Propafenone

Abstract

Propafenone¹ is a Class I antiarrhythmic agent with weak β-adrenoceptor antagonist activity which can be given both intravenously and orally. Dosage must be individualised because of dose-dependent pharmacokinetics, a wide range of clinically effective plasma concentrations (64 to 3271 µg/L) after comparable doses, the presence of an active metabolite (5-hydroxy-propafenone) and genetically determined metabolic oxidation. In non-comparative studies propafenone 450 and 900 mg/day orally significantly suppressed premature ventricular complexes and couplets in 96% and 75% of patients, respectively, and abolished ventricular tachycardia in 75% of patients. Efficacy was confirmed in placebo-controlled studies in which propafenone 300 to 900mg daily suppressed premature ventricular complexes (> 80%) in 77% of patients; 87% of patients had significant reductions in couplets and abolition of ventricular tachycardia. In patients with ventricular arrhythmias refractory to other antiarrhythmic agents, propafenone 450 to 1200 mg/day suppressed arrhythmias in 63% of patients (in long term therapy 66%). Electrically induced arrhythmias were prevented by intravenously administered propafenone in 12 to 23% of patients. However, long term oral therapy was effective in 77% of patients selected using programmed electrical stimulation. Propafenone was also effective in suppressing atrial and AV nodal/junctional re-entrant tachycardias and Wolff-Parkinson-White tachycardias involving accessory pathways. A limited number of comparisons with other antiarrhythmic drugs indicate that the antiarrhythmic efficacy of propafenone is superior or similar to that of quinidine, disopyramide and tocainide, and comparable to that of lignocaine (lidocaine), flecainide and metoprolol against ventricular arrhythmias and a smaller number of atrial arrhythmias. Cardiovascular side effects indicate a proarrhythmic effect similar to that with other Class I drugs, occasional precipitation of congestive heart failure and conduction abnormalities; the latter two occur more often in patients with underlying ventricular dysfunction. Non-cardiovascular side effects (neurological, gastrointestinal) are well tolerated and generally resolve with continued therapy or dosage reduction. Thus, propafenone is an effective antiarrhythmic agent, and is a useful addition to currently available drugs, although further studies will be required to determine clearly its place in therapy compared with more established antiarrhythmic drugs. In isolated tissues propafenone caused a dose-dependent decrease in the maximum rate of depolarisation and in the overshoot of the action potential; His-Purkinje (H-V) conduction is slowed and QRS widened in sinus rhythm, indicating Class Ic antiarrhythmic activity. Propafenone also exhibits weak β-adrenoceptor antagonist activity and to a lesser extent Class III and IV activity. In intact animals, the 5-hydroxy metabolite of propafenone (more potent antiarrhythmic) caused more marked prolongation of conduction time than the parent drug. In healthy volunteers, PR interval increased significantly with a small change in QRS duration. In patients with ventricular arrhythmias, propafenone consistently increased the atrioventricular nodal conduction time (A-H) and H-V intervals, the effective refractory period in atria and ventricles, the PR interval (16 to 28%) and the QRS duration (18 to 23%). No effect was seen on sinus cycle length. In patients with underlying conduction abnormalities, conduction slowing with propafenone was more marked indicating that it should be used with caution in patients with sinus node dysfunction. In patients with Wolff-Parkinson-White (WPW) syndrome, propafenone reduces conduction and increases refractoriness in the accessory pathway. Mean arterial pressure and heart rate were unchanged in patients, although intracardiac pressures were slightly increased resulting in depression of cardiac index; pulmonary and systemic vascular resistances were increased. In patients with impaired left ventricular function (ejection fraction less than 50%), a significant reduction in ejection fraction occurred, while in those with ejection fraction greater than 50% no change occurred. Propafenone can be administered both intravenously and orally. The pharmacokinetic properties of propafenone differ in extensive and poor metabolisers (defined by their ability to metabolise debrisoquine). It is well absorbed with peak plasma concentration occurring at 2 to 3 hours after administration. In extensive metabolisers a dose-dependent increase in peak plasma concentration and area under the curve occurs with increasing dose [10-fold increase in peak plasma concentration occurred with a 3-fold (300 to 900 mg/day) increase in oral dose]. Steady-state plasma concentrations on 900 mg/day ranged from 482 to 1812 µg/L (mean 1008 µg/L). Bioavailability for the 150mg tablets was 4.8% and for the 300mg tablet 12% indicating extensive presystemic metabolism. The pharmacokinetics following intravenous administration are best represented by a 2-compartment model. Mean plasma elimination half-life following intravenous administration is 2.8 hours in healthy volunteers, 5 hours in patients and 16.8 hours in poor metabolisers (depends on oxidative status). In poor metabolisers, however, plasma concentrations rose proportionally with dose and half-life is about 17 hours. During long term oral administration half-life was 6.2 hours in extensive metabolisers although there was large intersubject variability and values ranged from 2.4 to 11.8 hours. Mean total body clearance