山东大学药理学所

CHAPTER22

ANTIARRHYTHMICDRUGS医学院药理学研究所丁华

12Arrhythmia:Thereisanabnormalityinthesiteoforiginoftheimpulse,itsrateorregularity,oritsconduction.34ThetypeofArrhythmia:

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)

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ThePhysiologicalBasisofArrhythmiaTheelectrophysiologyofnormalcardiacrhythmSection167892.Theelectrophysiologicalmechanism

ofarrhythmias

(1)Disturbancesinimpulseformation:

1)Increasedautomaticity:2)Afterdepolarizationandtriggered:Earlyafterdepolarization(EAD)Delayedafterdepolarization(DAD)1011(2)Disturbancesinimpulseconduction1)Simpleconductiondisturbances:conduction↓↓,conductionblock,unidirectionalblock.2)Reentry(circusmovement)(3)Both1213Section2TheBasicElectrophysilogicActionofAntiarrhythmicDrugsandTheDrugClassification141.Thebasicelectrophysilogicaction1)↓↓automaticitya.↓↓slopofphase4depolarization:↓Na+inorCa2+inb.↑↑Thresholdpotentialc.↑↑maximumdiastolicpotential:↑K+ou↓↓EADorDAD:↑repolarization,blockNa+orCa2+3)↓↓reentry:a.↑↑conduction:unidirectionalblock↓↓b.↓↓conduction:unidirectionalblock→bidirectionalblockc.↑↑ERP202.TheclassificationVaughanWilliams（（1971）ClassⅠSodiumchannel-blockingagents:IA,IB,ICClassⅡββ-blockersClassⅢⅢprolongingrepolarizationClassⅣⅣcalciumantagonistsOthers:adenosine21Section3SpecificAntiarrhythmicAgents221.ClassⅠⅠSodiumchannel-blockingagents1)ClassⅠⅠAa.InhibitNa+influxmoderately:↓Vmax,↓conduction↓phase4slope,↓automaticityb.↓K+efflux,IncreasetheERP23Qunidine(奎尼丁)Pharmacologicaleffects:CardiacEffects:↓automaticity;↓conduction;↑ERP↓myocardialcontractilityExtracardiacEffects:α-adrenergicblockinganticholinergiceffect24Therapeuticuse:Broad-spectrumAtrialfibrillation;Atrialflutter;Supraventricularandventriculartachycardia;Supraventricularandventricularprematurebeat25Toxicity:CVS:Heartfailure;hypotension;quinidingsyncopyChichonicreaction(金鸡鸡纳反应））262)ClassIB↓Na+influxlightly↑K+efflux,shortentheAPD>ERP，ERP/APD↑27Lidocaine(利多多卡因)Pharmacologicaleffects:ActonPurkinjefibersandventricularcellsa.↓automaticity28b.Alteringtheconduction:Myocardialischemia→→↓conduction，，unidirectionalblock→bidirectionalblockK+↓→↑K+efflux→↑↑conduction→→↓unidirectionalblockc.RelativeincreaseERP:ERP/APD↑Pharmacokinetics:Therapeuticuse:Ventriculararrhythamias29PhenytoinIthasbeenusedintheacuteandchronicventriculararrhythamias,especiallyindigitalisintoxication.303)ClassICSeverelydepressNa+influx,markedly↓↓Vmax,↓phase4slope.Seriousadversereactionsareprovocationofpotentiallylethalarrhymias.31CAST试试验I（心心律失常抑抑制试验））心律失常抑抑制标准：：室早减少少80%以以上，室速速减少90%以上。。入选病人2309例例。结果可可见1727例心律律失常抑制制良好；135例部部分抑制；；447例例室性心律律失常增加加，死亡率率7.3%，安慰剂剂组死亡率率3.0%。其中心心律失常或或心跳骤停停者治疗组组4.5%，安慰剂剂组1.7%。结果说明英英卡胺和氟氟卡胺虽能能较好的抑抑制MI后后的心律失失常，但明明显增加所所致死亡率率及总病死死率，其原原因为该类类药物有负负性肌力作作用，另外外其致心律律失常作用用亦不容忽忽视。