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Cardiovascular Effects of Dihydropyridine Calcium Channel Antagonists and Their Relation to Drug Levels in Plasma

In a randomized, single-blind crossover study involving nine healthy male subjects, nifedipine (24 pg/kg), nitrendipine (40 pg/kg), and nisoldipine (10 pg/kg) were given intravenously on three separate occasions at intervals of 2 to 3 weeks. Before (30 minutes), during (4 minutes), and after (60 minutes) drug administration, heart rate, blood pressure, forearm blood flow, and drug levels in plasma were monitored, with the volunteers resting supine throughout. All three dihydropyridines evoked transient increases in heart rate and forearm blood flow and small decreases in blood pressure. While the oberved peak changes in heart rate were virtually identical for the three drugs (45% above baseline), the peak changes in forearm blood flow were more pronounced after administration of nitrendipine and nisoldipine (about 240% above baseline) than after administration of nifedipine (75% above baseline). Plots of the pharmacodynamic effects against the drug concentrations in plasma showed that the heart rate and forearm blood flow response to the dihydropyridines were directly dependent on the drug levels in plasma. In fact, the drug-level-response curves for both the heart rate and the forearm blood flow responses did not show any distortion by hysteresis effects and clearly obeyed Hill's equation. The analysis of these curves showed that the three drugs (although exhibiting certain differences in calculated maximum effects) differ predominantly with respect to their potencies in dilating the resistance vessels of the forearm: the relative vasodilator potencies of nifedipine, nitrendipine, and nisoldipine were 1, 2, and 13, respectively. Moreover, the values of ECSo (drug concentration sufficient to produce half of the maximum effect) obtained for the vasodilator responses were similar to those for the heart rate responses. In another double-blind crossover study, which involved nine healthy male subjects, the cardiovascular effects of oral doses of 20 mg nifedipine and 20 mg nisoldipine were compared with those of placebo. In this study the volunteers rested supine for 120 minutes after dosing, during which time heart rate, forearm blood flow, and forearm venous capacity were monitored. In addition, blood was sampled from a forearm vein to determine drug levels in plasma. As in the previous study, both drugs elicited about the same increase in heart rate, but produced distinctly different increases in forearm blood flow. As far as the peak responses of the forearm blood flow are concerned, nisoldipine was about 3 times as effective as nifedipine. Neither drug produced any change in the forearm venous capacity. The drug-induced changes in forearm blood flow were again directly dependent on the plasma levels. Equieffective drug concentrations in plasma differed by about a factor of 50, with nisoldipine being more potent than nifedipine.