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. Attempts to overcome nitrate tolerance by dose escalation, even to doses far in excess of those used acutely, have consistently failed. Only after nitrates have been absent from the body for several hours has their anti-anginal efficacy been restored.
Serum levels reach their maxima about an hour after ingestion.
Since the clearance exceeds hepatic blood flow, considerable extrahepatic metabolism must also occur. Both metabolites have biological activity, especially the 5-mononitrate. The daily dose-free interval sufficient to avoid tolerance to organic nitrates has not been well defined. Few well-controlled clinical trials of organic nitrates have been designed to detect rebound or withdrawal effects. In one such trial, however, subjects receiving nitroglycerin had less exercise tolerance at the end of the daily dose-free interval than the parallel group receiving placebo.