Twelfth Edition CLINICAL PHARMACOLOGY > f Morris J. Brown Pankaj Sharma ^ Fraz A. Mir Peter N. Bennett ELSEVIER Any screen. Any time. Anywhere. Activate the eBook version of this title at no additional charge. Student Consult eBooks give you the power to browse and find content, view enhanced images, share notes and highlights—both online and offline. Unlock your eBook today. 1 Visit studentconsult.inkling.com/redeem Scan this QR code to redeem your eBook through your mobile device: 2 Scratch off your code 3 Type code into “Enter Code” box 4 Click “Redeem” 5 Log in or Sign up 6 Go to “My Library” Place Peel Off It’s that easy! Sticker Here For technical assistance: email [email protected] call 1-800-401-9962 (inside the US) call +1-314-447-8200 (outside the US) Use of the current edition of the electronic version of this book (eBook) is subject to the terms of the nontransferable, limited license granted on studentconsult.inkling.com. Access to the eBook is limited to the first individual who redeems the PIN, located on the inside cover of this book, at studentconsult.inkling.com and may not be transferred to another party by resale, lending, or other means. 2015v1.0 Clinical Pharmacology And I will use regimens for the benefit of the ill in accordance with my ability and my judgement. The Hippocratic Oath c.400 BC But doctors are lucky: the sun shines on their successes and the earth hides their failures. Michael de Montaigne 1533–1592 Morals do not forbid making experiments on one’s neighbour or on one’s self … among the experiments that may be tried on man, those that can only harm are forbidden, those that are innocent are permissible, and those that may do good are obligatory. Claude Bernard 1813–1878 It may seem a strange principle to enunciate as the very first requirement in a Hospital that it should do the sick no harm. Florence Nightingale 1820–1910 The ingenuity of man has ever been fond of exerting itself to varied forms and combinations of medicines. William Withering 1741–1799 A desire to take medicine is, perhaps, the great feature which distinguishes man from other animals. William Osler 1849–1920 All things are poisons and there is nothing that is harmless, the dose alone decides that something is no poison. Paracelsus 1493–1541 Medical science aims at the truth and nothing but the truth. William J Mayo 1861–1939 What we find in books is like the fire in our hearths. We fetch it from our neighbors, we kindle it at home, we communicate it to others, and it becomes the property of all. Voltaire 1694–1778 Clinical Pharmacology Twelfth edition Morris J. Brown MA MSc FRCP FAHA FBPharmacolS FMedSci Professor of Endocrine Hypertension, William Harvey Research Institute of the Barts and the London School of Medicine and Dentistry, London, UK Pankaj Sharma MD PhD FRCP Professor of Neurology and Director, Institute of Cardiovascular Research, Royal Holloway College, University of London; and Consultant Neurologist, Imperial College Healthcare NHS Trust, London, UK Fraz A. Mir MA, FRCP Consultant Clinical Pharmacologist, Division of Experimental Medicine and Immunotherapeutics, Department of Medicine, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK Peter N. Bennett MD FRCP Formerly Reader in Clinical Pharmacology, University of Bath; and Consultant Physician, Royal United Hospital, Bath, UK Edinburgh London New York Oxford Philadelphia St Louis Sydney 2019 © 2019, Elsevier Limited. All rights reserved. First edition 1960 Second edition 1962 Third edition 1966 Fourth edition 1973 Fifth edition 1980 Sixth edition 1987 Seventh edition 1992 Eighth edition 1997 Ninth edition 2003 Tenth edition 2008 Eleventh edition 2012 No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds or experiments described herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors or contributors for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. ISBN: 978-0-7020-7328-1 IE: 978-0-7020-7329-8 Printed in China Last digit is the print number: 9 8 7 6 5 4 3 2 1 Content Strategist: Pauline Graham Content Development Specialist: Fiona Conn Senior Project Manager: Manchu Mohan Design: Amy Buxton Illustration Manager: Teresa McBryan Marketing Manager: Deborah Watkins The publisher’s policy is to use paper manufactured from sustainable forests Contents Preface ......................................................................vii 10 Poisoning, overdose, antidotes ................125 List of contributors ..................................................ix Stephen Haydock Acknowledgements ...............................................xiii 11 Drug dependence .......................................139 Stephen Haydock Section 1: General Section 3: Infection and inflammation 1 Clinical pharmacology ...................................2 Mike Schachter 12 Chemotherapy of infections ....................166 2 Topics in drug therapy ...................................5 David A. Enoch, Mark Farrington Mike Schachter 13 Antibacterial