Nitroglycerin

Nitroglycerin is a Vasodilator that acts as an antihypertensive agent used to treat or prevent angina pectoris due to coronary artery disease. It is also used to treat heart failure, hypertension, and anal fissures.

It is rapidly absorbed from sublingual mucosa and well absorbed from the gastrointestinal tract and through the skin with absolute bioavailability of approx 40% (sublingual). It is widely distributed into the body and crosses the placenta with the volume of distribution of approx 3 L/kg with plasma protein binding of 60%. It is rapidly metabolized in the liver by reductase enzyme to glycerol di- and mononitrate metabolites, further metabolised to glycerol and organic nitrate; undergoes extensive first-pass effect and nonhepatic metabolism via RBCs and vascular walls, and gets excreted via urine (as inactive metabolites) with elimination half-life: Approx 1-4 minutes.

The common side effects are Severe hypotension, shock, paradoxical bradycardia, increased intracranial pressure, dose-related headache, methemoglobinaemia, drug tolerance, and hypoxaemia. Ear and labyrinth disorders: Vertigo. Cardiac disorders: Tachycardia. Gastrointestinal disorders: Nausea, vomiting, etc.

Nitroglycerin is available in the form of a dosage form such as powder, aerosol, injection, capsules and tablets.

Nitroglycerin is available in Australia, Japan, India, the USA, UK

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.

Nitroglycerin is converted by mitochondrial aldehyde dehydrogenase in smooth muscle cells to nitric oxide (NO), a potent vasodilator. It causes protein kinase-dependent phosphorylation and activates downstream cascades that promote relaxation and increased blood flow in veins, arteries and cardiac tissue.

The onset of action of Nitroglycerin is within1 to 5 minutes.

The Duration of Action of Nitroglycerin was within 1.5 to 7.5 minutes.

The Tmax was about 4.4 minutes and 7.2 minutes and Cmax was about 2.56 ng/mL and 2.1 ng/mL

Nitroglycerin is available in the form of dosage form such as powder, aerosol, injection, patch, capsules and tablets.

For Powder:

Lift up the tongue. Pour all the powder in the packet under the tongue. Close the mouth tight right away and breathe normally through your nose. Allow the powder to dissolve before swallow

For Aerosol:-

Adults—1 or 2 sprays on or under the tongue at the first sign of chest pain. Sprays may be repeated every 5 minutes as needed. Wait for 5 minutes before administering a third spray if 2 sprays are used initially. Do not use more than 3 sprays in 15 minutes.

For injection:-

Nitroglycerin injection must be diluted in dextrose (5%) injection or sodium chloride (0.9%) injection prior to its infusion

Transdermal Patch

Apply the patch to a clean, dry skin area with little or no hair that is free of scars, cuts, or irritation. Always remove a previous patch before applying a new one. Apply a new patch if the first one becomes loose or falls off. Apply each patch to a different area to prevent skin irritation.

For Tablets and capsules

Nitroglycerin tablets and capsules should be taken orally by mouth with or without water.

Nitroglycerin reduces cardiac oxygen demand by decreasing preload and may modestly reduce afterload; dilates coronary arteries and improves collateral flow to ischaemic regions. It also decreases sphincter tone and intra-anal pressure when administered rectally. 

Nitroglycerin is a Vasodilator which acts as an antihypertensive agent used to treat or prevent angina pectoris due to coronary artery disease. It is also used to treat heart failure, hypertension, and anal fissures.

Nitroglycerin is approved for use in the following clinical indications

Oral

• Angina pectoris

Adult: Prophylaxis: As extended-release cap: Initially, 2.5-6.5 mg 3-4 times daily, may be increased up to 26 mg 4 times daily if necessary.

