CLINICAL-PHARMACOLOGY OF ORGANIC NITRATES

Although organic nitrates have been used in cardiovascular therapy for many years, various aspects of their pharmacology remain poorly understood. It is now known that organic nitrates produce nitric oxide (NO) in vascular smooth muscle cells, catalyzed by a membrane-bound enzyme that is not glutathione-S-transferase. Other nitrovasodilators, such as organic nitrites, sodium nitroprusside, and S-nitrosothiols, do not utilize the same enzyme for NO generation. The short-term hemodynamic action of various organic nitrates has been shown to be related to their pharmacokinetics, but their long-term therapeutic effects are limited by the development of pharmacologic tolerance. Nitrate sensitivity in patients can be restored dally after a nitrate-free period of 8-12 hours. Coadministration of nitrates with other vasodilators, such as captopril and hydralazine, may avoid the development of nitrate tolerance in patients with congestive heart failure.