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A Textbook of Clinical Pharmacology and Therapeutics
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A Textbook of Clinical Pharmacology and Therapeutics FIFTH EDITION JAMES M RITTER MA DPHIL FRCP FMedSci FBPHARMACOLS Professor of Clinical Pharmacology at King’s College London School of Medicine, Guy’s, King’s and St Thomas’ Hospitals, London, UK LIONEL D LEWIS MA MB BCH MD FRCP Professor of Medicine, Pharmacology and Toxicology at Dartmouth Medical School and the Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA TIMOTHY GK MANT BSC FFPM FRCP Senior Medical Advisor, Quintiles, Guy's Drug Research Unit, and Visiting Professor at King’s College London School of Medicine, Guy’s, King’s and St Thomas’ Hospitals, London, UK ALBERT FERRO PHD FRCP FBPHARMACOLS Reader in Clinical Pharmacology and Honorary Consultant Physician at King’s College London School of Medicine, Guy’s, King’s and St Thomas’ Hospitals, London, UK PART OF HACHETTE LIVRE UK
First published in Great Britain in 1981 Second edition 1986 Third edition 1995 Fourth edition 1999 This fifth edition published in Great Britain in 2008 by Hodder Arnold, an imprint of Hodden Education, part of Hachette Livre UK, 338 Euston Road, London NW1 3BH http://www.hoddereducation.com ©2008 James M Ritter, Lionel D Lewis, Timothy GK Mant and Albert Ferro All rights reserved. Apart from any use permitted under UK copyright law, this publication may only be reproduced, stored or transmitted, in any form, or by any means with prior permission in writing of the publishers or in the case of reprographic production in accordance with the terms of licences issued by the Copyright Licensing Agency. In the United Kingdom such licences are issued by the Copyright licensing Agency: Saffron House, 6–10 Kirby Street, London EC1N 8TS. Hachette Livre’s policy is to use papers that are natural, renewable and recyclable products and made from wood grown in sustainable forests. The logging and manufacturing processes are expected to conform to the environmental regulations of the country of origin. Whilst the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the publisher can accept any legal responsibility or liability for any errors or omissions that may be made. In particular, (but without limiting the generality of the preceding disclaimer) every effort has been made to check drug dosages; however it is still possible that errors have been missed. Furthermore, dosage schedules are constantly being revised and new side-effects recognized. For these reasons the reader is strongly urged to consult the drug companies’ printed instructions before administering any of the drugs recommended in this book. British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress ISBN 978-0-340-90046-8 1 2 3 4 5 6 7 8 9 10 Commissioning Editor: Sara Purdy Project Editor: Jane Tod Production Controller: Andre Sim Cover Design: Laura de Grasse Indexer: John Sampson Typeset in 9/12 pt palatino by Charon Tec Ltd (A Macmillan Company) www.charontec.com Printed and bound in Italy What do you think about this book? Or any other Hodder Arnold title? Please visit our website: www.hoddereducation.com
This fifth edition is dedicated to the memory of Professors Howard Rogers and John Trounce, two of the three authors of this textbook’s first edition.
COMPANION WEBSITE The fifth edition of A Textbook of Clinical Pharmacology and Therapeutics is accompanied by an exciting new website featuring the images from the book for you to download. To visit the book’s website, please go to www.hodderplus.com/clinicalpharmacology. Your username is: student009 Your password is: pharma
CONTENTS FOREWORD viii PART V THE RESPIRATORY SYSTEM 231 PREFACE ix 33 Therapy of asthma, chronic obstructive pulmonary ACKNOWLEDGEMENTS x disease (COPD) and other respiratory disorders 233 PART I GENERAL PRINCIPLES 1 PART VI THE ALIMENTARY SYSTEM 245 1 Introduction to therapeutics 3 34 Alimentary system and liver 247 2 Mechanisms of drug action (pharmacodynamics) 6 35 Vitamins and trace elements 265 3 Pharmacokinetics 11 4 Drug absorption and routes of administration 17 PART VII FLUIDS AND ELECTROLYTES 271 5 Drug metabolism 24 36 Nephrological and related aspects 273 6 Renal excretion of drugs 31 7 Effects of disease on drug disposition 34 PART VIII THE ENDOCRINE SYSTEM 283 8 Therapeutic drug monitoring 41 9 Drugs in pregnancy 45 37 Diabetes mellitus 285 10 Drugs in infants and children 52 38 Thyroid 292 11 Drugs in the elderly 56 39 Calcium metabolism 297 12 Adverse drug reactions 62 40 Adrenal hormones 302 13 Drug interactions 71 41 Reproductive endocrinology 307 14 Pharmacogenetics 79 42 The pituitary hormones and related drugs 316 15 Introduction of new drugs and clinical trials 86 PART IX SELECTIVE TOXICITY 321 16 Cell-based and recombinant DNA therapies 92 17 Alternative medicines: herbals and 43 Antibacterial drugs 323 nutraceuticals 97 44 Mycobacterial infections 334 45 Fungal and non-HIV viral infections 340 PART