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1、302PharmacogeneticsinAnesthesiaPage1EvanD.Kharasch,M.D.,Ph.D.St.Louis,MissouriPharmacogenetics(orpharmacogenomics)aimstounderstandtheinheritedbasisforvariabilityindrugresponse.Thepromiseofpharmacogeneticshasbeenachangefrom“onedruganddosefitsall”toindividualizedpredictivemedicine
2、,or“therightdrugattherightdoseintherightpatient”.Anesthesiologyasaspecialtyplayedakeyroleindevelopingpharmacogenetics.Prolongedapneaaftersuccinylcholine,thiopental-inducedacuteporphyria,andmalignanthyperthermiawereclinicalproblemsofthe1960’swhoseinvestigationhelpedcraftthenewsci
3、enceofpharmacogenetics.Todayweperhapstakeforgrantedtheknowledgethattheyaregenetically-basedproblems,duetovariantsinpseudocholinesterase,hemesynthesisandtheryanodinereceptor,respectively.Thisreviewwilladdressbasicprinciplesofpharmacogeneticsandtheirapplicationtodrugsusedinanesthe
4、ticpractice.Thetermpharmacogeneticswasoriginallydefined(1959)as“theroleofgeneticsindrugresponse”.Sincethescienceofpharmacokinetics(drugabsorption,distribution,metabolism,excretion)evolvedearlierthanpharmacodynamics,earlypharmacogeneticstudiesaddressedmainlypharmaco-kinetics.Appl
5、ication(fusion)ofthegenomicrevolutionandassociatedtechnologiestopharmaco-geneticsspawnedpharmacogenomics.Pharmacogeneticshasbeenusedbysomeinamorenarrowsense,toreferonlytogeneticfactorswhichinfluencedrugkineticsanddynamics(drugreceptoractions),whilepharmacogenomicshasbeenusedmore
6、broadlytorefertotheapplicationofgenomictechnologies(whole-genomeorindividualgenechanges)todrugdiscovery,pharmacokineticsandpharmacodynamics,pharmacologicresponse,andtherapeuticoutcome.Nonetheless,manyconsiderthisdistinctionunimportantandusethetwotermsinterchangeably,aswillthisre
7、view.BASICCONCEPTSApolymorphismisadiscontinuousvariationinapopulation(abimodalortrimodaldistribution).Itisdifferentthansimplecontinuousvariability(i.e.aunimodalpopulationdistribution,evenifquitewide).Ageneticpolymorphismisthepresenceofmultiplediscretestates(i.e.foraparticulartra
8、it)withinapopulation,whichhasaninheriteddiffere
