SynopsisAcecainide(N-acetylprocainamide), theN-acetylated metabolite of procainamide, is a Class III antiarrhythmic agent. It can be given either intravenously or orally, and is eliminated primarily by renal excretion. In a small number of noncomparative and placebo-controlled short term therapeutic trials acecainide markedly reduced premature ventricular beats and prevented induction of ventricular tachycardia in more than 70% of patients following intravenous administration and in about 50% after oral administration. Acecainide was effective in about one-quarter of patients refractory to other antiarrhythmic drugs. Interpretation of its effectiveness following long term oral therapy is complicated by the limited number of patients, and patients discontinuing due to adverse effects or lack of efficacy. However, about 40% of the small number treated for extended periods were controlled for periods of 6 months to 3 to 4 years. Comparative studies with other antiarrhythmic drugs have not been undertaken apart from a small study in atrial flutter where acecainide was better than quinidine plus digoxin. Thus, although further clinical experience is required before the relative place of acecainide in therapy can be determined, the drug nevertheless appears to offer advantages over procainamide, particularly with respect to the reduced formation of antinuclear antibodies.Pharmacodynamic PropertiesThe predominant effect of acecainide in isolated tissue and animal studies is a dose-dependent lengthening of the action potential duration and effective refractory period, indicating Class III antiarrhythmic activity (Vaughan Williams classification) with little or no effect on resting membrane potential, action potential amplitude or upstroke velocity (therefore apparently devoid of Class I activity). In patients with coronary artery disease, acecainide significantly increased corrected QT interval (QTc by 14%) and atrial (15%) and ventricular (8%) effective refractory periods. No changes occurred in sinus cycle length, sinus node recovery time, atrioventricular nodal conduction time, His-Purkinje conduction time, right intra-atrial conduction time, QRS conduction interval, atrioventricular nodal functional refractory period or Wenckebach cycle length; similar results were observed in patients with arrhythmias in whom increases in QTc ranged from 6 to 21%. In patients with bundle branch block or conduction dysfunction no worsening occurred, although 1 group of investigators suggested caution in patients with pre-existing His-Purkinje system disease.Haemodynamic studies in isolated and intact animal preparations demonstrated that acecainide has a small and short term positive inotropic effect at therapeutic plasma concentrations. These results were essentially confirmed in patients, with acecainide having no effect on heart rate and systolic blood pressure either at rest or during exercise, and no change in echocardiographic measurements of end diastolic dimension, end-systolic dimension, left ventricular internal diameter shortening, cardiac output or pulmonary artery pressure. The ratio of pre-ejection period to left ventricular ejection time (an indicator of left ventricular performance) was constantly reduced; this was accompanied by a significant decrease in pre-ejection period index, an increase in ejection time index and a decrease in systolic time intervals index. These results are compatible with acecainide being relatively free of myocardial depressant activity.Pharmacokinetic PropertiesIn healthy subjects, mean peak plasma concentrations following single oral doses of acecainide 1000mg were about 5.4 mg/L and were usually attained about 2.5 hours after administration. Similar values were reported in patients with cardiomyopathy. Plasma concentrations increased almost linearly with increasing dosages between 500 and 2500mg. Bioavailability in healthy subjects was 85%. At steady-state, volume of distribution was between 1.25 and 1.7 L/kg in healthy subjects and patients. Acecainide is 10% bound to plasma proteins. Some studies have noted that a small proportion of acecainide is converted to procainamide but this has not been a consistent finding. Acecainide, unlike procainamide, does not form a reactive metabolite, considered the initial step in procainamide-induced lupus. Renal clearance is generally reduced in patients with cardiomyopathy and ventricular arrhythmias and is dependent on creatinine clearance. Consequently, the elimination half-life has tended to be prolonged in patients relative to that in healthy subjects. Optimum therapeutic plasma concentrations have not been established.Therapeutic UseAcecainide has been investigated in a small number of noncomparative trials as well as in a few which were placebo controlled and has been compared with quinidine and procainamide in preliminary trials. Following intravenous administration spontaneously occurring premature ventricular contractions were significantly reduced in most patients and ventricular tachycardia abolished in about half of those treated. Arrhythmias following programmed electrical stimulation were prevented in about one-third of patients (2 studies) and ventricular tachycardia was induced at a slower rate. After short term oral administration, ventricular arrhythmias (premature ventricular contractions and ventricular tachycardia) were significantly reduced in about half of the patients including some of those patients whose arrhythmias were refractory to other antiarrhythmic drugs. Acecainide was effective in about one-quarter of the latter group of patients. Following long term administration of acecainide for periods ranging from 3 months to 3 to 4 years in responsive patients selected from previous short term studies, assessment of efficacy was complicated by the small numbers of patients, withdrawals, lack of continued efficacy in some cases, and a high incidence of sudden death. Results from the few long term studies reported indicate that about 40% of the patients involved remained controlled for periods of 6 to 48 months. However, the use of antiarrhythmic therapy in patients with asymptomatic arrhythmias is controversial.A preliminary short term comparative study suggested that acecainide was better tolerated and had greater efficacy than procainamide, while combined efficacy and tolerability with acecainide was significantly better than with quinidine plus digoxin in patients with atrial flutter. Acecainide has not been compared with other antiarrhythmic drugs and the dosage required to maintain antiarrhythmic effects is still not clear.Adverse EffectsThe predominant noncardiac adverse effects associated with acecainide administration involved the gastrointestinal tract (nausea, vomiting, diarrhoea) and the central nervous system (paraesthesias, fatigue, vivid dreams, light-headedness); the overall incidence ranged from 0 to 68%. Visual disturbances were also reported in 18% of patients. Systemic lupus erythematosus was not a common adverse effect with acecainide in comparison to the previously reported high incidence with procainamide. Worsening of arrhythmias, including the development of torsade de pointes, occurred in a small number of patients. There was a high incidence of sudden death among patients on long term oral therapy, although any direct association with acecainide therapy is unproven.Dosage and AdministrationThe dose of acecainide should be adjusted to control patients' arrhythmias with regard to their clinical state including age, renal function and concurrent administration of other drugs. Intravenous infusions of 0.45 mg/kg/min or 15 to 20 mg/kg appear to be effective in suppressing arrhythmias. For short term oral administration 1.5 to 2.0g as a single daily dose, or given as divided doses, appears to be satisfactory. However, in long term studies and in patients refractory to other antiarrhythmic drugs, doses were increased to 7.5 g/day. A number of studies indicated that tolerance developed and that higher doses were required with long term therapy. In those patients with decreased renal function, and possibly in the elderly, the dose should be decreased.