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Clinical pharmacology AndIwilluseregimensforthebenefitoftheillinaccordancewithmyabilityandmyjudgement. Hippocrates’Oath Theyusedtohaveamoreequitablecontractin(ancient)Egypt:forthefirstthreedays,thedoctortookonthepatientatthepatient’srisk andperil:whenthethreedayswereup,therisksandperilswerethedoctor’s.Butdoctorsarelucky:thesunshinesontheirsuccessesand theearthhidestheirfailures. MichaeldeMontaigne1533–92 Natureisnotonlyodderthanwethink,butitisodderthanwecanthink. JBSHaldane1893–1964 Moralsdonotforbidmakingexperimentsonone’sneighbouroronone’sself...amongtheexperimentsthatmaybetriedonman, thosethatcanonlyharmareforbidden,thosethatareinnocentarepermissible,andthosethatmaydogoodareobligatory. Menwhohaveexcessivefaithintheirtheoriesorideasarenotonlyillpreparedformakingdiscoveries;theymakeverypoorobservations... theycanseein[their]resultsonlyaconfirmationoftheirtheory...Thisiswhatmadeussaythatwemustnevermakeexperimentstoconfirm ourideas,butsimplytocontrolthem. Medicineisdestinedtogetawayfromempiricismlittlebylittle;likeallothersciences,itwillgetawaybythescientificmethod. Consideredinitself,theexperimentalmethodisnothingbutreasoningbywhosehelpwemethodicallysubmitourideastoexperience– theexperienceoffacts. ClaudeBernard1865 Idonotwanttwodiseases–onenature-made,onedoctor-made. NapoleonBonaparte1820 Theingenuityofmanhaseverbeenfondofexertingitselftovariedformsandcombinationsofmedicines. WilliamWithering1785 Allthingsarepoisonsandthereisnothingthatisharmless,thedosealonedecidesthatsomethingisnopoison. Paracelsus1493–1541 CommissioningEditor:JeremyBowes DevelopmentEditor:FionaConn ProjectManager:AndrewRiley Designer/DesignDirection:RussellPurdy IllustrationManager:JenniferRose Illustrator:AntbitsLtd. Clinical pharmacology 11th edition Peter N Bennett MD FRCP FormerlyReaderin Clinical Pharmacology,Universityof Bath, and ConsultantPhysician, Royal United Hospital, Bath, UK Morris J Brown MA MSc FRCPFAHAFMedSci Professor of Clinical Pharmacology, Universityof Cambridge;Consultant Physician, Cambridge UniversityHospitals NHS Foundation Trust, Cambridge; and Director of Clinical Studies, Gonvilleand Caius College,Universityof Cambridge,Cambridge, UK Pankaj Sharma MD PhD FRCP ReaderinClinical Neurology atImperial College London;ConsultantNeurologist atHammersmith Hospitals,London,UK Edinburgh London NewYork Oxford Philadelphia StLouis Sydney Toronto 2012 #2012DrPNBennett,ProfessorMorrisJBrownandDrPankajSharma. PublishedbyElsevierLtd.Allrightsreserved. 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Firstedition1960 Secondedition1962 Thirdedition1966 Fourthedition1973 Fifthedition1980 Sixthedition1987 Seventhedition1992 Eighthedition1997 Ninthedition2003 Tenthedition2008 ISBN978-0-7020-4084-9 InternationalISBN978-0-8089-2431-9 BritishLibraryCataloguinginPublicationData AcataloguerecordforthisbookisavailablefromtheBritishLibrary LibraryofCongressCataloginginPublicationData AcatalogrecordforthisbookisavailablefromtheLibraryofCongress Notices Knowledgeandbestpracticeinthisfieldareconstantlychanging.Asnewresearchandexperiencebroaden ourunderstanding,changesinresearchmethods,professionalpractices,ormedicaltreatmentmaybecome