32Propafenone(普普罗帕酮)BlockNa+andCa+channel,alsoblockβ-R↓conduction,↓↓automaticity,↑↑ERPusedtotreatSupraventricularandventriculartachycardia;Supraventricularandventricularprematurebeat,Atrialfibrillation.33ClassⅡββ-BlockersPropranololMetoprolol1)β-Rblockingaction2)Membrane-stabilizingeffect(↓Na+in)34Pharmacologicaleffects:a.↓automaticity.↓afterdepolarizationbyCAb.↓AVnodalandP-fconduction(100ng/ml)C.↑ERP,↓↓reentryd.improvemyocardialischemicTherapeuticuse:Supraventriculararrhythamias,Acutemyocardialinfarction(AMI)35BHAT（（急性心肌肌梗死后普普萘洛尔对对室性心律失常常的影响））美国，加拿拿大37个个临床中心心采用多中中心，随机机安慰剂双双盲对照试试验。入选选标准:AMI后后5-21天经ECG检查发发现频发室室性早搏，，短阵室速速，共入选选3837例。药物应用方方法为第一一天普萘洛洛尔20mg或安慰慰剂，如无无副作用第第二天用40mg，，每日三次次，之后逐逐渐增加到到80mg，每日三三次，最长长随访时间间36个月月。结果可见6周后安慰慰剂组心律律失常减少少1.6%，治疗组组减少15.4%，，安慰剂组组死亡率9.8%，，治疗组7.2%（（P<0.005））。研究结结果说明普普萘洛尔用用于AMI可明显降降低死亡率率，并可长长期应用,安全有效效。36ClassⅢProlongingAPDagentsBlockingK+channel,↓K+efflux↑repolarization,APDandERP↑37Amiodarone(胺碘碘酮)Pharmacologicaleffects:↓ionschannel:K+,Na+,Ca2+Blockingαα,βreceptor1)↑APDandERP,noreverseuse-dependence2)↓automaticity3)↓AVnodalandPurkinjefibersconduction4)Dilatationcoronaryartery,↓myocardialoxygenconsumption38Pharmacokinetics:F:30%~40%,t1/240d,last4~6wTherapeuticuses:Broad-spectrumantiarrhythmicdrug39Adverseeffects:CVSreactions:SinusbradycardiaAtrio-ventricularblockTorsadesdepointes(Tdp,longQTsyndrome,LQTS)PulmonaryfibrosisHypo-orhyperthyroidism40BASIS（巴塞尔尔心肌梗死死后心律失失常研究））；CASCADE（西雅雅图胺碘酮酮和其他抗抗心律失常常药物对心心脏骤停作作用的评价价）；CAMIAT（加拿拿大心肌梗梗死后胺碘碘酮抗心律律失常试验验）；EMIAT（（欧洲心心肌梗死后后胺碘酮试试验）；IAMT（（静脉内内胺碘酮抗抗心律失常常研究）。。入选病病人多多数为为AMI后后室性性心律律失常常患者者，服服药方方法为为：第第一周周每天天800mg，，第二二周每每天400mg用6天，，持续续12个月月，有有显著著心动动过缓缓，QT间间期明明显延延长者者剂量量减少少至100mg/日日。结果显显示：：胺碘碘酮组组心脏脏性死死亡率率明显显减少少（P=0.048）,严重重室性性心律律失常常的发发生率率胺碘碘酮组组7.5%，对对照组组19.5%(P<0.001)41Sotalol（索他他洛尔尔）Nonselectiveββ-RantagonistBlockIk,↑APD、、ERPF=90%～～100%Broad-spectrum42Dofetilide（（多非非利特特）阻滞Ikr，延延长不不应期期但不不减慢慢传导导，无无负性性肌力力和负负性血血流动动力学学效应应，用用于房房颤复复律和和维持持窦律律，有有效且且不增增加心心衰死死亡率率，左左室功功能重重度障障碍者者可用用。主主要副副作用用为Tdp（2%～～4%）应应监测测QTc变变化。。Ibutilide(伊波波利特特)Sematilide(司司美利利特)43Ikur只分布布于心心房肌肌，在在调控控心房房复极极中起起重要要作用用,而对对心室室肌无无影响响，开开发选选择性性Ikur阻滞滞剂用用于治治疗房房性心心律失失常，，是III类药药物开开发方方向之之一。。胺碘碘酮、、氨巴巴利特特(ambasilide)对Ikur有阻滞滞作用用。44ClassⅣⅣCalciumchannelblockingagentsBlocktheL-Ca2+channelofcardiac,↓sinusandAVnode.45Verapamil(维维拉帕帕米)Majorclinicaluses:Supraventriculararrhythamias.46OthersAdenosine(腺腺苷)AgonistA-R↑↑K+efflux↓↓cAMP-inducedCa2+influxChoiceforpromptconversionofparoxysmalsupraventriculartachycardia.47抗心律失失常药的的合理应应用用药原则则1.先先单用用药，后后联合用用药。2.个个体化化用药。。3.充充分注注意药物物的不良良反应，，特别是致致心律失失常作用用。48药物的致致心律失失常作用用Theproarrhythmiaactionofdrugs应用抗心心律失常常药物过过程中，，原有心心律失常常加重或或恶化，，或出现现新的心心律失常常。发生率：：6%~30%所有抗心心律失常常药物都都有引起起折返性性心动过过速的基基础，因因此是双双刃剑。。防治：明明确指征征，纠正正诱因，，抗心律律失常（（β阻阻断药、、胺碘酮酮）49TheChoiceofDrugTherapies1.Sinusaltachycardia:β-BlockersorVerapamil2.Atrialprematurebeat:β-Blockers,Verapamil3.Atrialfibrillation,Atrialflutter:Verapamil,β-Blockers,Amiodarone,Cardiacglycosides,4.S