Dept. of Pharmacology Faculty of Medicine AIMST Antiarrhythmic Drugs Dept. of Pharmacology Faculty of Medicine AIMST

Antiarrhythmic Drugs Lecture Objectives Cardiac Arrhythmias-What are they? Antiarrhythmic Drugs-Classification (Vaughan Williams/Sicilian Gambit/Miscellaneous agents) Pharmacology & uses of : Class I agents (Quinidine/Lidocaine/Phenytoin) Class II agents (Propranolol/Esmolol) Class III agents (Amiodarone) Class IV agents (Verapamil) Miscellaneous agents (Digoxin/Adenosine)

Cardiac Arrhythmias Definition Disorders of within the heart Rate Rhythm Impulse generation or Impulse conduction within the heart Arrhythmias disruption of normal sequence of myocardial activation seriously compromising cardiac mechanical efficiency reducing cardiac output

Antiarrhythmic Drugs Vaughan Williams Classification Class I (Na+ channel blockers) Ia (blocks conduction, ↑ERP) Quinidine Procainamide Disopyramide Ib (blocks conduction, ↓ERP) Lidocaine Mexiletine Phenytoin Ic (blocks conduction, no effect/↑ERP) Encainide Flecainide Propafenone Moricizine

Antiarrhythmic Drugs Vaughan Williams Classification Class II (β-adrenoceptor blockers) Propranolol l -Sotalol Esmolol Class III (K+ channel blockers) Amiodarone Bretylium d -Sotalol N-acetyl-procainamide(Acecainide) Dofetilide Ibutilide

Antiarrhythmic Drugs Vaughan Williams Classification Class IV (Ca2+ channel blockers) Verapamil Diltiazem Bepridil

Antiarrhythmic Drugs Miscellaneous Adenosine Digoxin Magnesium, etc.

Antiarrhythmic Drugs-Major Pharmacological & Electrophysiological Actions Class I Slowing/blocking conduction Class II ↓ SA nodal automaticity Sympatholytic activity Class III No effect on conduction Delay repolarization Class IV Slows conduction velocity in AV node

Antiarrhythmic Drugs (Class Ia) Quinidine Chemistry Dextro isomer of the alkaloid quinine Pharmacological Actions Cardiac Blocks Na+ channels ↓Phase 0 slope (atria/ventricles/Purkinje fibres) ↓Conduction velocity ↑ ERP → ↑ APD

Antiarrhythmic Drugs (Class Ia) Quinidine Pharmacological Actions Extracardiac Quinidine → α-blockade→ Vasodilation ↑ SA node rate ↓ PVR Quinidine ↓ conc. ↑ conc. Indirect Direct effect anticholinergic on cardiac myocytes effects predominate

Antiarrhythmic Drugs (Class Ia) Quinidine Pharmacokinetics Rapidly absorbed from GIT 80% PPB Hepatic metabolism Renal excretion Therapeutic Uses Atrial Fibrillation Atrial Flutter PSVT Premature Ventricular Contractions VT

Antiarrhythmic Drugs (Class Ia) Quinidine Adverse Effects Cardiac AV block ↓ myocardial contractility ↑ cardiac ERP ↑ APD ↑ QT interval ↑ Ventricular tachyarrhythmias (Torsades de pointes) Quinidine Syncope

Antiarrhythmic Drugs (Class Ia) Quinidine Adverse Effects Cardiac -ve inotropic action ↓ BP Cardiac failure GIT Nausea/Vomiting/Diarrhea Cinchonism Tinnitus/Headache

Antiarrhythmic Drugs (Class Ia) Quinidine Drug Interactions Quinidine increases plasma Digoxin concentrations (due to displacement from tissue binding + impairment of renal excretion) DOSE OF DIGOXIN SHOULD BE DECREASED WHEN THE DRUGS ARE USED TOGETHER

Antiarrhythmic Drugs (Class I b) Lidocaine Used principally for ventricular arrhythmias Kinetics makes it unsuitable for oral administration (the drug undergoes extensive presystemic (first-pass) hepatic elimination) Used by the i.v., or occasionally the i.m. route Adverse reactions uncommon unless there is significant cardiac failure or infusion is rapid Adverse effects include hypotension, dizziness, blurred sight, sleepiness, slurred speech, numbness, sweating, confusion and convulsions

Antiarrhythmic Drugs (Class Ib) Phenytoin Orally active anticonvulsant Antiarrhythmic properties similar to those of lidocaine Used to treat ventricular arrhythmias, digitalis overdose-induced arrhythmias, and torsades de pointes

Antiarrhythmic Drugs (Class II) Propranolol Pharmacological Actions β-adrenergic receptor blocker ↓ myocardial contractility (-ve inotropic action) ↓ heart rate (-ve chronotropic action) ↓ Automaticity ↓ Phase 4 slope of diastolic depolarization ↓ AV conduction

Antiarrhythmic Drugs (Class II) Propranolol Therapeutic Uses Supraventricular arrhythmias Re-entry arrhythmias Digoxin-induced arrhythmias Adverse Effects Sedation/Sleep disturbances/Depression Worsening of pre-existing asthma & other forms of airway obstruction Severe hypotension/bradycardia/Heart block or cardiac arrest (from over dosage) Heart failure

