indication

For the prevention of angina pectoris due to coronary artery disease and the treatment of acute and chronic angina pectoris, hypertension, and myocardial infarction.

pharmacology

Isosorbide-5-mononitrate, the long-acting metabolite of isosorbide dinitrate, is used as a vasodilatory agent in the management of angina pectoris. By dilating the vessels, it lowers the blood pressure and reduces the left ventricular preload and afterload, therefore, leads to a reduction of myocardial oxygen requirement.

mechanism of action

Similar to other nitrites and organic nitrates, Isosorbide Mononitrate is converted to nitric oxide (NO), an active intermediate compound which activates the enzyme guanylate cyclase (Atrial natriuretic peptide receptor A). This stimulates the synthesis of cyclic guanosine 3',5'-monophosphate (cGMP) which then activates a series of protein kinase-dependent phosphorylations in the smooth muscle cells, eventually resulting in the dephosphorylation of the myosin light chain of the smooth muscle fiber. The subsequent release of calcium ions results in the relaxation of the smooth muscle cells and vasodilation.

toxicity

Symptoms of overdose include vasodilatation, venous pooling, reduced cardiac output, and hypotension. There are no data suggesting what dose of isosorbide mononitrate is likely to be life-threatening in humans. In rats and mice, there is significant lethality at doses of 2000 mg/kg and 3000 mg/kg, respectively.

biotransformation

Hepatic

absorption

100%

half life

5 hours

route of elimination

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.

drug interactions

Dihydroergotamine: Possible antagonism of action

Dihydroergotoxine: Possible antagonism of action

Ergonovine: Possible antagonism of action

Ergotamine: Possible antagonism of action

Methylergonovine: Possible antagonism of action

Methysergide: Possible antagonism of action

Sildenafil: Possible significant hypotension with this combination

Tadalafil: The vasodilatory effects of Isosobide mononitrate may be increased by Tadalafil. Severe hypotension may occur. Concomitant therapy is contraindicated.

Telithromycin: Telithromycin may reduce clearance of Isosorbide Mononitrate. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Isosorbide Mononitrate if Telithromycin is initiated, discontinued or dose changed.

Treprostinil: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Udenafil: The vasodilatory effects of Isosobide mononitrate may be increased by Udenafil. Severe hypotension may occur. Concomitant therapy is contraindicated.

Vardenafil: The vasodilatory effects of Isosorbide mononitrate may be increased by Vardenafil. Severe hypotension may occur. Concomitant therapy is contraindicated.

Voriconazole: Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of isosorbide mononitrate by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of isosorbide mononitrate if voriconazole is initiated, discontinued or dose changed.