II THE NERVOUS SYSTEM 103 46 HIV and AIDS 351 18 Hypnotics and anxiolytics 105 47 Malaria and other parasitic infections 361 19 Schizophrenia and behavioural emergencies 110 48 Cancer chemotherapy 367 20 Mood disorders 116 21 Movement disorders and degenerative CNS PART X HAEMATOLOGY 387 disease 124 49 Anaemia and other haematological disorders 389 22 Anti-epileptics 133 23 Migraine 142 PART XI IMMUNOPHARMACOLOGY 397 24 Anaesthetics and muscle relaxants 145 50 Clinical immunopharmacology 399 25 Analgesics and the control of pain 155 PART XII THE SKIN 409 PART III THE MUSCULOSKELETAL SYSTEM 165 51 Drugs and the skin 411 26 Anti-inflammatory drugs and the treatment of arthritis 167 PART XIII THE EYE 421 PART IV THE CARDIOVASCULAR SYSTEM 175 52 Drugs and the eye 423 27 Prevention of atheroma: lowering plasma PART XIV CLINICAL TOXICOLOGY 431 cholesterol and other approaches 177 28 Hypertension 185 53 Drugs and alcohol abuse 433 29 Ischaemic heart disease 196 54 Drug overdose and poisoning 444 30 Anticoagulants and antiplatelet drugs 204 INDEX 451 31 Heart failure 211 32 Cardiac dysrhythmias 217
FOREWORD John Trounce, who was the senior author of the first edition of this textbook, died on the 16 April 2007. He considered a text in clinical pharmacology suitable for his undergraduate and postgradu- ate students to be an important part of the programme he developed in his department at Guy’s Hospital Medical School, London. It is difficult to imagine today how much resistance from the medical and pharmacological establishments Trounce had to overcome in order to set up an academic department, a focussed course in the medical curriculum and a separate exam in final MB in clinical pharmacology. In other words, he helped to change a ‘non-subject’ into one of the most important areas of study for medical students. He was also aware of the need for a high quality textbook in clinical pharmacology that could also be used by nurses, phar- macists, pharmacology science students and doctors preparing for higher qualifications. (For example, it has been said that nobody knows more about acute pharmacology than an anaesthetist.) The present edition of the textbook reflects the advances in therapeutics since the publica- tion of the fourth edition. It is interesting to follow in all the editions of the book, for example, how the treatment of tumours has progressed. It was about the time of the first edition that Trounce set up the first oncology clinic at Guy’s Hospital in which he investigated the value of combined radiation and chemotherapy and drug cocktails in the treatment of lymphomas. John Trounce was pleased to see his textbook (and his subject) in the expert hands of Professor Ritter and his colleagues. Roy Spector Professor Emeritus in Applied Pharmacology, University of London
PREFACE Clinical pharmacology is the science of drug use in humans. Clinicians of all specialties pre- scribe drugs on a daily basis, and this is both one of the most useful but also one of the most dangerous activities of our professional lives. Understanding the principles of clinical pharma- cology is the basis of safe and effective therapeutic practice, which is why this subject forms an increasingly important part of the medical curriculum. This textbook is addressed primarily to medical students and junior doctors of all special- ties, but also to other professionals who increasingly prescribe medicines (including pharma- cists, nurses and some other allied professionals). Clinical pharmacology is a fast moving subject and the present edition has been completely revised and updated. It differs from the fourth edition in that it concentrates exclusively on aspects that students should know and understand, rather than including a lot of reference material. This has enabled us to keep its length down. Another feature has been to include many new illustrations to aid in grasping mechanisms and principles. The first section deals with general principles including pharmacodynamics, pharmaco- kinetics and the various factors that modify drug disposition and drug interaction. We have kept algebraic formulations to a minimum. Drug metabolism is approached from a practical viewpoint, with discussion of the exciting new concept of personalized medicine. Adverse drug reactions and the use of drugs at the extremes of age and in pregnancy are covered, and the introduction of new drugs is discussed from the viewpoint of students who will see many new treatments introduced during their professional careers. Many patients use herbal or other alternative medicines and there is a new chapter on this important topic. There is a chap- ter on gene and cell-based therapies, which are just beginning to enter clinical practice. The remaining sections of the book deal comprehensively with major systems (nervous, musculo- skeletal, cardiovascular, respiratory, alimentary, renal, endocrine, blood, skin and eye) and with multi-system issues including treatment of infections, malignancies, immune disease, addiction and poisoning. JAMES M RITTER LIONEL D LEWIS TIMOTHY GK MANT ALBERT FERRO