necessary. Practitionersandresearchersmustalwaysrelyontheirownexperienceandknowledgeinevaluating andusinganyinformation,methods,compounds,orexperimentsdescribedherein.Inusingsuch informationormethodstheyshouldbemindfuloftheirownsafetyandthesafetyofothers,including partiesforwhomtheyhaveaprofessionalresponsibility. Withrespecttoanydrugorpharmaceuticalproductsidentified,readersareadvisedtocheckthemost currentinformationprovided(i)onproceduresfeaturedor(ii)bythemanufacturerofeachproducttobe administered,toverifytherecommendeddoseorformula,themethodanddurationofadministration, andcontraindications.Itistheresponsibilityofpractitioners,relyingontheirownexperienceand knowledgeoftheirpatients,tomakediagnoses,todeterminedosagesandthebesttreatmentforeach individualpatient,andtotakeallappropriatesafetyprecautions. Tothefullestextentofthelaw,neitherthePublishernortheauthors,contributors,oreditors,assume anyliabilityforanyinjuryand/ordamagetopersonsorpropertyasamatterofproductsliability, negligenceorotherwise,orfromanyuseoroperationofanymethods,products,instructions,orideas containedinthematerialherein. The Publisher's policy is to use paper manufactured from sustainable forests PrintedinChina Contributors MarkAbrahamsMBChBDAFRCAFFPMRCA ChrysothemisBrownMBBSBA LeadClinician,DepartmentofPainMedicine,Cambridge NIHRAcademicClinicalFellow,ImperialCollegeLondon,UK UniversityHospitalsNHSFoundationTrust,Cambridge,UK Chapter39Vitamins,calcium,bone Chapter18Painandanalgesics GraemeAlexanderMAMDFRCP DianaCBrownMDMScFRCP ConsultantHepatologist,DivisionofGastroenterologyand ConsultantEndocrinologist,CromwellHospital,London,UK Hepatology,DepartmentofMedicine,CambridgeUniversity Chapter35Adrenalcorticosteroids,antagonists,corticotrophin, HospitalsNHSFoundationTrust,CambridgeUK Chapter37Thyroidhormones,antithyroiddrugs Chapter34Liverandbiliarytract SaniHAliyuMBBSFRCPFRCPath SimonDaviesDM,MBBS,MRCPsychMScDipEpidemiol ClinicalLecturerinPsychiatry,UniversityofBristol,Bristol,UK ConsultantinMicrobiologyandInfectiousDiseases,Cambridge Chapter20Psychotropicdrugs UniversityHospitalsNHSFoundationTrust,Cambridge,UK Chapter15Viral,fungal,protozoalandhelminthicinfections WendyNErberMDDPhilFRCPathFRCPA JohnLouis-AugusteBAMBChBMRCP ProfessorofPathologyandLaboratoryMedicineUniversity SpecialistRegistrarinGastroenterology,CharingCrossHospital, ofWesternAustraliaWesternAustralia6009Australia London,UK Chapter30Redbloodcelldisorders Chapter32Oesophagus,stomachandduodenum,Chapter33 Intestines MarkEvansMDFRCP TrevorBaglinMAMBChBPhDFRCPFRCPath UniversityLecturer,UniversityofCambridge;Consultant Physician,CambridgeUniversityHospitalsFoundationTrust, ConsultantHaematologist,CambridgeUniversityHospitalsNHS Cambridge,UK FoundationTrust,CambridgeUniversityTeachingHospitalsNHS Chapter36Diabetesmellitus,insulin,oralantidiabetesagents, Trust,Cambridge,UK obesity Chapter29Drugsandhaemostasis MarkFarringtonMAMBBChirFRCPath DevinderSinghBansiBMDMFRCP ConsultantMedicalMicrobiologist,HealthProtectionAgency, ConsultantGastroenterologist,ImperialCollegeHealthcareNHS CambridgeUniversityHospitalsNHSFoundationTrust, Trust,London,UK Cambridge,UK Chapter32Oesophagus,stomachandduodenum,Chapter33 