Sublingual

• Angina pectoris

Adult: Treatment for acute attacks: As tab: 300-600 mcg placed under the tongue; dose may be repeated at 5-minute intervals for a total of 3 doses. As aerosol spray (400 mcg/spray): 1-2 sprays under the tongue, then close the mouth, dose may be repeated at 5-minute intervals if required. Max: 3 doses. Prophylaxis: As tab: 300-600 mcg, 5-10 minutes prior to activities that may precipitate an attack. As aerosol spray (400 mcg/spray): 1 or 2 sprays, 5-10 minutes prior to activities that may precipitate an attack. Seek medical care if symptoms are not resolved after a total of 3 doses.

Transdermal

• Angina pectoris

Adult: Prophylaxis: As monotherapy or in combination with other anti-anginal treatment: As patch releasing 5 or 10 mg/24 hours: Apply 1 patch daily onto a fresh area of skin (e.g. chest, upper arms, thigh or shoulder). Max: 20 mg daily. Alternatively, 0.2-0.4 mg/hour initially then titrate to 0.4-0.8 mg/hour. Patch may remain on the skin for 12-14 hours, followed by 10-12 hours patch-off period.

Topical/Cutaneous

• Angina pectoris

Adult: Prophylaxis: As 2% ointment: Apply 1-2 inches 3-4 hourly as necessary, onto a convenient area of the skin (e.g. chest, thigh, or arm), spread thinly without rubbing in. May cover the area after application. The dose may be titrated according to patient tolerance.

Although not approved there have been certain off label use documented for Nitroglycerin which includes:-

Intravenous

• Congestive heart failure

Adult: Initially, 20-25 mcg/min via slow infusion, may be decreased to 10 mcg/min, or increased in increments of 20-25 mcg/min every 15-30 minutes until desired response is achieved.

Reconstitution: IV infusion: Dilute a vial labeled as containing 50 mg/50 mL to 450 mL NaCl 0.9% inj or dextrose 5% inj to provide a solution containing 100 mcg/mL.

Incompatibility: Incompatible with phenytoin, alteplase, levofloxacin.

Intravenous

• Induction of hypotension or control of hypertension during surgery

Adult: Initially, 25 mcg/min via slow infusion, may be increased in increments of 25 mcg/min at 5-minute intervals. Usual dose range: 10-200 mcg/min, adjusted according to patient response. Max: 400 mcg/min.

Reconstitution: IV infusion: Dilute a vial labeled as containing 50 mg/50 mL to 450 mL NaCl 0.9% inj or dextrose 5% inj to provide a solution containing 100 mcg/mL.

Incompatibility: Incompatible with phenytoin, alteplase, levofloxacin.

Rectal

• Chronic anal fissure

Adult: As 0.2% ointment: Apply 1-1.5 cm strip of ointment into the anal canal tid. As 0.4% ointment: Apply 2.5 cm (approx 1.5 mg) 12 hourly for up to 8 weeks.

The dosage and the duration of treatment should be as per the clinical judgment of the treating physician

Nitroglycerin is available in various dosage strengths of 0.3mg, 0.4mg, 0.6mg, 25mg/250mL, 50mg/250mL, 100mg/250mL, 5mg/mL, 0.1mg/hr, 0.2mg/hr, 0.3mg/hr, 0.4mg/hr, 0.6mg/hr, 0.8mg/hr, 0.4mg/spray

Nitroglycerin is available in the form of dosage form such as powder, aerosol, injection, patch, capsules and tablets.

Dose Adjustment in Kidney patient:

● CrCl: 10-50 mL/min: Administer every 24-72hr

● CrCl: <10 mL/min: Administer every 72-96hr

Dose Adjustment in Hepatic Impairment Patient:

● No dose adjustment is required for Hepatic Impairment patient

Dose Adjustment in the pediatric patient:

● Safety and effectiveness in pediatric patients have not been established.

Nitroglycerin is a Vasodilator which acts as an antihypertensive agent used to treat or prevent angina pectoris due to coronary artery disease. It is also used to treat heart failure, hypertension, and anal fissures.

Angina pectoris:- Eat plenty of fruits, vegetables, and whole grains. Choose lean proteins, such as skinless chicken, fish, and beans. Eat non-fat or low-fat dairy products, such as skim milk and low-fat yogurt. Avoid foods that contain high levels of sodium (salt).

