Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Ethypharm, 194, Bureaux de la Colline – Bâtiment D, 92213 Saint-Cloud Cedex, France
Pharmacotherapeutic group: Vasodilator used in cardiac diseases
ATC code: C01DA14
Organic nitrates (including glyceryl trinitrate, isosorbide dinitrate and isosorbide mononitrate) are potent relaxers of smooth muscle. They have a powerful effect on vascular smooth muscle with less effect on bronchiolar, gastrointestinal, ureteral and uterine smooth muscle. Low concentrations dilate both arteries and veins.
Venous dilatation pools blood in the periphery leading to a decrease in venous return, central blood volume, and ventricular filling volumes and pressures. Cardiac output may remain unchanged or it may decline as a result of the decrease in venous return. Arterial blood pressure usually declines secondary to a decrease in cardiac output or arteriolar vasodilatation, or both. A modest reflex increase in heart rate results from the decrease in arterial blood pressure. Nitrates can dilate epicardial coronary arteries including atherosclerotic stenoses.
The cellular mechanism of nitrate-induced smooth muscle relaxation has become apparent in recent years. Nitrates enter the smooth muscle cell and are cleaved to inorganic nitrate and eventually to nitric oxide. This cleavage requires the presence of sulphydryl groups, which apparently come from the amino acid cysteine. Nitric oxide undergoes further reduction to nitrosothiol by further interaction with sulphydryl groups.
Nitrosothiol activates guanylate cyclase in the vascular smooth muscle cells, thereby generating cyclic guanosine monophosphate (cGMP). It is this latter compound, cGMP, that produces smooth muscle relaxation by accelerating the release of calcium from these cells.
This product has all the pharmacokinetic characteristics of a true modified release dosage form.
Compared with an immediate-release dosage form, the peak plasma concentration obtained is lower and occurs later, while the apparent elimination half-life is unchanged. Thus, compared to ordinary capsules, the absorption phase is prolonged and the duration of effect is extended.
The clinical effects of nitrates may be reduced following repeated administration due to too high and/or constant plasma levels. This can be avoided by allowing low plasma levels for a certain period between doses.
The slow continuous diffusion of the active ingredient from the modified-release microgranules makes it possible, at steady state, to maintain plasma concentrations above the putative effective level of 100ng/ml for a period of about 16 hours for the 40mg capsules and 20 hours for the 60mg capsules. Thus, no development of tolerance should be seen with isosorbide mononitrate SR capsules when they are taken in accordance with the recommended dosage regime.
In man, isosorbide mononitrate is absorbed completely and rapidly following oral administration. There is no effect of food on bioavailability.
Isosorbide mononitrate has a volume of distribution of about 40 litres and is not significantly protein bound.
Isosorbide mononitrate is extensively metabolised to nitric oxide (NO-which is the active ingredient) and isosorbide (inactive). Unlike isosorbide dinitrate, isosorbide mononitrate does not undergo first pass hepatic metabolism and provides a low degree of inter-individual variation of blood levels, leading to predictable and reproducible clinical effects.
Most of isosorbide mononitrate is excreted unchanged in the urine.
In patients with cirrhotic disease or cardiac failure or renal failure, parameters were similar to those obtained in healthy volunteers.
High concentrations of isosorbide mononitrate in rats is associated with prolonged gestation and parturition, stillbirths and deaths.
After chronic administration at high doses (60mg/kg), signs of toxicity have been detected in canine liver and kidneys. Tests conducted have shown no evidence of a teratogenic or mutagenic potential.
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