General pharmacology of diprafenone, a new class lc antiarrhythmic agent, and 5‐hydroxydiprafenone, an active metabolite

This study compareo the effects of diprafenone, a new class lc antiarrhythmic agent, and 5‐hydroxydiprafenone (5‐OHDP), an active metabolite of diprafenone, to standard class l antiarrhythmic agents (propafenone, flecainide, or lidocaine), in several pharmacologic models, to ascertain the potential for side effects relative to the currently available class l antiarrhythmic agents. Diprafenone and propafenone decreased blood pressure and heart rate in anesthetized rabbits at 3 and 7 mg/kg, i.v., respectively. Neuromuscular transmission in rabbit gastrocnemius muscle was partially (38%) inhibited after 3 mg/kg of diprafenone and 7 mg/kg of propafenone. Diprafenone and 5‐OHDP (10−4M), but not lidocaine, inhibited aggregation of human platelets evoked by sodium arachidonate and adenosine diphosphate. Diprafenone, fleoainide, and 5‐OHDP (10−4M) inhibited the contractile responses of guinea pig vas deferens to norepinephrine and spontaneous and bradykinin‐evoked contractions of the guinea pig uteri. Diprafenone and 5‐OHDP, but not flecainide, relaxed rabbit bronchial smooth muscle contracted by acetylcholine. Diprafenone, 5‐OHDP and propafenone (10−5M and 10−4M) also depressed the contractile responses of canine mesenteric arteries to transmural nerve stimulation. Thus, high concentrations of diprafenone (10−5M and 10−4M) depress smooth muscle and neural function. The depressant effects occur with 4ndash;40 times the antiarrhythmic concentration of diprafenone and are shared by propafenone and, in part, by 5‐OHDP and flecainide. It is unlikely that major peripheral side effects will occur with therapeutic doses of diprafenone in man.