Antiarrhythmic Drugs (Class II) Esmolol Pharmacological Actions Very short-acting β1-selective blocker (half-life ~ 9 min) Solely used in cardiac arrhythmias (for intraoperative & other acute arrhythmias) Concomitant IV administration of calcium channel blockers that affect cardiac conduction (e.g. Verapamil, Diltiazem) may lead to intense bradycardia and risk of AV block

Antiarrhythmic Drugs (Class II & III) Sotalol Pharmacological Effects l-Sotalol β-adrenergic blocking activity d-Sotalol Block K+ channels ↓ K+ outward current during repolarization Prolong repolarization ↑ cardiac APD & ERP

Antiarrhythmic Drugs Sotalol (Class II & III) Therapeutic Uses Life-threatening ventricular arrhythmias Maintenance of sinus rhythm in patients with atrial fibrillation Treatment of supraventricular and ventricular arrhythmias in pediatric age group Adverse Effects Extension of its pharmacologic actions Torsade de pointes (dose-dependent)

Antiarrhythmic Drugs (Class III) Amiodarone Pharmacological Actions Possess Class I, II, III & IV actions (broad spectrum) Blocks K+ channels Prolong repolarization ↑ ↑ cardiac APD & ERP

Antiarrhythmic Drugs (Class III) Amiodarone Therapeutic Uses Used in management of severe refractory atrial & ventricular tachyarrhythmias Maintaining normal sinus rhythm in patients with atrial fibrillation (in low doses: 100-200 mg/d) Prevention of recurrent VT

Antiarrhythmic Drugs (Class III) Amiodarone Side Effects Symptomatic bradycardia/Heart block/Polymorphic VT Reversible pulmonary fibrosis Hepatitis Corneal micro deposits (asymptomatic)/Optic neuritis/Blurred vision Skin deposits/photodermatitis/gray-blue discoloration Thyroid abnormalities

Antiarrhythmic Drugs (Class IV) Verapamil Chemistry Phenylalkylamine L-type Ca2+ channel blocker Pharmacological Actions ↓ Ca2+ entry in pacemaker cells (SA & AV nodes) ↓ automaticity

Antiarrhythmic Drugs (Class IV) Verapamil Pharmacological Actions (contd.) ↓ Ca2+ entry via L-type channels into cardiac myocytes ↓ myocardial contractility(-ve inotropic action) ↓ AV node ↓ Re-entry

Antiarrhythmic Drugs (Class IV) Verapamil Therapeutic Uses Supraventricular arrhythmias Re-entrant supraventricular tachycardia Reducing ventricular rate in Atrial Flutter/Atrial Fibrillation Less effective in ventricular arrhythmias Adverse Effects Nausea/Constipation/Headache/Lassitude/ Hypotension/Bradycardia/Heart block

Antiarrhythmic Drugs- Digoxin Therapeutic Uses Atrial Fibrillation/Atrio-ventricular Nodal Tachycardia Digoxin ↑ ERP of AV node ↓ Cond. velo. at AV node ↓ ventricular rate ↓ fatal VF/VT Paroxysmal Atrial Tachycardia

Antiarrhythmic Drugs- Adenosine Chemical Nature Endogenous purine nucleoside Rapidly metabolized by circulating adenosine deaminase Mechanism of Action Activation of an inward rectifier K+ current Hyperpolarization Inhibition of Ca2+ current Suppression of Ca2+ dependent action potentials

Antiarrhythmic Drugs Adenosine (contd.) Pharmacological Actions Brief residence in plasma (several seconds) Slows/Inhibits AV nodal conduction Increases AV nodal refractory period Therapeutic Use Prompt conversion of Paroxysmal Supraventricular Tachycardia to sinus rhythm (90-95% efficacy) A-V Nodal Reentrant Tachycardia & A-V Reciprocating Tachycardia

Antiarrhythmic Drugs Adenosine (contd.) Adverse Effects Flushing (~ 20% patients)/Shortness of breath/Chest burning (perhaps related to bronchospasm)/High-grade AV block/ Headache/Hypotension/Nausea/Paresthesias Drug Interactions Adenosine less effective in presence of adenosine receptor blockers (e.g., Caffeine, Theophylline) Potentiation of action in the presence of adenosine uptake inhibitors (e.g., Dipyridamole)

Antiarrhythmic Drugs Lecture Summary Cardiac Arrhythmias-What are they ? Antiarrhythmic Drugs-Classification Vaughan Williams Sicilian Gambit Miscellaneous agents Class I agents-Quinidine/Lidocaine/ Phenytoin Class II agents-Propranolol/Esmolol Class III agents-Amiodarone Class IV agents-Verapamil Miscellaneous- Digoxin/Adenosine

For Further Reading!.. Basic & Clinical Pharmacology by Bertram G. Katzung (9th Edition)(Chapter 14) Clinical Pharmacology by D. R. Laurence, P. N. Bennett & M. J. Brown (9th Edition) (Chapter 24) Goodman & Gilman’s The Pharmacologic Basis of Therapeutics (10th Edition)(Chapter 35) Drugs for the Heart by Lionel H Opie & Bernard J Gersh (6th Edition)(Chapter 8) Modern Pharmacology with Clinical Applications by Charles R Craig & Robert E Stitzel (6th Edition) (Chapter 16)