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CHAPTER 25

CHAPTER 25. ANTIARRHYTHMIC DRUGS. 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. The types of Arrhythmia:.

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CHAPTER 25

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  1. CHAPTER 25 ANTIARRHYTHMIC DRUGS

  2. Arrhythmia: Arrhythmias consist of cardiac depolarizations that deviate from thesinus 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 Section 1 • The electrophysiology of normal • cardiac rhythm

  5. 2. The electrophysiological mechanism of arrhythmias (1) Disturbances in impulse formation: Increased automaticity (2) Afterdepolarization and triggered activity: Early afterdepolarization (EAD) Delayed afterdepolarization (DAD)

  6. (3) Disturbances in impulse conduction • 1) Simple conduction disturbances: conduction ↓ conduction block • 2) Reentry (circus movement)

  7. Section 2 The Basic Electrophysiology Action of Antiarrhythmic Drugs and The Classification of Drugs

  8. 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 1. The basic electrophysiology action

  9. 2)↓EAD or DAD: • Accelerate repolarization, • Block Na+ inor Ca2+ in 3) Avoidreentry: • a.↑conduction:↓unidirectional block • b.↓conduction : unidirectional block → bidirectional block • c.↑ERP

  10. 2.The classificationClass byVaughan Williams（1971） • ClassⅠ Sodium channel-blocking agents: IA , IB, IC • ClassⅡ β-R blockers • Class Ⅲ Prolonging APD agents • Class Ⅳ Calcium channel blockers Sicilian gambit (1991)

  11. Section 3 Specific Antiarrhythmic Agents1. ClassⅠ Sodium channel-blocking agents

  12. 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 ++ 1—10秒 延长QT 激活态 IB 利多卡因 美西律 + <1秒 不明显 失活态 IC 普罗帕酮 氟卡尼 +++ >10秒 QRS增宽 激活态

  13. 1) ClassⅠA • a. Inhibit Na+ influx moderately : ↓Vmax, ↓conduction ↓phase 4 slope, ↓automaticity • b. ↓ K+ efflux , Increase the ERP

  14. Quinidine(奎尼丁) • Pharmacological Effects: • Cardiac Effects: ↓autorhythmicity;↓conduction;↑ERP ↓myocardial contractility • Extracardiac Effects: α-adrenergic blocking anticholinergic effect

  15. Therapeutic Uses: Broad-spectrum • Atrial fibrillation; Atrial flutter; • Supraventricular and ventricular tachycardia; • Supraventricular and ventricular premature beat

  16. Toxicity: • CVS: Heart failure; hypotension; quinidine syncopy • Chichonic reaction(金鸡纳反应）

  17. 2) Class IB • ↓Na+ influx lightly • ↑K+ efflux, shorten the APD>ERP， ERP/APD↑

  18. Lidocaine (利多卡因) Pharmacological effects: • Act on Purkinje fibers and ventricular cells • a. ↓autorhythmicity ↓the slope of phase 4 and ↑the threshold for excitability.

  19. b.Altering the conduction: Myocardial ischemia →↓conduction，unidirectional block→bidirectional block K+↓→↑K+ efflux →↑conduction → ↓unidirectional block • c.Relative increase ERP: ERP/APD↑ Pharmacokinetics: Therapeutic use: Ventricular arrhythmias

  20. Phenytoin sodium It has been used in the acute and chronic ventricular arrhythmias, especially in digitalis intoxication.

  21. 3) Class IC • Severely depress Na+ influx, markedly↓Vmax , ↓conduction. • ↓phase 4 slope. ↓automaticity • Serious adverse reactions are provocation of potentially lethal arrhythmias.

  22. 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。

  23. Propafenone(普罗帕酮) • Block Na+and Ca+ channel, also blockβ-R • ↓conduction, ↓automaticity, ↑ERP • Used to treat Supraventricular and ventricular tachycardia; Supraventricular and ventricular premature beat, Atrial fibrillation.

  24. Class Ⅱ β-R Blockers • Propranolol • Metoprolol • Atenolol 1) β-R blocking action 2) Membrane-stabilizing effect(↓Na+in)

  25. 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 ischemic Therapeutic uses Supraventricular arrhythmias Acute myocardial infarction(AMI)

  26. 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%（P<0.005）。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。

  27. Class Ⅲ Prolonging APD agents • Blocking K+ channel , ↓ K+ efflux , ↑ repolarization, ↑ APD and ERP

  28. Amiodarone(胺碘酮) Pharmacological effects: ↓ions channel: K+, Na+, Ca2+ Blocking α,βreceptor • 1) ↑APD and ERP, no reverse use-dependence • 2) ↓autorhythmicity • 3) ↓ conduction of AV node and Purkinje fibers • 4) Dilatation coronary artery, ↓ myocardial oxygen consumption

  29. Pharmacokinetics:F: 40%, t1/2 40 d, last 4~6 w Therapeutic uses: Broad-spectrum antiarrhythmic drug

  30. Adverse effects: • CVS reactions: Sinus bradycardia Atrio-ventricular block Torsades de pointes(Tdp, long QT syndrome, LQTS) • Pulmonary fibrosis • Hypo- or hyperthyroidism

  31. 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)

  32. Sotalol （索他洛尔）Nonselective β-R antagonist Block Ik, ↑APD、ERP F=90%～100%Broad-spectrum

  33. 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)

  34. 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。

  35. Class Ⅳ Calcium channel blocking agents Block the L-Ca2+ channel of cardiac,↓sinus and AV node.

  36. Verapamil(维拉帕米) Major clinical uses: Supraventricular arrhythamias.

  37. 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.

  38. 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。

  39. 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（ β阻断药、胺碘酮）

  40. The Choice of Drug Therapies 1. Sinusal tachycardia: β- Blockers or Verapamil 2. Atrial premature beat: β- Blockers , Verapamil 3. Atrial fibrillation, Atrial flutter: Verapamil, β- Blockers , Amiodarone, Cardiac glycosides, 4. Supraventricular tachycardia: Verapamil, Cardiac glycosides, β- blockers, Adenosine.

  41. 5. Ventricular premature beat: Lidocaine, Amiodarone ,Propafeone 6. Ventricular tachycardia: Lidocaine, Amiodarone, Propafeone 7. Ventricular fibrillation: Lidocaine, Amiodarone.

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