Isoket IV Mechanism of Action

Pharmacotherapeutic group: Vasodilators used in cardiac diseases; organic nitrates. ATC Code: C01DA08.
Pharmacology: Pharmacodynamics: Mechanism of Action and Pharmacodynamic effects: Isosorbide dinitrate is an organic nitrate, which in common with other cardioactive nitrates, is a vasodilator.
It produces decreased left and right ventricular end-diastolic pressures to a greater extent than the decrease in systemic arterial pressure, thereby reducing afterload and especially the preload of the heart.
Isosorbide dinitrate influences the oxygen supply to ischaemic myocardium by causing the redistribution of blood flow along collateral channels and from epicardial to endocardial regions by selective dilatation of large epicardial vessels.
It reduces the requirement of the myocardium for oxygen by increasing venous capacitance, causing a pooling of blood in peripheral veins, thereby reducing ventricular volume and heart wall distension.
Pharmacokinetics: Metabolism and Elimination: Isosorbide dinitrate (ISDN) is eliminated from plasma with a short half-life (about 0.7 h). The metabolic degradation of ISDN occurs via denitration and glucuronidation, like all organic nitrates. The rate of formation of the metabolites has been calculated for isosorbide-5-mononitrate (IS-5-MN) with 0.27 h^-1, followed by isosorbide-2-mononitrate (IS-2-MN) with 0.27 h^-1, and isosorbide (IS) with 0.16 h^-1. IS-5-MN and IS-2-MN are the primary metabolites which are also pharmacologically active. IS-5-MN is metabolised to isosorbide-5-mononitrate-2-glucuronide (IS-5-MN-2-GLU). The half-life of this metabolite (about 2.5 h) is shorter than that of IS-5-MN (about 5.1 h). The half-life of ISDN is the shortest of all and that of IS-2-MN (about 3.2 h) lies in between.
Toxicology: Non-Clinical Information: Acute toxicity: Acute toxicity of isosorbide dinitrate was related to an exaggerated pharmacodynamic effect. Animal studies showed good local tolerability of the undiluted isosorbide dinitrate solution.
Chronic toxicity: In chronic oral toxicity studies in rats and dogs, toxic effects including CNS symptoms and an increase in liver weight, were observed at exposures considered sufficiently in excess of the maximum human exposure levels indicating little relevance to clinical use.
Reproduction studies: There is no evidence from animal studies suggesting a teratogenic effect of isosorbide dinitrate. At high maternally toxic oral doses, isosorbide dinitrate was associated with increased post-implantation loss and reduced survival of offspring.
Mutagenicity: No evidence for mutagenic effects was found in several tests undertaken both in vitro and in vivo.
Carcinogenicity: A long-term study in rats did not provide any evidence for carcinogenicity.