Nitroglycerin (Glycerol Trinitrate)

Nitroglycerin is an antianginal agent belonging to Nitrate.

Nitroglycerin is a nitrate vasodilator used to treat or prevent angina, heart failure, hypertension, and anal fissures.

Nitroglycerin is rapidly absorbed following sublingual administration of Nitroglycerin tablets. Mean peak nitroglycerin plasma concentrations occur at a mean time of approximately 6 to 7 minutes post dose. The absolute bioavailability of nitroglycerin from Nitroglycerin tablets is approximately 40% but tends to be variable due to factors influencing drug absorption, such as sublingual hydration and mucosal metabolism. The volume of distribution of nitroglycerin following intravenous administration is 3.3 L/kg. At plasma concentrations between 50 and 500 ng/mL, the binding of nitroglycerin to plasma proteins is approximately 60%, while that of 1,2- and 1,3-dinitroglycerin is 60% and 30%, respectively.

A liver reductase enzyme is of primary importance in the metabolism of nitroglycerin to glycerol di- and mononitrate metabolites and ultimately to glycerol and organic nitrate. Nitroglycerin plasma concentrations decrease rapidly, with a mean elimination half-life of 2 to 3 minutes. Half-life values range from 1.5 to 7.5 minutes. Clearance (13.6 L/min) greatly exceeds hepatic blood flow. Metabolism is the primary route of drug elimination.

Nitroglycerin shows common side effects Vertigo, dizziness, weakness, palpitation, postural hypotension, nausea, vomiting, weakness, diaphoresis, pallor, and collapse, syncope and flushing, etc.

Nitroglycerin is available in the form of Oral capsule, sublingual powder, sublingual spray, sublingual tablet, Topical ointment, Transdermal patch and intravenous solution.

Nitroglycerin is available in India, US, UK, Japan, Austria, Canada, Russia, China and Japan.

Nitroglycerin belonging to the Nitrate acts as an antianginal agent.

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. These events lead to dephosphorylation of myosin light chains, which regulate the contractile state in smooth muscle, and result in vasodilatation.

The onset of action of Nitroglycerin is found to be 1-3 minutes (by sublingual tablet and translingual spray), 15-30 minutes (by topical ointment), 30 minutes (by transdermal patch), 60 minutes (by extended-release tablet) and immediately (by intravenous).

The Duration of Action for Nitroglycerin in the body is at least 25 minutes (by sublingual tablet and translingual spray), 7 hours (by topical ointment), 10-12 hours (by transdermal patch), 4-8 hours (by extended-release tablet) and 3-5 minutes (by intravenous).

The Tmax was found within 5 minutes (by sublingual tablet), 4-15 minutes (by translingual spray), ~60 minutes (by topical ointment), 120 minutes (by transdermal patch), 2-4 hours (by extended-release tablet) and immediately (by intravenous).

Nitroglycerin is available in the form of Oral capsule, sublingual powder, sublingual spray, sublingual tablet, Topical ointment, Transdermal patch and intravenous solution.

Nitroglycerin is a nitrate vasodilator used to treat or prevent angina, heart failure, hypertension, and anal fissures.

Nitroglycerin is an antianginal agent belonging to Nitrate.

Reduces cardiac oxygen demand by decreasing left ventricular pressure and systemic vascular resistance; dilates coronary arteries and improves collateral flow to ischemic regions.

Nitroglycerin is approved for use in the following clinical indications

• Nitroglycerin used to treat or prevent angina.
• Nitroglycerin used for treatment of heart failure.
• Nitroglycerin used for management of hypertension.
• Nitroglycerin also used to treat anal fissures.

Although not approved, there have been certain off-label indications. These include

• Pediatric Heart failure; cardiogenic shock
• Pediatric Extravasation (sympathomimetic vasopressors), treatment (alternative to phentolamine)

Adult Dosing:

• Angina Pectoris

Intravenous solution:

5 mcg/min continuous IV infusion via non-absorptive tubing; increase by 5 mcg/min every 3 to 5 minutes as needed up to 20 mcg/min, then by 10 or 20 mcg/min if needed.

lingual spray:

1 to 2 sprays (0.4 to 0.8 mg) on or under tongue every 5 minutes as needed, up to 3 sprays in 15 minutes; if pain persists after maximum dose, prompt medical attention is recommended.

Sublingual tablet:

0.3 to 0.6 mg sublingually or in the buccal pouch every 5 minutes as needed, up to 3 doses in 15 minutes; if pain persists after maximum dose, prompt medical attention is recommended.

