THE PHARMACOKINETICS AND HEMODYNAMIC-EFFECTS OF CONTINUOUS NICORANDILINFUSION IN HEALTHY-VOLUNTEERS

We have studied the pharmacokinetics and haemodynamic effects of nicor andil after a 12-h infusion. Nicorandil is a mixed vasodilator combini ng the actions of a nitrate and a potassium channel opener. Nicorandil was infused for 12 h in 21 healthy volunteers at rates of 0.05, 0.10, and 0.20 mug . kg-1 . min-1 using a placebo controlled, crossover des ign. Systemic blood pressure, heart rate, electrocardiographic (ECG) i ntervals, and cardiac output (impedance cardiography) were measured su pine and standing. Dose-related, steady-state plasma nicorandil concen trations occurred within 3 to 4 h. Nicorandil's pharmacokinetics were linear with dose. Four 0.20 mug . kg-1 . min-1 nicorandil infusions we re terminated early primarily because of moderate or severe headaches. There were no safety concerns (ECG intervals, laboratory assays). Blo od pressure fell versus placebo only in the standing position and hear t rate increased slightly (not significant). That is, standing blood p ressure in the 6 to 12 h interval fell from baseline 8.0/6.8, 1.6/5.1 , and 9.8/7.9* mmHg (systolic/diastolic, * = P < 0.05 versus placebo) at 0.05, 0. 10, and 0.20 mug . kg-1 . min-1 respectively. Cardiac out put increased slightly above placebo at lower doses. Haemodynamic chan ges correlated poorly with plasma nicorandil concentrations. Similar t otal doses were less well-tolerated when extended over 12 h. We saw no evidence of pharmacodynamic tolerance to nicorandil within 12 h.