Antiarrhythmic Drugs 抗心律失常药物. Shi-Hong Zhang ( 张世红 ) Pharmacology, Dept. of
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1 抗心律失常药物 Shi-Hong Zhang ( 张世红 ) Pharmacology, Dept. of shzhang713@zju.edu.cn 1
2 Outline Physiology of cardiac rhythm Mechanisms of arrhythmias Classification of antiarrhythmic drugs Antiarrhythmic drugs 2
3 3
4 Cellular Action Potential Rapid response Non-autorhythmic cell: Atrial muscle cell Ventricular muscle cell Rapid response autorhythmic cell: Purkinje cell Slow response autorhythmic cell: sinoatrial node Atrioventricular node Recall: ionic basis of cardiac electrophysiology 4
5 APD ERP Currents involved in action potentials in purkinje cells 5
6 Type of Arrhythmias Speed Too rapid--tachyarrhythmias Too slow--bradyarrhythmias Location Supraventricular Ventricular Rhythm Supraventricular arrhythmias: Atrial fibrillation ( 心房颤动 ) Atrial flutter ( 心房扑动 ) Paroxysmal supraventricular tachycardia (originating from atria or AV node) ( 阵发性室上速 ) Ventricular arrhythmias: Premature ventricular contraction ( 早搏 ) Ventricular tachycardia (VT) Polymorphic VT Ventricular Fibrillation (VF) 6
7 ECG (Electrocardiograph) 7
8 Main Causes of Tachyarrhythmias Ischemia Hypoxia Ischemia-reperfusion 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 8
9 Mechanisms of Arrhythmias 1. Dysfunction of impulse generation - Enhanced automaticity - After-depolarizations ( 后除极 ) and triggered activities( 触发活动 ) - Gene mutation 2. Dysfunction of impulse conduction - Reentry( 折返 ) 9
10 Mechanisms of Arrhythmias 1. Dysfunction of impulse generation 1.1 Enhanced automaticity: - Velocity of spontaneous depolarization in phase 4 - Maximum repolarization potential - Threshold potential 10
11 Mechanisms of Arrhythmias 1. Dysfunction of impulse generation 1.2 Afterdepolarizations and triggered activity EAD (arising before full repolarization; prolonged APD/Ca 2+ influx) DAD (arising after full repolarization; Ca 2+ overload) Generation of abnormal automaticity 11
12 Mechanisms of Arrhythmias 1. Dysfunction of impulse generation 1.3 Gene mutation: - Mutation of some genes coding ion channels 13 gene mutations have been identified: I k, I Na, I Ca, etc. (normal sinus beat) 12
13 Mechanisms of Arrhythmias 2. Dysfunction of impulse conduction Reentry( 折返 ) - Anatomically defined reentry: eg. preexcitation syndrome (WPW syndrome) - Functional defined reentry: unidirectional block, discordant ERP 13
14 房室旁路 14
15 Normal impulse conduction, unidirectional block and reentrant excitation in purkinje fibers 15
16 Strategies to treat arrhythmias A To decrease automaticity; B To inhibit afterdepolarizations and triggered activity; C To change the membrane reactivity and conductivity; D To decrease reentry by modifying ERP and APD (ERP/APD ). 16
17 β blockers 相对延长 ERP Na +, Ca 2+ channel blockers Adenosine 绝对延长 ERP K + channel blockers 降低自律性的四种方法 增加 ERP/APD 的两种方法 17
18 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 (block I k ) Ⅳ: Ca 2+ channel blockers And others (adenosine ) 18
19 Classification of anti- arrhythmic drugs Classification IA IB IC II III IV Representatives Quinidine 奎尼丁, procainamide 普鲁卡因胺 lidocaine, mexiletine 美西律, phenytoin Propafenone 普罗帕酮, flecainide 氟卡尼 propranolol, metoprolol, Amiodarone 胺碘酮, sotalol 索他洛尔 verapamil, diltiazem 19
20 1. class Ⅰ---sodium channel blockers 1.1 ⅠA Quinidine 奎尼丁 Cinchona 金鸡纳树 Quinidine Quinine 奎宁 20
21 Quinidine A Actions: Slows conduction velocity and decreases automaticity of purkinje cells (Na + channel blockade) Prolongs ERP and APD, ERP/APD (K + channel blockade) 21
22 Quinidine A Actions: and M antagonism (hypotension, sinus tachycardia and AV conductivity ) Negative inotropic effect (Ca 2+ channel blockade) 22
23 Quinidine B Therapeutic uses Atrial fibrillation and flutter and maintenance of sinus rhythm after current cardioversion 电复律 Ventricular tachycardia Frequent premature beat 23
24 C Adverse effects Quinidine Gastrointestinal responses (diarrhea) Chichonic reaction ( 金鸡纳反应 GI and CNS responses) Hypotension and negative inotropic effect Allergic reaction:rashes, angioedema, thrombocytopenia Atropine-like effects 24
25 C Adverse effects Quinidine 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 flutter) 25
26 Procainamide( 普鲁卡因胺 ) Compared with quinidine: Similar but weaker actions (slows ventricular conduction, prolongs ERP) 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
27 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
