The principal pharmacological action of isosorbide dinitrate 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 no more effective than 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 have been absent from the body for several hours has their anti-anginal efficacy been restored.

Pharmacokinetics

The kinetics of absorption of isosorbide dinitrate has not been well studied. Studies of immediate-release formulations of ISDN have found highly variable bioavailability (10% to 90%) with extensive first-pass metabolism in the liver. Most such studies have observed progressive increases in bioavailability during chronic therapy; it is not known whether similar increases in bioavailability appear during the course of chronic therapy with Isosorbide Dinitrate Extended-release Tablets.

Once absorbed, the volume of distribution of isosorbide dinitrate is 2 to 4 L/kg, and this volume is cleared at the rate of 2 to 4 L/min, so ISDN's half-life in serum is about an hour. Since the clearance exceeds hepatic blood flow, considerable extrahepatic metabolism must also occur. Clearance is effected primarily by denitration to the 2-mononitrate (15 to 25%) and the 5-mononitrate (75 to 85%).

Both metabolites have biological activity, especially the 5-mononitrate. With an overall half-life of about 5 hours, the 5-mononitrate is cleared from the serum by denitration to isosorbide, glucuronidation to the 5-mononitrate glucuronide, and denitration/hydration to sorbitol. The 2-mononitrate has been less well studied, but it appears to participate in the same metabolic pathways, with a half-life of about 2 hours.

The daily dose-free interval sufficient to avoid tolerance to ISDN has not been well defined. Studies of nitroglycerin (an organic nitrate with a very short half-life) have shown that daily dose-free intervals of 10 to 12 hours are usually sufficient to minimize tolerance. Daily dose-free intervals that have succeeded in avoiding tolerance during trials of moderate doses (e.g., 30 mg) of immediate-release ISDN have generally been somewhat longer (at least 14 hours), but this is consistent with the longer half-lives of ISDN and its active metabolites. A dose-free interval sufficient to avoid tolerance with Isosorbide Dinitrate Extended-release Tablets has not been demonstrated. Clinical trials using Isosorbide Dinitrate Extended-release Tablets in a regimen designed to avoid tolerance have not been conducted, but in a multiple-dose study of another controlled-release isosorbide dinitrate product, 40 mg capsules were administered at 0800 and 1400 hours. After two weeks of this regimen, the controlled-release isosorbide dinitrate product was statistically indistinguishable from placebo. For the formulation of controlled-release isosorbide dinitrate that was tested, the necessary dose-free interval must therefore be greater than 18 hours; the necessary interval for Isosorbide Dinitrate Extended-release Tablets remains unknown.

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. The incidence, magnitude, and clinical significance of similar phenomena in patients receiving ISDN have not been studied.

Clinical Trials

In clinical trials, immediate-release oral isosorbide dinitrate has been administered in a variety of regimens, with total daily doses ranging from 30 mg to 480 mg. Controlled trials of single doses of controlled-release isosorbide dinitrate have demonstrated effective reductions in exercise-related angina for up to 8 hours. Anti-anginal activity is present about 1 hour after dosing.

Adequate multiple-dose trials of Isosorbide Dinitrate Extended-release Tablets have not been reported.

Most controlled trials of multiple-dose immediate-release oral ISDN taken every 12 hours (or more frequently) for several weeks have shown statistically significant anti-anginal efficacy for only 2 hours after dosing. Once-daily regimens, and regimens with one daily dose-free interval of at least 14 hours (e.g., a regimen providing doses at 0800, 1400 and 1800 hours), have shown efficacy after the first dose of each day that was similar to that shown in the single-dose studies cited above. The efficacy of subsequent doses has not been demonstrated.

From large, well-controlled studies of other nitrates, it is reasonable to believe that the maximal achievable daily duration of anti-anginal effect from isosorbide dinitrate is about 12 hours. No dosing regimen for Isosorbide Dinitrate Extended-release Tablets has, however, ever actually been shown to achieve this duration of effect.