EFFECTS OF 8/00 AM AND 2/00 PM DOSES OF ISOSORBIDE-5-MONONITRATE DURING TWICE-DAILY THERAPY IN STABLE ANGINA-PECTORIS

Trough plasma concentrations of isosorbide-5-mononitrate (IS-5-MN), an active metabolite of isosorbide dinitrate, of <95 ng/ml are considered necessary to prevent development of tolerance to isosorbide dinitrate and IS-5-MN. In a double-blind, crossover, placebo-controlled study, the effects of IS-5-MN during twice daily eccentric therapy were evaluated in 18 patients with reproducible exercise-induced angina who were nitrate responders. In a random order, patients received either placebo or IS-5-MN (20 mg) at 8 A.M. and 2 P.M. for 1 week each. Average trough plasma IS-5-MN concentrations before the 8 A.M. and 2 P.M. doses were 67 and 226 ng/ml, respectively, and increased to 382 and 488 ng/ml 2 hours after the 8 A.M. and 2 P.M. doses, respectively. Despite a more than threefold higher trough plasma IS-5-MN concentration before the 2 P.M. dose than before the 8 A.M. dose, the increase in exercise duration 2 hours after the doses was similar (1.21 minutes [21%] after 8 A.M. dose, and 1.08 minutes [19%] after 2 P.M. dose). These increases in exercise duration after IS-5-MN were significantly (p <0.01) greater than those observed after placebo (0.17 minutes [3%] after 8 A.M. dose, and -0.05 minute [-0.5%] after 2 P.M. dose). Reduction in standing systolic blood pressure at 2 hours after the doses was also nearly identical after the 8 A.M. and 2 P.M. doses of IS-5-MN (21 [15%] and 19 [14%] mm Hg, respectively). Eleven patients had headaches during IS-5-MN therapy and 2 during placebo therapy (p <0.05). Thus, the circulatory and antianginal effects of IS-5-MN during chronic, eccentric, twice-daily therapy are not dependent on a given level of trough plasma IS-5-MN concentration, but are due to a rapid and substantial increase in plasma concentration after each dose.