ACKNOWLEDGEMENTS We would like to thank many colleagues who have helped us with advice and criticism in the revision and updating of this fifth edition. Their expertise in many specialist areas has enabled us to emphasize those factors most relevant. For their input into this edition and/or the previ- ous edition we are, in particular, grateful to Professor Roy Spector, Professor Alan Richens, Dr Anne Dornhorst, Dr Michael Isaac, Dr Terry Gibson, Dr Paul Glue, Dr Mark Kinirons, Dr Jonathan Barker, Dr Patricia McElhatton, Dr Robin Stott, Mr David Calver, Dr Jas Gill, Dr Bev Holt, Dr Zahid Khan, Dr Beverley Hunt, Dr Piotr Bajorek, Miss Susanna Gilmour- White, Dr Mark Edwards, Dr Michael Marsh, Mrs Joanna Tempowski. We would also like to thank Dr Peter Lloyd and Dr John Beadle for their assistance with figures.
PART I GENERAL PRINCIPLES
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CHAPTER 1 INTRODUCTION TO THERAPEUTICS ● Use of drugs 3 ● Formularies and restricted lists 4 ● Adverse effects and risk/benefit 3 ● Scientific basis of use of drugs in humans 4 ● Drug history and therapeutic plan 4 of doing harm. For example, cures of leukaemias, Hodgkin’s USE OF DRUGS disease and testicular carcinomas have been achieved through a preparedness to accept a degree of containable harm. Similar People consult a doctor to find out what (if anything) is wrong considerations apply in other disease areas. (the diagnosis), and what should be done about it (the treat- All effective drugs have adverse effects, and therapeutic ment). If they are well, they may nevertheless want to know judgements based on risk/benefit ratio permeate all fields of how future problems can be prevented. Depending on the diag- medicine. Drugs are the physician’s prime therapeutic tools, nosis, treatment may consist of reassurance, surgery or other and just as a misplaced scalpel can spell disaster, so can a interventions. Drugs are very often either the primary therapy thoughtless prescription. Some of the more dramatic instances or an adjunct to another modality (e.g. the use of anaesthetics make for gruesome reading in the annual reports of the med- in patients undergoing surgery). Sometimes contact with the ical defence societies, but perhaps as important is the morbid- doctor is initiated because of a public health measure (e.g. ity and expense caused by less dramatic but more common through a screening programme). Again, drug treatment is errors. sometimes needed. Consequently, doctors of nearly all special- How are prescribing errors to be minimized? By combining ties use drugs extensively, and need to understand the scien- a general knowledge of the pathogenesis of the disease to be tific basis on which therapeutic use is founded. treated and of the drugs that may be effective for that disease A century ago, physicians had only a handful of effective with specific knowledge about the particular patient. Dukes drugs (e.g. morphia, quinine, ether, aspirin and digitalis leaf) and Swartz, in their valuable work Responsibility for drug- at their disposal. Thousands of potent drugs have since been induced injury, list eight basic duties of prescribers: introduced, and pharmaceutical chemists continue to discover new and better drugs. With advances in genetics, cellular and 1. restrictive use – is drug therapy warranted? molecular science, it is likely that progress will accelerate and 2. careful choice of an appropriate drug and dose regimen huge changes in therapeutics are inevitable. Medical students with due regard to the likely risk/benefit ratio, available and doctors in training therefore need to learn something alternatives, and the patient’s needs, susceptibilities and of the principles of therapeutics, in order to prepare them- preferences; selves to adapt to such change. General principles are dis- 3. consultation and consent; cussed in the first part of this book, while current approaches 4. prescription and recording; to treatment are dealt with in subsequent parts. 5. explanation; 6. supervision (including monitoring); 7. termination, as appropriate; 8. conformity with the law relating to prescribing. ADVERSE EFFECTS AND RISK/BENEFIT As a minimum, the following should be considered when Medicinal chemistry has contributed immeasurably to human deciding on a therapeutic plan: health, but this has been achieved at a price, necessitating a new philosophy. A physician in Sir William Osler’s day in the 1. age; nineteenth century could safely adhere to the Hippocratic 2. coexisting disease, especially renal and or hepatic principle ‘first do no harm’, because the opportunities for impairment; doing good were so limited. The discovery of effective drugs 3. the possibility of pregnancy; has transformed this situation, at the expense of very real risks 4. drug history;