was 0.68 L/h/kg. Volume of distribution is 1.1 L/kg in healthy volunteers and 3.6 L/kg in patients. Protein binding ranges from 77 to 89%; propafenone binding to α₁-acid glycoprotein is more marked than that with lignocaine, verapamil and propranolol. The major metabolites are conjugates of 5-hydroxy-propafenone and N-depropylpropafenone. Less than 1% of propafenone is excreted unchanged in urine. The 5-hydroxy metabolite has been reported to have greater antiarrhythmic efficacy than propafenone in extensive metabolisers, but since it achieves concentration in plasma about one-fifth those of the parent drug, its therapeutic role is not clear. Lower doses of propafenone are required in elderly patients. Under steady-state conditions the plasma concentration of propafenone that suppressed premature ventricular contractions by over 70% has ranged between 42 and 1700 µg/L in different studies. Thus, there is a need for individualised dosage. Propafenone administered orally and intravenously has been evaluated for suppression of premature ventricular complexes, couplets and ventricular tachycardia in non-comparative and a limited number of double-blind comparative trials. Results in non-comparative studies indicate that propafenone 450 to 900 mg/day significantly suppressed premature ventricular complexes in 96% of patients and couplets in 75% of patients; ventricular tachycardia was abolished in virtually 100% of patients. Dose-dependent suppression of ventricular arrhythmias over the range of 450 to 900mg daily occurred in one study, and during a 12-month follow-up the frequency of arrhythmias decreased by over 80% in 10 of 13 patients. In placebo-controlled, crossover studies, the frequency of premature ventricular complexes was reduced by over 80% in 77% of patients, with 87% of patients having significant reductions in couplets and abolition of ventricular tachycardia. If the patients were ‘selected’ on the basis of their response to an initial screening with intravenous or oral propafenone, generally such patients were well controlled with significant suppression of arrhythmias. In patients with drug refractory ventricular arrhythmias propafenone 450 to 1200 mg/day was effective in suppressing arrhythmias in 63% of patients. In long term follow-ups (12 to 16 months), effective control was maintained in 66% of patients. In long term studies in patients selected on the basis of the ability to prevent arrhythmias induced by using programmed electrical stimulation, 77% of patients were either symptom-free or had no arrhythmias. Propafenone administered intravenously and orally was effective in about 50 to 70% of small numbers of patients with atrial tachycardias, AV nodal/junction re-entrant tachycardias and WPW tachycardias involving accessory pathways; during long term follow-up with propafenone 85% of patients were improved or asymptomatic. Comparisons with other antiarrhythmic agents demonstrated that propafenone was superior or comparable in efficacy to quinidine and disopyramide and comparable to lignocaine, tocainide, mexiletine, flecainide and metoprolol in suppressing ventricular and a small number of supraventricular arrhythmias. The combination of propafenone and a β-adrenoceptor antagonist significantly improved efficacy relative to either drug alone in ventricular arrhythmias. Cardiovascular side effects associated with propafenone include proarrhythmic effects in about 12% of patients as well as less frequent instances of sudden death, bundle branch block, AV block and induction of congestive heart failure. Conduction abnormalities and congestive heart failure with propafenone occur more often in patients with underlying dysfunction. Non-cardiovascular side effects (neurological and gastrointestinal mainly) are usually well tolerated and often resolve with continued therapy or dosage reduction. Such effects include dizziness, visual disturbances, metallic taste, nausea and constipation, and less commonly abnormal liver function tests, leucopenia and rash. Overall, only a small proportion (< 3%) of patients discontinued studies due to side effects. As propafenone can cause conduction abnormalities and may have negative inotropic effects in patients with underlying ventricular dysfunction, care must be taken when administering other cardioactive drugs with similar properties. The extensive metabolism, high protein binding and dose-dependent kinetics of propafenone suggest its potential for drug interactions. Interactions that have been reported include inhibition of debrisoquine metabolism by propafenone and an increase in plasma digoxin concentration not associated with digitalis toxicity. A possible interaction between propafenone and digoxin in patients receiving low dose diuretic therapy was suggested. Whole body potassium and magnesium depletion may have existed, thus possibly contributing to proarrhythmic events. β-Adrenoceptor antagonists combined with propafenone increased antiarrhythmic efficacy. Propafenone dosage should be adjusted to each patient’s needs. Selection of patients on the basis of the response to an initial oral or intravenous dose of propafenone and/or based on the ability of propafenone to prevent arrhythmias induced by programmed electrical stimulation prior to long term therapy improves the response rate. Care must be taken in patients with already compromised left ventricular function or conduction dysfunction as propafenone may potentiate these. In both ventricular and supraventricular arrhythmias intravenous administration of 1 to 2.5 mg/kg and oral administration of 300 to 900 mg/day (divided dose) is effective.