Transdermal kinetics and nitrate tolerance. Measurements of vasodilation by photoplethysmography.

Abstract

F’atches with glycetyl trinitrate (GTN) provide rather stable plasma concentrations for 24 hours, but clinical efficacy is not maintained. We examined further the pharmacokinetics of transdermal treatment, and the rlelationship between changes in GTN bioavailability and clinical efficacy. The mechanisms of nitrate tolerance were studied by finger plethysmography (FPG), with pulse curve analysis. The GTN plasma concentrations increased after local heating of the patch area, and decreased after cooling. An increase in GTN occurred during exercise in angina patients, but less so after 24 hours. After 24 hours, clinical tolerance was observed despite maintenance of the arterial vasodilating effects (FPG). FPG was well-suited in the rabbit, and proved sensitive also for vasodilation induced by acetylcholine (i.e. by nitric oxide). During patch treatment, changes in GTN bioavailability occur during exercise and over 24 hours, possibly affecting clinical efficacy. Counterregulatory mechanisms for the venous effects appear most important in the development of clinical nitrate tolerance.