4 INTRODUCTION TO THERAPEUTICS 5. the best that can reasonably be hoped for in this pharmaceutical industry. The BNF summarizes products individual patient; licensed in the UK. Because of the bewildering array, includ- 6. the patient’s beliefs and goals. ing many alternatives, many hospital and primary care trusts have reintroduced formularies that are essentially restricted lists of the drugs stocked by the institution’s pharmacy, from which local doctors are encouraged to prescribe. The objec- DRUG HISTORY AND THERAPEUTIC PLAN tives are to encourage rational prescribing, to simplify pur- chasing and storage of drugs, and to obtain the ‘best buy’ In the twenty-first century, a reliable drug history involves among alternative preparations. Such formularies have the questioning the patient (and sometimes family, neighbours, advantage of encouraging consistency, and once a decision other physicians, etc.). What prescription tablets, medicines, has been made with input from local consultant prescribers drops, contraceptives, creams, suppositories or pessaries are they are usually well accepted. being taken? What over-the-counter remedies are being used including herbal or ‘alternative’ therapies? Does the patient use drugs socially or for ‘life-style’ purposes? Have they suf- fered from drug-induced allergies or other serious reactions? SCIENTIFIC BASIS OF USE OF DRUGS IN Have they been treated for anything similar in the past, and if HUMANS so with what, and did it do the job or were there any prob- lems? Has the patient experienced any problems with anaes- The scientific basis of drug action is provided by the discipline thesia? Have there been any serious drug reactions among of pharmacology. Clinical pharmacology deals with the effects family members? of drugs in humans. It entails the study of the interaction of The prescriber must be both meticulous and humble, espe- drugs with their receptors, the transduction (second messen- cially when dealing with an unfamiliar drug. Checking ger) systems to which these are linked and the changes that contraindications, special precautions and doses in a formu- they bring about in cells, organs and the whole organism. lary such as the British National Formulary (BNF) (British These processes (what the drug does to the body) are called Medical Association and Royal Pharmaceutical Society of ‘pharmacodynamics’. The use of drugs in society is encom- Great Britain 2007) is the minimum requirement. The proposed passed by pharmacoepidemiology and pharmacoeconomics – plan is discussed with the patient, including alternatives, both highly politicized disciplines! goals, possible adverse effects, their likelihood and measures Man is a mammal and animal studies are essential, but to be taken if these arise. The patient must understand what is their predictive value is limited. Modern methods of molecu- intended and be happy with the means proposed to achieve lar and cell biology permit expression of human genes, includ- these ends. (This will not, of course, be possible in demented ing those that code for receptors and key signal transduction or delirious patients, where discussion will be with any elements, in cells and in transgenic animals, and are revolu- available family members.) The risks of causing harm must tionizing these areas and hopefully improving the relevance be minimized. Much of the ‘art’ of medicine lies in the ability of preclinical pharmacology and toxicology. of the prescriber to agree to compromises that are accept- Important adverse effects sometimes but not always occur able to an individual patient, and underlies concordance in other species. Consequently, when new drugs are used to treat (i.e. agreement between patient and prescriber) with a thera- human diseases, considerable uncertainties remain. Early-phase peutic plan. human studies are usually conducted in healthy volunteers, Prescriptions must be written clearly and legibly, conform- except when toxicity is inevitable (e.g. cytotoxic drugs used ing to legal requirements. Electronic prescribing is currently for cancer treatment, see Chapter 48). being introduced in the UK, so these are changing. Generic Basic pharmacologists often use isolated preparations, names should generally be used (exceptions are mentioned where the concentration of drug in the organ bath is controlled later in the book), together with dose, frequency and duration precisely. Such preparations may be stable for minutes to of treatment, and paper prescriptions signed. It is prudent to hours. In therapeutics, drugs are administered to the whole print the prescriber’s name, address and telephone number to organism by a route that is as convenient and safe as possible facilitate communication from the pharmacist should a query (usually by mouth), for days if not years. Consequently, the arise. Appropriate follow up must be arranged. drug concentration in the vicinity of the receptors is usually unknown, and long-term effects involving alterations in receptor density or function, or the activation or modulation of homeo- FORMULARIES AND RESTRICTED LISTS static control mechanisms may be of overriding importance. The processes of absorption, distribution, metabolism and elim- Historically, formularies listed the components of mixtures ination (what the body does to the drug) determine the drug prescribed until around 1950. The perceived need for hospital concentration–time relationships in plasma and at the recep- formularies disappeared transiently when such mixtures tors. These processes comprise ‘pharmacokinetics’. There is were replaced by proprietary products prepared by the considerable inter-individual variation due to both inherited
