Interaction Between Propranolol and Propafenone in Healthy Volunteers

Abstract

The effects of propafenone on the pharmacokinetics and pharmacodynamics of propranolol were evaluated in 12 healthy male subjects. Both propafenone and propranolol were each administered alone for one week followed by concomitant administration for an additional week. Blood samples, obtained at steady‐state, were analyzed for propafenone and its two metabolites as well as for propranolol and 4‐hydroxypropranolol. Left ventricular function, exercise performance and electrocardiographic intervals were assessed. Coadministration of propranolol did not produce any significant change in propafenone kinetics including peak plasma concentration (C_max), time to peak plasma concentration (T_max), elimination rate constant (t_1/2), mean steady‐state plasma concentration (C_ss), or area under the concentration vs time curves. However, concomitant propafenone administration significantly increased C_max (83%), T_max (55%), t_1/2 (30%), and C_ss (213%) which were accompanied by significant decreases in plasma levels of 4‐hydroxy‐propranolol. Propafenone and propranolol significantly reduced supine systolic and diastolic blood pressure by 2.5 to 15.4%. The combination did not reduce diastolic blood pressure further (64.0 ± 2.8 to 59.7 ± 1.7 mmHg) nor did it produce a supplemental reduction in heart rate (12% reduction with propranolol, 10% reduction with concomitant administration). Propranolol, but not propafenone, significantly decreased end‐diastolic volume index (13%), stroke volume index (15%), and velocity of circumferential fiber shortening (19%). The combination did not cause any further changes in echocardiography measurements. Electrocardiographic intervals were not altered by either drug used alone or in combination. We conclude that the concomitant administration of propafenone and propranolol can produce marked increases in propranolol plasma levels with only modest enhancement of beta‐adrenergic blocking effects when administered to patients with preserved left ventricular function, and a normal conduction system.