Hemodynamic, anti‐ischemic, and neurohumoral effects of slow‐release isosorbide‐5‐mononitrate in patients with coronary artery disease after short‐ and long‐term therapy

Abstract

In 20 patients with established coronary artery disease, stable angina pectoris and reproducible ST‐segment depression, the pharmacokinetics and pharmacodynamic effects of 60 mg slow‐release isosorbide‐5‐mononitrate (IS‐5‐MN) (10 patients) after a 7‐day therapy were compared with those of a placebo group (10 patients) using a randomized double‐blind, placebo‐controlled study design. Ten patients could be controlled after long‐term therapy over a mean of 399 ± 111 days. There was no significant change under IS‐5‐MN of either blood pressure, heart rate, rate–pressure product, or myocardial oxygen consumption. Treatment over one week significantly reduced ST‐segment depression 4 and 8 h after drug intake (38–48% of the placebo value, p<0.01). Maximum reduction in ST‐segment depression was found 4 and 8 h after IS‐5‐MN intake both after one‐week and long‐term therapy at the time of peak plasma drug concentration (341 ± 95 and 405 ± 125 ng/ml, respectively). At a residual plasma concentration below 100 ng/ml, ST depression was not significantly improved 24 h after drug intake compared with placebo. Technetium‐99m ventriculography showed an insignificant increase in ejection fraction and a slight reduction of ventricular volumes after both short‐ and long‐term therapy with IS‐5‐MN (p>0.05). The drug's plasma levels were higher under chronic than under short‐term therapy which may be due to enzyme saturation. Maximum IS‐5‐MN plasma concentrations at a mean of 445 ± 116 ng/ml were reached after 5.8 ± 2.9 h. Beta‐phase half‐life of elimination was 9 ± 3 h. IS‐5‐MN administered as a single 60 mg dose of a slow‐release preparation/day proved to have a favorable pharmacokinetic profile as well as an efficient anti‐ischemic activity after both short‐ and long‐term therapy. Problems of tolerance or activation of hormonal counter‐regulation due to vasodilation were not observed. Copyright © 1991 Wiley Periodicals, Inc.