Clinical Pharmacology

CLINICAL

PHARMACOLOGY

'Nature is not only odder than we think, but it is odder than we

can think.'

J B S Haldane 1893-1964

'Patients may recover in spite of drugs or because of them.'

J H Gaddum 1959

'But know also, man has an inborn craving for medicine ... the

desire to take medicine is one feature which distinguishes man

the animal, from his fellow creatures. It is really one of the most

serious difficulties with which we have to contend ... the doctor's

visit is not thought to be complete without a prescription.'

William Osier 1894

'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.' 'Men

who have excessive faith in their theories or ideas are not only ill

prepared for making discoveries; they make very poor

observations ... they can see in [their] results only a confirmation

of their theory ... This is what made us say that we must never

make experiments to confirm our ideas, but simply to control

them.' 'Empiricism is not the negation of science, as certain

physicians seem to think; it is only its first stage.'

'Medicine is destined to get away from empiricism little by little;

like all other sciences, it will get away by the scientific method.'

'Considered in itself, the experimental method is nothing but

reasoning by whose help we methodically submit our ideas to

experience — the experience of facts.'

Claude Bernard 1865

'I do not want two diseases — one nature-made, one doctor￾made.'

Napoleon Bonaparte 1820

'The ingenuity of man has ever been fond of exerting itself to

varied forms and combinations of medicines.'

William Withering 1785

'All things are poisons and there is nothing that is harmless, the

dose alone decides that something is no poison.'

Paracelsus 1493-1541

'First do no harm.'

'It is a good remedy sometimes to use nothing.'

Hippocrates 460-355 B.C.

CLINICAL

PHARMACOLOGY

P. N. Bennett MD FRCP

Reader in Clinical Pharmacology, University of Bath, and Consultant Physician, Royal United Hospital,

Bath, UK

M. J. Brown MA MSC MD FRCP

Professor of Clinical Pharmacology, University of Cambridge; Consultant

Physician, Addenbrooke's Hospital, Cambridge and Director of Clinical Studies

Gonville and Caius College, Cambridge, UK

NINTH EDITION

CHURCHILL

LIVINGSTONE

EDINBURGH LONDON NEW YORK OXFORD PHILADELPHIA ST LOUIS SYDNEY TORONTO 2003

CHURCHILL LIVINGSTONE

An imprint of Elsevier Science Limited

© D. R. Laurence 1960,1962,1966,1973

© D. R. Laurence and P. N. Bennett 1980,1987,1992

© D. R. Laurence, P. N. Bennett, M. J. Brown 1997

© P. N. Bennett, M. J. Brown 2003

The right of P N Bennett and M J Brown to be identified as

the authors of this work has been asserted by them in

accordance with the Copyright, Designs and Patents Act

1988.

No part of this publication may be reproduced, stored in a

retrieval system, or transmitted in any form or by any means,

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otherwise, without either the prior permission of the

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and then 'Obtaining Permissions'.

First edition 1960 Previous editions translated into

Second edition 1962 Italian, Chinese, Spanish,

Third edition 1966 Serbo-Croat, Russian

Fourth edition 1973

Fifth edition 1980

Sixth edition 1987

Seventh edition 1992

Eighth edition 1997

Standard edition ISBN 0443064806

International Student Edition ISBN 0443064814

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

Commissioning Editor: Timothy Home

Project Development Manager: Colin Arthur

Copy Editor: Leslie Smillie

Project Controller: Nancy Arnott

Designer: Erik Bigland

Printed in Spain

The

publisher's

policy is to use

paper manufactured

from sustainable forest!

Preface

For your own satisfaction and for mine, please

read this preface!1

Professor D. R. Laurence was either author or co￾author of this textbook from its 1st

edition in 1960 to

its 8th

in 1997. This is a long life for any textbook. Its

achievement bears testimony to a style of pre￾sentation that strives to be clear and readable, and

to retain the reader's interest whilst imparting

information about a subject that can be at times

both complex and confusing. As he withdraws from

active involvement in the book it is opportune to

pay tribute in this 9th

edition to an achievement in

authorship sustained over four decades, during

which 'Laurence's pharmacology' became the aid,

advisor and companion to generations of students

and doctors seeking guidance in the vital field of

medicinal therapeutics.

This book is about the scientific basis and practice of drug

therapy. It is particularly intended for medical students and

doctors, and indeed for anyone concerned with evidence-based

drug therapy and prescribing.

The scope and rate of drug innovation increases.

Doctors are now faced with a professional lifetime

handling drugs that are new to themselves — drugs

that do new things as well as drugs that do old

things better; drugs that become familiar during

training will be superseded.