• Angina Pectoris Prophylaxis

Lingual spray:

1 to 2 sprays (0.4 to 0.8 mg) on or under tongue 5 to 10 minutes prior to activity that might precipitate an acute attack

Sublingual tablet:

0.3 to 0.6 mg sublingually or in the buccal pouch 5 to 10 minutes prior to engaging in activities that might precipitate an acute attack

Topical ointment:

1/2 inch (7.5 mg) topically upon rising and 1/2 inch (7.5 mg) 6 hours later; titrate as needed and tolerated

Transdermal patch:

0.2 to 0.4 mg/hour patch applied topically once a day for 12 to 14 hours per day; titrate as needed and tolerated up to 0.8 mg/hour

Extended-release capsule:

2.5 to 6 mg orally 3 to 4 times a day; titrate as needed and tolerated.

• Myocardial Infarction

Intravenous solution:

5 mcg/min continuous IV infusion via non-absorptive tubing; increase by 5 mcg/min every 3 to 5 minutes as needed up to 20 mcg/min, then by 10 or 20 mcg/min if needed.

• Hypertension

Intravenous solution:

5 mcg/min continuous IV infusion via non-absorptive tubing; increase by 5 mcg/min every 3 to 5 minutes as needed up to 20 mcg/min, then by 10 or 20 mcg/min if needed.

• Anal Fissure and Fistula

Rectal ointment:

1 inch of ointment (375 mg of ointment equivalent to 1.5 mg of nitroglycerin) intra-anally every 12 hours for up to 3 weeks.

Pediatric Dosing:

• Heart failure; cardiogenic shock:

Infants and Children

Continuous IV infusion:

Initial: 0.25 to 0.5 mcg/kg/minute; titrate by 1 mcg/kg/minute every 15 to 20 minutes as needed; faster titration may be necessary in some patients; in adults, titration every 3 to 5 minutes has been suggested.

Usual dose range: 1 to 5 mcg/kg/minute.

Usual maximum dose: 10 mcg/kg/minute; doses up to 20 mcg/kg/minute may be used.

Adolescents

Continuous IV infusion:

Initial: 5 to 10 mcg/minute; titrate to a maximum dose of 200 mcg/minute.

• Extravasation (sympathomimetic vasopressors), treatment (alternative to phentolamine):

Infants, Children, and Adolescents

Topical: 2% ointment: 4 mm/kg applied as a thin ribbon to the affected areas; after 8 hours if no improvement, the dose may be repeated at the affected site.

The maximum reported dose is application of a 1-inch strip to the affected site in a neonate; however, this is greater than the usual initial adult dose (¹/₂ inch) for angina; hypotension may occur; carefully monitor blood pressure.

Nitroglycerin is available in various strengths as 0.2 mg/hour; 0.4 mg/ hour; 0.3 mg/ hour; 0.6 mg/ hour; 0.3 mg; 0.4 mg; 0.6 mg; 200 mg/mL-D5%; 100 mg/mL-D5%; 400 mg/mL-D5%; 5 mg/mL; 2.6 mg; 6.5 mg; 0.1 mg/ hour; 0.8 mg/ hour; 2%; 2.5 mg; 9 mg; 3 mg; 1 mg; 2 mg; 400 mg; 0.4%; 1 mg/mL.

Nitroglycerin is available in the form of an Oral capsule, sublingual powder, sublingual spray, sublingual tablet, Topical ointment, Transdermal patch, and intravenous solution.

No information available.

Nitroglycerin is contraindicated in patients with

● Allergic reactions to organic nitrates are extremely rare, but they do occur. Nitroglycerin is contraindicated in patients who are allergic to it.

● 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 is contraindicated in patients who are using a phosphodiesterase-5 (PDE-5) inhibitor (e.g., sildenafil citrate, tadalafil, vardenafil hydrochloride) since these compounds have been shown to potentiate the hypotensive effects of organic nitrates.

• Tolerance

Excessive use may lead to the development of tolerance. Only the smallest dose required for effective relief of the acute angina attack should be used. A decrease in therapeutic effect of sublingual Nitroglycerin may result from use of long-acting nitrates.

• Hypotension

Severe hypotension, particularly with upright posture, may occur with small doses of Nitroglycerin particularly in patients with constrictive pericarditis, aortic or mitral stenosis, patients who may be volume-depleted, or are already hypotensive. Hypotension induced by Nitroglycerin may be accompanied by paradoxical bradycardia and increased angina pectoris. Symptoms of severe hypotension (nausea, vomiting, weakness, pallor, perspiration and collapse/syncope) may occur even with therapeutic doses.

