山东大学药理学研究所

1CHAPTER22ANTIARRHYTHMICDRUGS医学院药理学研究所丁华23Arrhythmia:Thereisanabnormalityinthesiteoforiginoftheimpulse,itsrateorregularity,oritsconduction.45ThetypeofArrhythmia:缓慢型:窦性心动过缓(sinusbradycardia)房室传导阻滞(atrio-ventricularblock)快速型:房性早搏(atrialprematurecontraction)房性心动过速(atrialtachycardia,AT)心房颤动(atrialfibrillation,AF)心房扑动(atrialflutter,AFL)阵发性室上性心动过速(paroxysmalsupraventriculartachycardia)室性早搏(ventricularprematurecontraction)室性心动过速(ventriculartachycardia,VT)心室颤动(ventricularfibrillation,VF)6ThePhysiologicalBasisofArrhythmia1.TheelectrophysiologyofnormalcardiacrhythmSection1789102.Theelectrophysiologicalmechanismofarrhythmias(1)Disturbancesinimpulseformation:1)Increasedautomaticity:2)Afterdepolarizationandtriggered:Earlyafterdepolarization(EAD)Delayedafterdepolarization(DAD)1112(2)Disturbancesinimpulseconduction1)Simpleconductiondisturbances:conduction↓,conductionblock,unidirectionalblock.2)Reentry(circusmovement)(3)Both1314Section2TheBasicElectrophysilogicActionofAntiarrhythmicDrugsandTheDrugClassification151.Thebasicelectrophysilogicaction1)↓automaticitya.↓slopofphase4depolarization:↓Na+inorCa2+inb.↑Thresholdpotentialc.↑maximumdiastolicpotential:↑K+out16171819202)↓EADorDAD:↑repolarization,blockNa+orCa2+3)↓reentry:a.↑conduction:unidirectionalblock↓b.↓conduction:unidirectionalblock→bidirectionalblockc.↑ERP212.TheclassificationVaughanWilliams（1971）ClassⅠSodiumchannel-blockingagents:IA,IB,ICClassⅡβ-blockersClassⅢprolongingrepolarizationClassⅣcalciumantagonistsOthers:adenosine22Section3SpecificAntiarrhythmicAgents231.ClassⅠSodiumchannel-blockingagents1)ClassⅠAa.InhibitNa+influxmoderately:↓Vmax,↓conduction↓phase4slope,↓automaticityb.↓K+efflux,IncreasetheERP24Qunidine(奎尼丁)Pharmacologicaleffects:CardiacEffects:↓automaticity;↓conduction;↑ERP↓myocardialcontractilityExtracardiacEffects:α-adrenergicblockinganticholinergiceffect25Therapeuticuse:Broad-spectrumAtrialfibrillation;Atrialflutter;Supraventricularandventriculartachycardia;Supraventricularandventricularprematurebeat26Toxicity:CVS:Heartfailure;hypotension;quinidingsyncopyChichonicreaction(金鸡纳反应）272)ClassIB↓Na+influxlightly↑K+efflux,shortentheAPDERP，ERP/APD↑28Lidocaine(利多卡因)Pharmacologicaleffects:ActonPurkinjefibersandventricularcellsa.