Antiarrhythmic Drugs 抗心律失常药物

1. Antiarrhythmic Drugs抗心律失常药物 Shi-Hong Zhang (张世红) Dept. of Pharmacology shzhang713@zju.edu.cn

3. Types of Arrhythmia • Supraventricular arrhythmias: • Atrial fibrillation, flutter • Premature atrial contraction • Paroxysmal supraventricular tachycardia (originating from atria or AV node) Speed Too rapid--Tachyarrhythmias Too slow--Bradyarrhythmias Location • Ventricular arrhythmias: • Premature ventricular contraction • Ventricular tachycardia • Polymorphic VT • Ventricular Fibrillation (VF) Supraventricular Ventricular Rhythm

4. ECG (Electrocardiograph)

5. Outline • Physiology of cardiac rhythm • Mechanisms of arrhythmias • Classification of antiarrhythmic drugs • Antiarrhythmic drugs

7. Currents involved in action potentials in purkinje cells

8. Main Causes of Arrhythmia • Ischemia, esp. reperfusion within 5-10 • Hypoxia • Acidosis or alkalosis • Electrolyte abnormalities • Excessive catecholamine exposure • Drug toxicity (eg, digitalis or antiarrhythmic drugs) • Overstretching of cardiac fibers • Presence of scarred or otherwise diseased tissue • Gene mutation (genes encoding K+, Na+, Ca2+ channel protein)

9. Mechanisms of Arrhythmia 1. Disturbances of impulse formation - Enhanced automaticity - After-depolarizations (后除极) and triggered activities (触发活动) 2. Disturbances of impulse conduction - Reentry (折返)

10. Mechanisms of Arrhythmia 1. Disturbances of impulse formation 1.1 Enhanced automaticity: - Slope of spontaneous depolarization in phase 4 ↑ - Maximum repolarization potential↑ - Threshold potential ↓ - Newly developed abnormal automaticity

11. Mechanisms of Arrhythmia 1. Disturbances of impulse formation 1.2 After-depolarizations and triggered activity EAD (early, prolonged APD, calcium influx, low [K+]o) Formation of abnormal automaticity DAD (delayed, Ca2+ overload-induced)

12. Mechanisms of Arrhythmia 2. Disturbances of impulse conduction -------Reentry（折返） - Anatomically defined reentry: eg. preexcitation syndrome (Wolff-Parkinson-White syndrome, WPW syndrome) - Functional defined reentry: unidirectional block

13. Potential Reentry Circuit Paths Anatomically defined reentry

14. C. Multiple reentrant circuits

15. Strategies to suppress arrhythmia A Decrease automaticity; B Deduce after-depolarizations and triggered activity; C Change the membrane reactivity to decrease conduction and reentry by modifying ERP and APD (ERP/APD↑)

16. eg. β blockers eg. Na+ channel blockers 相对延长ERP eg. Adenosine 绝对延长ERP eg. K+ channel blockers 降低自律性的四种方法 增加ERP/APD的两种方法

17. Classification of anti- arrhythmic drugs Ⅰ: Sodium channel blockers ⅠA: moderate blockers: recovery 1~10 s ⅠB: mild blockers: recovery < 1 s ⅠC: strong blockers: recovery > 10 s Ⅱ:  adrenoreceptor blockers Ⅲ: Drugs selectively prolonging repolarization duration (APD↑, eg., block IKr) Ⅳ: Ca2+ channel blockers And others: adenosine, digitalis……

18. Classification of anti- arrhythmic drugs

19. Antiarrhythmic Drugs 1. Class Ⅰ---sodium channel blockers 1.1 ⅠA Quinidine 奎尼丁 Quinine奎宁 Quinidine Cinchona金鸡纳树

20. Antiarrhythmic Drugs Quinidine A Actions: • Slows conduction and decreases automaticity (blocks activated Na+ channel) • Prolongs ERP and APD, ERP/APD↑ (K+ channel blockade)

21. Antiarrhythmic Drugs Quinidine A Actions: •  and M antagonism (hypotension, sinus tachycardia  and AV conductivity ) • Negative inotropic effect (Ca2+ channel blockade, at high doses)