• Hypertrophic Obstructive Cardiomyopathy

Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy.

• Headache

Nitroglycerin produces dose-related headaches, especially at the start of Nitroglycerin therapy, which may be severe and persist but usually subside with continued use.

• Increased intracranial pressure

Nitroglycerin may precipitate or aggravate increased intracranial pressure and subsequently may worsen clinical outcomes in patients with neurologic injury (eg, intracranial hemorrhage, traumatic brain injury). Use is contraindicated in patients with increased intracranial pressure.

Consumption of alcohol is not recommended during treatment with Nitroglycerin due to the increased risk of side effects such as dizziness, lightheadedness, fainting and alcohol can increase the risk of hypotension.

It is not known whether nitroglycerin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when nitroglycerin is administered to a nursing woman.

Pregnancy category B and C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

No information available.

Common Adverse effects

• Headache, Hypotension, Abdominal pain, Dizziness, Asthenia, Dyspnea, pharyngitis, rhinitis, Flushing, orthostatic hypotension, Diaphoresis

Rare Adverse effects

• Drowsiness, exfoliative dermatitis, fixed drug eruption, hypersensitivity reaction, hypoxemia, lactic acidosis, methemoglobinemia, nausea, nonimmune anaphylaxis, pallor, palpitations, rebound hypertension, restlessness, skin rash, tachycardia, vertigo, vomiting.

• PDE-5-Inhibitors And sGC-Stimulators

Nitroglycerin is contraindicated in patients who are using a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE-5). PDE-5-Inhibitors such as avanafil, sildenafil, vardenafil, and tadalafil have been shown to potentiate the hypotensive effects of organic nitrates. Nitroglycerin is contraindicated in patients who are taking soluble guanylate cyclase (sGC) stimulators. Concomitant use can cause hypotension. The time course and dose dependence of these interactions have not been studied and use within a few days of one another is not recommended. Appropriate supportive care for the severe hypotension has not been studied, but it seems reasonable to treat this as a nitrate overdose, with elevation of the extremities and with central volume expansion.

• Ergotamine

Oral administration of nitroglycerin markedly decreases the first-pass metabolism of dihydroergotamine and subsequently increases its oral bioavailability. Ergotamine is known to precipitate angina pectoris. Therefore, patients receiving sublingual Nitroglycerin should avoid ergotamine and related drugs or be monitored for symptoms of ergotism if this is not possible.

• Aspirin

Coadministration of Nitroglycerin with high dose aspirin (1000 mg) results in increased exposure to Nitroglycerin. The vasodilatory and hemodynamic effects of Nitroglycerin may be enhanced by concomitant administration of Nitroglycerin with high dose aspirin.

• Tissue-Type Plasminogen Activator (t-PA)

Concomitant administration of t-PA and intravenous Nitroglycerin has been shown to reduce plasma levels of t-PA and its thrombolytic effect.

The common side effects of Nitroglycerin include the following

• Common
  

Vertigo, dizziness, weakness, palpitation, postural hypotension, nausea, vomiting, weakness, diaphoresis, pallor, and collapse, syncope and flushing.

• Serious

Fainting, fast/irregular/pounding heartbeat, rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

• Pregnancy

Pregnancy Category B and C

Animal reproduction and teratogenicity studies have not been conducted with nitroglycerin sublingual tablets. However, teratology studies conducted in rats and rabbits with topically applied nitroglycerin ointment at dosages up to 80 mg/kg/day and 240 mg/kg/day, respectively revealed no toxic effects on dams or fetuses. There are no adequate and well-controlled studies in pregnant women. Nitroglycerin should be given to a pregnant woman only if clearly needed.

• Nursing Mothers

It is not known whether Nitroglycerin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when nitroglycerin is administered to a nursing woman.

• Pediatric Use

The safety and effectiveness of Nitroglycerin in pediatric patients have not been established.

