Pharmacology: Pharmacodynamics: Relaxation of vascular smooth muscle is the principal pharmacologic action of MYONIT INSTA. Although venous effects predominate, MYONIT INSTA produces, in a dose-related manner, dilation of both arterial and venous beds. Dilation of the post-capillary vessels, including large veins, promotes peripheral pooling of blood and decreases venous return to the heart, reducing left ventricular end-diastolic pressure (preload). Arteriolar relaxation reduces systemic vascular resistance and arterial pressure (afterload). Myocardial oxygen consumption or demand (as measured by the pressure-rate product, tension-time index and stroke-work index) is decreased by both the arterial and venous effects of MYONIT INSTA, and a more favourable supply demand ratio can be achieved.
Therapeutic doses of MYONIT INSTA may reduce systolic, diastolic and mean arterial blood pressure. Effective coronary perfusion pressure is usually maintained, but can be compromised if blood pressure falls excessively or increased heart rate decreases diastolic filling time.
Evaluated central venous and pulmonary capillary wedge pressures, pulmonary vascular resistance and systemic vascular resistance are also reduced by MYONIT INSTA therapy. Heart rate is usually slightly increased, presumably a reflex response to the fall in blood pressure.
Mechanism of Action: The mechanism of action of MYONIT INSTA has been extensively studied. It is believed that MYONIT INSTA and the other organic nitrates lead to the formation of the reactive free radical nitric-oxide(NO), which can interact with and active guanylyl cyclase and increase the synthesis of cGMP in smooth muscle and other tissues. The increase in cGMP leads to the increased stimulation of a cGMP-dependent protein kinase, which results in the alteration of the phosphorylation of various proteins in smooth muscle. This eventually leads to the dephosphorylation of the light chain of myosin. Since phosphorylation of the myosin light chain regulates the maintenance of the contractile state in smooth muscle, this dephosphorylation causes a relaxation in the smooth muscle and hence vasodilation.
Pharmacokinetics: MYONIT INSTA is rapidly absorbed following sublingual administration. Its onset of action is approximately one to three minutes. Significant pharmacologic effects are present for 30 to 60 minutes following administration by the previously mentioned route.
MYONIT INSTA is rapidly metabolized to dinitrates and mononitrates, with a short half-life, estimated at 1 to 4 minutes. At plasma concentrations of between 50 and 500ng/ml, the binding of nitroglycerin to plasma proteins is approximately 60%, while that of 1,2 dinitroglycerin and 1,3 dinitroglycerin is 60% and 30% respectively. The activity and half-life of 1,2 dinitroglycerin and 1,3 dinitroglycerin are not well characterized.