Metabolism Of Nitrovasodilators

After oral administration, organic nitrates are metabolized rapidly by the liver, kidney, lungs, intestinal mucosa, and vascular tissue. Buccal absorption reduces the immediate hepatic destruction of the organic nitrates because only 15% of the cardiac output is delivered to the liver; this allows a transient but effective circulating level of the intact organic nitrate before it is inactivated.5

Organic nitrates, nitrites, nitroso compounds, and a variety of other nitrogen-containing substances, such as sodium nitroprusside, for the most part cause their pharmacological effects by generating or releasing NO in situ. In some ways, these drugs are viewed as "replacement agents" for the endogenous NO generated by the NO synthase pathway from arginine. The mechanisms by which vasodilatory drugs release NO have become better understood recently. Table 19.1 shows the oxidation state of various nitrosyl compounds that are common in nitrovasodilatory drugs. A common feature of these drugs is that they release nitrogen in the form of NO and contain nitrogen in an oxidation state higher than +3 (as would occur in ammonia, amines, amides, and most biological nitrogen compounds). The nitrogen in NO has an oxidation state of + 2. Compounds such as nitroprusside, nitrosoamines, and nitrothiols with oxidation states of + 3 release NO nonenzymatically. Although their spontaneous liberation of NO is by an unknown mechanism, it involves only a one-electron reduction, which may occur on exposure of these chemicals to various reducing agents in the tissue of vascular smooth muscle membranes. Organic nitrites such as amyl nitrite react with available thiol groups to form unstable S-ni-trosothiols, which rapidly decompose to NO by homolytic cleavage of their S—N bond. In mammalian smooth muscle, this will occur almost exclusively with glutathione as the most abundant thiol compound.6

The pharmacodynamic action of nitroglycerin is preceded by metabolic changes that follow various paths. Biotransformation of nitroglycerin to the dinitrates and the

TABLE 19.1 Nitrosyl Vasodilatory Substances and Their Oxidation State

Nitrosyl Compound


Nitrogen Oxidation State

Nitric oxide

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