Antiarrhythmic Drugs Huifang Tang Department of pharmacology Zhejiang University School of Medicine tanghuifang@zju.edu.cn

A. Electrophysiological basis of arrhythmias B A. Electrophysiological basis of arrhythmias B. Electrophysiological effects and classification of antiarrhythmic drugs C. Antiarrhythmic drugs D. Proarrhythmic effects of antiarrhythmic drugs

arrhythmias Too rapid; Too slow; Asynchronous; Reduce cardiac output

A. Electrophysiological basis of arrhythmias 1. Normal cardiac electrophysiology Excitability: ability to produce action potentials maximal diastolic potentials (MDP) threshold levels Automaticity: pacemaker phase 4 slope Conductivity: conduction pathways, phase 0 amplitude

Action potential and ion transport Fast response cell

Action potential and effective refractory period

Impulse generation and conduction in the heart

A. Electrophysiological basis of arrhythmias 2. Slow and fast response cells Slow response cells：pacemaker cells fast response cells：conduction and contraction cells Fast response Slow response phase 4 potential －90 mV －70 mV depolarization Na+, 120 mV, 1-2 ms Ca2+, 70 mV, 7 ms automaticity low（0.02 V/s） high（0.1 V/s） conduction fast（200-1000 V/s） slow（10 V/s） effects conduction pacemaker

Slow response Fast response ECG Schematic representation of the heart and normal cardiac electrical activity (intracellular recordings from areas indicated and ECG). Slow response Fast response ECG

A. Electrophysiological basis of arrhythmias 3. Abnormal generation of impulse (1) Augmented automaticity Augmented automaticity in the myocardial cells other than the sinoatrial node cells will produce arrhythmias Maximal diastolic potential (MDP) in phase 4: ischemia, digitalis, sympathetic excitation, imbalance of electrolytes Fast spontaneous depolarization in phase 4：fast response cells  slow response cells

a. increased phase 4 slope Slow response cells b. decreased thresold levels

A. Electrophysiological basis of arrhythmias (2) Afterdepolarization and triggered activity early afterdepolarization (EAD)： phases 2, 3; longer Q-T interval (Torsades de Pointes); Ca2+ inward flow increases induced by drugs, plasma K+  delayed afterdepolarization (DAD)： phase 4; Ca2+ inward flow leads to transient Na+ inward flow induced by digitalis intoxication, plasma Ca2+, K+ 

A. delayed afterdepolarization (DAD) Triggered beat Triggered beat A. delayed afterdepolarization (DAD) B. early afterdepolarization (EAD)

A. Electrophysiological basis of arrhythmias 4. Abnormal conduction of impulse (1) Simple conduction block slow and small depolarization in phase 0, reduced MDP level in phase 4 MDP  in ischemia, inflammation, metabolic disorders； Usually occurred in atrioventricular regions

A. Electrophysiological basis of arrhythmias (2) Reentrant reexcitation (reentry) Circuits (especially in enlarged ventricles) ( Wolff-Parkinson-White syndrome) Unidirectional (one-way) block (myocardial injury) Slow conduction Heterogeneity in ERP

Abnormal conduction pathway of Wolff-Parkinson-White syndrome

Class I : Na+ channel blockers Class II : receptor blockers B. Electrophysiological effects and classification of antiarrhythmic drugs 2. Classification of antiarrhythmic drugs Class I : Na+ channel blockers Class II : receptor blockers Class III : prolongation of APD Class IV : Ca2+ channel blockers

B. Electrophysiological effects and classification of antiarrhythmic drugs 1. Electrophysiological effects of antiarrhythmic drugs (1) Reducing abnormal automaticity decreasing phase 4 slope increasing threshold levels increasing MDP levels in phase 4 increasing action potential duration（APD）