Chapter12Chemotherapyofinfections,Chapter13 Intestines Antibacterialdrugs,Chapter14Chemotherapyofbacterial infections PaulBentleyMA,MRCP,PhD ClinicalSeniorLecturerandHonoraryConsultantinNeurology AndrewGracePhDFRCPFACC andStrokeMedicine,CharingCrossHospital,London,UK ResearchGroupHead,UniversityofCambridge;Consultant Chapter21Neurologicaldisorders-epilepsy,Parkinson’sdisease Cardiologist,PapworthHospital,Cambridge,UK andmultiplesclerosis Chapter25Cardiacarrhythmia BlancaBolea-AlamanacMD ThomasKKHaMDFRACPFRCP ConsultantPsychiatristandHonoraryLecturer,Universityof ConsultantDermatologist,CambridgeUniversityHospitalsNHS Bristol,Bristol,UK FoundationTrust,Cambridge,UK Chapter20Psychotropicdrugs Chapter17Drugsandtheskin vii Contributors StephenHaydockPhDFRCP JuneRaine ConsultantPhysician,MusgroveParkHospital,Taunton,UK Chapter4Evaluationofdrugsinhumans,Chapter6Official Chapter10Poisoning,overdose,antidotes,Chapter11Drug regulationofmedicines dependence SirMichaelRawlinsMDFRCPFMedSci MichaelCLeeMBBSFRCAPhDFFPMRCA Chairman,NationalInstituteforClinicalExcellence(NICE), Consultant,ChurchillHospital,Oxford,UK London,UK Chapter18Painandanalgesics Chapter5Healthtechnologyassessment JustinCMasonPhDFRCP SirPeterCRubinMADMFRCP ProfessorofTherapeutics,UniversityofNottingham,UK;Chair, ProfessorofVascularRheumatology,ImperialCollegeLondon, GeneralMedicalCouncil,UK UK Chapter2Topicsindrugtherapy:Practicalprescribing Chapter16Drugsforinflammationandjointdisease MikeSchachterMBBScFRCP KarimMeeranMDFRCPFRCPath SeniorLecturerinClinicalPharmacology,ImperialCollege, ProfessorofEndocrinology,FacultyofMedicine,Imperial London,UK CollegeLondon,UK Chapter1Clinicalpharmacology,Chapter2Topicsindrug Chapter38Hypothalamic,pituitaryandsexhormones therapy,Chapter8Generalpharmacology,Chapter9Unwanted effectsandadversedrugreactions JerryPNolanFRCAFCEMFRCPFFICM ConsultantinAnaesthesia&IntensiveCareMedicine,Royal SurenderKSharmaMDPhD UnitedHospital,Bath,UK Chief,DivisionofPulmonary,CriticalCareandSleepMedicine; Chapter19Anaesthesiaandneuromuscularblock Head,DepartmentofMedicine;AllIndiaInstituteofMedical Sciences,NewDelhi,India DavidNutt,DMFRCPFRCPsychFMedSci Chapter14Chemotherapyofbacterialinfections TheEdmondJSafraChairinNeuropsychopharmacology, ImperialCollegeLondon,UK ClareThorntonMAMRCP Chapter20Psychotropicdrugs WellcomeTrustClinicalResearchFellow,ImperialCollege London,UK Chapter16Drugsforinflammationandjointdisease KevinMO’ShaughnessyMABMBChDPhilFRCP SeniorLecturerinClinicalPharmacology,Universityof PatrickVallance Cambridge,UK President,PharmaceuticalsR&DGlaxoSmithKline,BrentfordUK Chapter22Cholinergicandantimuscarinic(anticholinergic) Chapter3Discoveryanddevelopmentofdrugs mechanismsanddrugs,Chapter23Adrenergicmechanismsand drugs,Chapter24Arterialhypertension,anginapectoris, HarpreetWasanMBBSFRCP myocardialinfarctionandheartfailure,Chapter26 Consultant&ReaderinMedicalOncology,Hammersmith Hyperlipidaemias,Chapter27Kidneyandgenitourinarytract, Hospital,ImperialCollegeHealthcareNHStrust,London,UK Chapter28Respiratorysystem Chapter31Neoplasticdiseaseandimmunosuppression MunirPirmohamedMBCHBPhDFRCP SueWilsonPhD NHSChairofPharmacogenetics,UniversityofLiverpool,UK