning, the number of chemicals involved, the

Figure 22.1 Principles associated with the management of poisoning

Clear airway

Maintain respiration

LIFE SUPPORT Treat fluid & electrolyte imbalances

Maintain circulation

Time of poisoning

Number of chemicals

Route(s) of administration

CLINICAL ASSESSMENT

Treatment already given

Emetic

Physical examination

DECONTAMINATION & DETOXIFICATION

Cathartic

NEUTRALISATION & ELIMINATION

Antidote

Adsorbent

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route of  administration, the circumstances surrounding the episode and the first aid that may already have been administered. A physical examination may reveal a set of clinical manifestations that suggests a particular chemical. This examination may inform the subsequent treatment.

Decontamination and detoxification In the first instance, the purpose of decontamination is to reduce the amount of poison absorbed systemically. For instance, it is important to cleanse the skin of any poison residues or, if the poison were inhaled, to move the person to where effective ventilation can occur. If the poison was ingested and the person has an intact gag reflex, an adsorbent or an iso-osmotic laxative or a combination of these may be administered. In order to be effective, a substantial amount of the poison must still be present in the gut. Therefore, administration of these medicines is often necessary even before the person arrives in hospital. If two hours have elapsed since ingestion of the poison, then gastrointestinal decontamination is rarely useful. Gastric lavage is now infrequently used and induction of emesis is no longer recommended.

ADSORBENTS Mechanism of action Activated charcoal is used as an adsorbent in poisoning. Charcoal particles bind to molecules of the ingested poison and reduce its absorption into the blood through the gut wall. It may also reduce absorption by interrupting enterohepatic recirculation, which was covered in Chapter 15. Clinical considerations The problem with using activated charcoal is that the dose necessary to effectively neutralise the poison is often underestimated. A dose ratio of at least ten parts charcoal to one part estimated dose of poison is recommended. Charcoal has proven effective in the treatment of overdosing with clinical medicines such as the cardiac glycosides and the methylxanthines, but is ineffective in cases of heavy metal or corrosive chemical poisoning because it does not bind to these toxins. The use of activated charcoal without gastric lavage or emesis is recommended because activated charcoal has been shown to be either as effective or superior to these other forms of gastrointestinal decontamination. Activated charcoal is discarded if it becomes moist because its binding ability is then greatly attenuated. Palatability of the activated charcoal suspension may be improved if it is administered chilled. It should be given orally if the person is conscious,

as this is a more tolerable form of administration than the nasogastric or orogastric routes.

I S O-O S M O T I C L A X AT I V E S Mechanism of action Iso-osmotic laxatives shorten the transit time of poisons through the gastrointestinal tract. In this way, the absorption of toxic substances is reduced. Iso-osmotic laxatives are not dependent on fluid shifts across the intestine and decontaminate the bowel by producing diarrhoea. The increase in intestinal bulk stimulates the peristaltic activity of the bowel. Appropriate solutions contain electrolytes and polyethylene glycols. Hyperosmolar laxatives or cathartics such as sorbitol are no longer used because they may lead to dehydration. Clinical considerations Iso-osmolar laxatives are considered useful in poisons that are not adsorbed onto activated charcoal, such as metals and strong acids or alkalis. The preparation may be administered orally or by nasogastric tube. Sometimes slowing the rate at which the iso-osmotic laxative is administered will control nausea and vomiting. An antiemetic may also be used to control nausea and vomiting. Iso-osmotic laxatives should not be used in people who have a suspected or proven bowel obstruction or perforation.

EMETICS Ipecacuanha (Ipecac syrup) is an extract from the root of the Caephalis plant. One of the active principal components in ipecacuanha is the alkaloid emetine. It is not as effective as activated charcoal and is certainly more toxic than activated charcoal. Ipecacuanha should never be used if activated charcoal is available. Mechanism of action Ipecacuanha has both central and peripheral emetic actions, but after oral administration the peripheral action is predominant. Vomiting is triggered by intense irritation of the mucosal layer of the intestinal wall. Not surprisingly, the central action comprises stimulation of the vomiting centre, via the chemoreceptor trigger zone, in the medulla. Clinical considerations The use of ipecacuanha has been largely superseded by activated charcoal. Ipecacuanha is not recommended for the treatment of poisoning in the home. The main reasons are that ipecacuanha does not induce complete emptying of the stomach; it can have a sedating effect in children; and in

C H A P T E R 2 2 P O I S O N I N G A N D E N V E N O M AT I O N

some cases of poisoning the substance cannot be identified and may be corrosive. It may counteract the desired benefit by causing propulsion of contaminated stomach contents into the duodenum.

Neutralisation and elimination The elimination and neutralisation of poisons is an important part of the management of poisoning. This aspect of management is covered in some detail in Chapter 23. If the poisonous chemical can be identified, there are a number of specific antidotes that can be used. In this section, the use of antidotes in the management of poisoning associated with a number of environmental chemicals (e.g.  heavy metals, methanol, cyanide or organophosphate sprays) is considered.

METAL POISONING Many metal ions, such as iron and zinc, are essential for normal body function. However, body requirements are such that only small amounts, mere traces, are sufficient. In excess, they produce widespread systemic toxic effects. Other metals, like lead, arsenic, bismuth, gold, antimony, thallium and mercury, do not play a role in normal physiological processes. On entering the body, they cause deleterious effects by displacing essential trace elements

and accumulating in tissues such as the brain, kidneys, skin, bone and blood. A number of substances bind strongly to metal ions, forming a ring structure around the offending substance. These are called chelating agents because they latch onto the ion firmly, just as a crab grabs something with its claws (chelae), and, by virtue of this bond, facilitate the elimination of the heavy metal. The main chelating agents, their specificities and adverse effects are listed in Table 22.1.

METHANOL POISONING Methanol, or methyl alcohol, has a number of industrial and domestic uses (e.g. as a solvent in photocopier solutions and window cleaners, and as a domestic heating material). Methanol is far more toxic to the human body than ethanol because it is metabolised into formaldehyde. Intoxication can lead to permanent disability and sometimes death. Like ethanol, it is a central nervous system depressant. Clinical manifestations of intoxication include visual disturbances, bradycardia, coma, metabolic acidosis, respiratory depression and seizures. Methanol and its metabolites can lead to permanent damage to the retina. The treatment of methanol poisoning is to administer ethanol, which is a competitive inhibitor of alcohol dehydrogenase. The rate of conversion of methanol into more toxic metabolites can be

Table 22.1 Chelating agents CHELATING AGENT

SPECIFICITIES

ADVERSE EFFECTS

Calcium disodium edetate

lead, plutonium, yttrium

Renal necrosis, gastrointestinal upset, muscle cramps, malaise

Calcium gluconate

magnesium, fluoride

Abdominal distension, constipation

Desferrioxamine mesylate (Desferal)

iron, aluminium

Allergic reactions, gastrointestinal upset, visual/ hearing disorders, liver/kidney impairment

Deferiprone (Ferriprox)

iron

Nausea, vomiting, athralgia, abdominal pain

Deferasirox (Exjade)

iron

Gastrointestinal upset, ulcer, haemorrhage

Dicobalt edetate

cyanide

Rare

Dimercaprol (BAL injection)

arsenic, gold, mercury, bismuth, antimony, thallium, lead (with versenate)

Hypertension, gastrointestinal upset, paraesthesias, muscle pain, headache Allergic reactions, nausea, vomiting, headache

Disodium edetate D-penicillamine

lead, copper, zinc, gold, mercury

Allergic reactions, liver/kidney impairment, gastrointestinal upset, hearing/taste impairment, blood dyscrasias

calcium lead

Decreased blood pressure Nephrotoxicity, gastrointestinal upset

(D-Penamine) Sodium calcium edetate Australia only New Zealand only

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slowed by the intravenous administration of a 10  per  cent solution of ethanol. Alcohol dehydrogenase is the hepatic enzyme responsible for the catabolism of both methanol and ethanol. By saturating this enzyme with ethanol, the degradation of methanol is competitively inhibited. Much of the methanol will then be eliminated via the lungs and kidneys. Haemodialysis, discussed in Chapter  23, is also effective in assisting the clearance of methanol from the body.

CYANIDE POISONING Cyanide, on entering the body, has a strong affinity for iron, particularly in the ferric form (Fe3+). This affinity leads to impairment in the function of the tissue cytochrome system. As a result, cellular energy, in the formation of ATP (adenosine triphosphate) molecules, is greatly diminished. An impairment of cellular metabolism is a life-threatening situation. Functionally, it is the same as a complete lack of oxygen within body cells. The treatment of this condition involves reactivation of the cytochrome system. To achieve this aim, the nitrites, vasodilators used in the treatment of angina pectoris (see Chapter 47), are put to good use. They act rapidly to convert haemoglobin (Fe2+) into methaemoglobin (Fe3+). As a result, a proportion of the cyanide will be drawn off the cytochromes onto methaemoglobin. Cellular cytochromes responsible for the energy production necessary for survival will function again. Amyl nitrite may be administered by inhalation, followed by intravenous administration of sodium nitrite or sodium thiosulfate. Alternatively, intravenous sodium nitrite is immediately followed by intravenous administration of sodium thiosulfate. Cyanide’s excretion from the body is facilitated by the intravenous administration of dicobalt edetate (see Table 22.1), but it is recommended for use only in cases of severe poisoning. This chemical forms non-toxic complexes with cyanide by displacing a cobalt ion for a cyanide molecule. Adverse reactions are relatively rare and are associated with either cobalt toxicity or allergy.

ORGANOPHOSPHATE POISONING Organophosphate sprays are principally used as agricultural and domestic pesticides. They are present in crop sprays, pet flea collars and some fly sprays. When absorbed into the body, the toxic effects arise out of the ability of the organophosphate to bind irreversibly to the enzyme cholinesterase, permanently disabling it. As a consequence, synaptic acetylcholine levels rise, leading to overstimulation of muscarinic and nicotinic receptors (see Chapter 28). The action of organophosphate pesticides is similar to that of the therapeutically valuable acetylcholinesterase inhibitors

(e.g.  neostigmine and physostigmine), except that the interaction between cholinesterase and the latter drugs is reversible. The manifestations of pesticide poisoning derive from this action and include pupil constriction, excessive sweating, drooling, diarrhoea, abdominal cramps, either bradycardia (if muscarinic stimulation is dominant) or tachycardia (if nicotinic stimulation is dominant), agitation, and skeletal muscle twitching followed by flaccidity (the latter leading to respiratory paralysis). The treatment involves the following interventions: respiratory support; blockade of cholinergic receptors; and the reactivation of the enzyme cholinesterase. The blockade of receptors is achieved through administration of the antimuscarinic agent atropine, and the reactivation of cholinesterase by injection of pralidoxime iodide.

ENVENOMATION A number of animals in this region, particularly snakes and spiders, produce venoms that are extremely toxic to humans (see Figure  22.2). The toxins contained within these venoms have the potential to cause profound tissue damage (cytolysis), neurological injury, clotting disorders, muscle injury and cardiovascular collapse, particularly after absorption into the bloodstream. The aims of the emergency care of someone who has been stung or bitten by one of these creatures follows the same principles associated with the management of poisoning (see Figure 22.1): that is, to maintain life support, to minimise systemic absorption of the venom and to facilitate the neutralisation of the venom.

Life support Life support involves maintaining a clear airway, initiating artificial ventilation in the event of respiratory collapse, and monitoring cardiovascular function.

Minimising systemic absorption In cases of envenomation by venomous snakes, the blueringed octopus, and funnel-web and mouse spiders, systemic absorption of the venoms, and, therefore, widespread injury, can be minimised through the application of a pressureimmobilisation bandage. The bandage traps the venom within the tissue and local lymphatic vessels, preventing absorption into the circulation. In the case of bites by the redback spider, the venom is absorbed into the bloodstream very slowly. For this reason, the application of a pressure-immobilisation bandage is not recommended. In fact, it can aggravate the injury by making

C H A P T E R 2 2 P O I S O N I N G A N D E N V E N O M AT I O N

Figure 22.2 Examples of terrestrial animals that pose a risk to humans

it more painful. Ice packs should be applied to restrict local blood supply through the tissue. A number of cases have been reported of serious injury caused by venomous jellyfish, particularly the box jellyfish or sea wasp. These animals possess spring-loaded needles on their tentacles, which inject the venom. In cases of jellyfish stings, the affected area should be flooded with vinegar in order to deactivate the stinging apparatus. Jellyfish stings can cause severe pain, such that the affected person may require treatment with narcotic analgesics.

Neutralisation of the venom Receiving raw venoms for terrestrial snakes and funnelweb spiders from the Australian Reptile Park, CSL Ltd has led the way internationally in developing antivenoms. Antivenoms are widely available in Australia against a variety of venomous animals (see Table 22.2), including the box jellyfish, funnel-web spider, redback spider, stonefish and a variety of terrestrial and sea snakes (e.g.  brown snake, tiger snake, king brown snake, death adder, taipan, black snake and sea snake). As a result, the mortality rate associated with envenomation by these animals has fallen significantly. Mechanism of action Antivenoms are derived from non-human sera (e.g.  from sheep, rabbits, horses or dogs). These animals are effectively immunised against the venoms by repeated low-dose exposure. The antibodies they make are directed against the venom and are present in the animal’s serum. When the antiserum from these animals is injected into envenomated humans, the preformed antibodies facilitate an immunemediated neutralisation of the life-threatening toxic constituents.

A

Common adverse effects Common adverse effects of non-human antisera comprise allergic reactions to serum contaminants: fever, chills, skin rashes and the more serious anaphylactoid reactions. Hypersensitivity to blood products is a contraindication for use. Clinical considerations

B A B

Redback spider. Snakes are milked for their venom, to produce an antivenom.

Source: Copyright © 2003 Australian Reptile Park, www.reptilepark.com.au.

It is important to inform individuals that antivenoms may cause a delayed serum sickness reaction, which manifests as fever, rash and arthralgias. Oral corticosteroids can be given prophylactically to reduce the chance of serum sickness developing in people who have received large doses of antivenom. However, their use is controversial. This controversy exists because oral corticosteroids can

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Table 22.2 Antivenoms and their sources CONDITION

TRADE NAME(S)

SOURCE

Box jellyfish sting

Box jellyfish antivenom

Sheep

Funnel-web spider bite

Funnel-web spider antivenom

Rabbit

Redback spider bite

Redback spider antivenom

Horse

Snake bite

Snake antivenoms (brown, tiger, taipan, king brown, death adder, black, sea snake, polyvalent)

Horse

Stonefish sting

Stonefish antivenom

Horse

Bush tick bite

Tick antivenom

Dog

Australia only

cause adverse events, such as increased susceptibility to infection. Due to the possibility of anaphylaxis, it is preferable for antivenoms to be administered in hospital to enable emergency treatment to be provided if necessary. The

health professional should ensure that adrenaline is readily available for use if it is required. The risk of an anaphylactic reaction is reduced if the antivenom is adequately diluted before administration.

CHAPTER REVIEW ■■

There are four main principles associated with the management of poisoning: – life support – clinical assessment – decontamination and detoxification – neutralisation and elimination.

■■ ■■

■■

■■ ■■

Life support involves maintaining a clear airway, respiration and circulation. Clinical assessment consists of a process of gathering information to guide management. It involves taking a good history and completing a thorough physical examination. The purpose of decontamination is to reduce systemic absorption of the poison. Adsorbents and iso-osmotic laxatives represent important treatments in this phase. Some antidotes are available that neutralise or promote the elimination of selected poisons. Envenomation is the injection of a biological toxin from a venomous animal by biting or stinging. Venoms can cause extensive tissue damage and are potentially fatal.

■■

The management principles in cases of envenomation are similar to those associated with poisoning.

■■

Antivenoms are very effective against a range of venoms and act to neutralise the toxins contained in the latter.

REVIEW QUESTIONS 1

Indicate the circumstances under which each of the following agents should not be administered: a

activated charcoal

b iso-osmotic laxative c

penicillamine

C H A P T E R 2 2 P O I S O N I N G A N D E N V E N O M AT I O N

2

What is a chelating agent?

3

Name the agent(s) used in the treatment of poisoning by each of the following substances: a

cyanide

b lead c

mercury

d pesticides 4

Define the term envenomation.

5

State the three aims of emergency care when someone is bitten or stung by a venomous animal.

6

Your neighbour visits you in an extremely distressed state. Joey, her three-year-old son, has just swallowed an unknown quantity of paracetamol tablets. What would you advise her to do? Why?

7

Mario Malodoro, a 60-year-old farmer, is brought into the emergency department with organophosphate poisoning. How would this form of poisoning be treated?

8

While clearing rubbish in his backyard, 28-year-old Jeffrey Abelcet is bitten on the hand by a redback spider. His partner bandages his hand and arm firmly. She then drives him to your clinic, which is only five minutes down the road. Comment on the suitability of this treatment. Describe the management of this type of envenomation.

22 MEDICINE SUMMARY TABLE FAMILY NAME

GENERIC NAME

Emetic

ipecacuanha

Adsorbent

activated charcoal + sorbitol

Carbosorb X Carbosorb XS

Iso-osmotic laxatives

electrolytes + polyethylene glycol + ascorbic acid

ColonLYTELY Glycoprep Glycoprep-C Klean Prep Movicol Movicol-Half Moviprep

Methanol intoxication

ethanol + glucose

Cyanide antidote

amyl nitrite dicobalt edetate sodium nitrite sodium thiosulfate

Organophosphate antidotes

atropine sulfate pralidoxime iodide

Australia only New Zealand only

TRADE NAME(S)

PAM injection

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C H A P T E R

23

THE MANAGEMENT OF ACUTE CLINICAL OVERDOSE

LEARNING OBJECTIVES

KEY TERMS

After completing this chapter, you should be able to:

Acute medicine overdose

State the four principles underlying the management of acute clinical overdose.

Antidotes

2

Identify the clinical manifestations of poisoning that require life support.

Decontamination

3

Outline the ways in which medicines are identified in cases of overdose.

Detoxification

4

Describe the general approach used to detoxify a poisoned person.

Gastric lavage

5

Identify the specific antidotes available, their common adverse effects, and important clinical considerations when using them.

Haemoperfusion

1

Clinical assessment

Haemodialysis Life support Neutralisation

In Chapter  22, the treatment of poisoning by the ingestion of household and industrial chemicals was discussed. In this chapter, the management of acute overdosage of medicines, either deliberate or accidental, is described. The importance of this area of pharmacology is self-evident. The probability that you will administer the wrong dose of a medicine some time in your professional career is high. If that dose puts the person you are treating above the minimum blood concentration considered toxic, then the consequences will be at best debilitating, at worst lethal. A significant proportion of hospital admissions result from serious adverse reactions to medications—some resulting from inappropriate therapeutic use, most from deliberate abuse. Serious illnesses arising from these reactions are termed iatrogenic (induced by a doctor or by medical treatment) conditions.

CHAPTER 23 THE MANAGEMENT OF ACUTE CLINICAL OVERDOSE

There are four principles underlying the management of acute clinical overdose: •

life support;

•

assessment of the affected person;

•

decontamination and detoxification;

•

neutralisation and elimination.

These principles and their components are summarised in Figure 23.1.

MANAGEMENT OF MEDICINE OVERDOSE Life support Medicine overdose often manifests itself as an acute clinical emergency. Failure to act quickly may result in the death of the poisoned person. Indeed, immediate supportive measures may take precedence over the identification and detoxification of the offending medicine. The kinds of life-threatening emergencies that can be induced by medicines include seizures, cardiac dysrhythmias, circulatory shock, coma, airway obstruction and respiratory arrest. Massive damage to vital organs, such as the liver, lungs or kidneys, caused by drug toxicity can also lead to death within a relatively short period of time. Obviously, the management of these conditions is the same no matter what specific medication is the cause. The management of such medical emergencies can be found in a suitable clinical reference, and will not be duplicated here.

Clinical assessment If the acute overdose occurs within the confines of a controlled clinical setting, it is relatively easy to determine the offending agent and the dose administered. On the other hand, if a person is admitted with a suspected medicine or drug overdose, such information may not be available. Drug identification and dosage may have to be deduced from a combination of their history, clinical manifestations and laboratory findings. A thorough physical examination of the person will reveal a syndrome of clinical manifestations of overdose, such as electrocardiogram (ECG) changes, alterations in consciousness and seizures. Knowledge of the manifestations that characterise a particular therapeutic agent is useful and usually comes with clinical experience and drug familiarity. It is also helpful to know that many medication entries in the Australian Medicines Handbook include information pertaining to overdosage and its treatment. Clearly, the most powerful diagnostic tool is detection of a drug in the blood by laboratory testing. Indeed, blood drug

levels may be necessary to guide the detoxification process. Laboratory testing provides information concerning pH changes, electrolyte imbalances and the extent of damage to the liver and kidneys. These values will also determine the kinds of supportive measures necessary to restore homeostasis.

DECONTAMINATION AND DETOXIFICATION General approach No matter what the route, once an acute overdose has been noticed, continued administration must cease until the crisis is under control. Irrespective of whether life support takes precedence over detoxification, this is the first action. The general approach employed to reduce systemic absorption of an ingested poison referred to in Chapter 22 (such as the use of activated charcoal and an isoosmotic laxative) has application in clinical overdose if the medicine were administered orally. Indeed, this form of treatment, if initiated quickly, is particularly effective for oral poisoning with medicines such as the cardiac glycosides, angiotensin-converting enzyme (ACE) inhibitors and methylxanthines.

NEUTRALISATION AND ELIMINATION Within the clinical environment, this general approach can be broadened to include more invasive medical procedures, such as gastric lavage and haemodialysis, which facilitate the elimination of the drug from the body. An antidote to the medicine may also be available to neutralise its effects.

Gastric lavage Gastric lavage involves the passage of a large-bore tube directly into the stomach. A solution of warmed isotonic saline is instilled into the stomach and then suctioned

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S E C T I O N V TO X I C O L O G Y

Figure 23.1 Principles associated with the management of an overdose

Clear airway

Maintain respiration

LIFE SUPPORT Treat fluid & electrolyte imbalances

Maintain circulation

Time of poisoning

Number of chemicals

Route(s) of administration

CLINICAL ASSESSMENT

Treatment already given

Emetic

Physical examination

DECONTAMINATION & DETOXIFICATION

Adsorbent

Cathartic

Gastric lavage

NEUTRALISATION & ELIMINATION

Haemodialysis & haemoperfusion

Antidote

out. This process is repeated a number of times until the aspirated solution is clear. The first sample of aspirate is usually sent to the laboratory for identification. The only problems with lavage are that the necessity for a large-bore tube restricts the use of this procedure in children (who have a smaller diameter oesophagus), and there is a risk of metabolic alkalosis due to excessive loss of chloride ions from the gastrointestinal tract. Figure 23.2 shows two examples of gastric tubes that can be used for rapid evacuation of gastric contents, and Figure  23.3 demonstrates the positioning of an unconscious patient for gastric lavage.

Haemodialysis and haemoperfusion Haemodialysis involves passing the person’s blood through a dialysis medium, where the drug and/or its metabolites are removed and electrolyte imbalances corrected. The detoxified blood is then recirculated to the affected person. The only hindrance is that a limited number of medications can be removed effectively by this method. Evidence indicates that haemodialysis can be used effectively in lithium and salicylate poisoning. A drug’s apparent volume of distribution, Vd, can also be an indicator of the likely success of haemodialysis (see Chapter  14). A low Vd can suggest the usefulness of haemodialysis in overdose.

CHAPTER 23 THE MANAGEMENT OF ACUTE CLINICAL OVERDOSE

Figure 23.2 Gastric tubes that can be used for

the rapid evacuation of gastric contents

The Ewald tube is a wide-bore, single-lumen tube that has several openings at its distal end. Its wide bore allows for rapid aspiration of stomach contents. The Levacuator tube is a wide-bore, double-lumen tube. The large lumen is for aspirating gastric contents, and the small lumen is for inserting irrigating fluid. Its wide bore allows for rapid aspiration of stomach contents. Ewald tube

Levacuator tube

adheres to the beads and remains within the medium, while the filtered blood returns to the affected person. Like haemodialysis, it has limited use because it is effective for only a handful of medications (e.g.  carbamazepine, theophylline, digoxin and phenobarbitone). Its disadvantage compared with haemodialysis is that it cannot correct electrolyte imbalances.

Special antidotes There are few specific detoxifying medicines available for use in situations of clinical overdosage. Antidotes neutralise, antagonise the effects of, or facilitate the elimination of, the medicine. They are available against poisoning with the following substances: paracetamol, acetylcholinesterase inhibitors, antimuscarinic agents, iron, narcotics, benzodiazepines, heparin, warfarin and digoxin. The advantage of specific antidotes is that other interventions (e.g. gastric lavage, artificial ventilation, brain scans) become unnecessary.

PARACETAMOL OVERDOSE

Figure 23.3 Patient positioning during gastric lavage During gastric lavage, the unconscious patient is positioned on the left side to facilitate pooling of gastric contents and to hinder their passage to the duodenum. Patient is lying on the left side

Gastric tube

Pooling of gastric contents

Haemoperfusion is a filtering system in which the person’s blood is passed through a medium containing adsorbent beads. The offending medicine, and/or its metabolites,

Normal doses of paracetamol are handled well by the liver’s metabolic processes. Most paracetamol is conjugated and the conjugates excreted directly, but some is metabolised to a highly reactive intermediate compound called N-acetyl-p-benzoquinone-imine (NAPQI), which is then conjugated with glutathione. Unfortunately, the body’s stores of glutathione are limited and, if excess paracetamol is consumed, NAPQI is produced in excess. NAPQI has an affinity for liver cells and their enzymes, to which it binds and it slowly destroys, leading to hepatic necrosis. Once this process has started, it becomes irreversible and death is usually inevitable. It takes only a relatively low dose of paracetamol for hepatotoxicity to occur. Two 500-mg tablets (1 g) is considered a toxic dose in a 10-kg child. For an adult, 8 g (sixteen 500-mg tablets) is sufficient to produce a toxic reaction. Treatment must be commenced as soon as possible after the overdose and is aimed at increasing body stores of glutathione. Glutathione itself is incapable of crossing into cells, but acetylcysteine, the acid derivative, can stimulate its production. Acetylcysteine is utilised in the synthesis of glutathione. A risk assessment of hepatotoxicity is calculated from an agreed nomograph of the serum paracetamol levels post-ingestion (see Figure  23.4). Treatment is required if the serum drug levels are above the plotted line, which starts at a value of 1000 µmol/L at 4 hours post-ingestion. The dose of acetylcysteine is 300 mg/kg over 20 hours and has to be given as an aerosol. It is effective if given

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S E C T I O N V TO X I C O L O G Y

Figure 23.4 Paracetamol treatment nomograph for Australia and New Zealand 160 150

1000

140

900

130 120

800

110

700

100 90

600

80

500

70 60

400

50

300

40 30

200

20

100 0

Blood paracetamol concentration (mg/L)

Blood paracetamol concentration (µmol/L)

222

10 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

0

Time (hours)

Note: A person with a blood paracetamol concentration equal to or above the line at a particular time should receive acetylcysteine therapy. Source: Daly FF, Fountain JS, Murray L, Graudins A & Buckley NA, 2008, Guidelines for the management of paracetamol poisoning in Australia and New Zealand—exploration and elaboration, Medical Journal of Australia, 188, 296–301. Box 2, p. 297. © Medicines and Healthcare products Regulatory Agency (MHRA).

within 10–15  hours of the ingestion of paracetamol. Depending on the circumstances, acetylcysteine may be beneficial more than 15 hours post-ingestion. Advice from doctors experienced in the management of paracetamol poisoning is essential. Allergic reactions have been reported after administration of acetylcysteine. Individuals at higher risk of hepatotoxicity include heavy alcohol drinkers, possibly due to the fact that the enzyme-inducing properties of ethanol raise the rate of conversion of paracetamol to its toxic metabolite.

ACETYLCHOLINESTERASE INHIBITOR OVERDOSE The antidotes for overdose of the acetylcholinesterase inhibitors (otherwise known as anticholinesterases) neostigmine, physostigmine and pyridostigmine are atropine and pralidoxime iodide. Atropine is a competitive antagonist to acetylcholine, whose synaptic activity is prolonged by the acetylcholinesterase inhibitors (see Chapter  28). Common adverse effects of atropine are antimuscarinic in nature, and include dry mouth, blurred vision, constipation, tachycardia and urinary retention. Atropine is contraindicated in obstructive and atonic conditions of both gastrointestinal tract and urinary bladder, and in cardiospasm. Pralidoxime iodide activates acetylcholinesterase, the

acetylcholine degradative enzyme. It is not as effective as atropine but is often used as an adjunct to atropine in this type of poisoning. Not surprisingly, the adverse effects are similar to that of atropine. It is contraindicated in cases of known hypersensitivity.

ATROPINE OVERDOSE When a patient has been poisoned by atropine administration, it makes sense to use a medicine that stimulates muscarinic receptors (see Chapter 28). The recommended medication is the acetylcholinesterase inhibitor physostigmine. Many of the more serious manifestations of atropine overdose are of central nervous system (CNS) origin (i.e.  delirium with hallucinations, agitation and aggression), and physostigmine readily crosses the blood– brain barrier. Following physostigmine administration, intravenous administration of a benzodiazepine, such as diazepam or midazolam, is recommended. Common adverse effects of physostigmine result from excessive cholinergic stimulation, and include muscarinic reactions (CNS stimulation, nausea, vomiting, diarrhoea, sweating, drooling, bradycardia and miosis) and nicotinic reactions (muscle cramps and fasciculations). It is contraindicated in obstructive bowel conditions and where hypersensitivity is evident.

CHAPTER 23 THE MANAGEMENT OF ACUTE CLINICAL OVERDOSE

IRON POISONING Acute iron poisoning is treated using desferrioxamine, which increases excretion of the excess iron by forming a water-soluble complex called ferrioxamine. Adverse effects include allergic reactions, gastrointestinal disturbances, alterations in vision and hearing, dizziness and hypotension. Administration of desferrioxamine involves slow continuous infusion, either subcutaneously or intravenously. Desferrioxamine is contraindicated if hypersensitivity is apparent. Deferiprone is approved for use in people with thalassaemia major experiencing iron overload. It is an oral chelating agent that promotes iron excretion. Deferiprone is particularly useful for people unable to take desferrioxamine or in cases where the latter treatment is ineffective. Common adverse effects include nausea, vomiting, arthralgia and abdominal pain. Administering deferiprone with food can help to reduce nausea and vomiting. Deferasirox is used for the treatment of chronic iron overload associated with blood transfusions. It chelates with non-transferrin-bound iron, and the resulting complex is excreted in the faeces. Deferasirox is available as a dispersible tablet that is taken during the time that a blood transfusion is being administered, and repeated in three to six months based on serum ferritin levels. The medication is taken 30 minutes before food, preferably at the same time each day. Serum creatinine and alanine aminotransferase (ALT) levels are monitored at baseline and every month. Common side-effects include nausea, vomiting, dyspepsia, diarrhoea and abdominal pain.

NARCOTIC OVERDOSE Narcotic drug overdose can be treated effectively using either the full antagonist naloxone or the partial antagonist nalorphine. Naloxone, the medication of choice, has a much stronger affinity for opiate receptors than most of the opiate agonists and can be used to reverse their action in cases of overdose. The result is quite dramatic. A person can, at one moment, be comatose and at death’s door because of respiratory depression and, on intravenous injection of naloxone, have an immediate recovery to more or less normality. There is one problem. Naloxone has a half-life of about one hour, which is much shorter than the agonists. Repeat doses may be necessary depending on the dose, duration of action and time interval since administration of the offending narcotic. Care must be taken to keep overdosed people under observation for a considerable time, especially with the longer half-life narcotics, to make sure that toxic signs do not return. Oxygen and ventilatory support should be provided and individuals should be

observed for at least two to three hours after naloxone has ceased to ensure relapse into unconsciousness does not occur. Careful observation is particularly important in situations involving longer acting opioids or those with active metabolites, such as methadone, diphenoxylate and codeine. Regular observation and monitoring are also needed for overdose involving controlled release opioid medications, where narcosis can persist for more than 24 hours. Naloxone works antagonistically with most of the narcotics, but with buprenorphine, which binds rather tenaciously to the receptors, the results are not so dramatic. Paediatric naloxone is available to counteract the respiratory depression that can occur in the newborn due to analgesic use in labour. Interestingly, naloxone blocks the analgesic effect of acupuncture, confirming the physiological basis of this form of therapy. It is suggested that the acupuncturist’s needles may stimulate endorphin release, the effect of which is blocked by naloxone. The clinical effects of nalorphine are similar to those of naloxone. However, being a partial antagonist, nalorphine can also induce sedation, pupil constriction and respiratory depression if given alone. These antidotes can, if administered too quickly, induce narcotic withdrawal symptoms, such as nausea, vomiting, tachycardia, tremor and sweating. Again, if hypersensitivity to nalorphine is present, it is contraindicated.

BENZODIAZEPINE OVERDOSE The benzodiazepines are among the safest of all CNS drugs. Their introduction was instrumental in reducing the use of barbiturates as sedatives. It has been suggested that, even with large amounts, the person is easily roused. But deaths have occurred when they are taken in excess with alcohol, a common combination. In the case of overdose of a benzodiazepine alone, the treatment is largely supportive as this is not usually considered a life-threatening situation. Flumazenil is a specific antagonist to the benzodiazepines and is useful in the management of life-threatening situations, such as can occur with alcohol/benzodiazepine combinations. Flumazenil is useful in the diagnosis of benzodiazepine overdose (note the use of the term diagnosis rather than treatment). If an overdose is suspected, rapid recovery after an intravenous injection of flumazenil is indicative of benzodiazepine overdose. If recovery is not apparent, further treatment and diagnosis need to be made. The recommended initial intravenous dose is 0.3 mg, followed by repeated doses until the affected person regains consciousness, up to a total dose of 2 mg.

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Flumazenil is usually well tolerated, although agitation, shivering, nausea and vomiting have been reported. It is important to remember that most benzodiazepines are characterised by long durations of action. Therefore, the individual may lapse back into a state of sedation after the antidote wears off (average elimination half-life of flumazenil is around one hour). This effect has implications for people discharged from hospital shortly after treatment. Hypersensitivity is a contraindication for use. Flumazenil administration can be very problematic when a benzodiazepine is combined with proconvulsant medicines, such as a tricyclic antidepressants or amphetamines. The action of the antagonist may induce severe seizures that can lead to death. It should also be used with caution in the management of someone who is a chronic benzodiazepine user. Again, its action may lead to an acute withdrawal state characterised by seizures and acute delirium.

HEPARIN OVERDOSE A protein derived from the sperm of salmon may sound a bizarre medium for neutralising a heparin overdose. It is, however, a reality. The protein protamine sulfate combines with the heparin molecule to form a complex that suppresses the pharmacological activity of the anticoagulant. Adverse cardiovascular effects, such as hypotension, bradycardia and facial flushing, can occur but these are minimised by slow intravenous infusion. Rapid injection can cause an anaphylactic reaction. In order for protamine sulfate to be effective, it must be given within three hours of the heparin injection. For every 100 units of heparin in the blood, 1 mg of protamine is administered. However, no more than 50 mg of protamine can be infused at any one time.

WARFARIN OVERDOSE An excessive anticoagulant effect brought about by warfarin overdose is best treated with vitamin  K1, administered

either orally or parenterally. In cases where serious bleeding is observed, the usual dose range for parenteral injection is 5–25  mg. In an emergency, where severe haemorrhage is present, a transfusion of whole blood or blood products will be necessary.

DIGOXIN OVERDOSE High doses of digoxin or any related cardiac glycoside can be fatal, even with life support provided. The most effective means of treating a potentially fatal dose of digoxin is an antibody preparation called digoxin-specific antibody, which is administered intravenously. It rapidly reverses the manifestations of digoxin poisoning, which can include ventricular tachycardia or fibrillation, and serious bradyarrhythmias that are not responsive to atropine. If someone has a potassium imbalance, and digoxin overdose occurs, cardiac dysrhythmias are even more marked. Digoxin-specific antibody is also effective following overdose of any other cardiac glycoside. At this time, it is only available in Australia. The preparation consists of antibody fragments specific to the digoxin molecule, which have been raised in sheep. Antibody fragments have been found to be less immunogenic than whole immunoglobulin. Nevertheless, being a protein derivative from an animal source, its most common adverse reactions are of an allergic kind. In Australia, this preparation is marketed as Digibind. Digoxin-specific antibody is given intravenously and one vial of the preparation comprising 38 mg of powder binds to approximately 0.5  mg of digoxin. When this preparation is not available, life support measures have to be relied on. Atropine and phenytoin are often used to control life-threatening dysrhythmias. Improvements in clinical manifestations of digoxin overdose occur usually within 30  minutes of digoxin-specific antibody administration and during treatment it is important to monitor blood pressure, cardiac rate and rhythm, and potassium concentration.

CHAPTER REVIEW ■■

The main principles associated with the management of acute clinical overdose are: – life support; – clinical assessment; – decontamination and detoxification; – neutralisation and elimination.

CHAPTER 23 THE MANAGEMENT OF ACUTE CLINICAL OVERDOSE

■■

■■

■■

Life support is concerned with maintaining a clear airway, respiration and circulation. It is also important to treat any seizures, cardiovascular or respiratory disturbances and any significant damage to any other organ system as a part of these supportive measures. Clinical assessment involves a thorough physical examination, taking a good history and performing any appropriate laboratory tests. During the detoxification phase the systemic absorption of the drug is reduced, the drug is neutralised and the elimination of the substance is facilitated. Adsorbents, iso-osmotic laxatives, haemodialysis/haemoperfusion and specific antidotes may be used to achieve detoxification.

REVIEW QUESTIONS 1 Briefly describe the four principles underlying the management of acute clinical medicine overdose. 2 What are the main tools used in clinical assessment to identify the specific agent in a suspected drug overdose? 3 Name the specific antidote(s) for overdose of the following medications: a

warfarin

b digoxin c

oxycodone

d diazepam 4 Under what circumstances might you use gastric lavage or haemodialysis to facilitate the elimination of a drug in

overdose? 5 Martha Majors, a 24-year-old woman, is admitted to the emergency room after the ingestion of twenty 500-

mg caplets of paracetamol. She has taken them less than two hours ago. Is this considered a hepatotoxic dose? Outline the treatment of her condition. 6 Phillip Jones, who sustained a deep vein thrombosis five days ago, is on an intravenous heparin infusion to

prevent the development of further clots. As his nurse, you notice that the infusion has been administered too quickly. He has experienced haematuria following a urinalysis test, bleeding gums and a bleeding nose. What would you suspect? How would this condition be treated? 7 Martin Cairns, 27 years old, is receiving treatment for a heart condition. You note that he has bradycardia, drooling,

diarrhoea, pupil constriction and hypotension. Is this a case of acetylcholinesterase inhibitor or atropine poisoning (you may need to refer to Chapter 28 for help)? What is the antidote for this overdose? 8 Baby Anna Riali is admitted to the emergency department after the ingestion of iron tablets. What antidote will be

administered? What information would you provide to Anna’s mother about this antidote? 9 Katrina Markowitz, a 22-year-old student, is admitted to the emergency department after an overdose of

diazepam. She was lying unconscious in her flat for about six hours before she was found by friends. An open bottle of whisky was found on the kitchen table. She was taken by ambulance to hospital and you assess her in the emergency room. Is there a specific antidote for diazepam overdose? What is the appropriate management in this situation? 10 John Roberts, an 18-year-old unemployed youth, is brought into the emergency department by a friend after a

heroin overdose. A dose of naloxone is administered. He suddenly regains consciousness and begins to tremble and sweat. How would you explain this phenomenon? Within 1½ hours of the naloxone administration, John is becoming lethargic, his breathing is changing character and his pupils are becoming constricted. Account for his changing state. 11 Bill Daniels is a 50-year-old business manager with a past history of rheumatic fever and a mechanical mitral valve

replacement. He takes warfarin to prevent clots forming associated with the valve replacement. While showering

225

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S E C T I O N V TO X I C O L O G Y

one day, he notices extensive bruising on his abdomen and thighs. He visits his general practitioner, who determines that the warfarin dose is too high. What medication could be administered to rectify this problem? 12 Heidi Reiter is a 68-year-old woman with a past history of cardiac dysrhythmias. She takes digoxin to control her

symptoms. She is found by her daughter collapsed on the floor and is brought into the emergency department, where she is diagnosed with a digoxin overdose. Digoxin-specific antibody is administered. What observations should the emergency department staff make during and following the administration of digoxin-specific antibody?

23 MEDICINE SUMMARY TABLE FAMILY NAME

GENERIC NAME

TRADE NAME(S)

Emetic

ipecacuanha

Adsorbent

activated charcoal + sorbitol

Carbosorb X Carbosorb XS

Iso-osmotic laxatives

electrolytes + polyethylene glycol + ascorbic acid

ColonLYTELY Glycoprep Glycoprep-C Klean Prep Movicol Movicol-Half Moviprep

Paracetamol overdose

acetylcysteine

Acetadote Fluimucil Parvolex

Anticholinesterase overdose

atropine sulfate pralidoxime iodide

PAM injection

Atropine overdose

physostigmine diazepam midazolam

Iron poisoning

desferrioxamine deferiprone deferasirox

Desferal Ferriprox Exjade

Narcotic overdose

naloxone hydrochloride

Narcan Narcan Neonatal

Benzodiazepine overdose

flumazenil

Anexate

Heparin overdose

protamine sulfate

Digoxin overdose

antidigoxin antibodies atropine phenytoin disodium edetate

Warfarin overdose Australia only New Zealand only

vitamin K1 (phytomenadione)

Digibind Dilantin Konakion

C H A P T E R

24

C O N T E M P O R A RY D R U G S OF ABUSE

LEARNING OBJECTIVES

KEY TERMS

After completing this chapter, you should be able to:

Chronic drug dependence

1 Describe the problems associated with alcohol.

Drug abuse

2 Describe the medications used to treat alcoholism.

Drug addiction

3 Describe the problems associated with nicotine and smoking tobacco. 4 Describe the medications used to treat nicotine addiction. 5 Describe the problems associated with caffeine. 6 Describe the problems associated with hallucinogens. 7 Describe the problems associated with ketamine. 8 Describe the problems associated with marijuana. 9 Describe the problems associated with cocaine. 10 Describe the problems associated with volatile substances.

Alcohol (ethanol), nicotine and caffeine are the most widely used of all drugs, so much so that many people would not consider them to be drugs at all as they are all used mainly for social rather than therapeutic purposes. Each of these substances has pronounced pharmacological effects on the body, and all have been used at one time or another as therapeutic substances. Today, their pharmacological use is very limited. In the case of nicotine, the pharmacological use is almost non-existent except as a research substance, occasionally as an insecticide or, in some substitute forms, to aid smoking cessation. As these substances are used a great deal in society for their ‘pleasurable’ effects, a short discussion on them is appropriate. The other drugs addressed in this chapter also have no distinct clinical use, and are used recreationally rather than therapeutically. With most of these drugs, harmful rather than beneficial effects are the norm. The misuse of drugs related to enhancing performance in sportspeople is dealt with in Chapter 25.

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ALCOHOL When most people talk about alcohol they are referring to ethanol rather than the numerous other organic compounds classed as alcohols. Ethanol has been known since antiquity (~3000 BCE) as an ingredient of fermented products of both plant and animal origin. It is, of course, best known today as an ingredient of fermented grapes, as in wine, fermented barley, beer and, in a more concentrated form, in the distilled liquors such as whisky, gin and brandy. The proposed mechanism of action of alcohol is that it disrupts the lipids in nerve cell membranes, altering their permeability and thus altering the neural transmission. There is also some evidence that alcohol augments the action of gamma-aminobutyric acid (GABA) at its receptor (see Chapter 35), hence its unofficial and inadvisable use as an anxiolytic. Contrary to popular belief, alcohol is a central nervous system (CNS) depressant and not a stimulant. The reason that many laypeople would classify it as a stimulant is that, in depressing some of the higher centres of the brain, it suppresses inhibitions and stimulates people to do things that they would not do normally. Pharmacologically, ethanol is classified as an anaesthetic, and small amounts lead to a sense of wellbeing and relaxation, more leads to a loss of inhibitions, even more leads to a complete lack of coordination, which is commonly called drunkenness, until eventually a stage of unconsciousness may be reached. Very large amounts can lead to coma and death due to respiratory depression. There have been several cases of people dying after drinking a whole bottle of spirits. Apart from being poisonous in excess, one of the more important aspects of alcohol is its potential to cause addiction. Alcohol addiction is one of the most common of the serious addictions, and can wreck not only an individual’s life but also that of his or her family. This can happen for three main reasons: alcoholic drinks are expensive and can consume a large part of a family’s budget; the effect on the person’s mind can lead to inadequate job performance; and loss of inhibitions can lead to violent outbursts in the family situation. These factors have led to many people wanting alcohol banned completely, as it can be classified as a dangerous drug. This happened earlier last century in the United States during a period known as ‘prohibition’. This period in American history is infamous: far from eliminating alcohol completely, it drove the sale of it underground and, in the process, led to an increase in organised crime with its involvement in the illicit sale of alcohol. There is evidence that, in moderation, alcohol can be

beneficial. When consumed in moderation, it may lengthen one’s lifespan when compared with that of tee-totallers. For instance, data from epidemiological studies have shown light to moderate consumption of red wine, which corresponds to one to two glasses each day, can reduce the risk of cardiovascular disease.

Effects of alcohol The exact mechanism of how alcohol in moderation may be beneficial is still unclear, but it appears to be related to the metabolism of cholesterol and its associated lipoproteins. High-density lipoprotein (HDL) (see Chapter 45) levels are raised in a person who drinks, and this reduces that person’s chances of developing atherosclerosis. Atheroma formation is infrequent in these individuals, which tends to confirm this observation. Alcohol may also decrease intravascular clotting, thus helping to prevent thrombotic episodes. This action will work synergistically with the decrease in atheroma formation, as atheromatous plaque can increase the formation of thrombi. However, heavy drinkers have a very high chance of dying from other cardiovascular diseases, such as hypertension and cardiac dysrhythmias. Alcohol increases plasminogen activator activity, which in turn strengthens the body’s fibrinolytic system, thus further decreasing the likelihood of thrombus formation. Stress may play an important part in the development of cardiovascular diseases, and alcohol, due to its relaxing effect, may counteract stress. According to the 2009 Australian Guidelines to Reduce Health Risks from Drinking Alcohol produced by the National Health and Medical Research Council, for healthy men and women, drinking no more than two standard drinks on any day reduces the lifetime risk of harm from alcoholrelated disease or injury. The Alcohol Advisory Council of New Zealand recommends that men have no more than six standard drinks and women have no more than four standard drinks in any one drinking occasion. However, if people are drinking every day, then it recommends that men should have no more than three standard drinks each day and women should have no more than two standard drinks each day. A standard drink is 10 g of alcohol, which equates to approximately 400  mL of mid-strength beer, 100 mL of wine or 30 mL of spirits. It is also recommended that an individual have one or two alcohol-free days each week. Research shows there is little difference between men and women in the risk of alcohol-related harm at low levels of drinking. However, at higher levels of drinking, the lifetime risk of alcohol-related disease increases more quickly for women, while the lifetime risk of alcohol-related

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injury increases more quickly for men. There are at least two reasons why, at higher levels of drinking, the lifetime risk of alcohol-related disease increases more quickly for women than for men. First, there is a lack of alcohol dehydrogenase (an enzyme that destroys alcohol) in the gastrointestinal tract of women. This is not the case in men, and therefore women absorb more alcohol than men. The other reason is that alcohol is taken up only slowly by adipose tissue, and per kilogram of bodyweight, women (in general) have more adipose tissue than men. Alcohol, being very soluble in water, is well distributed in body water and as, weight for weight, women have proportionally less body water than men, the concentration of alcohol in the body fluids of women is higher. This increased concentration also makes for higher blood levels in women and, consequently, a more pronounced effect. The problems associated with alcohol consumption are numerous. They include alcoholism, which is a true addiction. A hangover results from alcohol’s irritant effect on the stomach, leading to acute gastritis, often with nausea and vomiting. There is no reliable cure for a hangover, and many people recommend obscure remedies such as Worcestershire sauce with raw egg. Domperidone (see Chapter 58) and H1-receptor antagonists (see Chapter 30) may help the nausea and gastric problems, respectively. Alcohol inhibits the production of antidiuretic hormone (ADH) from the pituitary gland, and this leads to excessive urine output, resulting in dehydration. This dehydration of the cranial tissues leads to the typical malaise and headache of a hangover.

Alcohol addiction It is sometimes difficult to determine just when a heavy drinker becomes an alcoholic, the usual definitions of alcoholism being based on the following three premises: • physical dependence on alcohol; • physical damage caused by excessive drinking; • social problems attributed to alcohol misuse. The true alcoholic conforms, obviously, to all three statements—the heavy drinker only to the second and third. It is probable that most heavy drinkers descend slowly into true addiction eventually. Physical dependence on alcohol leads to withdrawal symptoms, which manifest after about 12  hours’ abstinence. The symptoms of withdrawal, apart from an overwhelming urge for a drink, are initially ‘the shakes’, and in a long-term alcoholic this withdrawal deteriorates into delirium tremens (DTs). The DTs can last for several days and can present with epileptiform seizures accompanied by severe nightmarish hallucinations. Death

from respiratory failure can occur. With proper medical care and the willingness of the patient, these symptoms can be avoided using anxiolytic agents such as oxazepam. The physical problems associated with heavy drinking and alcoholism are many. The most widespread is liver damage, which can lead to cirrhosis, eventual liver failure and death. Stomach ulcers and gastritis commonly occur. Pancreatitis often occurs and this can obviously lead to diabetes mellitus. The incidence of cancer of the mouth and oesophagus, breast and colon is higher than in the general population. Central nervous system (CNS) deterioration occurs with actual brain shrinkage. In men, the part of the CNS controlling libido may be permanently destroyed. Many individuals with an alcohol problem have a limited food intake and below-average absorption of vitamins, and suffer from a vitamin  B group deficiency, leading to Wernicke–Korsakoff syndrome, which results in multiple cerebral haemorrhages, confusion and amnesia. In pregnancy, heavy drinking can result in congenital damage to the fetus, known as fetal alcohol syndrome. Alcohol is officially recognised as a teratogen. The National Health and Medical Research Council of Australia and the Alcohol Advisory Council of New Zealand recommend that alcohol should be completely avoided in pregnancy. They also recommend that not drinking is the safest option for women who are breastfeeding.

