Tolerance to organic nitrates may develop in a few days or less, depending on the dose and frequency of administration. Continuous exposure to nitroglycerin through use of a transdermal skin patch has frequently caused nitrate tolerance. A daily 10-to-14-hour drug-free period will prevent nitrate tolerance. Nitrate tolerance is a cellular tolerance caused by depletion of sulfhydryl groups required for receptor signal transduction. The drug-free interval allows time for these groups to replenish before the next period of drug exposure. Nitrates are metabolized by hepatic nitroreductase, and there is neither evidence of cytochrome P 450 involvement nor of induction of this enzyme by drugs. Although the patient's symptoms could be caused by increased physical activity or onset of vasospasm, these are less likely causes in a patient with continuous nitroglycerin exposure. Vasospasm is also unlikely because the episodes occurred during exeion. Ref - Harrison's principles of internal medicine 20e pg427,1860 / researchgate.net