Description: Nitroglycerin, an organic nitrate available in many dosage forms, is a vasodilator proven to be the mainstay of therapy in the management of angina pectoris. Nitroglycerin is also used to control perioperative hypertension, to produce controlled hypotension during surgical procedures, to treat hypertensive emergencies, and to treat congestive heart failure associated with myocardial infarction. Nitroglycerin has also been used to treat pulmonary hypertension. Synthesized in 1846, nitroglycerin was found to cause severe headaches when placed on the tongue. The drug was later found to exhibit vasodepressor effects similar to those of the drug amyl nitrite, but with less adverse effects and better dosage control. The use of sublingual nitroglycerin for the relief of acute anginal attacks was established in 1879. Because it is inexpensive, has a rapid onset of action, and has a well-documented efficacy, sublingual nitroglycerin is still considered the drug of choice for the acute relief of angina. Although organic nitrates are still frequently prescribed for the relief of angina, they have recently come under scrutiny because of the controversy surrounding claims that nitrate tolerance and attenuation of pharmacodynamic effects have been demonstrated with all nitrate dosage forms. Nitroglycerin was granted FDA approval in 1938. In late December 2004, the FDA denied approval for Cellegesic™, a low strength 0.2% topical ointment, which was evaluated for treatment of pain associated with anal fissures and hemorrhoids.

Mechanism of Action: Similar to other nitrites and organic nitrates, nitroglycerin is converted to nitric oxide (NO), a reactive free radical. Nitric oxide, the active intermediate compound common to all agents of this class, activates the enzyme guanylate cyclase, thereby stimulating the synthesis of cyclic guanosine 3',5'-monophosphate (cGMP). This second messenger then activates a series of protein kinase-dependent phosphorylations in the smooth muscle cells, eventually resulting in the dephosphorylation of the myosin light chain of the smooth muscle fiber and the subsequent release, or extrusion, of calcium ions. The contractile state of smooth muscle is normally maintained by a phosphorylated myosin light chain (stimulated by an increase in calcium ions). Thus, the nitrite- or nitrate-induced dephosphorylation of the myosin light chain signals the cell to release calcium, thereby relaxing the smooth muscle cells and producing vasodilation.

It is believed that nitrates correct myocardial oxygen imbalances by reducing systemic and pulmonary arterial pressure (afterload) and decreasing cardiac output secondary to peripheral dilation rather than coronary artery dilation. Nitrates therefore relax peripheral venous vessels, causing a pooling of venous blood and decreased venous return to the heart, which decreases preload. Nitrates reduce both arterial impedance and venous filling pressures, resulting in a reduction of the left ventricular systolic wall tension, which decreases afterload. Thus, nitrate-induced vasodilation increases venous capacitance and decreases arteriole resistance, thereby reducing both the preload and afterload, and lowering the cardiac oxygen demand.

Total coronary blood flow can be increased by nitrites and nitrates in patients with normal hearts, but in patients with ischemia, nitroglycerin does not increase total coronary blood flow but simply redistributes blood to ischemic areas. This effect is believed to be due to the drug's preferential dilation of the larger conductive vessels of the coronary circulation, which, in the presence of coronary atherosclerosis, redirects the distribution of the coronary blood supply to ischemic areas.

Nitrates cause a transient compensatory increase in heart rate and myocardial contractility that normally would increase myocardial oxygen consumption, yet the nitrate-induced decrease in ventricular wall tension results in a net decrease in myocardial oxygen demand and amelioration of the pain of angina pectoris. In addition, nitroglycerin relaxes all other types of smooth muscle including bronchial, biliary, GI, ureteral, and uterine. Nitrites and nitrates are functional antagonists of acetylcholine, norepinephrine, and histamine.

In individuals who have minimal reflex tachycardia, syncope can result from the decrease in blood pressure that occurs following higher doses of nitrates and nitrites. Although this is not likely to occur with doses of nitrates that do not cause blood pressure reduction, patients should be sitting or lying down during and immediately after administration of nitroglycerine.

The antihypertensive actions of nitroglycerin are secondary to pharmacologic properties that make it an effective antianginal agent but are primarily a result of its peripheral vasodilatory effects. With the exception of greater vascular (venous) specificity and the greater variety of pharmaceutical preparations available, nitroglycerin (NTG) is similar to nitroprusside in many respects. Both agents are capable of producing venous (more so with NTG) and arterial dilation, with beneficial effects on redistribution of myocardial blood flow.

Pharmacokinetics: Nitroglycerin can be administered by the oral, lingual (spray), sublingual, intrabuccal, topical, or intravenous routes. Nitroglycerin is well absorbed across the oral mucosa, transdermally, and following systemic oral administration. Irrespective of the route of administration, organic nitrates are virtually completely metabolized by the enzyme glutathione-organic nitrate reductase, so the systemic or presystemic hepatic biotransformation is the key determinant of the bioavailability and duration of action of the various preparations.

The onset of action for each nitroglycerin preparation is as follows: IV, immediate; translingual, 2—4 minutes; extended-release capsules and tablets, 20—45 minutes; sublingual, 1—3 minutes; transmucosal (buccal) extended-release tablets, 2—3 minutes; ointment, 20—60 minutes; and transdermal, 40—60 minutes. Duration of action is as follows: IV, several minutes (dose-dependent); translingual, 30—60 minutes; extended-release capsules and tablets, 8—12 hours; sublingual, 30 minutes; transmucosal (buccal) extended-release, 5 hours; ointment, 4—8 hours; and transdermal, 18—24 hours.

Nitroglycerin distributes widely throughout the body tissues and is approximately 60% plasma protein-bound. The metabolites of nitroglycerin, 1,3- and 1,2-glyceryl dinitrate, are much less potent than the parent compound and have a half-life of approximately 40 minutes, compared to a parent half-life of 1—3 minutes. The metabolites are excreted by the kidneys.

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Gold Standard, Inc. � 2007