28 1.2 ⅠB A Actions: Lidocaine Blocks both open and inactivated Na+ channels Decreases automaticity of fast response cells (especially in depolarized, e.g ischemic, tissues) Shortens APD, ERP/APD (K+ efflux ) Modifies conduction (ischemic tissue: ; hypokalemia: ) 28
29 Lidocaine B Therapeutic uses: Ventricular arrhythmias: severe ventricular tachycardia and ventricular fibrillation Prevents ventricular fibrillation during acute phase of myocardial infarction 29
30 Lidocaine C Adverse effects: CNS symptoms: nystagmus 眼球震颤, dizziness, drowsiness, etc Decrease of heart rate, AV block Hypotension 30
31 Phenytoin sodium( 苯妥英钠 ) Compared with lidocaine: Similar actions Na+-K+-ATPase binding Mainly used for ventricular tachycardia, especially that is induced by cardiac glycoside ( 强心苷 ) Main adverse effects include hypotension, AV block, bradycardia, CNS symptoms (refer to antiepileptic drugs). 31
32 Mexiletine( 美西律 ) Compared with lidocaine: Similar actions Mainly used for ventricular tachycardia, especially that follows myocardial infarction 32
33 1. class Ⅰ---sodium channel blockers 1.3 ⅠC Propafenone( 普罗帕酮, 心律平 ) A Actions: Slows conduction remarkably Decreases automaticity Slightly prolongs APD, ERP, ERP/APD (K+ channel blockade) Blocks receptors and L-type Ca 2+ channels 33
34 Propafenone B Therapeutic uses Abroad spectrum antiarrhythmic agent: ventricular and supraventricular arrhythmias C Adverse effects Gastrointestinal responses Negative inotropic effect and asthma Proarrhythmic effects(reentrant excitation and AV block) Other ⅠC drugs: flecainide(strong K + channel blockade) 34
35 Summary of Class I 35
36 2. class Ⅱ--- adrenoreceptor blockers Catecholamine receptors Na + influx during phase 4 Ca 2+ influx during phase 0 K + efflux during repolarization Physiological effects of receptors in the heart 36
37 Antiarrhythmia Drugs 2. class Ⅱ--- adrenoreceptor blockers Propranolol ( 普萘洛尔, 心得安 ) A Actions: Decreases automaticity of autonomic cell Stabilizes membrane and slows conduction (Na + and Ca 2+ channels blockade ) prolongs ERP of AV node (K+ efflux ) 37
38 Propranolol B Therapeutic uses: Supraventricular and ventricular (hyperthyroidism, chromaffinoma) 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
39 3. class Ⅲ--- drugs prolonging repolarization selectively ( K + channel blockers) 39
40 3. class Ⅲ--- drugs prolonging repolarization selectively ( K + channel blockers) Amiodarone ( 胺碘酮, 可达龙 ) 40
41 3. class Ⅲ--- drugs prolonging repolarization selectively ( K + channel blockers) Amiodarone ( 胺碘酮, 可达龙 ) A Actions: Prolongs ERP and APD selectively (blocks I k ) without reverse use-dependence ( 反转使用依赖性 ) Decreases automaticity (blocks Na +, Ca 2+ channels) Slows conduction (blocks Na +, Ca 2+ channels) Increases blood flow of coronary vessels (blocks, receptors) 41
42 Amiodarone B Therapeutic uses: Abroad spectrum antiarrhythmic agent: Supraventricular arrhythmia (especially associated with pre-excitation syndrome), ventricular arrhythmia, severe refractory arrhythmias 42
43 Amiodarone C Adverse effects: Arrhythmias: AV block, polymorphic VT Iodine responses: (corneal iodine accumulation, iodine allergy, dysfunction of thyroid glands, interstitial pulmonary fibrosis) 43
44 New generation of class Ⅲ sotalol 索他洛尔, dofetilide 多菲利特 Inhibit I kr and prolong APD and ERP selectively Increase Ca 2+ influx and represent positive inotropic effect Used for ventricular and supraventricular tachycardia, maintenance of sinus rhythm May induce EAD and VT 44
45 4. class Ⅳ---Ca 2+ channel blockers Verapamil ( 维拉帕米, 异搏定 ) A Actions: Prolongs ERP of slow response autonomic cells Decreases automaticity of slow response autonomic cells and abnormal automaticity Slows conduction of slow response autonomic cells 45
46 46
47 Verapamil 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
48 48
49 5. Others Adenosine 腺苷 Activates I kach, accelerates repolarization ( ERP/APD) Decreases automaticity of sinus and AV node Slows conduction Used for acute supraventricular tachycardia Extremely short duration of action 49
50 50
51 51
52 Cautions in the Use of Anti-arrhythmic Drugs Prescript with caution on the basis of a firm diagnosis Use a single drug first when drug treatment is needed. Keep in mind the pro-arrhythmic effects ( 致心律失常作用 ) of antiarrhythmic drugs. Implantable cardioverter-defibrillator (ICD) as an alternative for severe arrhythmias. 52
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