A. decreasing phase 4 slope B. increasing threshold levels C. increasing MDP levels in phase 4 D. increasing action potential duration（APD） fast response cells

b. decreasing phase 4 slope Slow response cells c. increasing threshold levels；d. increasing MDP

class IV drugs decrease automaticity of slow response cells B. Electrophysiological effects and classification of antiarrhythmic drugs class IV drugs decrease automaticity of slow response cells class I drugs decrease automaticity of fast response cells class II drugs decrease the augmented automaticity caused by sympathetic excitation

(2) inhibiting afterdepolarization and triggered activity B. Electrophysiological effects and classification of antiarrhythmic drugs (2) inhibiting afterdepolarization and triggered activity EAD：repolarization  (class IB), inward current  (class I, IV) DAD： class IV, I Sympathetic excitation or digitalis：class II

B. Electrophysiological effects and classification of antiarrhythmic drugs (3) Abolishing reentry Modulating conduction Accelerating conduction one-way block  two-way block abolishing one-way block Modulating effective refractory period (ERP) prolonged ERP prolonged ERP/APD homogeneity of ERP

One-way block reentry normal Two-way block abolishing block

Reducing membrane responsiveness increasing APD and ERP

Class I : Na+ channel blockers Class II : receptor blockers B. Electrophysiological effects and classification of antiarrhythmic drugs 2. Classification of antiarrhythmic drugs Class I : Na+ channel blockers Class II : receptor blockers Class III : prolongation of APD Class IV : Ca2+ channel blockers

(Na+ channel blockers) Class Ia： recovery time of Na+ channels 1~10s moderately block Na+ channels conduction , APD and ERP  quinidine (奎尼丁) procainamide (普鲁卡因胺)

Class Ib： recovery time of Na+ channels <1s mildly block Na+ channels, no markedly inhibition on conduction, K+ outward flow  shorten APD or no lidocaine (利多卡因) phenytoin( 苯妥英)

Class Ic： recovery time of Na+ channels >10s markedly block Na+ channels, depolarization velocity in phase 0  conduction  no marked effect on repolarization propafenone (普罗帕酮) flecainide (氟卡尼)

B. Electrophysiological effects and classification of antiarrhythmic drugs (2) Class II ( receptor blockers) propranolol 普萘洛尔 (3) Class III (prolongation of APD) amiodarone 胺碘酮, sotalol 索他洛尔 (4) Class IV (Ca2+ channel blockers) verapamil 维拉帕米

B. Electrophysiological effects and classification of antiarrhythmic drugs Class I（Na+ channel blockers） Ia SV, V Ib V Ic SV, V Class II（ receptor blockers） SV*, V Class III（prolongation of APD） SV, V Class IV（Ca2+ channel blockers） SV*, V SV:Supraventricular arrhythmias; V: ventricular arrhythmias * primary action sites

Class I drugs: Na+ channel blockers Class Ia drugs Quinidine 奎尼丁

1. Pharmacological effects Na+ channel block muscarinic receptor block (1) Automaticity： depolarization slope in phase 4  abnormal automaticity  (2) Conduction : direct action, one-way  two-way block atrioventricular conduction  because of M receptor block (3) ERP and APD： ERP , APD , ERP/APD  (4) Other effects: hypotension: α receptor block

2. Clinical uses (1) Atrial fibrillation and flutter, pre- and post-cardioversion conversion to sinus rhythm (pretreated with digitalis) maintaining sinus rhythm (2) Other arrhythmias ventricular and supraventricular arrhythmias

3. Adverse effects (1) Extracardiac effects: GI reactions, hypotension, Chichonism, allergy (2) Cardiac toxicity: prolonged QRS and QT intervals, quinidine syncope, paradoxical ventricular tachycardia (3) Arterial embolism: after cardioversion

4. Drug interactions (1) Hepatic enzyme inducers (barbiturates, phenytoin, etc.): increase the metabolism of quinidine (2) Hepatic enzyme inhibitors (cimitidine, verapamil, etc.): decrease the metabolism of quinidine (3) Combined with digoxin: reducing the dose of digoxin

