Clinical pharmacology of propafenone.

Abstract

We determined the efficacy, pharmacokinetics, and plasma concentration-response relationships of propafenone, a promising new antiarrhythmic drug. Thirteen patients with frequent and complex ventricular premature beats were studied after receiving four increasing doses, during drug washout and during a randomized double-blind placebo-controlled trial, to evaluate the optimal dose in each patient. A nonlinear relationship was found between propafenone dose and steady-state mean concentration with a 10-fold increase in drug concentration as dose increased threefold from 300 to 900 mg/day. There was great intersubject variability in elimination half-life (mean 6 hr, range 2.4 to 11.8), steady-state mean concentration on 900 mg/day of propafenone (mean 1008 ng/ml, range 482 to 1812), and "therapeutic" plasma concentration (mean 588 ng/ml, range 64 to 1044). The interaction of these three parameters in individual patients determined the duration of the antiarrhythmic action of propafenone during washout (mean 11.5 hr, range 4 to 22). There was a greater than 90% reduction of ventricular premature beats in 10 subjects during dose ranging and in seven during double-blind crossover. Side effects requiring discontinuation of the drug occurred in three patients and included apparent worsening of arrhythmias in two. We conclude that propafenone effectively suppresses ventricular arrhythmias and that nonlinear drug accumulation and intersubject variability in elimination of half-life, steady-state mean plasma concentration, and therapeutic concentration indicate a need for individual therapy. Circulation 68, No. 3, 589-596, 1983. PROPAFENONE is a promising new antiarrhythmic drug. In microelectrode experiments with guinea pig atria and sheep Purkinje cells, the drug slows the rate of rise of the action potential and decreases the action potential duration.",2 Propafenone also has weak ,Bblocking and Ca+ + antagonist properties in isolated tissues.1 Initial placebo-controlled trials in humans show that propafenone is effective for suppressing ventricular ectopic activity.4' Previous studies suggest that propafenone has a short half-life of 3 to 4 hr but that the duration of its antiarrhythmic effects may last longer.6'7 Studies with limited data have yielded con flicting information on the ability to predict antiarrhythmic effect from propafenone concentration. between plasma concentration and antiarrhythmic effect. MethodsProtocol design. Patients with high-frequency ventricular premature beats (VPBs) were candidates for this study if they did not have disabling angina, heart failure, or unstable intercurrent illness. A complete history was obtained, physical and laboratory examinations were performed, and a baseline 48 hr ambulatory electrocardiogram (ECG) was taken to establish a minimum baseline VPB frequency of B 1440 VPBs/24 hr after antiarrhythmic drugs had been discontinued for at least five half-lives. Digoxin was continued in one patient with atrial fibrillation, and propranolol was continued in one pat...

Effects of propafenone on 45Ca movements and contractile responses in vascular smooth muscle

“…Propafenone hydrochloride is a class Ic antiarrhythmic drug effective both in experimental and clinical ventricular and supraventricular tachyarrhythmias (Seipel & Breidhardt, 1980;Connolly et al, 1983;Harron & Brogden, 1987;Somberg et al, 1988;Funk-Brentano et al, 1990). In isolated cardiac ventricular muscle propafenone exhibited a high affinity for the inactivated and activated states of the Na channel and dissociated very slowly from the Na channel receptor site (Kohlhardt & Seifert, 1983;Kohlhardt, 1984;Valenzuela et al, 1989).…”

Antiarrhythmic Medication Induced Multi-Organ Dysfunction

“…A nonlinear relationship between dose and steady state concentrations has been noted. This means a large increase in plasma concentration can result from a small dose increase [10]. We did not come across recommendations when adjusting the dose of propafenone on patients who have been on chronic therapy.…”

Electrophysiological effects of propafenone in untreated and propafenone‐pretreated guinea‐pig atrial and ventricular muscle fibres

“…The wide range of concentrations of propafenone tested (0.037-37.8 jig ml[') includes not only the therapeutic plasma levels (0.5-2 tg ml-': 1.3 x 10-6-5.3 x 10-6M; Keller et al, 1978;Karagueuzian et al, 1983;Conolly et al, 1983), but also the toxic plasma levels of the drug. The doses selected for pretreatment ofanimals were chosen from the results of Dieckmann et al (1981).…”

“…Propafenone (2'-[2-hydroxy-3-propylaminopropoxy]-3-phenyl-propiophenone hydrochloride), is a new antiarrhythmic drug which has been found to be clinically effective in the treatment of supraventricular and ventricular arrhythmias (Beck et al, 1975;Hochrein et al, 1977;Seipel & Breithardt, 1980;Conolly et al, 1983;Karagueuzian et al, 1983;Schlepper & Olsson, 1983). The electrophysiological effects of propafenone have been previously described in atrial (Ledda et al, 1981;Delgado et al, 1984;Dukes & Vaughan Williams, 1984) and ventricular (Bergmann & Holte, 1977;Kohlhardt, 1977;1982;Kohlhardt et al, 1983;Dukes & Vaughan Williams, 1984;Calleja et al, 1985) muscle fibres and in Purkinje fibres (Ledda et al, 1981;Dukes & Vaughan Williams, 1984;Tamargo et al, 1984;Calleja et al, 1985).…”