drugs .....................................178 3 Discovery and development of David A. Enoch, Mark Farrington drugs ................................................................28 14 Chemotherapy of bacterial infections ....198 Patrick Vallance David A. Enoch, Mark Farrington, 4 Evaluation of drugs in humans ..................37 Surender K. Sharma Ian Hudson, June Raine 15 Viral, fungal, protozoal and helminthic 5 Health technology assessment ....................56 infections ......................................................221 Michael Rawlins Sani Aliyu 6 Regulation of medicines ..............................63 16 Drugs for inflammation and joint Ian Hudson, Keith MacDonald, June Raine disease ..........................................................248 7 Classification and naming of drugs ...........71 Clare Thornton, Justin C. Mason Morris J. Brown 17 Drugs and the skin ....................................269 Thomas K. K. Ha Section 2: From pharmacology to toxicology Section 4: Nervous system 8 General pharmacology .................................76 18 Pain and analgesics ....................................288 Mike Schachter, Munir Pirmohamed Michael C. Lee, Mark Abrahams 9 Unwanted effects and adverse drug 19 Anaesthesia and neuromuscular reactions .......................................................112 block .............................................................308 Mike Schachter Jerry P. Nolan v Contents 20 Psychotropic drugs .....................................324 Section 7: Gastrointestinal David Nutt, Simon Davies, system Blanca M. Bolea-Alamanac 21 Neurological disorders – epilepsy, Parkinson’s 32 Oesophagus, stomach and disease and multiple sclerosis ..................365 duodenum ..................................................562 Paul Bentley, Pankaj Sharma Devinder Singh Bansi, Charlotte Hateley, John Louis-Auguste Section 5: Cardiorespiratory and 33 Intestines ......................................................570 renal systems Devinder Singh Bansi, Charlotte Hateley, John Louis-Auguste 22 Cholinergic and antimuscarinic 34 Liver and biliary tract .................................581 (anticholinergic) mechanisms Graeme Alexander and drugs ....................................................392 Morris J. Brown, Fraz A. Mir Section 8: Endocrine system, 23 Adrenergic mechanisms and drugs ..........403 metabolic conditions Morris J. Brown 24 Arterial hypertension, angina 35 Adrenal corticosteroids, antagonists, pectoris, myocardial infarction and corticotropin ...............................................594 heart failure ..................................................415 Diana C. Brown, Morris J. Brown Morris J. Brown 36 Diabetes mellitus, insulin, oral 25 Cardiac arrhythmia .....................................451 antidiabetes agents, obesity ......................608 Andrew Grace Mark Evans, Rahat Tauni 26 Hyperlipidaemias .......................................468 37 Thyroid hormones, antithyroid John P. D. Reckless drugs .............................................................625 27 Kidney and genitourinary tract ................479 Diana C. Brown Thomas F. Hiemstra 38 Hypothalamic, pituitary and sex 28 Respiratory system .....................................495 hormones ....................................................635 Lucinda Kennard Karim Meeran 39 Vitamins, calcium, bone ...........................655 Section 6: Blood and Chrysothemis Brown neoplastic disease Index ......................................................................667 29 Drugs and haemostasis ..............................512 Mike Laffan, Trevor Baglin 30 Red blood cell disorders ...........................528 M. Hasib Sidiqi, Wendy N. Erber 31 Neoplastic disease and immunosuppression .................................543 Harpreet Wasan vi Preface For your own satisfaction and for mine, please read this preface!1 A preface should tell the prospective reader about the subject of a book, its purpose and its plan. This book is about the scientific basis and practice of drug therapy. It addresses medical students and doctors in particular, but also anyone concerned with evidence-based drug therapy and prescribing. The scope and rate of drug innovation increase. Doctors now face a professional lifetime of handling drugs that are new to themselves – drugs that do new things as well as drugs that do old things better – and drugs that were familiar during medical training become redundant. We write not only for readers who, like us, have a special interest in pharmacology. We try to make pharmacology understandable for those whose primary interests lie elsewhere but who recognise that they need some knowledge of pharmacology if they are to meet their moral and legal ‘duty of care’ to their patients. We are aware, too, of medical curricular pressures that would reduce the time devoted to teaching clinical pharmacology and therapeutics, and such diminution is surely a misguided policy