SCIENTIFIC BASIS OF USE OF DRUGS IN H UMANS 5 and acquired factors, notably disease of the organs responsible Case history for drug metabolism and excretion. Pharmacokinetic modelling is crucial in drug development to plan a rational therapeutic A general practitioner reviews the medication of an 86-year-old woman with hypertension and multi-infarct regime, and understanding pharmacokinetics is also import- dementia, who is living in a nursing home. Her family used ant for prescribers individualizing therapy for a particular to visit daily, but she no longer recognizes them, and needs patient. Pharmacokinetic principles are described in Chapter 3 help with dressing, washing and feeding. Drugs include from the point of view of the prescriber. Genetic influences on bendroflumethiazide, atenolol, atorvastatin, aspirin, haloperi- pharmacodynamics and pharmacokinetics (pharmacogenet- dol, imipramine, lactulose and senna. On examination, she smells of urine and has several bruises on her head, but ics) are discussed in Chapter 14 and effects of disease are otherwise seems well cared for. She is calm, but looks pale addressed in Chapter 7, and the use of drugs in pregnancy and bewildered, and has a pulse of 48 beats/min regular, and at extremes of age is discussed in Chapters 9–11. and blood pressure 162/96 mmHg lying and 122/76 mmHg There are no good animal models of many important human standing, during which she becomes sweaty and distressed. diseases. The only way to ensure that a drug with promising Her rectum is loaded with hard stool. Imipramine was started three years previously. Urine culture showed only a light pharmacological actions is effective in treating or preventing mixed growth. All of the medications were stopped and disease is to perform a specific kind of human experiment, manual evacuation of faeces performed. Stool was nega- called a clinical trial. Prescribing doctors must understand the tive for occult blood and the full blood count was normal. strengths and limitations of such trials, the principles of which Two weeks later, the patient was brighter and more mobile. are described in Chapter 15, if they are to evaluate the litera- She remained incontinent of urine at night, but no longer during the day, her heart rate was 76 beats/min and her ture on drugs introduced during their professional lifetimes. blood pressure was 208/108 mmHg lying and standing. Ignorance leaves the physician at the mercy of sources of infor- Comment mation that are biased by commercial interests. Sources of It is seldom helpful to give drugs in order to prevent some- unbiased drug information include Dollery’s encyclopaedic thing that has already happened (in this case multi-infarct Therapeutic drugs, 2nd edn (published by Churchill Livingstone dementia), and any benefit in preventing further ischaemic events has to be balanced against the harm done by the in 1999), which is an invaluable source of reference. Publications polypharmacy. In this case, drug-related problems probably such as the Adverse Reaction Bulletin, Prescribers Journal and include postural hypotension (due to imipramine, ben- the succinctly argued Drug and Therapeutics Bulletin provide droflumethiazide and haloperidol), reduced mobility (due to up-to-date discussions of therapeutic issues of current haloperidol), constipation (due to imipramine and haloperi- importance. dol), urinary incontinence (worsened by bendroflumethi- azide and drugs causing constipation) and bradycardia (due to atenolol). Drug-induced torsades de pointes (a form of Key points ventricular tachycardia, see Chapter 32) is another issue. Despite her pallor, the patient was not bleeding into the gastro-intestinal tract, but aspirin could have caused this. • Drugs are prescribed by physicians of all specialties. • This carries risks as well as benefits. • Therapy is optimized by combining general knowledge of drugs with knowledge of an individual patient. FURTHER READING • Evidence of efficacy is based on clinical trials. • Adverse drug effects may be seen in clinical trials, but Dukes MNG, Swartz B. Responsibility for drug-induced injury. the drug side effect profile becomes clearer only when Amsterdam: Elsevier, 1988. widely prescribed. Weatherall DJ. Scientific medicine and the art of healing. In: Warrell • Rational prescribing is encouraged by local formularies. DA, Cox TM, Firth JD, Benz EJ (eds), Oxford textbook of medicine, 4th edn. Oxford: Oxford University Press, 2005.