Drug treatment of alcoholism DISULFIRAM Mechanism of action Disulfiram is an inhibitor of the enzyme aldehyde dehydrogenase, an enzyme involved in the metabolism of ethanol. Normally, ethanol is converted into acetaldehyde (ethanal) by alcohol dehydrogenase, the acetaldehyde in turn being converted to carbon dioxide and water. Disulfiram blocks the degradation of acetaldehyde, causing it to accumulate in the blood and tissues. Common adverse effects Acetaldehyde is a very noxious substance and causes many adverse symptoms, which include a massive vasodilation that results in flushing and, in many cases, a severe headache. Respiratory difficulties, vomiting, vertigo, confusion and chest pain are a few of the other symptoms—altogether not a pleasant experience considering that the symptoms can last for several hours. Therefore, if a person taking disulfiram has as little as 7  mL ethanol, these symptoms will occur and are intended to discourage people from

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drinking. This type of therapy is called avoidance therapy, and has been successful in many instances in the treatment of individuals with an alcohol problem. Unfortunately, the disulfiram reaction, as it is called, has led to some fatalities, which limits its use. Rare adverse effects of disulfiram include hepatitis, peripheral neuropathy, optic neuritis and blood dyscrasias. Clinical considerations People should be warned that unpleasant effects could occur after taking even very small amounts of alcohol used in cooking or in products containing alcohol (e.g. perfumes, body lotions, aftershave lotions and over-the-counter cough and cold medications). It is very important that individuals fully understand the implications of the problems involved with consuming alcohol while on disulfiram therapy. They also need to be aware that they may experience unpleasant effects if they consume alcohol within seven days of stopping disulfiram treatment.

A C A M P R O S AT E Mechanism of action Two neurotransmitters in the brain associated with alcoholism are GABA and glutamate (see Chapter  33). Alcohol causes GABA transmission to be decreased and glutamate activity to be increased. When alcohol is withdrawn, these neurotransmitters remain inhibited and increased respectively but, without the moderating effect of alcohol, withdrawal symptoms occur. You will remember that benzodiazepines are valuable in the treatment of alcoholism. This is because they increase GABA activity (see Chapter  35). Acamprosate is thought to decrease glutamate activity by a complex series of modulating steps at the glutamate receptor complex. Common adverse effects There are no serious or rate-limiting adverse effects associated with acamprosate. Diarrhoea affects about 10 per cent of patients. Rash and fluctuations in libido may also be associated with acamprosate. Other adverse effects are typically mild and transient. Clinical considerations It is important to note that acamprosate does not alter the central nervous effects of drinking alcohol and, unlike disulfiram, it does not produce unpleasant effects if alcohol is consumed during treatment.

N A LT R E X O N E Mechanism of action Naltrexone is an opioid antagonist, which can be used to reduce the craving for alcohol and possibly some of its pleasurable effects by blocking endogenous opioids. Common adverse effects The most common adverse effects occur transiently, lasting approximately one to two weeks following treatment. These effects include: nausea, headache, dizziness, anxiety, fatigue and insomnia. A more serious and rare adverse effect is hepatotoxicity, which may occur with doses greater than 50 mg daily. Clinical considerations Liver function is monitored before starting treatment and then each month for the first three months during treatment. This monitoring continues for the duration of the therapy. If individuals notice yellowing of the whites of their eyes, dark urine or white bowel motions, they should stop taking naltrexone and inform their doctor immediately. These clinical manifestations could be indicative of hepatotoxicity. To assess its effectiveness, it is useful to examine the quantity of alcohol consumption before and during stages of therapy.

THIORIDAZINE Mechanism of action Thioridazine antagonises dopamine D2-receptors, which can reduce some of the craving for alcohol. Common adverse effects The most common adverse effects involve sedation, postural hypotension, dry mouth, blurred vision, mydriasis, constipation and urinary retention. More rarely, pigmentary changes to skin and eyes may occur. Pigmentary changes to the eyes can be serious, leading to possible irreversible damage. Clinical considerations Thioridazine is contraindicated with medicines that can prolong the Q-T interval of the cardiac cycle because this combination may result in cardiac arrest and possible death. Examples of medications that can prolong the Q-T interval include sotalol, clomipramine, haloperidol, erythromycin and tacrolimus. The incidence of pigmentary changes to the skin and eyes is higher with doses exceeding 800  mg daily, which should be avoided. Regular eye examinations are required during thioridazine treatment.

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Therapeutic uses of ethanol The only common medical use for ethanol is as a skin antiseptic (as mentioned in Chapter  74). As a 70% solution it is also used to partially disinfect benchtops and implements, such as tweezers in cosmetic salons. Ethanol can be used as a rubbing agent on skin to prevent decubitus ulcers. Many lotions and astringent solutions use ethanol as a solute. Some medications for injection can be dissolved in ethanol (e.g. diazepam). In cases of methanol (wood alcohol) poisoning, ethanol is an effective antidote (see Chapter 22). Methanol is occasionally produced by home distillation of various fermentation products (in the hope of escaping excise duty). This is a common occurrence in parts of the world where alcoholic drinks are expensive. Home distillation is relatively common in India, and occasionally one reads in the newspapers that many wedding guests died after drinking home-distilled liquor. This type of poisoning has also resulted in hospitalisations, where someone has mistakenly added methanol instead of ethanol to a party punch. The reason why methanol is much more toxic than ethanol is that, when acted on by alcohol dehydrogenase, formaldehyde (methanal) is produced. Formaldehyde in dilute solution is called formalin and is used to permanently fix tissues by denaturing proteins. The optic nerve is particularly sensitive to formaldehyde and even if one does not die from methanol poisoning, permanent blindness can result. Ethanol competes with methanol for alcohol dehydrogenase and, if present in excess, allows the methanol to be excreted unchanged, thus preventing toxic results. Last, many people swear that whisky or brandy taken with hot water, sugar or honey, and lemon is just the thing for a head cold. This is known as a ‘hot toddy’ and may give a good night’s sleep due to the hypnotic effect of the alcohol. There is a quote from an old English book which goes ‘At the first inkling of a cold, hang one’s hat from the bedpost, drink from a bottle of good whisky until two hats appear, and then go to bed and stay there.’

NICOTINE When tobacco is used in any form, from snuff to cigars and cigarettes, the active principal component to which a craving develops is probably nicotine. Nicotine is a very powerful drug, which, as mentioned in Chapter  28, is a potent agonist at the nicotinic receptors in the nervous system. In the brain it acts mainly as a stimulant, but on other receptors in the nervous system it can act as a depressant. Its central action leads to its addictive properties. The action of nicotine on the adrenal medulla, stimulating the release of

catecholamines, is partly responsible for causing a rise in blood pressure in some smokers. This rise in blood pressure may be one of the factors involved in the higher incidence of cardiovascular disease in smokers. Nicotine, although a nicotinic agonist, has few therapeutic uses except as an adjunct in smoking cessation programs (this use of nicotine is further discussed below) and perhaps in the treatment of Tourette’s syndrome. It is well known that, generally, smokers weigh less than nonsmokers, and this may be due to the appetite-suppressing properties of nicotine. This fact was used therapeutically in Italy in the 1950s when cigarettes were prescribed to teenagers with weight problems. This use of cigarettes today would create an outrage, and quite rightly so. Even so, this is one reason why young people, especially women, smoke despite its dangers. The main problem with cigarettes is not so much the nicotine as the several thousand other ingredients of tobacco smoke, collectively known as tar. These ingredients include cyanide and many hydrocarbons, which are proven carcinogens. Carbon monoxide in cigarette smoke can contribute to some of the cardiovascular problems, the incidence of which is greatly increased in women who smoke and take the oral contraceptive pill. The evidence today is overwhelming that tobacco smoke is one of the leading causes of cancer and cardiovascular diseases. A person does not actually have to smoke to be at risk: passive smoking also increases the risk of all smoking-related diseases. These include emphysema and chronic bronchitis. Smoking in pregnancy increases the risk of spontaneous abortion, and resulting offspring may be born with a lower birth weight and lower intelligence. Unlike alcohol, which may have some beneficial effects, smoking has no significant redeeming features, although the incidence of Parkinson’s and Alzheimer’s diseases and ulcerative colitis is lower in smokers than in non-smokers. Whether this is due to the smoking habit is unclear, but it definitely cannot be even remotely considered as a reason to smoke. Smoking is, and always will remain, a dangerous habit—not just to the smokers themselves but also to the people around them who have to breathe in the noxious fumes. Pharmacologically speaking, nicotine is more addictive than heroin and vastly more addictive than alcohol.

Medication therapy in the cessation of smoking Various preparations have been used in an attempt to treat tobacco addiction. These include (with moderate success) the antihypertensive clonidine, and the tricyclic antidepressants, such as nortriptyline. The most widely

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used medicine at present is nicotine itself. This type of therapy is nicotine replacement therapy and involves substituting one form of nicotine with another. The person is then slowly weaned off the replacement therapy. Nicotine replacement therapy is available in the form of chewing gum, inhalers, lozenges, patches and sublingual tablets. Nicotine replacement therapy should only be offered to individuals smoking more than 10 cigarettes per day. There is no evidence of improvement in individuals who smoke less than this amount—in fact, it may lead to dependence on nicotine replacement therapy. In using the chewing gum, people should be instructed to chew slowly about 15 chews until a peppery or tingling sensation occurs, and to position the gum in the cheeks or tongue until the tingling subsides and then to chew again. This process is continued for about 30 minutes. The right chewing technique is important for maximum effectiveness, so time needs to be devoted in explaining it to people. Chewing gum cannot be used in people with dentures. Nicotine lozenges are a suitable alternative for people who wear dentures. In taking lozenges, they should be allowed to dissolve in the mouth for about 20  minutes without chewing or swallowing. Lozenges may cause hiccups in some people but they are easier to use than chewing gum. Sublingual nicotine tablets are available and should be placed under the tongue and allowed to dissolve slowly for about 30  minutes. These tablets should not be swallowed or chewed for maximum effectiveness. Nicotine inhalers are used in people who miss the hand-to-mouth action of smoking. Typically, around 6 to 12  cartridges of inhalers are used daily for about eight weeks and then gradually reduced. Unfortunately, inhalers may cause throat irritation, cough and taste disturbances, which can affect adherence with the therapy. Transdermal delivery systems of nicotine are available, the use of which maintains blood levels of nicotine for long periods and suppresses the desire for a cigarette, sometimes effectively. The dreadful taste of nicotine is avoided with this method of administration. Patches are also discreet to use and therefore have few compliance problems. Many smokers use these patches on long-haul flights in which smoking is banned to avoid discomfort during the flight as well as the stopovers in airports. Patches are applied to non-hairy areas above the waist. Patches are available as 16hour or 24-hour applications. The 16-hour patches are used if sleep disturbance occurs. The 24-hour patches are useful for people who need to smoke soon after waking, but this form of patch may cause vivid dreams. The other medications used to help smokers cease their addiction are bupropion and varenicline.

BUPROPION Mechanism of action Bupropion is a medicine that is used in other countries as an antidepressant and appetite suppressant as well as in the treatment of attention deficit hyperactivity disorder (ADHD).The exact mechanism of action of bupropion in smoking cessation treatment is unknown but may be related to an increase in dopamine levels in the nucleus accumbens area of the brain, a region associated with reward and addictive behaviours. It can also inhibit neuronal reuptake of noradrenaline. The effect of this medicine is to decrease the desire to smoke. When used together with nicotine replacement therapy, the efficacy is increased. Common adverse effects The commonest adverse effects are dizziness, difficulties in concentrating, dry mouth, insomnia, headache and rash. Alcohol can increase the possibility of seizures and other unpleasant effects. People should, therefore, be advised to consume only small amounts of alcohol during therapy. Clinical considerations Therapy with bupropion is commenced at least one week before the person stops smoking as it takes about eight days of administration before steady state levels are achieved. Tablets are swallowed whole and taken in the morning to prevent sleep disturbances. Effectiveness of therapy is assessed after eight weeks, and tablets are stopped if no marked reduction of smoking is observed.

VA R E N I C L I N E Mechanism of action Varenicline acts as a partial agonist on nicotinic acetylcholine receptors. In blocking nicotine binding to these receptors, it prevents the pleasurable effects of smoking. Its partial agonist activity reduces the symptoms of nicotine withdrawal as the individual ceases smoking. Common adverse effects Common effects include dizziness, nausea, vomiting, dyspepsia, insomnia and constipation. Less frequently, palpitations, dry mouth, abdominal pain and musculoskeletal pain may occur. Clinical considerations The initial dose of varenicline should be carefully titrated to reduce the incidence of nausea, which tends to be dose-

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related. Varenicline is commenced about 7 to 14 days before the individual stops smoking to enable steady state levels to be achieved. It is advisable that this medication is not used with nicotine replacement therapy because of the increased incidence of adverse effects, such as dizziness and nausea. The medication is swallowed whole and taken with food and a full glass of water. As the individual approaches the end of the treatment regimen, it is advisable to taper the dose slowly to prevent nicotine withdrawal symptoms. Dosage adjustments are necessary in renal impairment.

CAFFEINE Caffeine, found in many products, is one of the most widespread drugs consumed by society. It is present in tea, coffee, cocoa products and cola drinks. Even decaffeinated tea and coffee still have small amounts of caffeine remaining in the beverage. Weight for weight, most teas have more caffeine than coffee but, when made into a drink, most cups of coffee contain more caffeine than a similarly sized cup of tea. Caffeine belongs to the group of biochemicals known as purines, and, therefore, is closely related to such biochemicals as adenine and uric acid. The drugs theophylline and aminophylline (see Chapter  54) are closely related to caffeine. Theophylline is found in tea, from which its name is derived: it literally means ‘tea leaf ’ in Latin. Caffeine is a CNS stimulant and acts on adenosine receptors throughout the body. Its action is antagonistic at these receptors. Adenosine generally causes lethargy, lowers heart rate and blood pressure and diminishes gastrointestinal functions. Caffeine, therefore, reverses all of these processes, causing wakefulness, high blood pressure and raised heart rate, and an increase in gastric secretions. Many people are so sensitive to the action of caffeine on the cardiovascular system that they experience palpitations after a cup of coffee. Caffeine and other methylxanthines have another important inhibitory action on the enzyme phosphodiesterase, which is discussed in Chapters  27 and 54. So are people who consume caffeine-containing products addicted to a potentially harmful drug? The answer is, most likely, yes. This does not imply that the taking of such products actually does you any harm, but the potential for harm is always there, especially if large amounts are taken. Unless adverse effects accompany the taking of caffeinecontaining products, moderate consumption for the majority of the population is not harmful. If adverse effects do occur, the consumption of caffeine-free or decaffeinated products may be advocated.

Withdrawal effects may be apparent at weekends in the form of ‘weekend headaches’. This effect is due to excessive coffee drinking at the office during the week but less coffee drunk at home during the weekend, hence the withdrawal symptoms. Drinking more than eight cups of coffee per day may lead to abnormalities in cardiac rhythm, palpitations and muscle tremors. In addition, being a secretagogue (a substance that stimulates stomach acid secretion), caffeine has been termed ulcerogenic in susceptible people. It may, therefore, lead to deterioration in existing peptic ulcers. As a stimulant, caffeine has been used in tablet form by students as an aid to staying awake for studying purposes. Long-distance truck drivers are also frequent users of it. Used sparingly it probably does little, if any, harm. Its use as a stimulant by sportspeople was initially considered illegal in some competitions (such as the Olympic Games, see Chapter 25). However, caffeine has been removed from the banned list of agents for sports performance because of the increased availability of this drug in caffeine-containing drinks and over-the-counter preparations. In fact, in some sports competitions, such as Hawaii’s ironman triathlon, flat ‘cola’ is one of the acceptable refreshment drinks, along with water and an electrolyte mix. When combined with analgesics, caffeine potentiates their action, and it is often included in proprietary analgesic, cold and flu, and antimigraine preparations.

OTHER DRUGS OF ABUSE The drugs mentioned above are freely and legally available; therefore, they could sometimes be classified as recreational drugs. Here we shall discuss some drugs that are used for recreational purposes but which are illegal, sometimes even for medicinal use. Some of the drugs to be discussed are not always illegal but under certain circumstances can be considered to be drugs of abuse, for example, glue and petrol. This section does not include drugs of abuse that are normally classed as legitimate drugs, such as the benzodiazepines and the opiates, which are dealt with in Chapters 35 and 40, respectively. Stimulant amphetamines are discussed in Chapter 39 as well as later in this section. Ketamine is a dissociative anaesthetic used clinically for its analgesic and anaesthetic properties (refer to Chapter  43). It is also known as ‘K’, ‘super  K’, ‘vitamin  K’ and ‘special K’. Ketamine can also produce hallucinations, delirium, cardiovascular and respiratory stimulation, and hypothermia. Respiratory depression may also occur, especially following intravenous administration. Chronic use of ketamine may produce physical dependence, but cessation of the drug does not usually pose problems.

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Treatment for its adverse effects may include the use of oral anti-hypertensive agents, such as angiotensinconverting enzyme inhibitors and calcium antagonists, or intravenous vasodilators, such as glyceryl trinitrate and sodium nitroprusside. Supportive care for people who wish to reduce their dependence on ketamine includes the use of cognitive behavioural therapy and benzodiazepine medicines, such as diazepam. Benzodiazepines may also help those people who are under the influence of hallucinations associated with ketamine misuse. Drugs of abuse come under several headings depending on their action on the body. Apart from those dealt with in other chapters, there are four types of drugs commonly abused—the hallucinogens, the stimulants, marijuana and miscellaneous substances, which could include volatile substances. The substances mentioned in this chapter usually produce a psychological rather than a physical dependence. A psychological dependence describes a mental reliance on a specific drug or drugs for the pleasure and/or comfort derived from taking it; such dependence can produce intense craving. Alcohol, the barbiturates and the opiates usually produce a physical dependence. This can be defined as a state of cellular adaptation to a drug, which leads to a withdrawal syndrome if the drug is stopped. Both these dependencies can and often do occur together.

Hallucinogens The hallucinogens, psychomimetics or psychedelics are drugs that distort one’s perceptions or produce hallucinations. Hallucinations are not necessarily visual but can be auditory, olfactory, tactile or gustatory; that is, all or any of the senses can be affected. Occasionally the senses are actually mixed up, in that one ‘sees’ sounds. Aldous Huxley, in The Doors of Perception, describes how when he was under the influence of mescaline someone knocked at the door and instead of hearing the knocks he saw hallucinations in the form of coloured clouds emanating from the door wafting towards him. Hyoscine can also have hallucinogenic properties. Other more serious hallucinations have been known to occur, such as people thinking they could fly and then jumping out of upper-storey windows, or the case of three students who, under the influence of lysergic acid diethylamide (LSD), thought the sun was beautiful and stared at it long enough for permanent blindness to ensue. The discovery of LSD is well known. The biochemist Dr Alfred Hoffmann, working for a pharmaceutical firm in Switzerland, was experimenting with compounds derived from the ergot fungus, which is the source of the antimigraine medicine ergotamine as well as several

other therapeutic substances. One day when handling the compound he experienced a strange sensation of unease and dizziness, which forced him to go home. At home he lay down and experienced a multitude of visual, kaleidoscopic hallucinations, which were on the whole quite pleasant— apart from the fact that he found daylight annoyingly bright. He put this experience down to an accidental ingestion of the LSD (it was probably by transdermal absorption). To confirm this, he ingested about 250  mg of the substance and then experienced a trip away from reality much more pronounced than the first experience. This was not surprising, as this dose is about 2½ times the normal dose needed to produce an effect. LSD is one of the most potent of all drugs and occasionally results in what are known as flashbacks. These are recurrent episodes of hallucinatory or delusionary states that can occur weeks or months after the initial trip. The discovery of hallucinogens did not originate with LSD; such substances have been known since antiquity by various peoples throughout the world. Common examples are mescaline, obtained from the peyote cactus, and psilocybin, from ‘sacred’ mushrooms, the use of which dates back to 1000  BCE in Guatemala. These substances were used mainly for religious ceremonies in Central American cultures. Numerous other mind-altering drugs are found in many of the world’s cultures, but it was the discovery of LSD that promoted a renewed interest in these drugs to see whether they had any potential therapeutic use. Psychiatrists were initially very interested in the drugs and whether they could be used to treat various psychological illnesses. To date, little success has been achieved, although there have been a few reported cases of the hallucinogens helping people with a narcotic addiction to overcome their addiction and people with sexual maladjustments to control their problems. The only other condition that may be helped is the intractable pain of terminal cancer, but these drugs will probably not find their way into any pharmacopoeia in the future. The psychologist Timothy Leary, working at Harvard, promoted the use of LSD among his students. This created much publicity regarding hallucinogenic substances, and the word spread around the world that here was a new group of drugs that could enable one to escape from the ‘real world’. These drugs were quickly made illegal, which resulted in a thriving black market in hallucinogens that continues today. Since Hoffmann’s discovery, many more synthetic hallucinogens have been produced, some of which have become household names. Phencyclidine (PCP), sometimes called angel dust when mixed with mint, parsley or marijuana, was originally developed as an anaesthetic. It rapidly found its way onto the streets as a hallucinogen. PCP is one of the worst of this

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group of drugs, its effects being unpredictable. On occasion it will produce peace and tranquillity, and the next time users may become so violent as to be a danger to themselves and to others. PCP has been known to cause a permanent change, resulting in a chronic toxic psychosis similar to schizophrenia. Nutmeg, a common household spice, contains hallucinogenic substances. Abuse of nutmeg is not common, as one has to ingest several grams of the powder; this may or may not cause one to hallucinate but will definitely produce severe headaches, abdominal cramps and nausea. Interestingly, nutmeg is banned from prison kitchens in the United States. The number of plants containing hallucinogenic substances is large, and reference to the further reading lists will give many more examples. Of the other hallucinogens in existence, dimethyltryptamine is relatively well known. The mechanism of action of the hallucinogens is, as yet, not properly understood. LSD is antiserotonergic as well as being agonistic at other specialised receptors within the CNS. While individuals are under the influence of hallucinogens, benzodiazepines may help reduce anxiety and fear. Alternatively, antipsychotic medications can be used to reduce any persistent agitation that may occur. Hallucinogens do not usually cause problematic symptoms when they are withdrawn.

Stimulants Psychomotor stimulants include amphetamines (e.g. amphetamine, methamphetamine, dexamphetamine) as well as methylphenidate, ephedrine, and some appetite suppressants (e.g.  diethylpriopion, phentermine). Methamphetamine, which is one of the most widely used stimulants, is also called ‘speed’, ‘meth’ and ‘ice’. Another drug with amphetamine-like properties includes 3-methoxy-4,5-methylenedioxyamphetamine (MDMA). MDMA is commonly called ecstasy, and has gained notoriety because of deaths associated with its use. It is taken for its euphoric, calming and confidence-enhancing properties. Many other effects have been attributed to this drug and most of them, in both the short and long term, are not good news. The drug can lead to hyperthermia and if taken, as it often is, in nightclubs, the combination of hyperthermia and excessive physical activity can quickly lead to dehydration. This has been one of the major causes of death from this drug. Paradoxically, another major cause of death is water intoxication: the drug user, being aware of the problem of dehydration, drinks large amounts of water; this dilutes the blood so much that the resulting hypotonic

blood causes swelling of cells, which can lead to enlargement of the brain, the resulting expansion leading to it being crushed against the skull. There have been several deaths in Australia by both of these mechanisms, which have resulted in the drug’s notoriety. Ecstasy is fast becoming a scourge of many of the youth in developed countries. Ecstasy is almost certainly habit-forming and may lead to addiction. Long-term use leads to hypertension, liver failure and perhaps (although not yet proven in humans as it has been in rats) brain damage. Symptomatic treatment of water and electrolyte imbalances and of temperature irregularities may be required following ecstasy use. In treating individuals suffering from the effects of stimulants, de-escalation techniques use verbal communication, group negotiation with affected individuals and physical restraint. Sedation may also need to be administered to reduce the risk of the individuals harming themselves and others. In giving sedating medication, benzodiazepines are usually preferred to antipsychotic agents because benzodiazepines are more sedating and have fewer side-effects. The oral route of administration is preferred because it enables a greater sense of engagement and negotiation between the affected individual and health professional. In sedating individuals, it is preferable to start with a relatively high dose and then titrate downwards. The opposite applies when sedation is applied to an individual with schizophrenia, where it is better to start with a low dose and then titrate upwards. It should be noted also that frequent administration of ‘as needed’ (or pro re nata, prn) medication for over 24  hours usually indicates an inadequate regimen of control using regular or fixed medication. There is also evidence that frequent use of intramuscular prn antipsychotic medication, such as haloperidol or chlorpromazine, over extended periods of time increases the risk of neuroleptic syndrome and possible assaults on health professionals. No medications have been shown to be particularly useful in stimulant withdrawal. Nevertheless, benzodiazepines may help reduce irritability, and antidepressants may assist with depression arising from the effects of withdrawal. If hypertension occurs after stimulant use, α-blockers (e.g.  phentolamine) or direct vasodilators (e.g.  sodium nitroprusside) have been shown to be helpful. It is also important to ensure that individuals are provided with adequate nutrition and hydration, especially if they have been using the stimulant continuously for several days.

Marijuana Marijuana is considered in most countries to be a substance of abuse, as its effects are not considered to be of clinical

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significance. This drug comes from the plant Cannabis sativa, and has been used, off and on, since about 2700 BCE as a sedative or analgesic. After World War II particularly, it became a common recreational drug and was outlawed, as it was considered to be a drug of abuse with no therapeutic use by the World Health Organization. This view seems now to be incorrect, as recent research has shown that the main active substance of marijuana, δ-9-tetrahydrocannabinol, or THC, appears to have more potent antiemetic applications than most other antiemetics. Whilst marijuana is classified as an illegal drug in Australia and New Zealand, in the United States, marijuana has been legalised for medical use with permission from the patient’s doctor. As of 2010, marijuana has been legalised in 14 states. There has also been a change in perception of medical marijuana use in the US, as it is recognised publicly as being of significant anecdotal benefit for people with approved medical conditions, such as cancer sufferers. Two related compounds, dronabinol and nabilone, are used in some countries as antiemetics for treating the nausea and vomiting that occur during chemotherapy and in narcotic-induced emesis in terminal patient care (not yet in Australia or New Zealand). In its resinous form, marijuana is called hashish, which contains more THC and is more active. Marijuana is one of the most used—or should we say, abused—of the illicit drugs. It has been estimated that about one-third of all Americans have tried the drug, and this figure may not be much different in Australasia. Marijuana is unusual in that it can be taken by mouth or it can be smoked. Cookies or cakes spiked with marijuana are not uncommon at teenage parties. Marijuana in the form of a cigarette is commonly called ‘a joint’ or ‘a reefer’. The most common effect of THC on the person is to produce a dream-like state approaching euphoria. In this state audio stimuli, such as music, are enhanced. This effect is not unlike the hallucinogens, and in high doses THC could be classed as such. In some people the opposite effect may occur, resulting in paranoia and/or depression. Amnesia is common after THC ingestion. Some people would like to see marijuana legalised for anything other than medicinal use, arguing that it is less harmful than tobacco. This is not necessarily the case, as THC is a potent vasodilator, which induces a reflex tachycardia; the long-term cardiovascular effects are unknown, but caution is obviously needed here. Smoked marijuana almost certainly will produce carcinogenic tars, with their resultant effects. It is argued that people who smoke marijuana do not become physically addicted and tend to smoke the joints only sporadically; therefore, the incidence of adverse effects would be much lower than that of smoking tobacco. However, marijuana is obviously not

safe, and chronic use causes subtle changes in personality that tend to lead to a decrease in motivation in all aspects of the user’s life. This is termed amotivational syndrome. Recently, there has been noted a significant correlation between marijuana use and the development of both schizophrenia and clinical depression. Like alcohol, marijuana can impair driving performance. THC has been reported to be teratogenic and may actually cause changes in the morphology of sperm and cause abnormal ova to be produced. Testosterone levels are decreased in men, which may have deleterious effects on male secondary sexual characteristics, especially if marijuana is used during puberty. Legalisation of marijuana for anything other than medicinal use seems to be unlikely in view of all these and many more adverse effects; even legalisation for medicinal use of marijuana would need to be considered carefully by regulatory authorities to ensure the many potential risks did not outweigh the benefits. THC is very lipophilic and is readily taken up by adipose tissue, from where it diffuses back slowly into the bloodstream; its metabolites can be detected in body fluids months after ingestion. While withdrawal following cannabis use is mild, physical symptoms may persist for up to two weeks. Typical symptoms include depression, anxiety, loss of appetite, irritability and sleep disturbance. Treatment of withdrawal effects is usually symptomatic, and may involve the use of hypnotic therapy for sleep disturbance.

Cocaine Cocaine is an alkaloid derived from the coca plant, Erythroxylum coca, which grows in several South American countries. The leaves of this plant are chewed, and are used by natives of the Andes to combat altitude sickness by relieving fatigue and enhancing wellbeing. These Native Americans do not appear to become addicted to the cocaine in the leaves as, when they descend to lower altitudes, their need for the drug wanes. In Western societies, cocaine extracted from the coca leaves has become a favoured but dangerously addictive drug of abuse. Pure cocaine is a very powerful stimulant, creating an intense feeling of wellbeing and alertness. Two types of cocaine are used by drug experimenters: ‘crack’ and ‘free base’. Crack is now the most widely used form of cocaine, and is so named because of the crackling sound made when it is burnt. Whichever way it is used, the drug is highly addictive, perhaps not as a physical but as a strongly psychological addiction. One danger of snorting cocaine is nasal congestion, which can lead to necrosis of the nasal mucosa and septum. Systemic effects are many, with insomnia, impotence and

C H A P T E R 2 4 C O N T E M P O R A RY D R U G S O F A B U S E

headaches being common. Overdose can lead to cardiac dysrhythmias and death. Treatment of cocaine-related problems after chronic use involves symptomatic relief, as described under management for stimulant use.

Volatile substances The substances usually inhaled are hydrocarbons or halogenated hydrocarbons. Many of these substances are readily available from legitimate sources, and because of the widespread uses of many of them, control is impossible. The action of these substances is twofold: many of them have anaesthetic properties (see Chapter 43), and they also induce anoxia by displacing oxygen from the inhaled air. This combined effect produces a sense of detachment, leading to a delirious, semiconscious state of altered awareness. When inhaled, quantities slightly above the dose required to produce a ‘high’ can cause disorientation, severe confusion and coma, and death may result from asphyxiation and/or cardiac dysrhythmias. Prolonged use usually leads to both renal and hepatic damage. These drugs are mainly used by children and adolescents, adults only rarely resorting

to their use. The popular substances abused are modelaeroplane glue, paint thinners and lacquers, liquid paper, petrol and lighter fluid. Adequate education in susceptible populations may help prevent the many tragedies resulting from this behaviour. Some anaesthetists and others in the medical profession have been guilty of abusing inhalant anaesthetics such as halothane and diethyl ether. Another category of substances inhaled for pleasure comprises the volatile nitrites, principally amyl nitrite. Amyl nitrite is a potent vasodilator and has been used in the past to treat angina pectoris. Being a smooth muscle relaxant it has been used also in midwifery to slow down uterine contractions. This action on smooth muscle relaxes the internal anal sphincter, which makes it a possible drug of abuse by some men who have sex with other men. In fact, when AIDS first appeared, amyl nitrite was suggested as a possible cause. Inhaled during sexual climaxes, it reputedly increases the intensity of an orgasm. Amyl nitrite also causes a sudden drop in blood pressure with the potential to cause fainting; a throbbing headache may also result. The abuse of narcotic analgesics is covered in Chapter 40.

CHAPTER REVIEW ■■ ■■

■■ ■■

Recreational use of medicines or drugs is considered to be drug abuse. Some recreational drugs, notably alcohol, can be beneficial when consumed moderately; however, alcohol, if consumed even slightly more than moderately, can be devastating in its direct effect on the user and indirectly on the user’s family and associates. Alcohol has a very limited use in therapeutics. Tobacco, with the constituent nicotine and the thousands of compounds found in cigarette smoke, kills more people than all the other drugs of abuse put together.

■■

Caffeine found in coffee and tea can, if taken to excess, cause harm to its user.

■■

Hallucinogens and marijuana can lead to serious mental disorders.

■■

Volatile substances, such as modeller’s glue, have serious toxic effects on the CNS.

REVIEW QUESTIONS 1

What is the difference between a habit and a dependence?

2

What is meant by the term avoidance therapy?

3

Would one consider nicotine chewing gum as an alternative to smoking for people with severe cardiovascular disease? Give reasons for your answer.

4

Describe the management of a young woman admitted to the emergency department following ingestion of ecstasy at a street party. She is extremely agitated and anxious but her fluid status and electrolyte levels are normal.

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5

Explain the supportive care and management of adverse effects for a client who has taken ketamine for recreational purposes.

6

Describe the counselling you would offer a person who is about to commence a course of varenicline to assist with smoking cessation.

24 MEDICINE SUMMARY TABLE FAMILY NAME

GENERIC NAME

TRADE NAME(S)

Alcohol dependence

acamprosate disulfiram naltrexone

Campral Antabuse Naltraccord Revia

Nicotine dependence

bupropion

Prexaton Zyban Champix Habitrol (transdermal patch, lozenge and chewable gum) Nicabate (transdermal patch, chewable gum and lozenge) Nicorette (transdermal patches, chewable gum and inhaler) Nicorette (nasal spray) Nicorette (sublingual tablet) Nicotinell (chewable gum) (transdermal patches) Nicotrol (transdermal patch and chewable gum) QuitX (transdermal patches and chewable gum) Norpress

varenicline nicotine

nortriptyline Stimulant

Australia only New Zealand only

caffeine

No-Doz No-Doz Awakeners + nicotinic acid, thiamine No Doz-Plus

C H A P T E R

25

D R U G A B U S E I N S P O RT

LEARNING OBJECTIVES

KEY TERMS

After completing this chapter, you should be able to:

Drug doping

1

list the reasons why sportspeople use drugs to enhance performance;

Drug testing

2

identify major drug groups banned from sporting competitions;

Ethical behaviour

3

outline the physiological effects and major adverse reactions associated with the abuse of anabolic agents, stimulants, peptide hormones and diuretics.

We could be excused for thinking that the use of drugs by professional sportspeople for the purpose of enhancing performance is rife. When asked for examples of abuse, most of us can recall at least one notorious incident involving a high-profile sportsperson. These incidents result in rescinded awards, suspensions, ruined careers and sometimes death. Indeed, such episodes cast a pall over the integrity of elite sporting contests generally. However, the official statistics from the Australasian region’s sports drug agencies suggest that drug doping in this region is very low. Drug Free Sport NZ (formerly the New Zealand Sports Drug Agency) figures for the period 1995–2010 indicate that in 19 025 individual drug tests, the number of positive drug samples or refusals to provide a sample represented a violations rate of 0.95 per cent. For the period 2000–2011, the Australian Sports Anti-Doping Authority (ASADA) reported a similar rate in 74 542 tests. Despite these figures, doping in sport is a problem. The reasons often cited as to why sportspeople abuse drugs include gaining a competitive edge, dissatisfaction with current performance, developing the ideal body form for a particular sport (e.g. losing or gaining weight in order to qualify for a contest), coping with stress and the intense pressures to win, relaxation and recreation, to acquire the fame and fortune that success brings, and the perception that sporting peers have an advantage because they are already using drugs.

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Drug use in sport is not a new phenomenon. For reasons similar to those above, substance abuse occurred in ancient Greece during the original Olympic Games. This was anathema to the Olympic ideals, which embraced the purity of the athletic endeavour, sportsmanship and fair play. Cheating was offensive and wrongdoers suffered public shame and disgrace. The revival of the modern Olympic Games has brought with it again the taint of drug abuse for the purpose of enhancing performance. This was, and is still, seen to be in opposition to the spirit of the Olympics. Evidence of the use of performance-altering substances, such as mixtures of alcohol and strychnine, heroin, caffeine, cocaine, amphetamines and hormones, has been documented. Elite athletes fell ill or died under mysterious circumstances. Eventually, sportspeople spoke out about the harm being done to individuals and to sport in general. In 1968, the International Olympic Committee (IOC) developed a list of banned substances and began

drug testing athletes at the Mexico City Olympics of that year. The list of banned substances, now determined by the World Anti-Doping Agency (WADA), covers agents that might enhance sporting performance directly, alter body form, or mask the presence of other banned substances in the body. This list is regularly reviewed as novel substances become available. Major drug groups that are banned, and their physiological actions, are summarised in Table  25.1. Professional sportspeople may be tested in and out of competitions and individuals contracted to a team can be tested at any time, even during the off-season, for the duration of their contracts. Detection of some administered substances, such as hormones, can be problematic because they are naturally present in the body. In this case, levels in urine samples that reflect normal physiological conditions are permissible. Some substances (e.g. human chorionic gonadotrophin or

Table 25.1 World Anti-Doping Agency (WADA) list of banned substances SUBSTANCE GROUPING Anabolic agents Anabolic steroids β2 Agonists (excluding therapeutic use of salbutamol, (e)formoterol, salmeterol)

DESIRED EFFECTS Increase muscle strength Promote aggression Increase lean muscle Reduce body fat

CHAPTER

27

Diuretics

Dilute drug concentration in urine Weight reduction

49

Narcotics

Raise pain threshold Induce euphoria

40

Cannabinoids (natural & synthetic)

Pain relief May decrease sporting performance

24

Induce androgen production in males Induce euphoria Promote lean muscle growth and reduce body fat Increase blood oxygen-carrying capacity

59 59 59, 60 53

Stimulants

Increase concentration Increase competitiveness Reduce fatigue

24, 27

Glucocorticoids (by all routes)

Reduce inflammation Induce euphoria

59

Reduce anabolic steroid-induced feminisation Alter metabolism

63

Peptides Gonadotrophins Corticotrophins (e.g. ACTH) Growth hormone, IGF-1, insulin Erythropoietin and its derivatives

Hormones and metabolic modifiers Anti-oestrogens (e.g. SERMs, aromatase inhibitors) PPARδ

(ACTH = adrenocorticotropic hormone; IGF = insulin-like growth factor; PPARδ peroxisome proliferator activated receptor-δ; SERMs = selective oestrogen receptor modulators.) Source: Based on information from World Anti-Doping Agency, 2012, ‘Prohibited List—International Standard’, www.wada-ama.org/en/World-Anti-Doping-Program/Sports-and-Anti-Doping-Organizations/International-Standards/ Prohibited-List.

CHAPTER 25 DRUG ABUSE IN SPORT

luteinising hormones) are banned in male athletes because they stimulate androgen production but are permitted in female athletes. A therapeutic use exemption can be granted to a sportsperson when drug therapy is justifiable on medical grounds, although limits may be set where a particular concentration in urine is considered an adverse finding. Although the official statistics on drug doping are low, it would be naive to think that no clandestine drug use takes place. Drug cheats can use sophisticated dosing regimens rather than masking agents to avoid or limit the possibility of detection. Strategies such as cyclical dosing, rather than continuous doping, can be used. This process involves taking a drug for a set time interval, then stopping for a period to allow its elimination before starting the cycle again. In this way, a sportsperson can realise the benefits of doping but decrease the chances of getting caught. As you can see from Table 25.1, a number of medicines can be used to enhance sporting performance. We now examine the effects and health risks associated with some selected doping agents, focusing on anabolic agents, peptide hormones, β-blockers, stimulants and diuretics.

ANABOLIC AGENTS There are two categories of anabolic agents based on chemistry: steroids (specifically anabolic steroids) and the non-steroidal β2 agonist agents. Anabolic steroids are synthetic derivatives of androgens, but usually cause fewer masculinising effects than androgens. As both anabolic steroids and androgens can be used to promote anabolic effects, they are grouped together as anabolic–androgenic steroids (AASs) and, therefore, include both endogenous and exogenous substances. Sportspeople drawn towards the use of AASs include weightlifters, track and field athletes, footballers and bodybuilders. AASs are available in oral, nasal or injectable forms. Examples include stanozolol, oxymetholone and nandrolone, as well as AAS precursors such as androstenedione and dehydroepiandrosterone (DHEA). The latter two substances can be converted into endogenous androgens in the body. In many countries, the availability of the human clinical AASs is highly restricted; some use the more readily accessible veterinary formulations. DHEA is available in some nutritional supplements, and some sportspeople have unknowingly tested positive to an AAS after using these supplements as a part of their training. It would appear that international sports drug agencies are facing an uphill battle trying to control the use of steroids by sportspeople. There is evidence of an unregulated

development of drugs for use by sportspeople. This makes detection of steroid abuse even more challenging. Previously unheard of synthetic AASs, like tetrahydrogestrinone, have been used for doping and can go undetected by sports authorities for a prolonged period. An important aspect of drug testing to determine the use of AASs is not simply the blood level of these substances but the ratio of testosterone to one of its major metabolites, epitestosterone. A ratio of below 4:1 in a urine sample is considered acceptable; any higher level reflects drug taking. The perceived benefits of AASs in a sporting context are promoting increased skeletal muscle mass (producing greater strength or power), shortening injury recovery time and increasing endurance. In order to produce these effects, sportspeople tend to use significantly higher doses of AASs than would be needed for clinically therapeutic purposes. The behavioural effects of the AASs include increased selfconfidence, mood swings, euphoria, depression, paranoia and aggression. The use of high doses of AASs puts users at increased risk regarding the onset of serious adverse drug reactions, which can include liver disease, male infertility, acne, male baldness, testicular atrophy (shrunken testicles), masculinisation in women, altered menstruation, induction of an unhealthy blood lipid profile, stunted long bone growth, tumour development, and feminisation in men. The latter effect arises from conversion of the excess androgen to oestrogens, which can induce gynaecomastia (female breast development). In order to avoid adverse effects such as liver disease, users alter the route of administration (from oral to injectable) or ingest ‘protective’ herbal preparations. They can also take anti-oestrogens, such as the selective oestrogen receptor modulator (SERM) tamoxifen (see Chapter  63) and the aromatase inhibitors (see Chapter  80), to curtail the feminising effects. Furthermore, infectious disease is a health risk associated with the injection of these medicines when technique, purity and storage are questionable. The effects of AASs are summarised in Figure  25.1. It is interesting that there is a worrying trend towards the use of AASs by young males—not for gaining a sporting edge but more for the purpose of altering body image and improving self-esteem. The use of AASs in young women is also rising. The United States National Institute on Drug Abuse (NIDA) has been a leader in developing initiatives to alert the community, especially young people to the health risks associated with these medicines. Systemic administration of the β2 agonists, such as salbutamol (see Chapter 27), can also be used as anabolic agents. It is argued that at high doses, they promote lean muscle growth and reduce body fat levels. Unfortunately, these drugs can induce palpitations, tremor, tachycardia,

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Figure 25.1 Pharmacological effects of

anabolic steroids Baldness (males)

Increased libido

Increased muscle mass Increased strength Increased endurance Liver disease Increased body hair

Infertility Testicular atrophy (males)

Aggression Rage Psychosis Acne Feminisation (males) Gynaecomastia Masculinisation (females) Menstrual dysfunction (females)

Premature completion of long bone growth

muscle cramps and nausea. Inhaled salbutamol, (e)formoterol or salmeterol, the longer-acting β2 agonist, is permitted in competitive sport when it is medically appropriate. However, high urine concentrations are considered an adverse finding by sporting drug agencies. All other β2 agonists are banned substances.

PEPTIDE HORMONES A number of peptide hormones have been used by sportspeople in order to enhance their performances. These include growth hormone (see Chapter 59), insulin (see Chapter  61), insulin-like growth factor (IGF-1), erythropoietin or its derivatives (see Chapter 53) and the gonadotrophins (see Chapter  63). In 2013 a number of high profile Australian professional sporting teams were investigated by ASADA with respect to the use of banned peptides. To detect such substances poses a real challenge for sporting organisations and scientists alike, because they are regulatory messengers normally found in the human body. Research into the detection of these peptides is focusing

on identifying subtle structural variations to differentiate between the endogenous hormones and the formulations abused by sportspeople. Growth hormone, insulin and IGF-1 promote anabolic processes that lead to increased lean muscle and less fat. In younger sportspeople, growth hormone and IGF-1 can induce disproportional body growth (leading to distorted features such as enlarged hands and feet as well as a prominent forehead and jaw), heart disease and diabetes mellitus. The use of insulin is worrying, as an inappropriate dose could lead to hypoglycaemic coma and death. Erythropoietin and its derivatives induce increased erythrocyte production, which in this context increases the oxygen-carrying capacity of the blood. Increased red blood cell levels can lead to a thickening of the blood and clot formation. Gonadotrophin use in men stimulates androgen production, the effects of which are similar to anabolic steroids.

β-BLOCKERS β-Adrenergic receptor antagonists, or β-blockers, are subject to restrictions in certain sporting competitions, such as the precision sports (e.g.  archery and shooting), yachting, soccer and modern pentathlon. The effects of β-blockers are covered in detail in Chapter 27. As doping agents they act to counteract excessive sympathetic nervous system activation, which may manifest as anxiety, tremor and tachycardia. This counteraction can affect performance, particularly the ability to aim and shoot accurately. The side-effects of these medicines can include hypotension, bradycardia, headache and gastrointestinal disturbances.

STIMULANTS Nervous system stimulants, such as cocaine, amphetamines (see Chapter  24) and the sympathomimetics (see Chapter 27), are used to gain a competitive advantage. They prolong endurance, delay fatigue, enhance competitiveness and increase self-confidence. The dangers of using stimulants arise from the potential for overstimulation of the nervous system. They can induce cardiovascular problems such as cardiac dysrhythmias, alterations in blood pressure, agitation, aggression, rage and drug-induced psychotic states. They can also lead to drug dependence. WADA is currently monitoring the use of a number of stimulants. Urine concentrations of ephedrine or methylephedrine above 10 µg/mL or urine pseudoephedrine levels above 150  g/mL are considered adverse findings, resulting in sanctions against the accused sportsperson.

CHAPTER 25 DRUG ABUSE IN SPORT

DIURETIC AGENTS AND URINE TESTING Some sportspeople, such as wrestlers, boxers or jockeys, use diuretic drugs to accelerate weight loss prior to contests involving strict weight categories. Diuretics and plasma expanders (see Chapter  52) can also be used to mask or decrease the presence of other abused substances, such as AASs, by diluting their concentrations in urine. The possession of such diuretics can lead to disqualification from sporting competition on the basis of suspected AAS abuse. Adverse effects associated with injudicious use of diuretics include dehydration and imbalances in electrolyte levels. Drug treatments to manipulate the characteristics of urine have also been outlawed. The uricosuric agent probenecid (see Chapter  65) has been used to inhibit tubular secretion of some doping agents into the forming urine; thus, keeping the urine level of certain listed substances low.

ALCOHOL The use of alcohol is prohibited or restricted to certain levels in a number of sports. The effects of alcohol may impair performance and/or pose a danger to participants, officials and spectators. Sports such as motorcycling, automotive

racing, archery, shooting, skiing and aeronautics fall into this category. Interestingly, only motorcycling insists on a zero alcohol level during competition.

IMPLICATIONS OF DRUG USE AND ABUSE IN SPORT Drug use in sport is a very controversial issue. Sportspeople returning positive drug tests often claim to be unaware that the dietary supplement, the over-the-counter preparation or the prescribed medicine from their doctor contains a listed substance. Each case must be dealt with fairly, considering the individual’s circumstances. However, it is getting harder to plead ignorance as a defence, especially for health professionals involved with sporting clubs or federations. Information as to the status of most medicines is now clearly stated in clinical references, such as the MIMS Annual, Australian Medicines Handbook and New Ethicals Compendium, and by the national sports drug agencies. There is a fine line between drug use and abuse in sport. When does taking drugs to allow an ill or slightly injured sportsperson to demonstrate his or her natural abilities become an attempt to give that person the competitive edge? As students of pharmacology, it should be apparent to you that sometimes this line can be crossed by simply choosing a higher dose, a different route of administration or another drug with similar effects.

CHAPTER REVIEW ■■ ■■

■■

■■

■■

■■

Drugs can be abused by sportspeople to gain an unfair competitive advantage over their opponents. Lists of banned and restricted substances have been formulated by the World Anti-Doping Agency (WADA) and are backed up by a strict regimen of drug testing. Anabolic agents are used to increase muscle mass, strength, endurance and competitiveness. Anabolic androgenic steroids, used at high doses, can induce masculinising effects in women and feminising effects in men. They can cause reproductive dysfunction and liver disease. A number of peptide hormones, such as the gonadotrophins, insulin and growth hormone, also promote anabolic effects. Erythropoietin derivatives increase the oxygen-carrying capacity of the blood. This group of doping agents pose detection problems because they are naturally found in the body. β-blockers are prohibited in certain sports. They antagonise the effects of sympathetic activation to reduce anxiety, tremor and tachycardia. Stimulants are used to prolong endurance, delay fatigue, enhance competitiveness and increase self-confidence. They can overstimulate the nervous system, leading to cardiovascular problems as well as aggressive or psychotic states.

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■■

■■

Diuretics are used to lose weight quickly or mask the presence of other doping agents. Adverse effects include dehydration and electrolyte imbalances. The use of alcohol in some sports is restricted or prohibited as its effects may be considered hazardous or impair athletic performance.

REVIEW QUESTIONS 1

Suggest three reasons why elite and aspiring sportspeople might decide to use performance-enhancing drugs.

2

State two examples of groups of substances banned from sporting competitions, and indicate the reasons why each is prohibited.

3

Outline the problems associated with the detection of some banned substances through urine testing of sportspeople.

4

For each of the following substances, indicate whether administration would result in increased androgen production in a male athlete: a

a glucocorticoid

b dehydroepiandrosterone c

insulin-like growth factor

d luteinising hormone e 5

high dose salbutamol

For each of the following drug or drug groups, indicate one sport where its use as a doping agent has been established: a

β-blockers

b probenecid c

high dose β2 agonists

6

At 17 years of age, Marie Duphastin shows promise as a sprinter. She tells you that she has been offered anabolic– androgenic steroids (AASs) by her coach to boost her strength. Her coach has told her that there are no health risks associated with their use. She asks you whether this is true. What advice can you offer her about the health risks of these drugs?

7

Bob McArthur is a 20-year-old sportsman. He wants to play professional football but feels he needs to bulk up to have a decent chance. He is reluctant to use AASs but has heard that insulin can increase muscle mass. What are the hazards of this strategy?

8

Terry Sterculia, 28 years old, is a keen amateur boxer. He recently broke his leg in a work-related accident and has not been able to train during this period. A fight is coming up that he wants to qualify for, but he is a few kilograms overweight. In order to lose weight quickly, he is taking his father’s frusemide (Lasix) tablets, diuretics prescribed for his father’s heart condition. What kinds of fluid and electrolyte imbalances may result from this kind of drug abuse? State the clinical manifestations of each of these imbalances.

CHAPTER 25 DRUG ABUSE IN SPORT

C A S E S T U DY 1

4

Outline the effects of ecstasy.

A neighbour knocks on your door at home one evening. She is holding her two-year-old child in her arms and is extremely distressed. She manages to tell you that while she was preparing dinner, the child opened a cupboard and ate a number of paracetamol tablets. She isn’t too sure how many tablets the child has ingested, but estimates that it would be at least two. When asked, your neighbour says that the child weighs 12 kg.

