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Antiarrhythmic Drugs: Classification and Mechanisms

This article provides an overview of the types of arrhythmias, mechanisms of arrhythmia, and the classification of antiarrhythmic drugs. It explores the actions and therapeutic uses of sodium channel blockers like quinidine and procainamide.

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Antiarrhythmic Drugs: Classification and Mechanisms

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

  2. 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

  3. ECG (Electrocardiograph)

  4. Outline • Physiology of cardiac rhythm • Mechanisms of arrhythmia • Classification of antiarrhythmic drugs • Antiarrhythmic drugs

  5. Purkinje cells Currents involved in action potentials in cardiac cells

  6. 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)

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

  8. Mechanisms of arrhythmia 1. Disturbance of impulse formation 1.1 Enhanced automaticity: - Slope of spontaneous depolarization in phase 4 ↑ - Maximum repolarization potential ↑ - Threshold potential ↓

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

  10. Mechanisms of arrhythmia 2. Disturbance of impulse conduction Reentry（折返） - Anatomically defined reentry: eg. preexcitation syndrome (Wolff-Parkinson-White syndrome, WPW syndrome) - Functionally defined reentry: unidirectional block

  11. Anatomically defined reentry Potential Reentry Circuit Paths

  12. Functionally defined reentry A. Normal conduction B. Unidirectional block C. Multiple reentrant circuits

  13. Strategies to suppress arrhythmia A To decrease automaticity; B To decrease after-depolarizations and triggered activities; C To inhibit conduction and reentry by modifying he membrane reactivity, ERP and APD (ERP/APD↑)

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

  15. Classification of antiarrhythmic drugs Ⅰ: Sodium channel blockers （Nav1.5 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……

  16. Classification of antiarrhythmic drugs

  17. 抗心律失常药物现代分类法中八类药物的靶点（Lei et al., Circulation. 2018）

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

  19. Antiarrhythmic Drugs Quinidine A Actions: • Slows conduction and decreases automaticity (blocks Nav1.5 at open state) • Prolongs ERP and APD, ERP/APD↑ (K+ channel block)

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

  21. 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

  22. 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

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

  24. 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)

  25. 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.

  26. 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.

  27. Antiarrhythmic Drugs 1.2 ⅠB Lidocaine A Actions: • Blocks both inactivated (preferentially) and open Na+ channels • Decreases automaticity in fast response cells • Slightly shortens APD and ERP in normal myocytes (blocks Na+ influx during phase 2), but prolongs ERP in ischemic, partially depolarized cells

  28. 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.

  29. Antiarrhythmic Drugs Lidocaine C Adverse effects: • CNS symptoms: dizziness, somnolence, excitation, paresthesia感觉异常, nystagmus眼球震颤, etc • Decrease of heart rate, AV block • Hypotension

  30. 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.

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

  32. 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 both open and inactivated Na+ channels) • Blocks  receptors and L-type Ca2+ channels, decreases automaticity • Prolongs APD, ERP, ERP/APD (K+ channel blockade)

  33. Antiarrhythmic Drugs Propafenone B Therapeutic uses: • Broad spectrum antiarrhythmic agent: ventricular and supraventricular arrhythmias without organic cardiac diseases. C Adverse effects: • Gastrointestinal reactions • Proarrhythmic effects(reentrant excitation and AV block)

  34. Summary of Class I Increase mortality rate after long term use! , propafenone

  35. 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

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

  37. 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 • Rebound phenomenon

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

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

  40. Antiarrhythmic Drugs 3. class Ⅲ--- drugs prolonging APD ( K+ channel blockers) Amiodarone 胺碘酮 A Actions: • Prolongs ERP and APD selectively (blocks Ik) 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)

  41. 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

  42. 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 enzymes, extensive drug interactions

  43. Antiarrhythmic Drugs New generation of class Ⅲ sotalol索他洛尔, dofetilide多菲利特, nifekalant尼非卡兰, 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 • May induce EAD and VT

  44. 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

  45. 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

  46. 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

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