• Geriatric Use

Clinical studies of Nitroglycerin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

• Hemodynamic Effects

The effects of nitroglycerin overdose are generally the results of Nitroglycerin capacity to induce vasodilatation, venous pooling, reduced cardiac output, and hypotension. These hemodynamic changes may have protean manifestations, including increased intracranial pressure, with any or all of persistent throbbing headache, confusion, and moderate fever; vertigo; palpitations; tachycardia; visual disturbances; nausea and vomiting (possibly with colic and even bloody diarrhea); syncope (especially in the upright posture); dyspnea, later followed by reduced ventilatory effort; diaphoresis, with the skin either flushed or cold and clammy; heart block and bradycardia; paralysis; coma; seizures; and death. No specific antagonist to the vasodilator effects of nitroglycerin is known, and no intervention has been subject to controlled study as a therapy of nitroglycerin overdose. Because the hypotension associated with nitroglycerin overdose is the result of vasodilatation and arterial hypovolemia, prudent therapy in this situation should be directed toward increase in central fluid volume. Passive elevation of the patient’s legs may be sufficient, but intravenous infusion of normal saline or similar fluid may also be necessary. The use of epinephrine or other arterial vasoconstrictors in this setting is likely to do more harm than good. In patients with renal disease or congestive heart failure, therapy resulting in central volume expansion is not without hazard. Treatment of nitroglycerin overdose in these patients may be subtle and difficult, and invasive monitoring may be required.

• Methemoglobinemia

Methemoglobinemia has been rarely reported in association with organic nitrates. The diagnosis should be suspected in patients who exhibit signs of impaired oxygen delivery despite adequate cardiac output and adequate arterial PO2. Classically, methemoglobinemia blood is described as chocolate brown, without color change on exposure to air. If methemoglobinemia is present, intravenous administration of methylene blue, 1 to 2 mg/kg of body weight, may be required.

Pharmacodynamic

Consistent with the symptomatic relief of angina, digital plethysmography indicates that onset of the vasodilatory effect occurs approximately 1 to 3 minutes after sublingual nitroglycerin administration and reaches a maximum by 5 minutes post dose. Effects persist for at least 25 minutes following Nitroglycerin administration.

Pharmacokinetics

• Absorption

Nitroglycerin is rapidly absorbed following sublingual administration of Nitroglycerin tablets. Mean peak nitroglycerin plasma concentrations occur at a mean time of approximately 6 to 7 minutes post dose. Maximum plasma nitroglycerin concentrations (Cmax) and area under the plasma concentration-time curves (AUC) increase dose-proportionally following 0.3 to 0.6 mg Nitroglycerin. The absolute bioavailability of nitroglycerin from Nitroglycerin tablets is approximately 40% but tends to be variable due to factors influencing drug absorption, such as sublingual hydration and mucosal metabolism.

• Distribution

The volume of distribution (VArea) of Nitroglycerin following intravenous administration is 3.3 L/kg. At plasma concentrations between 50 and 500 ng/mL, the binding of nitroglycerin to plasma proteins is approximately 60%, while that of 1,2- and 1,3-dinitroglycerin is 60% and 30%, respectively.

• Metabolism

A liver reductase enzyme is of primary importance in the metabolism of Nitroglycerin to glycerol di- and mononitrate metabolites and ultimately to glycerol and organic nitrate. Known sites of extrahepatic metabolism include red blood cells and vascular walls. In addition to Nitroglycerin, 2 major metabolites 1,2- and 1,3-dinitroglycerin, are found in plasma. Mean peak 1,2- and 1,3-dinitroglycerin plasma concentrations occur at approximately 15 minutes post dose. The elimination half-life of 1,2- and 1,3-dinitroglycerin is 36 and 32 minutes, respectively. The 1,2- and 1,3-dinitroglycerin metabolites have been reported to possess approximately 2% and 10%, respectively, of the pharmacological activity of Nitroglycerin. Higher plasma concentrations of the dinitro metabolites, along with their nearly 10-fold longer elimination half-lives, may contribute significantly to the duration of pharmacologic effect. Glycerol mononitrate metabolites of Nitroglycerin are biologically inactive.

• Excretion
  

Nitroglycerin plasma concentrations decrease rapidly, with a mean elimination half-life of 2 to 3 minutes. Half-life values range from 1.5 to 7.5 minutes. Clearance (13.6 L/min) greatly exceeds hepatic blood flow. Metabolism is the primary route of drug elimination.

1. Hill NS, Antman EM, Green LH, Alpert JS. Intravenous nitroglycerin: a review of pharmacology, indications, therapeutic effects and complications. Chest. 1981 Jan 1;79(1):69-76.
2. Ferreira JC, Mochly-Rosen D. Nitroglycerin Use in Myocardial Infarction Patients–Risks and Benefits–. Circulation Journal. 2012;76(1):15-21.
3. Hollenberg M, Go M. Clinical studies with transdermal nitroglycerin. American Heart Journal. 1984 Jul 1;108(1):223-31.

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