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Pharmacologic Approaches to Arrhythmia Suppression Jaemin Shim, MD Yonsei University Health System Depolarization and Repolarization Depolarization and Contraction ____________ + + + + + + + + + + + + Repolarization and Relaxation + + + + + + + + + + + + ____________ Action Potential of Myocyte Arrhythmia Mechanism Enhanced Automaticity Non-pacemaker cells begin to spontaneously and abnormally initiate an impulse. Reduced (more positive) resting membrane potential bringing it closer to the threshold potential. Ischemia and electrolyte imbalances Automaticity NORMAL AUTOMATICITY ABNORMAL AUTOMATICITY (depolarized Purkinje myocyte) (SA myocyte) 1 sec 200 ms DD Emax 50 mV 50 mV Eth block IK1 Triggered Activity (Afterdepolarization) Triggered activity (afterdepolarizations): Spontaneous depolarizations requiring a preceding impulse (triggering beat) Early afterdepolarizaiton (EAD) − During phase 2 or 3 − Drug induced Torsade de pointes Delayed afterdepolarization (DAD) − During phase 4 − Digoxin toxicity Early afterdepolarizaiton (EAD) Delayed afterdepolarizaiton (EAD) EAD vs. DAD EAD (during phase 2 or 3) EAD DAD (during phase 4) DAD Inciters QT prolonging drugs Digitalis, catecholamine Exaggerated by Slow rates, ↓K+ Rapid rates Blunted by Rapid rates, K+, Mg2+ Ca2+ channel block Mechanism Net↑ inward plateau current Intracellular Ca2+ overload Putative clinical rhythm Torsades pointes Digitalis toxicity, ischemia Reentry Action of Antiarrhythmic Drugs Blocking the sodium channel Blocking the potassium channel Blocking the calcium channel Blocking the adrenergic receptor Slowing conduction (Na+ channel blockade) Lengthening the refractory period (K+ channel blockade) Reducing automaticiy of abnormal tissue Vaughan Williams Classification Class I – Fast sodium channel blocker Class II – Non-competitive beta-blocker Class III – Potassium channel blocker Class IV – Calcium channel blocker Class I Antiarrhythmic Agents Class IA (QT↑): quinidine, procainamide, Class IB (QT↓): lidocaine, mexiletine Class IC (QT→, QRS↑): flecainide (Tambocor), propafenone (Rytmonorm) Flecainide (Tambocor) Class IC antiarrhythmics Depresses sodium current, decreases conduction velocity − Lesser effect on refractoriness Use dependence − The faster the rate, the more binding and the drug’s anti arrhythmic effect Dual elimination − Kidney and Liver Contraindicated in CAD or HF M/80, palpitation with dizziness flecainide 100mg bid for AF TLC 320 ms, LBBB, LAD Wide QRS tachycardia probably due to flecainide related use dependency Rhythm strip after verapamil 5 mg IV bolus II Atrial flutter 1:1 conduction 2:1 conduction with normal QRS Cardiac Arrhythmia Suppression Trial (CAST trial) 1498 pts: 432 encainide, 323 flecainide Double-blinded, placebo controlled trial of PVC suppression with encainide and flecainide following MI Echt et al. NEJM 1991; 324:781-788 Cardiac Arrhythmia Suppression Trial (CAST trial) Study halted due to increased all-cause mortality in treatment arm 3.6 fold increase in fatal arrhythmias and non-fatal cardiac arrest Echt et al. NEJM 1991; 324:781-788 Beta Blockers Class II Metoprolol, Esmolol, Propranolol Inhibits normal sympathetic effects Decrease cardiac automaticity Decrease AVN conduction velocity Increases AVN refractoriness Cardio-protective: ↓myocardial contraction, O2 demand Sotalol Class III K+ channel blocker with beta blocking properties Renal excretion Serious side effect: Torsade de pointes The corrected QT (QTc) interval must be watched carefully for excess prolongation Amiodarone Class III Na+ channel, alpha and beta adrenoreceptor, and Ca2+ channel blockade Very long half-life: 40-50 days Hepatic excretion It rarely causes torsade de pointe and is safely used in patients with advanced cardiovascular disease 항부정맥 효과가 높고, 심근기능 저하가 적다. 구조적 심질환이 있는 환자에 적합 Amiodarone 장기 사용시 부작용 위험이 높다. − − − − − − Pulmonary fibrosis (5-10%, 10% 사망율) Hypo or hyperthyroidism Elevated liver enzyme Skin blue discoloration Corneal deposit Upto 25% of patients will have to discontinue it due to side effects. M/67, on amiodarone Pulmonary fibrosis Blue discoloration DLCO 67% Choi JS, # 3220914 Canadian Trial of AF Investigation NEJM 2000;342:913-20 Dronedarone Class III Iodine moieties in amiodarone play a role in mediating side effects Dronedarone is a derivative of amiodarone that lacks the iodine moieties Elimination half life is reduced to 1 day Dronedarone ADONIS / EURIDIS – moderately effective AAD in low risk non-permanent AF / AFL ATHENA –reduces adverse CV events in moderate risk non-permanent AF / AFL patients. PALLAS – dronedarone increases adverse cardiovascular outcomes in high risk permanent AF / AFL patients. Dronedarone should not be used in patients in permanent AF / AFL, in patients with a history of CHF, or in patients with reduced LVEF Calcium Channel Blockers Class IV Verapamil (Isoptin), Diltiazem (Herben) Blocks both activated and inactivated slow ICa − Decrease AVN conduction velocity − Increase AVN ERP − Reduce ventricular rate − Reduce Phase 4 potential -↓automaticity Mainly used in SVT and rate control in AF Other Drugs Adenosine − Negative dromotropic and chronotropic effects mainly on the SA and AV nodes. − May lead to transient complete AV block. − Quickly cleared with an elimination half-life of 10 seconds or less Digoxin − Enhances vagal activity and thus slows sinus node automaticity and prolongs AV nodal conduction − Used to control the ventricular rate in AF − Hypokalemia augments digitalis toxicity Take-home Messages 항부정맥제는 부정맥 억제에 효과적이지 못하다. 항부정맥제는 안전하지 않으며 일부 환자에서 오히려 사망률 을 증가시킨다 (CAST, SWORD, AFFIRM Trials). 구조적 심장질환이 있는 사람에서는 proarrhythmia의 위험 이 있으므로 amiodarone, dronedarone 이외에는 피한다. 항부정맥제의 급성/만성적 부작용에 대한 지속적인 모니터링 이 필수적이다. 심전도로 증명이 된 부정맥에 한해서 심전도로 효과를 확인 한 최소 용량을 선택적으로 사용한다. Non-pharmacologic Tx에 병용한 Hybrid Tx가 효과적이다. Thank you for you attention Action Potential of Myocyte