山东大学药理学研究所丁华dinghuasdueducnPPT文档.ppt

1,2,Arrhythmia:,Arrhythmias consist of cardiac depolarizations that deviate from the sinus rhythm-ie,There is an abnormality in the site of origin of the impulse,its rate or regularity,or its conduction.,3,The types of Arrhythmia:,缓慢型:窦性心动过缓(sinus bradycardia)房室传导阻滞(atrio-ventricular block)快速型:房性早搏(atrial premature contraction)房性心动过速(atrial tachycardia,AT)心房颤动(atrial fibrillation,AF)心房扑动(atrial flutter,AFL)阵发性室上性心动过速(paroxysmal supraventricular tachycardia)室性早搏(ventricular premature contraction)室性心动过速(ventricular tachycardia,VT)心室颤动(ventricular fibrillation,VF),4,The Physiological Basis of Arrhythmia,The electrophysiology of normal cardiac rhythm,Section 1,5,6,7,2.The electrophysiological mechanism of arrhythmias,(1)Disturbances in impulse formation:Increased automaticity(2)Afterdepolarization and triggered activity:Early afterdepolarization(EAD)Delayed afterdepolarization(DAD),8,9,(3)Disturbances in impulse conduction,1)Simple conduction disturbances:conduction conduction block2)Reentry(circus movement),10,11,Section 2 The Basic Electrophysiology Action of Antiarrhythmic Drugs and The Classification of Drugs,12,1.The basic electrophysiology action,1)automaticity(autorhythmicity)a.slope of phase 4 depolarization:Na+in or Ca2+in b.Threshold potential c.maximum diastolic potential:K+out D.APD K+out,13,14,15,16,17,2)EAD or DAD:Accelerate repolarization,Block Na+in or Ca2+in 3)Avoid reentry:a.conduction:unidirectional block b.conduction:unidirectional block bidirectional block c.ERP,18,2.The classificationClass by Vaughan Williams（1971）,Class Sodium channel-blocking agents:IA,IB,ICClass-R blockersClass Prolonging APD agentsClass Calcium channel blockers Sicilian gambit(1991),19,Section 3 Specific Antiarrhythmic Agents 1.Class Sodium channel-blocking agents,20,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,21,1)ClassA a.Inhibit Na+influx moderately:Vmax,conduction phase 4 slope,automaticity b.K+efflux,Increase the ERP,22,Quinidine(奎尼丁),Pharmacological Effects:Cardiac Effects:autorhythmicity;conduction;ERP myocardial contractilityExtracardiac Effects:-adrenergic blocking anticholinergic effect,23,Therapeutic Uses:Broad-spectrum Atrial fibrillation;Atrial flutter;Supraventricular and ventricular tachycardia;Supraventricular and ventricular premature beat,24,Toxicity:,CVS:Heart failure;hypotension;quinidine syncopy Chichonic reaction(金鸡纳反应）,25,2)Class IB,Na+influx lightly K+efflux,shorten the APDERP，ERP/APD,26,Lidocaine(利多卡因),Pharmacological effects:Act on Purkinje fibers and ventricular cellsa.autorhythmicity the slope of phase 4 and the threshold for excitability.,27,b.Altering the conduction:Myocardial ischemia conduction，unidirectional blockbidirectional block K+K+efflux conduction unidirectional blockc.Relative increase ERP:ERP/APD Pharmacokinetics:Therapeutic use:Ventricular arrhythmias,28,Phenytoin sodium,It has been used in the acute and chronic ventricular arrhythmias,especially in digitalis intoxication.,29,3)Class IC,Severely depress Na+influx,markedlyVmax,conduction.phase 4 slope.automaticitySerious adverse reactions are provocation of potentially lethal arrhythmias.,30,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。,31,Propafenone(普罗帕酮),Block Na+and Ca+channel,also block-R conduction,automaticity,ERP Used to treat Supraventricular and ventricular tachycardia;Supraventricular and ventricular premature beat,Atrial fibrillation.,32,Class-R Blockers,PropranololMetoprololAtenolol1)-R blocking action2)Membrane-stabilizing effect(Na+in),33,Pharmacological effects:,a.autorhythmicity，afterdepolarization by CA,prevent triggered activity.b.conduction of AV node and P-f(100ng/ml)c.ERP of AV node,reentry d.Improve myocardial ischemicTherapeutic uses Supraventricular arrhythmias Acute myocardial infarction(AMI),34,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。,35,Class Prolonging APD agents Blocking K+channel,K+efflux,repolarization,APD and ERP,36,Amiodarone(胺碘酮),Pharmacological effects:ions channel:K+,Na+,Ca2+Blocking,receptor1)APD and ERP,no reverse use-dependence2)autorhythmicity3)conduction of AV node and Purkinje fibers 4)Dilatation coronary artery,myocardial oxygen consumption,37,Pharmacokinetics:F:40%,t1/2 40 d,last 46 w,Therapeutic uses:Broad-spectrum antiarrhythmic drug,38,Adverse effects:CVS reactions:Sinus bradycardia Atrio-ventricular block Torsades de pointes(Tdp,long QT syndrome,LQTS)Pulmonary fibrosisHypo-or hyperthyroidism,39,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%(P 0.001),40,Sotalol（索他洛尔）Nonselective-R antagonist Block Ik,APD、ERP F=90%100%Broad-spectrum,41,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reverse use-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),42,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。,43,Class Calcium channel blocking agents Block the L-Ca2+channel of cardiac,sinus and AV node.,44,Verapamil(维拉帕米)Major clinical uses:Supraventricular arrhythamias.,45,Others Adenosine(腺苷),Act on A-R,KACh,K+efflux cAMP-induced Ca2+influx,ERP of AV node.Choice for prompt conversion of paroxysmal supraventricular tachycardia.,46,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。,47,药物的致心律失常作用The proarrhythmia action of drugs,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）,48,The Choice of Drug Therapies 1.Sinusal tachycardia:-Blockers or Verapamil 2.Atrial premature beat:-Blockers,Verapamil 3.Atrial fibrillation,Atrial flutter:Verapamil,-Blockers,Amiodarone,Cardiac glycosides,4.Supraventricular tachycardia:Verapamil,Cardiac glycosides,-blockers,Adenosine.,49,5.Ventricular premature beat:Lidocaine,Amiodarone,Propafeone 6.Ventricular tachycardia:Lidocaine,Amiodarone,Propafeone 7.Ventricular fibrillation:Lidocaine,Amiodarone.,50,抗心律失常药物作用最佳靶点假说,在心肌细胞膜上存在多种离子通道及亚型。正常情况下，各通道间有一定数目和比例，保持一定的平衡。当某种通道数目上调或下调到一定范围，通道间比例失调，将出现心律失常。与心律失常发生发展有关的通道，称为抗心律失常药作用的靶点。在心律失常发生发展中起主导作用的通道，称为抗心律失常药作用的最佳靶点。一个理想的抗心律失常药应对最佳靶点有作用，且至少对两种或两种以上的离子通道有作用。,