Pharmacokinetic and pharmacodynamic interactions between nisoldipine and propranolol

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Abstract
The pharmacokinetic and pharmacodynamic effects of nisoldipine, a 1,4-dihydroipyridine calcium entry blocker, and the lipophilic .beta.-adrenoceptor blocker propranolol were assessed alone and in combination in 12 healthy men. Oral nisoldipine, 20 mg, or placebo was followed 1 hour later by propranolol, 40 mg, or placebo using a randomized, crossover, double-blind design. Nisoldipine significantly increased the AUC (+43%) and peak plasma drug concentration (Cmax) (+68%) of propranolol resulting in a higher degree of .beta.-adrenoceptor blockade (as assessed by isoproterenol). Conversely, nisoldipine''s AUC (+30%) and Cmax (+57%) were increased with concomitant administration of propranolol. Nisoldipine did not affect blood pressure but caused significant decreases in total peripheral resistance (TPR) and increases in plasma catecholamines and cardiac index. Forearm vascular resistance and blood flow changed more markedly than did TPR and cardiac index. In contrast, propranolol had little effect on forearm hemodynamics despite significant decreases in cardiac index and increases in TPR. The data are compatible with changes in hepatic blood flow, accounting for the pharmacokinetic interaction of nisoldipine and propranolol. Different vascular beds appear to contribute to the effects of nisoldipine vs. propranolol on peripheral resistance.