Sustained effect of and lack of development of tolerance to controlled-release isosorbide-5-mononitrate in chronic stable angina

Abstract

Tolerance has been shown to develop when nitrate preparations are used in such a manner as to produce plasma levels within the therapeutic range continuously over a 24-hour period. However, a period of reduced or low nitrate plasma levels of a few hours per day may limit or completely prevent tolerance development. In 18 patients with chronic stable angina pectoris, a single 60-mg daily dose of a controlled-release preparation of isosorbide-5-mononitrate (ISMN) was compared with the administration of 30 mg, 4 times daily, of immediate-release isosorbide dinitrate (ISDN) in a double-blind, randomized, placebo-controlled, crossover study. The comparisons were carried out on the first day of therapy and after 11 to 14 days of continuous therapy to assess the duration of effectiveness and the development of tolerance. On short-term therapy, both drugs produced a significant improvement in treadmill walking times to moderate angina in comparison with placebo. The values for ISMN were 87 ± 99 seconds (23%) at 12:30 P.M., 72 ± 91 seconds (19%) at 5 p.m. and 51 ± 81 seconds (13%) at 8:30 P.M. For ISDN, the respective values were 71 ± 83 seconds (19%), 89 ± 98 seconds (24%) and 79 ± 87 seconds (21%). There were no significant differences between drugs. Plasma nitrate levels for each drug paralleled the improvements in exercise performance. After 11 to 14 days of sustained therapy, only ISMN retained any significant beneficial effects (61 ± 71 seconds [21%] at 12:30 p.m. and 42 ± 60 seconds [14%] at 5 P.M.), but no significant effect at 8:30 p.m., with plasma levels slightly higher than those achieved on short-term therapy. ISDN produced no effect at any time point. This loss of effectiveness for ISDN occurred despite a slight increase in serum nitrate levels in comparison with short-term dosing, at all time points. Thus, the use of controlled-release ISMN minimized the development of tolerance, presumably because the nitrate plasma levels decreased into the subtherapeutic range during the inactive hours of the late evening and night. ISMN provided significant antianginal effects both with short-term and sustained therapy for at least 8.5 hours after a single morning dose.