Procainamide 普鲁卡因胺 Effects and uses are similar to quinidine, but weak to atrial fibrillation and flutter induces GI reactions, hypotesion, allergy, occasionally systemic erythematosus lupus (long-term use)

Class Ib drugs Lidocaine 利多卡因

1. ADME 1. ADME Low bioavailability after oral administration Rapid elimination after i.v. injection Given by i.v. infusion ( i.v. gtt )

2. Pharmacological effects (1) Automaticity：reducing spontaneous depolarization in phase 4 of Purkinje fibers (2) Conduction: therapeutic dose: no remarkable effects larger doses, K+ , pH  : decrease MDP , K+ : increase (3) APD and ERP：Na+ inward flow  in phase 2 K+ outward flow  in phase 3 ERP , APD  , ERP/APD 

3. Clinical uses Ventricular arrhythmias: acute myocardial infarction intoxication of digitalis general anesthetics, etc.

4. Adverse effects (1) CNS depression (2) Hypotension (3) Arrhythmias: bradycardia, A-V block

Phenytoin Sodium 苯妥英钠 Effects and uses are similar to lidocaine More effective on digitalis toxicity because of competition to Na+-K+-ATPase

Class IC drugs Propafenone 普罗帕酮

1. Pharmacological effects Reducing automaticity and conduction of fast response cells in atrium and Purkinje fibers 2. Clinical uses Supraventricular and ventricular arrhythmias 3. Adverse effects GI reactions, postural hypotension, arrhythmias

Flecainide 氟卡尼

1. Pharmacological effects Similar to Propafenone 2. Clinical uses Supraventricular and ventricular arrhythmias, as a second choice 3. Adverse effects CNS, arrhythmias, etc.

Class II drugs: β adrenergic receptor blockers Propranolol 普萘洛尔

1. Pharmacological effects Reducing sinus, atrial, ventricular automaticity Reducing A-V and Purkinje fiber conduction Prolonging A-V node ERP 2. Clinical uses Supraventricular arrhythmias Ventricular arrhythmias caused by exercise, emotion, ischemic heart diseases, anesthetics, digitalis, etc. 3. Adverse effects Conduction block, bradycardia, contractility , and many other reactions

Class III drugs: prolongation of APD Amiodarone 胺碘酮

1. Pharmacological effects (1) Cardiac electrophysiological effects Na+, Ca2+, K+ channel block Prolonging repolarization: APD , ERP  Reducing sinus and Purkinje fiber automaticity, and A-V and Purkinje fiber conduction (2) Vasodilatation Reducing peripheral resistance Reducing cardiac oxygen consumption Increasing coronary blood flow

2. Clinical uses Supraventricular and ventricular arrhythmias Longer action duration (t1/2 25 ± 12 days), effects maintained after 4 – 6 weeks of withdrawal

3. Adverse effects (1) Arrhythmias Bradycardia, A-V block, prolonged Q-T intervals (2) Iodine reactions Iodine allergy, hypo- and hyperthyroidism, iodine accumulation in cornea and skin (3) Others Hypotension, tremor, interstitial pulmonary fibrosis, etc.

Sotalol 索他洛尔

Selectively blocks delayed rectifier K+ currents （快速激活的延迟整流钾通道Ikr） No-selective  receptor antagonist Prolonging repolarization: APD , ERP  No remarkable effects on conduction Used for supraventricular and ventricular arrhythmias, arrhythmias in acute myocardial infarction Prolonged Q-T, dysfunction of sinus, cardiac failure

Class IV drugs: Ca2+ channel blockers Verapamil 维拉帕米

1. Pharmacological effects (1) Antiarrhythmic effects: Reducing spontaneous depolarization in phase 4 and depolarization rate in phase 0 of slow response cells Reducing automaticity and conduction of sinus and atrial tissues Effective on abnormal pacemaker cells from fast response to slow response in cardiac injury (such as ischemia) (2) Other effects: depressing cardiac contraction, vasodilatation

