Nitroglycerin

NITROGLYCERIN- nitroglycerin tablet
Glenmark Generics Inc., USA

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DESCRIPTION

Nitroglycerin, an organic nitrate, is a vasodilating agent. The chemical name for nitroglycerin is 1,2,3-propanetriol trinitrate. The chemical structure is:

Chemical Structure for Nitroglycerin
(click image for full-size original)

Nitroglycerin tablets USP are compressed sublingual nitroglycerin tablets containing the non-volatile nitroglycerin fixing agent polyethylene glycol. The tablets contain 0.3 mg (1/200 grain), 0.4 mg (1/150 grain), and 0.6 mg (1/100 grain) nitroglycerin. Also contains lactose NF, polyethylene glycol 3350 NF, microcrystalline cellulose NF, colloidal silicon dioxide NF, and magnesium stearate NF.

CLINICAL PHARMACOLOGY

Relaxation of vascular smooth muscle is the principal pharmacologic action of nitroglycerin. The mechanism by which nitroglycerin produces relaxation of smooth muscle is unknown. Although venous effects predominate, nitroglycerin produces, in a dose-related manner, dilation of both arterial and venous beds. Dilation of the postcapillary 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 nitroglycerin, and amore favorable supply-demand ratio can be achieved.

Nitroglycerin also dilates large epicardial coronary arteries; however, the extent to which this effect contributes to the relief of exertional angina is unclear.

Therapeutic doses of nitroglycerin 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.

Elevated central venous and pulmonary capillary wedge pressures, pulmonary vascular resistance and systemic vascular resistance are also reduced by nitroglycerin therapy. Heart rate is usually slightly increased, presumably a reflex response to the fall in blood pressure. Cardiac index may be increased, decreased, or unchanged. Patients with elevated left ventricular filling pressure and systemic vascular resistance values in conjunction with a depressed cardiac index are likely to experience an improvement in cardiac index. On the other hand, when filling pressures and cardiac index are normal, cardiac index may be slightly reduced by intravenous nitroglycerin.

Mechanism of Action

Nitroglycerin forms free radical nitric oxide (NO) which activates guanylate cyclase, resulting in an increase of guanosine 3’5′ monophosphate (cyclic GMP) in smooth muscle and other tissues. This eventually leads to dephosphorylation of the light chain of myosin, which regulates the contractile state in smooth muscle, resulting in vasodilation.

Pharmacokinetics and Metabolism

Nitroglycerin 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 above route.

Nitroglycerin is rapidly metabolized to dinitrates and mononitrates, with a short half-life, estimated at 1 to 4 minutes. A liver reductase enzyme is of primary importance in the metabolism of nitroglycerin to glycerol nitrate metabolites and organic nitrate. Two active major metabolites 1,2- and 1,3-dinitroglycerols are less potent vasodilators and have longer half-lives than the parent compound. Dinitrates are metabolized to mononitrates and ultimately glycerol. The monohydrate is not considered biologically active with respect to cardiovascular effects.

At plasma concentrations of between 50 and 500 ng/mL, the binding of nitroglycerin to plasma proteins is approximately 60%, while that of 1,2dinitroglycerin 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. The mononitrate is not active.

INDICATIONS AND USAGE

Nitroglycerin is indicated for the acute relief of an attack or prophylaxis of angina pectoris due to coronary artery disease.

CONTRAINDICATIONS

Sublingual nitroglycerin therapy is contraindicated in patients with early myocardial infarction, severe anemia, increased intracranial pressure and those with a known hypersensitivity to nitroglycerin.

Administration of Nitroglycerin tablets USP is contraindicated in patients who are using Viagra® (sildenafil citrate). Viagra® has been shown to potentiate the hypotensive effects of organic nitrates.

WARNINGS

The use of nitroglycerin during the early course of acute myocardial infarction requires particular attention to hemodynamic monitoring and clinical status.

PRECAUTIONS

General

Only the smallest dose required for effective relief of the acute anginal attack should be used. Excessive use may lead to the development of tolerance. Nitroglycerin USP tablets are intended for sublingual or buccal administration and should not be swallowed. Severe hypotension, particularly with upright posture, may occur even with small doses of nitroglycerin. The drug should be used cautiously in patients with volume depletion or low systolic blood pressure.

Paradoxical bradycardia and increased angina pectoris may accompany nitroglycerin-induced hypotension.

Nitrate therapy may aggravate angina caused by hypertrophic cardiomyopathy.

Tolerance to the vascular and antianginal effects of nitroglycerin and cross-tolerance to other nitrates and nitrites may occur.

The drug should be discontinued if blurring of vision or drying of the mouth occurs. Excessive dosage of nitroglycerin may produce severe headaches.

Information for patients

If possible, patients should sit down when taking Nitroglycerin tablets USP. This eliminates the possibility of falling due to lightheadedness or dizziness.

Nitroglycerin may produce a burning or tingling sensation when administered sublingually; however, the ability to produce a burning or tingling sensation should not be considered a reliable method for determining the potency of the tablets.

Nitroglycerin should be kept in the original glass container, tightly capped. The cotton should be discarded once the bottle is opened.

Administration of Nitroglycerin tablets USP is contraindicated in patients who are using Viagra® (sildenafil citrate). Viagra® has been shown to potentiate the hypotensive effects of organic nitrates (see CONTRAINDICATIONS).

Interactions

Drug interactions

Concomitant use of nitrates and alcohol may cause hypotension. Patients receiving antihypertensive drugs, beta-adrenergic blockers or phenothiazines and nitrates should be observed for possible additive hypotensive effects. Marked orthostatic hypotension has been reported when calcium channel blockers and organic nitrates were used concomitantly. Dose adjustment of either class of agent may be necessary.

Aspirin may decrease the clearance and enhance the hemodynamic effects of sublingual nitroglycerin. A decrease in the therapeutic effect of sublingual nitroglycerin may result from use of long-acting nitrates.

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