Antiarrhythmic Drugs

October 6, 2006 Frank F. Vincenzi

Antiarrhythmic drug list

adenosine (Adenocard) amiodarone (Cordarone) atropine bretylium (Bretylol) digoxin (Lanoxin) diltiazem (Cardizem)

isoproterenol (Isuprel) lidocaine (Xylocaine) procainamide (Pronestyl) propranolol (Inderal) quinidine (Quinidex) verapamil (Calan, Isoptin)

Fundamental features of cardiac excitation

Automaticity
capacity for self excitation

Excitability
ability to respond to stimuli and conduct action potentials

Refractory period
time following excitation during which a second action potential can not be elicited and conducted

Membrane responsiveness
relationship between membrane activation voltage and the maximal rate of rise of the action potential

Excitable tissues in heart

Slow response tissues (mainly Ca channels) SA node AV node Fast response tissues (mainly Na channels) atrium ventricle bundle of His Purkinje fibers

Typical action potential in SA nodal cells

Typical action potential in AV nodal cells

Typical action potential in cardiac muscle cells

Influence of diastolic membrane potential on action potential upstroke rate in a given cell: Membrane Responsiveness

Treatment for bradyarrhythmias

Atropine prevents vagally-induced inhibition of supraventricular pacemakers and vagally induced inhibition of AV nodal conduction Isoproterenol increases automaticity of all parts of the heart and promotes AV nodal conduction Artificial pacemaker - transvenous or or implantable

Treatment for tachyarrhythmias

Decrease automaticity of ectopic pacemakers (e.g., reflex activation of vagus, adenosine, quinidine, beta blockers, Ca channel blockers) Prevent re-entry excitation (lidocaine, amiodarone, quinidine, etc.) Partially block AV nodal conduction of supraventricular arrhythmias (digitalis, betablockers, Ca channel blockers)

Agents which partially block AV nodal conduction may be useful in the treatment of supraventricular tachyarrhythmias
Digitalis - by increasing vagal tone increases AV nodal refractory period Beta blockers - by preventing sympathetically mediated increases in AV nodal conduction slow or block conduction, also depress catecholamine augmented automaticity Ca channel blockers - by inhibiting Ca channels depress AV nodal conduction velocity and increase refractory period, also suppress automaticity

adenosine (unclassified)(suppresses automaticity)

Metabolite of ATP, etc., released in heart under conditions of ischemia (rapidly causes vasodilation) Increases potassium conductance and inhibits cAMP mediated increase in calcium influx Useful in the acute treatment of supraventricular tachyarrhythmias Extremely short half life, used IV only (also used as a test for coronary dilation)

Vaughan Williams Classification of Antiarrhythmic Drugs

I. Drugs with direct membrane action (e.g., Na channel blockade
A. moderate phase 0 depression B. minimal phase 0 depression, usually shorten repolarization C. marked phase 0 depression, little effect on repolarization

II. Sympatholytic drugs III. Drugs that prolong repolarization IV. Calcium channel blockers
For a less arbitrary classification based on arrhythmogenic mechanisms and potentially vulnerable parameters, see the report of the Task Force of the Working Group on Antiarrhythmias of the European Society of Cardiology, Circulation 84: 1831-1851, 1991

Examples of Antiarrhythmic Drugs According to the Vaughan Williams Classification

Class I A - quinidine, procainamide B - lidocaine C - (encainide, flecainide) Class II - propranolol Class III - amiodarone, bretylium Class IV - verapamil, diltiazem

Antiarrhythmic drugs: a common theme

Effective antiarrhythmic drugs increase the refractory period compared to action potential duration: ERP/APD

Relatively speaking, this gives more time for recovery of membrane potential and makes slow conduction less likely. Slow conduction is a formula for disaster.

quinidine (Class IA) (moderate inhibition of Na channels)

Generally useful in supraventricular arrhythmias
(decreases automaticity, increases refractory period)

Atropine-like properties
(may promote AV conduction - paradoxical tachycardia)

Mild adrenergic blockade

(hypotension)

High doses promote bizarre cardiac arrhythmias, torsades des pointes Cinchonism
GI upset, tinnitus, loss of hearing, blurred vision, headache, diplopia, delerium, psychosis, rarely thrombocytopenia

Quinidine decreases membrane responsiveness (moderate inhibition of Na channels)

Quinidine

Membrane Responsiveness: Relation between membrane activation voltage and max dV/dt

procainamide (Class IA) (moderate inhibition of Na channels)

Generally useful in ventricular arrhythmias Little or no atropine-like properties Cardiac toxicity, hypotension, CNS effects, rarely agranulocytosis or systemic lupus erythematosus (SLE)-like syndrome

lidocaine (class IB) (minor inhibition of [normal] Na channels)

