Attenuation of nitrate effect during an intermittent treatment regimen and the time course of nitrate tolerance

The long-term efficacy of transdermal nitrate therapy, in particularthe ability of a single patch to provide 24 hprophylaxis againstangina, has been questioned. Two mechanisms have been suggestedfor this loss of effect: the development of pharmacologicaltolerance, and premature patch exhaustion. This study was designedto investigate this problem, and in particular to investigatethe time course of treatment failure. It comprised a randomized,double-blind, cross-over comparison of transdermal glyceryltrinitrate and matching placebo transdermal patches. Significant treatment effects were demonstrated by several criteriafor 8 h of continuous therapy, with some limited effect persistingfor 15 h. Loss of effect began to develop very soon after treatmentwas initiated and progressed in a steady, linear fashion sothat there was virtually no treatment effect after 24 h. Incontrast, during intermittent therapy, treatment effects weremaintained on the second day following a nitrate-free interval.Significant benefit was demonstrated for up to 32 h (i.e. 8h of treatment on day 2). Both nitrate-free intervals (12 and16 h) seemed lobe equally effective in maintaining efficacyafter 3 h of treatment on the second day, although this wasstill somewhat attenuated compared with day 1. These resultsconfirm that loss of therapeutic efficacy of transdermal nitrateis due to the development of tolerance and not premature patchexhaustion. In contrast to previous studies, however, they suggestthat tolerance can only partly be reversed by intermittent therapyand also that the onset of tolerance is so rapid that it iswell established in less than a day's treatment.