山東大學(xué)藥理學(xué)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:緩慢型 : 竇性心動(dòng)過緩 (sinus bradycardia) 房室傳導(dǎo)阻滯 (atrio-ventricular block) 快速型 : 房性早搏 (atrial premature contraction) 房性心動(dòng)過速 (atrial

2、 tachycardia,AT) 心房顫動(dòng) (atrial fibrillation, AF) 心房撲動(dòng) (atrial flutter, AFL) 陣發(fā)性室上性心動(dòng)過速 (paroxysmal supraventricular tachycardia) 室性早搏 (ventricular premature contraction) 室性心動(dòng)過速 (ventricular tachycardia,VT) 心室顫動(dòng) (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(金雞納反應(yīng)）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試驗(yàn)I（心律失常抑制試驗(yàn)） 心律失常抑制標(biāo)準(zhǔn)：室早減少80%以上，室速減少90%以上。 入選病人230

11、9例。結(jié)果可見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%，安慰劑組死亡率3.0%。其中心律失常或心跳驟停者治療組4.5%，安慰劑組1.7%。 結(jié)果說明英卡胺和氟卡胺雖能較好的抑制MI后的心律失常，但明顯增加所致死亡率及總病死率，其原因?yàn)樵擃愃幬镉胸?fù)性肌力作用，另外其致心律失常作用亦不容忽視。32Propafenone(普羅帕酮) 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爾對(duì)室 性心律失常的影響） 美國，加拿大37個(gè)臨床中心采用多中心，隨機(jī)安慰劑雙盲對(duì)照試驗(yàn)。入選標(biāo)準(zhǔn): AMI后5-21天經(jīng)ECG檢查發(fā)現(xiàn)頻發(fā)室性早搏，短陣室速，共入選3837例。 藥物應(yīng)用方法為第一天普萘洛爾20mg或安慰劑，如無副作用第二天用40mg，每日三次，之后逐漸增加到80mg，每日三次，最長隨訪時(shí)間36個(gè)月。 結(jié)果可見

14、6周后安慰劑組心律失常減少1.6%，治療組減少15.4%，安慰劑組死亡率9.8%，治療組7.2%（P0.005）。研究結(jié)果說明普萘洛爾用于AMI可明顯降低死亡率，并可長期應(yīng)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（巴塞爾心肌梗死后心律失常研究）；CASCADE （西雅圖胺碘酮和其他抗心律失常藥物對(duì)心臟驟停作用的評(píng)價(jià)）；CAMIAT （加拿大心肌梗死后胺碘酮抗心律失常試驗(yàn)）；EMIAT （歐洲心肌梗死后胺碘酮試驗(yàn)）；IAMT （靜脈內(nèi)胺碘酮抗心律失常研究）。 入選病人多數(shù)為AMI后室性心律失?；颊?，服藥方法為：第一周每天800mg，第二周每天400mg用6天，持續(xù)12個(gè)月，有顯著心動(dòng)過緩，QT間期明

17、顯延長者劑量減少至100mg/日。 結(jié)果顯示：胺碘酮組心臟性死亡率明顯減少（P=0.048）,嚴(yán)重室性心律失常的發(fā)生率胺碘酮組7.5%，對(duì)照組19.5%(P 0.001)41 Sotalol （索他洛爾） Non selective -R antagonist Block Ik, APD、ERP F=90%100% Broad-spectrum42 Dofetilide（多非利特） 阻滯Ikr，延長不應(yīng)期但不減慢傳導(dǎo)，無負(fù)性肌力和負(fù)性血流動(dòng)力學(xué)效應(yīng)，用于房顫復(fù)律和維持竇律，有效且不增加心衰死亡率，左室功能重度障礙者可用。 主要副作用為Tdp（2%4%）應(yīng)監(jiān)測(cè)QTc變化。 Ibutilide (

18、伊波利特) Sematilide (司美利特)43 Ikur只分布于心房肌，在調(diào)控心房復(fù)極中起重要作用 ,而對(duì)心室肌無影響，開發(fā)選擇性Ikur阻滯劑用于治療房性心律失常，是III類藥物開發(fā)方向之一。胺碘酮、氨巴利特(ambasilide)對(duì)Ikur有阻滯作用。 44 Class Calcium channel blocking agents Block the L-Ca2+ channel of cardiac,sinus and AV node.45Verapamil(維拉帕米) 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 抗心律失常藥的合理應(yīng)用 用藥原則 1. 先單用藥，后聯(lián)合用藥。 2. 個(gè)體化用藥。 3. 充分注意藥物的不良反應(yīng)， 特別是致心律失常作用。48藥物的致心律失常作用The proarrhythmia action of drugs 應(yīng)用抗心律失常藥物過程中，原有心律失常加重或惡化，或出現(xiàn)新的心律失常。 發(fā)生率：6%30% 所有抗心律失常藥物都有引起折返性心動(dòng)過速的基礎(chǔ)，因此是雙刃劍。 防治：明確指征，糾正誘因，抗心律失常（ 阻斷藥、胺碘酮）49The Choice of Drug Therapies 1. Sinusal tachycardi