Source: Υπουργείο Υγείας (CY) Revision Year: 2019 Publisher: Remedica Ltd, Aharnon Street, Limassol Industrial Estate, 3056 Limassol, Cyprus
Pharmacotherapeutic group: Cardiac therapy; Vasodilator used in cardiac diseases
ATC code: C01DA14
Isosorbide mononitrate 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 mononitrate 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 dilation 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.
Like all organic nitrates, isosorbide mononitrate 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 smooth muscle tone.
Isosorbide-5-mononitrate is rapidly absorbed and peak plasma levels occur approx. 1 hour following oral dosing.
Isosorbide-5-mononitrate is completely bioavailable after oral doses and is not subject to pre-systemic elimination processes.
Isosorbide-5-mononitrate is eliminated from the plasma with a half-life of about 5.1 hours. It is metabolised to Isosorbide-5-MN-2-glucoronide, which has a half-life of approximately 2.5 hours. As well as being excreted unchanged in the urine.
After multiple oral dosing plasma concentrations are similar to those that can be predicted from single dose kinetic parameters.
Evidence was provided that the plasma profiles in healthy volunteers and patients suffering from chronic stable angina are similar.
Isosorbide mononitrate is dialysable.
Studies on acute toxicity in mice and rats with different routes of administration indicate a low acute toxicity (LD50 oral approximately 2,000-2,500 mg/kg b.w.).
Long term toxicity has been tested in rats for 78 weeks and in dogs for 52 weeks. First toxic reactions occurred in dosages of 90 mg/kg (dog) and 405 mg/kg (rat), respectively. Thus taking into account the recommended dosage of 20 to 30 mg/d in humans, the therapeutic index can be stated as high.
These studies included a fertility and breeding study over two generations in rats; teratology studies in rats and rabbits; and a rat peri-postnatal study. The dosage levels used were generally high and produced maternal toxic effects at the highest dose. No teratogenic effects of isosorbide mononitrate were observed.
Isosorbide mononitrate was tested in different studies both in vitro and in vivo (Ames test, Human peripheral lymphocytes, Bone marrow of rats and hamsters, V 79 test, SCE test) on possible mutagenic effects. As all tests were negative the mutagenic risk in humans is considered low.
Neither the long term toxicity studies in rats and dogs nor a special carcinogenicity study, performed in rats over 125 weeks (males) and 138 weeks (females), indicated neoplastic properties of isosorbide mononitrate. Therefore, it can be concluded that the carcinogenic risk in humans is low.
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