CHAPTER 2 MECHANISMS OF DRUG ACTION (PHARMACODYNAMICS) ● Introduction 6 ● Partial agonists 9 ● Receptors and signal transduction 6 ● Slow processes 9 ● Agonists 7 ● Non-receptor mechanisms 10 ● Antagonism 8 (in which case they are termed ‘antagonists’). Examples include INTRODUCTION oestrogens (used in contraception, Chapter 41) and anti- oestrogens (used in treating breast cancer, Chapter 48), alpha- Pharmacodynamics is the study of effects of drugs on biological and beta-adrenoceptor agonists and antagonists (Chapters 29 processes. An example is shown in Figure 2.1, demonstrating and 33) and opioids (Chapter 25). and comparing the effects of a proton pump inhibitor and of a Not all drugs work via receptors for endogenous medi- histamine H2 receptor antagonist (both drugs used for the treat- ators: many therapeutic drugs exert their effects by combining ment of peptic ulceration and other disorders related to gastric with an enzyme or transport protein and interfering with its hyperacidity) on gastric pH. Many mediators exert their effects function. Examples include inhibitors of angiotensin convert- as a result of high-affinity binding to specific receptors in ing enzyme and serotonin reuptake. These sites of drug action plasma membranes or cell cytoplasm/nuclei, and many thera- are not ‘receptors’ in the sense of being sites of action of peutically important drugs exert their effects by combining with endogenous mediators. these receptors and either mimicking the effect of the natural Whether the site of action of a drug is a receptor or another mediator (in which case they are called ‘agonists’) or blocking it macromolecule, binding is usually highly specific, with precise steric recognition between the small molecular ligand and the 10 binding site on its macromolecular target. Binding is usually 9 reversible. Occasionally, however, covalent bonds are formed Pre Rx 8 pH n with irreversible loss of function, e.g. aspirin binding to cyclo- Median gastric pH 7 ≥ 5.0 90 oxygenase (Chapter 30). 37 6 Most drugs produce graded concentration-/dose-related 4.1-5.0 38 effects which can be plotted as a dose–response curve. Such 5 41 curves are often approximately hyperbolic (Figure 2.2a). If plot- 4 ted semi-logarithmically this gives an S-shaped (‘sigmoidal’) 3 2.0-4.0 37 shape (Figure 2.2b). This method of plotting dose–response 25 2 curves facilitates quantitative analysis (see below) of full agonists < 2.0 21 1 15 (which produce graded responses up to a maximum value), 0 antagonists (which produce no response on their own, but Predose Postdose Predose Postdose Predose Postdose reduce the response to an agonist) and partial agonists (which 1 1 2 2 3 3 produce some response, but to a lower maximum value than that Figure 2.1: Effect of omeprazole and cimetidine on gastric pH in a of a full agonist, and antagonize full agonists) (Figure 2.3). group of critically ill patients. This was a study comparing the effect of immediate-release omeprazole with a loading dose of 40 mg, a second dose six to eight hours later, followed by 40 mg daily, with a continuous i.v. infusion of cimetidine. pH monitoring RECEPTORS AND SIGNAL TRANSDUCTION of the gastric aspirate was undertaken every two hours and immediately before and one hour after each dose. Red, omeprazole; blue, cimetidine. (Redrawn with permission from Drugs are often potent (i.e. they produce effects at low concen- Horn JR, Hermes-DeSantis ER, Small, RE ‘New Perspectives in the tration) and specific (i.e. small changes in structure lead to pro- Management of Acid-Related Disorders: The Latest Advances in PPI Therapy’. Medscape Today found changes in potency). High potency is a consequence of http://www.medscape.com/viewarticle/503473_9 17 May 2005.) high binding affinity for specific macromolecular receptors.
