After using transdermal nitroglycerin skin patches for 1 week, a patient with an 8-month history of chronic stable angina pectoris observes an increasing frequency of mild angina episodes during exertion. The patient has been conscientiously applying a new patch every morning immediately after removing the old one. The patient’s increased frequency of anginal attacks is most likely because of

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 nitro reductase, 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 ex­ertion.