Chemical formula: C₆H₈N₂O₈ Molecular mass: 236.136 g/mol PubChem compound: 6883
Like all organic nitrates, isosorbide dinitrate acts as a donor of nitric oxide (NO). NO causes a relaxation of vascular smooth muscle via the stimulation of guanylyl cyclase and the subsequent increase of intracellular cyclic guanosine monophosphate (cGMP) concentration. A cGMP-dependent protein kinase is thus stimulated, with resultant alteration of the phosphorylation of various proteins in the smooth muscle cell. This eventually leads to the dephosphorylation of the light chain of myosin and the lowering of contractility.
Isosorbide dinitrate causes a relaxation of vascular smooth muscle thereby inducing a vasodilation.
Both peripheral arteries and veins are relaxed by isosorbide dinitrate. The latter effect promotes venous pooling of blood and decreases venous return to the heart, thereby reducing ventricular end-diastolic pressure and volume (preload).
The action on arterial, and at higher dosages arteriolar vessels, reduce the systemic vascular resistance (afterload). This in turn reduces the cardiac work.
The effect on both preload and afterload lead subsequently to a reduced oxygen consumption of the heart.
Furthermore, isosorbide dinitrate causes redistribution of blood flow to the subendocardial regions of the heart when the coronary circulation is partially occluded by arteriosclerotic lesions. This last effect is likely to be due to a selective dilation of large coronary vessels. Nitrate-induced dilation of collateral arteries can improve the perfusion of poststenotic myocardium. Nitrates also dilate eccentric stenoses as they can counteract possible constricting factors acting on the residual arch of compliant smooth muscle at the site of the coronary narrowing. Furthermore, coronary spasms can be relaxed by nitrates.
Nitrates were shown to improve resting and exercise haemodynamics in patients suffering from congestive heart failure. In this beneficial effect several mechanisms including an improvement of valvular regurgitation (due to the lessening of ventricular dilation) and the reduction of myocardial oxygen demand are involved.
By decreasing the oxygen demand and increasing the oxygen supply, the area of myocardial damage is reduced. Therefore, isosorbide dinitrate may be useful in selected patients who suffered a myocardial infarction.
Effects on other organ systems include a relaxation of the bronchial muscle, the muscles of the gastrointestinal, the biliary and the urinary tract. Relaxation of the uterine smooth muscles is reported as well.
After administration of one tablet of isosorbide dinitrate at least two peak concentrations of isosorbide dinitrate occurred in the plasma. The initial peak (mean 1.9 ng/ml, range 1.0 to 3.4 ng/ml) occurred during 0.5 to 2 hours and then the mean plasma concentrations declined to 1.3 ng/ml at 3 hours. The concentration then increased again to reach a major peak level (mean 6.2 ng/ml range 1.6 to 12.3 ng/ml) during 4 to 6 hours after dosing. Plasma concentrations of isosorbide dinitrate have been measured after administration of increasing doses in the range 20 to 100 mg as isosorbide dinitrate tablets. Means of peak concentrations of 4.2 ng/ml, 13.1 ng/ml, 20.7 ng/ml, 36.8 ng/ml and 34.9 ng/ml were measured after doses of 20mg, 40mg, 60mg, 80mg and 100mg respectively.
Gastrointestinal absorption is slower than absorption through the oral mucosa. The first pass effect is higher when given orally. Isosorbide dinitrate is metabolised to isosorbide 2-mononitrate with a half life of 2.01 h (±0.4 h) to 2.5 h and isosorbide 5-mononitrate with a half-life of 4.6 h (±0.8 h). Both metabolites are pharmacologically active.
The relative bioavailability of isosorbide dinitrate prolonged release tablet in comparison to the non-sustained-release tablet amounts to more than 80% after oral use.
Isosorbide dinitrate (ISDN) is eliminated from plasma with a short half-life (about 0.7h). 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, 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 2.5h) is shorter than that of IS-5-MN (about 5.1h). The half-life of ISDN is the shortest of all and that of IS-2-MN (about 3.2h) lies in between.
None stated.
Acute toxicity of isosorbide dinitrate was related to an exaggerated pharmacodynamic effect. Animal studies showed good local tolerability of the undiluted isosorbide dinitrate solution.
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.
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.
No evidence for mutagenic effect was found in both in vitro and in vivo tests.
A long-term study in rats did not provide any evidence for carcinogenicity.
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