We do not write 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 try to tell them 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

1

St Francis of Sales: Preface to Introduction to the devout life

(1609)

does not always demand wearying solemnity. An

author, poet and critic said that he judged fiction

thus: 'Could I read it? If I could read it, did I believe

it? If I believed it, did I care about it, what was the

quality of my caring, and did it last?'2

It would be

presumptuous for us to aspire to satisfy the criteria

for fiction but we have been mindful of them in

producing this book.

All who prescribe drugs would be wise to keep

in mind that the expectations of patients and of

society in general are becoming ever more exacting

and that 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 pharma￾cology. These principles are not difficult to grasp

and are not so many as to defeat even the busiest

doctors who take on themselves the responsibility

of introducing manufactured medicines into the

bodies of their patients.

The principles of pharmacology and drug

therapy will be found in chapters 1-8 and they are

applied in the subsequent specialist chapters which

are offered as a reasonably brief solution to the

problem of combining practical clinical utility with

some account of the principles on which clinical

practice rests.

How much practical technical detail to include is

difficult to decide. In general, where therapeutic

practices that are complex, potentially dangerous

and commonly up-dated, e.g. anaphylactic shock,

we provide more detail together with web-sites that

list the latest advice; less, or even no detail is given

on therapy that is generally conducted only by

specialists, e.g. anticancer drugs and i.v. oxytocin.

But always, especially with modern drugs with which

the prescriber may not be familiar, formularies,

approved guidelines, or the manufacturer's current

literature should be consulted.

2

Philip Larkin: 1922-85

v

PREFAC E

Use of the book. Students are, or should be,

concerned to understand and to develop a rational,

critical attitude to drug therapy and they should

therefore chiefly concern themselves with how drugs

act and interact in disease and with 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 between them, which should never

be required of them in examinations. Thus the text

has not been encumbered with exhaustive lists

of preparations which properly belong in a

formulary, although it is hoped that enough have

been mentioned to cover much routine prescribing,

and many drugs have been included solely for

identification.

The role and status of a textbook. If a book is to

be a useful guide to drug use it must offer clear

conclusions and advice. If it is to be of reasonable

size, alternative acceptable courses of action will

often have to be omitted. What is recommended

should be based on sound evidence where this

exists, and on an assessment of the opinions of the

experienced where it does not.

Increasingly, the selection of drugs is influenced

by guidelines produced by specialist societies and

national bodies. We have provided or made reference

to these as representing a consensus of best practice

in particular situations. Similarly, it is assumed that

the reader possesses a formulary, local or national,

which will provide guidance on the availability,

including doses, of a broad range of drugs. But the

practice of therapeutics by properly educated and

conscientious doctors working in settings com￾plicated 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 so that an optimal result may be achieved

by informed selection and use of drugs.

The guide to further reading at the end of each

chapter generally comprises a few references to

original papers, to referenced editorials and review

articles from a small range of English language

journals that are likely to be available in most hospital

libraries in order to enable anyone, anywhere, to gain

access to the original literature and to informed

opinion, and also to provide interest and sometimes

amusement. We urge readers to select a title that

looks interesting and to read the article. We do not

attempt to document all the statements we make,

which would be impossible in a book of this size.

Bath, Cambridge

2003

P.N.B.,

M.J.B.

vi

Farewell

This book originated in 1957 when I, then senior

lecturer in the Department of Pharmacology and in

the Department of Medicine at University College

and Medical School London, told the Professor of

Medicine that there was no book on Clinical

Pharmacology that I could recommend to our

medical students. He replied that if that was so then

I should get down to it and write such a book. I

doubted that I could accomplish the task. He

marched me off to a nearby medical publisher and a

contract was soon signed. Without this pressure

and the long-sustained support of Max Rosenheim

(later Lord Rosenheim of Camden and President of

the Royal College of Physicians of London) this

book would not have materialised in its first edition

in 1960. Since that date, both in collaboration and

alone, there have been eight editions. I am deeply

grateful to my collaborators.

Now, after above 40 years with the book, and in

my eightieth year, the time has come to stand aside.

I have seen too many elderly academics become

unable, or unwilling, to recognise that they are no

longer quite the people that they once were and that

they have become an embarrassment to their

younger colleagues, who are often too kind to

enlighten them; though they may murmur behind

their senior's back. I long ago decided that I must

not join that group, and I hope I may just have

escaped doing so.

Perhaps my greatest reward has been the

kindness of people from all over the world who

have taken the trouble to communicate to me that

they have not only profited from, but have actually

enjoyed, reading Clinical Pharmacology.

The world of clinical pharmacology has greatly

changed since 1957 when I took up my pen, and I

wish my successors well.

