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Encainide1 is an antiarrhythmic drug with class IC activity which has been used in the treatment of life-threatening ventricular arrhythmias, symptomatic ventricular arrhythmias and supraventricular arrhythmias. The antiarrhythmic activity is due to the parent drug and its two principal active metabolites, and in the extensive metabolising phenotype (90% of patients), metabolites are present in plasma at higher concentrations than encainide itself Encainide produces little haemodynamic change in patients with left ventricular dysfunction and thus has considerable therapeutic potential in view of its efficacy in patients with ventricular tachycardia, premature ventricular complexes and the Wolff-Parkinson-White syndrome. However, this potential is reduced by a tendency for encainide to aggravate arrhythmia in a proportion of patients. At present there is no reliable method of identifying patients at risk for this potentially serious side effect. The most common non-cardiac side effects are dizziness and blurred vision which seldom necessitate withdrawal of treatment.
Thus, encainide has proved effective in controlling ventricular tachyarrhythmias including those which have not been controlled by other antiarrhythmic drugs.
In a variety of studies of isolated cardiac tissue, the predominant effect of encainide and its metabolites was a significant decrease in maximum upstroke velocity of cardiac action potential indicative of a reduction in peak inward sodium current during depolarisation. Of the active metabolites of encainide, O-demethylencainide (ODE) and 3-methoxy-O-demethylencainide (MODE), ODE has the greater efficacy. In intact animal models, single intravenous doses of encainide prolonged His-Purkinje conduction time (HV interval) and intraventricular conduction time (QRS duration), but not refractoriness. However, 45 minutes after infusion, refractory periods of atrium and ventricle were prolonged, suggesting accumulation of the active metabolites, which were found more active than the unchanged drug in slowing conduction. In humans, as in animals, the electrophysiological effects of encainide after oral administration, or at least 30 minutes after intravenous infusion, differ from those immediately following intravenous injection.
Encainide differs from conventional sodium channel antagonists, such as quinidine, procainamide and disopyramide, in that it affects the ventricular refractory period to a lesser extent, is devoid of anticholinergic effects, and influences accessory pathway characteristics in patients with Wolff-Parkinson-White syndrome.
Encainide demonstrated antiarrhythmic properties in a variety of animal models, which has been confirmed in patients with ventricular or supraventricular arrhythmias. Administration of ODE and MODE to animals has clearly demonstrated their antiarrhythmic activity, although such activity is also exhibited by encainide itself.
When administered orally at dosages required to control ventricular arrhythmias encainide generally had little effect on haemodynamic variables and did not influence left ventricular function in patients with mild to moderate congestive heart failure. Radionuclide ventriculograms revealed no significant changes in ejection fraction or double product during exercise or at rest following encainide at a mean dose of 75mg 4 times daily orally.
The pharmacology of encainide is influenced by the formation of active metabolites and the effects of genetic polymorphism of the debrisoquine/sparteine type on the metabolism and disposition of the drug. Absorption is almost complete after oral administration and peak plasma concentrations of encainide are attained in 1.1 to 3 hours, whereas those of the metabolites occur at a mean of 1.4 (ODE) and 5.7 hours (MODE). Mean steady-state plasma concentrations of ODE and MODE are 3 to 5 times higher than those of encainide in extensive metabolisers (90% of the Caucasian population), although this ratio is roughly reversed in poor metabolisers. The lower systemic bioavailability in extensive metabolisers (mean 26 to 30%) than in poor metabolisers (mean 83 to 88%) indicates that there is extensive ‘first-pass’ extraction in the extensive metabolisers. Protein binding is similar in both phenotypes, however. The pattern of urinary excretion of encainide differs according to phenotype, with ODE accounting for about 20% of the total dose recovered in urine in 24 hours in extensive metabolisers and for 5% of the dose in poor metabolisers. The pattern of excretion of other metabolites also differs. Although the phenotypic differences in the metabolism of encainide are important to the pharmacokinetic profile, their clinical significance is less clear. In fact, suppression of arrhythmias in poor metabolisers may be expected at the same dosages that are effective in extensive metabolisers, since plasma concentrations of encainide in poor metabolisers reach high levels. The elimination half-life of encainide in extensive metabolisers is short (about 2 hours), whereas that of the metabolites is much longer (5 to 37 hours for ODE). Consequently the metabolites cumulate during repeated oral administration. In poor metabolisers, however, the half-life of encainide is prolonged on average to between 11 and 22 hours.
Although patients with liver disease exhibit decreased oral and systemic clearance and increased oral bioavailability of encainide no significant change in dosage is required, whereas in patients with impaired renal function, changes in oral clearance, systemic bioavailability, and steady-state volume of distribution of the active metabolites necessitate a reduction in dosage to about one-third that in patients with normal renal function.
The majority of patients treated with encainide have presented with arrhythmias that were not controlled by previous treatment with other antiarrhythmic drugs.
In a few comparative trials, the efficacy of encainide was at least equivalent to that of disopyramide and quinidine with respect to the proportion of patients who responded with a 75 to 80% or greater reduction in the frequency of premature ventricular complexes per hour. However, in these few studies encainide was superior to either disopyramide or quinidine in completely suppressing arrhythmias. Initial findings indicate that encainide remains effective during long term treatment, but these results in patients with ventricular ectopy require confirmation in double-blind trials comparing encainide with other antiarrhythmic drugs in larger numbers of patients.
Several studies in patients with heart disease and symptomatic ventricular tachycardia or ventricular fibrillation have found encainide 50 to 200mg daily to be effective in suppressing arrhythmias in about 50% of patients, nearly all of whom had not responded to treatment with other drugs. These results obtained during both short term and longer periods of oral administration are encouraging. However, the risk of aggravation of preexisting arrhythmias appears greatest in over patients presenting with cardiomyopathy and/or sustained ventricular tachycardia. Since these events cannot be reliably predicted, further investigation into methods of minimising aggravation is needed.
Encainide has also been effective in preventing recurrence of a variety of supraventricular arrhythmias, usually in over 60% of patients, including those with Wolff-Parkinson-White syndrome. Initial studies in children with medically refractory supraventricular tachycardia have also been promising, and if initial results are confirmed in comparative trials, encainide could become a treatment of choice in view of its minimal haemodynamic effects.
The most common non-cardiac side effects associated with usual therapeutic doses of encainide are blurred vision, dizziness (7 to 10%) with headache, nausea and taste perversion occurring in 2 to 3% of patients. Like other antiarrhythmic drugs, encainide has the potential to aggravate and provoke cardiac arrhythmias and in comprehensive analyses of patients treated to date the overall incidence of proarrhythmic events (new arrhythmias, increased frequency of pre-existing arrhythmia, conversion from non-sustained to sustained ventricular tachycardia, incessant arrhythmia) has been about 9 to 16%. Overall, the incidence of such events has decreased in studies initiated since 1983, compared with the incidence in earlier studies, when dosage regimens were modified. Encainide has seldom aggravated congestive heart failure and is generally well tolerated by the elderly.
Dosage and Administration
The recommended initial dosage in adults with ventricular arrhythmias is 25mg 3 times daily. The dose can be increased to 35mg 3 times daily after 3 to 5 days and then, if necessary, to 50mg 3 times daily. The usual maximum recommended dose is 200mg daily in 4 divided doses. In patients with life-threatening (malignant) arrhythmias, treatment should be initiated where cardiac monitoring and advanced life support systems are available. Dosage adjustment is required in patients with moderate to severely impaired renal function.
KeywordsVentricular Tachycardia Ventricular Arrhythmia Antiarrhythmic Drug Disopyramide Extensive Metabolisers
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