Effects of dosing intervals on the development of tolerance to high dose transdermal nitroglycerin

To investigate the antiischemic efficacy and development of tolerance to transdermal nitroglycerin, 14 patients with chronic, stable angina pectoris were studied using continuous ambulatory electrocardiographic monitoring. Patients demonstrated initial hemodynamic responsiveness to sublingual nitroglycerin and were titrated to a maximally tolerated dose of 30 to 60 mg/24 hours (52 +/- 5 mg). Two crossover phases were use in a randomized, double-blind, placebo-controlled manner: continuous nitroglycerin therapy (patches containing active drug worn for 24 hours) and intermittent nitroglycerin therapy (12-hour active drug followed by a 12-hour nitrate-free period). There were no differences in frequency or duration of ischemic episodes between the placebo days of each phase. A significant effect in frequency of episodes was observed between placebo and treatment days of continuous therapy (p less than 0.05). Nonsignificant reductions in frequency and duration of ischemic episodes also occurred during intermittent therapy. The major antiischemic effect of transdermal nitroglycerin therapy occurred during the first day of treatment but was lost by 48 hours. Reductions in frequency and duration of ischemic episodes (p less than 0.05) were present on day 1 of continuous therapy but ischemic episodes returned to placebo levels by day 2, suggesting the development of tolerance. Intermittent therapy did not prevent the development of tolerance on day 2 of treatment. The results demonstrate that the use of high doses of transdermal nitroglycerin in patients with chronic, stable coronary artery disease produced a beneficial reduction in the frequency and duration of ischemia. However, the antiischemic benefit was lost between 24 nd 48 hours after the onset of continuous and intermittent therapy, presumably due to tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)