Nitrate tolerance.

Abstract

Nitrate tolerance may be defined as that condition in which increasing nitrate doses are required to induce a given hemodynamic or antianginal effect. Tolerance may be due to changes in pharmacokinetics or to alterations in the property of target tissues, making them less sensitive to the nitrate effect. The question of nitrate tolerance has been addressed using 4-times-a-day therapy with oral isosorbide dinitrate, daily therapy with long-acting isosorbide dinitrate ointment and once-a-day therapy with nitroglycerin patches. Each of these treatment modalities is associated with initial beneficial effects, but during sustained therapy, there is marked attenuation of the effect both in magnitude and duration. Thus the concept that stable nitroglycerin blood levels over 24 hours are desirable appears to be incorrect. Preliminary hemodynamic studies suggest that short periods of nitrate withdrawal restore the hemodynamic effect of the nitrates, and it is postulated that intermittent nitrate therapy may be desirable in the management of angina. Transmucosal nitroglycerin administration for a 15-hour period with a 9-hour washout period was recently undertaken. The results demonstrated that this method of nitrate administration is not associated with development of tolerance to its antianginal effects. Large doses of transdermal nitroglycerin, varying from 45 to 100 mg during short-term studies, have been shown to result in only minimal increases in exercise tolerance at 24 hours. These findings, plus evidence that with smaller doses tolerance occurs after only 1 week of once-a-day therapy, challenge the concept that larger nitroglycerin dosages, administered once a day by transdermal patches, could be effective throughout a 24-hour period in patients with angina pectoris.(ABSTRACT TRUNCATED AT 250 WORDS)