Plasma Level-Effect Relationships for some Acute Cardiovascular Effects of Nisoldipine and Other Dihydropyridine Calcium Channel Antagonists

Abstract

In a randomized, single-blind, crossover study involving nine healthy male subjects, 24 µg/kg nifedipine, 40 µg/kg nitrendipine, or 10 µg/kg nisoldipine were given intravenously on three separate occasions at intervals of 2–3 weeks. After drug administration, heart rate (HR), blood pressure (BP), forearm blood flow (FBF), and drug levels in plasma were monitored while the volunteers resting supine. The three dihydropyridines evoked increases in HR and FBF and small decreases in BP. These cardiovascular effects were transient in nature, and baseline values were reached again 20–60 min after dosing. While the observed peak changes in HR were virtually identical for the three drugs (about 45% above baseline), the peak changes in FBF were more pronounced in response to nitrendipine and nisoldipine (more than 200% above baseline) than in response to nifedipine (79% above baseline). The HR and FBF responses to the dihydropyridines were directly dependent on the drug levels in plasma. In fact, the drug level-response curves did not show any hysteresis effect and obeyed Hill’s equation. The results show that the dihydropyridines 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, 2.2, and 13.5, respectively.