CAS RN:55-63-0

Toxicity Summary

IDENTIFICATION: Glyceryl trinitrate is used as an anti-anginal vasodilating agent. It slightly volatile odorless oily liquid with sweet, aromatic and pungent taste. Soluble in water, ethanol, methanol and miscible with ether, acetone and chloroform. Indications: Prophylaxis and treatment of angina and left ventricular failure. Control of hypertension during cardiac surgery. Congestive cardiac failure unresponsive to usual therapy. HUMAN EXPOSURE: Main risks and target organs: Toxic effects of glyceryl trinitrate are caused by vasodilatation and methemoglobinemia. Venous and arterial vasodilatation causes lowering of blood pressure leading to shock. Heart, blood vessels and red blood cells are the target organs in glyceryl trinitrate poisoning. Summary of clinical effects: Features of poisoning may appear within a few minutes to one hour or more after exposure. There is tachycardia and hypotension followed by bradycardia and collapse. Flushing of the face, headache, dizziness, restlessness, syncope, convulsions and coma may be present. Some of the other features are vomiting, diarrhoea, cyanosis and methaemoglobinaemia and respiratory failure. Effects of glyceryl trinitrate are enhanced by alcohol. Contraindications to the use of glyceryl trinitrate is in patients with hypo, head injury, severe anemia, cerebral hemorrhage and in patients predisposed to closed-angle glaucoma. Intravenous administration contraindicated in constrictive pericarditis and uncorrected hypovolaemia. Routes of entry: Oral: Toxic effects can occur by ingestion. Inhalation: Inhalation of dust may cause toxic effects. Dermal: Toxic effects may occur when absorbed through skin. Prolonged skin contact can cause skin eruptions. Parenteral: Toxic effects can occur by the administration of excessive intravenous doses. Absorption by route of exposure: Oral: Glyceryl trinitrate is readily absorbed from the oral mucosa but rapidly metabolized so that it has only a fleeting duration of action. It is also readily absorbed from the gastrointestinal tract, but owing to extensive first-pass metabolism in the liver its bioavailability is reduced. A study involving 5 healthy persons indicated a bioavailability of less than 1% following administration by mouth of glyceryl trinitrate capsule and oral solution. However the weakly pharmacologically active dinitrate metabolites reached relatively high concentrations after oral glyceryl trinitrate administration and it was suggested that these metabolites may be responsible for the activity of oral glyceryl trinitrate. Dermal: Glyceryl trinitrate is also absorbed through the skin from an ointment base. Distribution by route of exposure: The time to peak concentration depends on the route of administration; it occurs after 2 minutes, 40 minutes and one hour after sublingual, oral and dermal administration respectively. Bioavailability is 38% after sublingual and 1% for oral administration. Biological half-life by route of exposure: This drug has a very short plasma half life. Elimination half-life of nitroglycerin is 1.7 to 2.9 minutes. When glyceryl trinitrate was given sublingually peak plasma concentrations appeared within 4 minutes and at least half of the intact glyceryl trinitrate was cleared from the blood in 1 to 3 minutes. Peak plasma concentration following dermal application of 45 mg nitroglycerin ointment occurred in about 1 hour. Metabolism: Glyceryl trinitrate is metabolized by hydrolysis to dinitrates and the mononitrate. The half-life for dinitrate metabolites is about 40 minutes approximately 20 times that of glyceryl trinitrate. Elimination by route of exposure: In 10 healthy volunteers given glyceryl trinitrate 560 ug sublingually, about 22% of the administered dose was excreted in the urine after 24 hours mainly as the mononitrate. Mode of action Toxicodynamics: Glyceryl trinitrate has dilator properties on vascular smooth muscle in virtually all vascular beds. The beneficial effects in therapeutic doses and the effects seen with overdose are attributable to the physiologic consequences of systemic venous and arteriolar vasodilatation. The cardiac preload, systemic blood pressure and systemic vascular resistance all show a progressive decrease. A state of hypotension and circulatory collapse and shock may result. methemoglobinemia may occur in patients following an overdose or after therapy. Pharmacodynamics: Glyceryl trinitrate relaxes smooth muscle including vascular smooth muscle, and reduces systolic blood pressure. It is thought that the anti-anginal effect mainly depends on reducing myocardial oxygen demand by means of peripheral vasodilatation which causes decreased venous return permitting a reduction in left ventricular volume and energy expenditure. The effect of glyceryl trinitrate in relaxing coronary vessels is not considered to increase appreciably coronary blood flow. Interactions: Alcohol enhances the effects of glyceryl trinitrate. Undue dizziness and faint feeling may occur when sublingual nitrates are taken with beta-adrenoceptor blocking drugs. Complete AV block has been reported after use of sublingual nitrates in patients receiving lignocaine by infusion. Even cardiac asystole may occur. Disopyramide (by producing dryness in mouth) may prevent dissolution of sublingual isosorbide dinitrate tablets. This may also occur with tricyclic antidepressants. Delayed dissolution of glyceryl trinitrate tablets in patients with dry mouths has been reported in a patient taking imipramine and in another patient treated with atropine. A patient developed resistance to the effects of heparin on two occasions directly after intravenous administration of glyceryl trinitrate. The interactions could not be attributed to propylene glycol in the solvent since resistance also occurred during administration of a formulation of glyceryl trinitrate without propylene glycol. Explosion flush has been observed in patients with transdermal patch when electric defibrillation was performed. Main adverse effects: The toxicity of the nitrates is unaffected by the chemical form or by the route of administration and all the nitrates have a common profile of adverse effects. Hypotension, reflex tachycardia and palpitations may occur. Postural hypotension and syncope is seen, especially in elderly patients. Rarely severe bradycardia has been reported. Throbbing headache is quite common. This symptoms is likely to recede as tolerance develops. Peripheral edema is also frequently seen. Transient hypoxemia with precipitation of angina is seen occasionally. Transient cerebral ischemic episodes unrelated to changes in blood pressure are rarely seen. In patients with cerebrovascular disease, it is recommended to initiate treatment with small doses. Although tolerance has long been associated with nitrates, its clinical implications are not clear. Tolerance is best defined as a decreasing pharmacological effect over time, often with a need for an increasing dose to achieve a given action. Tolerance may be partial or incomplete and may occur to one aspect of nitrate therapy and not to others. Disappearance of the throbbing headache is useful. However, due to an attenuation of the antihypertensive effect, these agents are not useful in the long term management of hypertension. The part played by the arterial and venous side of the circulation pertaining to the development of tolerance is not clear. By having a long (approximately 8 hours) nitrate free interval, the development of tolerance may be avoided or reduced. Decreasing the number of daily doses of glyceryl trinitrate also helps to achieve this effect. Sustained release preparations are more likely to produce tolerance than the short acting preparations.
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