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Pharmacology: Pharmacodynamics: Isosorbide-5-mononitrate (ISMN), an active metabolite of isosorbide dinitrate, acts by relaxing vascular smooth muscles producing vasodilatation of both arteries and veins, with the latter effect predominating. The effect of treatment is dependent on the dose. Low plasma concentrations lead to venous dilation, resulting in peripheral pooling of blood, decreased venous return and reduction in left ventricular end-diastolic pressure (preload). High plasma concentrations also dilate the arteries, reducing systemic vascular resistance and arterial pressure leading to a reduction in cardiac afterload. Dilatation of coronary arteries also occurs. By decreasing end-diastolic pressure and volume, ISMN decreases intramural pressure resulting in improvement in subendocardial blood flow. Thus, after administering ISMN, there is reduced cardiac workload and improved oxygen supply/demand balance in the myocardium.
Pharmacokinetics: ISMN in sustained-release (SR) formulation is gradually released over a 10-hr period, independent of pH, according to a first order process. This prolonged absorption phase results in reduced and delayed peak plasma levels compared to conventional tablets of ISMN. Peak plasma levels of about 3,000 nmol/L were reported to be obtained within approximately 4 hrs after administration of 60 mg ISMN SR tablets. Plasma concentrations gradually decrease to 500 nmol/L 24 hrs after dose intake. Bioavailability of ISMN in oral SR formulation is about 90% compared to conventional immediate-release tablets. Food does not significantly affect ISMN absorption.
The bioequivalence of ISMN, 1 x 120-mg capsule versus 2 x 60-mg tablets, was assessed in a randomized, 2-treatment, 2-period, 2-way, crossover study. After a single oral dose of 120-mg capsule to healthy fasted adults, peak plasma concentration (Cmax) of ISMN (804.249 ng/mL) was achieved within 2.917 hrs (Tmax). Values of Cmax, Tmax and area under the plasma concentration-time curve from time 0-24 hrs (AUC0-24) were comparable for the tablet and capsule and the 2 formats were bioequivalent.
ISMN's plasma protein binding is about 5%. The volume of distribution is about 0.6 L/kg and the total clearance is around 115 mL/min. ISMN is metabolized primarily by the liver but is not subject to first-pass effect. About 50% of a dose of ISMN undergoes denitration to form isosorbide, followed by partial dehydration to form sorbitol. ISMN also undergoes glucuronidation to form 5-mononitrate glucuronide. About 96% of the administered dose is excreted in urine within 5 days and only about 1% is eliminated in the feces; most excretion (about 93%) occurs within 48 hrs. At least 6 different compounds have been detected in urine, with about 2% of the dose excreted as the unchanged drug and at least 5 metabolites. The metabolites are not pharmacologically active. The mean plasma elimination t½ of ISMN is about 5 hrs.
In patients with various degrees of renal insufficiency, liver cirrhosis or cardiac dysfunction, the disposition of ISMN was found to be similar to that observed in healthy subjects.
The elimination t½ of ISMN was not prolonged and there was no drug accumulation in patients with chronic renal failure after multiple oral dosing.
Impairment of the liver or kidney has no major influence on the pharmacokinetic properties of ISMN.
ISMN SR formulations have been shown to be effective in monotherapy as well as in combination with chronic β-blocker therapy. The clinical effects may be attenuated during repeated administration with nitrates in high doses and/or frequent administration. This can be avoided by allowing low plasma levels for a certain period of the dosage interval. The SR formulation of ISMN produces a plasma profile that provides high plasma levels during daytime and low night-time plasma levels when administered once daily in the morning.