5

Compare and contrast the effects of ecstasy with those of amphetamines.

6

There have been a number of deaths associated with ecstasy administration. In what ways would ecstasy contribute to death?

7

One of the men dancing with HR was of similar age and bodyweight. They both had consumed the same number of vodkas over the same time interval. She claimed that he was more affected by the alcohol. From a physiological perspective, is she likely to be correct? Give your reasons.

8

What are the effects of the nicotine absorbed during cigarette smoking?

9

What are some of the other known ingredients in cigarettes besides nicotine that are absorbed into our bodies while smoking?

The child is conscious, pale and sweating. You invite them into your home and call an ambulance. While you are on the telephone, the child vomits. As you wait for the ambulance, you comfort both mother and child and take some observations of the child’s condition.

Questions 1

Is this dose of paracetamol harmful to the child? Why?

2

What information can you refer to check whether the amount of paracetamol taken was toxic to this child?

3

Would you try to induce emesis before the ambulance arrives? Give your rationale for this decision.

4

Outline the treatment that will be followed when the child arrives at the hospital.

C A S E S T U DY 2 HR is 18 years old and is heading to her first ‘rave’ party in the city. The party is in full swing by the time she and her friends arrive. About 200  people have crowded into a warehouse on the city’s edge. It is hot and a little stuffy in the warehouse, but the atmosphere is lively. HR has a couple of vodkas, smokes three cigarettes and takes in the scene before enjoying a number of dances with her friends. As the night progresses, while sitting with her friends she watches them take some white pills out of their bags and swallow them. They tell her it is ecstasy and offer her two tablets. HR takes them and joins her friends on the dance floor. Within a short period she is aware of a sense of wellbeing and calm. Her sense of the music and movement is heightened. She feels less self-conscious about her dancing, and dances feverishly. A guy she is dancing with buys her another vodka. About an hour later she collapses on the dance floor unconscious. She is transferred to hospital by ambulance and treated for severe dehydration.

Questions 1

What factors have combined to induce severe dehydration in HR?

2

Briefly outline the treatment for this condition.

3

What is the chemical name for ecstasy? To which class of drugs is it closely related?

C A S E S T U DY 3 A man in his twenties is found unconscious in a back lane of the central business district of the capital city. He is pale and breathing very shallowly. There is a smell of alcohol on his breath. A syringe and empty vial are found nearby. An ambulance is called and arrives within 10  minutes. After completing an assessment, the ambulance officers administer an intravenous injection of naloxone. There is a rapid improvement in the man’s condition; his breathing rate and depth improve, but he remains in a stuporous state. The ambulance officers take him to the nearest public hospital for further treatment. At the hospital, he is provided with supportive therapy and receives infusions of naloxone over the next four hours. Later in the day he has recovered sufficiently to discharge himself.

Questions 1

What situation do you think is represented in this case study?

2

Describe the mechanism of action of naloxone.

3

Why does this person require repeat infusions of naloxone in hospital?

4

Describe the mechanism of action of alcohol. Is alcohol a central nervous system stimulant or a depressant?

5

Will alcohol potentiate or diminish the effects of the illicit drug that the person injected? Why?

6

Outline the nature of the supportive therapy that was provided to the man in hospital.

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C A S E S T U DY 4 ME is a 22-year-old woman enjoying a summer holiday at a resort in northern Australia. While snorkelling off the beach she feels a stinging sensation on her legs. Suddenly she experiences severe and excruciating pain. She notes what look like tentacles stuck to her skin. She calls for assistance. First aid for box jellyfish stings is administered at the beach, but she is crying and screaming about the pain. ME is taken to hospital for further care.

Questions 1

Define the term envenomation.

2

What is the appropriate first aid treatment for this form of envenomation? What is the rationale for this treatment?

3

How does envenomation occur in the case of box jellyfish stings?

4

Broadly outline the hospital treatment that ME will receive.

C A S E S T U DY 5 Mr JJ, aged 55 years, has been abstinent from alcohol for a couple of weeks after experiencing many years of alcohol dependence. His local doctor places him on a course of acamprosate to assist with his situation. Mr JJ explains to his doctor that many years ago he was prescribed disulfiram, which caused many unpleasant effects, especially when he occasionally ‘forgot’ and drank alcohol during therapy.

Questions 1

Explain how acamprosate produces its effect in maintaining abstinence in alcohol dependence.

2

Explain how disulfiram produces its effect in maintaining abstinence in alcohol dependence.

3

What is a major difference between acamprosate and disulfiram in the effects they produce if alcohol is consumed?

4

Acamprosate is available as an enteric-coated formulation in an attempt to reduce symptoms of diarrhoea, nausea, vomiting and abdominal pain. How should Mr JJ consume this formulation?

C A S E S T U DY 6 Ms RM, aged 45  years, has been prescribed a seven-week course of bupropion to assist her to stop smoking. She has had many previous attempts to stop smoking, which have all proved to be unsuccessful. Ms RM has some nicotine chewing gum in her medicine cupboard from a previous unsuccessful attempt. Her doctor tells her to start taking bupropion for seven days before she actually stops smoking. She then commences treatment, with bupropion prescribed at 150  mg once daily in the morning for three days and thereafter 150 mg twice daily for seven weeks.

Questions 1

Explain the mechanism of action of bupropion in producing its effect to assist with smoking cessation.

2

Explain whether nicotine replacement therapy can be used in conjunction with bupropion therapy.

3

What counselling would you offer Ms RM in the use of bupropion?

4

Ms RM likes to have alcohol with her evening meal each night. What would you advise her about consuming alcohol during her treatment regimen?

FU R T H ER RE A DI N G Daly FF, Fountain JS, Murray L, Graudins A, & Buckley NA, 2008, Guidelines for the management of paracetamol poisoning in Australia and New Zealand—exploration and elaboration, Medical Journal of Australia, 188, 296–301. Isbister G, 2006, ‘Snake bite: a current approach to management’, Australian Prescriber, 29, 125–9. Isbister G, 2006, ‘Spider bite: a current approach to management’, Australian Prescriber, 29, 156–8. Isbister G, 2007, ‘Managing injuries by venomous sea creatures in Australia’, Australian Prescriber, 30, 117–21. Isbister G, Bowe S, Dawson A & Whyte I, 2004, ‘Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose’, Journal of Toxicology and Clinical Toxicology, 42, 277–85. Klaassen CD, ed., 2007, Casarett & Doull’s Toxicology, 7th edn, McGraw-Hill, New York. Larzelere MM & Williams DE, 2012, ‘Promoting smoking cessation’, American Family Physician, 85, 591–8. Litt J, 2005, ‘What’s new in smoking cessation?’ Australian Prescriber, 28, 73–5. National Health and Medical Research Council, 2009, Australian Guidelines to Reduce the Health Risks from Drinking Alcohol, Australian Government, Canberra.

CHAPTER 25 DRUG ABUSE IN SPORT

McQuade DJ, Aknuri S, Dargan PI & Wood DM, 2012, Management of acute paracetamol (acetaminophen) toxicity: a standardised proforma improves risk assessment and overall risk stratification by emergency medicine doctors, Emergency Medicine Journal, doi:10.1136/emermed-2011-200889 (accessed 2 July 2012). Zwar N, Richmond R, Borland R, Peters M, Stillman S, Litt J, Bell J & Caldwell B, 2007, Smoking Cessation Pharmacotherapy: An Update for Health Professionals, The Royal Australian College of General Practitioners, Melbourne.

W E B R E S O UR C E S Addiction links (US site) www.drugnet.net/metaview.htm Alcohol Advisory Council of New Zealand www.alac.org.nz/PoliciesAndSubmissions.aspx Australian Drug Information Network www.adin.com.au Australian National Drug Strategy www.nationaldrugstrategy.gov.au Australian Sports Anti-Doping Authority (ASADA) www.asada.gov.au Australian Venom Research Unit www.avru.org Case Studies in Environmental Medicine (US site) www.atsdr.cdc.gov/HEC/CSEM/csem.html Clinical Toxinology Resources (subscription-only website) www.toxinology.com Drug Free Sport NZ www.drugfreesport.org.nz DrugInfo Clearinghouse (Australian Drug Foundation) www.druginfo.adf.org.au Health Insite: Emergencies www.healthinsite.gov.au/topics/Emergencies National Health and Medical Research Council, Alcohol, Drugs and Substance Abuse www.nhmrc.gov.au/publications/subjects/substance.htm National Institute on Drug Abuse (US site) www.drugabuse.gov/NIDAHome.html NZ Government National Drug Policy www.ndp.govt.nz NZ Drug Foundation www.nzdf.org.nz Royal Australian College of General Practitioners—Smoking Cessation Guidelines www.racgp.org.au/guidelines/smokingcessation World Anti-Doping Agency www.wada-ama.org

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A U TO N O M I C PHARMACOLOGY Ah yes, the nervous system. I used to think the knee joint one of the finest anatomical creations, but now I think this system of minute signals, far too small for us to see, may be the masterpiece. S E B A S T I A N FAU L K S — H U M A N T R A C E S

To know the brain … is equivalent to … discovering the intimate history of life in its perpetual duel with external forces. S A N T I A G O R A M O N Y C A J A L , N E U R O S C I E N T I S T, N O B E L P R I Z E W I N N E R

The nervous system is, indeed, a masterpiece. It is one of the primary regulatory systems in our bodies, controlling and coordinating the activities of cells, tissues and organs. It achieves this regulation by precise minute signalling along nerve pathways. It detects and responds to alterations in our internal and external environment in order to maintain homeostasis; changes often due to external forces. The autonomic nervous system controls the function of involuntary body tissues. A thorough examination of the way in which the autonomic nervous system is organised and operates (Chapter 26) will facilitate your understanding of the mechanism of action and adverse effects of many clinical agents you will be working with in clinical practice. Several important drugs used during surgery, and in cardiovascular, pulmonary and ophthalmic medicine, act by altering autonomic nervous system function (Chapters 27 and 28).

C H A P T E R

26

GENERAL ASPECTS OF NEUROPHARMACOLOGY

LEARNING OBJECTIVES

KEY TERMS

After completing this chapter, you should be able to:

Acetylcholine

Dopamine

Adrenaline

Neuromodulation

Adrenergic nerves/ receptors

Noradrenaline

1

Outline briefly the major divisions of the human nervous system and their respective functions.

2

Identify the chemical transmitters involved in autonomic nervous system function.

3

Compare and contrast the anatomical and physiological characteristics of the sympathetic and parasympathetic divisions.

Autonomic nervous system Cholinergic nerves/ receptors

Parasympathetic nervous system Sympathetic nervous system

For the purposes of classification, the human nervous system is partitioned into central and peripheral divisions (see Figure  26.1). The brain and spinal cord constitute the former, while the nerves connecting peripheral tissues with the central nervous system (CNS) form the latter. Functionally, the nervous system can be divided into the afferent division, bringing sensory information back to the CNS for interpretation, and the efferent division, which directs the motor responses of peripheral tissues and organs (otherwise known as effectors). The peripheral nervous system can be further subdivided into that portion under voluntary or conscious control, the somatic nervous system, and that portion serving involuntary effectors, the autonomic nervous system (ANS). All nervous system communication to connecting nerves or tissues is achieved via the release of chemical transmitters across a minute junction called a synapse, rather than by direct contact. These chemical messengers interact with specific surface receptors on either the receiving nerve or the tissue. Activation of these tissue receptors is what underlies the observed effects (e.g. muscle contraction, glandular secretion).

CHAPTER 26 GENERAL ASPECTS OF NEUROPHARMACOLOGY

Figure 26.1 Divisions of the nervous system Central nervous system (brain and spinal cord)

Peripheral nervous system (receptors and peripheral nerves)

Sensory division (afferent)

Subdivisions of the autonomic nervous system

Motor division (efferent)

Somatic nervous system (voluntary tissues) —skeletal muscle

receptors. Some nerves release dopamine (they are dopaminergic) onto specific dopamine receptors that are located within the peripheral vasculature. Noradrenaline and adrenaline are manufactured from dopamine, which itself is formed from the amino acid tyrosine. Collectively, the three chemicals are called catecholamines.

Autonomic nervous system (involuntary tissues)

Sympathetic nervous system (‘fight or flight’ responses)

Parasympathetic nervous system (‘resting and digesting’ responses)

ORGANISATION OF THE AUTONOMIC NERVOUS SYSTEM The ANS is the efferent pathway controlling the action of involuntary organs and tissues. Secretion of products from glands, the rate and force of contraction of heart muscle, and the contraction and relaxation of smooth muscle, of the bronchioles, blood vessels and gastrointestinal tract are all controlled by this division of the nervous system. Sensory information concerning the activity of these involuntary structures is relayed back to the control centres of the brain via afferent pathways to determine the appropriate response.

Chemical transmitters The two major chemical transmitters involved in ANS function are acetylcholine and noradrenaline. A nerve that releases acetylcholine (ACh) as its chemical transmitter is said to be cholinergic, while one that releases noradrenaline as its transmitter is adrenergic. In many instances, autonomic tissues bear surface receptors for both transmitters. Indeed, the response of that tissue to each chemical is completely different. This is the means by which the tissue carries out the correct intention of the brain to either raise or lower the level of activity. Other classic chemical messengers involved in ANS function include dopamine and the blood-borne hormone adrenaline. Both chemicals stimulate peripheral adrenergic

There are two subdivisions of the ANS: the sympathetic and parasympathetic nervous systems. The physiological effects induced by each division are, for the most part, antagonistic. Broadly speaking, the sympathetic nervous system is activated in an emergency or stressful situation, and the effects are classified as ‘fight or flight’ responses. On the other hand, the parasympathetic division has a restorative function, and the effects are classified as ‘resting and digesting’ responses. The processes of digestion and elimination are activated by this division. Table 26.1 shows the effects of sympathetic and parasympathetic stimulation on a variety of effectors.

SYMPATHETIC AND PARASYMPATHETIC DIVISIONS Similarities Anatomical studies of ANS pathways have revealed some similarities. The pathways consist of two neurones. The first has its cell body located within the CNS and its axon is myelinated. The second has its cell body located in the periphery and its axon is unmyelinated. Between the terminal end of the first neurone and the cell body of the second is a synaptic gap. This synaptic region is called an autonomic ganglion, getting its name from the peripheral cell body of the second neurone. The myelinated neurone feeding into the autonomic ganglion is called the preganglionic axon or fibre, while the unmyelinated second neurone feeding out from the ganglion is called the postganglionic fibre. Without exception, the chemical transmitter released from preganglionic fibres is ACh, and it interacts with specific surface receptors on postganglionic fibres. This interaction enables the continuation of the message to the tissue (see Figure 26.2). Effectors that are innervated by both divisions of the ANS are said to be dual-innervated (see Table 26.1). Many effectors receive continual baseline stimulation in order to maintain a constant level of functioning. In other words, these effectors have a resting ‘autonomic tone’. Examples of such effectors are vascular smooth muscle (maintaining blood vessel diameter), the iris of the eye

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Table 26.1 Effects of the parasympathetic and sympathetic divisions on various organs TARGET ORGAN/SYSTEM

PARASYMPATHETIC EFFECTS

SYMPATHETIC EFFECTS

Eye (iris)

Stimulates constrictor muscles; constricts pupils

Stimulates dilator muscles; dilates pupils

Eye (ciliary muscle)

Stimulates muscles, which results in bulging of the lens for accommodation and close vision

No effect

Glands (nasal, lacrimal, salivary, gastric, pancreatic)

Stimulates secretory activity

Inhibits secretory activity; causes vasoconstriction of blood vessels supplying the glands

Sweat glands (cholinergic fibres)

No effect

Stimulates copious sweating

Adrenal medulla

No effect

Stimulates medulla cells to secrete adrenaline and noradrenaline

Arrector pili muscles attached to hair follicles

No effect

Stimulates contraction (erects hairs and produces ‘goosebumps’)

Heart muscle

Decreases rate; slows and steadies heartbeat

Increases rate and force of heartbeat

Heart: coronary blood vessels

Constricts coronary vessels

Causes vasodilation

Bladder/urethra

Causes contraction of smooth muscle of bladder wall; relaxes urethral sphincter; promotes voiding

Causes relaxation of smooth muscle of bladder wall; constricts urethral sphincter; inhibits voiding

Lungs

Constricts bronchioles

Dilates bronchioles and mildly constricts blood vessels

Digestive tract organs

Increases motility (peristalsis) and amount of secretion by digestive organs; relaxes sphincters to allow movement of foodstuffs along tract

Decreases activity of glands and muscles of digestive system and sphincters (e.g. internal anal sphincter)

Liver

No effect

Stimulates liver to release glucose into blood

Gallbladder

Excites (gallbladder contracts to expel bile)

Inhibits (gallbladder is relaxed)

Kidney

No effect

Causes vasoconstriction; decreases urine output; promotes renin formation

Penis

Causes erection (vasodilation)

Causes ejaculation

Vagina/clitoris

Causes erection (vasodilation) of clitoris

Causes reverse peristalsis (contraction) of vagina

Blood vessels

Little or no effect

Constricts most vessels and increases blood pressure; constricts vessels of abdominal viscera and skin to divert blood to muscles, brain and heart when necessary; dilates vessels of the skeletal muscles (via cholinergic fibres and adrenaline) during exercise; dilates coronary and cerebral blood vessels

Blood coagulation

No effect

Increases coagulation

Cellular metabolism

No effect

Increases metabolic rate

Adipose tissue

No effect

Stimulates lipolysis (fat breakdown)

Mental activity

No effect

Increases alertness

Source: Marjeb, EN & Hoehn, K, 2010, Human Anatomy and Physiology, 8th ed., p. 538, Table 14.4. Reprinted and electronically reproduced by permission of Pearson Education, Inc., Upper Saddle River, New Jersey.

CHAPTER 26 GENERAL ASPECTS OF NEUROPHARMACOLOGY

Figure 26.2 Schematic representation of a typical autonomic nervous system pathway A typical autonomic nerve pathway consists of two nerve fibres communicating with an autonomic effector. The cell body of the preganglionic fibre resides within the central nervous system and is a cholinergic myelinated nerve. The cell body of the postganglionic fibre lies within an autonomic ganglion, is unmyelinated and synapses with the effector. The chemical transmitter released from this second fibre depends on the autonomic division to which it belongs. (ACh = acetylcholine, ANS = autonomic nervous system.) Effector Chemical transmitter and receptor

ACh

Preganglionic fibre • Myelinated

Postganglionic fibre • Unmyelinated

• Cholinergic Autonomic ganglion Central nervous system

• Transmitter released depends on ANS division

Peripheral nervous system

(determining the size of the pupil), salivary glands and the gastrointestinal tract (maintaining gastrointestinal motility). A change in function is brought about by a change in the level of stimulation. Altering autonomic tone is a particularly important way of maintaining control over effectors that are not dual-innervated.

Differences Sympathetic preganglionic fibres arise from the spinal cord at the level of the first thoracic nerve down to the level of the second lumbar nerve (T1–L2). This gives rise to the alternative name for the sympathetic division: the thoracolumbar outflow. The preganglionic fibres of the parasympathetic division arise from two locations in the CNS: the spinal cord from the second sacral nerve down to the fourth sacral nerve (S2–S4), and the brain as the motor components of the oculomotor (III), facial (VII), glossopharyngeal (IX) and vagus (X) cranial nerves. The alternative name for this division is the craniosacral outflow. The effects of sympathetic stimulation are more widespread than those of parasympathetic stimulation due to greater branching of postganglionic fibres. Furthermore, there is only sympathetic stimulation of glands and the smooth muscle of the body wall. Tissues such as sweat glands, the

piloerector muscle of hair follicles, and blood vessels to both the skin and skeletal muscle are the beneficiaries of this stimulation. There are also differences in the chemical transmitter released from postganglionic fibres onto tissue receptors. All parasympathetic postganglionic fibres release acetylcholine as their transmitter: that is, they are cholinergic. On the other hand, most of the sympathetic postganglionic fibres release noradrenaline as their transmitter: they are adrenergic. A number of postganglionic fibres associated with the sympathetic division are cholinergic. Tissues that have been found to be innervated by cholinergic sympathetic postganglionic fibres are sweat glands (sweat glands also receive adrenergic stimulation), as well as peripheral blood vessels associated with skeletal muscle (which also respond to adrenergic stimulation) and those associated with the skin of the head and neck (resulting in blushing and flushing). In the sympathetic division, the preganglionic fibre is relatively short and the postganglionic fibre is long. In the parasympathetic division, the converse is true— long preganglionic fibres and short postganglionic fibres. Figures  26.3A and 26.3B and Table 26.2 summarise the differences between the two divisions.

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Figure 26.3A The characteristics of a sympathetic nerve pathway Sympathetic pathways consist of a short preganglionic fibre connecting to a relatively long postganglionic fibre. Most sympathetic postganglionic fibres are adrenergic, some are cholinergic. A.

Short preganglionic fibre

Long postganglionic fibre

• Cholinergic

• Most adrenergic, some cholinergic

Central nervous system

Peripheral nervous system

Figure 26.3B The characteristics of a parasympathetic nerve pathway Parasympathetic pathways consist of long preganglionic and short postganglionic fibres. The parasympathetic postganglionic fibre is always cholinergic. B.

Central nervous system

Long preganglionic fibre

Short postganglionic fibre

• Cholinergic

• Cholinergic

Peripheral nervous system

NEUROMODULATION OF AUTONOMIC NERVOUS SYSTEM FUNCTION Neuromodulation is a term that describes the phenomenon of altering the responsiveness of nerve fibres or body tissues

to nervous stimulation. In some instances responsiveness may be enhanced, in others it is decreased. Such alterations are brought about by the actions of chemical mediators and neurotransmitters. A number of these chemicals can affect ANS function. Using an analogy of a radio or MP3 player, the release of neuromodulators is like twiddling the volume dial to either increase or decrease volume. You cannot turn

CHAPTER 26 GENERAL ASPECTS OF NEUROPHARMACOLOGY

Table 26.2 Anatomical and physiological differences between the parasympathetic and

sympathetic divisions

CHARACTERISTIC

PARASYMPATHETIC

SYMPATHETIC

Origin

Craniosacral outflow: brain stem nuclei or cranial nerves III, VII, IX and X; spinal cord segments S2–S4

Thoracolumbar outflow: lateral horn of grey matter of spinal cord segments T1–L2

Location of ganglia

Ganglia in (intramural) or close to visceral organ served

Ganglia within a few cm of CNS: alongside vertebral column (paravertebral ganglia) and anterior to vertebral column (prevertebral ganglia)

Relative length of preand postganglionic fibres

Long preganglionic; short postganglionic

Short preganglionic; long postganglionic

Degree of branching of preganglionic fibres

Minimal

Extensive

Functional goal

Maintenance functions; conserves and stores energy

Prepares body to cope with emergencies and intense muscular activity

Neurotransmitters

All fibres release acetylcholine (cholinergic fibres)

All preganglionic fibres release acetylcholine; most postganglionic fibres release noradrenaline (adrenergic fibres); some postganglionic fibres (e.g. those serving sweat glands and blood vessels of skeletal muscles) release acetylcholine; neurotransmitter activity augmented by release of adrenal medullary hormones (noradrenaline and adrenaline)

Source: Marjeb, EN & Hoehn, K, 2010, Human Anatomy and Physiology, 8th ed., p. 534, Table 14.1. Reprinted and electronically reproduced by permission of Pearson Education, Inc., Upper Saddle River, New Jersey.

the appliance on or off with this dial, you just alter the character of the signal. This is also true of neuromodulators. You cannot activate nerve transmission through this system, but you can alter the frequency of the transmission. Neuromodulation can occur presynaptically (at the point of transmitter release called the nerve terminal) and postsynaptically (on the tissue that responds to the chemical message, which, for example, could be another nerve cell or a muscle cell). In presynaptic modulation, the release of noradrenaline from a sympathetic postganglionic fibre can inhibit the release of acetylcholine from a parasympathetic postganglionic fibre and vice versa. Autonomic transmitter function is self-regulated (or feedback controlled) such that the release of noradrenaline from the nerve terminal may, under some circumstances, inhibit further release of this transmitter or, under other conditions, enhance its release. An example of where this feedback can be manipulated pharmacologically is in the management of depression using tetracyclic antidepressants (see Chapter  36). This kind of feedback control is also evident for selected cholinergic nerves.

The ANS also responds to chemicals other than noradrenaline and ACh. Some of these neuromodulators are released with the main neurotransmitter (either noradrenaline or ACh) to enhance the desired tissue effect. Neuromodulators may further act to stimulate the release of the principal neurotransmitter from either cholinergic or adrenergic nerves. Other neuromodulators act to inhibit neurotransmitter release from autonomic nerves. Neuromodulators can be formed and released from cells adjacent to nerves. This type of neuromodulator is exogenous. They may also be made within the autonomic nerve terminal; these are called endogenous neuromodulators. It is now recognised that endogenous neuromodulators play a significant role in autonomic transmission. Their contribution to autonomic function is covered by the rather dull, but descriptive, term nonnoradrenergic non-cholinergic transmission. Some examples of ANS neuromodulators are provided in Table  26.3. There is a more detailed discussion of the physiological roles of chemical mediators in Section VII. Clearly, the role of neuromodulation in the control and

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Table 26.3 Examples of neuromodulators of the autonomic nervous system SUBSTANCE

EFFECTS

Nitric oxide (Parasympathetic cotransmitter)

Facilitates erection of genitalia Promotes gastric emptying

Serotonin

Inhibits noradrenaline release from sympathetic nerves Enhances peristalsis

Neuropeptide Y (Sympathetic cotransmitter)

Enhances vasoconstriction

Vasoactive intestinal peptide (Parasympathetic cotransmitter)

Facilitates bronchodilation

Dopamine

Inhibits noradrenaline release from sympathetic nerves Promotes vasodilation in some tissues (e.g. kidneys)

regulation of the autonomic transmission illustrates the functional complexity of this body system. The simplified overview of the ANS presented in this chapter will certainly assist you in your understanding of adrenergic and cholinergic pharmacology (see Chapters  27 and 28), but you should keep in mind that the actual physiology is more complex.

Now, with this foundation in place, we are ready to explore the areas of adrenergic, cholinergic and dopaminergic pharmacology. In so doing, we will gain an understanding of an extraordinary number of commonly prescribed medicines.

CHAPTER 26 GENERAL ASPECTS OF NEUROPHARMACOLOGY

CHAPTER REVIEW ■■ ■■

■■

■■ ■■

■■

The autonomic nervous system (ANS) is an efferent pathway controlling involuntary body structures. There are two subdivisions of the ANS. The sympathetic division is activated in emergency or stressful situations, and is associated with ‘fight or flight’ responses. The parasympathetic division has a restorative function, and is associated with ‘resting and digesting’ responses. There are two nerve fibres in an autonomic pathway: the preganglionic and postganglionic fibres. The synapse connecting the fibres is the autonomic ganglion. The body structure receiving stimulation is called an effector. The two principal transmitters associated with the ANS are acetylcholine (ACh) and noradrenaline. Nerve fibres that release ACh and the receptors that respond to this transmitter are cholinergic, while nerve fibres that release noradrenaline or respond to this transmitter are adrenergic. Neuromodulators are chemicals that may alter the responsiveness of nerves and tissues to ANS stimulation.

REVIEW QUESTIONS 1

a

What are the two major divisions of the human nervous system?

b Outline the subdivisions of the peripheral nervous system. 2

What are the two divisions of the autonomic nervous system?

3

For each of the following aspects of autonomic nervous system, indicate whether it is a part of sympathetic or parasympathetic organisation: a

long preganglionic and short postganglionic axons

b extensive branching of preganglionic fibres c

adrenergic postganglionic fibres

d preganglionic cell bodies located in the thoracic region of the spinal cord 4

For each of the following effectors, deduce the effects (if any) of sympathetic and parasympathetic stimulation: a

pupil size

b blood vessel diameter c

lacrimal glands

d sweat glands e 5

bronchiole diameter

For each of the following effects, determine whether it is due to sympathetic or parasympathetic innervation: a

increased heart rate

b increased salivation c

urinary retention

d increased blood pressure

6

e

defecation

f

pupil constriction

a

Define the term neuromodulation.

b Give four examples of neuromodulation.

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C H A P T E R

27

ADRENERGIC PHARMACOLOGY

LEARNING OBJECTIVES

KEY TERMS

After completing this chapter, you should be able to:

Adrenaline

1

Identify the types and subtypes of adrenergic receptors.

Adrenergic receptors

2

List the effects observed after either stimulation or blockade of peripheral adrenoreceptors.

Catecholamines

Outline the central nervous system effects of adrenergic stimulation and blockade.

G proteins

4

Describe the role of dopamine in autonomic nervous system function.

Second messengers

5

Derive the side-effects and clinical indications of adrenergic agents from knowledge of receptor distribution and sympathetic nervous system effects.

3

Dopamine Noradrenaline Sympathetic nervous system

Adrenergic pharmacology is within the exclusive domain of sympathetic nervous system function. In the peripheral nervous system only sympathetic postganglionic fibres are adrenergic (i.e.  nerves that release the transmitter noradrenaline), releasing their noradrenaline directly onto adrenergic receptors on the surface of effectors. The hormone adrenaline, released into the circulation from the adrenal gland, also stimulates adrenergic receptors but does not always mimic noradrenaline. The purpose of these interactions is to prepare the body for a ‘fight or flight’ situation. Other names widely substituted for noradrenaline and adrenaline in the literature are norepinephrine and epinephrine, respectively. In this book, noradrenaline and adrenaline are preferred because they can be linked to terms such as adrenergic receptor and adrenal gland, and they are approved names in this region of the world. Administration of adrenergic agonist agents will induce effector responses of a ‘fight or flight’ character. Stimulants such as these are sometimes referred to as sympathomimetics (drugs that mimic sympathetic stimulation), while blocking agents prevent these responses and are termed sympatholytics (drugs that block or inhibit sympathetic stimulation). The rationale for the clinical

CHAPTER 27 ADRENERGIC PHARMACOLOGY

use of adrenergic stimulants or blockers depends on how illness has altered normal body function. In conditions where the activity of adrenergic effectors is excessive (e.g.  a fast heart rate causing the pain of angina pectoris or elevated blood pressure in hypertension), the use of an adrenergic blocker is warranted. Adrenergic stimulants are used when the illness state leaves effector activity inadequate (e.g. narrowing of bronchioles in asthma or diminished circulation in neurogenic shock).

MECHANISM OF ADRENERGIC ACTION When an adrenergic nerve is stimulated, the action potential passes to the axon terminal. The axon terminal has small swellings along its length called varicosities, where the transmitter is stored in packets called synaptic vesicles. Depolarisation of the varicosity’s membrane causes the vesicles to fuse with that membrane, rupture and release noradrenaline into the synaptic gap. There are many varicosities along the length of the branching axon terminals, which leads to multiple sites of communication with the effector. The transmitter diffuses across the synaptic gap and reversibly interacts with an adrenergic receptor, or adrenoceptor, postsynaptically on the effector’s surface. Adrenoceptors are G-protein-coupled receptors, which interact with a cytoplasmic second messenger system (see later in this chapter). This interaction, in turn, triggers a series of intracellular events that manifest as the desired ‘fight or flight’ response. In order to maintain control of the effector’s function, the free transmitter must be removed from the synapse or inactivated by degradative enzymes. Persistence of the transmitter in the synaptic gap can lead to overstimulation of the effector. To facilitate its inactivation, noradrenaline is subject to the processes of synaptic removal and enzymatic breakdown. There are two different synaptic removal mechanisms that involve adrenergic catecholamine uptake. Noradrenaline and related catecholamines are removed from the synapse by a neurotransmitter transporter system, an amine pump, located on the surface of the presynaptic terminal. Another name for this transporter system is uptake-1. The purpose of this pump is both inactivation and conservation—to remove synaptic noradrenaline and return it to the nerve terminal for later use. On re-entry to the nerve terminal, the noradrenaline is restored to the synaptic vesicles. When these storage areas are full, any transmitter remaining free in the terminal is broken down by the mitochondrial enzyme monoamine oxidase (MAO). Any noradrenaline escaping

the amine pump is subject to extraneuronal uptake, termed uptake-2, into the surrounding tissues (such as muscle and endothelium) and degradation by the enzyme catechol-Omethyltransferase (COMT) (see Figure 27.1 for a schematic representation of this mechanism). In addition to their synaptic locations, other characteristic differences between uptake-1 and uptake-2 include selectivity for noradrenaline and adrenaline, as well as their rate of uptake. Uptake-1 has been shown to be selective for noradrenaline, while both adrenaline and noradrenaline are substrates for uptake-2. Some drugs directly target one or the other transporter system as the basis of their mechanism of action. For example, cocaine inhibits uptake-1, resulting in a prolonged synaptic action of noradrenaline, while amphetamines can be transported into the axon terminal by uptake-1, causing the release of stored noradrenaline. Adrenergic agonists and antagonists are structurally similar to the endogenous catecholamines that bind to adrenergic receptors. Many of these drugs bind reversibly to the adrenoreceptor and are subject to the processes of reuptake and/or enzymatic breakdown by MAO and COMT.

ADRENERGIC RECEPTOR STIMULATION Two principal types of adrenoceptors have been identified: α (alpha) and β (beta) receptors. These receptor types have been further subdivided. The main subtypes, from a therapeutic point of view, are α1, α2, β1 and β2 receptors. The activation of these receptors through the administration of adrenergic agonists will produce effects consistent with sympathetic (‘fight or flight’) stimulation. Adrenoceptors are distributed widely, but not evenly, throughout the body. Figure 27.2 summarises the effects resulting from the stimulation of peripheral adrenergic receptors. β3 receptors have been found in adipose tissue and may also be present in the heart and on blood vessels. Moreover, a case has been made for the existence of a putative cardiovascular β4  receptor. However, recent evidence

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Figure 27.1 Adrenergic nerve action A The branching nerve terminal of a sympathetic postganglionic fibre shows a series of small swellings known as varicosities along the length of each branch. B A summary of events involved in adrenergic nerve stimulation. The action potential travels along the axon until it reaches the varicosities of the axon terminals (1). Depolarisation of the membrane of the varicosity causes the release of chemical transmitter, noradrenaline (NA), into the synaptic gap (2). NA diffuses across the gap and interacts with the adrenergic postsynaptic receptors, triggering an effector response via a G protein-coupledsecond messenger system (3). The transmitter is removed from the synaptic gap by the uptake-1 transporter (4) and is restored to the synaptic vesicles. Any excess transmitter within the terminal not restored to the vesicles is degraded by the mitochondrial enzyme, monoamine oxidase (MAO) (5). Any excess transmitter remaining within the synaptic gap is subject to extraneuronal reuptake (uptake-2). The release of transmitter from the varicosity is also subject to modulation by presynaptic adrenoceptors (enhancement of release by one type, inhibition by another) (6). Such control of transmitter release is known as autoregulation. A. Sympathetic postganglionic fibre

Presynaptic varicosity B. Synaptic vesicles containing noradrenaline (NA) 1 Action potential

5

6

Mitochondrion containing MAO 2

Presynaptic adrenoceptor Postsynaptic adrenoceptor

4

3

Response

Uptake-1

CHAPTER 27 ADRENERGIC PHARMACOLOGY

Figure 27.2 Adrenergic agonist effects A summary of agonist responses following systemic stimulation of each subtype of adrenoceptor. Presynaptic α2 receptors, when stimulated, inhibit further release of transmitter. Presynaptic β2 receptors enhance transmitter release. (GI = gastrointestinal.) Synaptic vesicles containing noradrenaline (NA)

Mitochondrion containing MAO

Presynaptic adrenoceptor

Uptake-1 Postsynaptic adrenoceptors

β1

α1

β2

α1 Agonist action

β1 Agonist action

β2 Agonist action

• Vasoconstriction (increases blood pressure; relieves congestion)

• Cardiac acceleration (increases heart rate, stroke volume, cardiac output)

• Bronchodilation

• Pupil dilation

• Lipolysis

• Decreases GI motility and secretions

• Decreases GI motility and secretions

• Vasodilation of blood vessels in skeletal muscle

• Glycogen breakdown (increases blood glucose levels)

• Renin release (triggers reninangiotension-aldosterone system)

• Urinary retention

• Fine skeletal muscle tremor

• Glycogen breakdown • Relaxation of pregnant uterus • Mast cell stabilisation

• Contraction of smooth muscle of the vas deferens (facilitates sperm transport and ejaculation) • Contraction of the non-pregnant uterus • Sweating • Gooseflesh

suggests that this receptor may be just an atypical form of another β receptor subtype, so they are not included in the following discussion. Interestingly, subtypes of α1 and α2 adrenoceptors have also been identified: α1a, α1b and α1d, as well as α2A, α2B and α2C subtypes. It is hoped that research will reveal differences in tissue distribution and cellular repsonses that may yield a range of novel and selective therapeutic agents.

α 1 R E C E P TO R S α1 Receptors are located on blood vessels and influence both blood pressure and tissue perfusion. Resistance to blood flow is determined by the diameter of these vessels. These receptors are also found on the radial muscle of the iris, the sphincters and smooth muscle of the gastrointestinal tract, liver cells, sweat glands, the arrector pili muscles of the hair follicles, the smooth muscle of both the male and female

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reproductive tracts, and the sphincters and smooth muscle associated with the urinary bladder. Mechanism of action As represented in Figure  27.2, stimulation of α1  receptors causes the following effects: • vasoconstriction of blood vessels. This effect has a significant influence on tissue perfusion and is used primarily as a means to redirect blood flow from one tissue to another. In addition, in many vessels this stimulation provides resting vasomotor tone. Vasoconstriction of major systemic blood vessels results in a significant elevation of blood pressure. Vasoconstriction is also an effective means to decongest blocked nasal passages; medicines that do this are called nasal decongestants. Localised vasodilation and increased vascular permeability of nasal capillaries underlie this congestion. In conditions characterised by red eyes, vasoconstriction of scleral blood vessels can greatly diminish this manifestation; medicines that do this are called ophthalmic decongestants; • contraction of the radial muscle of the iris resulting in pupil dilation (mydriasis); • contraction of the gastrointestinal sphincters and decreased gastrointestinal motility resulting in slowed digestion and transport through the gut; • contraction of the external sphincter and loss of bladder tone leading to urinary retention; • decreased bile secretion and increased glycogenolysis; the latter leads to raised blood sugar levels; • contraction of the smooth muscle of the vas deferens and the non-pregnant uterus to facilitate emission and ejaculation in the former and sperm transport to the fallopian tubes in the latter; • stimulation of sweat glands resulting in generalised sweating; • contraction of the arrector pili muscles, resulting in goosebumps. Common adverse effects The effects of α1 agonists are shown in Figures 27.3 and 27.4. Common adverse effects include hypertension, blurred vision, constipation and urinary retention. Clinical considerations Clinical applications for α1  receptor stimulation include control of hypotension (particularly as an emergency measure for elevating blood pressure), nasal congestion

and red eyes. Another application worth noting is the use of these medicines as a vasoconstrictor administered in combination with another medicine. This vasoconstriction facilitates a slow systemic absorption of the other medicine, enhancing its action locally; or it produces a relatively bloodless field for minor surgery. Such a combination is often used in local anaesthesia (see Chapter 44). Midodrine, naphazoline, oxymetazoline, phenyl– ephrine and xylometazoline are all direct-acting α1  agonists. The non-selective sympathomimetic agents, including noradrenaline, pseudoephedrine, metaraminol, adrenaline, ephedrine and dopamine, which induce both α and β effects, may be used clinically for their α 1 effects. Use of non-selective sympathomimetic agents, such as noradrenaline, adrenaline and dopamine, involves close monitoring and titration of doses against haemodynamic parameters, including heart rate and rhythm, blood pressure and urine output. When administering α1 agonists systemically, such as for local anaesthesia, it is important to closely scrutinise their effects on peripheral perfusion. Observe for colour and warmth of the peripheries. Decongestant topical preparations are not recommended for prolonged use, as rebound congestion and hyperaemia may occur.

β 1 R E C E P TO R S β1 Receptors are located on the myocardium. They are also associated with adipocytes, smooth muscle and sphincters of the gastrointestinal tract, and renal arterioles. Mechanism of action As represented in Figure  27.2, stimulation of β1  receptors results in the following effects: • increased rate and force of contraction of the heart. The increased cardiac output that ensues can lead to an elevation in blood pressure. This is a good opportunity to introduce two important terms relating to altered myocardial function. Any change in heart rate is called a chronotropic effect, while any change in contractile force is known as an inotropic effect. An increase in either property is termed positive, a decrease is negative. Therefore, β1 receptors generate positive chronotropic and positive inotropic effects; • lipolysis in adipose tissue, leading to a rise in blood lipid levels. These lipids (predominantly free fatty acids) will be converted into energy (β3 receptors may also play a role in lipolysis); • decreased digestion and gastrointestinal motility;

Hypertension

which may progress to

Increases in blood pressure

resulting in

Increases in SVR

leading to

Vasoconstriction

inducing

Blood vessels

Decreases in peristalsis

inducing

Gut

resulting in

Reductions in congestion

which may progress to

Constipation

which may become

Nasal decongestion

Blurred vision

which may become

Pupil dilation

inducing

Iris

Ocular decongestion

resulting in

Increases in blood glucose levels

which may become

Glycogen breakdown

inducing

Liver

Decreases in voiding

inducing

Urinary bladder

Urinary retention

which may become

stimulate α1 receptors on

α1 Agonists

Gooseflesh

inducing

Arrector pili muscle

Sweating

inducing

Sweat glands

CHAPTER 27 ADRENERGIC PHARMACOLOGY

Figure 27.3  Flowchart showing the effects of α1 agonists

Therapeutic effects are shown in white boxes. (SVR = systemic vascular resistance.)

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Figure 27.4  The effects of α1 agonists Ocular decongestion

Restlessness, headache

Nasal decongestion Gooseflesh

β 2 R E C E P TO R S

Sweating Pupil dilation Reflex bradycardia Cardiac dysrhythmia Vasoconstriction & increased blood pressure

Constipation

Nervousness

Urinary retention

•

blood pressure, heart rate and rhythm, oxygenation, urinary output and conscious state are regularly and strictly scrutinised.

release of renin from the juxtaglomerular apparatus into the renal blood, resulting in the formation of angiotensin II. This substance is a potent vasoconstrictor, which causes an increase in renal blood flow and pressure and, as a result, increased glomerular filtration. Common adverse effects

The effects of β1 agonists are shown in Figures 27.5 and 27.6. Common adverse effects include hypertension, tachycardia and constipation. Clinical considerations Clinical applications for β1  stimulation are as positive inotropic agents in circulatory shock, hypotension and cardiac arrest. Dobutamine, a selective β1  agonist, and isoprenaline, a non-selective β1 agonist, are important representatives of this group. The non-selective sympathomimetic agents may be used therapeutically for their β1 agonist effects. As these medicines increase the cardiac workload and output, they must be closely monitored within the confines of a specialty unit, such as intensive care. The person’s

These adrenoreceptors are distributed on the smooth muscle of the bronchioles. They are also associated with skeletal muscle, mast cells, uterus, liver cells and blood vessels supplying the brain, heart, kidneys and skeletal muscle. Mechanism of action As represented in Figure  27.2, stimulation of β2  receptors results in the following effects: • bronchodilation; • increased skeletal muscle excitability, resulting in fine muscle tremors; • vasodilation of blood vessels to the brain, heart, kidneys and skeletal muscle, leading to increased blood flow through those tissues. This effect is mediated by nitric oxide release (see Chapter 32) from endothelial cells. • relaxation of the pregnant uterus, and rhythmic contraction of the non-pregnant uterus during sexual intercourse to promote sperm transport towards the fallopian tubes; • decreased bile secretion and increased glycogenolysis; • stabilisation of the membrane of the mast cell, preventing the release of inflammatory mediators. β2 receptors are also located on the presynaptic terminal of adrenergic nerves and are thought to facilitate the release of stored noradrenaline. This is a form of positive feedback control. Common adverse effects The effects of β2  agonists are shown in Figures  27.7 and 27.8. Common adverse effects include fine muscle tremor (especially involving the hands) and, in some people, increased muscle tension and feelings of warmth (the latter due to increased blood flow through skeletal muscles). Although this drug group is relatively selective for β2 receptors, some residual β1 stimulation may result in tachycardia. Rises in blood glucose and insulin levels are metabolic effects associated with parenteral or nebuliser therapy, the latter leading to a fall in serum potassium levels. When β2  agonists are administered by these routes, the person should be closely monitored for hypokalaemia.

CHAPTER 27 ADRENERGIC PHARMACOLOGY

Figure 27.5  Flowchart showing the effects of β1 agonists Therapeutic effects are shown in white boxes. β1 Agonists stimulate β1 receptors on

Juxtaglomerular apparatus

Heart muscle

Gut

which

which Stimulates renin release

Increases heart rate

resulting in

which Increases force of contraction

resulting in

resulting in Increases in cardiac output & workload

Increases in angiotension II production

Adipose tissue

which

Decreases peristalsis

Increases blood lipid levels

which may progress to Constipation

which leads to

Increases in blood pressure

which may progress to

Hypertension

Clinical considerations Clinical applications for β2  stimulation include chronic obstructive pulmonary disease, circulatory shock, premature labour and peripheral vascular disease. Eformoterol, indacaterol, salbutamol, salmeterol and terbutaline are relatively selective β2  agonists (see Chapter 54). Salmeterol is notable in that, unlike the other drugs in this group, its effect on mast cell membranes lasts

long enough to be clinically significant. Indacaterol is only available in Australia. The short-acting β2  agonists, such as salbutamol, have a quick onset of action (5–15 minutes) and are, therefore, recommended to relieve acute symptoms of asthma. On the other hand, long-acting β2 agonists, such as salmeterol, eformoterol and indacterol, should be used as maintenance treatment for asthma. Corticosteroid anti-inflammatory use is considered if a short-acting β2 agonist is required for more

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Figure 27.6  The effects of β1 agonists Headache, dizziness, nervousness

α 2 R E C E P TO R S Mechanism of action

Sweating Increased heart rate Increased force of contraction Cardiac disturbances

Increased blood pressure Increased blood lipid level

Constipation Tremor

than three or four times each week. Long-acting β2 agonists such as eformoterol and salmeterol can be used as alternative forms of therapy to higher doses of inhaled corticosteroids in patients already receiving inhaled corticosteroids. It should be noted, however, that long-acting β2  agonists should not be substituted for inhaled corticosteroids in the treatment of asthma. Long-acting β2  agonists and inhaled corticosteroids are to be used concurrently. High doses of β2  agonists are normally delivered by nebuliser, which can increase the incidence of hypokalaemia. Nebulisers should be used mainly in the hospital setting and reserved for severe or life-threatening acute asthma. In relation to management of chronic obstructive pulmonary disease (COPD), short-acting β2  agonists, such as salbutamol or terbutaline, are used to provide prompt relief of symptoms. Long-acting β2  agonists, such as salmeterol, can be used to treat symptoms of COPD in those individuals who continue to experience symptoms following short-acting β2 agonist therapy or in those who have more than two or more exacerbations each year.

The α2 receptor is located presynaptically and is found on all adrenergic nerve terminals. Its purpose is one of negative feedback control, or autoinhibition, at the local level. When adrenergic nerve stimulation is excessive and leads to a build-up of transmitter in the synapse, activation of the α2 receptor results in inhibition of transmitter release from the terminal even though the stimulation persists. This prevents overstimulation of the effector. It is also located postsynaptically on the surface of some effector organs, such as the pancreas. Clinical considerations Clonidine, dexmedetomidine, apraclonidine and brimonidine are selective α2  agonists. Clonidine is used mainly in the treatment of hypertension. It is also used as a premedication before surgery, and as an adjunct during induction of, maintenance of and recovery from anaesthesia. Dexmedetomidine is used intravenously as a postsurgical form of sedation of intubated patients for up to 24  hours. Rapid intravenous administration of dexmedetomidine can cause bradycardia and sinus arrest. During administration of dexmedetomidine, individuals are rousable and alert if they are stimulated. This is not a sign that inadequate sedation has been administered. Apraclonidine and brimonidine are used as an adjunct in controlling glaucoma. In effect, they act by blocking sympathetic nerve transmission associated with vasomotor tone. Clonidine acts centrally at the level of the medulla, while apraclonidine and brimonidine, applied topically, affect the rate of aqueous humour production. A rebound phenomenon may occur with clonidine whereby a rapid rise in blood pressure, flushing, headache, sweating, insomnia, agitation and tremor occur approximately 18–72 hours after the last dose. To avoid this phenomenon, clonidine should be gradually withdrawn over a period of at least seven days. The use of apraclonidine in the treatment of glaucoma is limited because of its tendency to cause local allergic reactions and its loss of effect after three months of treatment. Brimonidine is better tolerated and more effective when used for long-term treatment. Clonidine is discussed in Chapter 46. Apraclonidine and brimonidine are described further in Chapter 83.

Fine muscle tremor

triggering

Skeletal muscle

Stabilise the cell's membrane

Increase insulin secretion

which may

Pancreas

Falls in serum potassium levels

*which may lead to

can, if it is a long-lasting agonist,

Mast cells

Increases in tissue perfusion

triggering

Vasodilation

triggering

Blood vessels in skeletal muscle, coronary and cerebral circulation

*More likely when systemic absorption is greater (e.g. after intravenous injection or frequent nebuliser use)

Bronchodilation

triggering

Bronchioles

stimulate β2 receptors associated with

β2 Agonists

Rises in blood glucose levels

which may lead to

Glycogen breakdown

triggering

Liver

Relaxation

inducing

Uterine smooth muscle (pregnant)

Increase in rate and force of contraction

triggering an

Heart

although there is some residual β1 stimulation of the

CHAPTER 27 ADRENERGIC PHARMACOLOGY

Figure 27.7  Flowchart showing the effects of β2 agonists

Therapeutic effects are shown in white boxes.

