The effect of entacapone on the disposition and hemodynamic effects of intravenous isoproterenol and epinephrine*

BACKGROUND: Entacapone is a potent, selective catechol-O-methyltransferase (COMT) inhibitor. Entacapone could potentiate the hemodynamic effects of exogenously administered catecholamines, which are substrates of the COMT enzyme. DESIGN AND METHODS: Originally, the study was to follow a placebo-controlled, randomized crossover design. Because of two cases of ventricular arrhythmia, a decision was made to terminate the study before its completion. Six subjects went through the isoproterenol and epinephrine infusions while taking placebo and five other subjects while taking entacapone. The actual design was thus one with two parallel groups with random allocation and double-blind drug administration. The subjects were given either a single dose of 400 mg entacapone or placebo 30 minutes before the start of isoproterenol or epinephrine infusions. Four dosages of epinephrine (1.5, 3, 6, or 12 micrograms/min) and isoproterenol (0.5, 1, 1.5, or 2 micrograms/min) were infused (5 minutes for each level). Heart rate and blood pressure were measured and ECG was monitored. The concentrations of isoproterenol and epinephrine in plasma were determined by HPLC. RESULTS: The maximal increase in heart rate during isoproterenol infusion after entacapone administration (40 +/- 11 beats/min, mean +/- SD) was statistically greater (p = 0.0496) than after placebo administration (27 +/- 7 beats/min). The increase in heart rate during epinephrine infusion was 25 +/- 13 beats/min after entacapone administration and 14 +/- 9 beats/min after placebo administration (p = 0.127). There were no statistically significant differences between entacapone and placebo in blood pressure or in plasma concentrations of isoproterenol and epinephrine. CONCLUSION: We conclude that entacapone may potentiate the chronotropic and arrhythmogenic effects of exogenously administered isoproterenol and epinephrine.