ResearchFellow,UniversityofBristol,UK Chapter8Generalpharmacology;Pharmacogenomics Chapter20Psychotropicdrugs viii Preface Foryourownsatisfactionandformine,pleasereadthispreface!1 Aprefaceshouldtelltheprospectivereaderaboutthesubjectofabook,itspurpose,anditsplan. Thisbookisaboutthescientificbasisandpracticeofdrugtherapy.Itaddressesmedicalstudentsand doctorsinparticular,butalsoanyoneconcernedwithevidence-baseddrugtherapyandprescribing. Thescopeandrateofdruginnovationincrease.Doctorsnowfaceaprofessionallifetimeofhand- lingdrugsthatarenewtothemselves–drugsthatdonewthingsaswellasdrugsthatdooldthings better;anddrugsthatwerefamiliarduringmedicaltrainingbecomeredundant. Wewritenotonlyforreaderswho,likeus,haveaspecialinterestinpharmacology.Wetrytomake pharmacologyunderstandableforthosewhoseprimaryinterestslieelsewherebutwhorecognisethat theyneedsomeknowledgeofpharmacologyiftheyaretomeettheirmoralandlegal‘dutyofcare’ totheirpatients.Weareawaretoo,ofmedicalcurricularpressuresthatwouldreducethetimedevoted toteachingclinicalpharmacologyandtherapeutics,andsuchdiminutionissurelyamisguidedpolicy forasubjectthatissointegraltothesuccessfulpracticeofmedicine.Thus,wetrytotellreaderswhat theyneedtoknowwithoutburdeningthemwithirrelevantinformation,andwetrytomakethesub- jectinteresting.Weareveryserious,butseriousnessdoesnotalwaysdemandwearyingsolemnity. Allwhoprescribedrugswouldbewisetokeepinmindthechangingandevermoreexactingex- pectationsofpatientsandofsocietyingeneral.Doctorswhoprescribecasuallyorignorantlynowface notonlyincreasingcriticismbutalsocivil(orevencriminal)legalcharges.Theabilitytohandlenew developmentsdepends,nowmorethanever,oncomprehensionoftheprinciplesofpharmacology. Theseprinciplesarenotdifficulttograspandarenotsomanyastodefeateventhebusiestdoctors whotakeuponthemselvestheresponsibilityofintroducingmanufacturedmedicinesintothebodies oftheirpatients. TheprinciplesofpharmacologyanddrugtherapyappearinChapters1–11andtheirapplicationin thesubsequentspecialistchapterswherewedrawontheknowledgeandauthorityofarangeofex- perts in these fields. The current edition includes new contributions from Sir Michael Rawlins, SirPeterRubin,ProfessorMunirPirmohamedandProfessorPatrickVallance.Weseektoofferarea- sonablybriefsolutiontotheproblemofcombiningpracticalclinicalutilitywithanaccountofthe principlesonwhichclinicalpracticerests. Thequantityofpracticaltechnicaldetailtoincludeisamatterofjudgment.Ingeneral,wherether- apeutic practices are complex, potentially dangerous, and commonly updated, e.g. anaphylactic shock,weprovidemoredetail,togetherwithwebsitesforthelatestadvice;wegivelessorevenno detailontherapythatspecialistsundertake,e.g.anticancerdrugs.Nevertheless,especiallywithmod- erndrugsthatareunfamiliar,theprescribershouldconsultformularies,approvedguidelines,orthe manufacturer’scurrentliterature. Useofthebook.FrancisBacon2wrotethat‘Somebooksaretobetasted,otherstobeswallowed, andsomefewtobechewedanddigested.’Perhapselementsofeachactivitycanapplytopartsofour text. Students and doctors are, or should be, concerned to understand and to develop a rational, 1StFrancisofSales:PrefacetoIntroductiontothedevoutlife(1609). 