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Figure 27.8  The effects of β2 agonists Restlessness, headache

Increased blood flow to brain, heart muscle & skeletal muscle

Bronchoconstriction

Tachycardia

Increased blood glucose levels Increased insulin secretion

Tremor

Relaxation of pregnant uterus

SECOND MESSENGER SYSTEMS The activation of a receptor on a cell’s surface is only the first step in an elaborate intracellular signalling system that results in the desired cell response. In this section, aspects of this system will be described. In general, the chemical that makes contact with the effector cell is regarded as the ‘first’ messenger. This could be a neurotransmitter, a hormone, an agonist or a chemical mediator. A progression of intracellular events then commences (see Figure 27.9). For adrenergic receptors the first step is to alter the activity of a G protein, which then interacts with a membrane-bound enzyme. The membrane-bound enzyme is responsible for the synthesis of the ‘second’ messenger in the cytoplasm. Examples of second messengers are cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), calcium ion, diacylglycerol (DAG) and inositol triphosphate (IP3). Table  27.1 provides examples of important second messengers, the membrane-bound enzymes that catalyse their formation and some tissues where they can be found. The second messenger usually activates a cascade of enzymes, particularly the protein

kinases, or opens an ion channel in the membrane, which more directly induces the appropriate cellular response. The interaction of one first messenger chemical with the cell leads to the synthesis of a number of second messenger molecules, which, in turn, produce numerous enzymic cascades. In effect, this amplifies the original cellular message. Cellular responses can include the activation of particular genes, an alteration in the cell’s permeability, the relaxation (or contraction) of a muscle cell, increased (or decreased) nerve cell firing or the synthesis and release of a certain cell product. Interestingly, some lipid-soluble chemical mediators can by-pass the extracellular receptor and directly activate the membrane-bound enzyme to produce the cell’s second messenger (see Figure  27.9). An example of this is nitric oxide (see Chapter 32). However, it still requires the second messenger to produce the desired cellular response. Second messenger systems are finely controlled. Once the second messenger is produced, it needs to be broken down. Phosphodiesterases are important in the breakdown of some second messengers. Moreover, activation of one receptor may stimulate the production of the second messenger, while activation of another receptor on that cell inhibits the production of this second messenger. This is a key role of the G protein. There are many types of G proteins. One type of G  protein stimulates the membrane-bound enzyme and is generally called a Gs  protein; another type inhibits the membrane-bound enzyme and is generally called a Gi protein (see Figure 27.9). Some tissues that receive innervation by both sympathetic and parasympathetic divisions are mediated by G proteins: one division activates a Gs protein, while the other activates a Gi protein on the same second messenger. The two most well-established second messengers associated with adrenergic receptors are cAMP and IP3 (see Figure  27.10). The intracellular levels of these messengers determine whether the ‘fight or flight’ response will occur. β1 and β2 receptor activation is associated with elevated intracellular levels of cAMP. The membrane-bound enzyme adenylate cyclase is responsible for the conversion of cytoplasmic ATP into cAMP. Then, depending on the cell type, a sequence of events takes place that culminates in the desired response. The effect is terminated by the degradation of cAMP by phosphodiesterase. The methylxanthines theophylline and caffeine produce their stimulatory effects on the body (see Chapters  24, 54 and 55) through the inhibition of cAMP degradation by phosphodiesterase, which leads to elevated cAMP levels. Phosphodiesterase inhibitors also have therapeutic applications in the management of erectile dysfunction (see

CHAPTER 27 ADRENERGIC PHARMACOLOGY

Figure 27.9  Intracellular events triggered by the action of a first messenger A representation of the signal transduction process associated with the activation of a G-coupled receptor. Transmitter A stimulates Receptor A, which activates a Gs protein linked to a membrane-bound enzyme. The enzyme catalyses the production of a second messenger , which leads to a set of cellular responses. Transmitter B stimulates Receptor B, resulting in the activatation of a Gi protein linked to the same membrane-bound receptor. However, the Gi protein inhibits the enzyme, and halts second messenger production. The dependent set of cellular responses does not occur. It is also possible that another chemical mediator could by-pass the G protein and activate the membrane-bound enzyme directly. Extracellular environment Chemical mediator Transmitter A

Transmitter B

Receptor A

Receptor B

Membrane-bound enzyme

Cell membrane

Cytoplasm

Gs protein

Gi protein

+

–

Enzyme substrate

Second messenger Inactivation

Cellular responses

Table 27.1 Examples of autonomic second messenger systems EXAMPLE OF TISSUE RESPONSE

SECOND MESSENGER

CATALY TIC ENZYME

LINKED RECEPTOR

Inositol triphosphate (IP3) Diacylglycerol (DAG)

Phospholipase C (PLC)

Adrenergic α1 (activates PLC via G protein)

Vasoconstriction

Cholinergic M1 and M3 (activates PLC via G protein)

Smooth muscle contraction

Adrenergic β (activates AC via Gs protein)

Increased heart rate

Adrenergic α2 (inhibits AC via Gi protein)

Membrane hyperpolarisation

Cholinergic M2 (inhibits AC via Gi protein)

Decreased heart rate

Cyclic adenosine monophosphate (cAMP)

Adenylate cyclase (AC)

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Figure 27.10 Second messengers involved in adrenergic function A The receptor–chemical interaction on the surface of an effector triggers the activation of the membrane-bound enzyme adenylate cyclase. This enzyme facilitates the conversion of cytoplasmic reactions which manifest as altered cell activity. The enzyme phosphodiesterase is responsible for the inactivation of cyclic adenosine monophosphate (cAMP) into 5-AMP. B Receptor stimulation results in the activation of a membrane-bound enzyme called phospholipase C. The enzyme facilitates the production of inositol triphosphate (IP3) and diacylglycerol (DAG) from lipids contained within the cell membrane. IP3 stimulates the release of calcium from intracellular storage sites. DAG activates a cascade of cytoplasmic reactions. These responses result in altered cellular activity. A.

B.

Cell membrane

Phospholipase C

Adenylate cyclase

Phosphodiesterase Cytoplasm

Cytoplasm cAMP

5-AMP

Endoplasmic reticulum

IP3

DAG

Protein kinase cascade

Activate genes Activate protein kinase

Calcium ion release

Nucleus

Cell response

Chapter 47), thrombosis (see Chapter 48) and heart failure (see milrinone in Chapter 50). IP3 is associated with α1  receptor activation and is produced from a phospholipid component of the cell membrane by phospholipase C. Another second messenger, called diacylglycerol (DAG), is also produced in this reaction. When the cytoplasmic levels of IP3 rise, calcium ions are released from intracellular stores, which catalyse a cascade of calcium-dependent enzymic reactions to produce the biological effect. DAG activates a cascade of cytoplasmic reactions which also contribute to the effect. IP3 is deactivated by dephosphorylation (the removal of a phosphate group) and calcium is subsequently returned to its cytoplasmic storage sites. DAG is deactivated by phosphorylation (the addition of a phosphate group).

Cell response

DIRECT- AND INDIRECT-ACTING SYMPATHOMIMETICS Sympathomimetic agents can be either direct-acting or indirect-acting. The two mechanisms are represented in Figure  27.11. Direct-acting agents are agonists that bind to and interact with adrenergic receptors, causing a change in the effector’s activity. Agonists can also possess the property of receptor selectivity. An agonist can show selectivity for either α or β  receptors, or even selectivity for one subpopulation of α or β receptors (i.e. β1-specific). Selectivity is desirable in a clinical agent because effects associated with stimulation of adrenergic receptors that do not contribute to the desired outcome are diminished.

CHAPTER 27 ADRENERGIC PHARMACOLOGY

Figure 27.11 Direct- and indirect-acting sympathomimetics A The action of agonist drugs does not primarily involve the presynaptic terminal. The agonist triggers an effector response once it binds to a postsynaptic receptor. B Indirect-acting drugs are taken up into the presynaptic terminal by the uptake-1 mechanism and trigger the release of chemical transmitter from synaptic vesicles into the synapse. The transmitter substance interacts with the postsynaptic receptor, causing an effector response. Some indirect-acting sympathomimetics have agonist activity as well. (MAO = monoamine oxidase.) A. Direct-acting agent Synaptic vesicles containing noradrenaline (NA)

Mitochondrion containing MAO

Presynaptic adrenoceptor

Uptake-1 Postsynaptic adrenoceptor

α1

Response B. Indirect-acting agent Synaptic vesicles containing noradrenaline (NA)

Mitochondrion containing MAO Presynaptic adrenoceptor

Uptake-1 Postsynaptic adrenoceptor

α1

Response

Sympathomimetic drug molecules

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Indirect-acting agents cause the release of a stored transmitter from within the adrenergic nerve terminal. The transmitter noradrenaline then stimulates adrenergic receptors on the effector. Some sympathomimetic agents (e.g.  ephedrine, metaraminol and pseudoephedrine) possess a mixed action or release of transmitter plus direct agonist activity. Noradrenaline and adrenaline are the least specific of adrenergic agonists and can stimulate both α and β  receptors. However, there are differences in potency. Subtle differences in chemical structure cause the effects of noradrenaline at α receptors to be more pronounced than at β receptors, whereas the converse is true of adrenaline.

ADRENERGIC ACTION IN THE CNS The catecholamines have a prominent role in central nervous system (CNS) function: noradrenaline, adrenaline and dopamine are brain transmitters. These neurotransmitters have been implicated in arousal and wakefulness, mood, emotional behaviour, hormone release, libido, motor control and coordination—important effects in ‘fight or flight’ situations. Therefore, it is not surprising that adrenergic drugs capable of crossing the blood–brain barrier can induce alterations in the CNS. Generally, the kinds of effects observed when sympathomimetics with central activity are administered relate to stimulation of these functions. As a result, an excessive level of arousal is observed. Manifestations such as restlessness, insomnia, anxiety, nervousness, euphoria, a sense of wellbeing, irritability, talkativeness and aggression may be seen.

ADRENERGIC SIDE-EFFECTS In the main, the side-effects of adrenergic agents derive from the widespread distribution of these receptors around the body. If an adrenergic drug has affinity for β receptors, effects will be observed in all effectors bearing these receptors around the body: heart, bronchioles, adipose tissue, renal arterioles, brain, and blood vessels to brain, heart, skeletal muscle and so on (see Figure  27.2: β1 and β2  actions). However, the only desirable effect might be that produced in the heart (e.g. cardiac acceleration due to β1 agonist action). If this is the case, then all other β effects not related to that therapeutic goal, both peripheral and central, are side-effects. An effective approach to raise your awareness of adrenergic side-effects would be to learn the distribution

of various subtypes of adrenoreceptors in the body. If you know the effects of sympathetic stimulation on particular effectors (see Chapter  26), you will be able to recognise clinical applications and side-effects of sympathomimetic agents. As a general rule, the effects of antagonists will be either opposite to that of the agonist or not clinically manifested. Examples of this approach are included in the study questions at the end of this chapter.

SYMPATHOLYTICS Like sympathomimetic agents, sympatholytics can act either directly or indirectly. Direct-acting sympatholytics are antagonists that have affinity for a receptor but block the normal response. Like adrenergic agonists, antagonists can show specificity for one receptor or subtype. Indirectacting agents block adrenergic nerve transmission, usually by inhibiting the release of neurotransmitter or depleting the stores of transmitter. Tetrabenazine acts by depleting the stores of transmitter centrally. It is useful in treating some forms of dystonia and dyskinesia (see Chapter  37). The principal clinical use of this adrenergic nerve blocker has been to control hypertension but, because of its sideeffects, it is rarely used (most of the information pertaining to this medicine is detailed in Chapter 46). The results of either blocking adrenoreceptors on the surface of an effector or preventing transmission by an adrenergic nerve are the same: the normal effector response cannot take place. As many effectors receive dual innervation from both divisions of the autonomic nervous system, the observed drug effect is often opposite to that of stimulation. The effects of adrenoreceptor blockade are summarised in Figure  27.12. Sympatholytic agents that have central activity trigger diminished levels of function: lethargy, depression of mood, reduced anxiety and a loss of libido are examples. It is worth mentioning that there are no natural antagonists or adrenergic nerve blockers present in the body. Antagonism of adrenergic effects is achieved either by parasympathetic innervation of the effector or by decreasing the degree of sympathetic stimulation. A discussion of specific antagonists follows.

α A N TA G O N I S T A C T I O N Mechanism of action Phenoxybenzamine, phentolamine, prazosin, doxazosin, tamsulosin and terazosin are α-adrenergic antagonists. All but the first two medicines are relatively selective to α1  receptors. As stated earlier, presynaptic α2  receptors, when activated, suppress overstimulation of postsynaptic

CHAPTER 27 ADRENERGIC PHARMACOLOGY

Figure 27.12 Adrenergic antagonist effects A summary of antagonistic responses following systemic blockade of each subtype of adrenergic receptor. Blocking presynaptic α2 receptors leads to enhanced transmitter release, while blocking presynaptic β2 receptors inhibits transmitter release. (GI = gastrointestinal.) Synaptic vesicles containing noradrenaline

Mitochondrion containing MAO

Pre-synaptic adrenoceptor

Uptake-1 Post-synaptic adrenoceptors

β1

β2

α1 Antagonist action

β1 Antagonist action

β2 Antagonist action

• Vasodilation (decreases blood pressure) • Pupil constriction

• Cardiac deceleration (decreases heart rate, stroke volume, cardiac output)

• Bronchospasm • Glycogen synthesis

• Increases GI motility and secretions

• Increases GI motility and secretions

• Glycogen synthesis (decreases blood glucose levels) • Promotes micturition

• Inhibition of renin release (inhibits renin-angiotensionaldosterone system)

α1

• Impotence

adrenoreceptors. A consequence of phenoxybenzamine and phentolamine blocking peripheral α2  receptors is tachycardia—an unwanted effect in the context of the clinical indications. Common adverse effects The effects of α  antagonists are shown in Figures  27.13 and  27.14. Common adverse reactions include nasal congestion, postural hypotension, inhibition of ejaculation and a lack of energy. A contraindication for use is known hypersensitivity to any of these medicines.

Clinical considerations Applications for α  antagonists include the control of hypertension, peripheral vascular disease, adrenal medulla tumour (phaeochromocytoma) and urinary retention. In the first three conditions the desired effect is peripheral vasodilation. In using phenoxybenzamine for phaeochromocytoma, β  antagonists are also required to control reflex tachycardia. β  Antagonists are not commenced until after an effective dose of phenoxybenzamine has been obtained. Phentolamine is employed for the treatment of

273

Hypotension

which may progress to

Decreases in blood pressure

resulting in

Decreases in SVR

leading to

Vasodilation

inducing

Blood vessels

Increases in peristalsis

inducing

Gut

causing

Increases in congestion

which may progress to

Diarrhoea

which may become

Nasal congestion

Pupil constriction

inducing

Iris

Ocular congestion

causing

Decreases in blood glucose levels

which may become

Glycogen synthesis

inducing

Liver

block α receptors on

α Antagonists

Micturition

leading to

Increases in voiding

inducing

Urinary bladder

Impotence

which may induce

Inhibition of ejaculation

inducing

Vas deferens muscle

Tachycardia

giving rise to

Overstimulation of postsynaptic receptors

inducing

Presynaptic terminal (α2)

274 S E C T I O N V I A U TO N O M I C P H A R M A C O L O G Y

Figure 27.13  Flowchart showing the effects of α antagonists

Therapeutic effects are shown in white boxes. (SVR = systemic vascular resistance.)

CHAPTER 27 ADRENERGIC PHARMACOLOGY

Figure 27.14  The effects of α antagonists Headache, drowsiness Nasal congestion

Pupil constriction Dry mouth

Vasodilation Decreased blood pressure

Reflex tachycardia

β-blockers were developed to reduce potentially lifethreatening reactions, such as bronchospasm, resulting from β2 receptor blockade. Acebutolol, oxprenolol and pindolol are partial agonists, and will induce sympathomimetic effects when there is low sympathetic tone. Uniquely, nebivolol produces a therapeutic mild vasodilating effect through an interaction with the nitric oxide synthesis pathway. Common adverse effects

Increased peristalsis

Promotes micturition Impotence

The effects of β-blockers are shown in Figures  27.15 and  27.16. Common adverse effects include dizziness, lethargy, insomnia and diarrhoea. Contraindications include known hypersensitivity, heart block, severe heart failure, cardiogenic shock and other severe circulatory disorders, bradycardia with a heart rate of less than 45–50 beats per minute, sick sinus syndrome, atrioventricular block, severe hypotension or uncontrolled heart failure. They should also not be used in people with a history of asthma or chronic obstructive pulmonary disease. Clinical considerations

erectile dysfunction, but it must be used with papaverine or alprostadil to be effective. Selective α  antagonists are used for control of hypertension. All α1  antagonists may cause a rapid fall in blood pressure after the first dose. The patient should be advised to take the first dose at bedtime to reduce the consequences of this effect. The dose is then titrated slowly at two-weekly intervals. This hypotensive effect is likely to be more severe in the older person and in the individual who takes diuretics. It is recommended, therefore, that diuretics be withheld for a few days before commencing an α  antagonist. Postural hypotension and dizziness may occur and the person is advised to get up gradually from a lying or sitting position. Advise individuals to sit down if they become dizzy.

β A N TA G O N I S T A C T I O N Mechanism of action Acebutolol, carvedilol, nadolol, oxprenolol, pindolol, propranolol, sotalol and timolol are non-selective β antagonists or blockers. Atenolol, betaxolol, bisoprolol, esmolol, nebivolol and metoprolol are relatively β1selective (cardioselective) blocking drugs. Cardioselective

Applications for β1 antagonists are to be found in the control of cardiac disease, hypertension, migraine prophylaxis, situational anxiety and thyrotoxicosis. In a seemingly counter-intuitive way, metoprolol, bisoprolol and carvedilol have been used judiciously in the management of heart failure (for details see Chapter  50). There are no clinical applications for β2 antagonists. Abrupt withdrawal of β  antagonists may accentuate angina or produce rebound hypertension, myocardial infarction or ventricular dysrhythmias. It is, therefore, important that β  antagonists be slowly reduced when treatment is to cease. Cardioselective β antagonists may be preferred in conditions such as peripheral vascular disease, Raynaud’s syndrome or diabetes mellitus because of their decreased effect on altering glucose metabolism and causing peripheral vasoconstriction. In diabetes, non-selective β antagonists may mask important signs of hypoglycaemia, including tachycardia and tremor, therefore increasing the severity of the condition. However, β1 selectivity diminishes with higher doses of the medicine.

NON-SELECTIVE ADRENERGIC BLOCKING AGENTS Mechanism of action Celiprolol and labetalol non-selectively block both α and β adrenoreceptors in the periphery.

275

Decreases in angiotensin II production

leading to

Decreased renin release

inducing

Juxtaglomerular apparatus

Hypotension

and then

Decreases in blood pressure

β1

Decreased force of contraction

Decreases in cardiac output & workload

then

inducing

Heart muscle

Decreased heart rate

which may develop into

β1

Diarrhoea

which may lead to

Increased peristalsis

inducing

Gut

β1 β2

block β receptors on

β-Blockers

Hypoglycaemia

which may lead to

Decreases in blood glucose levels

leading to

Glycogen synthesis

inducing

Liver

β2

Bronchoconstriction

inducing

Bronchioles

276 S E C T I O N V I A U TO N O M I C P H A R M A C O L O G Y

Figure 27.15  Flowchart showing the effects of β antagonists

Therapeutic effects are shown in white boxes.

CHAPTER 27 ADRENERGIC PHARMACOLOGY

Figure 27.16  The effects of β antagonists Lassitude, nightmares, depressed mood

Bronchoconstriction

Loss of libido

Decreased heart rate & force of contraction Cardiac disturbances

Decreased blood pressure Decreased blood glucose levels

Increased peristalsis, flatulence

PERIPHERAL ACTIONS OF D O PA M I N E Mechanism of action Dopamine has a role in sympathetic nervous system function. It can stimulate β1  receptors on heart muscle and, at high doses, α  receptors associated with systemic blood vessels. It does this indirectly through the release of noradrenaline from the nerve terminal, rather than by direct receptor stimulation itself. Specific dopamine receptors are associated with the vasculature of a number of vital tissues (kidneys, heart, brain and mesentery) and mediate vasodilation. The effects of dopamine are particularly important during stress. Dopamine indirectly stimulates the heart’s pumping action and directly enhances blood flow through vital tissues. Common adverse effects The effects of dopamine agonists are shown in the flowchart in Figure  27.17. Common adverse effects include effects on cardiac function (e.g.  anginal pain, tachycardia and dysrhythmias), vascular function (e.g.  hypotension or vasoconstriction) and gastrointestinal function (nausea and vomiting). The latter disturbances occur because dopamine stimulates the vomiting centre in the medulla. Clinical considerations

Common adverse effects The adverse effects you expect to observe when using adrenergic blocking agents derive from the antagonist actions shown in Figure  27.12. These medicines are not very well tolerated. Specifically, you would expect adverse effects, such as postural hypotension, bradycardia, lethargy, blurred vision, bronchospasm, urinary retention, swollen ankles, nasal congestion and failure to ejaculate. Clinical considerations These non-selective agents are used as antihypertensive agents; by virtue of their effects on both the heart and vasculature they can be used to treat all grades of hypertension. Individuals should be told that they may feel dizzy upon standing when taking these medicines. They need to get up gradually from sitting or lying positions to minimise this effect.

These effects have clinical application in circulatory shock, which is characterised by deterioration in blood pressure and flow. Dopamine and its derivative, dobutamine, are used in this context to produce positive inotropic effects on the heart, reduce its workload and maintain renal blood flow through the stimulation of both dopamine and adrenergic receptors. The advantage of dobutamine over dopamine is that dobutamine is a direct-acting β1 agonist (see earlier in this chapter). As a consequence, dobutamine produces its inotropic effects without making the heart work harder by increasing its rate (positive chronotropy) as well. Both dopamine and dobutamine are administered in specialty units, which have facilities to enable the monitoring of blood pressure, cardiac rate and rhythm, central venous pressure, cardiac output and oxygenation. Dopamine should be administered in a large vein to prevent tissue necrosis. Neither dopamine nor dobutamine should be administered in strongly alkaline solutions, as such solutions can inactivate them.

277

Increases in organ perfusion

promoting

Arterial vasodilation

inducing

Renal, mesenteric, coronary, cerebral blood vessels

on

Dopamine and β2 receptors

at low doses stimulate

Hypertension

and possibly

which may result in

Increases in cardiac output

leading to

Increases in the force of contraction

Increases in blood pressure

Increases in cardiac workload

inducing

Increases in heart rate

inducing

Heart muscle

on

β1 Receptors

at moderate doses stimulate

Dopamine agonists

Decreases in renal perfusion

inducing

leading to

Increases in SVR

Arterial vasoconstriction

triggering

α1 Receptors

at higher doses stimulate

278 S E C T I O N V I A U TO N O M I C P H A R M A C O L O G Y

Figure 27.17 Flowchart showing the effects of dopamine agonists

Therapeutic effects are shown in white boxes. (SVR = systemic vascular resistance.)

CHAPTER 27 ADRENERGIC PHARMACOLOGY

CLINICAL MANAGEMENT S Y M PAT H O M I M E T I C S Assessment ■■

■■

Obtain baseline vital signs for the person. Report any abnormal findings. These include blood pressure and rate, and rhythm of pulse. Assess colour and temperature of the person’s extremities (for drugs with α1 effects). Conscious state is assessed to determine cerebral perfusion (this is an important consideration if the medicine is administered intravenously for the purpose of maintaining blood pressure). Determine rate, rhythm and depth of respiration. Assess for wheezing if the medicine is used for asthma. Listen to the heart with a stethoscope for dysrhythmias and palpitations (for drugs with α1 or β1 effects). Compare the person’s apical beat with the radial rate. A difference indicates irregularity in rhythm. Determine urinary output and assess for bladder distension (for drugs with α1 effects). Assess whether the person has a history of the following: – glaucoma or prostatic hypertrophy (for drugs with α1 effects); – cardiovascular, cerebrovascular or circulatory disease, hyperthyroidism (for drugs with α1 or β1 effects); – diabetes mellitus (for drugs with α1 or β1 effects). The sympathomimetic agent may intensify the condition, therefore, leading to elevated blood glucose levels from increased glycogen breakdown. The situation would require further clarification with the prescriber.

■■

Determine whether the person is taking monoamine oxidase inhibitors, β-blockers or digoxin, as their effects can be either nullified or intensified by the administration of sympathomimetics.

dosages. Their haemodynamic effects should, therefore, be carefully monitored and recorded. Dosages are then titrated according to the person’s response. A large central vein should be used for the administration of intravenous sympathomimetics to prevent peripheral necrosis. The use of intravenous sympathomimetics is restricted generally to clinical settings in which close monitoring of venous and arterial pressures, electrocardiogram and urinary output can be performed, such as intensive care or coronary care units. ■■

■■

■■

■■

■■

■■

■■

■■

The person’s vital signs will remain within an acceptable range for the person. The person will experience minimal or no adverse effects from the sympathomimetic.

■■

Implementation ■■

■■

Carefully and regularly monitor the person’s vital signs, conscious state and urinary output. Sympathomimetics administered intravenously can produce profound effects on vital organs at small

Regularly monitor the person’s urinary output (for drugs with α1 effects). Prolonged use of a sympathomimetic may lead to a diminished clinical effect, which is caused by a regulatory decrease in receptor numbers.

Medicine education

Planning ■■

Report and record adverse effects of the sympathomimetic, including palpitations, tachycardia (pulse greater than 100 beats/min), tremors or increased glucose levels.

Drugs with β2 effects are usually given by inhalation or nebuliser. Check the methods for inhalation and nebulisation (refer to Chapter 7, Tables 7.17 and 7.18, for a description of methods). Instruct the person on the method of administering cold or flu preparations by nasal spray and drops (refer to Chapter 7, Tables 7.7 and 7.8, for description of methods). Instruct the person that nasal sprays used in excess could lead to a rebound nasal congestion. Directions for dosage should be carefully followed. Excessive use of bronchodilator inhalers could lead to adverse effects, such as tachycardia and skeletal muscle tremor. If asthma symptoms appear to be getting worse, the doctor should be consulted. Instruct the person to read all labels of over-thecounter preparations. Many of these preparations contain sympathomimetics and should not be taken if the person has a history of cardiac disease, diabetes, hypertension or cardiac dysrhythmias.

Evaluation ■■

Examine the person’s response to the sympathomimetic for expected and adverse effects. Continue to monitor

279

280

S E C T I O N V I A U TO N O M I C P H A R M A C O L O G Y

vital signs and other aspects of assessment depending on the medicine used. ■■

■■

Evaluate the effectiveness of the medicine according to its expected action. The expected therapeutic effect may be to treat allergic reactions, anaphylactic shock, asthma or cardiac arrest.

Examine the person’s use of preparations for selfadministration. The use of these preparations may need to be reviewed to ensure safety and effectiveness.

S Y M PAT H O LY T I C S Assessment ■■

■■

Assess the person’s vital signs and conscious state. If the purpose of the sympatholytic is to lower blood pressure, assess difference between lying and standing blood pressure, and dizziness on standing. This gives an indication of postural hypotension. If the medicine is for chest pain, assess its effects on location, intensity and duration.

– congestive cardiac failure, bradycardia, heart block and cardiogenic shock (for drugs that block β1 receptors). These medicines have the effect of slowing the heart, leading to pooling of blood in peripheries and decreased force of contraction. The effects of such medicines can aggravate these disease states. It should be noted, however, that β-blockers have been shown to reduce mortality and hospitalisation in people with stabilised heart failure when used with an angiotensin converting enzyme inhibitor and a diuretic.

■■

■■

■■

β-blockers with a β1-selective effect, such as atenolol or metoprolol, tend to produce less bronchospasm, less peripheral vasoconstriction and fewer alterations to glucose and lipid metabolism than other β-blockers. They may be preferred in people with peripheral vascular disease, Raynaud’s syndrome or diabetes. However, all β-blockers are contraindicated in asthma. β-blockers with an intrinsic sympathomimetic activity, such as oxprenolol or pindolol, may cause less bradycardia and less coldness of the extremities and fewer alterations to lipid profiles than other β-blockers. They may, therefore, be preferred in people with peripheral vascular disease; however, they could be less effective in treating angina and tachydysrhythmias.

The person’s vital signs will remain within an acceptable range for the person. The person will experience minimal or no adverse effects from the sympatholytic.

Implementation ■■

Assess whether the person has a history of the following: – reversible airways disease such as asthma. People with reversible airways disease should not take β-blockers as they may cause severe bronchoconstriction;

■■

Planning

■■

■■

■■

Monitor the person’s vital signs. Report and document changes, such as falls in blood pressure and pulse rate (for drugs that block β1 receptors) or wheezing and dyspnoea (for drugs that block β2 receptors). Report and document any manifestations of dizziness due to vasodilation by α1-blockers. The dosage may need adjustment. Check the person’s lungs for oedema (indicated by crackles) and peripheries for oedema (indicated by pitting mark when skin is pressed). Oedema is caused by vasodilation (an α1-blocking effect) and decreased force and rate of contraction (a β1-blocking effect). If the person has diabetes and is receiving a medicine that has α1- or β2-blocking properties, the dose of insulin or oral hypoglycaemic agent may need adjustment.

Medicine education ■■

■■

■■

■■

If the person is taking a sympatholytic agent for hypertension, teach the person and family how to take blood pressure and pulse so that these vital signs can be monitored at home. Teach the person how to avoid dizziness and postural hypotension, which are conditions that commonly occur with non-selective and selective α antagonists (refer to Chapter 11, Tables 11.3 and 11.6). The person should be strongly advised not to stop taking the medicine abruptly. This can lead to rebound hypertension, angina attacks or rebound tachycardia. People with diabetes should be encouraged to check their blood glucose levels regularly, as β-blocking drugs

CHAPTER 27 ADRENERGIC PHARMACOLOGY

can mask the manifestations of hypoglycaemia. The manifestations masked include tachycardia and anxiety. ■■

Inform the person and family that β-blocking drugs can cause mood changes, such as vivid dreams or depression. If these adverse effects occur, the dosage or medicine may need to be altered.

Evaluation ■■

signs and other aspects of assessment depending on the medicine used. ■■

Evaluate the effectiveness of the medicine according to its expected action. The expected therapeutic effect may include the alleviation of hypertension, dysrhythmias, angina and the complications of acute myocardial infarction.

Examine the person’s response to the sympatholytic for expected and adverse effects. Continue to monitor vital

CHAPTER REVIEW ■■

■■

■■

■■ ■■

■■

■■

Adrenergic receptors are predominately associated with sympathetic effectors. There are four main subtypes of adrenergic receptors: α1, α2, β1 and β2. The catecholamines are important messengers in adrenergic function and comprise noradrenaline, adrenaline and dopamine. Adrenergic pharmacology is concerned with the following drug groups: α agonists and antagonists, β agonists and antagonists. In some instances, relatively selective drug groups have been developed to stimulate or block the subtypes of α and β receptors. This selectivity reduces the side-effects of drug therapy. Agonists may also be called sympathomimetics; antagonists can be called sympatholytics. After the activation of an extracellular receptor, a membrane-bound enzyme catalyses the formation of a second messenger chemical. The second messenger can activate a number of cellular processes, which produce the desired cell response. Second messenger systems may also include an intermediary between the receptor and the membrane-bound enzyme. This intermediary is called a G protein. G proteins can activate or inhibit the membrane-bound enzyme. Sympathomimetics can be used in the management of hypotension, asthma, nasal and ocular congestion, shock and cardiac arrest. Sympatholytics can be used in the treatment of hypertension, glaucoma, cardiac disease and thyroid disease.

REVIEW QUESTIONS 1 Outline the process of adrenergic neurotransmission. 2 Name the major classic chemical messengers involved in adrenergic stimulation of sympathetic effectors. 3 Indicate whether the following effects are related to an action at α1, α2, β1 or β2 receptors and whether the action

is that of an agonist or antagonist: a

elevated blood pressure

b decreased heart rate c

pupil dilation

d bronchodilation e

glycogenolysis

281

282

S E C T I O N V I A U TO N O M I C P H A R M A C O L O G Y

4 State three adverse reactions associated with each of the following adrenergic drug groups: a

α1 agonists

b β1 antagonists c

β2 agonists

d non-selective α and β antagonists 5 Outline the processes involved in a second messenger system that is associated with a G-protein-coupled

adrenoceptor. 6 What are the major adverse effects of sympathomimetics? How would you educate a person who has commenced

therapy with a drug from this grouping? 7 Dopamine produces sympathetic effects in the periphery. Does it induce these effects by stimulating

dopaminergic or adrenergic receptors? For what conditions could dopamine administration be therapeutically beneficial? 8 What are the major adverse effects of sympatholytics? How would you educate a person who has commenced

therapy with a drug from this grouping? 9 Can a person with congestive cardiac failure receive therapy with a β-blocker? Explain your answer with reference

to the mechanism of action of β-blockers. 10 β2 agonists produce bronchodilation as a therapeutic effect and tachycardia and skeletal muscle tremor as adverse

effects. Explain these effects with reference to the mechanism of action of this group.

11 Cecilia Wong is diagnosed with glaucoma. Her drug therapy for this condition comprises the β-blocker timolol

and the α2 agonist apraclonidine. These medicines are administered as eye drops. What are the advantages of this route of administration? 12 Bill Caries is 28 years of age and is suffering from depression. He is being treated for this with a monoamine

oxidase (MAO) inhibitor. What is the role of the MAO in adrenergic nerve function? What would you expect this medicine to do to the synaptic levels of the neurotransmitter noradrenaline? 13 Janet Brown, 44 years old, is suffering from mild persistent asthma. Her medication therapy includes salbutamol,

100–200 µg as required, for an acute asthma attack, and budesonide (inhaled corticosteroid), 100 µg twice daily, for maintenance treatment of asthma. Unfortunately, her asthma condition continues to worsen and her doctor commences her on salmeterol 25 µg twice daily. What type of drug is salmeterol? How does salmeterol compare with salbutamol in terms of use in asthma and duration of action? 14 Daniel Chung, aged 35, is treated for phaeochromocytoma with phenoxybenzamine, with a starting dose of

10 mg daily. What counselling would you offer Mr Chung? After a period of treatment for one week where the dose of phenoxybenzamine has increased to a maintenance dose of 40 mg, the doctor decides to commence Daniel on a course of atenolol therapy. Explain the rationale for using atenolol in conjunction with phenoxybenzamine. Why has the doctor waited one week before starting atenolol? 15 Jan Roos, aged 55 years, is administered dexmedetomidine following surgery to provide sedation. Explain the

rationale for administering the medicine slowly during intravenous administration.

CHAPTER 27 ADRENERGIC PHARMACOLOGY

27 MEDICINE SUMMARY TABLE FAMILY NAME

GENERIC NAME

TRADE NAME(S)

Non-selective sympathomimetics

adrenaline

Anapen preparations Aspen preparations Epipen preparations

dopamine ephedrine metaraminol noradrenaline pseudoephedrine

α1 Agonists

midodrine naphazoline

oxymetazoline

phenylephrine

xylometazoline α2 Agonists

apraclonidine brimonidine

Levophed Chemist’s Own Sinus Relief tablets Logicin Sinus tablets selected Sudafed preparations Sudomyl Gutron Albalon Clear Eyes Murine Clear Eyes Naphcon Forte Dimetapp 12 h Decongestant Nasal Spray Drixine Logicin Rapid Relief Vick’s Sinex Dimetapp PE Nasal Decongestant Albalon Relief Isopto Frin Maxiclear Sinus Relief Minims, Phenylephrine Neosynephrine preparations Nyal Decongestant Nasal Spray Prefrin Robitussin Cold & Flu Robitussin Cold & Flu Jnr Sudafed PE Nasal Decongestant FLO Xylo-POS Nasal Spray Otrivin

dexmedetomidine

Iopidine Alphagan eye drops Alphagan P eye drops Enidin Combigan Catapres Dixarit Precedex

β Agonists (non-selective)

isoprenaline

Isuprel

β1 Agonists (cardioselective)

dobutamine

Dobutrex

+ timolol clonidine

283

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S E C T I O N V I A U TO N O M I C P H A R M A C O L O G Y

FAMILY NAME

GENERIC NAME

TRADE NAME(S)

β2 Agonists

eformoterol

Foradile Foradil Oxis Onbrez

indacaterol salbutamol

+ ipratropium salmeterol + fluticasone terbutaline α Antagonists (non-selective)

phenoxybenzamine phentolamine + aviptadil

α1 Antagonists

doxazosin prazosin

tamsulosin terazosin β-Blockers (non-selective)

acebutolol carvedilol

levobunolol nadolol oxprenolol pindolol propranolol

sotalol

timolol

Airomir Asmol Asthalin Butamol Epaq Respigen Salamol Salapin Ventolin Combivent Duolin Serevent Seretide Bricanyl Dibenyline Dibenzyline Regitine Invicorp Apo-prazo Minipress Pressin Flomaxtra Hytrin ACB Dilasig Dicarz Dilatrend Kredex Vediol

Corbeton Barbloc Visken Cardinol Deralin Inderal Cardol Solavert Sotacor Apo-timol Apo-timop Nyogel Tenopt Timoptol

CHAPTER 27 ADRENERGIC PHARMACOLOGY

FAMILY NAME

GENERIC NAME

TRADE NAME(S)

β-Blockers (cardioselective)

atenolol

Anselol Noten Tenormin Tensig Betoptic Betoquin Bicard Bicor Bispro Bosvate Brevibloc Betaloc Lopresor Metohexal Metrol Minax Myloc CR Slow-Lopresor Toprol-XL Nebilet

betaxolol bisoprolol

esmolol metoprolol

nebivolol celiprolol labetalol

Celol

Centrally acting sympathetic depressant

methyldopa

Aldomet Hydopa Prodopa

Adrenergic nerve blockers

tetrabenazine

Motetis Xenazine

β and α Receptor blockers

Australia only New Zealand only

Hybloc Presolol Trandate

285

C H A P T E R

28

CHOLINERGIC PHARMACOLOGY

LEARNING OBJECTIVES

KEY TERMS

After completing this chapter, you should be able to:

Autonomic nervous system

1

Outline the mechanism of cholinergic nerve stimulation, transmitter release and deactivation.

2

Identify the subtypes and distribution of cholinergic receptors in the body.

Cholinergic receptors

3

List the effects of cholinergic receptor stimulation and from this derive the effects of cholinergic receptor blockade.

Nicotinic receptors

4

Derive the side-effects and clinical applications of cholinergic agents from knowledge of cholinergic receptor distribution and autonomic nervous system effects.

5

Compare aspects of cholinergic and adrenergic pharmacology in terms of similarities and differences.

Cholinergic nerves Muscarinic receptors Parasympathetic nervous system Sympathetic nervous system

Within the periphery all parasympathetic effectors, some sympathetic effectors, all autonomic ganglia and voluntary muscles bear cholinergic receptors. As a consequence, cholinergic agents may affect the function of both divisions of the autonomic nervous system (i.e. the sympathetic and the parasympathetic), as well as the somatic nervous system. Drugs that interact with these receptors, therefore, induce diverse responses.

CHAPTER 28 CHOLINERGIC PHARMACOLOGY

MECHANISMS OF CHOLINERGIC ACTION When a cholinergic nerve is stimulated, the action potential travels to the presynaptic terminal (see Figure  28.1). The action potential triggers the release of the chemical transmitter acetylcholine (ACh) from the synaptic vesicles into the synaptic gap. The transmitter diffuses across the gap, eventually interacting with postsynaptic cholinergic receptors located on the surface of either the effector or the postganglionic cell body. This interaction will trigger either an effector response or a continuation of the nerve impulse along the postganglionic fibre, respectively.

Inactivation of the transmitter is achieved mostly through rapid enzymatic degradation within the synaptic gap. The enzyme responsible for this is called acetylcholinesterase. Acetylcholinesterase is highly specific to acetylcholine and localised to nervous and skeletal muscle tissue. It breaks acetylcholine down into choline and acetate molecules. Chemical conservation comes into play here; nothing is wasted. The choline fragment of the acetylcholine molecule is taken back up into the presynaptic terminal, where it may be reformed as acetylcholine and returned to the synaptic vesicles for reuse. The acetate is used in energy production. Compared with the inactivation of noradrenaline, the neuronal and extraneuronal breakdown of acetylcholine

Figure 28.1 Cholinergic nerve stimulation A summary of events involved in cholinergic nerve stimulation. The action potential travels along the axon until it reaches the nerve terminal (1). Depolarisation of the terminal causes the release of chemical transmitter, acetylcholine (ACh), into the synaptic gap (2). ACh diffuses across the gap and interacts with cholinergic postsynaptic receptors, triggering an effector response (3). In this instance the postsynaptic receptor is a G-coupled receptor. The transmitter is removed from the synaptic gap by an enzyme called acetylcholinesterase, which degrades ACh to choline and acetate (4). Choline is taken back up into the presynaptic terminal to contribute to the synthesis of new transmitter (5). The release of transmitter is also subject to inhibition by presynaptic cholinergic receptors, in this case a G-coupled receptor (6). Such control of transmitter release is known as autoregulation.

1

Action potential Presynaptic terminal

Presynaptic cholinergic receptor

Synaptic vesicles containing ACh 5

6

2 Postsynaptic membrane Postsynaptic cholinergic receptor

3

Response

4

Acetylcholinesterase degrading ACh

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is swift. As a result, the action of acetylcholine is relatively short-lasting. Other relatively non-specific cholinesterases, called pseudocholinesterases, are present in blood and other tissues. Their role is not fully elucidated but appears to be the local modulation of the response to acetylcholine.

Therapy is contraindicated in pregnancy/lactation, where known hypersensitivity exists, or in individuals with serious cardiovascular conditions (e.g.  acute myocardial infarction, unstable angina, recent cerebrovascular accident or dysrhythmia).

CHOLINERGIC RECEPTOR STIMULATION

Clinical applications of nicotinic receptor stimulation include overcoming skeletal muscle weakness (which characterises both motor neurone disease and muscle-wasting disorders) and controlling nicotine dependence associated with cigarette smoking. There are no direct-acting nicotinic agonists used in the treatment of conditions affecting skeletal muscle function. These conditions are best treated using acetylcholinesterase inhibitors (see later in this chapter). People who want to give up smoking are treated using preparations containing nicotine in the form of transdermal patches, lozenges, chewing gum, sublingual tablets, a nasal spray or an oral inhalant (see Chapter 24). Therapy is centred on a behavioural modification program, while the drug treatment decreases the symptoms of nicotine withdrawal. Treatment should be continued for at least 12  weeks, which includes a tapering period. Nicotine dependence is a chronic condition with a high rate of relapse, and many individuals will need to make many attempts to quit before they finally succeed. Individuals who have had multiple attempts to stop smoking may also benefit from combining the patch formulation with the gum. It is important to remember that nicotine is a poison, which needs to be kept away from children and pets. Smoking while taking nicotine preparations can lead to toxicity, resulting in vomiting, palpitations, nausea and chest pain. An adjunct in the management of nicotine dependence is a medicine originally developed as an antidepressant called bupropion. This medicine is discussed in Chapter 24.

Like adrenergic receptors, two main subtypes of cholinergic receptors have been identified. One group of receptors responds to stimulation by nicotine. These are termed nicotinic receptors. The other group responds to a chemical, muscarine, extracted from the toadstool Amanita muscaria. These are termed muscarinic receptors. Both of these subtypes can be activated by acetylcholine but bear subtle structural differences, which have enabled the pharmacologist to develop cholinergic agents specific to one subtype of receptor.

N I C O T I N I C R E C E P TO R S Nicotinic receptors are located centrally, in autonomic ganglia and in the neuromuscular junction of skeletal muscles. Mechanism of action The effects of stimulating these receptors are as follows: • an increase in skeletal muscle tone; • behavioural changes, including feelings of relaxation and wellbeing; • an increase in ‘autonomic tone’ above the resting state of activity of both parasympathetic and sympathetic effectors; • release of adrenaline and noradrenaline from the adrenal medulla. This occurs because the adrenal medulla is, in reality, a modified autonomic ganglion. Common adverse effects The effects of stimulating nicotinic receptors, both wanted and unwanted, are shown in Figures  28.2 and 28.3. Essentially, at the doses absorbed during smoking, nicotine is a stimulant in which many of the peripheral effects (particularly cardiovascular) occur via an increase in autonomic tone. Nicotine treatment, for people trying to quit cigarette smoking, will mimic these effects. Adverse effects include cardiovascular stimulation, headache, nausea and insomnia. Nicotine patches can cause skin reactions such as itching, burning and redness.

Clinical considerations

M U S C A R I N I C R E C E P TO R S Muscarinic receptors are located both centrally and peripherally. Peripheral muscarinic receptors are found on the surfaces of effectors stimulated by cholinergic nerves: that is, all parasympathetic and some sympathetic effectors. More specifically, these receptors are found on the following peripheral tissues: iris, sweat glands, lacrimal glands, digestive glands, myocardium, bronchioles, gastrointestinal tract, urinary tract, liver and sex organs, as well as blood vessels of the skin, genitalia and skeletal muscle. Mechanism of action Five distinct functional subtypes of muscarinic receptors have been identified and are known as M1, M2, M3, M4 and

Hypertension

which may result in

Increases in blood pressure

leading to

Diarrhoea

which may result in

Increases in gastrointestinal motility

and

Increases autonomic nervous system tone

Body relaxation

which may result in and a

Sense of wellbeing

Induces behavioural changes

Increased heart rate

Increases skeletal muscle tone

Muscle spasms

and

Rigidity

and

Increased muscle tension

triggering

which may result in

producing effects including

Sympathetic stimulation

and

Adrenaline & noradrenaline release

triggering

Stimulates adrenal medulla

stimulate nicotinic receptors, which

Nicotinic receptor agonists

Tremor

CHAPTER 28 CHOLINERGIC PHARMACOLOGY

Figure 28.2 Flowchart showing the effects of nicotinic receptor agonists

Therapeutic effects are shown in white boxes.

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Figure 28.3 The effects of nicotinic

receptor agonists

Nausea

Altered heart rate

Sense of wellbeing, body relaxation Initial increase in skeletal muscle tension followed by paralysis

Increased blood pressure Stimulates adrenal medulla

Vomiting, diarrhoea

M5 receptors. The physiological roles of muscarinic receptor subtypes are yet to be fully elucidated. Muscarinic receptor activation may also be involved in nitric oxide production, inflammation and cell proliferation. Muscarinic receptors are also believed to be involved in release of noradrenaline from sympathetic postganglionic fibres and the modulation of responses at autonomic ganglia. Therapeutic applications of these responses are yet to be determined. All five subtypes have been found in the brain. The roles of M4 and M5 receptors are yet to be fully unravelled. These subtypes are implicated in dopaminergic nerve function within the brain, particularly in regions involved in voluntary muscle control and limbic system function, as well as altering blood flow within the cerebral vasculature. Moreover, M4  receptors within the spinal cord appear to have an anti-nociceptive role. At present, there are no therapeutic agents available that target these receptors, so we will concentrate on drugs that act on M1–M3 receptors. M1 muscarinic receptors are associated predominantly with the brain and mediate higher cerebral function; reduction in receptor numbers within the cerebral cortex may be linked to dementias such as Alzheimer’s disease

(see Chapter  37). Indeed, a reduction in the number of presynaptic M2 autoreceptors in these central pathways has also been linked to Alzheimer’s disease. M1 receptors are also found peripherally on the parietal cells of the stomach, and stimulate increased acid secretion. M2 receptors are located on the myocardium; when stimulated they trigger a decrease in the rate and force of contraction of the heart (negative inotropic and chronotropic effects; see Chapter 27). M3 muscarinic receptors are associated with visceral smooth muscle and exocrine glands. Stimulation of these receptors causes the following parasympathetic-like effects: • pupil constriction (miosis) and increased rate of drainage of aqueous humour from the anterior cavity of the eye; • relaxation of gastrointestinal sphincters, increased gastrointestinal motility and an increased secretion of digestive juices (saliva, pancreatic juice and bile); • promotion of micturition and defecation; • promotion of glycogenesis and gluconeogenesis (increases insulin secretion); • promotion of lacrimal secretion (tears); • bronchoconstriction and increased bronchial mucus secretion. Stimulation of these receptors induces the following sympathetic responses: • vasoconstriction of blood vessels associated with the skin and external genitalia; • vasodilation of blood vessels to skeletal muscle; • generalised sweating. Common adverse effects Figures  28.4A, 28.4B and 28.5 show the effects, both therapeutic and adverse, of muscarinic receptor stimulation. Figure  28.6 summarises the agonist effects associated with the stimulation of all types of peripheral cholinergic receptors. Common adverse effects depend on the desired clinical effect but can include bradycardia, hypotension, pupil constriction, sweating, bronchoconstriction, drooling and diarrhoea. Contraindications include intestinal and urinary obstruction. Clinical considerations Acetylcholine, bethanechol, carbachol and pilocarpine are direct-acting muscarinic agonists. Bethanechol and carbachol are only available in Australia. Cisapride is available in New Zealand, but can only be accessed through the Special Access Scheme in Australia.

CHAPTER 28 CHOLINERGIC PHARMACOLOGY

Figure 28.4A Flowchart showing the effects of muscarinic receptor (M1 and M2) agonists Therapeutic effects are shown in white boxes. Muscarinic (M1 & M2) receptor agonists stimulate M1 and M2 receptors, which M1 Enhances cognitive processes

M2

M1 Increases gastric acid secretion

which may lead to

Decreases the rate and force of heart contraction which may progress to

Improved memory

Clinical applications for the muscarinic agonists include the treatment of mydriasis, glaucoma, xerostomia (dry mouth), constipation or other gastrointestinal conditions characterised by diminished gastrointestinal motility/ secretion, urinary retention and tachycardia. When using these medicines for the treatment of glaucoma, it is important to start with a low dose and increase slowly to minimise the incidence of adverse effects. It is possible for miosis to become a permanent effect after long-term use, which can therefore constrict the visual field and impair vision in dim light. If people need to use more than one eye drop at the same time, they should be advised to wait several minutes between using each eye drop (refer to Chapter 7). For medicines such as bethanechol and carbachol, used to stimulate bladder emptying, it is advisable to exclude the possibility of bladder neck obstruction before treatment. The degradation of bethanechol and carbachol by acetylcholinesterase is poor, so these medicines have a longer duration of action compared to acetylcholine and pilocarpine. Cisapride is an indirect-acting cholinergic agent that stimulates the release of acetylcholine from the myenteric plexus. It is available in New Zealand. The release of endogenous transmitter from this plexus stimulates gastrointestinal motility. It interacts with many medicines and with grapefruit juice (see Chapter 16), leading to serious adverse effects, such as prolongation of the Q-T interval for the cardiac rhythm. Advise people to inform their doctor

Bradycardia

and pharmacist that they are taking cisapride. Its use is now restricted to severe reflux oesophagitis and gastroparesis when other therapies have failed, due to several reports of serious adverse effects and death, particularly in relation to the consequences of such drug interactions.

