Glyceryl trinitrate Other names: Nitro Trinitroglycerin Nitroglycerine

Glyceryl trinitrate is a vasodilator and is used for angina of effort. Vasodilation is achieved by the releasing of free redical nitric oxide which activates guanylate cyclase and increases synthesis of guanosine 3′ and 5′-monophosphate with resultant effects on the phosphorylation of proteins in smooth muscle. If taken in excess, its vasodilatory effect can cause headache.

Glyceryl trinitrate exerts a spasmolytic action on smooth muscle, particularly in the vascular system. The predominant effect is an increase in venous capacitance resulting in marked diminution of both the left ventricular filling pressure and volume (preload). There is also a reduction in afterload due to moderate dilation of the arteriolar resistance vessels. These haemodynamic changes lower the myocardial oxygen demand. By direct action and through the reduction of myocardial wall tension glyceryl trinitrate also lowers the resistance to flow in the coronary collateral channels and allows re-distribution of blood flow to ischaemic areas of the myocardium.

Administration of glyceryl trinitrate by intravenous infusion to patients with congestive heart failure results in a marked improvement in haemodynamics, reduction of elevated left ventricular filling pressure and systolic wall tension, and an increase in the depressed cardiac output. It reduces the imbalance that exists between myocardial oxygen demand and delivery, thereby diminishing myocardial ischaemia and controlling ischaemia-induced ventricular arrhythmias.

Topical application of a NO donor (glyceryl trinitrate) relaxes the anal sphincter, resulting in a reduction of anal pressure and an improvement in anoderm blood flow.

Glyceryl trinitrate is rapidly absorbed sublingually. Rapid metabolism occurs mainly in the liver and blood by glutathione – organic nitrate reductase to dinitrates which are less potent vasodilators than trinitrates.

Glyceryl trinitrate is also readily absorbed from the gastrointestinal tract, but owing to extensive first-pass metabolism in the liver its bioavailability is reduced (Half-life is 1 to 4 minutes).

The volume of distribution of glyceryl trinitrate is about 3 L/kg and is cleared from this volume at extremely rapid rates, with a resulting serum half-life of about 3 minutes. The observed clearance rates (close to 1 L/kg/min) greatly exceed hepatic blood flow. The known sites of extrahepatic metabolism include red blood cells and vascular walls. The initial products in the metabolism of glyceryl trinitrate are inorganic nitrate and the 1,2 and 1,3-dinitroglycerols. The dinitrates are less effective vasodilators than glyceryl trinitrate, but they are longer lived in the serum. Their contribution to the relaxation of the internal anal sphincter is unknown. The dinitrates are further metabolised to non-vasoactive mononitrates and ultimately to glycerol and carbon dioxide.

In six healthy subjects, the average bioavailability of glyceryl trinitrate applied to the anal canal as a 0.2% ointment was approximately 50% of the 0.75 mg dose.

After intravenous administration, glyceryl trinitrate is widely distributed in the body with an estimated apparent volume of distribution of approximately 200 litres, and is rapidly metabolised to dinitrate and mononitrate with an estimated half life of 1 to 4 minutes, resulting in plasma levels of less than 1 microgram/ml. It is important that the dose be titrated against the individual clinical response.

When the transdermal patch of glyceryl trinitrate is applied to the skin, nitroglycerin is absorbed continuously through the skin into the systemic circulation and thus reaches the target organs (heart, vascular system) before deactivation by the liver. Minitran gives continuous release of nitroglycerin over 24 hours maintaining constant plasma levels. Nitroglycerin is metabolised by hydrolysis to dinitrates and the mononitrate.

Repeat Dose Toxicity

No systemic toxicity studies have been conducted with glyceryl trinitrate. Published data suggest that high oral doses of glyceryl trinitrate may have toxic effects (methaemoglobinaemia, testicular atrophy and aspermatogenesis) in long term treatment. However, these findings represent no special hazards for humans under the conditions of therapeutic use.

Mutagenicity and carcinogenicity

Data from preclinical studies with GTN indicate genotoxic effects in the repair deficient S. typhimurium strain TA1535 only. Lifetime dietary administration of GTN to rodents led to the conclusion that nitroglycerin has no carcinogenic effects relevant for the therapeutic dose range in humans.

Reproductive Toxicity

Reproductive toxicity studies, in rats and rabbits with intravenous, intraperitoneal, and dermal administration of glyceryl trinitrate did not show any adverse effects on fertility or embryonic development at dosages which did not induce parental toxicity. No teratogenicity had been observed. In rats foetotoxic effects (decreased birth weights) were seen at dosages above 1 mg/kg/d (i.p.) and 28 mg/kg/d (dermal) after in utero exposure during foetal development.