Useful mainly in ventricular arrhythmias Minor effects on normal automaticity or membrane responsiveness, greatly suppresses membrane responsiveness in sick fibers (by binding to inactive Na channels) Major toxicity in CNS; disorientation, convulsions, respiratory arrest

Lidocaine decreases membrane responsiveness (selective inhibition of Na channels in depolarized cells)

Lidocaine

Class IC antiarrhythmics (major inhibition of Na channels)

Flecainide for prevention of paroxysmal atrial fibrillation (PAF) and paroxysmal supraventricular tachycardia (PSVT) prevention and ventricular arrhythmias. Flecainide and encainide (off market?) were associated with increased mortality
CAST, Cardiac Arrhythmia Suppression Trial Echt et al., Mortality and morbidity in patients receiving encainide, flecainide, or placebo, New Engl. J. Med. 324: 781-788, 1991.

Class IC antiarrhythmics: major inhibition of membrane responsiveness (major inhibition of Na channels)

Flecainide or encainide

beta-blockers (class II)

Decrease cardiac automaticity and contractility, partly by blocking beta-adrenergic receptors (& partly by direct effects on cardiac cell membranes). Antagonize the effects of catecholamines on Ca channels (reduce automaticity and slow conduction in partially depolarized cells and decrease myocardial contractility) Useful in supraventricular arrhythmias Increase effective refractory period of AV node AV block, asystole, sudden withdrawal can precipitate angina, arrhythmias or myocardial infarction Contraindicated in asthma (relatively for beta-1 selective), may mask tachycardia of hypoglycemia, CNS effects

amiodarone (Class III) (but also has Class I, II and IV effects)

A dirty drug, inhibits K channels, (delays repolarization), Na channels and Ca channels (slight), blocks betareceptors non-competitively, blocks alpha receptors, potent suppressor of ectopic automaticity (only rarely causes torsades des pointes), and some vagolytic effects. Approved for ventricular tachycardia, ventricular fibrillation and paroxysmal supraventricular tachycardia, used in other arrhythmias as well; has anti-anginal properties Adverse reactions (too many to list) occur in about 70% of patients, sufficient to cause discontinuation in 5-20%. Extremely long, biphasic, half life (initial about 10 days, terminal about 50 days), metabolized in liver, Vd ~ 70 l/kg

Amiodarone: selected adverse reactions (far too many to list)

ARDS Ataxia AV block Bronchiolitis obliterans Dyspnea Epididymitis Heart failure Hepatitis Hyper/hypothyroidism Macular degeneration Optic neuritis Pancreatitis Peripheral neuropathy Pneumonitis QT prolongation Sinus bradycardia Thrombocytopenia Torsade de pointes Toxic epidermal necrolysis Vasculitis

Amiodarone in out-of-hospital Resuscitation of REfractory sustained ventricular Tachyarrhythmias (ARREST) (504 pts, out of hospital arrest, >= 3 precordial shocks, 1 mg EPI, IV then:

Kudenchek et al., NEJM 341:871-878, 1999

bretylium (class III)

Effects on cardiac (ventricle >> atrium) cell membranes in addition to its effects on adrenergic nerve terminals Useful in drug resistant ventricular fibrillation (with cardioversion) or sustained ventricular tachycardia in intensive care situations Classified as an agent that prolongs action potential duration; actually increases ERP more than APD

verapamil (class IV)

Blocks mainly L-type calcium channels Decreases SA and Purkinje fiber automaticity, slows conduction through and increases refractory period of AV node Useful mainly in supraventricular arrhythmias or ventricular arrhythmias caused by coronary spasm GI disturbances, cardiac toxicity including heart failure, AV block

diltiazem (class IV)

Blocks mainly L-type calcium channels Decreases SA and Purkinje fiber automaticity, slows conduction through and increases refractory period of AV node Useful mainly in supraventricular arrhythmias or ventricular arrhythmias caused by coronary spasm GI disturbances, cardiac toxicity, including heart failure, AV block

Long QT syndrome: genetic &/or drug-induced

Oral erythromycin and the risk of sudden death from cardiac causes*
Erythromycin is metabolized by CYP3A4 Commonly prescribed drugs increase the AUC of erythromycin by at least 2-fold:
Nitroimidazole antifungals Diltiazem, Verapamil

Incidence ratio of sudden cardiac death was 5.35 (1.72-16.64, 95% CI) in patients using erythromycin and a CYP3A inhibitor
*Ray et al., NEJM 351:1089-1096, 2004

Drugs and the QT Interval - Caveat Doctor*

1A2
Amitriptyline, haloperidol, imipramine, clozapine

2C9
Amitriptyline, tamoxifen

2D6
Amitriptyline, desipramine, imipramine, haloperidol, thioridazine, tamoxifen

3A4
Cisapride, disopyramide, quinidine, pimozide, tamoxifen, erythromycin, clarithromycin

*Liu & Juurlink, NEJM 351: 1053-1056, 2004