ACETYLCHOLINESTERASE I N H I B I TO R S Mechanism of action Muscarinic agonists specifically stimulate muscarinic receptors and, therefore, mimic the effects of acetylcholine at these receptors, but there is another important group of cholinergic stimulants yet to be discussed. These agents reversibly inactivate the cholinesterase enzymes responsible for the degradation of acetylcholine. Remember from the mechanism of cholinergic action earlier that the predominant form of cholinesterase in nervous and muscle tissue is acetylcholinesterase, whereas pseudocholinesterases are found in blood and other tissues. As a result, the action of acetylcholine in the synapse and in other tissues is prolonged. This group of indirectacting drugs are called acetylcholinesterase inhibitors— otherwise known as anticholinesterases. As it is easy to confuse anticholinesterases with the anticholinergic (antimuscarinic) agents, which are antagonists; we will restrict ourselves to the term acetylcholinesterase inhibitor. Acetylcholinesterase inhibitors enhance the action of endogenous acetylcholine at both nicotinic and muscarinic

291

Bronchoconstriction

which produces

Bronchioles

Increased mucus secretion Increased voiding

inducing

Urinary bladder

Increased sweating

inducing

Sweat glands Gut

Decreased intraocular pressure

Diarrhoea

Eye

Pupil constriction

resulting in

Increased aqueous humour drainage

Defecation progressing to

triggering

Increased secretions (saliva, gastric, bile etc.). Increased peristalsis

inducing

Drooling

Increased glucose storage

which may result in

Increased insulin secretion. Increased glycogenesis

inducing

Pancreas & liver

stimulate M3 receptors on the following tissues

Muscarinic (M3) receptor agonists

Lacrimation

triggering

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Figure 28.4B Flowchart showing the effects of muscarinic receptor (M3) agonists

Therapeutic effects are shown in white boxes.

CHAPTER 28 CHOLINERGIC PHARMACOLOGY

Figure 28.5 The effects of muscarinic

receptor agonists Increased cognition Increased arousal

Decreased heart rate & force of contraction Increased blood flow to skeletal muscles

Pupil constriction, lacrimation, decreased intraocular pressure Salivation Bronchoconstriction Increased mucus secretion Increased gastric juice secretion

Generalised sweating

Micturition

Increased peristalsis & digestive secretions abdominal discomfort

receptors. Therefore, the observed effects (both desired and adverse) will be represented by the agonist actions of both nicotinic and muscarinic receptors shown in Figure 28.6. Common adverse effects The effects, both desirable and undesirable, of the anticholinesterases are shown in the flowcharts in Figures 28.2, 28.4A and 28.4B. Common adverse effects include pupil constriction, hypotension, bradycardia, diarrhoea, muscle twitching, bronchoconstriction, increased lacrimation and sweating. Clinical considerations The principal uses of the acetylcholinesterase inhibitors are in the treatment of postoperative urinary retention, Alzheimer’s disease (see Chapter 37) and conditions of the neuromuscular junction, such as myasthenia gravis and motor neurone disease. They are also used in cases of overdose with either the muscarinic antagonist atropine or muscle relaxants (nicotinic antagonists). Acetylcholinesterase inhibitors include donepezil, edrophonium, galantamine, pyridostigmine, neostigmine and rivastigmine.

The use of donepezil, galantamine or rivastigmine in dementias appears to delay deterioration in cognition for six months in one-quarter to one-half of people affected by this condition, and for one year in about one-fifth of affected people. A full reassessment of cognitive state is carried out after three months of treatment to determine effectiveness. The preparation is stopped if there is no improvement in the cognitive state or if the person experiences severe adverse effects. When giving acetylcholinesterase inhibitors, such as neostigmine, to reverse the effects of neuromuscular blocking agents, atropine or propantheline are also necessary to minimise the muscarinic adverse effects. In using an acetylcholinesterase inhibitor to treat myasthenia gravis, it is important to know how to distinguish between drug-induced weakness and weakness of the disease itself. Medicines used for myasthenia gravis should be taken early in the day, because it is during this time that muscle weakness and fatigue are most severe. Overdosage with an acetylcholinesterase inhibitor may lead to a cholinergic crisis, as demonstrated by excessive sweating, defecation, nausea, vomiting, hallucinations, urination, miosis, salivation, bradycardia and muscle weakness. As it may be difficult to determine the difference between a cholinergic crisis (excessive dose) or a myasthenic crisis (insufficient dose), an edrophonium test can be used as a diagnostic tool. If the weakness improves, it is due to the myasthenia disease and more acetylcholinesterase inhibitor is warranted. However, there is a risk that in cholinergic crises overstimulation of nicotinic receptors at the neuromuscular junction will prevent repolarisation of the end-plate and induce paralysis. Resuscitation equipment should be on hand in these circumstances.

CHOLINERGIC SECOND MESSENGER SYSTEMS While nicotinic receptor activation leads to the opening of ion channels, muscarinic receptor activation involves second messenger systems. Stimulation of M2 receptors on the heart muscle results in a decrease in intracellular cyclic adenosine monophosphate (cAMP) via an inhibition of adenylate cyclase (see Chapter  27). Not surprisingly, the myocardial responses observed following muscarinic receptor stimulation are opposite those seen after β  adrenoreceptor activation. Stimulation of other muscarinic receptor subtypes leads to inositol triphosphate (IP3) production (see Chapter 27), which acts as a second messenger.

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Figure 28.6 Cholinergic agonist effects This figure provides a summary of the effects of systemic stimulation of each subtype of muscarinic receptor, as well as nicotinic receptors located within autonomic ganglia and the neuromuscular junction. (ACh = acetylcholine, GI = gastrointestinal.)

Presynaptic terminal

Synaptic vesicles containing ACh Acetylcholinesterase degrading ACh

Presynaptic cholinergic receptor

M1

Nicotinic

M3

M2

Postsynaptic membrane Nicotinic agonist action

M1 Agonist action

M2 Agonist action

M3 Agonist action

Autonomic ganglia • Increases autonomic tone

• Enhances cognition

• Decreases rate and force of cardiac muscle contraction

• Pupil constriction and increases aqueous humour drainage

Neuromuscular junction • Increases skeletal muscle tone

• Increases gastric acid secretion

• Increases GI motility • Increases secretion of digestive juices • Promotes micturition • Defecation • Increases insulin secretion • Promotes glycogenesis and gluconeogenesis • Lacrimal gland secretion • Generalised sweating • Increases blood flow to skeletal muscle • Bronchoconstriction and increased bronchial mucus secretion

CHOLINERGIC RECEPTOR BLOCKADE

N I C O T I N I C A N TA G O N I S T S

Like adrenergic receptor blockade, cholinergic antagonism prevents the normal effector response occurring. As a result, the usual observed effects of antagonist agents are often opposite to those of stimulation. The effects of cholinergic receptor blockade are represented in Figure 28.7.

Clinically, antagonists at nicotinic receptors have been used for one of two purposes: (1) as ganglionic blockers, to control blood pressure; or (2) as neuromuscular blocking agents given either prior to surgery (e.g. in order to intubate a client) or in the treatment of painful skeletal muscle spasms caused by trauma or disease.

Clinical considerations

CHAPTER 28 CHOLINERGIC PHARMACOLOGY

Figure 28.7 Cholinergic antagonist effects Effects of systemic blockade of nicotinic receptors and each subtype of muscarinic receptor. (ACh = acetylcholine, GI = gastrointestinal.)

Presynaptic terminal

Synaptic vesicles containing ACh Acetylcholinesterase degrading ACh

Presynaptic cholinergic receptor

M1

Nicotinic

M3

M2

Postsynaptic membrane Nicotinic antagonist action

M1 Antagonist action

M2 Antagonist action

Autonomic ganglia • Decreases autonomic tone

• Diminishes cognition

Neuromuscular junction • Skeletal muscle relaxation

• Decreases gastric acid secretion

• Increases rate and force of cardiac muscle contraction

M3 Antagonist action • Pupil dilation and decreases aqueous humour drainage • Decreases GI motility • Decreases secretion of digestive juices • Urinary retention • Constipation • Decreases insulin secretion • Reduces glycogenesis and gluconeogenesis • Lacrimal gland secretion • Decreases generalised sweating (warm, dry skin) • Flushed face • Bronchodilation and reduces mucus secretion

GANGLIONIC BLOCKERS Mechanism of action Ganglionic blockers diminish transmission through autonomic ganglia, reduce sympathetic outflow and induce vasodilation of systemic blood pressure. They have now largely been replaced in the management of hypertension by safer adrenergic antagonists (see Chapter  27). Propantheline has some ganglionic blocker activity but its predominant action is as a muscarinic receptor antagonist (described later in this chapter).

Common adverse effects Common adverse reactions occur as a result of decreased autonomic tone: diminished gastrointestinal motility, urinary retention and impaired accommodation. It is contraindicated in people with serious cardiovascular disease or pyloric stenosis. The effects, both desirable and undesirable, of the nicotinic receptor antagonists are shown in Figures 28.8 and 28.9. Clinical considerations Blood pressure should be regularly checked to determine the effect of ganglionic blockers on the systemic

295

Hypotension

which may result in

Decreases in blood pressure

Decreases in gastrointestinal motility

Constipation

which may result in

leading to

Urinary retention

Decreases autonomic nervous system tone

Impaired ocular accommodation

Blocks adrenal medulla

Inhibition of adrenaline & noradrenaline release

which may result in

block nicotinic receptors, which

Nicotinic receptor antagonists

Muscle relaxation & paralysis

triggering

Decreases skeletal muscle tone

296 S E C T I O N V I A U TO N O M I C P H A R M A C O L O G Y

Figure 28.8 Flowchart showing the effects of nicotinic receptor antagonists

Therapeutic effects are shown in white boxes.

CHAPTER 28 CHOLINERGIC PHARMACOLOGY

Figure 28.9 The effects of nicotinic

receptor antagonists

Impaired accommodation

after it is injected: the muscles of the affected person’s body, from toes to the scalp, go into a spasm. The spasms are very noticeable and are known as muscle fasciculations. This response lasts only a second or so and then the person goes flaccid. Common adverse effects

Decreased blood pressure

Suppresion of adrenal glands

Muscle relaxation & paralysis Decreased peristalsis

Urinary retention

circulation. Urine output and gastric motility also need to be monitored.

Neuromuscular blocking agents Neuromuscular blocking agents that act at the neuromuscular junction, as opposed to the true muscle relaxants discussed in Chapter  38, are classified as either depolarising or non-depolarising.

DEPOLARISING NEUROMUSCULAR BLOCKING AGENTS Mechanism of action Suxamethonium (also known as succinylcholine) is the only clinical representative of a depolarising nicotinic agonist. Suxamethonium is similar to acetylcholine and acts as an acetylcholine agonist on nicotinic receptors. Unlike acetylcholine, suxamethonium is not destroyed by acetylcholinesterase; therefore, when it acts on the nicotinic receptors its action is sustained. This prevents repolarisation of the end-plate, and paralysis ensues. The action of suxamethonium as an agonist can be seen immediately

Suxamethonium may cause muscular pain during administration as well as when the person returns to consciousness; this effect may be due to the muscle fasciculations. Suxamethonium can also cause hyperkalaemia, which can result in cardiac arrest, and raised intraocular pressure. Another problem occasionally seen with suxamethonium is that of malignant hyperthermia, which results in severe muscle rigidity and body temperatures of over 41  °C. The apparent cause of this condition is the release of large numbers of calcium ions into the sarcoplasm. This increases the metabolic activity of all the body’s skeletal muscle, resulting in the muscle rigidity and hyperthermia. This is a life-threatening condition and requires prompt treatment to reduce the body temperature and to reverse the muscle spasm. Body temperature can be lowered by conventional methods. and the muscle spasm relieved by the use of intravenous dantrolene (see Chapter 38). Malignant hyperthermia does not necessarily occur during surgery but can happen postoperatively in the ward, hence the need for close surveillance of individuals after anaesthetic procedures. Those known to be at risk can be given dantrolene prophylactically. Suxamethonium is contraindicated in narrow-angle glaucoma, in penetrating eye injuries and in burns patients. Evidence of pharmacogenetic variation in pseudocholinesterase levels (see Chapter  19) is also a contraindication, as is a known drug hypersensitivity. Clinical considerations The action of suxamethonium is terminated by the enzyme pseudocholinesterase after about four to five minutes, so if sustained paralysis is required the medicine must be administered by a drip set. Other longer-acting neuromuscular blocking agents are normally used for prolonged paralysis. As suxamethonium acts rapidly, it is useful in abolishing the gag reflex and enables speedy intubation of the patient. It is also the preferred neuromuscular blocking agent for electroconvulsive therapy. It does not require a reversal agent because its duration of action is very short. However, severe bradycardia may occur after a second dose of suxamethonium, especially

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in children. In these situations, unless contraindicated, atropine can be administered prophylactically to reduce the risk of bradycardia. Warn people that they may have muscle pains for about 24 hours after the procedure, particularly in the neck, shoulders and chest.

NON-DEPOLARISING NEUROMUSCULAR BLOCKING AGENTS

safety—to people with circulatory, hepatic and renal problems. Pancuronium does not cause histamine release but can produce tachycardia. Vecuronium does not produce tachycardia, nor does it induce histamine release. It is commonly used during and following open-heart surgery. These medicines are contraindicated where there is known evidence of hypersensitivity. Clinical considerations

Mechanism of action Non-depolarising blockers are antagonistic towards acetylcholine and completely block the receptors. This antagonism results in non-depolarisation of the motor end-plate, and complete paralysis sets in without any fasciculations occurring. Non-depolarising agents comprise atracurium, cisatracurium, mivacurium, pancuronium, pipecuronium, rocuronium and vecuronium. Cisatracurium is a stereoisomer of atracurium. It is available in Australia but not in New Zealand. The prototype drug in this class is tubocurarine. Its clinical use has been superseded by these newer, safer medicines. Tubocurarine use remains of historical interest and is outlined in Chapter 1. The non-depolarising agents have an advantage over suxamethonium in that their action can be reversed. As they compete with acetylcholine for the receptors, their reversal can be attained by increasing the amount of acetylcholine at the neuromuscular junction. This is done by giving an acetylcholinesterase inhibitor, such as neostigmine. Common adverse effects Some non-depolarising neuromuscular blocking agents, such as mivacurium, rocuronium and atracurium, can induce histamine release, which can lead to a drop in blood pressure as well as bronchospasm. Atracurium is unusual in that it is metabolised by a chemical process (i.e. enzymes are not involved). Therefore, it can be given—with comparative

The non-depolarising agents vary somewhat in onset and duration of action. The pharmacokinetic profile of each drug determines which is chosen in a particular clinical situation (see Table 28.1 for examples). When the effects of neuromuscular blockade are reversed,  the return of normal neuromuscular function should be assessed. If these medicines are administered long-term to a critically ill person, they must be accompanied by a suitable sedative, such as a benzodiazepine. It is important to keep in mind that the non-depolarising agents do not have any sedative or analgesic effects and should be administered only with adequate anaesthesia. Emergency cardiac and respiratory equipment and medicines (e.g. endotracheal intubation, oxygenation, ventilation and adrenaline) must be available in case respiratory depression or circulatory collapse occurs. Non-depolarising agents, for example atracurium and cisatracurium, require a reversal drug in the form of an acetylcholinesterase inhibitor, such as neostigmine. Since acetylcholinesterase inhibitors can produce profound muscarinic effects (e.g.  hypotension, bradycardia and increased gastric motility), a muscarinic antagonist such as atropine or glycopyrrolate may be administered to reduce the likelihood of their occurrence. In Australia, glycopyrrolate is available on the Special Access Scheme. As myopathy can occur with prolonged use (of greater than 48 hours), neuromuscular function is monitored very closely.

Table 28.1  Pharmacokinetic profiles of some non-depolarising neuromuscular blocking agents

MEDICINE

ELIMINATION HALF-LIFE (MIN)

TIME TAKEN TO ONSET OF MUSCLE RELAXATION

DURATION OF EFFECT (MIN)

atracurium cisatracurium mivacurium pancuronium rocuronium vecuronium

20 10 2 120 73 60–80

120 sec 120 sec 120–150 sec 45–90 sec 60 sec 90–120 sec

35–40 20–40 15–20 25 30–40 20–30

Australia only

CHAPTER 28 CHOLINERGIC PHARMACOLOGY

Atracurium, cisatracurium and mivacurium can be used in renal and hepatic impairment. On the other hand, pancuronium, rocuronium and vecuronium produce prolonged action in severe renal and hepatic impairment. Atracurium, cisatracurium, mivacurium and vecuronium have little effect on heart rate and are useful medicines to administer during heart surgery. Conversely, pancuronium and rocuronium can produce tachycardia and are less beneficial for treatment during heart surgery. An antidote to excessive neuromuscular blockade by rocuronium or vecuronium is available. It is called sugammadex. It acts by forming a complex with the drug, thereby reducing the amount available to bind to nicotinic receptors.

cholinergic agents but are more correctly called antimuscarinic agents. The group consists of the following medicines: atropine, hyoscine and hyoscyamine (the Atropa belladonna alkaloids, available in Australia), cyclopentolate, darifenacin, diphemanil, glycopyrrolate, ipratropium, homatropine, mebeverine, oxybutynin, propantheline, solifenacin, tiotropium, tolterodine and tropicamide. Diphemanil is only available in New Zealand. Darifenacin is relatively selective for M3  receptors and is used in the management of urinary dysfunction. At this time it is only available in Australia.

M U S C A R I N I C A N TA G O N I S T S

The effects of the muscarinic antagonists are shown in Figures  28.10A, 28.10B and 28.11. Common adverse reactions can be derived from Figure  28.7 and include drowsiness, tachycardia, constipation, blurred vision, dry mouth and facial flushing. They are contraindicated

Mechanism of action Muscarinic antagonists block muscarinic receptors. Muscarinic antagonists are generally known as anti-

Common adverse effects

Figure 28.10A Flowchart showing the effects of muscarinic (M1 and M2) antagonists Therapeutic effects are shown in white boxes. Muscarinic (M1 & M2) receptor antagonists block M1 and M2 receptors, which

M1 Decreases cognitive processes

which may lead to

Decreased arousal

resulting in

Sedation

M1 Decreases gastric acid secretion

M2 Increases the rate and force of heart contraction

which may progress to Tachycardia

299

Bronchodilation

which produces

Bronchioles

Reduced mucus secretion

Urinary retention

which may result in

Decreased voiding

inducing

Urinary bladder

Warm dry skin

which may result in

Decreased sweating

inducing

Sweat glands

Facial flushing

which may result in

Decreased insulin secretion. Decreased glycogenesis

inducing

Pancreas & liver Gut

Dry mouth

triggering

Decreased secretions (saliva, gastric, bile etc.). Decreased peristalsis

inducing

Constipation

Decreased glucose storage

which may result in

Vasodilation

inducing

Skin blood vessels (head, neck)

block M3 receptors on the following tissues

Muscarinic (M3) receptor antagonists

Reduced gastric juice secretion

Increased intraocular pressure

which may result in

Decreased aqueous humour drainage

Blurred vision

causing

Pupil dilation

inducing

Eye

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Figure 28.10B Flowchart showing the effects of muscarinic (M3) antagonists

Therapeutic effects are shown in white boxes.

CHAPTER 28 CHOLINERGIC PHARMACOLOGY

Figure 28.11 The effects of muscarinic

antagonists

Decreased cognition Sedation Facial flushing Increased heart rate

Decreased peristalsis & secretions

Pupil dilation & increased intraocular pressure Dry mouth Bronchodilation & inhibition of mucus secretion Decreased gastric juice secretion

Urinary retention

in obstructive diseases of the gastrointestinal tract and bladder, as well as cardiospasm. Clinical considerations These medicines have widespread clinical applications: • as antispasmodics, to counteract gastrointestinal muscle spasm; • as antiulcerants, because they suppress gastric acid secretion; • as antidysrhythmics, to counteract bradycardias; • as antiemetics, to treat motion sickness, because of their central action; • as mydriatics/cycloplegics, for ophthalmic procedures (see Chapter 83); • as premedication agents, given prior to anaesthesia; • as antiasthma agents or maintenance therapy for chronic obstructive pulmonary disease, because they enhance bronchodilation and (theoretically) suppress respiratory mucus production; • as treatment for urinary frequency, enuresis and urinary urge incontinence.

It is important to ensure that people with glaucoma, urinary retention or gastrointestinal obstruction avoid taking muscarinic antagonists. As drowsiness is a common adverse effect with these medicines, people should be advised to avoid driving or operating machinery after administration. They may also need assistance with daily activities. It is recommended for people who develop mydriasis (pupil dilation), which occurs mainly from the use of eye drops, to wear sunglasses in bright light to prevent the light sensitivity associated with photophobia. Vital signs, bowel sounds and movements, and urine output should be regularly monitored. Atropine, hyoscyamine, glycopyrrolate, ipratropium, homatropine, solifenacin, tropicamide, tiotropium, tolterodine and cyclopentolate all act both centrally and peripherally. At low doses, mebeverine’s effects are restricted to the periphery. Hyoscine and propantheline are less active orally and tend to produce fewer central nervous system effects. Care must be taken with using muscarinic antagonists in older people because they are particularly sensitive to adverse effects, including confusion. These medicines often cause a dry mouth, which may reduce the person’s ability to adhere to a fluid restriction regimen in heart failure and renal failure. People need to be counselled about the importance of maintaining their fluid restriction regimen during therapy with these medicines. The frequent use of mouth washes and a fluid balance diary may help (see also Table 11.9 in Chapter 11).

CHOLINERGIC NERVE BLOCKADE Botulinum toxin is produced by Clostridium botulinum bacteria and is well known as a cause of severe food poisoning. The toxin acts by blocking the release of acetylcholine from somatic motor nerves, causing skeletal muscle paralysis. It has clinical applications in the treatment of blepharospasm and strabismus (see Chapter 83).

CHOLINERGIC ACTION IN THE CNS Acetylcholine is a prominent neurotransmitter in the brain. Cholinergic nerves form a part of motor and sensory pathways, and have a role in the control of wakefulness, cognitive and intellectual functioning, as well as behaviour. Generally speaking, the dose of the cholinergic agent will greatly affect the kind of effects observed. At standard therapeutic doses, antimuscarinic agents lower the levels

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of arousal, resulting in sedation. However, if the dose is increased, excitement may be observed. Benztropine, benzhexol, biperiden, orphenadrine and procyclidine are centrally acting antimuscarinic agents used to control the motor disturbances associated with Parkinsonism (see Chapter  37) and antipsychotic drug therapy (see Chapter 34). As for cholinergic agonists, light-headedness and dizziness have been reported. Moreover, agonists can induce motor disturbances such as tremor and rigidity. Procyclidine is only available in New Zealand, while benzhexol is available in Australia.

CHOLINERGIC SIDE-EFFECTS Again, as in adrenergic pharmacology, the side-effects of cholinergic agents derive from the distribution of these receptors around the body. Cholinergic agents are selected clinically according to a particular desired action. All the

other observed effects are the side-effects. Learning about all effects related to agonist action at a particular cholinergic receptor subtype will enable you to recognise both clinical effects and side-effects of the whole drug class. As a general rule, the effects of antagonists will be the opposite of those of the agonist. You will have an opportunity to practise this approach in the study questions at the end of this chapter. The identification of muscarinic receptor subtypes will lead to the further development of drugs (agonists and antagonists) with specificity for one particular subtype. The clinical consequence of this will be a reduction in undesirable drug effects. Side-effects are also dramatically reduced by administering cholinergic medications directly to the required site of action rather than systemically. An example of this is inhaling an antimuscarinic agent, such as ipratropium, into the lungs as part of the therapy for asthma.

CLINICAL MANAGEMENT ACETYLCHOLINESTERASE INHIBITORS Assessment ■■

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The person should be reviewed for a history of peptic ulcer, hypotension, coronary artery disease, asthma, epilepsy or Parkinsonism. The prescriber should be contacted and the order verified, as acetylcholinesterase inhibitors are contraindicated in these conditions. Assess the person for the presence of gastrointestinal conditions, such as intestinal obstruction, acute inflammatory bowel disease, peritonitis, and for surgery involving the bladder and gastrointestinal tract. Extreme caution should be used in these conditions, as acetylcholinesterase inhibitors can intensify the symptoms. If the acetylcholinesterase inhibitor is being administered for Alzheimer’s disease, a full assessment of cognitive state is undertaken at the start of treatment to obtain baseline information. Obtain a set of baseline observations for vital signs. Subsequent observations are compared with the baseline values.

Planning ■■

– for myasthenia gravis, the person will have increased neuromuscular strength;

Depending on the therapeutic use of the acetylcholinesterase inhibitors:

– to stimulate gastric motility or for urinary retention, the person will have increased bladder and gastrointestinal tone; – to reverse paralysis post surgery, the person will regain normal neuromuscular strength.

Implementation ■■

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On intravenous administration of these medicines, the person should have vital signs and level of consciousness regularly checked every 15 minutes. Atropine (0.6 mg intravenously) is kept on hand to reverse any decrease in pulse. Be prepared for any decrease in pulse, blood pressure or respiration, or any progressive change in the depth and rhythm of respiration. In this instance, the medicine should be withheld and the prescriber notified. Be aware of the possibility of cholinergic crisis (overdose). Symptoms include muscle weakness, abdominal cramps, ocular pain, bronchoconstriction, increased salivation and diarrhoea. These effects can be reversed by the administration of atropine or propantheline. However, atropine and propantheline should not be routinely given at the beginning of

CHAPTER 28 CHOLINERGIC PHARMACOLOGY

instructed not to drive at night due to their poor visual perception.

acetylcholinesterase inhibitor treatment because they may mask the signs of an overdose. ■■

Monitor for the presence of unwanted effects, such as excessive salivation, involuntary defecation, urinary urgency, abdominal cramping, wheezing and vomiting.

Evaluation ■■

– for myasthenia gravis, the person will have improved neuromuscular strength;

Medicine education ■■

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Instruct the person with myasthenia gravis to take the medicine at the specified times to avoid muscle weakness.

– for lack of gastric motility or urinary retention, the person will have increased bladder and gastrointestinal tone;

Advise the person on how to determine changes in muscle strength. The person should be able to determine the difference between the effect of an underdose or overdose of the medicine. An explanation of the symptoms of a cholinergic crisis should help the person to determine the difference. To avoid tripping, unnecessary obstacles should be removed from hallway areas. Passageways around the home should be well lit. These people should be

Depending on the therapeutic use of the acetylcholinesterase inhibitor:

– to reverse muscle relaxation post-surgery, the person will regain normal neuromuscular strength; – to improve the state of cognition in a person with Alzheimer’s disease. ■■

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Evaluate the stability of the person’s vital signs and conscious state following administration of the medicine. Observe, document and report the presence of adverse effects.

MUSCARINIC AGONISTS Assessment ■■

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Refer to information contained in the clinical management of acetylcholinesterase inhibitors. ■■

Planning ■■

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Anticipate the effect of the medicine to improve the condition for which it is intended. This effect may involve the stimulation of gastric motility, improvement in bladder tone or the reduction of intraocular pressure. Ensure that atropine is close at hand in case the person has a cholinergic crisis. Adult dose is 0.6–1.2 mg intravenously.

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Implementation ■■

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Monitor the person’s vital signs for decreases in pulse rate and blood pressure. When using these medicines for gastric atony, listen for bowel sounds with a stethoscope. Report and document the level of peristaltic movement. Auscultate breath sounds for crackles (fluid secretions in lungs) and wheezing (narrowed airway passages). Report and document adverse findings.

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Give oral muscarinic agents one hour before and two hours after meals to reduce the incidence of nausea and vomiting. When using these medicines to treat urinary retention, monitor fluid balance for level of urinary output. Cisapride interacts with many medicines and with grapefruit juice, which could lead to serious adverse effects. People need to be reminded to tell their doctor and pharmacist that they are taking cisapride every time they start a new medicine. These medicines have a rapid onset of action when administered parenterally. As a desire to urinate may develop quickly, ensure that a bedpan is next to the bed or that the person is close to the bathroom. People receiving these medicines are prone to diaphoresis (excessive sweating), so the bed linen may need to be changed regularly.

Medicine education ■■

Instruct the person to report adverse effects such as dizziness or a slowing of the pulse rate (show them how to take their own pulse if going home with these medicines).

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Teach people various methods to avoid problems associated with dizziness and postural hypotension. One strategy involves moving slowly from a lying to a standing position. (Refer to Chapter 11, Tables 11.3 and 11.20, for other strategies.) When these medicines are used as eye preparations, the person should be instructed on the correct method of instillation. (See Chapter 7, Table 7.3, for further information.) As these eye preparations can cause blurred vision, the person should be instructed not to drive or work with dangerous tools (power saws, drills, hammers, etc.) immediately after instillation.

Evaluation ■■

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After systemic administration, people should be observed for a sudden drop in blood pressure, decreased pulse rate, changes in rate, rhythm and depth of respiration, and abdominal cramps. These symptoms could indicate a cholinergic crisis, requiring the administration of atropine. To evaluate the presence of residual urine after the use of these medicines for urinary retention, a urinary catheter may be inserted after voiding. After topical ophthalmic use of muscarinic agents, the doctor will check the intraocular pressure with a tonometer to evaluate their effectiveness in glaucoma.

M U S C A R I N I C A N TA G O N I S T S Assessment ■■

Prior to administration, the person’s history should be checked for documentation of glaucoma, hypertension, coronary artery disease, urinary obstruction, renal disease, respiratory conditions and gastrointestinal obstruction. These medicines raise the heart rate, leading to aggravation of conditions affecting the heart. Secretions of the respiratory tract glands are depressed, and this action can affect respiratory conditions. The mydriasis produced by these medicines can block aqueous humour drainage, leading to raised intraocular pressure. They also decrease gastrointestinal motility and secretions, and urinary bladder tone, thus aggravating gastrointestinal obstruction and renal conditions.

Implementation ■■

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Care must be taken with using muscarinic antagonists in older people because these individuals are particularly sensitive to adverse effects, including confusion, blurred vision, dry mouth and constipation. The person’s baseline observations are obtained and compared with those obtained following administration. Assess bowel sounds and urinary output prior to administration.

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Planning ■■

Anticipate the effect of the medicine to improve the condition for which it is intended. This effect may involve a decrease in the person’s secretions preoperatively, decrease in gastrointestinal spasms, bradycardia, treatment of asthma or alleviation of motion sickness.

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Regularly monitor the person’s vital signs. Tachycardia is a common adverse effect. Regularly monitor bowel sounds if the medicine is used to modify gastrointestinal function. An absence of bowel sounds signifies decreased gastrointestinal motility (paralytic ileus). Check for constipation due to decreased gastrointestinal motility. Advise the person to eat foods that are high in fibre, to drink adequate fluids and to exercise (if able). (Refer to Chapter 11, Table 11.4, for further information about action to take for constipation.) Monitor the person’s fluid balance. Report any decrease in urine output. These medicines often cause a dry mouth, which may reduce the person’s ability to adhere to a fluid restriction regimen in heart failure and renal failure. If these agents are given as part of preoperative medicine, the person should remain in bed, and the side rails should be raised to prevent falls. When instilling these medicines into the eye, the person should be allowed to rest comfortably until the effects of mydriasis and cycloplegia wear off. These effects prevent the person from accommodating for near vision and, therefore, increase the person’s risk of injury. Do not administer less than 0.25 mg atropine intravenously in adults, as a paradoxical slowing of the heart may occur with a low dosage.

CHAPTER 28 CHOLINERGIC PHARMACOLOGY

Medicine education ■■

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Instruct the person with glaucoma, urinary retention or gastrointestinal obstruction to avoid antimuscarinic agents. These people should alert their pharmacist about their condition so that any over-the-counter preparations sought out are thoroughly checked beforehand. Have food items such as hard lollies, drinks, ice chips or chewing gum available if the mouth becomes dry. (See Chapter 11, Table 11.9, for other measures that can be used with a dry mouth.) If the person is using ipratropium inhalation as asthma therapy or maintenance treatment for chronic obstructive pulmonary disease, ensure that the person is familiar with the technique of administration. (Refer to Chapter 7, Table 7.17, for further information.) Caution the person to comply with the recommended number of inhalations per day to prevent adverse effects of therapy. If the person is using tiotropium powder by inhalation for maintenance treatment of chronic obstructive pulmonary disease, ensure that the person understands that this medicine is not helpful in relieving immediate symptoms. β2 Agonists such as salbutamol are used for this purpose. Make sure that the person knows how to use the HandiHaler inhalation device that administers the required dose. Instruct the person to open the HandiHaler device and insert the tiotropium capsule. The mouthpiece should be closed firmly against the base until a click is heard. The piercing button is pressed once until it is flat flush against the base, and then released. The person should breathe out completely. Then, with the HandiHaler in the mouth, the person should breathe in deeply until the lungs are full. The

capsule should vibrate or rattle during this process. For a person to take the full daily dose of tiotropium, two inhalations should be made from the same capsule. Advise the person that tiotropium may cause eye pain or discomfort, blurred vision or visual halos. ■■

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Instruct the person not to drive or operate machinery following administration of these medicines. Drowsiness is a common adverse effect. Advise the person with mydriasis (pupil dilation) to wear sunglasses in bright light due to photophobia. (See Chapter 11, Table 11.13, for other measures that may be used with photophobia.) Encourage the person to use artificial tears for dry eyes. Contact lenses will be fairly uncomfortable to wear during this time. Encourage the person to avoid hot environments and strenuous exercise in these conditions, as inhibition of sweat gland activity can lead to raised body temperature.

Evaluation ■■

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Evaluate the person’s response to the antimuscarinic agent depending on the purpose of administration. Determine whether adverse effects such as constipation, increased pulse rate or urinary retention remain a problem. For people using an ipratropium inhaler, evaluate the therapeutic response by listening to the person’s chest and the use of peak flow meters. Also evaluate the person’s long-term tolerance for the preparation. Note that peak flow meters cannot be used in children under the age of six years because they are unable to perform reproducible peak flow measurements.

N I C O T I N I C A N TA G O N I S T S ( N E U R O M U S C U L A R B LO C K I N G A G E N T S ) Assessment ■■

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Assess baseline vital signs and compare with subsequent observations. The presence of renal, liver, cardiac or respiratory disease is reported and documented because of the possibility of adverse effects associated with these systems. Atracurium, cisatracurium and mivacurium can be used in renal and hepatic impairment. On the other hand, pancuronium, rocuronium and vecuronium produce prolonged action in severe renal and hepatic impairment and should be avoided in these conditions.

Note that suxamethonium is contraindicated in severe burns, severe trauma and neurological lesions, as these conditions cause the release of potassium from damaged muscle and nerve cells, leading to a massive rise in serum potassium levels (around 10–15 mmol/L), which may cause cardiac dysrhythmias and cardiac arrest.

Planning ■■

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The person’s vital signs will remain within acceptable limits. Full neuromuscular blockade is achieved for the duration of the procedure or intended therapy.

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There is no indication of adverse effects following the use of these medicines.

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Implementation ■■

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Monitor vital signs carefully and regularly. These medicines can produce tachycardia. Hypotension is also a possibility through the release of histamine.

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Body temperature must be regularly monitored, as these medicines can cause malignant hyperthermia.

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Following administration of suxamethonium severe bradycardia may occur after a second dose, especially in children. Unless contraindicated, atropine can be administered prophylactically to reduce the risk of bradycardia. Following administration of suxamethonium warn people that they may have muscle pains for about 24 hours, particularly in the neck, shoulders and chest. Atracurium, cisatracurium, mivacurium and vecuronium have little effect on heart rate and are, therefore, useful medicines to administer during heart surgery. It is vital to assess for return of neuromuscular function when the effects of blockade are reversed. Recovery occurs in longer muscle groups first, followed by recovery in short muscle groups. For example, the intercostal muscles, larynx, diaphragm, neck, shoulder and abdominal muscles recover first. These groups will then be followed by recovery of the tongue, pharynx, limbs, and finally the oculomotor muscles, eyelids, mouth, facial muscles and fingers. Monitor the person’s urinary output. Except for atracurium and vecuronium, most of these medicines are excreted by the kidneys. Ensure that the person maintains an adequate output.

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These medicines are usually administered only by an anaesthetist because the person is intubated. An acetylcholinesterase inhibitor is administered following non-depolarising competitive agents to reverse their effects. Usually, neostigmine is used because of its long duration of action. Atropine (an antimuscarinic agent) is administered either before or in conjunction with neostigmine to minimise the muscarinic effects (bradycardia, hypotension, bronchoconstriction). The person should be connected to a cardiac monitor during the reversal process, as neostigmine may cause dysrhythmias. If bradycardia develops from the neostigmine/ atropine combination, glycopyrrolate, a long-acting antimuscarinic agent, can be administered to reverse the bradycardia. Bradycardia is due to the long duration of action of neostigmine compared with that of atropine. If profound hypotension occurs following the administration of neuromuscular blocking agents, a sympathomimetic (e.g. adrenaline) may need to be administered.

Evaluation ■■

Monitor electrolyte levels. Electrolyte imbalances can lead to cardiac arrest because of circulatory collapse. People usually have an endotracheal breathing tube inserted following administration of these medicines. These breathing tubes are subsequently attached to some form of ventilation, such as an oxygen rebreathing bag or a mechanical ventilator. Nevertheless, it is important to auscultate for breath sounds to ensure equal air entry in both lungs. Listen for a wheeze, which is indicative of bronchospasm.

If the person is receiving these medicines on a longterm basis for muscle paralysis, adequate sedation should also be used. Benzodiazepines are commonly employed. Ensure that the person is adequately sedated by examining the vital signs. Inadequate sedation is shown by tachycardia and hypertension.

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It is important regularly to evaluate the person’s recovery from neuromuscular blockade. General evaluation parameters include the ability to open eyes wide, sustained protrusion of tongue, sustained hand grip, sustained head lift (for at least five seconds) and the ability to cough effectively. Respiratory parameters include a vital capacity of at least 15–20 mL/kg using a peak flow meter. A peripheral nerve stimulator can be attached at the wrist to stimulate the ulnar nerve. If symptoms of neuromuscular blockade persist, the reversal agent neostigmine must be kept up until symptoms disappear. Vital signs should continue to be monitored and evaluated against the baseline levels.

CHAPTER 28 CHOLINERGIC PHARMACOLOGY

CHAPTER REVIEW ■■

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Cholinergic nerves are associated with the activation of all parasympathetic effectors, some sympathetic effectors, skeletal muscles and all autonomic ganglia. Cholinergic action at these synapses tends to be short-lived, and most of the deactivation of acetylcholine (ACh) occurs in the synaptic gap through the action of cholinesterases. There are two subtypes of cholinergic receptors: nicotinic and muscarinic. Most nicotinic receptors are associated with the neuromuscular junction and the autonomic ganglia. The remainder are predominately muscarinic; distributed on autonomic effectors and on nerve cells within the CNS. Drug groups associated with cholinergic action consist of nicotinic agonists and antagonists, muscarinic agonists and antagonists, as well as the acetylcholinesterase inhibitors (drugs that inhibit the action of the degradative enzyme, thus prolonging the action of acetylcholine in the synapse). Muscarinic antagonists are sometimes called anticholinergic agents, but are more correctly known as antimuscarinic agents. Depending on their site of action, nicotinic antagonists are known as ganglionic blockers or neuromuscular blocking agents. Acetylcholine plays a key role in central nervous system function. Muscarinic antagonists tend to lower the levels of arousal, leading to drowsiness and sedation. Muscarinic agonists tend to induce light-headedness and motor disturbances. Cholinergic agonists can be used in the treatment of cigarette-smoking dependence, muscle weakness, glaucoma, gastrointestinal disorders characterised by diminished motility, and urinary retention. Cholinergic antagonists can be used in the management of asthma, cardiac disease, in gastrointestinal disorders and as premedication prior to surgery.

REVIEW QUESTIONS 1 Outline the process of cholinergic neurotransmission at a synapse. 2 Compare and contrast the characteristics of cholinergic and adrenergic neurotransmission. 3 Indicate whether the following effects are related to an action at nicotinic or muscarinic receptors and whether

the action is that of an agonist or antagonist: a

pupil constriction

b skeletal muscle relaxation c

decreased gastrointestinal secretions

d decreased autonomic tone e

increased intraocular pressure

4 State the locations of M3 muscarinic receptors around the body. 5 State the major adverse effects of muscarinic agonist agents. 6 State three conditions that are contraindications for antimuscarinic therapy. For each condition explain the basis

of the contraindication. 7 Why is a depolarising agent usually chosen for administration before a non-depolarising agent? 8 State three serious adverse effects associated with suxamethonium therapy. 9 Maryanne Svagi, who is about to undergo surgery, is ordered the depolarising nicotinic antagonist

suxamethonium as part of the anaesthetic course of treatment. As a health professional working in the operating room, what are the clinical considerations associated with this medicine of which you should be aware?

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10 Soo Wong, a 65-year-old smoker, has been ordered nicotine patches as part of her ‘quit smoking’ program.

As Ms Wong’s clinical health educator, what would you tell her about the possible adverse effects of nicotine patches? 11 Margaret Sunfaste is a 70-year-old woman with moderate asthma. She is about to commence therapy with an

ipratropium inhalation device. She politely complains to you that as she is using a number of inhalers as a part of her treatment it would be easier if she could take this medicine as a tablet. What would be the disadvantages of taking this medicine as a tablet? 12 Beth Winker is receiving pilocarpine treatment for dry mouth following radiotherapy for a neck tumour. She

develops severe diarrhoea a couple of days after commencement of administration. With reference to this drug’s mechanism of action, explain how diarrhoea occurs. 13 Christianne Van Dyke is having a rhinoplasty procedure. You are part of the health team caring for her in the

operating theatre. What observations would lead you to suspect that insufficient neostigmine was used to reverse the effects of atracurium, the non-depolarising neuromuscular blocking agent given for muscle relaxation? 14 Jack Brown, aged 80 years, is prescribed the antimuscarinic agent tolterodine to treat urinary urge incontinence.

Mr Brown also suffers from heart failure and is on a 1.5 L fluid restriction. How would you counsel Mr Brown about ensuring he maintains his fluid restriction? 15 Mandy Watsonia, aged 49 years, has commenced tiotropium as maintenance treatment for chronic obstructive

pulmonary disease. What advice would you give Ms Watsonia about her therapy?

CHAPTER 28 CHOLINERGIC PHARMACOLOGY

28 MEDICINE SUMMARY TABLE FAMILY NAME

GENERIC NAME

TRADE NAME(S)

Nicotinic agonists

nicotine

Habitrol (chewing gum, transdermal patches, lozenges) (transdermal patches, chewing gum, Nicabate lozenges) , Nicorette (chewing gum, inhaler, nasal spray transdermal patches, sublingual tablet  ) Nicotinell (chewing gum, transdermal patch  ) (transdermal patches, chewing gum) Nicotrol (chewing gum, transdermal patches) QuitX

Cholinergic nerve blocker

botulinum toxin type A

Botox Dysport

Muscarinic agonists

acetylcholine bethanechol carbachol

Miochol Urocarb Isopto Carbachol Miostat Prepulsid Isopto Carpine Minims, Pilocarpine Pilopt

cisapride pilocarpine

Acetylcholinesterase inhibitors

donepezil edrophonium galantamine neostigmine pyridostigmine rivastigmine

Antimuscarinic agents

atropine + diphenoxylate

belladonna (hyoscine, atropine and hyoscyamine) benzhexol benztropine biperiden cyclopentolate darifenacin diphemanil glycopyrrolate homatropine hyoscine

Aricept Donezil Camsilon Galantyl Reminyl Mestinon Exelon Atropt Minims, Atropine Diastop Lofenoxal Lomotil Donnatab Artane Benztrop Cogentin Akineton Cyclogyl Minims, Cyclopentolate Enablex Prantal powder Robinul Injection Isopto Homatropine Buscopan Gastro-Soothe Kwells Scopoderm TTS Setacol Stomex

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FAMILY NAME

GENERIC NAME

Antimuscarinic agents (continued) + dimenhydrinate and caffeine ipratropium

+ salbutamol mebeverine orphenadrine + paracetamol oxybutynin procyclidine solifenacin tiotropium tolterodine tropicamide

TRADE NAME(S) Travacalm HO Travacalm Original Aeron Apo-Ipravent Apoven Atrovent preparations Ipratrin Ipravent Univent Combivent Duolin Colese Colofac Disipal Norflex Norgesic Ditropan Oxytrol transdermal system Kemadrin Vesicare Spiriva Detrusitol Minims, Tropicamide Mydriacyl

Antimuscarinic/ganglionic blocker

propantheline

Nicotinic agonist (depolarising)

suxamethonium

Nicotinic antagonists (non-depolarising)

atracurium cisatracurium mivacurium pancuronium rocuronium vecuronium

Tracrium Nimbex Mivacron Esmeron

sugammadex

Bridion

Miscellaneous agent Australia only New Zealand only

Pro-Banthine

Norcuron

CHAPTER 28 CHOLINERGIC PHARMACOLOGY

C A S E S T U DY 1

Questions

Mrs JH is a 62-year-old woman who has had rheumatoid arthritis in her hands, hips and knees for about eight years. She is receiving weekly assistance from her local district nursing service because of impaired mobility. For the arthritis, she is taking the non-steroidal anti-inflammatory drug ibuprofen daily and receives intermittent hydrocortisone therapy when the condition worsens.

1

Underlying Mr FT’s condition is a change in the level of activity of a division of the autonomic nervous system. Which division is affected and what is the nature of the change?

2

Which type or types of tissue receptor are involved in this condition?

3

Explain the mechanism by which the organophosphate insecticides induce this state.

4

Which clinical drug group do the organophosphate insecticides closely resemble in terms of their action? Why?

5

Which drug group can be used as an antidote to oppose the effects of the insecticide? Why?

You are caring for Mrs JH. She tells you that her eyes have ‘not been the best of late’ and she is finding it hard to see things out of the corners of her eyes. She is referred to her family doctor. He, in turn, refers her to the local eye clinic where a diagnosis of open-angle glaucoma is made. Mrs JH is prescribed eye drops containing a miotic agent. This medicine causes pupil constriction and facilitates the drainage of aqueous humour through the canal of Schlemm.

Questions 1

a Applying your knowledge of adrenergic and cholinergic pharmacology, which groups of drugs are well suited as miotics? b What receptor types are they acting on and how are they affecting the function of these receptors?

2

a State three common side-effects associated with each of these drug groups. b Would you expect to observe systemic side-effects associated with this therapy? Why?

3

Referring to Chapter 19, explain why Mrs JH may be predisposed to glaucoma.

C A S E S T U DY 3 Mr JJ, aged 68 years, visits the outpatient clinic for a checkup relating to his asthma condition. He has occasional bouts of acute asthma, which is adequately controlled using a salbutamol inhaler. Mr JJ indicates that he has just been diagnosed with open-angle glaucoma, which is being treated with timolol 0.25% eye drops. He inserts one drop in each eye twice daily. The outpatient nurse ascertains that he has used the eye drops for two days.

Questions 1

To which drug group does salbutamol belong and how does it act to relieve asthma? You may wish to refer to Chapter 27.

2

To which drug group does timolol belong, and how does it act to lower intraocular pressure? You may wish to refer to Chapters 27 and 83.

3

What is the potential problem for Mr JJ using salbutamol and timolol?

C A S E S T U DY 2 Mr FT is a 22-year-old man who has been admitted to your hospital emergency department. He has been working as a labourer at a nearby market garden that specialises in growing flowers. He was spraying the crops with the organophosphate insecticide malathion when he collapsed. He was not wearing the appropriate protective clothing. You observe that he is conscious and complains of gastrointestinal cramps and nausea. He vomited a couple of times in the ambulance as he was transported to hospital. You note the following manifestations: profuse sweating, drooling, lacrimation, bradycardia, agitation, muscle twitching and constricted pupils. Supportive treatment is implemented, which involves respiratory support and the administration of antidotes. His progress is carefully monitored during this critical period. His recovery is without complications. He is discharged from hospital several days later.

C A S E S T U DY 4 Ms RW is a 50-year-old woman who is suffering from sinus bradycardia (a slow heart rate). Recently, she has had some problems maintaining a normal blood pressure. She is given a medicine that acts on the autonomic innervation of the heart and returns her heart rate to normal.

Questions 1

State the divisions involved, the transmitters released, the receptors concerned and the effects associated with autonomic nervous system innervation of the heart.

2

Name the possible cholinergic and/or adrenergic drug groups that could be used to reverse Ms RW’s bradycardia.

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3

From your knowledge of the mechanisms of action of cholinergic and adrenergic drug groups, what would be the common side-effects of each of these treatments?

4

Which of these drug groups would have less effect on blood pressure?

5

Which one of the possible drug groups would you select to use in Ms RW’s case? Why?

C A S E S T U DY 5 Ms MM, aged 50  years, arrives at the open-heart intensive care unit following graft surgery to her heart. Unfortunately, she experiences difficulties in coping with the ventilator. When her cardiac surgeon reviews her condition, the surgeon decides that she would benefit from the administration of a non-depolarising neuromuscular blocking agent to stabilise her breathing.

C A S E S T U DY 6 Mr MW, aged 78  years, visits his local doctor complaining about ‘wanting to go to the toilet all the time’. The doctor conducts urological tests and asks the patient to keep a fluid balance diary for two 24-hour periods. Mr MW is diagnosed with urinary urge incontinence.

Questions 1

What group of drugs are used to treat urinary urge incontinence?

2

Give four examples of medicines that are in this drug group.

3

By considering the mechanism of action and the kind of receptor this group of drugs works on, what adverse effects would you anticipate?

4

In view of Mr MW’s age, what particular adverse effects would need to be carefully monitored?

Questions 1

Which of the non-depolarising neuromuscular blocking agents would be suitable for administration?

2

Explain the mechanism of action of non-depolarising neuromuscular blocking agents with reference to cholinergic pharmacology.

3

What other types of medicines should be administered? Provide a rationale for your answer.

4

What equipment needs to be on hand during administration of non-depolarising neuromuscular blocking agents?

5

What assessment parameters should be monitored during treatment?

C A S E S T U DY 7 Mr WB, aged 66 years, has mild chronic obstructive pulmonary disease. He takes tiotropium once daily as maintenance therapy using a HandyHaler device. In addition, Mr WB takes salbutamol by metered dose inhalation whenever he requires it to treat his symptoms of breathlessness.

Questions 1

What type of medicine is tiotropium? How does tiotropium work to treat chronic obstructive pulmonary disease?

2

What type of medicine is salbutamol? How does salbutamol work to treat the symptoms of breathlessness?

3

Can tiotropium be used to relieve the symptoms of breathlessness in chronic obstructive pulmonary disease? Provide a rationale for your answer.

4

Explain the process of using a HandyHaler device.

FU R T H ER RE A DI N G Bruntner L, Chabner B & Knollman B (eds), 2010, Goodman and Gilman’s Pharmacological Basis of Therapeutics, 12th edn, McGraw-Hill, New York. Marieb EN & Hoehn K, 2010, Human Anatomy and Physiology, 8th edn, Benjamin Cummings, Redwood City, CA. Rang HP, Dale MM, Ritter JM & Flower RJ & Henderson G, 2012, Pharmacology, 7th edn, Churchill-Livingstone, Edinburgh.