D R Laurence, Professor Emeritus of Pharmacology

and Therapeutics, University College London

vii

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Contributors

It is not possible for two individuals to cover the

whole field of drug therapy from their own

knowledge and experience. For the first time in this

9

th

edition, we invited selected experts to review

chapters in their specialty. They were given free rein

to add, delete or amend existing text as they deemed

appropriate. As a result, some chapters exhibit

substantial changes from the 8th

edition, and all

have benefited greatly from the knowledge and

experience of these individuals. We are deeply

indebted for their contributions. They are:

Nigel S Baber BSc, FRCP, FRCPEd, FFPM, Dip Clin

Pharmacol

Head of Renewals, Reclassification and Patient

Safety, Medicines Control Agency, London, UK and

Visiting Professor, Queen Mary and Westfield

College, University of London, London, UK

Chapter 3. Discovery and development of drugs

Chapter 4. Evaluation of drugs in man

Chapter 5. Official regulation of medicines

Chapter 6. Classification and naming of drugs

Mark Farrington MA, MB, BChir, FRCPath

Consultant Microbiologist, Addenbrooke's

Hospital, Cambridge, UK

Chapter 11. Chemotherapy of infections

Chapter 12. Antibacterial drugs

Chapter 13. Chemotherapy of bacterial infections

Chapter 14. Viral, fungal, protozoal and helminthic

infections

Nicola J Minaur BSc, MB ChB, PhD

Specialist Registrar in Rheumatology, Royal National

Hospital for Rheumatic Diseases, Bath, UK

Neil John McHugh MB, ChB, FRACP, MD, FRCP

Consultant Rheumatologist, Royal National

Hospital for Rheumatic Diseases, Bath, UK

Chapter 15. Inflammation, arthritis and nonsteroidal

anti-inflammatory drugs

Christopher R Lovell MD FRCP

Consultant Dermatologist, Royal United Hospital,

Bath, UK

Chapter 16. Drugs and the skin

G R Park MD, DMedSci

Director of Intensive Care Research, Addenbrooke's

Hospital, Cambridge, UK

J Grewal MBBS

SHO, The John Farman Intensive Care Unit,

Addenbrooke's Hospital, Cambridge, UK

Chapter 17. Pain and analgesics

Jerry Nolan FRCA

Consultant in Anaesthesia and Intensive Care,

Royal United Hospital, Bath, UK

Chapter 18. Anaesthesia and neuromuscular block

Simon J C Davies MA (Oxon), MBBS (Lond),

MRCPsych

Clinical Research Fellow, University of Bristol,

Bristol, UK

Sue Wilson PhD

Research Fellow, University of Bristol, Bristol, UK

David J Nutt MB BChir, MA, DM, FRCP,

FRC Psych, FMedSci

Professor of Psychopharmacology, Head of the

Department of Clinical Medicine,

Dean of Clinical Medicine and Dentistry,

University of Bristol, Bristol, UK

Chapter 19. Psychotropic drugs

D Bateman MD FRCP

Consultant Neurologist, Royal United Hospital

NHS Trust, Bath, UK

Chapter 20. Epilepsy, parkinsonism and allied

conditions

ix

CONTRIBUTOR S

Kevin M O'Shaughnessy MA, BM, BCh, DPhil,

FRCP

University Lecturer in Clinical Pharmacology and

Honorary Consultant Physician, Addenbrooke's

Hospital, Cambridge, UK

Chapter 21. Cholinergic and antimuscarinic

(anticholinergic) mechanisms and drugs

Chapter 22. Adrenergic mechanisms and drugs

Chapter 23. Arterial hypertension, angina pectoris,

myocardial infarction

Chapter 24. Cardiac arrhythmia and cardiac failure

Chapter 25. Hyperlipidaemias

Chapter 26. Kidney and urinary tract

Chapter 27. Respiratory system

Andrew Grace PhD, FRCP, FACC

Consultant Cardiologist, Papworth Hospital,

Cambridge, UK

Chapter 24. Cardiac arrhythmia and cardiac failure

Charles R J Singer BSc, MB, ChB, FRCP, FRCPath

Consultant Haematologist, Royal United Hospital,

Bath, UK

Chapter 28. Drugs and haemostasis

Chapter 29. Cellular disorders and anaemias

Pippa G Corrie PhD, FRCP

Consultant and Associate Lecturer in Medical

Oncology, Addenbrooke's Hospital and University

of Cambridge, Cambridge, UK

Charles R J Singer BSc, MB, ChB, FRCP, FRCPath

Consultant Haematologist, Royal United Hospital,

Bath, UK

Chapter 30. Neoplastic disease and immunosuppression

Michael Davis MD FRCP, Consultant

Gastroenterologist, Royal United Hospital, Bath,

UK

Chapter 31. Stomach, oesophagus and duodenum

Chapter 32. Intestines

Chapter 33. Liver, biliary tract, pancreas