2. Clinical uses Supraventricular: tachycardia, atrial arrhythmias Ventricular: myocardial ischemia, digitalis toxicity 3. Adverse effects Depressing cardiac electrophysiological function and contractility, hypotension, etc. Combined with class II drugs and quinidine: potentiating cardiac depression

Other antiarrhythmic drugs Adenosine 腺苷 Activating adenosine receptors and ACh-sensitive K+ channels, prolonging ERP of A-V node, decreasing conduction and automaticity Rapid elimination, t1/2 10～20 seconds, i.v. injection Used for acute superventricular tachycardia Cardiac and respiration depression (i.v. injection)

Drug choice Sinus tachycardia: β antagonists; verapamil Atrial premature contraction: β antagonists; verapamil; class I drugs Atrial flutter or fibrillation: Cardioversion: quinidine (digitalis) Ventricular rate control: β antagonists, verapamil, digitalis Paroxysmal superventricular tachycardia: verapamil; digitalis, β antagonists, adenosine, etc. Ventricular premature contraction: procainamide, lidocaine, phenytoin, etc. Ventyricular fibrillation: lidocaine, procainamide, amiodarone, etc.

D. Proarrhythmoc effects of antiarrhythmic drugs All antiarrhythmic drugs have the proarrhythmic effects 表现为： 原有的心律失常加重 出现新的心律失常 严重者有： 尖端扭转型室性心动过速 室颤 心脏停搏 对策： 谨慎用药 控制病因 合理选择和应用 用药的个体化

D. Proarrhythmoc effects of antiarrhythmic drugs Other drugs digitalis ions (iv)： Ca2+, K+ antimicrobials： amantadine, SMZ, TMP, chloroquine, erythromycin neuroleptics： haloperidol antidepressants：imipramine, amitryline antihistamines： terfenadine, cimitidine

抗心律失常药的致心律失常作用 几乎所有的抗心律失常药物都有致心律失常的副作用 原有心律失常加重或恶化； 引起新的心律失常（室性心动过速、室颤、心脏停搏）

抗心律失常药的致心律失常作用 目前主张对一般心律失常少用Ⅰa、Ⅰc 类。 对策： 谨慎用药；控制病因；合理选择和应用；用药的个体化

记住几种疾病的首选药物 心律失常 首选药 窦性心动过速 病因治疗，心得安 房颤、房扑 转律：奎尼丁 ↓心室率：强心苷 房早 心得安 阵发性室上速 维拉帕米 急性心梗致室速 利多卡因 强心苷中毒致室速 苯妥英钠 阵发性室速 室颤

抗心律失常药引起心律失常 大多数抗心律失常药可引起心律失常．抗心律失常药引起的快速心律失常包括室上性心动过速和室性心动过速。洋地黄中毒可引起房颤、房扑、交界心律、房速伴传导阻滞。

如I类(钠通道阻滞剂)、Ⅱ类(β-受体阻滞剂)、Ⅳ类(钙拮抗剂)等抗心律失常药及洋地黄均可引起窦性心动过缓、窦房阻滞或窦性静止，大剂量或高浓度时可引起房室传导阻滞等缓慢型心律失常。

I类抗心律失常药也可引起室上性心动过速。Ia类药物如奎尼丁、丙吡胺、普鲁卡因胺，Ⅲ类(延长复极过程药)如胺碘酮、溴苄胺及Ⅳ类硝苯地平等均可致Q-T间期延长伴扭转型室速。I类药物特别是Ia、Ic以及心律平、乙吗噻嗪可引起多型室速、单型室速、非持续室速转变的持续室速及室早次数增加等。