W E B R E S O UR C E S Autonomic Nervous System (US site) faculty.washington.edu/chudler/auto.html Virtual ChemBook Adrenergic Drugs I www.elmhurst.edu/~chm/vchembook/663adrenergic.html Virtual ChemBook Cholinergic Drugs I www.elmhurst.edu/~chm/vchembook/662cholinergic.html

S E C T I O N

VII CHEMICAL M E D I AT O R S Ugly bags of mostly water. C R Y S TA L L I N E L I F E F O R M D E S C R I B I N G H U M A N S — S TA R T R E K : T H E N E X T G E N E R AT I O N

This quote is an amusing way of describing humans from a different perspective, which does actually capture the essence of our composition. The remaining constituents, besides water in these ‘ugly bags’, would be other chemicals. Taking this analogy a step further, human cells represent ‘tiny bags’ of mostly water suspended within this larger bag. These ‘tiny bags’ produce chemicals that regulate and coordinate their functions and the functions of a diverse range of other ‘tiny bags’. These chemical messengers, or chemical mediators, are secreted in this watery medium and can act locally or be transported to some distant part of the body. In Section VI you were introduced to the group of chemical messengers associated with the autonomic nervous system called neurotransmitters, as well as neuromodulators, which influence peripheral nervous system function. In this section you will be introduced to a number of important chemical mediators involved in neural, muscle and immune function, as well as body development. The focus will be on histamine (Chapter 30), prostaglandins and serotonin (Chapter 31), as well as nitric oxide and the endothelins (Chapter 32). These substances are very often involved in disease states and, as such, are given special consideration in Chapters 29–32.

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LEARNING OBJECTIVES

KEY TERMS

After completing this chapter, you should be able to:

Autacoids

1

Provide examples of the functions in which chemical mediators are involved.

Endocrine mediators

2

Compare and contrast neurocrine, endocrine, paracrine and autocrine communication.

Neurocrine mediators

3

Define the role of a chemical modulator.

Paracrine mediators

4

Provide examples of peptide mediators.

5

State the limitations of peptides as medicines.

Neuromodulation Peptide mediators

Chemical messenger systems are an integral part of body regulation and coordination, allowing for effective cell-to-cell communication throughout the body. Broadly speaking, the substances involved in cell-to-cell signalling are known as chemical mediators. Substances as diverse as neurotransmitters, hormones, growth factors, peptides and derivatives of cell membranes are examples of chemical mediators involved in cell communication. The means by which they communicate with cells may vary greatly and result in quite different cellular responses. Chemical mediators are involved in diverse functions, such as cognition, motor control, mood, inflammation, the control of blood pressure and tissue perfusion, gastrointestinal secretion and motility, stress responses, cell proliferation and specialisation, as well as pain transmission. Chemical mediators also play significant roles in pathophysiological processes. Many commonly used medicines produce their effects by altering this cell-to-cell communication. In this section, medicines are discussed that are used in the treatment of motion sickness, inflammation and allergy, problematic pregnancies, myocardial ischaemia and hypertension. You will be introduced to a number of key groupings of chemical mediators, their physiological roles are described and their pharmacological manipulation explained. In this chapter we concentrate on the classification of chemical mediators.

C H A P T E R 2 9 A N I N T R O D U C T I O N T O C H E M I C A L M E D I AT O R S

CLASSIFICATION OF CHEMICAL MEDIATORS Neuroendocrine communication is a good place to start our discussion of chemical mediators. In Section  VI, the pharmacology of the peripheral nervous system was explained. The focus of that discussion was on the phenomenon of neurotransmission and the way we use medicines to alter this process. In Section  XII, endocrine pharmacology is covered. Here the focus is on altering hormone action. Traditionally, the way in which the nervous and endocrine systems function is nicely contrasted. The chemical mediators associated with the endocrine system are called hormones and those linked to the nervous system are neurotransmitters. Hormones are made in and released from endocrine glands directly into the bloodstream in order to communicate with distant target tissues, whereas neurotransmitters are released from nerves and interact with short-range targets. Hormones are generally thought to produce their responses relatively slowly and for a prolonged period compared with neurotransmitters. This classification system has presented endocrine and neurocrine communication in a dichotomous, or nonoverlapping, way. It has become apparent that this classification system, although useful in many respects, is an oversimplification. Non-nervous cells can produce chemical mediators that act at short range on a near target and produce effects relatively rapidly. These mediators are known as paracrine secretions or local hormones. Examples of local hormones are histamine and prostaglandins, which both play key roles in inflammation. The pharmacology of histamine

and prostaglandins is covered in Chapters  30 and 31, respectively. Another important local hormone is serotonin, or 5-hydroxytryptamine (5-HT). You may already be aware that serotonin is a neurotransmitter with a key role in the control of mood and behaviour (see Chapter  36). It is also produced by non-nervous cells in the periphery and is regarded as a paracrine secretion (see Chapter 31). Indeed, the other mediators examined in this section, nitric oxide and the endothelins (see Chapter  32), can also be synthesised by nerve cells and by non-nervous peripheral cells alike. Thus, the classification of a chemical mediator as a paracrine or neurocrine secretion is determined by context, rather than by an inflexible and rigid categorisation. A cell may also secrete a chemical mediator that acts within the confines of a localised region, such as a lesion, or even upon itself. These mediators induce their effect without entering the circulation and are referred to as autocrine secretions or autacoids. For example, many of the cytokines produced by immune cells (e.g. interferons, interleukins and lymphokines) to regulate immune processes are regarded as autacoids. Immunomodulating chemical mediators such as these are covered in Chapter 79. Generally speaking, it is better to regard the classification of chemical mediators in a less rigid way than was proposed originally. You should keep in mind that there may be significant overlap in the roles of chemical mediators and in the types of cells that release them. In some contexts, a chemical mediator may act as a neurocrine secretion and in others be regarded as a paracrine secretion or autacoid. The classification of chemical mediators is summarised in Table 29.1. Another important concept related to chemical mediator function is that of modulation. A chemical

Table 29.1  The classification of chemical mediators CLASSIFICATION

MEDIATOR TYPE

CHARACTERISTICS

EXAMPLE

Neurocrine secretions

Neurotransmitter

Stored in and released from axon terminal Acts over short range Relatively rapid action

Acetylcholine

Endocrine secretions

Classic hormone

Released from endocrine gland into blood Acts on distant target Relatively prolonged action

Growth hormone

Paracrine secretions

Local hormone

Released from tissue Enters circulation Acts on neighbouring cells Relatively rapid action

Cholecystokinin (CCK)

Autocrine secretions

Autacoid

Released from tissue Confined to tissue Acts locally (may act on secreting cell)

Cytokines

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modulator is not primarily responsible for initiating a particular physiological response but it can modify it (i.e.  decrease or increase the physiological response). An example of this is nerve impulse transmission. Imagine a sensory nerve being stimulated by tissue injury. A train of impulses is transmitted towards the brain along the sensory pathway, triggered by neurotransmitter release at the synapse. Neighbouring cells release chemical mediators, such as prostaglandins, which increase the frequency of nerve impulse transmission, making the perception of the sensation stronger. In this instance, the prostaglandins are chemical modulators that have affected nervous system function. The prostaglandins have not initiated the impulses. This is called neuromodulation. Neuromodulation plays a significant role in human nervous system control. Important neuromodulators are discussed in Chapters 26 and 33.

PEPTIDE AND PROTEIN MEDIATORS Peptides play important physiological roles as chemical mediators. Throughout this book you will encounter these mediators and the diverse roles they play in physiological and pathophysiological processes. Peptides are implicated in cardiovascular function, pain transmission, inflammation, neurotransmission, gastrointestinal regulation and endocrine communication. Indeed, they can function as neurocrine, endocrine, paracrine and autocrine mediators. They range in size from around 3 to 200 amino acids. Examples of peptide mediators are provided in Table 29.2.

From a pharmacological perspective, peptide mediators are attracting a lot of attention. Analogues and antagonists of these peptides have been, and are being, investigated as therapeutic agents. More recently the use of selected peptides to enhance sporting performance has attracted controversy. Advances in molecular biology, and especially recombinant DNA technology, have facilitated this development. In peptide pharmacology, the physiological properties of the peptide can be altered by a slight manipulation of its structure. As an example, changing one or two amino acids in human insulin creates an insulin analogue. Although it retains the same functional characteristics of insulin, the altered chemical properties of the analogue means that it can be released from the injection site much faster or very much slower than regular insulin (see Chapter  61). It is also possible to substitute amino acids within a sequence in order to turn a peptide mediator into an antagonist. However, it must be said that peptide medicines may be of only limited use in clinical practice. As with therapeutic insulin, peptides generally cannot be given orally. This is because they are broken down in the gut or poorly absorbed. They also tend to have short half-lives, as peptide enzyme degradation systems are well established in the blood and tissues. Nevertheless, there are many situations where peptide mediators are targeted in the treatment of common diseases. You will discover that peptide mediators are important in pain control (see Section  IX), cardiovascular and respiratory pharmacology (see Section  X), the regulation of gastrointestinal function (see Section  XI), endocrine pharmacology (see Section XII), immunomodulation (see Chapter 79) and cytotoxic therapy (see Chapter 80).

Table 29.2  Examples of peptide and protein mediators MEDIATOR Angiotensin II

SIZE*

PHYSIOLOGICAL ROLE

CHAPTER

8

Vasoconstriction

46

Substance P

11

Pain transmission

40

Endothelin–1

21

Vasoconstriction

32

Endorphin

31

Analgesia

40

Neuropeptide Y

40

Vasoconstriction

26

Insulin

51

Glucose metabolism

61

Inflammation

79

Most cytokines * Approximate number of amino acids.

120–220

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CHAPTER REVIEW ■■

■■ ■■

Chemical mediators are involved in cell-to-cell communication. Mediators may be classified as neurocrine, endocrine, paracrine or autocrine secretions. Chemical modulators modify cell-to-cell communication without activating the actual cell response. Peptide mediators are involved in a diverse range of physiological and pathophysiological processes. Advances in peptide pharmacology are being made, but their use as medicines may be limited.

REVIEW QUESTIONS 1

What is a chemical mediator?

2

Compare and contrast the characteristics of neurocrine, endocrine, paracrine and autocrine mediators.

3

For each of the following chemical mediators, indicate whether it is generally regarded as a neurocrine, endocrine, paracrine or autocrine secretion: a

acetylcholine

b prostaglandins c

interleukin-1

d insulin 4

Define the term neuromodulation and provide an example.

5

State four examples of peptide mediators and indicate their physiological roles.

6

State the limitations of peptides as medicines.

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LEARNING OBJECTIVES

KEY TERMS

After completing this chapter, you should be able to:

Allergy

1 2

Describe the role of histamine as a chemical modulator of certain physiological functions.

Anaphylaxis

Describe the mechanism of action and pharmacological effects of antihistamines.

Histamine

3

Describe the problems associated with antihistamine therapy.

4

Identify the various therapeutic uses of antihistamines.

Antihistamine Inflammation

Histamine is widely distributed in mammalian tissues and, as histo means tissue, it is aptly named. It is found in most body cells but is especially plentiful in the lungs, skin and the gastrointestinal tract wall. In these sites it is mainly contained within mast cells, cells that are involved in inflammatory and allergic reactions. Basophils and platelets in the bloodstream also contain histamine. Histamine is synthesised from the amino acid histidine, but the rate of production varies greatly depending on location and functional role. Histamine has significant roles in a number of physiological processes. It plays a major role in modulating allergic and hypersensitivity reactions and is an important mediator in the regulation of the secretion of gastric acid in the stomach. In addition, it is a neurotransmitter in the brain, and is considered a neuromodulator with both central and peripheral actions.

C H A P T E R 3 0 H I S TA M I N E A N D A N T I H I S TA M I N E S

HISTAMINE RECEPTORS Four types of histamine receptor have been identified— H1, H2, H3 and, more recently, H4. Histamine receptors are G-protein-coupled receptors linked to second messenger systems. H2, H3 and H4 receptor subtypes alter the activity of adenylate cyclase and cyclic adenosine monophosphate (cAMP) production. H1 receptors act via activation of phospholipase  C, raising the production of inositol triphosphate and increasing the availability of intracellular calcium. Their distribution and effects are summarised in Table 30.1. H1 Receptors are found on the endothelium, on mucussecreting cells, in the brain and on peripheral nerve endings. All four types of histamine receptors are associated with immune cell regulation. Activation of H1  receptors associated with the endothelium induces increased permeability. It is a common belief that this effect occurs

in capillaries, but this is incorrect. The target vessel type is actually the postcapillary venule, but the effect is the same: a shift of plasma proteins and fluid into the interstitial space, resulting in oedema. Histamine decreases mucus viscosity. In the brain, H1  receptors are associated with increased wakefulness and appetite suppression. When stimulated, histamine receptors on peripheral nerve endings cause itching, burning and pain. H2 Receptors are found mainly in the parietal cells of the stomach and their activation can cause the release of significant amounts of gastric acid. Both H1 and H2 receptors are found on smooth muscle, in the central nervous system (CNS) and on cardiac muscle. Activation of either type of histamine receptor triggers dilation of vessels in vascular beds. However, H1 receptors mediate a rapid, short-lived response, whereas the response at H2  receptors is slow and prolonged. In regard to non-vascular smooth muscle (such as the intestines and bronchioles), H1 receptor stimulation tends

Table 30.1  Histamine receptor subtype locations and effects RECEPTOR SUBTYPE & ACTIVE STATE H1 (activates phospholipase C)

LOCATIONS

EFFECTS

Postcapillary venules Vascular beds Central nervous system (CNS)

Increased permeability Vasodilation (rapid, short-lived) Increased wakefulness Appetite suppression Control of fluid balance, blood pressure, body temperature Pain and itching sensations Contraction

Peripheral nerve endings Respiratory and gastrointestinal smooth muscle Heart Immune cells

H2 (activates adenylate cyclase)

Stomach Vascular beds Respiratory and gastrointestinal smooth muscle CNS Heart Immune cells

H3 (inhibits adenylate cyclase)

H4 (inhibits adenylate cyclase)

Axon terminals CNS

Positive chronotropy and inotropy Enhanced release of histamine from mast cells and basophils; Thelper cell priming; enhanced antigenpresenting cell capacity Increased gastric acid secretion Vasodilation (slow, prolonged) Relaxation Control of fluid balance, blood pressure, body temperature Positive chronotropy Modulation of immune function

Immune cells

Autoinhibition Regulates release of neurotransmitter from dopaminergic, cholinergic, adrenergic and serotonergic nerves Control of locomotion, bodyweight, body temperature Immunomodulation

Immune cells

Chemotaxis; a role in autoimmune disease

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to cause contraction, whereas H2 receptors generally induce relaxation. In the CNS, H1 and H2 receptors are involved in the homeostatic control of fluid intake, blood pressure and body temperature. There is also evidence that these receptors are involved in the secretion of antidiuretic hormone, control of equilibrium associated with motion and pain perception. In the heart, stimulation of the H2 receptors is positively chronotropic (induces increased heart rate). On the other hand, stimulation of the H1 receptors is positively chronotropic and inotropic (induces an increased force of contraction). H3  Receptors are located presynaptically on a variety of nerve terminals and have a role in autoinhibition—that is, a feedback mechanism designed to inhibit the release of transmitter from the axon terminal. Interestingly, H3  receptors are not only associated with histaminergic neurones. They appear to be present in and modulate the activity of dopaminergic, cholinergic, adrenergic and serotonergic nerve terminals both centrally and peripherally. This subtype has also been implicated in cognition, as well as the central control of locomotion, bodyweight and body temperature. It is hoped that the development of antagonists at this receptor could be useful in the treatment of attention deficit hyperactivity disorder, schizophrenia and Alzheimer’s disease.

ALLERGY AND ANAPHYLAXIS Histamine plays a very important part in both allergic and anaphylactic reactions. Localised allergy can occur in the presence of antigenic substances (i.e. medicines or natural chemicals in the environment, such as venoms or plant toxins), causing a local anaphylactoid reaction. Although some of these antigenic compounds are actually innocuous, in many people they can induce adverse reactions. In susceptible persons, the local release of histamines in the nasal epithelia, due to, for example, pollen grains, can lead to hay fever or allergic rhinitis. Release in the skin as a result of an insect bite (e.g. from a horsefly) can lead to a reaction characterised by swelling and itching called urticaria. Damage to tissue cells can also initiate histamine release. These responses can be treated effectively with medicines known as antihistamines, which are discussed below. In severe cases, an immediate, systemic allergic reaction called anaphylaxis can, without treatment, lead to death within minutes. Anaphylaxis is a medical emergency that usually responds to treatment if it is administered quickly enough. It is important that health professionals who are involved with the administration of medicines or in immunisation programs be competent in

the management of anaphylaxis, as prompt action is lifesaving. Anaphylaxis can also be triggered by particular foods, such as peanuts. Another name for this type of allergic reaction is type I hypersensitivity. The reaction can be either localised or systemic and is strongly associated with mast cells and, to a lesser extent, basophils. The reaction is described in Chapter  18. It involves an interaction between antigens, antibodies and mast cells, and results in the rupture of the mast cell membrane and release of chemical mediators such as histamine, 5-hydroxytryptamine (5-HT, or serotonin), leukotrienes, prostaglandins and kinins. This process is called mast cell degranulation. In anaphylaxis, these mediators can lead to a massive vasodilatory response, with resultant hypotension causing shock and perhaps death. At the same time bronchoconstriction can lead to laboured breathing and, if allowed to continue unabated, asphyxiation. As there are a number of mediators involved in this systemic reaction, the use of antihistamines alone in the treatment is not satisfactory. The goal is to reverse these manifestations as quickly as possible, and adrenaline administration treats the hypotension/shock and the bronchoconstriction (see Chapter  27). Adrenaline itself can prevent further histamine release. Since noradrenaline is not an effective bronchodilator due to its low efficacy on β2  receptors, it is not indicated in the treatment of this reaction. The route of administration of adrenaline in such an emergency can vary depending on the severity of anaphylaxis. If adrenaline is administered intravenously, it can cause ventricular fibrillation. However, the intravenous route is preferred if hypovolaemic shock is present or the response following other routes of administration is not adequate. If given subcutaneously, absorption can be erratic; therefore, subcutaneous injection is not recommended. This means intramuscular injection into the mid-anterolateral thigh is the best route. It should not be administered in the buttocks as this site does not allow for effective absorption compared to the anterolateral thigh site. Adrenaline should be administered slowly and the electrocardiogram needs to be regularly monitored. Only clinical experience will determine which route to use, depending on the severity of the reaction. Many people who are allergic to insect stings, certain foods or the like carry adrenaline in a pen-like syringe or autoinjector for self-administered intramuscular injection in case of an emergency. Adrenaline autoinjectors need to be stored in the dark between 15  and 25  degrees Celsius, but they do not need to be refrigerated. Insulated carry pouches can be used if needed. Corticosteroids are often given to stabilise the immunological cells causing the problem (see Chapter 62).

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Promethazine can be used as an intravenous formulation to stop any further histaminic action. Corticosteroids have been shown to be more effective than the antihistamines in the management of allergic rhinitis. However, antihistamines do produce beneficial effects in the treatment of urticaria.

A N T I H I S TA M I N E S We focus here on the classic H1 antihistamine agents that have been used in the management of allergic conditions. H2 receptor antagonists, whose clinical use is in disorders associated with excessive gastric acid secretion, are discussed in Chapter 56. There are numerous medicines available for both topical and systemic use that have antihistaminic activity. Apart from treating allergies, H1 antihistamines are useful in the treatment of nausea, especially travel or motion sickness. Some other uses are mentioned below. Mechanism of action  The term antihistamine is usually reserved for drugs acting at the H1 receptor. Historically they have been considered to be receptor antagonists, but the current thinking is that they act as inverse agonists (see Chapter 17). With respect to inverse agonism it is argued that, at rest, H1 receptors in a tissue are thought to be in equilibrium between the inactive and active state with respect to the agonist’s target enzyme. In other words, there is some degree of constitutive activity associated with these receptors without the presence of histamine. The presence of histamine in the tissue shifts the equilibrium towards the active state. In the presence of a H1 antihistamine the equilibrium shifts towards the inactive state (see Figure 30.1). The accepted classification system for these antihistamines is to divide them into first and second-generation medicines. The first-generation antihistamines consist of antazoline, brompheniramine, chlorpheniramine, cyclizine, cyproheptadine, dexchlorpheniramine, diphenhydramine, doxylamine, pheniramine, promethazine, trimeprazine and triprolidine. Azelastine, cetirizine, levocarbastine, levocetirizine, loratadine, desloratadine and fexofenadine are second-generation antihistamines. Desloratadine is an active metabolite of loratadine. First-generation antihistamines are all able to cross the blood–brain barrier and, therefore, have effects on the CNS; as H1  receptors in the brain are involved in wakefulness, blockade of these leads to drowsiness and sedation. The major difference between the first- and second-generation antihistamines is that the latter are less lipophilic and, hence, cross the blood–brain barrier in only relatively small amounts. Cetirizine, considered the most potent

H1-antihistamine, has the added advantage of inhibiting eosinophil migration to inflammatory sites, minimising the inflammatory response by another mechanism. There is also evidence that the second-generation antihistamines induce anti-inflammatory effects unrelated to their histamine receptor antagonist activity that include a decrease in mediator release, chemotaxis and cytokine secretion, as well as an increase in neutrophil activity and the number and responsiveness of β receptors. Interestingly, the tricyclic antidepressant doxepin (see Chapter 36) is a very potent H1 antihistamine. It has been used in the management of refractory allergic conditions, such as chronic urticaria. Common adverse effects  In using antihistamines, what really matters is the person’s response and preference. Finding one that does not adversely affect an individual may involve trial and error. Cetirizine, loratadine, desloratadine and fexofenadine are reputedly less likely to cross the blood–brain barrier. This lack of access makes them relatively free of the drowsiness effect in many people. However, they are more expensive than the first-generation antihistamines. Even though cetirizine is relatively lipophobic, it crosses the blood– brain barrier in about 15  per  cent of people and, thus, is more likely to induce drowsiness than the other secondgeneration antihistamines. People taking any antihistamine should be warned of concurrent drowsiness and told, if so affected, not to drive or operate hazardous machinery. Some antihistamines, such as promethazine and trimeprazine, are excellent at promoting drowsiness. They are, therefore, sometimes used to induce sedation. For instance, promethazine is used as a sedative in premedication before surgery. This is a good example of an adverse effect of a drug group in one context being a therapeutic effect in another. Sedating first-generation antihistamines can interact with other CNS depressants, and they should not be taken together because of a potentiated CNS depressant effect. Although the second-generation antihistamines tend not to produce sedation in most people, they may still produce drowsiness in a small percentage of users. Generally speaking, apart from drowsiness, antihistamines are well-tolerated medicines. The other most common side-effects are dizziness, lassitude and gastrointestinal disturbances. In high doses, convulsions and cardiac depression can occur. Some first-generation antihistamines have antagonist activity at muscarinic receptors (see Chapter 28). This may result in antimuscarinic (atropine-like) adverse effects, such as dry mouth, urinary

321

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Figure 30.1  The action of histamine and antihistamines at H1 receptors A. Resting state G-protein-coupled H1 receptor

Cell membrane

Phospholipase C Inactive state

2nd messenger production

Active state

B. Histamine present Histamine

Inactive state

Active state

2nd messenger production

Active state

2nd messenger production

C. H1-Antihistamine present H1-Antihistamine

Inactive state

Source: Adapted from Simons FER & Simons KJ, 2011, Histamine and H1 antihistamines: celebrating a century of progress, Journal of Allergy and Clinical Immunology, 128, 1139–1150, Fig. 2, p. 1142.

C H A P T E R 3 0 H I S TA M I N E A N D A N T I H I S TA M I N E S

retention and decreased respiratory secretions (which may result in coughing). The second-generation antihistamines do not possess this cross-reactivity with muscarinic receptors. When used topically, antihistamines can themselves be antigenic and elicit an allergic reaction. This makes the use of antihistamine creams relatively unsatisfactory for the topical treatment of skin allergies and pruritus. Moreover, there are both H1 and H2 receptors in the skin. The H1  receptors predominate, but this explains why H1  antihistamines are not 100  per  cent effective in the treatment of such skin conditions. Combinations of H1 and H2  antihistamines may eventually be used for conditions such as an allergic itch. The desirable and undesirable effects of the classic antihistamines are shown in Figure 30.2. Clinical considerations  The main use of H1  antihistamines, and indeed the most effective use, is in the management of a number of acute allergic conditions where histamine release has a prominent role, such as rhinitis, urticaria and conjunctivitis. Symptoms Figure 30.2  The effects of the classic  antihistamines Prevent motion sickness Treat allergic rhinitis, hay fever

Sedation Drowsiness, lassitude, dizziness Dry mouth, reduced respiratory secretions

Alleviate allergic reactions Gastrointestinal disturbance

Urinary retention

that appear to respond best are runny nose (rhinorrhoea), sneezing and itching. These medicines also have a role in the treatment of conditions characterised by pruritus. Some argue that antihistamines have a place as adjuvant therapy in bronchial asthma. However, corticosteroids (see Chapter 62) have been shown to be more effective than the antihistamines in the management of chronic and severe allergic conditions. Most of the first-generation antihistamines have a short duration of action (around six hours), whereas most of the second-generation agents have a more prolonged action (12–24  hours). Loratadine acts faster than fexofenadine and has a longer half-life, which on paper makes it a better alternative. As mentioned earlier, antihistamines are quite effective as sedatives in premedication before surgery. Sedating antihistamines should not be used in children younger than two years of age, as they have been associated with increased risk of adverse effects such as dizziness, blurred vision and lack of coordination. Antihistamines are useful in the management of motion (travel) sickness (e.g.  dimenhydrinate, pheniramine and promethazine). They are most effective if taken prophylactically and offer little therapeutic benefit once the nausea and vomiting occur. As the most effective medicine for the prevention and treatment of this condition is the antimuscarinic agent hyoscine (otherwise known as scopolamine), it is argued these antihistamines are most likely acting via their antimuscarinic action. Antiemetic agents are covered in detail in Chapter 58. Doxylamine is used in combination with analgesics, and may afford a beneficial effect in the treatment of pain when drowsiness or sedation poses no problems. As such, doxylamine is sometimes termed a calmative. Doxylamine was previously used to treat nausea during pregnancy but is no longer recommended for this purpose. Levocabastine is an antihistamine available only for topical application to the nasal mucosa in cases of allergic rhinitis, and to the eyes in allergic conjunctivitis (see Chapter  83). The systemic absorption of this medicine is minimal; thus, avoiding CNS effects. The medicine has a relatively long half-life when used via these routes and only two applications daily are required for the relief of symptoms. Irritation to the mucosal surfaces and mild eye irritation have been reported. Ketotifen and olopatadine are also used for allergic conjunctivitis in the form of a topical application. As mast cell stabilisers, they have a delayed onset of action and should, therefore, be tried for two to four weeks before their effects are evaluated. Advise the person that topical nasal antihistamine preparations

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should be given about half an hour before meals, so that the nasal passages are clear to facilitate eating or drinking. Ensure that the person consumes sufficient amounts of fluids, as antihistamines can dry up mucous membranes and thicken bronchial secretions. In the common cold, histamine is not involved in the production of respiratory secretions, so the use of antihistamines in cold and flu preparations is not particularly beneficial. Having said that, there a number of combination preparations available for use in these conditions (see the Medicine Summary Table). These preparations consist of various combinations of an antihistamine, decongestant, analgesic and/or cough suppressant and are said to provide symptomatic relief. However, there is little rationale for these combination preparations and their use should be avoided. For example, overuse of combination preparations containing the decongestants pseudoephedrine or phenylephrine can lead to rebound congestion. Single formulations of antihistamine agents are, therefore, preferred. Sedating antihistamines may be helpful at night in the promotion of sleep. As already mentioned, sedating antihistamines should be avoided in children younger than two years due to their tendency to cause adverse effects. On the other hand, if nasal stuffiness is due to an allergy in an adult, the short term use of an antihistamine nasal spray and/or corticosteroid preparations may be of benefit. It should be noted that even less-sedating antihistamines may make some people sleepy. With all antihistamines,

alcohol and other sedating medicines should be avoided. If individuals notice that they do get sleepy following consumption, they should not drive or operate machinery. Antihistamines that have been used in infants to improve sleep (e.g.  promethazine and trimeprazine) should be avoided because epidemiological research has demonstrated a link between the use of these preparations and an increased incidence of sudden infant death syndrome. The earliest age at which children can safely consume antihistamines is about two to three years. However, other age requirements relate to particular antihistamines. For instance, fexofenadine is not recommended for use in children younger than one year, and levocetirizine or doxylamine is not used in children younger than 12 years. Similarly, older people are at greater risk of adverse effects of antihistamines, which include dizziness, sedation, confusion, hypotension and falls. Antihistamines can have varying uses. Cyproheptadine has serotonin antagonist activity and is sometimes beneficial in the prophylaxis of migraine. It also has appetitestimulatory effects, which can be useful in convalescence. In summary, antihistamine agents have varied uses in therapeutics, and deciding which one to use can be difficult. It is often a matter of trial and error to see which one is of help to a person and produces the fewest adverse effects. Response to antihistamines may vary widely and the person is, therefore, advised to try different preparations to determine the one that is best tolerated and most effective.

CLINICAL MANAGEMENT A N T I H I S TA M I N E S Assessment ■■

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Assess the person for a history of convulsions, as paradoxical effects of antihistamines include irritability, insomnia and an increased tendency to convulsions. People with asthma should also avoid these preparations as they have a tendency to increase the thickness of bronchial secretions and to dry mucous membranes. Avoid using in older people and young children in view of the medicines’ sedative property. When used for allergy, determine with the person any obvious deviations from usual habits (e.g. diet, environment or stress) that may have caused the allergic reaction.

Planning ■■

Depending on the therapeutic use of the medicine, the following symptoms will be alleviated: – symptoms of allergy, including nasal congestion, bronchoconstriction, sneezing, rhinorrhoea and pruritus of the nose, eyes and throat – symptoms of motion or travel sickness. Ensure that the medicine is taken about 30 minutes prior to travel – symptoms of the common cold and influenza, including nasal congestion, sneezing and rhinorrhoea. A secondary bacterial infection does not occur – anxiety and sleeplessness prior to a surgical procedure following the use of sedating antihistamines.

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Observe the colour of bronchial secretions. Yellow or green mucus indicates a bronchial infection, and an antibiotic may be required.

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Give the medicine with milk or food to minimise the gastrointestinal effects. In cough and cold preparations with antihistamines, determine the nature of other medicines present. Sympathomimetic decongestants can lead to an elevation in blood pressure. Preparations containing codeine can cause tolerance and those with pseudoephedrine can lead to rebound congestion. Generally, antihistamines contained in cough and cold preparations are not particularly useful because histamine is not involved in the production of respiratory secretions. Antihistamines should not be used for the symptomatic treatment of a respiratory infection in a young child, particularly those younger than two years of age, because of the self-limiting nature of the infection and the lack of benefit associated with these preparations.

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The person should be forewarned that antihistamines can cause drowsiness, and should avoid driving or using machinery. Note that the antihistamines cetirizine, desloratadine, fexofenadine, levocetirizine and loratadine are less sedating but can induce drowsiness in susceptible persons. The CNS depressant effects of these medicines can be accentuated by alcohol and by other medicines, such as sedatives, hypnotics and anxiolytics.

The person should be advised to take plenty of fluids, as antihistamines can thicken bronchial secretions and dry mucous membranes. Instruct the person on the proper use of nasal sprays (refer to Chapter 7, Table 7.8, for further information). Inform the person that rebound congestion can occur with overuse. Advise people to read the container of over-the-counter preparations. The relevant health care professionals should be consulted to ensure that other ingredients would not affect the person’s health status, such as with hypertension or hyperthyroidism. Topical antihistamine preparations should be given about half an hour before meals so that the nasal passages are clear to facilitate eating or drinking. Mast cell stabilisers (e.g. ketotifen and olopatadine) have a delayed onset of action as topical eye preparations. Advise people they should be tried for two to four weeks before their effects are evaluated. Inform people that topical eye preparations can cause stinging and eye irritation on application. If they need to use more than one type of eye drop at the same time, they should wait a few minutes between using each drop.

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Evaluate the effectiveness of antihistamine therapy, depending on the reason for use. Evaluate for adverse effects, including sedation, dizziness, diplopia, loss of appetite, nausea and vomiting. Observe closely for any additive effects if used with other substances that depress the CNS.

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Histamine is an autacoid that plays a significant role in a number of physiological processes, such as allergic and inflammatory reactions, and gastric acid secretion. There are four types of histamine receptors that are widely distributed around the body, including in blood vessels, nerve cells, smooth muscle, heart muscle and blood cells. The medicines termed antihistamines are usually compounds that antagonise H1 receptors. Antihistamines are useful in the treatment of allergic conditions such as rhinitis, urticaria, pruritus and conjunctivitis. The symptoms that respond best to this treatment are runny nose, sneezing and itching.

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There are two types of antihistamines: first-generation agents (sedating) and second-generation agents (non-sedating). Second-generation antihistamines are non-sedating because they do not cross the blood–brain barrier efficiently. First-generation antihistamines are strongly sedating and are sometimes used as sedatives/hypnotics, especially in children. Some antihistamines have diversified uses, for example, in the treatment of migraine, in the management of motion sickness and for eating disorders.

REVIEW QUESTIONS 1 Identify two tissues in the body that bear H1 receptors. Indicate the effect of blocking each of these tissue

receptors with an antihistamine.

2 State three tissues that bear both H1 and H2 receptors. In general, how successful would the application of

an  antihistamine be in blocking the action of histamine at these sites? Explain your reasons.

3 H3 receptors are located presynaptically on histaminergic nerves. Assuming that the tissue receiving stimulation

from these nerves has H1 receptors, would activating these H3 receptors have the same effect as using an antihistamine on this tissue or the opposite effect?

4 When taking first-generation antihistamines, a person should be advised not to drive or use machinery, yet it may

be safe to do so when taking loratadine. Why? 5 Alfredo Adumo is taking an antihistamine preparation for allergy-induced sinusitis. What medicine education

would you offer Mr Adumo? 6 Explain why the following conditions cannot be treated with second-generation H1 antihistamines: a

peptic ulcer

b travel sickness 7 Cristina Vicario, a 70-year-old widow, has been ordered doxylamine for insomnia and diazepam for anxiety

following the death of her husband. What is the problem involved with this combination of medicines? 8 Joe Guthrey, a 40-year-old truck driver, suffers from severe allergic rhinitis. What type of antihistamine preparation

would you recommend for him? 9 Aleka Vousolous, a 35-year-old mother with severe sinusitis, often experiences difficulty sleeping because of her

condition. Which antihistamine preparation would you recommend for her to take at night? 10 Jean Wasslow, aged 44 years, has started to use olopatadine eye drops to treat her allergic conjunctivitis. When

would Ms Wasslow expect to see any benefits from therapy? 11 A woman with a five-month-old baby says that she is having difficulty establishing a regular sleeping pattern in

the infant. She has heard that Phenergan (promethazine) is a safe sedative for use in children and wants to try it on her child. What do you tell her about the use of this medicine? 12 Jack Benton, aged 25 years, informs his doctor that he is going on a long bus trip and is worried about developing

motion sickness. His doctor suggests that promethazine tablets can be very helpful in managing this condition. What advice should his doctor give him about using promethazine for this purpose?

C H A P T E R 3 0 H I S TA M I N E A N D A N T I H I S TA M I N E S

30 MEDICINE SUMMARY TABLE FAMILY NAME

GENERIC NAME

TRADE NAME(S)

The medicines in this medicine summary table are generally restricted to single-medicine preparations. There are many preparations available in Australia and New Zealand containing an antihistamine combined with medicines from various other drug groups. H1 Antagonists (antihistamines)

antazoline + naphazoline azelastine brompheniramine + multiple actives cetirizine

chlorpheniramine cyclizine cyproheptadine desloratadine dexchlorpheniramine diphenhydramine

doxylamine fexofenadine

ketotifen levocabastine levocetirizine lodoxamide loratadine

Albalon-A Antistine-Privine Azep Eyezep

Allerid C tablets Alzene Razene Zep Allergy Zetop Zilarex Zodac Zyrtec Histafen Piriton Nausicalm Valoid Periactin Aerius Claramax Polaramine in Benadryl preparations Children’s Paedamin Antihistamine Oralliquid in Gold Cross Cough Medicine Snuzaid Unisom Sleepgels Dozile Restavit Allerfexo Fexal Fexofast Fexotabs Tefodine Telfast Xergic Zaditen Livostin Levrix Xysal Lomide Alledine Allereze Claratyne Loraclear Lorano Lorapaed Lorfast

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FAMILY NAME

GENERIC NAME

H1 Antagonists (antihistamines) (continued) mepyramine olopatadine pheniramine promethazine

trimeprazine triprolidine + mutiple actives Australia only New Zealand only

TRADE NAME(S) Lorastyne Lora-Tabs Anthisan Patanol Avil Avomine Allersoothe Gold Cross Antihistamine Phenergan Sandoz Fenezal Vallergan

C H A P T E R

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P R O S TA G L A N D I N S A N D S E R O TO N I N

LEARNING OBJECTIVES

KEY TERMS

After completing this chapter, you should be able to:

Prostaglandins

1

List the main functions of prostaglandins.

Serotonin (5-HT)

2

Identify the clinical uses of prostaglandins.

3

Describe the main functions of serotonin.

Serotonin receptor agonists Serotonin receptor antagonists

In this chapter the prostaglandins and serotonin are discussed. The properties and functions of these chemical mediators are outlined and an overview of their clinical uses is provided.

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PROSTAGLANDINS Prostaglandins are so named because they were first isolated from semen and were assumed to come from the prostate gland. Since their discovery in the early 1930s it is clear that many tissues can make prostaglandins, but the original name remains. The function of these compounds depends on two factors: their chemical nature and their location. Because they have a very short half-life, their action is mainly confined to the tissues in which they are produced. In this way they are regarded as autacoids. Any prostaglandin that

escapes into the general circulation is destroyed before it can act elsewhere. As they act where they are produced, they are also given the name ‘local hormone’. All prostaglandins are derived from the 20-carbon fatty acid arachidonic acid (see Figure 31.1) as are a number of other mediators. The term ‘eicosanoid’ (from the Greek word for 20) is often used to describe all the derivatives of arachadonic acid. Other common eicosanoids are the thromboxanes, leukotrienes and the hydroperoxyeicosatrienoic acids (HPETEs). Prostaglandins are usually designated by a letter, often followed by a subscript number and sometimes a Greek

Figure 31.1  Pathway for prostaglandin synthesis and sites of drug action (5-HPETE = 5-hydroperoxyeicosatrienoic acid.) MEMBRANE PHOSPHOLIPIDS Phospholipase A2 ARACHIDONATE

5-Lipoxygenase

Cyclo-oxygenase

Inhibitors: NSAIDs

5-HPETE Cyclic endoperoxides Leukotrienes PGF2 Vasodilator, stops platelet aggregation, hyperalgesic

PGE2 Vasodilator, hyperalgesic, increases mucus and decreases acid secretion in stomach, contracts pregnant uterus

Prostaglandin analogues Misoprostol: inhibits gastric secretion

TXA2 Platelet aggregator, vasoconstrictor

PGD2 Vasodilator, stops platelet aggregation, relaxes most smooth muscle but contracts bronchi

PGF2α Spasmogen, luteolytic

Prostaglandin Dinoprost, carboprost: abortifacient

C H A P T E R 3 1 P R O S TA G L A N D I N S A N D S E R O T O N I N

letter. This naming is done according to differences in chemical structure. Some general actions of prostaglandins are listed in Table 31.1. As the prostaglandins have so many diverse functions, it is not surprising that medicines that inhibit the synthesis of these local hormones have an important place in therapy. A number of prostaglandin agonists and analogues are available for clinical use, and it might be expected that the number of such medicines will increase in the future. Prostaglandins have been used for many years to induce abortions and labour, either by intra-amniotic infusions or as pessaries. Prostaglandins are very unstable and must usually be kept frozen. After thawing, any excess should be discarded. They must not be refrozen. The prostaglandins commonly used in obstetrics and gynaecology and in other reproductive processes are dealt with later on in this chapter. Other medicines that act on the eicosanoids or as eicosanoids are dealt with in the appropriate chapters, as indicated in Table 31.1. From Table  31.1 it can be seen that prostaglandins have many functions in the body. Medicines that affect prostaglandins and their synthesis are discussed in Chapters 41, 47, 48 and 56.

Termination of pregnancy and  induction of labour The most commonly used method of termination of pregnancy in the first trimester in most countries is vacuum aspiration of the uterine contents. The procedure is made easier if the cervix is both softened and dilated. This can be achieved by the use of prostaglandins. Prostaglandin E and prostaglandin F2α have actions on the uterus and cervix. As these prostaglandins can also cause uterine contractions if given in large doses, the need for surgical procedures can sometimes be avoided. Analogues of prostaglandin E2 (dinoprostone), prostaglandin  E1 (gemeprost and misoprostol) and prostaglandin  F2α (dinoprost and carboprost) are available for this purpose. Table 31.1  General actions of prostaglandins • Inhibit gastric secretion and promote mucus secretion in stomach (see Chapter 56) • Stimulate pancreatic and small intestine secretions • Induce water and electrolyte flow into the intestinal lumen • Sensitise nerve endings, causing pain (see Chapter 41) • Stimulate release of anterior pituitary hormones • Maintain renal blood flow

Common adverse effects  The prostaglandins, as already mentioned, have short half-lives and, therefore, minimal systemic adverse effects; nausea, vomiting and diarrhoea are usually observed. Vaginal bleeding, fever and uterine pain are also commonly observed. As they have bronchoconstrictor properties they must be used with extreme caution in any patient with obstructive airways disease. In the induction of labour, they can produce excessive uterine contractions, and this can lead to uterine rupture and fetal distress. Clinical considerations  Dinoprost is administered by intramyometrial injection for the treatment of postpartum haemorrhage and termination of first or second trimester of pregnancy. Dinoprostone is given intravaginally as a gel for the induction of labour. It also comes in a pessary form for insertion into the posterior fornix. Gemeprost is administered as a pessary for surgical termination of first or second trimester pregnancy. This medication is more commonly used than dinoprost because of its lower incidence of adverse effects. Misoprostol is used either sublingually or vaginally for surgical termination of pregnancy, first or second trimester miscarriage or intrauterine fetal death. The progesterone antagonist mifepristone (RU486), given orally, greatly enhances the actions of these prostaglandins on the myometrium. However, its use as an abortifacient has become controversial since it was proven to make second-trimester abortions safer and easier. It is currently available in New Zealand and has restricted access in Australia. All prostaglandin analogues should be used only in facilities where emergency obstetric and gynaecological care is available. Uterine activity and fetal condition must be monitored during therapy. There are a number of contraindications associated with these prostaglandin analogues and they vary across the types of preparations. Health professionals administering these medicines will have to consider the stage of pregnancy, the number of times the woman has been pregnant, uterine integrity, the presence of uterine infection and renal function.

Treatment for impotence An estimated ten per cent of men over the age of 21 suffer from erectile dysfunction or impotence. Prostaglandins have been known for some time to be associated with normal erectile function. Prostaglandin  E1 (alprostadil) relaxes the smooth muscle of the spongy tissue and arteries

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of the penis, increasing blood flow and facilitating an erection. It is available for the treatment of impotence and is discussed in detail in Chapter 47.

Maintenance of a patent ductus  arteriosus  In utero, the fetus does not use its lungs and the pulmonary circulation is bypassed by the ductus arteriosus, a vessel connecting the pulmonary artery with the descending aorta. This vessel normally closes at birth due to a fall in prostaglandin levels. Occasionally closure does not occur, and this condition is termed patent ductus arteriosus. Sometimes the condition can be treated using a prostaglandin inhibitor, such as the non-steroidal antiinflammatory drug indomethacin (see Chapter  41), but surgery is often needed to close off the offending vessel. If surgery is necessary, it may not be possible to carry out the procedure immediately, and patency of the ductus arteriosus may be advantageous in some neonates with other cardiovascular defects to maintain sufficient oxygenation of the blood. If this is the case, prostaglandin E1 (alprostadil) can be utilised to maintain patency until surgery is convenient and feasible. Alprostadil is thought to relax the vascular smooth muscle of the ductus arteriosus, maintaining patency. Common adverse effects  Common adverse effects include fever, apnoea, flushing, bradycardia, hypotension and seizures. Bone defects and disseminated intravascular coagulation have also been observed. This necessitates extreme watchfulness on the part of health professionals. Clinical considerations  For this condition, alprostadil is administered by continuous intravenous or intra-arterial infusion. However, the ductus arteriosus becomes desensitised to alprostadil quite rapidly. As a consequence, the period of effective therapy lasts for only four days after birth. Infants receiving therapy require close monitoring of cardiovascular and respiratory functions during this time.

Treatment of pulmonary hypertension As prostacyclin induces vasodilation, it is useful in the management of pulmonary hypertension. Prostacyclin, or prostaglandin I2 (epoprostenol), is available as a medicine in Australia. The prostacyclin analogues treprostinil (available only in Australia) and iloprost can also be used for this purpose. They serve to improve the exercise capacity in pulmonary hypertension.

Common adverse effects  Common adverse effects associated with epoprostenol and iloprost are typical of a vasodilator substance: vasodilation, headache and hypotension. Iloprost may also induce a cough. For treprostinil, the common adverse reactions include bruising, bleeding and redness at the injection site. Dyspnoea, fatigue and chest pain may also be observed. Clinical considerations These medicines can be used only by specialists experienced in the treatment of primary pulmonary hypertension. Their administration should not be stopped suddenly, as this can lead to rapid clinical deterioration in the individual being treated. Epoprostenol is given by continuous intravenous injection through a central venous catheter. Iloprost is given by nebuliser through a mouthpiece. The nebuliser solution should not contact the skin or eyes, as irritation may occur. Treprostinil is given as a continuous subcutaneous infusion.

SEROTONIN Serotonin, or 5-hydroxytryptamine (5-HT), is a chemical mediator which, depending on its location, can act as a primary neurotransmitter, a neuromodulator or an autacoid. In recent years there has been an upsurge of interest in the role of this substance in the body. Most of the body’s serotonin is found in the enterochromaffin cells of the gastrointestinal tract where its function remains obscure, but it probably acts as an autacoid in the control of gastrointestinal motility. Serotonin causes many of the pathophysiological symptoms associated with the socalled carcinoid tumours. Platelets also contain significant amounts of serotonin, which appears to play a role in platelet aggregation. Its role as a peripheral neuromodulator is complex. Serotonin promotes the release of both acetylcholine and noradrenaline at efferent nerve endings. However, in the gut the release of serotonin can be triggered by adrenergic or cholinergic stimulation. Serotonin acts on smooth muscle and tends to induce contraction (especially in the walls of blood vessels and the gastrointestinal tract), but in some circumstances it can induce relaxation. The observed physiological effects of serotonin are often a consequence of a compound interaction between afferent and efferent activation coupled with local chemical mediator release. There is a lot of interest in the role of serotonin in the central nervous system as a neurotransmitter. It acts as an inhibitory neurotransmitter, being principally involved in the regulation of sleep, mood, behaviour, sensory

C H A P T E R 3 1 P R O S TA G L A N D I N S A N D S E R O T O N I N

perception, temperature regulation and hunger (see Section VIII). Serotonin is synthesised from the amino acid tryptophan and is primarily metabolised by monoamine oxidase (MAO), an enzyme important in the metabolism of adrenaline, noradrenaline and dopamine (see Chapter 27). The action of serotonin can also be terminated through the action of cellular uptake by a serotonin transporter. As platelets do not contain enzymes to make serotonin, this transporter system is the only means by which these cells accumulate this substance. Many drugs are active either as agonists or antagonists at serotonin receptors, of which seven different subtypes have been identified. However, at this time the functional roles of only four subtypes are known. Table  31.2 shows some of the actions of serotonin at the different receptor sites and some drugs that act at these sites. Drugs that act on

serotonergic receptors have important clinical applications in the treatment of migraine (see Chapter 42) and affective disorders (see Chapter  36), as well as the management of nausea and vomiting (see Chapter 58). It is highly likely that many more selective serotonin agonists and antagonists will appear on the market for clinical use in the future for the treatment of many centrally and peripherally related conditions. In less than 12 months in the early 1990s, four very different and novel medicines with actions on serotonin receptors were released in this region: fluoxetine for the treatment of depression (see Chapter 36); ondansetron for the treatment of severe nausea (see Chapter 58); cisapride for the treatment of gastric reflux (see Chapter  56); and sumatriptan for the treatment of migraine (see Chapter 42). All these medicines are still used in this region in the management of these conditions, although cispride is available in New Zealand and through the Special Access

Table 31.2  Some actions of serotonin at different receptor sites RECEPTOR

PRINCIPAL ACTIONS

AGONISTS

ANTAGONISTS

5-HT1

Neuroinhibition: CNS tryptaminergic terminals (autoreceptors); raphe cell bodies; peripheral adrenergic terminals; intestinal cholinergic terminals. Neuroexcitation: spinal motor neurones; centrally mediated hypotension; smooth muscle contraction in some vascular and gastrointestinal tissues; smooth muscle relaxation; endothelium-derived relaxing factor release

• buspirone (partial) • LSD • sumatriptan

• LSD (peripheral) • propranolol

5-HT2

Neuroexcitation: cortical cell bodies; neuroendocrine functions; smooth muscle contractions in many vascular and other smooth muscle tissues; platelet aggregation; increased capillary permeability

• LSD • α-methyl-5-HT • methysergide (partial)

• • • • •

5-HT3

Afferent neuroexcitation: vagal afferents; chemoreceptors; gastrointestinal sensory afferents; pain afferents (and axon reflex-mediated neurogenic inflammation). Efferent neuroexcitation: superior cervical ganglion; some cardiac adrenergic terminals; bladder parasympathetic ganglion; intestinal substance P-containing neurones; intestinal neurones mediating fluid secretion; modulation of gastric emptying; nausea and vomiting

• 2-methyl-5-HT

• cocaine • metoclopramide • ondansetron

5-HT4

Efferent neuroexcitation in gastrointestinal tissues; cardiac stimulation

• cisapride • metoclopramide

5-HT5

Unknown, but present in CNS

• LSD (partial) • ergotamine

5-HT6

Present in the CNS; modulates cholinergic and glutamatergic transmission; regulation of cognition, feeding and possibly involved in affect

• lisuride (partial)

5-HT7

Mediates smooth muscle relaxation, particularly gastrointestinal and cardiovascular; possible role in circadian rhythm and sleep

cyproheptadine methysergide mianserin pizotifen nefazodone

• clozapine

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Scheme in Australia. It has been reported that ondansetron may help to control memory loss in older people, although this action is currently not listed as a recommended use.

A glance at Table  31.2 suggests tremendous therapeutic possibilities that exist in this area of pharmacology.

