山东大学药理学研究所丁华dinghua@sdueducn.ppt

1,CHAPTER25,ANTIARRHYTHMICDRUGS,2,3,Arrhythmia:,Arrhythmiasconsistofcardiacdepolarizationsthatdeviatefromthesinusrhythm-ie,Thereisanabnormalityinthesiteoforiginoftheimpulse,itsrateorregularity,oritsconduction.,4,ThetypesofArrhythmia:,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),5,ThePhysiologicalBasisofArrhythmia,Theelectrophysiologyofnormalcardiacrhythm,Section1,6,7,8,2.Theelectrophysiologicalmechanismofarrhythmias,(1)Disturbancesinimpulseformation:Increasedautomaticity(2)Afterdepolarizationandtriggeredactivity:Earlyafterdepolarization(EAD)Delayedafterdepolarization(DAD),9,10,(3)Disturbancesinimpulseconduction,1)Simpleconductiondisturbances:conductionconductionblock2)Reentry(circusmovement),11,12,Section2TheBasicElectrophysiologyActionofAntiarrhythmicDrugsandTheClassificationofDrugs,13,1.Thebasicelectrophysiologyaction,1)automaticity(autorhythmicity)a.slopeofphase4depolarization:Na+inorCa2+inb.Thresholdpotentialc.maximumdiastolicpotential:K+outD.APDK+out,14,15,16,17,18,2)EADorDAD:Acceleraterepolarization,BlockNa+inorCa2+in3)Avoidreentry:a.conduction:unidirectionalblockb.conduction:unidirectionalblockbidirectionalblockc.ERP,19,2.TheclassificationClassbyVaughanWilliams（1971）,ClassSodiumchannel-blockingagents:IA,IB,ICClass-RblockersClassProlongingAPDagentsClassCalciumchannelblockersSiciliangambit(1991),20,Section3SpecificAntiarrhythmicAgents1.ClassSodiumchannel-blockingagents,21,钠通道阻滞剂的分类,分类药物钠阻滞强度结合/解离常数心电图表现状态依赖IA奎尼丁普鲁卡因胺+110秒延长QT激活态IB利多卡因美西律+10秒QRS增宽激活态,22,1)ClassAa.InhibitNa+influxmoderately:Vmax,conductionphase4slope,automaticityb.K+efflux,IncreasetheERP,23,Quinidine(奎尼丁),PharmacologicalEffects:CardiacEffects:autorhythmicity;conduction;ERPmyocardialcontractilityExtracardiacEffects:-adrenergicblockinganticholinergiceffect,24,TherapeuticUses:Broad-spectrumAtrialfibrillation;Atrialflutter;Supraventricularandventriculartachycardia;Supraventricularandventricularprematurebeat,25,Toxicity:,CVS:Heartfailure;hypotension;quinidinesyncopyChichonicreaction(金鸡纳反应）,26,2)ClassIB,Na+influxlightlyK+efflux,shortentheAPDERP，ERP/APD,27,Lidocaine(利多卡因),Pharmacologicaleffects:ActonPurkinjefibersandventricularcellsa.autorhythmicitytheslopeofphase4andthethresholdforexcitability.,28,b.Alteringtheconduction:Myocardialischemiaconduction，unidirectionalblockbidirectionalblockK+K+effluxconductionunidirectionalblockc.RelativeincreaseERP:ERP/APDPharmacokinetics:Therapeuticuse:Ventriculararrhythmias,29,Phenytoinsodium,Ithasbeenusedintheacuteandchronicventriculararrhythmias,especiallyindigitalisintoxication.,30,3)ClassIC,SeverelydepressNa+influx,markedlyVmax,conduction.phase4slope.automaticitySeriousadversereactionsareprovocationofpotentiallylethalarrhythmias.,31,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，治疗组死亡率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%。结果说明英卡尼和氟卡尼虽能较好的抑制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。,32,Propafenone(普罗帕酮),BlockNa+andCa+channel,alsoblock-Rconduction,automaticity,ERPUsedtotreatSupraventricularandventriculartachycardia;Supraventricularandventricularprematurebeat,Atrialfibrillation.,33,Class-RBlockers,PropranololMetoprololAtenolol1)-Rblockingaction2)Membrane-stabilizingeffect(Na+in),34,Pharmacologicaleffects:,a.autorhythmicity，afterdepolarizationbyCA,preventtriggeredactivity.b.conductionofAVnodeandP-f(100ng/ml)c.ERPofAVnode,reentryd.ImprovemyocardialischemicTherapeuticusesSupraventriculararrhythmiasAcutemyocardialinfarction(AMI),35,BHAT（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。药物用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。,36,ClassProlongingAPDagentsBlockingK+channel,K+efflux,repolarization,APDandERP,37,Amiodarone(胺碘酮),Pharmacologicaleffects:ionschannel:K+,Na+,Ca2+Blocking,receptor1)APDandERP,noreverseuse-dependence2)autorhythmicity3)conductionofAVnodeandPurkinjefibers4)Dilatationcoronaryartery,myocardialoxygenconsumption,38,Pharmacokinetics:F:40%,t1/240d,last46w,Therapeuticuses:Broad-spectrumantiarrhythmicdrug,39,Adverseeffects:CVSreactions:SinusbradycardiaAtrio-ventricularblockTorsadesdepointes(Tdp,longQTsyndrome,LQTS)PulmonaryfibrosisHypo-orhyperthyroidism,40,BASIS（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),41,Sotalol（索他洛尔）Nonselective-RantagonistBlockIk,APD、ERPF=90%100%Broad-spectrum,42,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。具有reverseuse-dependence,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),43,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。,44,ClassCalciumchannelblockingagentsBlocktheL-Ca2+channelofcardiac,sinusandAVnode.,45,Verapamil(维拉帕米)Majorclinicaluses:Supraventriculararrhythamias.,46,OthersAdenosine(腺苷),ActonA-R,KACh,K+effluxcAMP-inducedCa2+influx,ERPofAVnode.Choiceforpromptconversionofparoxysmalsupraventriculartachycardia.,47,抗心律失常药的合理应用用药原则1.先单用药，后联合用药。2.小剂量,个体化用药,。3.充分注意药物的不良反应，特别是致心律失常作用。,48,药物的致心律失常作用Theproarrhythmiaactionofdrugs,应用抗心律失常药物过程中，原有心律失常加重或恶化，或出现新的心律失常。发生率：6%30%所有抗心律失常药物都有引起折返性心动过速的基础，因此是双刃剑。防治：明确指征，纠正诱因，抗心律失常（阻断药、胺碘酮）,49,TheCh