Heart failure:- Choose plenty of fresh fruits and vegetables.They contain only small amounts of salt. Choose foods that are low in salt, such as fresh meats, poultry, fish, dry and fresh legumes, eggs, milk and yogurt. Plain rice, pasta and oatmeal are good low-sodium choices.

Hypertension:- It has been observed that the low-salt Dietary Approaches to Stop Hypertension (DASH) diet lowers blood pressure. Sometimes after a few weeks, its effects on blood pressure become noticeable.

The dietary restriction should be individualized as per the patient requirements.

Nitroglycerin may be contraindicated in the following

• Allergic reactions to nitroglycerin are extremely rare, but reports do exist. Nitroglycerin is contraindicated in patients that have reported allergic symptoms to the medication.

• Known history of increased intracranial pressure, severe anemia, right-sided myocardial infarction, or hypersensitivity to nitroglycerin are contraindications to nitroglycerin therapy.

• Concurrent use of nitroglycerin with PDE-5 inhibitors (e.g., sildenafil citrate, vardenafil hydroxide, tadalafil) is absolutely contraindicated. PDE-5 inhibitors have proven to accentuate the hypotensive effects of nitrates and precipitate syncopal episodes.

• 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 the 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.

Nonclinical Toxicology

• Carcinogenesis, Mutagenesis, Impairment Of Fertility

Animal carcinogenesis studies with sublingually administered nitroglycerin have not been performed.

The carcinogenicity potential of nitroglycerin was evaluated in rats receiving up to 434 mg/kg/day of dietary nitroglycerin for 2 years. Rats developed dose-related fibrotic and neoplastic changes in the liver, including carcinomas, and interstitial cell tumors in testes. At high dose, the incidences of hepatocellular carcinomas in males was 48% and in females was 33%, compared to 0% in untreated controls. Incidences of testicular tumors were 52% vs. 8% in controls. Lifetime dietary administration of up to 1058 mg/kg/day of nitroglycerin was not tumorigenic in mice.

Nitroglycerin was mutagenic in Ames tests performed in 2 different laboratories. Nevertheless, there was no evidence of mutagenicity in an in vivo dominant lethal assay with male rats treated with doses up to about 363 mg/kg/day, PO, or in ex vivo cytogenetic tests in rat and dog cells.

In a 3-generation reproduction study, rats received dietary nitroglycerin at doses up to about 434 mg/kg/day for 6 months prior to mating of the F0 generation, with treatment continuing through successive F1 and F2 generations. The high dose was associated with decreased feed intake and body weight gain in both sexes at all matings. No specific effect on the fertility of the F0 generation was seen. Infertility noted in subsequent generations, however, was attributed to increased interstitial cell tissue and spermatogenesis in the high-dose males. In this 3-generation study, there was no clear evidence of teratogenicity.

Alcohol consumption with Nitroglycerin may increase the risk of low blood pressure and cause adverse effects, such as dizziness, fainting, light-headedness, or headache.

• Sublingual nitroglycerin has not been studied in lactating women. It is not known if nitroglycerin is present in human milk or if nitroglycerin has effects on milk production.

US FDA pregnancy category 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.

The adverse reactions related to molecule Nitroglycerin can be categorised as

● Common Adverse effects:

Severe hypotension, shock, paradoxical bradycardia, increased intracranial pressure, dose-related headache, methaemoglobinaemia, drug tolerance, hypoxaemia, Dizziness, drowsiness, paraesthesia.

● Less Common adverse effects:

Asthenia; application site reactions (e.g. irritation, rash, pruritus, erythema, burning or stinging sensation).

Rare adverse effects:

Cerebral ischaemia, Orthostatic hypotension, flushing, syncope.

The clinically relevant drug interactions of Nitroglycerin is briefly summarized here.