CLINICAL MANAGEMENT P R O S TA G L A N D I N S , P R O S TA C YC L I N A N D P R O S TA C YC L I N A N A LO G U E S Assessment ■■

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Assess women for untreated pelvic infection or previous caesarean section or major uterine surgery. These conditions are contraindicated in prostaglandin therapy for the induction or augmentation of labour. Care must be exercised in using prostaglandin therapy for the induction of labour in people with asthma, chronic obstructive pulmonary disease, cardiac disease or raised intraocular pressure (e.g. glaucoma). These conditions may be aggravated during prostaglandin therapy. Before using alprostadil in men, assess whether anticoagulants are used or whether he suffers from coagulopathies. These conditions increase the risk of urethral bleeding following alprostadil therapy and extreme care must be taken. Assess the person for severe left ventricular dysfunction, which is contraindicated in epoprostenol therapy. Assess the person for contraindications of iloprost therapy, which include active peptic ulcer and other conditions where there is an increased risk of bleeding, severe coronary heart disease, unstable angina, myocardial infarction over the past six months, severe dysrhythmias, cerebrovascular accident over the past three months and valvular defects. Before administering therapy for the treatment of pulmonary hypertension, assess baseline vital sign parameters, including heart rate and rhythm, blood pressure and respiration.

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For the induction of labour, care is taken not to produce excessive contractions with prostaglandin therapy because this may lead to uterine rupture. A qualified medical practitioner administers the first dose of alprostadil. Self-administration of the intracavernosal injection can subsequently be undertaken by the man after adequate instruction. The man is advised to stop treatment if fibrosis or pain develops in the penile shaft. Prostacyclin (epoprostenol) and prostacyclin analogues, such as treprostinil and iloprost, can be used only by specialists experienced in the treatment of primary pulmonary hypertension. Administration of epoprostenol, treprostinil or iloprost for pulmonary hypertension should not be stopped suddenly, as this can lead to rapid clinical deterioration. Epoprostenol is given by continuous intravenous injection through a central venous catheter. Treprostinil is given as a continuous subcutaneous infusion and titrated for an effective response for the treatment of pulmonary hypertension. Iloprost is given by nebuliser through a mouthpiece. The nebuliser solution should not contact the skin or eyes, as irritation may occur.

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The symptoms of erectile dysfunction will decrease with alprostadil therapy. The person’s symptoms of pulmonary hypertension will decrease when using epoprostenol, treprostinil or iloprost therapy.

Prostaglandin therapy for labour induction is used only in facilities where emergency obstetric and gynaecological care is available.

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Evaluate the effectiveness of therapy with prostaglandin, prostacyclin or prostacyclin analogues. The dose may need to be carefully titrated to achieve more effective control of symptoms. Evaluate the presence of adverse effects of the medicine.

C H A P T E R 3 1 P R O S TA G L A N D I N S A N D S E R O T O N I N

S E R O T O N I N A G O N I S T S A N D A N TA G O N I S T S Assessment ■■

■■

■■

■■

Assess the person for symptoms associated with migraine, affective disorders or nausea and vomiting. Determine whether the person has epilepsy as selective serotonin reuptake inhibitors can reduce the seizure threshold. Assess whether the person has a high risk of bleeding or is taking medicines that increase the bleeding tendency, such as warfarin, non-steroidal anti-inflammatory drugs, or aspirin as selective serotonin reuptake inhibitors can further increase this tendency. Assess whether the person has uncontrolled hypertension or peripheral vascular disease, or a past history of myocardial infarction or ischaemic heart disease. Triptan preparations used for the acute relief of migraine are contraindicated in these conditions.

Planning ■■

■■

■■

The acute symptoms of migraine will decrease following tripan therapy. The symptoms of major depression, anxiety disorders, or obsessive compulsive disorders will decrease following use of selective serotonin reuptake inhibitors. The symptoms of nausea and vomiting will decease following the use of 5-HT3 antagonists.

Implementation ■■

Treatment using a number of medicines that increase serotonin concentration levels can lead to serotonin toxicity. This combination should be avoided.

Evaluation ■■

■■

Evaluate the effectiveness of the management of affective disorders, or the treatment of migraine, or the management of nausea and vomiting. Evaluate the presence of adverse effects of the medicine.

CHAPTER REVIEW ■■

Prostaglandins and related compounds affect every organ system in the body.

■■

Prostaglandins are used in the treatment of impotence, initiation of labour and to close a patent ductus arteriosus.

■■

Serotonin is a chemical mediator that has important functional roles in the body as an autacoid, neuromodulator and neurotransmitter.

REVIEW QUESTIONS 1 To which chemical group do prostaglandins belong? Name two other chemicals that are members of this

chemical group. 2 From what cell substrate are prostaglandins formed? From what cell structure is this substance derived? Can you

suggest one reason why most tissues can make prostaglandins? 3 State two physiological effects associated with the each of the four prostaglandins covered in this chapter. 4 What is the key enzyme reaction in the formation of prostaglandins? 5 What are some common adverse reactions to be expected when prostaglandin preparations are used clinically? 6 In what two parts of the body is serotonin most abundant? 7 For each of the following physiological responses, indicate the serotonergic receptor agonist or antagonist that

you would use to change the response in the direction marked: a

decreased nausea and vomiting

b vasoconstriction

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8 What medicine education would you offer a man who has recently commenced alprostadil therapy for the

treatment of erectile dysfunction? 9 Mandy Pulit, aged 55 years, is in intensive care and receiving iloprost therapy by nebulisation for the treatment of

pulmonary hypertension. Comment on how iloprost is delivered by nebulisation. 10 Baby Jason is ordered prostaglandin E1 (alprostadil) during his stay in a neonatal intensive care unit to maintain

patency of the ductus arteriosus until surgery is scheduled. Comment on the clinical management of alprostadil required for baby Jason.

31 MEDICINE SUMMARY TABLE FAMILY

GENERIC NAME

TRADE NAME(S)

Prostaglandins E1

alprostadil

Caverject Prostin VR

E2 F2α

dinoprostone dinoprost carboprost

Cervidil Prostin E2 Prostin F2 alpha Prostin 15M

I2

epoprostenol

Flolan

Prostaglandin analogues

gemeprost iloprost

Cervagem

treprostinil

Ilomedin Ventavis Cytotec Arthrotec 50 Remodulin

Serotonin antagonists

cyproheptadine dihydroergotamine ergotamine, caffeine methysergide pizotifen

Periactin Dihydergot Cafergot Deseril Sandomigran

Setrons

dolasetron granisetron ondansetron

Anzemet Kytril Ondaz Onsetron Zofran Navoban

misoprostol + diclofenac

tropisetron Serotonin agonists Triptans

rizatriptan sumatriptan

naratriptan zolmitriptan Australia only New Zealand only

Maxalt Rizamelt Imigran Mygran Sumagran Sumatab Suvalan Naramig Zomig

C H A P T E R

32

NITRIC OXIDE AND THE ENDOTHELINS

LEARNING OBJECTIVES

KEY TERMS

After completing this chapter, you should be able to:

Endothelins

1

Briefly describe the physiological effects of nitric oxide and the endothelins.

Neuromodulation

2

Identify the pathophysiological conditions to which nitric oxide and the endothelins contribute.

Nitric oxide

3

Outline the therapeutic applications of these mediators which derive from knowledge of their pathophysiological roles.

Nitric oxide synthase (NOS) Non-noradrenaline, non-cholinergic (NANC) transmission

Nitric oxide (NO) and the endothelins are important signalling molecules that appear to play significant regulatory roles in health and disease. They affect physiological processes as diverse as vascular responsiveness, neurotransmission, cell differentiation, airway tone, cardiac contractility and inflammation. Indeed, there is some interplay between the two mediators. In some tissues, nitric oxide produces similar effects to the endothelins, while in others they counteract each other. Broadly speaking, in low concentrations they tend to be beneficial to health, while at high concentrations they tend to produce detrimental effects. There is persuasive evidence to suggest that these substances participate in the development of some human diseases. As mediators of physiological and pathophysiological processes they have recently attracted a lot of attention. A greater understanding of the properties of these substances and their roles has led to the development of therapeutic agents that alter either the tissue levels of these molecules or their effects. Up to now our knowledge of their functions is far from complete. Further research will, no doubt, yield new medicines derived from these substances for use in the treatment of debilitating chronic diseases.

S E C T I O N V I I C H E M I C A L M E D I AT O R S

The purpose of this chapter is to provide an overview of the functions of nitric oxide and the endothelins, and to discuss the current, and potential, therapeutic applications of these molecules in disease.

NITRIC OXIDE Nitric oxide, also known as nitrogen monoxide, is a highly reactive gas formed endogenously from the amino acid L-arginine. The reaction that forms nitric oxide is catalysed by the enzyme nitric oxide synthase (NOS). During its relatively brief existence (less than a second in the blood and several minutes in tissue), nitric oxide exerts its physiological effects and then is rapidly converted into various other metabolites (nitrogen dioxide, nitrite, nitrate and, under some conditions, peroxynitrite ion). When it was first identified, nitric oxide was shown to induce vasodilation following release by vascular endothelial cells. Its role here is considered constitutive, exerting a homeostatic regulatory effect on tissue blood flow. The nitrates (e.g.  glyceryl trinitrate) and related substances used in angina (see Chapter  47) and in hypertensive emergencies (see Chapter  46) act as nitric oxide donors, providing an exogenous supply of nitric oxide to the endothelium for this purpose. Nitric oxide also reduces haemoglobin to methaemoglobin, converting the iron in haem from the ferrous ion (Fe2+) to the ferric ion (Fe3+). In the presence of nitric oxide, cyanide is drawn off the cytochromes and onto methaemoglobin, reactivating cellular energy production. For this reason the nitric oxide donors, amyl nitrite and sodium nitrite, are used as an antidote in cyanide poisoning (see Chapter 22). An understanding of the possible physiological roles of nitric oxide has expanded greatly (see Figure  32.1). It plays a significant role in nervous system function. There is evidence that nitric oxide acts as a neurotransmitter in some neural pathways and is involved in autonomic nervous system pathways (see Chapter  26). Indeed, noradrenaline and acetylcholine are not the only neurotransmitters operating in this system. Neurotransmission involving chemical messengers such as nitric oxide can also contribute to autonomic function and fall under the category of non-noradrenaline, non-cholinergic (NANC) transmission. The role of nitric oxide and other novel chemical transmitters has forced us to reconsider the nature of neurotransmission and paracrine communication. Unlike classic neurotransmitters, nitric oxide is not stored in the axon terminal in vesicles and released to produce a rapid, short-lived response. It is synthesised when required (i.e.  de novo synthesis) and produces a relatively slow

response. As an autonomic nervous system transmitter it has been implicated in human physiology in the respiratory passages (it induces bronchodilation) and in the stomach (it  stimulates gastric emptying). Nitric oxide is also considered a modulator of neural transmission. This means that it can influence the release of neurotransmitter from the axon terminal and has been shown to enhance the release of acetylcholine from autonomic postganglionic fibres (see Section VI). Moreover, nitric oxide has a role in early nervous system development. This role is achieved through its involvement in the regulation of apoptosis (programmed cell death). Its role is complex, as it appears to promote apoptosis in some cells and protect others from this fate. It is believed to contribute to the formation of appropriate synaptic connections in the developing nervous system. The role of nitric oxide in inflammation is primarily to enhance this response. As a vasodilator it contributes to the vascular phase of inflammation. It also increases the permeability of the blood vessels and induces prostaglandin synthesis. Nitric oxide plays a part in the non-specific host defence against a range of microbes and cancerous cells. It also inhibits the aggregation of a number of formed elements in the blood, particularly platelets and neutrophils, and the tendency for them to adhere to the blood vessel wall. Three forms of the synthesising enzyme nitric oxide synthase have been identified. One form is associated with neuronal tissues and is called nNOS or NOS1. The second form, isolated from macrophages, is associated with immune/inflammatory functions and is called mNOS, iNOS or NOS2. The ‘i’ stands for inducible, because all body cells have the potential to express this form in response to cellular signals such as bacterial products, cytokines or lipid mediators (e.g. leukotriene B4). The third form is allied with endothelial cells and is called eNOS or NOS3. The nitric oxide induced in response to stimulation in nervous and endothelial cells (via the activation of nNOS and eNOS) is produced relatively rapidly at very low concentrations, and is short-lived. This pattern of production is associated with homeostasis. Its cellular effects are associated with the activation of a calcium-dependent second messenger system: cyclic guanosine monophosphate (cGMP) (see Chapter  27). In contrast, the nitric oxide induced in response to immune and inflammatory signals (derived via iNOS) is produced slowly, at higher concentrations, and can be sustained for a prolonged period.

CHAPTER 32

Figure 32.1  The physiological effects of 

nitric oxide

Methaemoglobin production

NITRIC OXIDE AND THE ENDOTHELINS

Nitric oxide synthase inhibitors may provide a useful strategy, particularly if they show selectivity for the different forms of nitric oxide synthase. For diseases associated with deficiencies in nitric oxide levels, the nitric oxide-donating nitrovasodilators (e.g.  glyceryl trinitrate and sodium nitroprusside) have been used for decades. Gene therapy (see Chapter  81) may also provide a means to treat such conditions by introducing the nitric oxide synthase gene into diseased tissues.

THE ENDOTHELINS Vasodilation

Inflammation

Apoptosis

Neurotransmission

Modulate cholinergic transmission

Alterations in normal production of nitric oxide have been implicated in some human disease states. There is evidence that inadequate nitric oxide production may contribute to the pathophysiology of diabetes mellitus, atherosclerotic diseases, impaired wound healing and hypercholesterolaemia. Excessive or chronic nitric oxide production has been proposed as a factor in neurodegenerative disorders such as Parkinson’s disease, as well as septic shock, pain, cancer and chronic inflammation. There is a lot of interest related to the development of therapeutic agents that act by altering nitric oxide levels in the body. For diseases characterised by excessive nitric oxide production, research is continuing on L-arginine analogues that compete with L-arginine for nitric oxide synthase binding sites (for more on enzyme competition see Chapter 17) and result in lower nitric oxide production.

The endothelins are a group of three related endogenous peptides—endothelin-1 (ET-1), endothelin-2 (ET-2) and endothelin-3 (ET-3)—produced by endothelial cells. The focus of this discussion is on endothelin-1, as more of its functions have been described. ET-1 produces contraction of smooth muscle cells (a spasmogenic action), induces increased vascular permeability, acts as a tissue growth factor and stimulates cellular proliferation (a mitogenic action). At this stage, two endothelin receptor subtypes have been identified, ETA and ETB, which are G  protein coupled and linked to second messenger production. The second messenger in this case is inositol trisphosphate (see Chapter  27). The ETA  receptor is relatively selective for ET-1 and ET-2, while the ETB receptor shows no particular selectivity for one or other of the endothelins. The role of ET-1 in each of the body systems has been described, at least to some degree (see Figure 32.2). In the cardiovascular system it acts as a potent vasoconstrictor at ETA  receptors. It has been suggested that this effect may be due, at least in part, to the release of renin, aldosterone, angiotensin  II, vasopressin, the catecholamines and the modulation of nitric oxide and atrial natriuretic hormone release. Clearly, the role of endothelins in blood pressure control is complex, as stimulation of ETB  receptors stimulates vasodilation; this is due to the release of nitric oxide and prostacyclin (see Chapter  31) from endothelial cells. The seemingly paradoxical effects can be explained by the finding that the distribution of these receptor subtypes varies across blood vessel types, which results in different net effects on blood pressure and perfusion in various parts of the circulation. ET-1 is believed also to have positive inotropic effects on the heart and may even have negative chronotropic effects. Endothelins are thought to play a part in the pathophysiology of cardiovascular-related diseases such as hypertension (both the systemic and pulmonary forms), ischaemic heart disease, myocardial infarction, congestive cardiac failure and cerebral vasospasm. This effect on cardiovascular-related diseases is due to the

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Figure 32.2  The physiological effects of 

the endothelins

The endothelins have been shown to play a role in embryonic tissue development and differentiation as a growth factor. Animal studies have indicated that these peptides contribute to the normal development of facial and throat structures, the middle ear, the aorta, and adjacent arteries and intestines.

E N D O T H E L I N R E C E P TO R A N TA G O N I S T S Tissue growth Cellular proliferation

Predominantly vasoconstriction Increased vascular permeability

Medicines that are emerging from a better understanding of the role of endothelins in health and disease are the endothelin receptor antagonists. This group of drugs shows some promise in treating cardiovascular disease. Two endothelin receptor antagonists are available in this region for use in the treatment of pulmonary arterial hypertension: bosentan and ambrisentan. Mechanism of action 

Sodium and water balance Acid-base balance

Bosentan binds to both ETA and ETB  receptors and blocks access to ET-1. Ambrisentan is more selective for ETA  receptors. Receptor blockade triggers arterial vasodilation, as well as decreases the inflammation and tissue remodelling. Common adverse effects 

Neuromodulation balance Catecholamine release

Common adverse effects include raised serum liver enzyme levels, headache, flushing, palpitations, chest pain and oedema. A dose-related decrease in haemoglobin levels is associated with bosentan treatment. Nasal congestion may develop during ambrisentan treatment. Clinical considerations 

vasoconstricting action and also the mitogenic action (which leads to the remodelling processes of fibrosis, hypertrophy and hyperplasia) in the vasculature and heart. In the lungs, ET-1 can induce bronchoconstriction, increase mucus secretion and activate inflammatory cells. It has been implicated in the development of allergic rhinitis. In the central nervous system the endothelins appear to modulate endocrine function, cardiorespiratory function and possibly behaviour. In the adrenal gland, ET-1 increases the release of catecholamines into the circulation from the adrenal medulla. In the endometrium, there is evidence that ET-1 stimulates a vasoconstrictive response to reduce menstrual bleeding and may stimulate endometrial regeneration after menstruation. In the kidney, the endothelins play a role in sodium and water excretion, as well as acid–base balance. Research has shown that these substances are implicated in renal failure.

Liver function needs to be monitored monthly during therapy for evidence of hepatotoxicity. People with moderate to severe liver impairment should not receive treatment with this medicine. People who have aminotransferase (ALT/AST) levels that are three times the upper limit of normal before treatment should not receive bosentan. ALT/AST levels are monitored before starting treatment and then each month during therapy. During therapy, people should inform their doctor immediately if they experience nausea, vomiting, abdominal pain, fatigue, dark urine and jaundice, because these clinical manifestations may be an indication of liver impairment. Treatment is stopped indefinitely if ALT/AST levels rise to five to eight times the upper limit of normal or if individuals experience clinical manifestations of liver impairment. The medicine dose is reduced or temporarily stopped if ALT/AST levels rise above three to five times over the upper limit of normal.

CHAPTER 32

Haemoglobin levels and blood pressure should also be monitored regularly during bosentan therapy, because it can exacerbate anaemia and hypotension. These medicines are contraindicated in pregnancy. Women need to confirm they are not pregnant before starting treatment and pregnancy tests are recommended each month during treatment and for three months after stopping treatment. Non-hormonal contraceptive

NITRIC OXIDE AND THE ENDOTHELINS

therapy (such as a barrier method) is recommended with bosentan as it may reduce the effectiveness of hormonal contraception. Concurrent therapy with the immunosuppressant cyclosporin or the sulfonylurea glibenclamide is also contraindicated. Cyclosporin increases plasma ambrisentan or bosentan levels, while glibenclamide induces elevations in serum liver enzyme levels.

CLINICAL MANAGEMENT E N D O T H E L I N R E C E P T O R A N TA G O N I S T S Assessment ■■

■■

■■

Assess for presence of moderate to severe liver impairment, as generally these people should not receive treatment with bosentan or ambrisentan.

■■

■■

In women, assess for pregnancy. Use of bosentan or ambrisentan is contraindicated in pregnancy. Assess whether the person is receiving concurrent therapy with the immunosuppressant cyclosporin or the sulfonylurea glibenclamide. Bosentan therapy is contraindicated when the person is receiving these medicines.

■■

■■

Planning ■■

The person’s symptoms of pulmonary hypertension will decrease when using bosentan or ambrisentan.

■■

Observe for raised serum liver enzyme levels, headache, flushing and oedema during therapy. Aminotransferase (ALT/AST) levels are monitored before starting treatment and then each month during therapy.

Treatment is stopped indefinitely if ALT/AST levels rise to five to eight times the upper limit of normal or if people experience clinical manifestations of liver impairment. The dose of bosentan or ambrisentan is reduced or temporarily stopped if ALT/AST levels rise above three to five times over the upper limit of normal. Haemoglobin levels and blood pressure should also be monitored regularly during therapy.

Evaluation ■■

Implementation ■■

During therapy, people should inform their doctor immediately if they experience nausea, vomiting, abdominal pain, fatigue, dark urine or jaundice.

■■

Evaluate the effectiveness of therapy with bosentan or ambrisentan. The dose may need to be carefully titrated to achieve more effective control of symptoms. Evaluate the presence of adverse effects of the therapy.

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CHAPTER REVIEW ■■

Nitric oxide and the endothelins are important signalling molecules.

■■

Nitric oxide and endothelin-1 play a role in normal homeostasis and in the development of disease.

■■

A number of medicines are being developed to alter the levels of, or the responses to, these mediators in order to treat selected diseases. Endothelin-1 antagonists called bosentan and ambrisentan are available in this region for the treatment of pulmonary arterial hypertension.

REVIEW QUESTIONS 1

For each of the following processes, indicate whether nitric oxide and/or the endothelins have a role and briefly outline that role: a

inflammation

b airway responsiveness c

vascular responsiveness

d embryonic tissue development e 2

neurotransmission

For each of the following diseases, indicate whether nitric oxide and/or the endothelins have a role to play: a

hypertension

b chronic inflammation c

diabetes mellitus

d renal failure 3

Outline the rationale for the development of medicines that affect nitric oxide levels.

4

Outline the rationale for the development of medicines that affect the responses to the endothelins.

5

Robert Druga, aged 58 years, is ordered a course of bosentan therapy to treat pulmonary hypertension. Outline the biochemical parameters that will need to be monitored during therapy.

32 MEDICINE SUMMARY TABLE FAMILY NAME

GENERIC NAME

TRADE NAME(S)

Endothelin receptor antagonists

ambrisentan bosentan

Volibris Tracleer

CHAPTER 32

NITRIC OXIDE AND THE ENDOTHELINS

C A S E S T U DY 1

C A S E S T U DY 3

Ms FJ, aged 35  years, has pulmonary hypertension and is prescribed bosentan 62.5 mg twice daily for an initial period of four weeks. She also has type 2 diabetes, which is treated with diet and oral hypoglycaemic therapy. Before bosentan therapy, her doctor orders a series of pathology tests and counsels her about clinical manifestations she should look out for during therapy.

Ms CC, aged 59 years, is in intensive care for the treatment of pulmonary hypertension. She is ordered an intravenous epoprostenol infusion. The infusion is administered through a volumetric pump into a central venous catheter. Her dose is titrated according to cardiopulmonary haemodynamic parameters and the onset of adverse effects.

Questions

Questions 1

What is the mechanism of action of epoprostenol?

1

What pathology tests are required before and during bosentan therapy? Give reasons for your answer.

2

Explain why epoprostenol needs to be administered through a volumetric pump.

2

Which oral hypoglycaemic agent is contraindicated during bosentan therapy?

3

What adverse effects limit the therapeutic effectiveness of epoprostenol?

3

What precautions will Ms FJ need to take during bosentan therapy?

4

How should epoprostenol therapy be ceased? Explain your answer.

4

What counselling would the doctor offer Ms FJ?

5

What clinical management is required of the intravenous infusion administered through the volumetric pump? (Refer to Chapter 7, Table 7.16, for assistance.)

C A S E S T U DY 2 Mr JJ, aged 40 years, has symptoms of allergic conjunctivitis in the spring and buys some ketotifen eye drops to treat the condition. His pharmacist says that one drop administered once daily should help with his allergic condition. After about one week of therapy Mr JJ notices that his symptoms have not improved. He is also unsure about the most appropriate way to administer the eye drops.

Questions

C A S E S T U DY 4 Mr JK, aged 50  years, experiences severe allergic rhinitis, especially during windy spring days. He often takes 4  mg cyproheptadine tablets to treat his condition, However, Mr JK finds that he experiences dizziness after taking his medicine but perseveres with treatment since he finds it very effective.

Explain why Mr JJ’s symptoms of allergic conjunctivitis have not improved after one week of therapy.

QUESTIONS 1

What type of antihistamine is cyproheptadine?

2

What adverse effects are commonly experienced following eye instillation of ketotifen?

2

Are there any alternative antihistamines that you could recommend to Mr JK that are less likely to cause dizziness?

3

What education would you provide Mr JJ with about the correct way to administer the eye drops? (Refer to Chapter 7, Table 7.3, for assistance.)

3

What precautions should Mr JK take if he continues to take cyproheptadine?

4

Aside from the treatment of allergic rhinitis, what are other uses for cyproheptadine?

1

FU R T H ER RE A DI N G Badesch DB, Feldman J, Keogh A, Mathier MA, Oudiz RJ, Shapiro S, Farber HW, McGoon M, Frost A, Allard M, Despain D, Dufton C, Rubin LJ and the ARIES-3 Study Group, 2012, ‘ARIES-3: ambrisentan therapy in a diverse population of patients with pulmonary hypertension’. Cardiovascular Therapeutics, 30, 93–9. Elsenshade TA, Browman KE, Bitner RS, Strakhova M, Cowart MD, Brioni JD, 2008, ‘The histamine H3 receptor: an attractive target for the treatment of cognitive disorders’, British Journal of Pharmacology, 154, 1166–81. Jandeleit-Dahm KA & Watson AM, The endothelin system and endothelin receptor antagonists, Current Opinion in Nephrology and Hypertension, 2012, 21, 66–71. Liu C, Chen J, Gao Y, Deng B, Liu K, 2009, ‘Endothelin receptor antagonists for pulmonary arterial hypertension’, Cochrane Database of Systematic Reviews, Issue 4, Art. No.: CD004434. O’Mahony L, Akdis M & Akdis CA, 2011, Regulation of the immune response and inflammation by histamine and histamine receptors, Journal of Allergy and Clinical Immunology, 128, 1153–1162.

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Sica DA, 2008, ‘Endothelin receptor antagonism: what does the future hold?’ Hypertension, 52, 460–1. Simons FER, & Simons KJ, Histamine and H1 antihistamines: celebrating a century of progress, 2011, Journal of Allergy and Clinical Immunology, 128,1139–1150.

W E B R E S O UR C E S Cardiovascular Pharmacology Concepts: Endothelin Receptor Antagonists www.cvpharmacology.com/vasodilator/ETblockers.htm Cardiovascular Physiology Concepts: Nitric Oxide www.cvphysiology.com/Blood%20Flow/BF011.htm Prostanoids – Prostaglandins, Prostacyclins, and Thromoboxanes. The Lipid Library lipidlibrary.aocs.org/Lipids/eicprost/index.htm

S E C T I O N

VIII

T H E M O D U L AT I O N O F B E H AV I O U R , COGNITION AND M O TO R A C T I V I T Y The brain is the man; its health is essential for normal living; its disorders are surely the most profound of human miseries; and its destruction annihilates a person humanly, however intact his body. H. CHANDLER ELLION—THE SHAPE OF INTELLIGENCE: THE EVOLUTION OF THE HUMAN BR AIN

The brain is a world consisting of a number of unexplored continents and great stretches of unknown territory. S A N T I A G O R A M O N Y. C A J A L , N E U R O S C I E N T I S T , N O B E L P R I Z E W I N N E R

In the study of brain functions we rely upon a biased, poorly understood, and frequently unpredictable organ in order to study the properties of another such organ; we have to use a brain to study a brain. WILLIAM C. CORNING AND MARTIN BALABAN—THE MIND: BIOLOGICAL APPROACHES TO ITS FUNCTIONS

The consequences of conditions that affect the brain can be profound. Disorders of the brain can affect our behaviour and emotions, our thought processes, our perspective on the world and our place in it, as well as the manner in which we interact with our friends and family. Such illnesses can sometimes affect our ability to move normally. In many cases, once a brain illness is diagnosed it may continue to progress, leading to deteriorating brain function.

S E C T I O N V I I I T H E M O D U L AT I O N O F B E H AV I O U R , C O G N I T I O N A N D M O T O R A C T I V I T Y

One of the major problems associated with the management of central nervous system (CNS) illness is that our knowledge of the brain is still quite incomplete. Having said this, the CNS  disorders are often described in terms of defects in the normal functioning of neurotransmitters. Considerable emphasis is placed on developing an understanding of CNS neurotransmitter systems (Chapter 33), their role in brain function and the effects of drugs on neurotransmission. This section deals with medicines that are used in the management of CNS disorders, such as psychosis (Chapter  34), anxiety and insomnia (Chapter  35), depression (Chapter  36), neurodegenerative disorders (e.g. Parkinson’s disease, Huntington’s disease, multiple sclerosis, motor neurone disease and Alzheimer’s disease; see Chapter 37) and seizures (Chapter 38), as well as attention disorders and narcolepsy (Chapter 39).

C H A P T E R

33

GENERAL CONCEPTS OF PSYCHOPHARMACOLOGY

LEARNING OBJECTIVES

KEY TERMS

After completing this chapter, you should be able to:

Brain functions

1

Identify the major brain regions and their functions.

Drug specificity

2

Indicate how discrete brain regions interact to control some functions.

Neuromodulation

3

Identify the principal chemical transmitters involved in brain function and the functions they influence.

Neurotransmitters

4

Identify some examples of illnesses that are based on alterations in neurotransmitters in the brain.

The human brain is a very complex organ, and our present understanding of it can best be described as rudimentary. It is responsible for all affective (emotional) and cognitive (thinking) processes, and is as capable of coordinating corporeal functions (e.g. eating, sleeping, walking, talking) as it is of pursuing abstract thought. Sometimes imbalances in mental functioning occur that can result in one of a number of brain disturbances: disorders such as schizophrenia, depression, anxiety or Parkinsonism. (The pathophysiology of these conditions is discussed in subsequent chapters in this section.) The onset of such conditions can make normal functioning within society difficult, if not impossible. The use of psychopharmacology in their treatment may be a necessary part of the reintegration of affected individuals in the community. The medicines used to treat brain disturbances are known as psychotropic agents. The mechanism of action of many of these medicines is not well understood. This is not surprising, as our understanding of how the brain works is far from complete. Essentially, psychotropic agents act on chemical transmitter–receptor systems within the brain. Depending on the nature of the brain disturbance, it may be desirable to either mimic endogenous transmitters or block them in order to produce favourable mental effects.

S E C T I O N V I I I T H E M O D U L AT I O N O F B E H AV I O U R , C O G N I T I O N A N D M O T O R A C T I V I T Y

To gain an understanding of how these medicines work, it is necessary first to look at the functions of the principal brain regions and then the nature of the chemical transmitter– receptor systems found within these regions.

DIVISIONS OF THE BRAIN Moving in a rostrocaudal (i.e. superior to inferior) direction through the brain, the first anatomical region is the cerebrum, comprising the left and right cerebral hemispheres, cortex and associated subcortical nuclei (hippocampus, basal ganglia and amygdala). The next region is the diencephalon, encompassing the thalamus and the hypothalamus. Then, most inferiorly, are the brainstem and cerebellum. The brainstem consists of the midbrain, pons and medulla oblongata. The cerebellum is positioned posteriorly between the pons and medulla. These anatomical regions are represented in Figure 33.1. Functionally, some processes are the exclusive domain of one particular brain region. However, it is apparent that many brain regions are interconnected so that the control of certain cerebral functions can be achieved in an integrated and cooperative way. A brief summary of the main functions of these regions follows.

Cerebrum The cerebrum is responsible for the precise perception and interpretation of sensation, the initiation of skeletal muscle movement and communication. It is also the seat of the intellect and of abstract thought.

Diencephalon The thalamus acts as a relay for incoming sensory information by sorting out one type of sensation from another and sending it to the most appropriate region of the cortex for processing. It also relays motor impulses from the cortex to lower motor centres. The hypothalamus is the principal integration centre of visceral function. It regulates appetite, body temperature, fluid levels, hormone production and secretion, as well as biological rhythms.

Cerebrum–diencephalon interactions The cerebrum and diencephalon cooperate in memory formation, as well as in the control of emotions and behaviour. The network involved with these functions is called the limbic system, and includes areas of the cortex, hippocampus, amygdala, fornix, thalamus and hypothalamus.

Brainstem The brainstem acts as a conduction pathway between higher and lower brain centres for both sensory and motor information. The medulla oblongata contains control centres for important visceral functions, such as heart rate (cardiac centre), blood pressure (vasomotor centre),

Figure 33.1 Principal parts of the human brain A sagittal cross-section indicating the principal parts located within the right side of the human brain. Cerebrum

Corpus callosum Hypothalamus Pituitary gland

Thalamus Midbrain

Pons Cerebellum Medulla oblongata

Spinal cord Source: © Dorling Kindersley.

CHAPTER 33 GENERAL CONCEPTS OF PSYCHOPHARMACOLOGY

respiratory rate (respiratory centres), coughing (cough centre) and vomiting.

Brainstem–diencephalon–cerebrum interactions The brainstem, thalamus and cerebral cortex cooperate to control the level of consciousness via an integrated network called the reticular activating system.

Cerebellum The cerebellum is involved in the maintenance of equilibrium and posture. It monitors and modifies motor impulses from higher centres to provide smooth and coordinated skeletal muscle movements. It may also be involved in the control of behaviour.

Motor pathways The motor pathways from cerebrum to spinal cord that control skeletal muscles incorporate two discrete systems: the pyramidal and extrapyramidal pathways. The pyramidal pathways are responsible for the activation of skeletal muscles, whereas the extrapyramidal pathways modulate voluntary muscle movements. The extrapyramidal pathways are involved in the maintenance of muscle tone and balance as well as being concerned with the coordinated movement of the head and eyes towards visual stimuli.

CHEMICAL TRANSMITTERS Chemical transmitters known to be involved in mental processes include noradrenaline, adrenaline, dopamine, serotonin, acetylcholine, glutamate and gammaaminobutyric acid (GABA). The number of putative neurotransmitters thought to be involved in brain function is ever-increasing. The list includes glycine and histamine. In addition to their classic role in synaptic transmission, some neurotransmitters may act as neuromodulators in certain nerve pathways. Before describing the characteristics of each of the major transmitters, it is useful to define the term neuromodulation.

Neuromodulation Classically, neurotransmitters are released from one neurone to activate another. The activation involves triggering an action potential in the receiving cell. Neuromodulators bias a nerve cell’s response to its neurotransmitter. They alter the response of a nerve cell or a nerve circuit to its neurotransmitter(s) to either enhance or suppress impulse transmission. Importantly, neuromodulators produce negligible effects on the nerve membrane potential of the target neurone in the pathway.

As we examine each of the following neurotransmitters, we should note that in some pathways the chemical may act to modulate activity, and in others it may primarily activate nerve cells.

Acetylcholine Acetylcholine is thought to play a major role in cognitive function and memory formation as well as motor control. Cholinergic nerves are associated with the pyramidal pathway, thalamocortical sensory pathways (particularly those involved in hearing and sight), the hippocampus (involved in memory), and the reticular activating system controlling arousal and consciousness. The motor pathways are essentially nicotinic, whereas in cognitive function, memory and consciousness, M1  muscarinic receptors predominate (see Chapter 28).

Dopamine Dopamine is involved in behaviour, hormone release, motor control and emesis. Areas of the brain that are found to contain dopaminergic nerves are the limbic system, the extrapyramidal pathway (where dopamine modulates the activation of cholinergic neurones), the chemoreceptor trigger zone within the medulla (which can stimulate the vomiting centre) and the pathways connecting the hypothalamus with the pituitary gland (involved in the release of prolactin and other hormones). At least five subtypes of central dopamine receptor have been identified and are called D1, D2, D3, D4 and D5  receptors. Central dopamine receptor activation has been linked to the development of addiction. The distribution of dopamine receptor subtypes is yet to be fully elucidated.

Noradrenaline and serotonin Both transmitters seem to be involved in similar functions within the brain: arousal, sleep, mood, appetite, temperature control and hormone release. Noradrenaline can stimulate α- and β-adrenergic receptor subtypes (see Chapter  27). Serotonin (also known as 5-hydroxytryptamine, or 5-HT) may also have a role in pain perception and behaviour. At least six subtypes of central serotonin receptors have been identified and are called 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7 receptors. The effects of serotonin receptor activation are described in Chapter 31. Consistent with this, these neurotransmitters are distributed throughout similar areas of the brain, predominantly in lower brain centres: the hypothalamus and brainstem (important parts of the reticular activating system). The raphe nuclei of the midbrain are rich in serotonin-containing neurones.

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GABA GABA is widely distributed throughout the brain and spinal cord. It is now considered to be the major inhibitory neurotransmitter in the central nervous system (CNS), and it acts to modulate the activity of excitatory pathways. It is formed from the excitatory transmitter glutamate (see below). There are two subtypes of GABA receptors: GABAA and GABAB receptors. Motor control, consciousness, level of arousal and memory formation are all inhibited by GABA.

Glutamate Like GABA, glutamate is widely distributed throughout the CNS. It is considered the major excitatory CNS neurotransmitter. It can stimulate a number of receptor types in the brain and spinal cord, the most important being N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5methyl-isoxazole propionic acid and kainate receptors. When stimulated, NMDA receptors promote calcium movement into cells, and this underlies the excitation. The psychotropic agents ketamine and phencyclidine (see Chapters 24 and 43) are, in fact, selective NMDA receptor antagonists. Glutamate appears to have a modulatory influence on CNS circuitry. Glutamate facilitates learning and memory. The brain is very vulnerable to glutamate-mediated

overexcitation; this results in excitotoxicity. In this state, calcium influx into the nerve cell is enhanced. Raised intracellular calcium levels lead to the activation of enzymes and free radicals. Ultimately, cell integrity is disrupted and the nerve cell dies. Excitotoxicity has been demonstrated in strokes and some neurodegenerative diseases. Glutamate has also been implicated in the development of epilepsy. A summary of the functions controlled by particular brain regions, the transmitters involved and the conditions with which they are associated can be found in Table 33.1.

DRUG SPECIFICITY One of the problems associated with psychotropic agents is specificity. For example, the particular brain function we want to alter may be mediated by dopamine receptors. However, dopamine receptors are known to be involved in a number of brain functions. These other functions will be affected by the drug therapy because we have no way of restricting the site of action to one region once the drug enters the brain. This lack of specificity accounts for many of the profound side-effects associated with psychotropic therapy. The only way to overcome these side-effects is to identify subtypes of receptors that may lead to the development of more specific medicines. As you will see in the following chapters, to some extent, this approach has proven successful.

Table 33.1 Brain regions and chemical transmitters TRANSMIT TER

BRAIN REGION

FUNCTIONS

RELATED CONDITION

Acetylcholine

Cerebral cortex, thalamocortical tracts, pyramidal pathway, reticular activating system

Cognition, skeletal muscle movement, memory, consciousness

Parkinson’s disease, dementia

Dopamine

Extrapyramidal pathway, limbic system, chemoreceptor trigger zone, hypothalamus

Skeletal muscle movement, behaviour, emesis, hormone release

Parkinson’s disease, inhibition of hormone release, aberrant behaviour

Noradrenaline

Hypothalamus, reticular activating system

Arousal, sleep, mood, appetite, hormone release, body temperature

Eating disorders, depression, insomnia

Serotonin

As for noradrenaline

As for noradrenaline, behaviour, pain transmission

As for noradrenaline

GABA

All regions

Motor control, memory, consciousness

Aberrant behaviour, insomnia, anxiety

Glutamate

All regions, but abundant in cortex and basal ganglia

Learning and memory

Epilepsy, excitotoxicity, neurodegenerative disease

CHAPTER 33 GENERAL CONCEPTS OF PSYCHOPHARMACOLOGY

CHAPTER REVIEW ■■ ■■

■■

■■

The major parts of the human brain are the cerebrum, diencephalon, brainstem and cerebellum. The cerebrum is involved in motor and sensory function and is the seat of the intellect. The diencephalon comprises the thalamus, which acts as an information sorting area, and the hypothalamus, which is an integration area for visceral functioning. The brainstem contains control centres for heart rate, respiratory rate and blood pressure. The cerebellum controls muscle tone and posture, and facilitates smooth and coordinated muscle movements. Neuromodulators act to modify neurotransmission, but do not actually activate nerve transmission along a pathway. Acetylcholine, dopamine, noradrenaline and serotonin are key neurotransmitters in the brain. Glutamate and GABA can act as neuromodulators in the CNS.

REVIEW QUESTIONS 1

State the function(s) of the following brain regions: a

thalamus

b cerebellum 2

c

cerebrum

d medulla

Identify the brain regions that participate in the control of the following functions: a

consciousness

b motor control c 3

behaviour

Which neurotransmitter(s) is/are involved in the control of the following functions? a

mood

b behaviour c 4

emesis

skeletal muscle movement GABA

b dopamine c

d serotonin e

glutamate

noradrenaline

State which neurotransmitter(s) is/are involved in the following conditions: a

Parkinsonism

b depression 6

e

Which brain functions are thought to be associated with the following neurotransmitters? a

5

d arousal

c

aberrant behaviour

d stroke

Identify the receptor subtypes associated with the following transmitters: a

dopamine

b glutamate c

GABA

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34

ANTIPSYCHOTIC AGENTS

LEARNING OBJECTIVES

KEY TERMS

After completing this chapter, you should be able to:

Atypical (second generation) antipsychotics

1

Explain what is meant by psychoses.

2

Outline the characteristics of schizophrenia.

3

Describe the use, mechanism of action and adverse effects of antipsychotic medications.

4

Compare and contrast the typical (first generation) and atypical (second generation) antipsychotic medications.

Extrapyramidal effects Neuroleptic malignant syndrome (NMS) Oculogyric crisis Psychoses Schizophrenia Typical (first generation) antipsychotics

Psychoses are mental health disorders characterised by aberrant behaviour and disturbed emotional states. They include conditions such as schizophrenia, severe agitation and some forms of dementia. The underlying pathophysiology of the psychoses remains unclear; however, it has been argued that they may be associated with a disturbance in catecholamine levels in the central nervous system (CNS). It has long been known that people with schizophrenia have a higher urinary output of catecholamine metabolites than the general population. The most effective medicines in the treatment of the psychoses are the central dopamine receptor antagonists. They are thought to redress the chemical imbalance; however, they do not effect a cure. Indeed, the adverse effect profile of these medicines can be quite incapacitating, which greatly affects treatment adherence.

CHAPTER 34 ANTIPSYCHOTIC AGENTS

SCHIZOPHRENIA AND DOPAMINE RECEPTORS Schizophrenia is a relatively common, chronic and debilitating form of psychosis. It affects around 1 per cent of the population, with the majority of people having their first psychotic episode between the ages of  15 and 25. The pathophysiological brain changes underlying schizophrenia may occur early in development while we are in the uterus, and genetic factors have been implicated in the development of this condition. For some people there is a strong predisposition towards schizophrenia, but the condition tends to remain subclinical. A traumatic life event or the use of psychotrophic drugs, such as marijuana or LSD, may be all that is needed to trigger the first episode in these individuals. Symptoms of schizophrenia are described as either negative or positive. Positive symptoms involve characteristics that are either present when they would normally not be expected or manifest in the extreme. Positive symptoms include delusions, disorganised speech and/or thought, distorted perceptions and emotions, hallucinations and the belief that one is under the control of an external agency. Negative symptoms are characteristics that should normally be expected to be seen but are now absent or deficient. Negative symptoms include toneless speech, vacant eyes, social withdrawal, anhedonia (lack of enjoyment) and apathy. The causes of schizophrenia are still a mystery, but some have argued that the condition is associated with increased dopaminergic activity in certain parts of the brain, particularly the prefrontal cortex, limbic areas (areas important in behaviour and emotion) and the striatum. This is known as the dopamine hypothesis of schizophrenia. While it is a useful theory, it is seen as a bit simplistic and fails to provide a consistent picture of the condition. As stated in Chapter 33, there are 5 subtypes of dopamine receptors: D1 to D5. Dopamine receptors are G-proteincoupled receptors that alter the activity of adenylate cyclase, either increasing or decreasing the production of the second messenger cyclic adenosine monophosphate (cAMP). Generally, the 5 subtypes are grouped into two classes: one class increases cAMP and are exclusively located postsynaptically (D1 and D5 receptors), while the other class decrease cAMP (D2, D3 and D4 receptors). Table 34.1 shows the effects on cAMP levels of each dopamine receptor subtypes, their functions and locations in the CNS. The D2 subtype of receptors is probably the most important in psychotic illnesses. Positron emission

tomography scanning of the brains of people with schizophrenia has demonstrated an increase in D2 receptors in the nucleus accumbens area of the brain (a region associated with reward and addictive behaviour). The relationship between antipsychotic agent effects and D2  selectivity is well established. Antipsychotic agent selectivity for D2  receptors in the higher centres of the cerebrum appears to produce greater therapeutic benefit. In part, this is because the receptor specificity produces fewer adverse effects. There is evidence that D1, D3 and D4 receptors may also be involved in antipsychotic activity. Table  34.1 shows the possible functions and second messengers associated with dopamine receptor subtypes.

Table 34.1  Classification of dopamine 

receptor subtypes TYPE

EFFECT ON cAMP

LOCATION IN THE CNS AND POSSIBLE FUNCTIONS

D1

cAMP ↑

Postsynaptic stimulation of function. Important in the control of locomotion. Located in the midrain, cortex, limbic system, hypothalamus, cerebellum, thalamus and hippocampus.

D2

cAMP ↓

Presynaptic inhibition of dopamine synthesis, release and neurone firing (autoregulation). Also found postsynaptically. Important in locomotion. Highest concentration in corpus striatum, reward centres; also found in the limbic system. Many antipsychotics act on this receptor.

D3

cAMP ↓

Located both presynaptically and postsynaptically. Mostly found in the limbic part and cortex of the brain. Some modulation of behaviour and cognition. Involved in inhibition of locomotion, reward and reinforcement.

D4

cAMP ↓

Similar to the D3 receptors. Clozapine has an affinity for D4 receptors. Located in midbrain, cortex, thalamus and amygdala.

D5

cAMP ↑

Postsynaptic stimulation of function. Located in cortical regions, midbrain, hypothalamus and hippocampus.

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Serotonergic, GABAergic and glutamatergic receptor systems in the brain have also been implicated in psychosis. Antipsychotic agents can be classified as either typical or atypical agents. Typical antipsychotics (otherwise known as first generation or classic antipsychotics) are much more active on the D2 receptors than are the atypical ones. The atypical agents (also known as second generation antipsychotics), having less affinity for the D2 receptors, usually have a lower incidence of debilitating motor disturbances (see below). The lower frequency of these motor adverse effects has led to an increased use of the atypical antipsychotic agents as first-line therapy in preference to the classic group. The term atypical was developed as a label for the newer group of antipsychotics because of the differences in receptor affinity compared to the classic medicines. However, the term atypical is increasingly regarded as inappropriate given that atypical can also mean irregular or abnormal. This is clearly not the case regarding the therapeutic usefulness of these medicines in psychosis. As a consequence, the term atypical is falling out of favour, being supplanted by the term second generation antipsychotics. In the following section we examine the characteristics of these two major classes of antipsychotic agent.

ANTIPSYCHOTIC AGENTS First generation (typical) antipsychotics Mechanism of action The antipsychotic agents, sometimes referred to as neuroleptics or major tranquillisers, are normally classified according to their chemical structure. The term neuroleptic is derived from neurolepsy, which has been used to define a state of apathy and mental detachment (Greek, neuron, nerve and lepsis, seizure). There are at least seven basic types of antipsychotic agent (based on their chemistry) used in Australia and New Zealand. The three first generation (or typical) antipsychotic drug groups are the phenothiazines, butyrophenones and the thioxanthenes (see Table 34.2 for a complete list of specific medicines). These three groups of drugs probably have similar mechanisms of action on the CNS. Their exact mode of action remains unclear. As previously mentioned, their main action is to antagonise dopamine receptors, but they also have antimuscarinic, antihistaminic (H1) and antiserotonergic action as well as acting as α1-blockers. Due to their broad spectrum of activity, many adverse effects are associated with these groups of drugs.

Common adverse effects The adverse effect profile of the classic antipsychotic agents is largely due to the diffuse distribution of dopaminergic neural systems in the brain. Dopaminergic neurons are involved in the control of behaviour and emotions and are the primary therapeutic targets of these medicines. This transmitter system is also associated with central motor control, endocrine regulation at the hypothalamic– pituitary level and modulation of the vomiting centre in the medulla. Blockade of these other dopaminergic centres results in severe motor disturbances (also called extrapyramidal effects), endocrine disruption and inhibition of vomiting.

EXTRAPYRAMIDAL DISTURBANCES The extrapyramidal system is a neuromodulatory pathway that acts to modify the activity of the excitatory (pyramidal) pathway to skeletal muscles. It is responsible for ensuring smooth, coordinated voluntary muscle movement and the appropriate level of muscle tone. The extrapyramidal symptoms produced by the antipsychotics can be classified into four types. First, drug-induced Parkinsonian symptoms (including tremor, rigidity and poverty of movement) are the most common. An antimuscarinic agent (see Chapter 28) such as benzhexol is often given with these antipyschotic agents to treat the symptoms of Parkinsonism. It is advisable to administer these antimuscarinic agents with the oral preparations if they are to be given for prolonged periods, and especially with high doses. Interestingly, other anti-Parkinsonian agents (see Chapter  37) are ineffective in treating the extrapyramidal symptoms induced by antipsychotics. The second type is the dystonic reactions, which include facial grimacing, torticollis (wry neck) and spasticity of the limbs. A severe type of dystonia is termed an oculogyric crisis. This can occur after only one dose of an antipsychotic and is particularly common in children. The orbital muscles of the eye go into spasm and the pupils may disappear, usually upwards into the eye socket. This is distressing to both affected person and observers. More seriously, the tongue muscles are affected, and choking may result. Prompt parenteral treatment with an antimuscarinic agent is lifesaving in such crises. Oculogyric crises can occur with other phenothiazine-like compounds, such as metoclopramide (see Chapter  58), a common antiemetic agent. A rare but most disturbing effect is opisthotonos, in which the muscles of the head, neck and back cause the body to arch; in extreme cases this may cause the spine to snap. Third, there is akathisia, with restlessness being the

CHAPTER 34 ANTIPSYCHOTIC AGENTS

Table 34.2 Tendency of antipsychotics to cause adverse effects EXTRAPYRAMIDAL SYMPTOMS

SEDATION

HYPOTENSION

ANTIMUSCARINIC ACTIVITY

Phenothiazines • chlorpromazine • fluphenazine • methotrimeprazine • pericyazine • pipothiazine • thioridazine • trifluoperazine

** *** ** * *** * ***

*** * *** *** * ** *

** * *** ** *** ** *

** * ** *** * *** *

Butyrophenones • droperidol • haloperidol

*** ***

** *

* *

* *

Thioxanthenes • flupenthixol • zuclopenthixol

** ***

* ***

** *

*** **

**

*

*

–

Diphenylbutylpiperidines • pimozide

*

*

*

*

Dibenzodiazepines and related medicines • clozapine • quetiapine • olanzapine

* * **

*** *** *

*** ** *

*** * *

Benzisoxazole • paliperidone • risperidone • ziprasidone

** ** *

** ** **

** *** **

– – *

Miscellaneous • aripiprazole • asenapine • sertindole

* * –

** ** *

* * *

– – –

ANTIPSYCHOTIC

Benzamide • amisulpride

Key: * = uncommon; ** = moderately common; *** = very common; – = not applicable. Australia only New Zealand only

predominant symptom. Affected persons fidget, smack their lips, tap their feet and may pace constantly about the room. Antimuscarinic agents may also alleviate this condition, but a reduction in dose of the antipsychotic agent is often necessary. Fourth, there is tardive dyskinesia, which seriously affects muscular coordination. This occurs only after prolonged treatment, especially in older people. It is characterised by stereotyped involuntary movements, commonly seen in feature films depicting mental institutions. Affected people commonly smack their lips, their tongues dart in and out, their jaws move continually and they slaver. Purposeless movements of the limbs may also occur. This condition is

not responsive to antimuscarinic agents and tends to be permanent. The prospect of tardive dyskinesia makes longterm antipsychotic use problematic.

