Tài liệu CLINICAL PHARMACOLOGY 2003 (PART 1) docx

Professor of Clinical Pharmacology, University of Cambridge; ConsultantPhysician, Addenbrooke's Hospital, Cambridge and Director of Clinical Studies Gonville and Caius College, Cambridge

PHARMACOLOGY

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

'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 innocentare permissible, and those that may do good are obligatory.' 'Menwho have excessive faith in their theories or ideas are not only illprepared 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 nevermake experiments to confirm our ideas, but simply to controlthem.' 'Empiricism is not the negation of science, as certainphysicians 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 butreasoning by whose help we methodically submit our ideas toexperience — the experience of facts.'

Professor of Clinical Pharmacology, University of Cambridge; Consultant

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

Gonville and Caius College, Cambridge, UK

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,

electronic, mechanical, photocopying, recording or

otherwise, without either the prior permission of the

publishers or a licence permitting restricted copying in the

United Kingdom issued by the Copyright Licensing Agency,

90 Tottenham Court Road, London WIT 4LP Permissions

may be sought directly from Elsevier's Health Sciences

Rights Department in Philadelphia, USA: phone: (+1) 215 238

7869, fax: (+1) 215 238 2239, e-mail:

healthpermissions@elsevier.com You may also complete

your request on-line via the Elsevier Science homepage

(http://www.elsevier.com), by selecting 'Customer Support'

and then 'Obtaining Permissions'.

First edition 1960 Previous editions translated into

Second edition 1962 Italian, Chinese, Spanish,

Third edition 1966 Serbo-Croat, Russian

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!

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 Anauthor, poet and critic said that he judged fictionthus: 'Could I read it? If I could read it, did I believeit? If I believed it, did I care about it, what was thequality of my caring, and did it last?'2 It would bepresumptuous for us to aspire to satisfy the criteriafor fiction but we have been mindful of them inproducing this book

All who prescribe drugs would be wise to keep

in mind that the expectations of patients and ofsociety in general are becoming ever more exactingand that doctors who prescribe casually or ignorantlynow face not only increasing criticism but also civil(or even criminal) legal charges The ability to handlenew developments depends, now more than ever,

on comprehension of the principles of cology These principles are not difficult to graspand are not so many as to defeat even the busiestdoctors who take on themselves the responsibility

pharma-of introducing manufactured medicines into thebodies of their patients

The principles of pharmacology and drugtherapy will be found in chapters 1-8 and they areapplied in the subsequent specialist chapters whichare offered as a reasonably brief solution to theproblem of combining practical clinical utility withsome account of the principles on which clinicalpractice rests

How much practical technical detail to include isdifficult to decide In general, where therapeuticpractices that are complex, potentially dangerousand commonly up-dated, e.g anaphylactic shock,

we provide more detail together with web-sites thatlist the latest advice; less, or even no detail is given

on therapy that is generally conducted only byspecialists, e.g anticancer drugs and i.v oxytocin.But always, especially with modern drugs with whichthe prescriber may not be familiar, formularies,approved guidelines, or the manufacturer's currentliterature should be consulted

2 Philip Larkin: 1922-85

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 thatthe reader possesses a formulary, local or national,which will provide guidance on the availability,including doses, of a broad range of drugs But thepractice of therapeutics by properly educated andconscientious doctors working in settings com-plicated by intercurrent disease, metabolic differences

or personality, involves challenges beyond the rigidadherence to published recommendations The role

of a textbook is to provide the satisfaction ofunderstanding 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 eachchapter generally comprises a few references tooriginal papers, to referenced editorials and reviewarticles from a small range of English languagejournals that are likely to be available in most hospitallibraries in order to enable anyone, anywhere, to gainaccess to the original literature and to informedopinion, and also to provide interest and sometimesamusement We urge readers to select a title thatlooks interesting and to read the article We do notattempt to document all the statements we make,which would be impossible in a book of this size

Bath, Cambridge2003

P.N.B.,M.J.B

vi

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 becomeunable, or unwilling, to recognise that they are nolonger quite the people that they once were and thatthey have become an embarrassment to theiryounger colleagues, who are often too kind toenlighten them; though they may murmur behindtheir senior's back I long ago decided that I mustnot join that group, and I hope I may just haveescaped doing so

Perhaps my greatest reward has been thekindness of people from all over the world whohave taken the trouble to communicate to me thatthey have not only profited from, but have actually

enjoyed, reading Clinical Pharmacology.

The world of clinical pharmacology has greatlychanged since 1957 when I took up my pen, and Iwish my successors well

D R Laurence, Professor Emeritus of Pharmacologyand Therapeutics, University College London

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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

9th 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

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

FRC Psych, FMedSciProfessor of Psychopharmacology, Head of theDepartment of Clinical Medicine,

Dean of Clinical Medicine and Dentistry,University of Bristol, Bristol, UK

Chapter 19 Psychotropic drugs

D Bateman MD FRCPConsultant Neurologist, Royal United HospitalNHS Trust, Bath, UK

Chapter 20 Epilepsy, parkinsonism and allied conditions

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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, FRCPathConsultant Haematologist, Royal United Hospital,Bath, UK

Chapter 30 Neoplastic disease and immunosuppression

Michael Davis MD FRCP, ConsultantGastroenterologist, 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, FRCPConsultant 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

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 theirknowledge and practical experience of the use ofdrugs at our disposal We hope that this collectiveacknowledgement will be acceptable Errors are ourown

In addition, permission to quote directly fromthe writings of some authorities has been generouslygranted and we thank the authors and theirpublishers who have given it If we have omittedany acknowledgement that ought to have beenmade we will make such amends as we can as soon

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 thepractitioner, relying on experience and knowledge

of the patient, to determine dosages and the besttreatment for each individual patient Neither thePublisher nor the authors assumes any liability forany injury and/or damage to persons or propertyarising from this publication

xi

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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

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

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

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