Nitroglycerin (GTN) and other nitrates have been used in cardiovascular medicine for more than 120 years. GTN was first synthesized in 1847 by an Italian, Ascanio Sobrero, who described a “violent headache” upon self-administration of a “minute quantity” of the drug (1). Because of this side effect, investigation of possible pharmacological applications of GTN was limited for several years, until the reports of Brunton and Murrell, who employed nitrates in the treatment of angina (2,3). Although sublingual GTN has been commonly used for more than a century to treat acute attacks of angina, the development of organic nitrates with sustained activity was limited by their poor oral bioavailability. Eventually, this difficulty was overcome and long-acting formulations of GTN and other long-acting organic nitrates, including isosorbide dinitrate, isosorbide-5-mononitrate, and pentaerythritol tetranitrate, have been developed and marketed. More details on the pharmacologic characteristics, formulations, and indications of different nitrates have been reviewed recently (4).

BIOTRANSFORMATION AND HEMODYNAMIC EFFECTS

Organic nitrates are prodrugs that release their active principle, nitric oxide (NO) or a NO-containing compound, via an intracellular enzyme-dependent denitrification (5) (Figure 181.1). The exact determination of the enzyme system involved in this bioconversion has remained elusive, despite extensive investigation. Multiple enzymatic candidates have been identified, including cytochrome P450, endothelial NO synthase, and glutathione transferase (6–10). There has been intense interest in identifying the denitrification pathway because it was felt that the development of abnormalities in this process might explain the loss of nitrate effects during sustained therapy, a phenomenon termed nitrate tolerance (discussed later). Spontaneous thiol-dependent denitrification of GTN also has been proposed as the mechanism of GTN biotransformation.