AGONISTS 7 100 100 Effect (%) Effect (%) 0 0 5 10 1 10 100 (a) [Drug] (b) [Drug] Figure 2.2: Concentration/dose–response curves plotted (a) arithmetically and (b) semi-logarithmically. Despite this complexity, it turns out that receptors fall into 100 only four ‘superfamilies’ each linked to distinct types of signal transduction mechanism (i.e. the events that link receptor acti- vation with cellular response) (Figure 2.4). Three families are Effect (%) A B located in the cell membrane, while the fourth is intracellular (e.g. steroid hormone receptors). They comprise: C • Fast (millisecond responses) neurotransmitters (e.g. nicotinic receptors), linked directly to a transmembrane 0 ion channel. 1 10 100 • Slower neurotransmitters and hormones (e.g. muscarinic [Drug] receptors) linked to an intracellular G-protein (‘GPCR’). Figure 2.3: Concentration/dose–response curves of two full • Receptors linked to an enzyme on the inner membrane agonists (A, B) of different potency, and of a partial agonist (C). (e.g. insulin receptors) are slower still. • Intranuclear receptors (e.g. gonadal and glucocorticosteroid hormones): ligands bind to their receptor in cytoplasm and Receptors were originally classified by reference to the relative the complex then migrates to the nucleus and binds to potencies of agonists and antagonists on preparations contain- specific DNA sites, producing alterations in gene ing different receptors. The order of potency of isoprenaline Ͼ transcription and altered protein synthesis. Such effects adrenaline Ͼ noradrenaline on tissues rich in β-receptors, such occur over a time-course of minutes to hours. as the heart, contrasts with the reverse order in α-receptor- mediated responses, such as vasoconstriction in resistance arteries supplying the skin. Quantitative potency data are best AGONISTS obtained from comparisons of different competitive antag- onists, as explained below. Such data are supplemented, but not Agonists activate receptors for endogenous mediators – e.g. replaced, by radiolabelled ligand-binding studies. In this way, salbutamol is an agonist at β2-adrenoceptors (Chapter 33). adrenoceptors were divided first into α and β, then subdivided The consequent effect may be excitatory (e.g. increased into α1/α2 and β1/β2. Many other useful receptor classifications, heart rate) or inhibitory (e.g. relaxation of airway smooth including those of cholinoceptors, histamine receptors, sero- muscle). Agonists at nicotinic acetylcholine receptors (e.g. tonin receptors, benzodiazepine receptors, glutamate receptors suxamethonium, Chapter 24) exert an inhibitory effect and others have been proposed on a similar basis. Labelling (neuromuscular blockade) by causing long-lasting depolariza- with irreversible antagonists permitted receptor solubilization tion at the neuromuscular junction, and hence inactivation of and purification. Oligonucleotide probes based on the deduced the voltage-dependent sodium channels that initiate the action sequence were then used to extract the full-length DNA potential. sequence coding different receptors. As receptors are cloned Endogenous ligands have sometimes been discovered long and expressed in cells in culture, the original functional classifi- after the drugs that act on their receptors. Endorphins and cations have been supported and extended. Different receptor enkephalins (endogenous ligands of morphine receptors) subtypes are analogous to different forms of isoenzymes, and a were discovered many years after morphine. Anandamide is a rich variety has been uncovered – especially in the central ner- central transmitter that activates CB (cannabis) receptors vous system – raising hopes for novel drugs targeting these. (Chapter 53).
8 MECHANISMS OF DRUG ACTION (PHARMACODYNAMICS) Slow (s) Direct effect (min) Control (hours) Fast (ms) neurotransmitter on protein of DNA/new neurotransmitter or hormone phosphorylation protein synthesis (e.g. glutamate) (e.g. ␤-adrenoceptor) (e.g. insulin) (e.g. steroid hormones) Ion channel Cell G E membrane E Second messengers Change in Ca2ϩ release Protein membrane phosphorylation potential Cytoplasm Cellular effects Nucleus Figure 2.4: Receptors and signal transduction. G, G-protein; E, enzyme; Ca, calcium. 100 100 A A Aϩ[B]1 Aϩ[B]2 Effect (%) Aϩ[C]1 Aϩ[C]2 0 0 1 10 100 1 10 100 (a) [Agonist] (b) [Agonist] Figure 2.5: Drug antagonism. Control concentration/dose–response curves for an agonist A together with curves in the presence of (a) a competitive antagonist B and (b) a non-competitive antagonist C. Increasing concentrations of the competitive antagonist ([B]1, [B]2) cause a parallel shift to the right of the log dose–effect curve (a), while the non-competitive antagonist ([C]1, [C]2) flattens the curve and reduces its maximum (b). ANTAGONISM known as the dose ratio (r). This results in the familiar parallel shift to the right of the log dose–response curve, since the add- Competitive antagonists combine with the same receptor as an ition of a constant length on a logarithmic scale corresponds to endogenous agonist (e.g. ranitidine at histamine H2-receptors), multiplication by a constant factor (Figure 2.5a). β-Adrenoceptor but fail to activate it. When combined with the receptor, they antagonists are examples of reversible competitive antagonists. prevent access of the endogenous mediator. The complex By contrast, antagonists that do not combine with the same between competitive antagonist and receptor is reversible. receptor (non-competitive antagonists) or drugs that combine Provided that the dose of agonist is increased sufficiently, a irreversibly with their receptors, reduce the slope of the log maximal effect can still be obtained, i.e. the antagonism is sur- dose–response curve and depress its maximum (Figure 2.5b). mountable. If a dose (C) of agonist causes a defined effect when Physiological antagonism describes the situation where two administered alone, then the dose (CЈ) needed to produce the drugs have opposing effects (e.g. adrenaline relaxes bronchial same effect in the presence of antagonist is a multiple (CЈ/C) smooth muscle, whereas histamine contracts it).
