CLINICAL PHARMACOLOGY
Mechanism of Action
The mechanisms of the antiarrhythmic effects of ENKAID are unknown but probably are the result of its ability to slow conduction, reduce membrane responsiveness, inhibit automaticity, and increase the ratio of the effective refractory period to action potential duration. ENKAID produces a differentially greater effect on the ischemic zone as compared with normal cells in the myocardium. This could result in the elimination of the disparity in the electrophysiologic properties between these two zones and eliminate pathways of abnormal impulse conduction, development of boundary currents and/or sites of abnormal impulse generation.
Electrophysiology
ENKAID is a Class IC antiarrhythmic agent, ie, is a blocker of the sodium channel of Purkinje fibers and the myocardium.
In isolated Purkinje and myocardial cells its electrophysiologic profile is characterized by a dose-related slowing of phase 0 depolarization and little effect on either the action potential duration or repolarization. This profile differs from that of Class IA drugs (eg, quinidine, disopyramide, procainamide) that slow phase 0 depolarization and prolong action potential duration or Class IB agents (eg, lidocaine, tocainide and mexiletine) that slow phase 0 depolarization only slightly and shorten the action potential duration.
In the intact animal and man, the electrophysiologic effects of encainide are a result not only of encainide but of two metabolites as well, each of which is present in most patients (over 90%) at therapeutically active levels. Encainide and its metabolites produce a dose-related decrease in intracardiac conduction in all parts of the heart, with slowing of conduction in the His-Purkinje system and AV node and an increase in the refractoriness of the atrium and ventricle. (See WARNINGS: Electrocardiographic Changes.)
Each variable studied in normal and ischemic tissues is altered in the same manner in both, but more markedly in ischemic tissues.
ENKAID has also been shown to slow conduction and increase refractoriness in accessory atrioventricular pathways and in the AV node.
HEMODYNAMICS
In oral studies of hemodynamic effects, using invasive and noninvasive measurements of cardiac function. ENKAID had no effects on measurements of cardiac performance such as cardiac or stroke volume index, pulmonary capillary wedge pressure or peripheral blood pressure either at rest or during exercise. In noninvasive studies that included both geriatric patients and younger patients with impaired left ventricular function (New York Heart Association Class III & IV) there were no detrimental effects on ejection fractions acutely or after more than 12 months of therapy in some cases. Doses of 75-300 mg/day of ENKAID, which reduced the incidence of premature ventricular complexes by at least 80%, did not adversely affect exercise tolerance, and were well tolerated clinically by patients with markedly impaired left ventricular function. In a few instances, however, apparent new or worsened congestive heart failure has developed during treatment with ENKAID (See WARNINGS).
CLINICAL ACTIONS
Although ENKAID should not be used for the treatment of nonlife-threatening arrhythmias, in premarketing, placebo-controlled trials ENKAID caused a dose-related reduction in the occurrence of single, repetitive and multiform premature ventricular complexes. ENKAID has been shown to reduce the incidence of nonsustained ventricular tachycardia. Doses of 75-150 mg per day were needed in most patients to attain 75% or greater suppression. In programmed electrical stimulation studies, ENKAID has prevented the induction of ventricular tachycardia in about 20% to 30% of the patients. ENKAID has also been shown to reduce the recurrence of sustained ventricular tachycardia in patients with a history of malignant arrhythmias.
ENKAID is effective in treating ventricular arrhythmias in patients with and without organic heart disease and has frequently been effective in patients who were unresponsive to, or intolerant of, one or more other antiarrhythmic agents.
When ENKAID therapy was discontinued, such as during placebo phases in the premarketing clinical trials, ventricular ectopy returned to rates that did not differ significantly from the baseline values. That is, no clinical evidence of arrhythmia exacerbation or “rebound” has been noted following discontinuation.
PHARMACOKINETICS
The absorption of ENKAID after oral administration is nearly complete with peak plasma levels present 30 to 90 minutes after dosing.
There are two major genetically determined patterns of encainide metabolism. In over 90% of patients the drug is rapidly and extensively metabolized with an elimination half-life of 1 to 2 hours. These patients convert encainide to two active metabolites, O-demethylencainide (ODE) and 3-methoxy-O-demethylencainide (MODE), that are more active (on a per mg basis) than encainide itself. These metabolites are eliminated more slowly than encainide, with half-lives of 3 to 4 hours for ODE and 6-12 hours for MODE. A radiolabeled dose of encainide is excreted in approximately equal amounts in the urine and feces. A major urinary metabolite is ODE, with lesser amounts of encainide and MODE present.
In less than 10% of patients, metabolism of encainide is slower and the estimated encainide elimination half-life is 6 to 11 hours. Slow metabolism of encainide is associated with a diminished ability to metabolize debrisoquin. In these patients the renal excretion of encainide is a major route of elimination and little if any MODE and only small amounts of ODE are present in their plasma.
Despite the differences in pharmacogenetics, in all patients 3 to 5 days of dosing are required to achieve steady state conditions. Based on clinical experience and pharmacokinetic considerations, the recommended dosage regimen (see DOSAGE AND ADMINISTRATION) is appropriate for all patients regardless of their genetically determined capacity to metabolize encainide.
Encainide, ODE, and MODE follow a nonlinear pharmacokinetic disposition, although ODE and MODE differ from linearity only to a small extent. The absorption of ENKAID is retarded by food, but the overall bioavailability is not altered. The pharmacokinetics of ENKAID do not change with increasing age over 21, and are not different between men and women.
The clearance of encainide and conversion to active metabolites is reduced in patients with hepatic disease, but serum concentrations of ODE and MODE are similar to those in normal patients. There is insufficient experience to be certain about the need for alteration in the normal dose and/or dosing interval when ENKAID is administered to patients with hepatic disease, but it is prudent to increase doses cautiously.
The clearance of encainide is reduced, and plasma levels of the active metabolites ODE and MODE are increased in patients with significant renal impairment and the dosage should be reduced in these patients (see PRECAUTIONS).
Encainide and ODE are bound to a moderate extent to plasma proteins (75%-85%) while the binding of MODE, at about 92%, is somewhat greater.
For information on potential drug interactions see PRECAUTIONS: Drug Interactions.
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