Antiarrhythmics.pptx

Antiarrhythmics Advanced Pharmacology Dru Riddle Performance Objectives • Know the ionic basis of antiarrhythmics in SA node, atrial, AV node, and Purkenje cells and how they related to EKG • Know the difference between slow response and fast response cells in the myocardium • Know the classificat...

Antiarrhythmics Advanced Pharmacology Dru Riddle Performance Objectives • Know the ionic basis of antiarrhythmics in SA node, atrial, AV node, and Purkenje cells and how they related to EKG • Know the difference between slow response and fast response cells in the myocardium • Know the classification of Class I-IV agents based on mechanisms of action • Know important pharmacokinetic properties and side effects of major antiarrhythmic drugs Antiarrhythmics Drug List/Class • Class 1 • • • • • • Lidocaine Mexiletine Quinidine Procanamide Profafenone Flecanide • Class 2 • Atenolol • Esmolol • Metoprolol • Class 3 • • • • • Amiodarone Dofetilide Dronedarone Sotalol Ibutilide • Class 4 • Verapamil • Diltiazem • Others • Adenosine • Digoxin • Magnesium Katzung, 2021-15th ed, pg. 236 Differences in fast and slow response cell type FAST SLOW Characteristics of Fast & Slow Cells in Myocardium FAST RESPONSE SLOW RESPONSE Location: atria, ventricle, His-Purkinje Located: SA and AV node Rate of depolarization: fast Rate of depolarization: slow Conduction velocity: rapid Conduction velocity: slow Major ionic species involved in depolarization: Na+ Major ionic species involved in depolarization: Ca2+ Inhibitors of depolarization: Class I antiarrhythmic agents (quinidine) Inhibitors of depolarization: calcium-entry blockers (verapamil, diltiazem) Recovery of excitability: prompt; ends with repolarization Recovery of excitability: delayed; outlasts repolarization Catecholamines (SNS): little effect on depolarization Catecholamines: enhance depolarization Acetylcholine (PS): no effect on depolarization Acetylcholine: significantly depresses depolarization Three main mechanisms of arrhythmias 1. Enhanced automaticity (impulse formation) 2. Triggered automaticity (normal action potential is interrupted or followed by an abnormal depolarization) 3. Reentry (abnormal impulse conduction) 4 ways antiarrhythmic drugs reduce spontaneous discharge Functionally defined re-entry Classification based on drug action Class I: Sodium Channel Blockers • Act on fast response cells • Reduce membrane responsiveness • Reduce Vmax (depress conduction velocity) • Prolong effective refractory period (ERP) Class 1A Drugs (Quinidine)-EP Effects Direct Effects Decrease Vmax Increase ERP (effective refractory period) Indirect Effects Use Blocks K+ channels  afterdepolarizations Atrial flutter or fibrillation Prevent V-tach and fibrillation Quinidine Side Effects • Variable therapeutic concentration • Severe GI effects - anticholinergic • Metabolized in liver • Inhibits P450 system (metabolism of narcotics) Class 1B Drugs (Lidocaine) Direct Effects Increases Block of Na+ channels (Vmax) at high HR or in depolarized cells Decreases AP duration and ERP Dissociates rapidly at resting Em Side Effects Use Dizziness, seizures V-tach Digitals-induced arrhythmias Class 1C Drugs (Flecainide) Direct Effects Decreases Vmax (conduction velocity) Variable effects on ERP Dissociates from Na+ channel slowly Side Effects Use Pro-arrhythmic (CAST Trial) Atrial and ventricular arrhythmias resistant to other drugs Effect of Class II Drugs on Diastolic Depolarization Class II: Beta-Adrenergic Blockers Long acting (oral) Metoprolol: Esmolol: Short acting (IV)  Bind to ß-adrenergic receptors on cardiac cell membranes to competitively inhibit norepinephrine binding.  No effect in absence of catecholamines.  In the presence of catecholamines, the main action of Class II agents is to decrease diastolic depolarization. Uses  Used for all atrial arrhythmias, ventricular tachycardia and fibrillation  Major side effects are negative inotropic effect, and bronchospasm Class III: K+ Channel Blockers Amiodarone • • • • Sotalol The common property is K+ channel block Very heterogeneous group Na+ channel blocking properties (amiodarone) ß-Adrenergic blocking properties (sotalol) Amiodarone – very heterogeneous • Potent K+ channel blocker • Modest Na+ channel blocker • Modest Ca2+ channel blocker • Modest and ß adrenergic receptor blocker Uses  Used for all arrhythmias (V Tach) Amiodarone – Side Effects • pulmonary fibrosis • altered thyroid function (inhibits conversion of T4 to T3) Class IV: Ca2+ Channel Blockers Diltiazem Verapamil  Acts primarily on slow response cells (SA & AV node), which are dependent on Ca2+ influx for Phase 0 of the action potential. Major EP Effects of Ca2+ Channel Blockers • Depress phase 4 depolarization • Depress Vmax • Depress conduction velocity 0.1 0.2 0.5 1 mg/ml Effect of Verapamil on AP of SA node cell Uses – Atrial Tachycardias Paroxysmal atrial tachycardia Atrial flutter Major Side Effects of Ca2+ Channel Blockers • Negative chronotropic effect – decreases automaticity of SA node • Negative inotropic effect – decreases Ca2+ influx during plateau phase of ventricular action potential • Hypotension – decreases Ca2+ influx into vascular smooth muscle cells Major Side Effects of Ca2+ Channel Blockers • Peripheral edema • Constipation – decreases Ca2+ influx into GI smooth muscle cells • Interacts with digitalis to slow conduction velocity in the AV node heart block Adenosine • Activates K+ channels to reduce ERP • Blocks Ca2+ channels at the AV node • Indicated for supraventricular tachycardia • Purinergic (P1) receptor Digitalis • Enhances vagal parasympathetic activity to slow conduction at the AV node • Indicated for atrial fibrillation and SVT to control ventricular response rate Magnesium Sulfate • Indicated for torsades de pointes • Mechanism of action is unknown