2FrancisBacon(1561–1626)Essays(1625)‘Ofstudies’.Philosopherandscientist,Baconintroducedtheideaofthe experimentalorinductivemethodofreasoningforunderstandingnature. ix Preface criticalattitudetodrugtherapyandtheyshouldthereforechieflyaddressissuesofhowdrugsactand interactindiseaseandhowevidenceoftherapeuticeffectisobtainedandevaluated. Tothisend,theyshouldreadselectivelyandshouldnotimpedethemselvesbyattemptstomem- oriselistsofalternativedrugsanddosesandminordifferencesbetweenthem,whichshouldneverbe requiredoftheminexaminations.Thus,wedonotencumberthetextwithexhaustivelistsofprep- arations,whichproperlybelonginaformulary,althoughwehopethatenoughhasbeenmentioned tocovermuchroutineprescribing,andmanydrugshavebeenincludedsolelyforidentification. Theroleandstatusofatextbook.Ausefulguidetodrugusemustofferclearconclusionsand advice.Ifitistobeofreasonablesize,itmayoftenomitalternativeacceptablecoursesofaction.What itrecommendsshouldrestonsoundevidence,wherethisexists,andonanassessmentoftheopin- ionsoftheexperiencedwhereitdoesnot. Increasingly,guidelinesproducedbyspecialistsocietiesandnationalbodieshaveinfluencedthe selectionofdrugs.Weprovideorrefertotheseasrepresentingaconsensusofbestpracticeinpartic- ularsituations.Similarly,weassumethatthereaderpossessesaformulary,localornational,thatwill provideguidanceontheavailability,includingdoses,ofabroadrangeofdrugs.Yetthepracticeof medicinaltherapeuticsbyproperlyeducatedandconscientiousdoctorsworkinginsettingscompli- catedbyintercurrentdisease,metabolicdifferencesorpersonality,involveschallengesbeyondthe rigidadherencetopublishedrecommendations.Theroleofatextbookistoprovidethesatisfaction ofunderstandingthebasisforarecommendedcourseofactionandtoachieveanoptimalresultby informedselectionanduseofdrugs.Asthecurrenteditionofthebook,initiatedandforyearsmain- tainedbyDesmondLaurence,nowcrossesthelandmarkof50yearsinprint,wecanbutreassertour beliefinthisprinciple. Bath,Cambridge,London.P.N.B.,M.J.B.,P.S.2012 x Acknowledgements Itisnotpossibleforthreeindividualstocoverthewholefieldofdrugtherapyfromtheirownknowl- edgeandexperience.Aswithpreviouseditions,weinvitedselectedexpertstoreviewchaptersintheir specialty.Theyreceivedfreereintoadd,amendordeleteexistingtext,astheydeemedappropriate.We considerthatthebookhasbenefitedgreatlyfromtheproficiencyoftheseindividuals;theirnames appearinthelistofContributorsalongsidetheirchapters. Additionally,weexpressourgratitudetootherswhohave,withsuchgoodgrace,givenusoftheir timeandenergytosupplyvaluablefactsandopinionsforthisandpreviouseditions;theyprincipally include:ProfessorNigelSBaber,DrGeraldSConway,DrPippaGCorrie,DrFrancisHall,DrIan Hudson,thelateProfessorBNCPritchard,DrJPDReckless,DrCatrionaReid,DrCharlesSinger. Muchofanymeritthisbookmayhaveisduetothegenerosityofthosereferredtoabove,aswellas otherstoonumeroustomentionwhohaveputtheirknowledgeandpracticalexperienceoftheuseof drugsatourdisposal.Wehopethatthiscollectiveacknowledgementwillbeacceptable.Errorsareour own.Wearegratefultoreaderswhoalertustoerrorsandmakeothersuggestionsforfutureeditions. Inaddition,wethank theauthors andpublisherswhogenerouslygranted permissiontoquote directlyfromtheirwritings.Ifwehaveomittedanydueacknowledgements,wewillmakeamends assoonaswecan. P.N.B M.J.B. P.S. xi