HST-151 1 Antidysrhythmics I. Ventricular muscle cell action potential a. Phase 0: Upstroke b. Phase 1: Early-fast repolarization c. Phase 2: Plateau d. Phase 3: Repolarization e. Phase 4: Diastole Antidysrhythmics.doc Harvard-MIT Division of Health Sciences and TechnologyHST.151: Principles of PharmacologyHST-151 2 II. Cardiac arrhythmia: a. Abnormal impulse formation i. Early afterdepolarizations (EADs): interrupts phase 3 -exacerbated at slow heart rates and may contribute to development of long QT-related arrhythmias ii. Delayed afterdepolarizations (DADs): interrupts phase 4 - occurs when intracellular calcium is increased; is exacerbated by fast heart rates, may relate to digitalis excess, catecholamines, and myocardial ischemia b. Abnormal impulse propagation: i. Abnormal depolarization (QRS) ii. Abnormal repolarization (QTc) III. Cellular mechanism of arrhythmia: a. Enhanced automaticity: sinus and AV node, His-Purkinje system i. Beta-adrenergic stimulation, hypokalemia, mechanical stretch increase phase 4 slope & pacemaker rate b. Reentry: impulse reenters and excites areas of the heart more than once i. Obstacle for homogeneous conduction (anatomic, physiologic) ii. Unidirectional block in conduction circuit iii. Path length X conduction velocity > refractory period Antidysrhythmics.docHST-151 3 c. Polymorphic ventricular tachycardia (Torsades de Pointes): ("twisting of the points") or drug-induced long QT syndrome (DILQTS)  Polymorphic arrhythmia that can rapidly develop into ventricular fibrillation  Associated with drugs that have Class III actions (potassium channel blockers)  Also seen with other drugs such as terfenadine, cisapride, under certain circumstances  Usually occurs within the first week of therapy  Preexisting prolonged QTc intervals may be indicator of susceptibility  Potentiated by bradycardia  Often associated with concurrent electrolyte disturbances (hypokalemia, hypomagnesemia) IV. Classification of Antiarrhythmic drugs: • Although several of the drugs used to treat cardiac arrhythmias have been used for many years (e.g.- quinidine and digitalis since the early 1900s), most of the agents approved for use today have only been available for a decade or less. • Research in recent years has provided much information regarding the cellular mechanisms of arrhythmias and the mechanisms by which some of the antiarrhythmic drugs act, but the general approach to antiarrhythmic therapy remains largely empirical. • The recent results of several clinical trials, including the Cardiac Arrhythmia Suppression Trial (CAST), have indicated that many antiarrhythmic drugs may significantly increase mortality compared to placebo. • All of the antiarrhythmic drugs act by altering ion fluxes within excitable tissues in the myocardium. The three ions of primary importance are Na+, Ca++, and K+. Antiarrhythmic drugs can be classified by their ability to directly or indirectly block flux of one or Antidysrhythmics.docHST-151 4 more of these ions across the membranes of excitable cardiac muscle cells. • Class I drugs, those that act by blocking the sodium channel, are subdivided into 3 subgroups, IA, IB, and IC based on their effects on repolarization and potency towards blocking the sodium channel o Subclass IA drugs have high potency as sodium channel blockers (prolong QRS interval), and also usually prolong repolarization (prolong QT interval) through blockade of potassium channels o Subclass IB drugs have the lowest potency as sodium channel blockers, produce little if any change in action potential duration (no effect on QRS interval) in normal tissue, and shorten repolarization (decrease QT interval) o Subclass IC drugs are the most potent sodium channel blocking agents (prolong QRS interval), and have little effect on repolarization (no effect on QT interval) • Class II drugs act indirectly on electrophysiological parameters by blocking beta-adrenergic receptors (slow sinus rhythm, prolong PR interval, little effect on QRS or QT intervals) • Class III drugs prolong repolarization (increase refractoriness) by blocking outward potassium conductance (prolong QT interval), with typically little effect on the rate of depolarization (no effect on QRS interval) • Class IV drugs are relatively selective AV nodal L-type calcium-channel blockers (slow sinus rhythm, prolong PR interval, no effect on QRS interval) • Miscellaneous In addition to the standard classes, IA-C, II, III, and IV, there is also a miscellaneous group of drugs that includes digoxin, adenosine, magnesium, alinidine (a chloride channel blocker) and other compounds whose actions don't fit the standard four classes Antidysrhythmics.docHST-151 5 Ventricular Action Potential Na+ IKr Ca++ IKs Class I Class I & III* Depolarization Table 1. Vaughan Williams Classification of Antiarrhythmic Drugs Class Action Drugs I Sodium Channel Blockade IA Prolong repolarization Quinidine, procainamide, disopyramide IB Shorten repolarization Lidocaine, mexiletine, tocainide, phenytoin IC Little effect on repolarization Encainide, flecainide, propafenone, moricizine(?) II Beta-Adrenergic Blockade Propanolol, esmolol, acebutolol, l-sotalol III Prolong Repolarization (Potassium Channel Blockade; Other) Ibutilide, dofetilide, sotalol (d,l), amiodarone, bretylium IV Calcium Channel Blockade Verapamil, diltiazem, bepridil Miscellaneous Miscellaneous Actions Adenosine, digitalis, magnesium Antidysrhythmics.docHST-151 6 Table 2. Class Toxicities of Antiarrhythmic Drugs (Adapted from Woosley, 1991) Class I Class II Class III Class IV Proarrhythmic effects: • IA- Torsades de pointes • IC- CAST proarrhythmia Negative inotropic effect Infranodal conduction block Sinus bradycardia AV block Depression of LV function (adrenergic-dependent) Sinus bradycardia Torsades de pointes Sinus bradycardia AV block Negative inotropic effect V. Mechanism of antiarrhythmic drugs: Antiarrhythmic drugs act by altering the flux of ions across the membranes of excitable cells in the heart. The primary mechanisms of action correspond to the mechanisms used in developing the Vaughan Williams classification system, and include inhibition of sodium channels (Class I drugs), inhibition of calcium channels (Class IV drugs), inhibition of potassium channels (Class III drugs), and blockade of beta-adrenergic receptors in the heart (Class