Nitrate tolerance

Nitrates are widely used in anginal prophylaxis. In spite of the fact that the concept of nitrate tolerance was first put forward many years ago, the question of tolerance has remained controversial. There is widespread agreement that tolerance does occur to the effects of nitrates on arterial pressure. In contrast, tolerance to the venous and pulmonary effects is disputed. Similarly, the possibility of tolerance to the antianginal effects remains at issue. In this review, I discuss the factors which may have contributed to conflicting results in different studies, in particular recent findings on the rapidity of onset and reversal of tolerance. Tolerance develops rapidly on initiation of treatment and disappears equally rapidly on its discontinuation. In addition, tolerance appears to be a function of plasma nitrate profile. It is most likely to occur when plasma nitrate levels are constant and least likely when nitrate levels fluctuate. Furthermore, the provision of a daily nitrate free interval may protect against the development of tolerance. I then discuss the implications of these findings for patient management. They suggest that nitrate prophylaxis should not be used continuously, if this can be avoided. Rather, prophylaxis should be tailored to the individual to provide protection at times of maximum susceptibility, while allowing nitrate levels to fall at other times. The adequacy of antianginal protection with drug regimens incorporating a nitrate free interval requires further assessment. Similarly, the possibility that a nitrate free interval might lead to withdrawal effects and exacerbation of angina needs to be excluded.