Nifedipine-propranolol interaction: dependence of cardiovascular effects on plasma drug concentrations

The relationships between plasma drug concentrations and cardiovascular effects during combined administration of nifedipine and propranolol were evaluated in dogs anesthetized with thiopental. Three received small intravenous (i.v.) doses of nifedipine followed by propranolol, and 6 were given higher doses of nifedipine followed by propranolol; in 5, the order of drug doses was reversed, with propranolol administration followed by nifedipine. When dosing regimens that produced stable plasma levels of both drugs were used, the observed effects were closely related to the plasma concentrations of the individual agents. When small doses of nifedipine were combined with propranolol, at plasma levels associated with a significant degree of beta-adrenoceptor blockade, moderate decreases in spontaneous heart rate and cardiac output as well as increases in atrioventricular conduction time were produced. With higher doses of nifedipine, combined infusion with propranolol resulted in more pronounced depression in cardiac function, characterized by decreases in cardiac output, heart rate, and mean pulmonary arterial pressure, as well as increases in atrioventricular conduction time. When propranolol administration was followed by nifedipine, similar dose-dependent cardiovascular effects resulted, with profound toxicity apparent when large doses of nifedipine were used. These studies in an acute anesthetized dog model suggest that the magnitude of cardiovascular depression resulting from nifedipine and propranolol in combination is dependent on the plasma concentrations of both agents. Furthermore, in the presence of beta-adrenoceptor blockade, the direct effects of nifedipine on myocardial conducting tissue, which are usually absent when this calcium antagonist is given alone, may become apparent and result in depression of atrioventricular and sinoatrial nodal functions.