D C Brown MD, MSc, FRCP

Consultant Endocrinologist, Cromwell Hospital,

London, UK

Chapter 34. Adrenal corticosteroids, antagonists,

corticotrophin

Chapter 35. Diabetes mellitus, insulin, oral

antidiabetes agents, obesity

Chapter 36. Thyroid hormones, antithyroid drugs

Chapter 37. Hypothalamic, pituitary and sex hormones

Chapter 38. Vitamins, calcium, bone

X

Acknowledgements

Aditionally, we express our gratitude to others who

have, with such good grace, given us their time and

energy to supply valuable facts and opinions for

this and previous editions; they principally include:

Dr E S K Assem, Dr Stella Barnass, Dr N B Bennett,

Dr Noeleen Foley, Dr Sheila Gore, Professor J

Guillebaud, Professor D H Jenkinson, Dr H Ludlam,

Professor P J Maddison, Dr P T Macgee, the late

Professor Sir William Paton, Professor B N C Prichard,

Dr J P D Reckless, Dr Catriona Reid, Dr Andrew

Souter, Professor P L Weissberg.

Other acknowledgements are made in the

appropriate places.

Much of any merit this book may have is due to

the generosity of those named above as well as

others too numerous to mention who have put their

knowledge and practical experience of the use of

drugs at our disposal. We hope that this collective

acknowledgement will be acceptable. Errors are our

own.

In addition, permission to quote directly from

the writings of some authorities has been generously

granted and we thank the authors and their

publishers who have given it. If we have omitted

any acknowledgement that ought to have been

made we will make such amends as we can as soon

as we can.

P.N.B.

M.J.B.

Note from the authors and

publisher

Medical knowledge is constantly changing. Standard

safety precautions must be followed, but as new

research and clinical experience broaden our

knowledge, changes in treatment and drug therapy

may become necessary or appropriate. Readers are

advised to check the most current product

information provided by the manufacturer of each

drug to be administered to verify the recommended

dose, the method and duration of administration,

and contraindications. It is the responsibility of the

practitioner, relying on experience and knowledge

of the patient, to determine dosages and the best

treatment for each individual patient. Neither the

Publisher nor the authors assumes any liability for

any injury and/or damage to persons or property

arising from this publication.

xi

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Contents

Preface v

Farewell vii

Contributors ix

Acknowledgements xi

Note from the authors and publishers xi

Section 1

GENERAL

1. Topics in drug therapy 3

2. Clinical pharmacology 37

3. Discovery and development of drugs 41

4. Evaluation of drugs in man 51

5. Official regulation of medicines 73

6. Classification and naming of drugs 83

Section 2

FROM PHARMACOLOGY TO TOXICOLOGY

7. General pharmacology 89

8. Unwanted effects and adverse drug

reactions 135

9. Poisoning, overdose, antidotes 151

10. Nonmedical use of drugs 165

Section 3

INFECTION AND INFLAMMATION

11. Chemotherapy of infections 201

12. Antibacterial drugs 215

13. Chemotherapy of bacterial infections 237

14. Viral, fungal, protozoal and helminthic

infections 257

15. Inflammation, arthritis and nonsteroidal anti￾inflammatory drugs 279

16. Drugs and the skin 299

Section 4

NERVOUS SYSTEM

17. Pain and analgesics 319

18. Anaesthesia and neuromuscular block 345

19. Psychotropic drugs 367

20. Epilepsy, parkinsonism and allied conditions

413

Section 5

CARDIORESPIRATORY AND RENAL

SYSTEMS

21. Cholinergic and antimuscarinic

(anticholinergic) mechanisms and drugs 432

22. Adrenergic mechanisms and drugs 447

23. Arterial hypertension, angina pectoris,

myocardial infarction 461

24. Cardiac arrhythmia and cardiac failure 497

25. Hyperlipidaemias 521

26. Kidney and Genitourinary tract 529

27. Respiratory system 549

Section 6

BLOOD AND NEOPLASTIC DISEASE

28. Drugs and haemostasis 567

29. Cellular disorders and anaemias 587

30. Neoplastic disease and immunosuppression

603

Section 7

GASTROINTESTINAL SYSTEM

31. Stomach, oesophagus and duodenum 625

32. Intestines 639

33. Liver, biliary tract, pancreas 651

xiii