SLOW PROCESSES 9 100 2 log (dose ratio) –1 Dose ratio –1 50 1 Slope ϭ 1/KB Slope ϭ 1 pA2 0 0 Ϫ9 10Ϫ8 Ϫ9 Ϫ8 Ϫ7 10 5ϫ10Ϫ9 (a) [Antagonist]→ (b) log[Antagonist]→ Figure 2.6: Competitive antagonism. (a) A plot of antagonist concentration vs. (dose ratio Ϫ1) gives a straight line through the origin. (b) A log–log plot (a Schildt plot) gives a straight line of unit slope. The potency of the antagonist (pA2) is determined from the intercept of the Schildt plot. The relationship between the concentration of a competi- compete. Second, it is more difficult to reverse the effects of a tive antagonist [B], and the dose ratio (r) was worked out by partial agonist, such as buprenorphine, with a competitive Gaddum and by Schildt, and is: antagonist such as naloxone, than it is to reverse the effects of a full agonist such as morphine. A larger fraction of the recep- r Ϫ 1 ϭ [B]/KB, tors is occupied by buprenorphine than by morphine, and a much higher concentration of naloxone is required to compete where KB is the dissociation equilibrium constant of the successfully and displace buprenorphine from the receptors. reversible reaction of the antagonist with its receptor. KB has units of concentration and is the concentration of antagonist needed to occupy half the receptors in the absence of agonist. SLOW PROCESSES The lower the value of KB, the more potent is the drug. If sev- eral concentrations of a competitive antagonist are studied Prolonged exposure of receptors to agonists, as frequently and the dose ratio is measured at each concentration, a plot of occurs in therapeutic use, can cause down-regulation or (r Ϫ 1) against [B] yields a straight line through the origin with desensitization. Desensitization is sometimes specific for a a slope of 1/KB (Figure 2.6a). Such measurements provided particular agonist (when it is referred to as ‘homologous the means of classifying and subdividing receptors in terms of desensitization’), or there may be cross-desensitization to dif- the relative potencies of different antagonists. ferent agonists (‘heterologous desensitization’). Membrane receptors may become internalized. Alternatively, G-protein- mediated linkage between receptors and effector enzymes PARTIAL AGONISTS (e.g. adenylyl cyclase) may be disrupted. Since G-proteins link several distinct receptors to the same effector molecule, this Some drugs combine with receptors and activate them, but are can give rise to heterologous desensitization. Desensitization incapable of eliciting a maximal response, no matter how high is probably involved in the tolerance that occurs during their concentration may be. These are known as partial agonists, prolonged administration of drugs, such as morphine or and are said to have low efficacy. Several partial agonists are benzodiazepines (see Chapters 18 and 25). used in therapeutics, including buprenorphine (a partial agonist Therapeutic effects sometimes depend on induction of tol- at morphine μ-receptors, Chapter 25) and oxprenolol (partial erance. For example, analogues of gonadotrophin-releasing agonist at β-adrenoceptors). hormone (GnRH), such as goserelin or buserelin, are used to Full agonists can elicit a maximal response when only a treat patients with metastatic prostate cancer (Chapter 48). small proportion of the receptors is occupied (underlying the Gonadotrophin-releasing hormone is released physiologically concept of ‘spare’ receptors), but this is not the case with par- in a pulsatile manner. During continuous treatment with tial agonists, where a substantial proportion of the receptors buserelin, there is initial stimulation of luteinizing hormone need to be occupied to cause a response. This has two clinical (LH) and follicle-stimulating hormone (FSH) release, followed consequences. First, partial agonists antagonize the effect of a by receptor desensitization and suppression of LH and FSH full agonist, because most of the receptors are occupied with release. This results in regression of the hormone-sensitive low-efficacy partial agonist with which the full agonist must tumour.