有些抗心律失常药物可加重原有的或引发新的心律失常。如快通道阻滞剂奎尼丁、普鲁卡因胺、达舒平等易致Q-T间期延长；安卡因由于可使除极传导速度减慢，易致QRS间期延长；溴苄胺可兴奋交感神经，导致自主神经功能失调，加重心律失常；心律平抑制窦房结和心脏传导功能，可造成窦性心动过缓，窦性停搏及多种不同类型的传导阻滞；

β受体阻滞剂可抑制儿茶酚胺加快心室肌内除极速度的效应，而使各部分心肌传导速度不一致，造成折返性心律失常等。这种致心律失常作用的发生率在10％以上，甚至可引起突然死亡。左心室功能减退、室性心律失常引起血液动力学障碍的病人，更易诱发心律失常，用药须谨慎。

胺碘酮：其所致心血管不良反应中，发生无症状窦性心动过速占23％，严重心动过缓占3％，房室传导阻滞占9. 1％，窦房传导阻滞占1 胺碘酮：其所致心血管不良反应中，发生无症状窦性心动过速占23％，严重心动过缓占3％，房室传导阻滞占9.1％，窦房传导阻滞占1.5％，室内传导阻滞占3％，早搏占1.5％。

奎尼丁：该药中毒时可致室性期前收缩，室性心动过速及室颤等，可能是由于心内传导减慢导致局限性单向性阻滞，导致折返性心率紊乱。普鲁卡因胺对心脏的毒性与奎尼丁相似。

钙拮抗剂：维拉帕米可引起窦性停搏和房室阻滞。硝苯吡啶亦可引起房室传导阻滞，心动过缓，窦性停搏。

洋地黄制剂：可引起各类型心律失常，包括冲动形成和传导异常，或两者并存。常见心律失常有：房性心动过速、心房纤颤及扑动、房性早搏、交界性心动过速、房室传导阻滞、室性期前收缩、室性心动过速等。心律失常发生率可高达66％。

普罗帕酮(心律平)：其致心律失常的发生率在10％以上。有快速型与缓慢型心律失常两类，前者表现为窦性心动过速、室上性心动过速、尖端扭转型室性心动过速、阿-斯综合征及小儿心律失常。

其发生机制为：抗迷走神经作用，导致自主神经功能失调；干扰心肌电生理活动。后者表现为严重窦性心动过缓，房内、房室、室内传导阻滞、顽固性室性早搏、窦性停搏、心脏骤停致晕厥甚至死亡。这可能是由于普罗帕酮的β阻滞作用，以及对整个传导系统的抑制。此作用与药物剂量、疗程有关，停药后可逆转。老年患者，剂量过大以及服药前肝肾功能不良者，可增加其致心律失常的作用。

其他：小剂量利多卡因静脉注射偶尔可引起室性心动过速及室颤，大剂量静脉注射可引起心脏传导阻滞。普鲁卡因胺是一种抗心律失常药物，但对心脏有抑制作用，引起心脏毒性与奎尼丁相似，可出现室性心律失常(室性早搏、室性心动过速及室颤)。安搏律定引起不完全双束支阻滞以及美西律所致的完全性右束支传导阻滞等。抗心律失常药的不合理联用或剂量过大，是产生新的心律失常的重要诱因。胺碘酮与奎尼丁联用时，有出现室性心动过速的潜在危险。普罗帕酮能从血浆蛋白结合部位置换出地高辛，两者联用时可致严重心律失常。地高辛与维拉帕米联用可引起Ⅱ度房室传导阻滞。普萘洛尔与维拉帕米合用可致窦性骤停。

抗心律失常药致心律失常的发生率较高，所以使用时应根据个体差异选择适当的药物及剂量，尽量避免或减少新的心律失常的发生。抗心律失常药所致心律失常确诊后，应立即停用有关药物，并尽可能消除诱发因素，如纠正低钾、低镁血症等，同时根据所致心律失常的类型及危险性拟定相应的治疗方案。