22. Antiarrhythmic Drugs Quinidine B Therapeutic uses • Atrial fibrillation/flutter and maintenance of sinus rhythm after DC cardioversion （直流电复律） • Ventricular tachycardia (VT) • Frequent premature beat

23. Antiarrhythmic Drugs Quinidine C Adverse effects • Gastrointestinal responses (diarrhea, 30-50%) • Cinchonic reaction (金鸡纳反应， GI and CNS responses) • Hypotension and negative inotropic effect • Atropine-like effects

24. Quiz time Which one of the following symptoms is not due to M-receptor antagonism? A Hypotension B Palpitation C Blurred vision D Dry mouth E Urine retention

25. Antiarrhythmic Drugs Quinidine C Adverse effects • Pro-arrhythmic effects and quinidine syncope (奎尼丁晕厥) - APD elongation, long Q-T interval, EAD triggered activity - AV and ventricular conduction block at toxic doses - Increase of sinus frequency, AV conductivity, ventricular automaticity (add CCBs,  blockers, digoxin to prevent VT before cardioversion of atrial fibrillation/flutter)

26. Antiarrhythmic Drugs Procainamide (普鲁卡因胺) Compared with quinidine: • Similar actions (slows ventricular conduction, prolongs ERP), less effective in suppressing abnormal ectopic pacemaker activity, but more effective in blocking sodium channels in depolarized cells • Without effect on  and M receptors • Mainly used for the acute treatment of supraventricular and ventricular tachycardia • Main adverse effects include gastrointestinal responses, hypotension, hypersensitivity (lupus), CNS responses.

27. Antiarrhythmic Drugs Disopyramide（丙吡胺, 达舒平） Compared with quinidine: • Similar actions(slows conduction, prolongs ERP ) • Evident effect on M receptors • Used for ventricular and supraventricular tachycardia, ventricular premature beat, arrhythmias induced by myocardial infarction • Main adverse effects include hypotension, cardiac inhibition, atropine- like symptoms and arrhythmia.

28. Antiarrhythmic Drugs 1.2 ⅠB Lidocaine A Actions: • Blocks both open and inactivated Na+ channels • Decreases automaticity of fast response cells (especially in depolarized, e.g ischemic, tissues) • Shorten or has no effect on APD (block Na+ influx during phase 2)

29. Antiarrhythmic Drugs Lidocaine B Therapeutic uses: • Treatment and prevention (?) of severe ventricular arrhythmias (iv injection due to high first-pass elimination): heart surgery, cardiac catheterization, acute myocardial infarction, etc.

30. Antiarrhythmic Drugs Lidocaine C Adverse effects: • CNS symptoms: nystagmus眼球震颤, etc • Decrease of heart rate, AV block • Hypotension

31. Antiarrhythmic Drugs Phenytoin sodium（苯妥英钠） Compared with lidocaine: • Similar actions (blocks inactivated Na+ channel) • Na+-K+-ATPase binding • Mainly used for ventricular tachycardia, especially that induced by cardiac glycoside (强心苷) • Main adverse effects include hypotension, AV block, bradycardia, CNS symptoms.

32. Antiarrhythmic Drugs Mexiletine（美西律） Compared with lidocaine: • Similar actions • Mainly used for ventricular tachycardia, especially that follows myocardial infarction

33. Antiarrhythmic Drugs 1. class Ⅰ---sodium channel blockers 1.3 ⅠC Propafenone（普罗帕酮, 心律平） A Actions: • Slows conduction remarkably (blocks open and inactivated Na+ channel) • Decreases automaticity • Prolongs APD, ERP, ERP/APD (K+ channel blockade) • Blocks  receptors and L-type Ca2+ channels

34. Antiarrhythmic Drugs Propafenone B Therapeutic uses: • Broad spectrum antiarrhythmic agent: ventricular and supraventricular arrhythmias C Adverse effects: • Gastrointestinal responses • Proarrhythmic effects（reentrant excitation and AV block）