ENDOCRINE AND HYPOTHALAMIC DISTURBANCES Antipsychotic agents, as dopamine antagonists, sometimes inhibit the action of prolactin inhibitory factor (PIF). This is because PIF is dopamine. PIF acts on the anterior pituitary gland to continually inhibit prolactin, except during lactation. Dopamine receptor blockade can lead to milk production. When the milk production is not postpartum, this is called galactorrhoea. In women this can be accompanied by amenorrhoea, and in men by

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loss of libido. Breast development in males (known as gynaecomastia) can also result from antipsychotic agent use. These medicines also disrupt the release of growth hormone and corticotrophin-releasing hormone. A number of the classic antipsychotic agents have been shown to impair temperature regulation at the hypothalamic level. In some circumstances this may lead to an elevation in body temperature; in other conditions it may result in a hypothermic state. This property of the antipsychotic agents has been used during surgery, where a lower body temperature is desired.

BLOCKADE OF MUSCARINIC, HISTAMINIC AND ADRENERGIC RECEPTORS Sedation is associated with the use of these antipsychotic agents. However, the degree of sedation induced varies from medicine to medicine. The sedative effect, at least in part, is related to antagonism at central H1 receptors. The sedation accompanying some of the classic antipsychotics may be therapeutically useful or troublesome, depending on the circumstances of their use. The typical antipsychotic agents have central and peripheral α1 antagonist activity. The α1-blocking effect can cause hypotension in many patients and also fainting, especially in the first few days of treatment. People should be warned of this effect. The α-blocking effect of these medicines can also lead to suppression of the ejaculatory response. The peripheral antimuscarinic activity of these medicines can result in blurred vision, constipation, as well as decreased salivation and gastric juice secretion. Interestingly, the degree of antimuscarinic activity has been linked to antipsychotic potency. The lower the potency of the agent, the greater the antimuscarinic effect.

NEUROLEPTIC MALIGNANT SYNDROME A rare but potentially serious result of administration of antipsychotics is neuroleptic malignant syndrome (NMS). It is characterised by fever, muscle rigidity, altered consciousness, and autonomic instability, such as problems involving blood pressure and breathing. This syndrome can occur early in the treatment and is similar to severe Parkinsonism with concurrent hyperthermia. Treatment is urgent and involves administration of dantrolene (see Chapter 38) and a dopamine agonist such as bromocriptine (see Chapter  37). This condition can also result from antidepressant use.

OTHER ADVERSE EFFECTS The antipsychotics may induce a range of other adverse effects. Cholestatic jaundice is much more likely to occur

with chlorpromazine than the other phenothiazines. The butyrophenones rarely cause this condition. Cholestatic jaundice, which tends to occur after several weeks of therapy, can be identified by the appearance of bile pigments in the urine, and resembles obstructive jaundice. Cessation of the therapy will usually reverse the condition, but permanent liver damage has been known to result. The incidence of chlorpromazine-induced cholestatic jaundice can be as high as 4  per cent. The incidence is even higher in those with a history of alcohol dependency. Close observation of people taking chlorpromazine is, therefore, necessary. The cause of cholestatic jaundice is unknown but it may be a type of hypersensitivity reaction. Hypersensitivity reactions may sometimes result in blood dyscrasias, but these are not common. The phenothiazines sometimes accumulate in the skin and this can result in abnormal pigmentation, skin rashes or urticaria. As the sun can exacerbate these effects, this condition is called photosensitivity. Handling the medicine can have adverse effects on the skin, so care should be taken with these preparations. Deposits of the drugs can also accumulate in the eye, leading to opacities in the lens with resulting vision defects. The butyrophenones haloperidol and droperidol can produce a prolonged Q-T interval in the cardiac cycle. There has also been a link between these medicines and sudden cardiac death relating to prolongation of the Q-T interval. Table 34.2 details the antipsychotics and their tendency to cause common adverse effects, including extrapyramidal effects, sedation, antimuscarinic effects and hypotension. The list of adverse effects of the antipsychotic agents appears abnormally long and debilitating. It must be remembered, however, that these medicines have revolutionised the treatment of many severe mental disorders. Before their introduction, many individuals with a mental illness were placed in psychiatric institutions. These medicines have resulted in many people with psychosis being able to lead comparatively normal lives in the general community. The effects of the typical antipsychotic agents are summarised in Figure 34.1. Clinical considerations Antipsychotic agents are used to treat a wide variety of mental disorders, including schizophrenia, delirium and dementia. It is not recommended that they be used to treat minor anxiety problems, but some clinicians would recommend the use of a phenothiazine with a low adverse effect profile to treat short-term severe anxiety. The rationale for this view is that antipsychotics are generally not addictive. It is recommended, however, that antipsychotic

Galactorrhoea

The control of psychosis

may

Gynaecomastia

which

Endocrine effects

Pseudoparkinson’s symptoms

Sedation

Amenorrhoea

induce

Dystonia

such as

Extrapyramidal effects

Loss of libido

Akathisia

leading to

Rashes

Tardive dyskinesia (permanent)

Antiemetic effects

Central dopamine receptors

block

Antipsychotic drugs

Postural hypotension

such as

Antiadrenergic effects

as

may

Altered pigmentation

such

Skin reactions

which

Photosensitivity

Cholestatic jaundice

induce

Hypersensitivity reactions

Antimuscarinic effects

CHAPTER 34 ANTIPSYCHOTIC AGENTS

Figure 34.1  Flowchart showing the effects of first-generation (typical) antipsychotics

The therapeutic effects are shown in white boxes.

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agents not be used routinely to treat disturbed behaviour in anxiety disorders outside the hospital setting because of the difficulties in monitoring the person’s condition. Antipsychotics are potent antiemetic agents because of their antidopaminergic effects on the chemoreceptor trigger zone in the medulla. This antiemetic property can occasionally prove to be disadvantageous in that nausea induced by toxicity of other medicines or organic disorders may be masked, leading to incorrect diagnoses. A novel use of antipsychotics is to suppress severe, intractable hiccoughs (singultus); the mechanism of action is unknown. There is, overall, a great similarity between the antipsychotic agents, and the decision about which one to use is often based on clinical intuition and expert judgment. The ideal one to use is that which will cause a remission of symptoms at the lowest dose—a criterion not easy to achieve. Because the onset of the antipsychotic effect is often delayed for several weeks from the commencement of drug therapy, an additional issue involves the need to titrate dosage stringently in line with antipsychotic response. In severe mental illness, therapy may have to be continued indefinitely. Some of the major problems with conventional antipsychotic agents are non-adherence to therapy, inadequate dosing and substance misuse. Clinical improvement should be monitored carefully and possible reasons for lack of improvement considered. Some of these medicines are obtainable in a depot injectable form, which enables long-term action from one injection. Depot injections are used for chronic psychotic conditions once the person is stabilised on oral antipsychotic therapy. They are particularly effective in situations where non-adherence (non-compliance) is due to forgetfulness or reduced insight into the severity of the condition. If non-adherence is due to a conscious decision not to take antipsychotic therapy, depot injections are unlikely to be of benefit. A small test dose of the depot injection is administered first to check for adverse effects. Unfortunately, extrapyramidal effects are common, and the incidence is similar for all depot formulations. Once depot therapy has started, oral treatment is gradually tapered off. It can take several months for a person receiving treatment to become stabilised on depot therapy, and oral supplementation therapy may be required. Haloperidol, flupenthixol, pipothiazine, zuclopenthixol and fluphenazine are available in this form as their decanoate or other long-chain fatty acid derivatives. Long-chain fatty acids, combined with a basic drug, increase the lipophilicity of the drug. The resulting ester dissociates slowly into the free base, which is then slowly absorbed into the muscle blood vessels. Remember, there are no bile salts in

muscle tissue to emulsify lipophilic substances to aid their absorption. The thioxanthenes, such as flupenthixol and zuclopenthixol, are available in oral and parenteral formulations. These two medicines may have moodelevating properties, which can be of benefit in depressed or ‘flat’ patients. Zuclopenthixol has the added advantage of being effective in cases of mania and exacerbated psychotic symptoms. Both of these thioxanthenes are formulated in coconut oil for use as depot injections for sustained action. In the case of flupenthixol this lasts two to four weeks, whereas the action of similarly formulated zuclopenthixol lasts only several days. Nevertheless, they both have a speedy onset of action, particularly zuclopenthixol, which is beneficial when a rapid onset of antipsychotic or antimanic activity is needed. Zuclopenthixol is one of the most powerful of all antipsychotics and, not unexpectedly, has more adverse effects. Hence, treatment with this medicine is not recommended for more than two weeks. Methotrimeprazine, which is available in New Zealand, is sometimes used to augment the analgesic action of narcotic agents and to help allay severe anxiety states. It is important to warn individuals about the symptoms of extrapyramidal reactions, which may be quite distressing. They should also be advised about the need to avoid taking illicit substances, such as cannabis and amphetamines, because these substances can severely diminish the effectiveness of antipsychotic agents. Ensuring compliance helps to prevent relapse of psychotic symptoms and suicide. Individuals should, therefore, be counselled about taking their medicine regularly to prevent symptoms. Individuals experiencing agitation respond better to the more sedating medicines, such as chlorpromazine and thioridazine. Concurrent use of more than one antipsychotic agent is not recommended, except when required to accentuate an intramuscular depot treatment or when replacing one antipsychotic agent with another. If decreasing the dose of antipsychotic agent, this should be done gradually to avoid relapse and withdrawal symptoms such as tachycardia, sweating, and insomnia. Withdrawal symptoms are more apparent with those antipsychotic agents that have dominant anticholinergic effects such as chlorpromazine. Care must be taken to avoid using antipsychotic agents that prolong the Q-T interval in individuals who already have a prolonged Q-T interval. Other medicines that can prolong the Q-T interval (e.g.  amiodarone, sotalol, clarithromycin, erythromycin, fluconazole, cisapride, dolasetron, tacrolimus and vardenafil) should be avoided during this therapy.

CHAPTER 34 ANTIPSYCHOTIC AGENTS

Second-generation (atypical)  antipsychotics The most important difference between the first and second generation antipsychotics is the tendency of the latter to induce fewer extrapyramidal disturbances. Differences in their affinities for various central receptors may explain why the second generation antipsychotics are less prone to producing these adverse effects. The profile of common adverse effects associated with second generation antipsychotic therapy differs from that of the classic agents and can differ depending on the specific agent used. Figure 34.2 shows some important adverse effects to watch for in people receiving second generation antipsychotics. As is the case for the classic antipsychotic agents, the classification of the second generation antipsychotic agents is by chemistry. Groupings include the benzisoxazoles (paliperidone, risperidone and ziprasidone), diphenylbutylpiperidines (pimozide), benzamides (amisulpride), as well as the dibenzodiazepines and related agents (clozapine,

Figure 34.2 Important adverse effects

associated with the second-generation  (atypical) antipsychotics Sedation

Seizures

Cardiac dysrhythmias

Blood dyscrasias, blood pressure changes

Galactorrhoea

olanzapine, quetiapine). Aripiprazole, asenapine and sertindole are grouped as miscellaneous agents.

BENZISOXAZOLES Mechanism of action The benzisoxazoles in use in Australia and New Zealand are risperidone, paliperidone and ziprasidone. Risperidone is a selective antagonist with a high affinity for 5-HT2 (see Chapter  31) and D2  receptors. It has no affinity for muscarinic receptors. This affinity for 5-HT receptors may be somehow responsible for the reduction in extrapyramidal effects seen with risperidone when compared with other D2 antagonists. Paliperidone is the major active metabolite of risperidone. Ziprasidone also has antagonist activity at 5-HT2 and D2  receptors, but is less selective than risperidone. It also acts as an agonist at 5-HT1A  receptors, and an antagonist at D3  and other 5-  receptor subtypes. It has no effect at muscarinic receptors. Common adverse effects The 5-HT antagonism of these agents combined with its antihistaminic effect often causes weight gain (central H1 receptors suppress appetite; see Chapter 30), which is not always desirable. Risperidone and paliperidone have α2 and α1  antagonistic properties, which can cause orthostatic hypotension and swelling of the nasal mucosa, particularly in the initial stages of therapy. Ziprasidone has α1 antagonist activity, which can lead to orthostatic hypotension. NMS has been reported during treatment with these agents, as have most of the other antipsychotic adverse effects, except for a lower incidence of Parkinsonism and galactorrhoea. It is likely that the incidence of tardive dyskinesia will be decreased with this medicine, but adequate studies have not yet been carried out to show this conclusively. Clinical considerations

Weight gain Increased risk of type 2 diabetes

As with other second-generation antipsychotic agents, risperidone has been associated with an increased incidence of type 2 diabetes. Risperidone can be overlapped with other antipsychotics when switching to risperidone, provided there is close supervision by a health professional. Clinical responses to risperidone occur after about two weeks, with full clinical effects observed after three months of treatment. Wafer formulations may be useful for people who experience problems in swallowing tablets, and can, therefore, improve adherence.

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As paliperidone is administered as a controlled-release tablet, people need to swallow the tablets whole. They are not to be chewed or crushed. To ensure steady blood levels, paliperidone tablets should be taken in the same way each day; either with food or on an empty stomach. If the person has had a recent acute myocardial infarction, dysrhythmia or uncontrolled heart failure, caution should be exercised during ziprasidone administration. The dose is usually taken as a capsule formulation twice daily with food. Ziprasidone can be used for schizophrenia as well as acute mania.

DIPHENYLBUTYLPIPERIDINES The only representative of this grouping available in Australasia is pimozide. Mechanism of action Pimozide is a potent antipsychotic that has a similar mechanism of action to the first-generation agents as a centrally acting dopamine receptor antagonist. In contrast to a number of first-generation agents, it has a slow onset of action and a prolonged half-life. Common adverse effects The profile of adverse effects of pimozide is similar to that of the classic antipsychotics, but the incidence of these reactions is relatively low. Pimozide can prolong the Q-T interval and should be avoided when a person has a prolonged Q-T interval or is concurrently taking another medicine that can induce this effect. Clinical considerations The major advantages associated with the use of pimozide are its potency and prolonged action. This enables onceper-day dosage.

DIBENZODIAZEPINES AND R E L AT E D A G E N T S Mechanism of action The mechanism of action of clozapine is as a dopamine antagonist. It acts on D1 and D4  receptors and not on the D2  receptors, which cause the major side-effects of the other dopamine antagonists. The drug also has potent sympatholytic, antimuscarinic, antiserotonergic, antihistaminic and arousal-inhibiting effects. All these actions may contribute to the pharmacological action of clozapine. Quetiapine and olanzapine are chemically related agents with a slightly different pharmacological profile. These agents show greater affinity for 5-HT2 receptors than

D2 receptors, which is thought to underlie the low incidence of extrapyramidal effects. Quetiapine and olanzapine have significant antagonist activity at histaminic and α1 receptors, but olanzapine has stronger antimuscarinic effects. These agents appear to have greater selectivity than the typical antipsychotics for dopamine receptors in certain regions of the brain. Common adverse effects Clozapine (which is chemically related to the benzodiazepines but is not similar in action) has been around for several years but was abandoned as an antipsychotic after causing the death of several people due to the development of irreversible neutropenia, a type of agranulocytosis. However, it has been reintroduced as an antipsychotic for use in people who do not respond to or are intolerant of other medicines. On the positive side is the almost complete lack of extrapyramidal effects or of the development of tardive dyskinesia. Clozapine is also devoid of endocrine effects. Compared with the other antipsychotics, the adverse effects are minimal, apart from the potentially fatal neutropenia. The common adverse effects are sedation and mild epileptic attacks (absence seizures), in addition to the expected effects from the list of actions given above. NMS has been known to occur. Olanzapine may trigger neutropenia in some individuals. Weight gain may occur with olanzapine, as well as somnolescence. Unlike clozapine, it does not appear to trigger epileptiform seizures. Quetiapine has a similar profile to that of chlorpromazine but a significantly lower incidence of adverse effects. It is also more efficacious in treating symptoms such as flat affect and lack of motivation, compared with its ability to treat symptoms such as hallucinations, thought disorders and delusions. Clinical considerations Clozapine is effective in over 30 per cent of people who are unresponsive to other medicines. It can be prescribed only by suitably experienced psychiatrists, who are obliged to report its use and the development of any serious adverse effects. In Australia, a national distribution system of clozapine requires registration of medical practitioners, pharmacists and patients. Treatment can only be commenced if the individual’s white cell count and neutrophil count are normal. Health professionals must report details regarding people’s reactions and submit regular differential blood counts. Both clozapine and olanzapine can produce blood dyscrasias. Needless to say, frequent full blood examinations

CHAPTER 34 ANTIPSYCHOTIC AGENTS

are also required during therapy, as early detection of blood abnormalities is critical. Immediately stopping the medicine may reverse any abnormalities detected. Medical supervision and resuscitation equipment must be readily available when beginning treatment with clozapine. There is the possibility of profound postural hypotension with respiratory or cardiac failure when initiating treatment. When switching from one antipsychotic agent to clozapine, the dose of the other medicine is reduced over one week and stopped for 24 hours before starting clozapine. Clozapine, olanzapine and quetiapine have a tendency to cause weight gain and hyperglycaemia. If people gain an enormous amount of weight while taking these medicines, they may be at risk of developing type 2 diabetes. Quetiapine is the most sedating of the atypical antipsychotics, and may therefore be beneficial in the treatment of symptoms associated with agitation. As an antipsychotic agent that affects the Q-T interval of the cardiac cycle, quetiapine should not be given with other medicines that prolong the Q-T interval. The cause of this cardiac abnormality should be rectified first before quetiapine is administered. Olanzapine is available as neutral-tasting wafers, which are dissolved in the mouth, followed by a drink of water for those who have difficulty in swallowing tablets. This type of formulation may also assist with medicine adherence.

BENZAMIDES The sole benzamide antipsychotic is amisulpride. Amisulpride has a lower incidence of adverse effects than other antipsychotics, both first and second generation. Mechanism of action Interestingly, amisulpride is quite unusual in its mechanism of action. It has significant dopamine receptor antagonist activity at D2 and D3 receptors. However, it has little activity at other dopamine receptors, adrenergic, muscarinic, histaminic or serotonergic receptors. It appears to be relatively selective for dopamine receptors located in the limbic areas of the brain. Common adverse effects As with all antipsychotics, there is a risk of NMS. During therapy, people should be monitored for prolongation of the Q-T interval, extrapyramidal disturbances, amenorrhoea, galactorrhoea and impotence. Clinical considerations Amisulpride can interact with many medicines, and these interactions should be referred to before prescribing. It

should be avoided in individuals with a history of seizures and in Parkinson’s disease. As with other atypical antipsychotic agents, amisulpride has been associated with an increased incidence of type  2 diabetes. The dose is halved in mild renal impairment and decreased to one-third in moderate renal impairment. Amisulpride can produce a prolonged Q-T interval in the cardiac cycle. The Q-T interval can be prolonged by electrolyte disturbances (e.g.  hypomagnesaemia, hypokalaemia, hypocalcaemia), increasing age, bradycardia, heart failure and coronary heart disease. Attempts should be made to correct the underlying cause. Avoid combining amisulpride with other medicines that prolong the Q-T interval (e.g. amiodarone and erythromycin).

MISCELLANEOUS AGENTS Novel second generation antipsychotic agents aripiprazole, asenapine and sertindole are available for use for the treatment of schizophrenia. Asenapine is also indicated in the management of bipolar disorder. Mechanism of action Aripiprazole acts as a partial agonist at D2 receptors and a subtype of 5-HT1 receptors, while acting as an antagonist at a subpopulation of 5-HT2 receptors. Clinical trials have shown comparable efficacy to haloperidol against a number of criteria. Asenapine and sertindole both act as antagonists at D2 and 5-HT2 receptors. Asenapine is appears to have activity at other serotonin receptor subtypes, D3 and α2 receptors; these actions may contribute to its antipsychotic effect. Sertindole is relatively selective for mesolimbic dopaminergic neurones. Common adverse effects Aripiprazole appears to be well tolerated. The most common adverse effects reported are somnolence and weight gain. Common adverse effects of asenapine include gastrointestinal upset, somnolence, headache and fatigue. Sertindole therapy can induce postural hypotension, prolongation of the QT interval, weight gain, dizziness, paraesthesias and peripheral oedema. Clinical considerations As with other antipsychotic agents, it is important to monitor the person for signs of suicidal intention, NMS, changes in blood pressure and altered body temperature. Aripiprazole should be used with caution in people with a history of seizures.

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Asenapine is available in wafer form, which is placed under the tongue and allowed to dissolve. It is not crushed, chewed or swallowed. The person should not eat or drink for about ten minutes after taking it. The wafer may cause tingling or numbness in the mouth for around one hour after taking the wafer. Sertindole is recommended for people who have received no response or intolerance with another antipsychotic medication. As this medicine can cause prolongation of the Q-T interval, the electrocardiogram should be checked on commencement and at regular periods during therapy. Serum potassium and magnesium are also checked at baseline and during treatment, as problems with electrolyte imbalances can affect Q-T prolongation. Blood pressure is also checked at baseline and during treatment.

Other uses of antipsychotics Apart from the treatment of nausea, vertigo and singultus mentioned above, there are some other uses for antipsychotic agents. Haloperidol can be useful in the rare but notorious Tourette’s syndrome, in which affected people may repeat almost everything that is said to them (echolalia) or continually use obscene words in inappropriate situations (coprolalia). Haloperidol is also occasionally of use in ballismus, which involves the flailing of arms and legs, and in the management of Huntington’s disease (see Chapter  37). The butyrophenones are used in neuroleptoanalgesia (see Chapter 40). Pimozide may also be useful in the management of Tourette’s syndrome and Huntington’s disease. It can be used to alleviate the pain of trigeminal neuralgia.

CLINICAL MANAGEMENT ANTIPSYCHOTIC AGENTS Assessment ■■

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Assess the person for liver disease, coronary heart disease, Parkinsonism, hypotension, hypertension and blood dyscrasias. These conditions can worsen during antipsychotic therapy. Use these medicines with caution in people with glaucoma, diabetes, epilepsy, ulcers, cardiovascular disease, renal disease, prostatic hypertrophy, chronic respiratory disease and in older people. Determine concurrent use of other CNS depressants, such as alcohol and anxiolytics. Medicines with antimuscarinic activity can also potentiate the action of antipsychotic agents. Obtain baseline observations of vital signs, including lying and standing blood pressures. Compare with subsequent observations. Determine bodyweight prior to initial therapy. Amisulpride, quetiapine, thioridazine, haloperidol, pimozide, sertindole and droperidol can produce a prolonged Q-T interval in the cardiac cycle. Assess people for prolongation of the Q-T interval and for use of other medicines that may also prolong the Q-T interval. Avoid using these antipsychotic agents in such individuals and avoid giving them with other medicines that can prolong the Q-T interval (e.g. amiodarone and erythromycin).

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Assess people on paliperidone for renal impairment. The dose should be reduced depending on the person’s creatinine clearance rate. Assess people for a history of myocardial infarction and unstable heart disease. Aripiprazole and ziprasidone should be used with caution in these conditions. Assess people with mild to moderate hepatic impairment. Sertindole needs to be titrated very slowly in these people.

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The person’s psychotic activity will be controlled by the antipsychotic agent and psychotherapy. The person will experience minimal adverse effects.

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Regularly monitor observations during administration. Check lying, sitting and standing blood pressures. Remain with the person while the medicine is taken, and make certain it is swallowed. Fluid input and output needs regular monitoring due to the ability of conventional antipsychotic agents to block muscarinic receptors, therefore inhibiting parasympathetic function and causing urinary retention.

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gain an enormous amount of weight while taking these medicines, they may be at risk of developing type 2 diabetes.

Observe for adverse effects of conventional antipsychotic therapy, including: – Parkinsonian effects, such as slowing of voluntary movements, associated with a masked face, tremor at rest, decreased arm movements when walking;

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– dystonic effects, such as facial grimacing, and uncoordinated spastic movements of body and limbs;

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– akathisia, where the person fidgets and paces constantly, and tardive dyskinesia, where the person makes lateral jaw movements, fly-catching movements with the tongue, and quick, jerky movements with the extremities;

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– antimuscarinic effects, such as dry mouth, urinary retention, constipation, blurred vision and decreased tear production.

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When administering antipsychotics intramuscularly, discomfort can be reduced by mixing with saline.

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For intravenous antipsychotic therapy, administer at the required rate to minimise hypotension.

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Care must be taken when administering antipsychotics to older adults, who are at greater risk of suffering from adverse effects. Common adverse effects in older people include confusion, dizziness, Parkinsoniantype symptoms and hypothermia. Treatment should therefore be initiated at a lower dose than normal and increased gradually. Antipsychotics should be withdrawn slowly to avoid a rapid relapse and to avoid withdrawal symptoms. Depot injections are useful in chronic psychotic conditions once the person is stabilised on oral antipsychotic therapy. They are particularly effective where non-adherence is due to forgetfulness or reduced insight into the severity of psychotic conditions. Wafer formulations of risperidone and olanzapine may be useful for people who experience problems in swallowing tablets, and can therefore improve adherence. Both clozapine and olanzapine can produce blood dyscrasias. Individuals must have normal blood counts before treatment. Regular full blood examinations are also required during therapy. Paliperidone is provided as a controlled-release tablet formulation, which is swallowed whole and taken in the same way each day. Clozapine, olanzapine and quetiapine have a tendency to cause weight gain and hyperglycaemia. If people

Ziprasidone has a tendency to cause orthostatic hypotension or dysrhythmias in people who have had a recent myocardial infarction or uncontrolled heart failure. Medical supervision and resuscitation equipment must be readily available when beginning treatment with clozapine. There is the possibility of profound postural hypotension with respiratory or cardiac failure when initiating treatment. When switching from one antipsychotic agent to clozapine, the other medicine is reduced over one week, and stopped for 24 hours before starting clozapine. The possibility of orthostatic hypotension should be checked in people commencing sertindole. Sertindole can cause Q-T interval prolongation and the person’s electrocardiogram needs to be assessed at the commencement of treatment and during therapy.

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Suggest hard lollies, lozenges or ice chips for a dry mouth caused by conventional antipsychotic therapy (see Chapter 11, Table 11.9, for further information). Inform the person not to drive a car or operate machinery until a maintenance dose has been established. Instruct people to continue taking the medicine. If problems occur, medical advice should be sought to determine whether a change in dose or medicine will help. Antipsychotics do not cure psychotic illnesses but can alleviate psychotic symptoms. The medicine should never be abruptly discontinued. Oral candidiasis is a common effect of dry mouth caused by conventional antipsychotic agents. Oral candidiasis can be avoided by frequent sips of water and good oral hygiene (see Chapter 11, Table 11.7, for further information). Instruct the person taking phenothiazines such as chlorpromazine that urine may turn pink or reddishbrown. This discoloration is not harmful. Constipation, a common effect of conventional antipsychotic agents, can be minimised by consuming a high-fibre diet, adequate fluids and having sufficient exercise (see Chapter 11,Table 11.4, for further information).

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Instruct the person not to consume alcohol, as it intensifies the sedative effect of the antipsychotic agent. The person taking chlorpromazine should take precautions when going into direct sunlight because of photosensitivity. Instruct the person to wear protective clothing and use a sunscreen. The sun should be avoided during its hottest period, between 10 am and 3 pm (see Chapter 11, Table 11.19, for further information). As several over-the-counter medicines interact with antipsychotic agents, the person should first consult the doctor and pharmacist. Effects of postural hypotension can be reduced by advising the person to arise slowly from a lying to sitting or standing position (see Chapter 11, Table 11.20, for further information).

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Inform the person that sexual changes may occur with conventional antipsychotic agents. For women, menstruation can become irregular or stop temporarily (amenorrhoea). Men may experience gynaecomastia (enlarged breast tissue) or loss of libido. Changing the antipsychotic drug group may assist in alleviating these effects. Inform the person on ziprasidone that it should be taken with food. Inform the person on asenapine to put the wafer under the tongue and to allow it to dissolve. Warn the person that it may make the mouth feel tingly or numb.

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Antipsychotics are used in the treatment of psychoses such as schizophrenia, dementia and severe agitation. To some extent, all antipsychotics exert their effect on dopamine receptors and antagonise dopaminergic activity in the CNS. However, serotonergic, GABAergic, glutamatergic, adrenergic and histaminergic receptor systems have been implicated in antipsychotic agent activity. There are two principal groups of antipsychotics, the typical and atypical. As the atypical antipsychotic agents are becoming the medicines of choice in psychosis, some practitioners prefer the terms first- and second-generation antipsychotic agents. Typical (first generation) antipsychotics act on D2 receptors and can cause extrapyramidal adverse effects. Atypical (second generation) antipsychotics may be less potent at D2 receptors and tend not to cause extrapyramidal effects. Antipsychotics have a diverse and potentially debilitating adverse effect profile, which includes motor disturbances, endocrine dysfunction, sedation, hypotension and seizures.

REVIEW QUESTIONS 1 State three positive and three negative symptoms of schizophrenia. 2 Outline the dopamine hypothesis of schizophrenia. 3 What are the major categories of adverse effects associated with first-generation (typical) antipsychotic

treatment? 4 Briefly describe the four types of extrapyramidal disturbances associated with antipsychotic therapy. 5 In what ways do the second-generation (atypical) antipsychotics differ from the first-generation agents?

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6 For each of the following antipsychotic agents, indicate the drug group to which it belongs and whether it is a

first- or second-generation agent: a

trifluoperazine

b clozapine c

flupenthixol

d haloperidol e

paliperidone

7 Joe Smith, a 35-year-old with schizophrenia, has been put on the phenothiazine fluphenazine to treat his

condition. What medicine education would you provide for Mr Smith? 8 During his visit to the psychiatric clinic, John Brown indicated his frustration at forgetting to take his oral

droperidol medicine. What alternative formulation can you offer Mr Brown? 9 Barbara Lowe, who is newly diagnosed with schizophrenia, asks you about the possibility of taking alcohol with

her antipsychotic medicine. What would you say to Ms Lowe? Why? 10 A person complains to you about severe tremor and rigidity while receiving treatment with the butyrophenone

haloperidol. What alternative antipsychotic agent is less likely to elicit these symptoms? 11 Cindy Nash, who is taking chlorpromazine therapy, enjoys spending time in the sun. What instructions would you

provide for Ms Nash when she goes outdoors? 12 John Brown has been stabilised on quetiapine therapy for a period of one year. Following a respiratory tract

infection, his general practitioner orders a course of erythromycin therapy. What problem may be associated with this medicine combination? 13 A person is about to commence clozapine therapy after being unresponsive to other antipsychotic therapy.

What pathology test should be done before and during therapy? What facilities should be readily available when treatment starts? 14 Judy Judd is about to commence paliperidone therapy for the treatment of schizophrenia. What counselling

would you offer Ms Judd about the use of this preparation? 15 Norris Smith has taken various antipsychotic agents without achieving an effective response. His psychiatrist

has decided to prescribe sertindole for him. What diagnostic and pathology tests should be undertaken with Mr Smith?

34 MEDICINE SUMMARY TABLE FAMILY NAME

GENERIC NAME

TRADE NAME(S)

Phenothiazines

chlorpromazine fluphenazine methotrimeprazine pericyazine pipothiazine prochlorperazine

Largactil Modecate Nozinan Neulactil Piportil Antinaus Buccastem Nausetil Pharmacor Prozine Procalm Stemetil

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FAMILY NAME

GENERIC NAME

TRADE NAME(S)

trifluoperazine

Stemzine Stelazine

Phenothiazines (continued) Butyrophenones

droperidol haloperidol

Droleptan Haldol Serenace

Thioxanthenes

flupenthixol zuclopenthixol

Fluanxol Clopixol

Diphenylbutylpiperidines

pimozide

Orap

Dibenzodiazepines and related medicines

clozapine

Clopine Closyn Clozaril Lanzek Olanzine Ozin Zylap Zypine Zyprexa Delucon Quetapel Quetiaccord Quipine Sequase Seroquel

olanzapine

quetiapine

Benzamide

amisulpride

Amipride Solian Sulprix

Benzisoxazole

paliperidone risperidone

Invega

Miscellaneous agents

Australia only New Zealand only

ziprasidone

Ozidal Resdone Ridal Rispa Risperdal Risperon Rixadone Zeldox

aripiprazole asenapine sertindole

Abilify Saphris Serdolect

C H A P T E R

35

A N X I O LY T I C S AND HYPNOTICS

LEARNING OBJECTIVES

KEY TERMS

After completing this chapter, you should be able to:

Anxiety

1

State the difference between an anxiolytic and a hypnotic.

2

List the uses of anxiolytics and hypnotics.

3

Outline the problems associated with anxiolytics and hypnotics.

4

Recognise the various types of anxiolytics and hypnotics.

Gamma-aminobutyric acid (GABA) Insomnia Rapid eye movement (REM) Sleep

The general definition of a sedative is a substance that diminishes the activity of an organ or tissue, but today the meaning of this word is confined to this action on the central nervous system (CNS). Sedatives calm a person receiving therapy, and moderate excitability. This effect on the CNS, in many circumstances, can relieve anxiety; hence, sedatives are often termed anxiolytics. The term ‘minor tranquilliser’ was another name for a sedative. ‘Hypnotic’ is the term used to describe a substance that induces sleep (hypnosis). It is difficult to distinguish, in most cases, between an anxiolytic agent and a hypnotic, as sleep could be considered to be an extension of sedation. Therefore, it is not surprising that the majority of the medicines that can be used to promote sleep can also be used in lesser dosages as sedatives. The converse is also true, with only a few exceptions. Many of the medicines in these categories can induce psychological dependence if taken regularly, even for short periods. In some cases, this form of addiction has been known to occur in about ten days. So it is clear that the use of these medicines is controversial. If prescribed, they should be taken only for limited periods (no more than seven days under normal circumstances).

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ANXIETY Anxiety states are common in our society, and there is considerable pressure exerted on the medical profession to provide a fast form of pharmacological relief. In many cases, the anxiety is self-limiting and recourse to medicine is not necessary. Anxiety and stress are part of everyday life, and it is important that education programs include life skills that help people develop coping mechanisms. However, anxiety can become excessive, prolonged and debilitating, and in these cases therapy may be required. There are a number of forms of anxiety disorder, and they are associated with physical and affective symptoms. The main types are generalised anxiety disorder, panic attacks, phobias and stress disorders. The types and characteristics of common anxiety disorders is shown in Table  35.1. The symptoms may include excessive worry, fear, feelings of doom and gloom, poor concentration, sleep disturbances, restlessness, palpitations, sweating and trembling. Furthermore, anxiety may be accompanied by mild reactive or endogenous depression.

SLEEP DISORDERS Sleep and its necessity for normal life is still little understood. Sleep disturbances are common and, if continuous, have the potential to seriously disrupt normal day-to-day living. Many people with a sleep disorder seek out drug therapy. The use of medicines in these situations may be undesirable. A non-pharmacological approach and an evaluation of

the causes of the sleeplessness may be all that is required to alleviate the condition. Appropriate texts should be consulted for further information on sleep disturbances. The use of hypnotics in the treatment of short-term insomnia is often beneficial in cases where the insomnia can be predicted. Indications for such treatment could be to help people overcome the disruption to circadian rhythms that occurs when crossing several time zones, resulting in jet lag. Likewise, hypnotics can be of benefit to people who carry out shift work, to help them adjust to changes in their shifts. Other indications could be to give individuals a good night’s rest before operative procedures and in cases of bereavement. There is some evidence that the use of hypnotics and/or anxiolytics in bereaved persons is less than beneficial, as the grieving process may be a condition that people have to go through to accept rationally what has happened. Prolonged use of all hypnotics tends to lead to a degree of drug tolerance, where sleep is no longer induced without increasing the dosage. Tolerance can develop within about a fortnight for many of the commonly used hypnotics. Another problem experienced with many of the hypnotics is rebound insomnia. After hypnotic withdrawal, several nights of disturbed sleep may ensue. There are two main phases of sleep; one called REM (rapid eye movement), which is where dreaming occurs, and the other the non-REM sleep (in fact, there are four stages of non-REM sleep, one of which is deep sleep). During normal sleep we cycle through the various stages.

Table 35.1 Types of common anxiety disorders DISORDER

FEATURES

Panic attack

A short-lived period of intense fear and discomfort.

Generalised anxiety disorder

Excessive anxiety over a number of events, occurring on more days than not for at least six months.

Agoraphobia

Fear of being trapped in places or situations where escape or help might not be possible.

Post-traumatic stress disorder (PTSD)

Anxiety associated with exposure to a traumatic event where the person was confronted by death or serious injury and their response involved fear, helplessness or horror.

Obsessive–compulsive disorder (OCD)

Anxiety or distress associated with recurrent and persistent thoughts experienced as intrusive and inappropriate that are products of their own mind. The person engages in repetitive, ritualised behaviours in order to reduce anxiety.

Social phobias

Fear of social situations where the person is exposed to unfamiliar people or scrutiny by others where they will act in an embarrassing manner.

Specific phobias

Unreasonable and persistent fear triggered by the presence or anticipation of specific situations or objects.

Source: Bullock S & Hales M, 2012, Principles of Pathophysiology, Pearson Australia, Frenchs Forest, NSW, p. 324.

C H A P T E R 3 5 A N X I O LY T I C S A N D H Y P N O T I C S

It seems that many hypnotics upset the REM stage of sleep, sometimes abolishing it altogether. This disruption can lead to psychological disturbances, which can be difficult to treat and may necessitate psychiatric intervention. This intervention is particularly true for the older types of hypnotics, but is less common with the newer hypnotic agents. Withdrawal of some of these older medicines at the end of therapy often resulted in vivid dreams or nightmares, as if the brain were trying to make up for the loss of its usual REM sleep. It is important to remember that, as yet, no hypnotic induces what could be termed natural sleep. As already mentioned, the difference between most hypnotics and anxiolytics is in the dosage, not the medicine itself. In view of this, the medicines are dealt with according to their chemical classification rather than their therapeutic classification, except where there is no overlap.

BENZODIAZEPINES Benzodiazepines are the most commonly prescribed anxiolytics/hypnotics. Most of the benzodiazepines have the suffix -azepam and so are readily identifiable; but please note that there are a few exceptions.

Mechanism of action This group of medicines acts on gamma-aminobutyric acid (GABA) receptors in the CNS to potentiate its inhibitory action. A number of receptor subtypes are associated with the GABA receptor complex, and selective stimulation of these subtypes leads to differing physiological responses. Hence, stimulation of one subtype may decrease anxiety, and stimulation of another may lead to the induction of sleep. The two main subtypes of GABA receptors are GABAA and GABAB. It is the GABAA receptor complex that is critical in the mechanism of action of the benzodiazepines. The GABAA receptor complex is an ion channel activated by GABA that, when open, allows an influx of chloride ions into the cell. The increase in intracellular negatively charged ions hyperpolarises the cell membrane, reducing its excitability. Associated with the GABAA receptor complex are at least two benzodiazepine receptors—BZ1 and BZ2. When the benzodiazepines stimulate their receptor sites they enhance the inhibitory action of GABA by increasing chloride influx through the membrane (see Figure 35.1). When there is no GABA available, no benzodiazepine action is observed.

Figure 35.1 Mechanism of action of the benzodiazepines on GABA receptors The benzodiazepines bind to a benzodiazepine (BZ) receptor on the GABAA receptor complex. They enhance the action of gamma-aminobutyric acid (GABA) at its receptor, resulting in increased chloride ion influx. The benzodiazepines cannot induce their effects in the absence of GABA.

GABA molecule at its binding site

Chloride ion Benzodiazepine molecule at its binding site

Extracellular fluid

Cell membrane

Cytoplasm

Change in membrane potential

–

+ mV

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BZ1 receptors are found mainly in the cerebellum and are related to anxiety and sedation. BZ2 receptors are found mainly in the basal ganglia and hippocampus and are associated with muscle relaxation, as well as memory and learning. This helps explain the differences between some of the benzodiazepines and their actions. For example, midazolam strongly acts on the BZ2  receptors, causing amnesia. Other receptors in this complex are associated with seizure activity. This explains the use of some of the benzodiazepines in epilepsy and in other convulsive conditions. It may also help to explain the differing actions of many of the benzodiazepines and why some are superior as anxiolytics and some as hypnotics. Common adverse effects Some of the effects of this group of medicines may be adverse in some situations but not others. Clonazepam would have sedation as an adverse effect if used as an antiseizure agent, but not if used as a sedative. Midazolam is used as a hypnotic in minor medical and surgical procedures. It produces amnesia as an effect, which is useful but would be considered an adverse effect if it were taken as a night-time hypnotic. There are many other adverse effects of benzodiazepines, including diplopia and blurred vision, slurring of speech, paradoxical rage, paradoxical insomnia, depression and dizziness. More details regarding adverse effects are given under the headings of some selected benzodiazepines detailed below. The benzodiazepines are among the safest of all CNS agents as far as toxicity is concerned; however, they are addictive. It has been suggested that even during significant benzodiazepine intoxication the subject may be easily aroused. Unfortunately, deaths have occurred when they were taken in excess with alcohol, a common combination. A specific antagonist to the benzodiazepines called flumazenil is useful in the treatment of life-threatening situations, such as can occur with alcohol–benzodiazepine combinations (see Chapter 23). The effects of the benzodiazepines, both desirable and unwanted, are summarised in Figure 35.2. Clinical considerations The development of long-term memory may be dependent on increased activity in the higher parts of the brain, and increased GABA activity may cause impairment of this faculty. This accounts for the development of amnesia after the use of some benzodiazepines—a property

Figure 35.2 The effects of the benzodiazepines Addiction, withdrawal symptoms

Paradoxical excitement

Alleviation of seizures

Depression, amnesia

Sedation, sleep promotion Slurred speech

Dizziness Visual disturbances

Muscle relaxation

sometimes useful in, for example, endoscopic procedures. As endoscopies often require the cooperation of the person but are unpleasant procedures, a benzodiazepine such as midazolam is efficient at producing anterograde amnesia, and is, therefore, often used as an adjunct in such procedures. Some benzodiazepines, such as clonazepam and diazepam, are effective muscle relaxants. Their action is thought to be by potentiating the action of GABA on the brainstem and on the spinal cord. This potentiation makes them useful as antiseizure agents in epilepsy and in muscle spasticity therapy (see Chapter 38). Other benzodiazepines can also be used as antiseizure agents but have unacceptable side-effects, especially drowsiness. One pharmacokinetic property of the benzodiazepines that often determines their clinical use is their half-life (t 1 ). Short-half-life benzodiazepines, such as triazolam 2 (t 1  = 2–3 hours), are useful for the initiation of sleep where 2 the person has difficulty getting to sleep. Drugs having such a short half-life are not of much use as anxiolytics, as frequent dosing is required. If the problem is earlymorning awakening, a benzodiazepine with a longer half-life is desirable. Temazepam, which has a half-life of approximately eight hours, is ideal for such problems. Benzodiazepines with longer half-lives tend to produce undesirable subsequent drowsiness. Those with longer half-lives tend to be better used for their anxiolytic effect, but it may be preferable to use them in some cases of sleep induction. This is particularly the case where longterm therapy is envisaged. Those with short half-lives are cleared from the bloodstream fairly quickly and may induce withdrawal effects, such as rebound excitement and insomnia. For instance, short-acting benzodiazepines such as triazolam may cause confusion and delirium. Those with longer half-lives are cleared less quickly, resulting in a decrease in withdrawal effects. For example, as nitrazepam

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may take several days to be cleared from the bloodstream, the resulting slow drop in blood levels allows the body to adjust to the lack of medicine more effectively. For similar reasons, addiction to benzodiazepines is easier to treat when the specific medicine has a long half-life. This use of half-lives to determine the choice of benzodiazepines is not always followed, and there often appears to be no reason why one is used as an anxiolytic and another as a hypnotic. It has already been mentioned that differing chemical structures may affect receptor subtypes differently, and receptors for promoting sleep are different from those that promote peace and calm. There is not much doubt that nitrazepam, even in large doses, would never attain the hypnotic effect of flunitrazepam or midazolam. In at least one overdose case with nitrazepam, involving about 50  tablets, the individual did not even fall asleep. Table  35.2 lists the benzodiazepines available, with their respective half-lives and their usual therapeutic use. Some of the half-lives given are not just for the parent compound but also for active metabolites. There is a great deal of similarity between many of the benzodiazepines. Therefore, only those with unusual properties and uses are discussed individually. In general, the benzodiazepines are a well-tolerated group of drugs with only infrequent adverse effects apart from drowsiness. The following effects and precautions are applicable to all of the benzodiazepines. As benzodiazepines cause sedation, the person should be advised to avoid driving, operating machinery, and Table 35.2  Half-lives and therapeutic uses 

of some benzodiazepines

GENERIC NAME

BIOLOGICAL HALF-LIFE THERAPEUTIC (HOURS) USE

alprazolam

16–20

bromazepam clobazam diazepam flunitrazepam lorazepam lormetazepam midazolam nitrazepam oxazepam temazepam triazolam

12 35–42 50–100 25–29 12–15 9 2–3 26–30 4–13 8–10 2–3

Australia only New Zealand only

Anxiolytic, antidepressant Anxiolytic Anxiolytic Anxiolytic Hypnotic Anxiolytic Hypnotic Hypnotic Hypnotic Anxiolytic Hypnotic Hypnotic

using other CNS depressant agents, including alcohol. More than two to four weeks of continuous use may result in dependence and tolerance. Consequently, they are considered merely as a short-term regimen for about two to four weeks, and as part of a more extensive treatment plan. A sudden decrease in dose of benzodiazepines may lead to withdrawal symptoms, such as anxiety, dysphoria, irritability, nightmares, sweating, memory impairment and tremors. Withdrawal symptoms may not occur until many days after stopping the medicine, and could last for several weeks after prolonged use. Therefore, a gradual drop in dose can avoid or alleviate withdrawal symptoms. Longacting benzodiazepines such as diazepam are preferred for the prophylactic treatment of alcohol, barbiturate or benzodiazepine withdrawal. This is because use of the shorter-acting benzodiazepines is more likely to lead to acute withdrawal symptoms. There is little evidence to suggest that benzodiazepines are effective in treating depression. However, they are appropriate for short-term relief of severe anxiety and agitation in individuals waiting for a therapeutic response to antidepressants.

Specific benzodiazepines ALPRAZOLAM Alprazolam is unique among the benzodiazepines, as it possesses antidepressant activity and so can be useful in the treatment of depression associated with anxiety. Like other medicines used in the treatment of depression, its onset of antidepressant action takes up to two weeks to appear. A potential problem with alprazolam when compared with the other antidepressants (see Chapter 36) is addiction. It is classified as a short-acting benzodiazepine (half-life of 6–12 hours).

B R O M A Z E PA M This medicine is useful in the management of severe anxiety and agitation. The older person should receive half the normal dose. Bromazepam is classed as a medium-acting benzodiazepine (half-life 12–24 hours). It is only available in Australia.

CLOBAZAM Clobazam is useful in the treatment of anxiety, sleep disturbance and epilepsy. It is classified as a long-acting benzodiazepine (half-life > 24 hours).

C L O N A Z E PA M Clonazepam is one of the most potent benzodiazepines, and has strong muscle-relaxant properties, which make it a medicine usually employed in the treatment of

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epilepsy rather than anxiety or insomnia (see Chapter 38). This medicine is useful in the treatment of restless leg syndrome and some other parasomnias. Drowsiness and the potential for addiction are the major problems, although the drowsiness usually dissipates with time. Clonazepam is classified as a long-acting benzodiazepine (half-life > 24 hours).

L O R A Z E PA M Lorazepam is less lipid-soluble than most of the other benzodiazepines and thus enters and leaves the CNS at a slow and controlled rate. This causes fewer problems with the onset and cessation of action. Lorazepam is one of the most addictive of the benzodiazepines. It is commonly associated with the production of retrograde amnesia and diplopia. Lorazepam is classified as a medium-acting benzodiazepine (half-life 12–24 hours). It is used for the treatment of anxiety and insomnia, and as a premedication in surgery.

O X A Z E PA M Oxazepam is used for the short-term treatment of insomnia and mild to severe anxiety. It is available in tablet form. Oxazepam is classified as a short-acting benzodiazepine (half-life 6–12 hours).

TRIAZOLAM Triazolam is problematic because of the high incidence of psychotic episodes, depression and severe amnesia that have resulted from its prolonged use, especially in older people. Triazolam has been withdrawn from the pharmacopoeias in some countries. There is some dispute as to the wisdom of this decision, as many benzodiazepines have similar problems. Triazolam’s remarkably short halflife (  24  hours), diazepam is also used for the treatment of benzodiazepine withdrawal. In this situation, a dose equivalent to the approximated total daily benzodiazepine intake is administered in three to four divided doses each day. The dosage is then gradually reduced by about 10–20  per cent each week over several weeks. Regular supervision is required for review of the withdrawal process in an outpatient setting.

F L U N I T R A Z E PA M Flunitrazepam is one of the most potent and effective hypnotics of the benzodiazepine range: when taken orally it induces a deep sleep, almost unconsciousness, in about 10–20 minutes. Flunitrazepam also has a very long half-life (> 24 hours). For these reasons it is not recommended for initial treatment of anxiety or insomnia. It is also completely tasteless, a property that has lead to its misuse in spiking drinks in social settings. Flunitrazepam now has been reclassified from Schedule 4 to Schedule 8 in most states of Australia.

MIDAZOLAM Midazolam is used more often as an anaesthetic than as a hypnotic. It has a very short half-life (