山东大学药理学研究所

1、CHAPTER 22 ANTIARRHYTHMIC DRUGS 12 Arrhythmia: There is an abnormality in the site of origin of the impulse, its rate or regularity , or its conduction .34The type 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

2、 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)5The Physiological Basis of Arrhythmia The electrophysiology

3、 of normal cardiac rhythmSection 167892. The electrophysiological mechanism of arrhythmias(1) Disturbances in impulse formation: 1) Increased automaticity: 2) Afterdepolarization and triggered: Early afterdepolarization (EAD) Delayed afterdepolarization (DAD) 1011(2) Disturbances in impulse conducti

4、on 1) Simple conduction disturbances: conduction ,conduction block,unidirectional block.2) Reentry (circus movement)(3) Both 1213Section 2 The Basic Electrophysilogic Action of Antiarrhythmic Drugs and The Drug Classification 14 1. The basic electrophysilogic action1)automaticity a.slop of phase 4 d

5、epolarization: Na+in or Ca2+in b.Threshold potential c.maximum diastolic potential: K+out1516171819 2)EAD or DAD: repolarization, block Na+ or Ca2+ 3)reentry: a.conduction: unidirectional block b.conduction : unidirectional blockbidirectional block c.ERP202.The classification Vaughan Williams（1971）C

6、lass Sodium channel-blocking agents: IA , IB, ICClass -blockersClass prolonging repolarizationClass calcium antagonistsOthers: adenosine21Section 3 Specific Antiarrhythmic Agents 221. Class Sodium channel-blocking agents 1) ClassA a. Inhibit Na+ influx moderately : Vmax, conduction phase 4 slope, au

7、tomaticity b. K+ efflux , Increase the ERP 23Qunidine(奎尼丁) Pharmacological effects:Cardiac Effects: automaticity;conduction;ERP myocardial contractilityExtracardiac Effects: -adrenergic blocking anticholinergic effect24 Therapeutic use: Broad-spectrum Atrial fibrillation; Atrial flutter;Supraventric

8、ular and ventricular tachycardia;Supraventricular and ventricular premature beat25Toxicity: CVS: Heart failure; hypotension; quiniding syncopy Chichonic reaction(金鸡纳反应）262) Class IB Na+ influx lightly K+ efflux, shorten the APDERP ， ERP/APD 27Lidocaine (利多卡因)Pharmacological effects:Act on Purkinje f

9、ibers and ventricular cellsa. automaticity28b. Altering the conduction: Myocardial ischemia conduction，unidirectional blockbidirectional block K+K+ efflux conduction unidirectional blockc. Relative increase ERP: ERP/APD Pharmacokinetics: Therapeutic use: Ventricular arrhythamias29Phenytoin It has be

10、en used in the acute and chronic ventricular arrhythamias, especially in digitalis intoxication. 303) Class ICSeverely depress Na+ influx, markedlyVmax ,phase 4 slope.Serious adverse reactions are provocation of potentially lethal arrhymias. 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230

11、9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。32Propafenone(普罗帕酮) Block Na+and Ca+ channel, also block-R conduction, automaticity, ERP used to treat Supraventricular and ventricu

12、lar tachycardia; Supraventricular and ventricular premature beat, Atrial fibrillation. 33Class - Blockers PropranololMetoprolol1) -R blocking action2) Membrane-stabilizing effect(Na+in)34Pharmacological effects:a.automaticity .afterdepolarization by CAb.AV nodal and P-f conduction (100ng/ml)C.ERP,re

13、entry d. improve myocardial ischemicTherapeutic use: Supraventricular arrhythamias, Acute myocardial infarction(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

14、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。36Class Prolonging APD agents Blocking K+ channel , K+ efflux repolarization, APD and ERP 37Amiodarone(胺碘酮) Pharmacological effects: ions channel: K+, Na+, Ca2+ Blocking ,receptor1) APD and ERP, no reverse u

15、se- dependence2) automaticity3) AV nodal and Purkinje fibers conduction4) Dilatation coronary artery, myocardial oxygen consumption38 Pharmacokinetics: F:30%40%, t1/2 40d, last 46wTherapeutic uses: Broad-spectrum antiarrhythmic drug39Adverse effects:CVS reactions: Sinus bradycardia Atrio-ventricular

16、 block Torsades de pointes(Tdp, long QT syndrome,LQTS)Pulmonary fibrosisHypo- or hyperthyroidism40 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

17、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)41 Sotalol （索他洛尔） Non selective -R antagonist Block Ik, APD、ERP F=90%100% Broad-spectrum42 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 (

18、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 Class Calcium channel blocking agents Block the L-Ca2+ channel of cardiac,sinus and AV node.45Verapamil(维拉帕米) Major clinical uses: Supraventricular arrhythamias.46 Ot

19、hers Adenosine(腺苷)Agonist A-R K+ efflux cAMP-induced Ca2+ influxChoice for prompt conversion of paroxysmal supraventricular tachycardia. 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. 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）49The Choice of Drug Therapies 1. Sinusal tachycardi