for a subject that is so integral to the successful practice of medicine. Thus, we try to tell readers what they need to know without burdening them with irrelevant information, and we try to make the subject interesting. We are very serious, but seriousness does not always demand wearying solemnity. All who prescribe drugs would be wise to keep in mind the changing and ever more exacting expectations of patients and of society in general. Doctors who prescribe casually or ignorantly now face not only increasing criticism but also civil (or even criminal) legal charges. The ability to handle new developments depends, now more than ever, on comprehension of the principles of pharmacology. These principles are not difficult to grasp and are not so many as to defeat even the busiest doctors who take upon themselves the responsibility of introducing manufactured medicines into the bodies of their patients. The exercise of prescribing calls for the meticulous selection of medicines and so the avoidance of polypharmacy, which now seems rampant. The principles of pharmacology and drug therapy appear in Chapters 1–11 and their application in the subsequent specialist chapters, where we draw on the knowledge and authority of a range of experts, to whom we express our gratitude. The names of those who contributed to the present and previous editions appear on subsequent pages. We seek to offer a reasonably brief solution to the problem of combining practical clinical utility with an account of the principles on which clinical practice rests. The quantity of practical technical detail to include is a matter of judgment. In general, where therapeutic practices are complex, potentially dangerous or commonly updated, e.g. anaphylactic shock, we provide more detail, together with websites for the latest advice; we give less or even no detail on therapy that specialists undertake, e.g. anticancer drugs. Nevertheless, especially with modern drugs that are unfamiliar, prescribers should consult formularies, approved guidelines or the manu- facturer’s current literature, relevant to their country of practice. 1St Francis of Sales: Preface to Introduction to the devout life (1609). vii Preface Use of the book. Francis Bacon2 wrote that ‘Some books are to be tasted, others to be swallowed, and some few to be chewed and digested.’ Perhaps elements of each activity can apply to parts of our text. Students and doctors are, or should be, concerned to understand and to develop a rational, critical attitude to drug therapy, and they should therefore chiefly address issues of how drugs act and interact in disease and how evidence of therapeutic effect is obtained and evaluated. To this end, they should read selectively and should not impede themselves by attempts to memorise lists of alternative drugs and doses and minor differences among them, which should never be required of them in examinations. Thus, we do not encumber the text with exhaustive lists of preparations, which properly belong in a formulary, although we hope that enough has been mentioned to cover much routine prescribing, and many drugs have been included solely for identification. The role and status of a textbook. In this computer age, a textbook still plays a coveted role. Unlike electronic search engines, a textbook allows one to browse and amble a route to the question posed, perhaps acquiring information along the way that one had never thought existed. We aspire to provide one such route. A useful guide to drug use must offer clear conclusions and advice. If it is to be of reasonable size, it may often omit alternative acceptable courses of action. What it recommends should rest on sound evidence, where this exists, and on an assessment of the opinions of the experienced where it does not. Increasingly, guidelines produced by specialist societies and national and international bodies have influenced the selection of drugs. We provide or refer to these as representing a consensus of best practice in particular situations. Similarly, we assume that the reader possesses a formulary, local or national, that will provide guidance on the availability, including doses, of a broad range of drugs. Yet the practice of medicinal therapeutics by properly educated and conscientious doctors working in settings complicated by intercurrent disease, metabolic differences or personality, involves challenges beyond the rigid adherence to published recommendations. The role of a textbook is to provide the satisfaction of understanding the basis for a recommended course of action and to achieve an optimal result by informed selection and use of drugs. In this our twelfth edition, we can but reassert our belief in this principle. The textbook is dead: long live the textbook. MJB, PS, FAM, PNB 2Francis Bacon (1561–1626) Essays (1625) ‘Of studies’. Philosopher and scientist, Bacon introduced the idea of the experimental or inductive method of reasoning for understanding nature. viii