Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Vasodilators 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.

Mechanism of action
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.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
Immediate release tablets:
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-glucuronide 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.

Slow release formulation:
Isosorbide mononitrate is rapidly absorbed following oral administration. The bioavailability is 80-90% when compared to the immediate release isosorbide mononitrate tablets.
Isosorbide mononitrate is extensively metabolised to nitric oxide (NO – which is the active agent) and isosorbide (inactive). In patients with cirrhotic disease or cardiac failure or renal failure, pharmacokinetic parameters were similar to those obtained in healthy volunteers.

Characteristics in patients:
Evidence was provided that the plasma profiles in healthy volunteers and patients suffering from chronic stable angina are similar.
Isosorbide mononitrate is dialysable.