Clinical pharmacokinetics of the newer antiarrhythmic agents

Abstract

This article reviews clinical pharmacokinetic data on 8 new antiarrhythmic agents. Some of these drugs have been studied extensively while others are relatively new, with incomplete data due to limited evaluation. Amiodarone is a class III antiarrhythmic drug which is effective in treating many atrial and ventricular arrhythmias that are refractory to other drugs. Amiodarone accumulates extensively in tissues and its disposition characteristics are best described by models with 3 and 4 compartments. Its apparent volume of distribution is very large (1300 to 11,000L) and its elimination half-life very long (53 days). A delay of up to 28 days from of treatment to onset of antiarrhythmic effect may be observed, and the antiarrhythmic effect may persist for weeks to months following cessation of therapy. Clinically significant drug interactions have been observed with amiodarone and warfarin, digoxin, quinidine and procainamide. Encainide is a class Ic antiarrhythmic drug. Although it has a short elimination half-life (1 to 3h), 2 major metabolites with antiarrhythmic effects accumulate in the plasma of patients during long term therapy. Plasma concentrations of O-demethyl encainide appear to correlate with the antiarrhythmic effect. Flecainide, another class Ic antiarrhythmic agent, has an elimination half-life of 14 hours which makes it suitable for twice daily dosing. Flecainide elimination is prolonged in patients with low output heart failure. Significant drug interactions with digoxin and cimetidine have been reported. Lorcainide is also a class Ic antiarrhythmic drug, the bioavailability of which is nonlinear. Clearance of the drug is reduced during long term therapy. A major active metabolite, norlorcainide, accumulates in the plasma of patients during long term therapy and its concentration exceeds that of lorcainide by a factor of 2. The elimination half-lives of lorcainide (9h) and norlorcainide (28h) allow for once or twice daily dosing. Mexiletine, a class Ib antiarrhythmic drug, is structurally similar to lignocaine (lidocaine). A sustained release formulation provides effective plasma concentrations when administered twice daily. The apparent volume of distribution of mexiletine is 5.0 to 6.6 L/kg, and the elimination half-life varies from 6 to 12 hours in normal subjects and from 11 to 17 hours in cardiac patients. Mexilitine is extensively metabolised but the metabolites are not pharmacologically active. Renal elimination of mexiletine is pH dependent. Drugs which induce hepatic metabolism significantly alter the pharmacokinetics of mexiletine.(ABSTRACT TRUNCATED AT 400 WORDS)