CLINICAL PHARMACOLOGY:
The principal pharmacological action of nitroglycerin is relaxation of vascular smooth muscle and consequent dilatation of peripheral arteries and veins, especially the latter. Dilatation of the veins promotes peripheral pooling of blood and decreases venous return to the heart, thereby reducing left ventricular end-diastolic pressure and pulmonary capillary wedge pressure (preload). Arteriolar relaxation reduces systemic vascular resistance, systolic arterial pressure, and mean arterial pressure (afterload). Dilatation of the coronary arteries also occurs. The relative importance of preload reduction, afterload reduction, and coronary dilatation remains undefined.
Dosing regimens for most chronically used drugs are designed to provide plasma concentrations that are continuously greater than a minimally effective concentration. This strategy is inappropriate for organic nitrates. Several well-controlled clinical trials have used exercise testing to assess the anti-anginal efficacy of continuously-delivered nitrates. In the large majority of these trials, active agents were indistinguishable from placebo after 24 hours (or less) of continuous therapy. Attempts to overcome nitrate tolerance by dose escalation, even to doses far in excess of those used acutely, have consistently failed. Only after nitrates had been absent from the body for several hours was their anti-anginal efficacy restored.
Pharmacokinetics: The volume of distribution of nitroglycerin is about 3 L/kg, and nitroglycerin is cleared from this volume at extremely rapid rates, with a resulting serum half-life of about three minutes. The observed clearance rates (close to 1 L/kg/min) greatly exceed hepatic blood flow; known sites of extrahepatic metabolism include red blood cells and vascular walls.
The first products in the metabolism of nitroglycerin are inorganic nitrate and the 1,2- and 1,3-dinitroglycerols. The dinitrates are less effective vasodilators than nitroglycerin, but they are longer-lived in the serum, and their net contribution to the overall effect of chronic nitroglycerin regimens is not known. The dinitrates are further metabolized to (non-vasoactive) mononitrates and, ultimately, to glycerol and carbon dioxide.
To avoid development of tolerance to nitroglycerin, drug-free intervals of 10 - 12 hours are known to be sufficient; shorter intervals have not been well studied. In one well-controlled clinical trial, subjects receiving nitroglycerin appeared to exhibit a rebound or withdrawal effect, so that their exercise tolerance at the end of the daily drug-free interval was less than that exhibited by the parallel group receiving placebo.
Reliable assay techniques for plasma nitroglycerin levels have only recently become available, and studies using these techniques to define the pharmacokinetics of nitroglycerin ointment have not been reported. Published studies using older techniques provide results that often differ, in similar experimental settings, by an order of magnitude. The data are consistent, however, in suggesting that nitroglycerin levels rise to steady state within an hour or so of application of ointment, and that after removal of nitroglycerin ointment, levels wane with a half-life of about half an hour.
The onset of action of transdermal nitroglycerin is not sufficiently rapid for this product to be useful in aborting an acute anginal episode.
The maximal achievable daily duration of anti-anginal activity provided by nitroglycerin ointment therapy has not been studied. Recent studies of other formulations of nitroglycerin suggest that the maximal achievable daily duration of anti-anginal effect from nitroglycerin ointment will be about 12 hours.
It is reasonable to believe that the rate and extent of nitroglycerin absorption from ointment may vary with the site and square measure of the skin over which a given dose of ointment is spread, but these relationships have not been adequately studied.
Clinical Trials: Controlled trials have demonstrated that nitroglycerin ointment can effectively reduce exercise-related angina for up to 7 hours after a single application. Doses used in clinical trials have ranged from 1/2 inch (1.3 cm; 7.5 mg) to 2 inches (5.1 cm; 30 mg), typically applied to 36 square inches (232 square centimeters) of truncal skin.
In some controlled trials of other organic nitrate formulations, efficacy has declined with time. Because controlled, long-term trials of nitroglycerin ointment have not been reported, it is not known how the efficacy of nitroglycerin ointment may vary during extended therapy.
|