35. Summary of Class I Increase mortality rate after long term use!

36. Antiarrhythmic Drugs 2. class Ⅱ--- adrenoreceptor blockers Catecholamine  receptors Ca2+ influx ↑ during phase 0 Na+ influx ↑ during phase 4 K+ efflux ↑ during repolarization Physiological effects of  receptors in the heart

37. Antiarrhythmic Drugs 2. class Ⅱ--- adrenoreceptor blockers Propranolol A Actions: • Decreases automaticity of autonomic cells • Prolongs ERP of AV node (K+ efflux )

38. Antiarrhythmic Drugs Propranolol B Therapeutic uses: • Supraventricular and ventricular arrhythmias related to sympathetic excitation • Reduces the incidence of sudden arrhythmic death after myocardial infarction (reduces the mortality rate) C Adverse effects: • Cardiac inhibition and asthma (non-selective agents) • Rebound phenomenon

39. Antiarrhythmic Drugs 3. class Ⅲ--- drugs prolonging APD( K+ channel blockers)

40. Antiarrhythmic Drugs 3. class Ⅲ--- drugs prolonging APD ( K+ channel blockers) Amiodarone 胺碘酮, 可达龙 Amiodarone T4

41. Antiarrhythmic Drugs 3. class Ⅲ--- drugs prolonging APD ( K+ channel blockers) Amiodarone 胺碘酮 A Actions: • Prolongs ERP and APD selectively (blocks esp. Ikr) without evident reverse use-dependence（反转使用依赖性） • Decreases automaticity (blocks Na+, Ca2+ channels) • Slows conduction (blocks Na+, Ca2+ channels) • Increases blood flow of coronary vessels, decrease O2 consumption (blocks ,  receptors)

42. Antiarrhythmic Drugs Amiodarone B Therapeutic uses: • Broad spectrum and long-lasting (maintaining 1-3 m): Supraventricular arrhythmia (especially associated with pre-excitation syndrome) Ventricular arrhythmia NOT associated with an increase in mortality

43. Antiarrhythmic Drugs Amiodarone C Adverse effects: • Hypotension • Arrhythmias: AV block, polymorphic VT • Iodine responses: corneal iodine accumulation, iodine allergy, dysfunction of thyroid glands, interstitial pulmonary fibrosis; Dronedarone (决奈达隆) lacks iodine atoms. • CYP3A4 substrate and inhibitor of several P450 enzyme, has extensive drug interactions

44. Antiarrhythmic Drugs New generation of class Ⅲ sotalol索他洛尔, dofetilide多菲利特, ibutilide伊布利特 • Inhibit Ikr and prolong APD and ERP selectively • Used for ventricular and supraventricular tachycardia, restore and maintenance of sinus rhythm in pts with AF. • May induce EAD and VT

45. Antiarrhythmic Drugs 4. Class Ⅳ---Ca2+ channel blockers Verapamil 维拉帕米，异搏定 Diltiazem地尔硫䓬，恬尔心 A Actions: • Decreases automaticity of slow response autonomic cells and abnormal automaticity (Ca2+ blockade) • Prolongs ERP (blocks Ikr) • Slows conduction of AV node

46. Antiarrhythmic Drugs Verapamil, diltiazem B Therapeutic uses: • Atrial and reentrant supraventricular tachycardia, especially paroxysmal tachycardia • Ventricular premature beat induced by acute myocardial infarction, ischemia, and cardiac glycoside poisoning C Adverse effects: • Cardiac inhibition

47. Antiarrhythmic Drugs 5. Others Adenosine 腺苷 • Activates IkAch,accelerates repolarization (↑ERP/APD) • Decreases automaticity of sinus and AV node due to lowering maximal repolarization potential • Slows conduction • Used for acute supraventricular tachycardia • Extremely short duration of action

50. Principles in the Use of Anti-arrhythmic Drugs • Keep in mind the pro-arrhythmic effects (致心律失常作用)of antiarrhythmic drugs. • Prescript with caution on the basis of a firm diagnosis (ECG) • Use a single drug first; reduce dosage when combination; avoid the combination of drugs with similar adverse effects and in the same category. • Implantable cardioverter-defibrillator (ICD，复律除颤器) as an alternative for severe arrhythmias.