↓automaticity29b.Alteringtheconduction:Myocardialischemia→↓conduction，unidirectionalblock→bidirectionalblockK+↓→↑K+efflux→↑conduction→↓unidirectionalblockc.RelativeincreaseERP:ERP/APD↑Pharmacokinetics:Therapeuticuse:Ventriculararrhythamias30PhenytoinIthasbeenusedintheacuteandchronicventriculararrhythamias,especiallyindigitalisintoxication.313)ClassICSeverelydepressNa+influx,markedly↓Vmax,↓phase4slope.Seriousadversereactionsareprovocationofpotentiallylethalarrhymias.32CAST试验I（心律失常抑制试验）心律失常抑制标准：室早减少80%以上，室速减少90%以上。入选病人2309例。结果可见1727例心律失常抑制良好；135例部分抑制；447例室性心律失常增加，死亡率7.3%，安慰剂组死亡率3.0%。其中心律失常或心跳骤停者治疗组4.5%，安慰剂组1.7%。结果说明英卡胺和氟卡胺虽能较好的抑制MI后的心律失常，但明显增加所致死亡率及总病死率，其原因为该类药物有负性肌力作用，另外其致心律失常作用亦不容忽视。33Propafenone(普罗帕酮)BlockNa+andCa+channel,alsoblockβ-R↓conduction,↓automaticity,↑ERPusedtotreatSupraventricularandventriculartachycardia;Supraventricularandventricularprematurebeat,Atrialfibrillation.34ClassⅡβ-BlockersPropranololMetoprolol1)β-Rblockingaction2)Membrane-stabilizingeffect(↓Na+in)35Pharmacologicaleffects:a.↓automaticity.↓afterdepolarizationbyCAb.↓AVnodalandP-fconduction(100ng/ml)C.↑ERP,↓reentryd.improvemyocardialischemicTherapeuticuse:Supraventriculararrhythamias,Acutemyocardialinfarction(AMI)36BHAT（急性心肌梗死后普萘洛尔对室性心律失常的影响）美国，加拿大37个临床中心采用多中心，随机安慰剂双盲对照试验。入选标准:AMI后5-21天经ECG检查发现频发室性早搏，短阵室速，共入选3837例。药物应用方法为第一天普萘洛尔20mg或安慰剂，如无副作用第二天用40mg，每日三次，之后逐渐增加到80mg，每日三次，最长随访时间36个月。结果可见6周后安慰剂组心律失常减少1.6%，治疗组减少15.4%，安慰剂组死亡率9.8%，治疗组7.2%（P0.005）。研究结果说明普萘洛尔用于AMI可明显降低死亡率，并可长期应用,安全有效。37ClassⅢProlongingAPDagentsBlockingK+channel,↓K+efflux↑repolarization,APDandERP↑38Amiodarone(胺碘酮)Pharmacologicaleffects:↓ionschannel:K+,Na+,Ca2+Blockingα,βreceptor1)↑APDandERP,noreverseuse-dependence2)↓automaticity3)↓AVnodalandPurkinjefibersconduction4)Dilatationcoronaryartery,↓myocardialoxygenconsumption39Pharmacokinetics:F:30%~40%,t1/240d,last4~6wTherapeuticuses:Broad-spectrumantiarrhythmicdrug40Adverseeffects:CVSreactions:SinusbradycardiaAtrio-ventricularblockTorsadesdepointes(Tdp,longQTsyndrome,LQTS)PulmonaryfibrosisHypo-orhyperthyroidism41BASIS（巴塞尔心肌梗死后心律失常研究）；CASCADE（西雅图胺碘酮和其他抗心律失常药物对心脏骤停作用的评价）；CAMIAT（加拿大心肌梗死后胺碘酮抗心律失常试验）；EMIAT（欧洲心肌梗死后胺碘酮试验）；IAMT（静脉内胺碘酮抗心律失常研究）。入选病人多数为AMI后室性心律失常患者，服药方法为：第一周每天800mg，第二周每天400mg用6天，持续12个月，有显著心动过缓，QT间期明显延长者剂量减少至100mg/日。结果显示：胺碘酮组心脏性死亡率明显减少（P=0.048）,严重室性心律失常的发生率胺碘酮组7.5%，对照组19.5%(P0.001)42Sotalol（索他洛尔）Nonselectiveβ-RantagonistBlockIk,↑APD、ERPF=90%～100%Broad-spectrum43Dofetilide（多非利特）阻滞Ikr，延长不应期但不减慢传导，无负性肌力和负性血流动力学效应，用于房颤复律和维持窦律，有效且不增加心衰死亡率，左室功能重度障碍者可用。主要副作用为Tdp（2%～4%）应监测QTc变化。Ibutilide(伊波利特)Sematilide(司美利特)44Ikur只分布于心房肌，在调控心房复极中起重要作用,而对心室肌无影响，开发选择性Ikur阻滞剂用于治疗房性心律失常，是III类药物开发方向之一。胺碘酮、氨巴利特(ambasilide)对Ikur有阻滞作用。45ClassⅣCalciumchannelblockingagentsBlocktheL-Ca2+channelofcardiac,↓sinusandAVnode.46Verapamil(维拉帕米)Major