• Enhanced hypotensive effects with other vasodilators and antihypertensives (e.g. ACE inhibitors, β-blockers, calcium channel blockers, diuretics), neuroleptics, TCAs, MAOIs, sapropterin, sublingual apomorphine. Increased vasodilating effects with N-acetylcysteine.

• Reduced absorption of sublingual nitrates with drugs that cause dry mouth (e.g. anticholinergics).

• May increase serum concentrations of ergot derivatives (e.g., dihydroergotamine).

• May diminish the anticoagulant effect of heparin.

• May accelerate plasma clearance of tissue plasminogen activators (IV).

• Potentially Fatal: Potentiated hypotensive effects with phosphodiesterase type 5 inhibitors (e.g. sildenafil, vardenafil, tadalafil) and riociguat..

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

No overall differences in safety or effectiveness have been observed between elderly and younger patients.

Symptoms:

Increased intracranial pressure with cerebral symptoms, colicky pain, diarrhoea, flushing, severe headache, dizziness, vertigo, reflex tachycardia, feeling of suffocation, hypotension, weak pulse, asthenia, pallor. Rarely, cyanosis, methaemoglobinaemia, shock with nausea, vomiting, weakness, sweating, syncope.

Management:

Supportive and symptomatic treatment. Assess vital signs and mental status. Elevate the leg and/or lower the head of the patient to promote venous return during mild hypotension. Perform arterial blood gas estimation if the patient is clinically cyanosed or if acidosis is present. Administer 1-2 mg/kg methylene blue IV over 5 minutes to treat methaemoglobinaemia (except for patient with G6PD deficiency or methaemoglobin reductase deficiency); oxygen if necessary.

Pharmacodynamics:

● Nitroglycerin causes the relaxation of vascular smooth muscles, causing arteriolar and venous dilatation.17 It increases blood flow to the myocardium and reduces cardiac preload and afterload, decreasing myocardial wall stress and ameliorating anginal symptoms.3,10,12 Nitroglycerin also reduces coronary artery spasm, decreasing systemic vascular resistance as well as systolic and diastolic blood pressure.17

● Like other organic nitrates, repeated and prolonged administration of nitroglycerin can lead to the development of tolerance or desensitization of vascular smooth muscle to further nitroglycerin-induced vasorelaxation. This loss of efficacy may be associated with the inhibition of mitochondrial aldehyde dehydrogenase, which is an important enzyme involved in the bioactivation of nitroglycerin.1,2,3 Nitroglycerin tolerance may be accompanied by pro-oxidant effects, endothelial dysfunction, and increased sensitivity to vasoconstrictors.3

Pharmacokinetics:

Absorption:

Rapidly absorbed from sublingual mucosa. Well absorbed from the gastrointestinal tract and through the skin. Absolute bioavailability: Approx 40% (sublingual).

Distribution:

Widely distributed into the body. Crosses placenta. Volume of distribution: Approx 3 L/kg. Plasma protein binding: 60%.

Metabolism:

Rapidly metabolised in the liver by reductase enzyme to glycerol di- and mononitrate metabolites, further metabolised to glycerol and organic nitrate; undergoes extensive first-pass effect and nonhepatic metabolism via RBCs and vascular walls.

Excretion:

Via urine (as inactive metabolites). Elimination half-life: Approx 1-4 minutes.

It gets excreted Via faeces (approx 53%); urine (approx 40%). Elimination half-life: Approx 7 hours

1. https://pubmed.ncbi.nlm.nih.gov/6428209/

2. https://pubmed.ncbi.nlm.nih.gov/6430666/

3. https://clinicaltrials.gov/ct2/show/NCT03777605

1. https://www.nejm.org/doi/full/10.1056/NEJMoa1915928

2. https://www.statpearls.com/ArticleLibrary/viewarticle/134517

3. http://www.druginformation.com/rxdrugs/V/Nitroglycerin Tablets.html#PD

4. https://reference.medscape.com/drug/verquvo-Nitroglycerin -4000131

5. https://www.webmd.com/drugs/2/drug-180731/Nitroglycerin -oral/details/list-contraindications