Pharmacotherapeutic group: Anti-Angina.
Pharmacology: Isosorbide mononitrate sustained-release tablets are an oral sustained-release formulation of Isosorbide mononitrate, the major active metabolite of isosorbide dinitrate is attributed to the mononitrate. The principal pharmacological action of Isosorbide mononitrate and all organic nitrates in general is relaxation of vascular smooth muscle, producing dilatation of peripheral arteries and veins, especially the latter. Dilatation of the veins promotes peripheral pooling of blood, 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, and systolic arterial pressure and mean arterial pressure (after load). Dilatation of the coronary arteries also occurs. The relative importance of preload reduction, after load reduction, and coronary dilatation remains undefined.
Isosorbide Mononitrate sustained-release tablets are indicated for the prevention of angina pectoris due to coronary artery disease. The onset of action of oral Isosorbide mononitrate is not sufficiently rapid for this product to be useful in aborting an acute angina episode.
Pharmacodynamics: 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. In the large majority of these trials, active agents were indistinguishable from placebo after 24 hours (or less) of continuous therapy. Attempts to overcome 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 antianginal efficacy been restored. Isosorbide mononitrate at 4 hours and at 12 hours after dosing, but its effects (although better than placebo) are less than or, at best, equal to the effects of the first dose of 60 mg.
Bioavailability and Pharmacokinetics: After oral administration of Isosorbide mononitrate as a solution or immediate-release tablets, maximum plasma concentrations of Isosorbide mononitrate are achieved in 30 to 60 minutes with an absolute bioavailability of approximately 100%. After intravenous administration, Isosorbide mononitrate is distributed into total body water in about 9 minutes with a volume of distribution of approximately 0.6 to 0.7 L/kg. Isosorbide mononitrate is approximately 5% bound to human plasma proteins and is distributed into blood cells and saliva. Isosorbide mononitrate is primarily metabolized by the liver, but unlike oral Isosorbide dinitrate, it is not subject to first-pass metabolism. Isosorbide mononitrate is cleared by denitration to Isosorbide and glucuronidation as the mononitrate, with 96% of the administered dose excreted in the urine within 5 days and only about 1% eliminated in the feces. At least six different compounds have been detected in urine, with about 2% of the dose excreted as the unchanged drug and at least five metabolites. The metabolites are not pharmacologically active. Renal clearance accounts for only about 4% of total body clearance. The mean plasma elimination half-life of Isosorbide mononitrate is approximately 5 hours. The disposition of Isosorbide mononitrate in patients with various degrees of renal insufficiency, liver cirrhosis, or cardiac dysfunction was evaluated and found to be similar to that observed in healthy subjects. The elimination half-life is Isosorbide mononitrate was not prolonged, and there was no drug accumulation in patients with chronic renal failure after multiple oral dosing. The pharmacokinetics and/or bioavailability of Isosorbide mononitrate sustained-release tablets have been studied in both normal volunteers are patients following single and multiple-dose administration. Data from these studies suggest that the pharmacokinetics of Isosorbide mononitrate sustained-release tablets are similar between normal healthy volunteers and patients with angina pectoris. In single- and multiple-dose studies, the pharmacokinetics of Isosorbide mononitrate was done proportional between 30 mg and 240 mg. In a multiple-dose study, the effect of age on the pharmacokinetic profile of Isosorbide mononitrate 60 mg and 120 mg and (2 x 60 mg) sustained-release tablets was evaluated in subjects ≥ 45 years. The results of that study indicate that there are no significant differences in any of the pharmacokinetic variables of Isosorbide mononitrate between elderly (≥ 65 years) and younger individuals (45 to 64 years) for Isosorbide mononitrate sustained-release 60 mg dose. The administration of Isosorbide mononitrate sustained-release tablets 120 mg (2 x 60) mg tablets every 24 hours for 7 days) produced a dose-proportional increase in Cmax and AUC, without changes in Tmax or the terminal half-life. The older group (65 to 74 years) showed 30% lower apparent oral clearance (Cl/F) following the higher dose, i.e., 120 mg, compared to the younger group (45 to 64 years); Cl/F was not different between the two groups following the 60 mg regimen. While Cl/F was independent of dose in the younger group, the older group showed slightly lower Cl/F following the 120 mg regimen compared to the 60 mg regimen. Differences between the two age groups, however, were not statistically significant. In the same study, females showed a slight (15%) reduction in clearance when the dose was increased. Females showed higher AUC and Cmax compared to males but these differences were accounted by differences in the body weight between the two groups. When the data were analyzed using age as a variable, the results indicated that there were no significant differences in any of the pharmacokinetic variables of Isosorbide mononitrate between older (≥ 65 years) and younger individuals (45 to 64 years). The results of this study, however, should be viewed with caution due to the small numbers of subjects in each age subgroup and consequently the lack of sufficient statistical power.