Patients should be counseled about these ad- verse effects and advised to seek medical treatment if syncope or resistant chest pain occurs. The ointment can cause permanent discoloration of clothing. Long-acting nitrate preparations (eg, nitroglycerin, isosor- bide dinitrate, isosorbide-5-mononitrate) are recommended for treatment of angina when initial therapy with a beta blocker or nondihydropyridine calcium channel blocker is contraindicated or poorly tolerated or when additional ther- apy to control angina is necessary. Isosorbide dinitrate undergoes rapid high first-pass metabolism, resulting in low bioavailability. However, substantial interpatient variability exists in the metabolic enzyme systems responsible for isosorbide dinitrate conversion. Isosorbide mononitrate, the active metabolite of the dinitrate formulation, is 100% bio- available. Nitroglycerin also can be delivered through sili- cone gel or polymer matrix release patch systems. The rate of release varies between these systems, necessitating individu- alization of dosing. With all formulations, titration of dose is important to gain adequate anginal control with the lowest possible dose to limit the occurrence of headaches, avoid nitrate tolerance, and facilitate long-term adherence. The effectiveness of all of these formulations seems to be roughly equivalent despite differences in the preparation and dosing schedules.843,882 With all of them, it is necessary to maintain a daily nitrate-free interval of 10 to 14 hours to avoid development of nitrate tolerance.843 Nitrate tolerance does not develop with the sublingual route of administration. Use of long-acting nitrates also does not result in tolerance to the use of sublingual products. Nitrates are relatively well tolerated if a titration schedule is used at initiation and with discontinuation. The most common side effects are headache, flushing, and hypotension. Patients should be instructed to remain seated when taking rapid-acting nitrate products as a safety precaution to avoid syncope from vasodilation. 