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Nitroglycerin (medication)

Nitroglycerin, also known as glyceryl trinitrate (GTN), is a vasodilator used for heart failure, high blood pressure, anal fissures, painful periods, treating the pain from esophageal spasm, and to treat and prevent chest pain caused by decreased blood flow to the heart (angina) or due to the recreational use of cocaine.[1][2][3][4] This includes chest pain from a heart attack. It is taken by mouth, under the tongue, applied to the skin by cream or a patch, as a spray, or by injection into a vein.[5][6]

Common side effects include headache and low blood pressure.[5] The low blood pressure can be severe.[5] It is unclear if use in pregnancy is safe for the fetus.[5] It should not be used together with medications within the PDE5 inhibitor family such as sildenafil due to the risk of low blood pressure.[5] Nitroglycerin is in the nitrate family of medications.[5] While it is not entirely clear how it works, it is believed to function by dilating blood vessels.[5]

Nitroglycerin was written about as early as 1846 and came into medical use in 1878.[7][8] The drug nitroglycerin is a dilute form of the same chemical used as the explosive, nitroglycerin.[8] Dilution makes it non-explosive.[8] In 2023, it was the 207th most commonly prescribed medication in the United States, with more than 2million prescriptions.[9][10]

Medical uses

Nitroglycerin is used for the treatment of angina, acute myocardial infarction, severe hypertension, and acute coronary artery spasms.[5][11] It may be administered intravenously, as a sublingual spray/tablet, or as a patch applied to the skin.

Angina

Nitroglycerin is useful in decreasing angina attacks, perhaps more so than reversing angina once started, by supplementing blood concentrations of NO, also called endothelium-derived relaxing factor, before the structure of NO as the responsible agent was known. This led to the development of transdermal patches of nitroglycerin, providing 24-hour release.[12] However, the effectiveness of nitroglycerin is limited by development of tolerance/tachyphylaxis within 2–3 weeks of sustained use. Continuous administration and absorption (such as provided by daily pills and especially skin patches) accelerate onset of tolerance and limit the usefulness of the agent. Thus, nitroglycerin works best when used only in short-term, pulse dosing. Indeed, studies show that a dosing regimen should include nitrate-free days, and in the case of transdermal patches (such as with Nitro-dur), which provide 10-12 hours daily of sustained release for at least 1 month[13] but don't yet have an established minimum time for nitrate-free windows, periods of 10-12 hours is sufficient for preventing tolerance build-up; therefore, an appropriate dosing schedule when used as patches (such as in the case with Nitro-dur) would include 12-14 hours of patch-on followed by a window of 10-12 hours of patch-off.[13]

Other forms of the drug are more effective for treatment of acute episodes of angina once they have started (while most forms are not due to the lack of rapid administration of the drug), and some are useful in the prophylaxis of angina before activities which may precipitate an episode, like having sexual intercourse. Nitroglycerin when used as a spray can treat ongoing episodes with no more than three sprays in a 15-minute period and the same as prophylaxis of an angina attack.[14]

Nitroglycerin is useful for myocardial infarction (heart attack) and pulmonary edema, again working best if used quickly, within a few minutes of symptom onset.[15] It may also be given as a sublingual or buccal dose in the form of a tablet placed under the tongue or a spray into the mouth for the treatment of an angina attack.[16]

Other uses

Tentative evidence indicates efficacy of nitroglycerin in the treatment of various tendinopathies, both in pain management and acceleration of soft tissue repair.[17][18][19][20][21]

Nitroglycerin is also used in the treatment of anal fissures, though usually at a much lower concentration than that used for angina treatment.[1]

Nitroglycerin has been used to decrease pain associated with dysmenorrhea.[3]

Nitroglycerin was once researched for the prevention and treatment of osteoporosis; however, the researcher Sophie Jamal was found to have falsified the findings, sparking one of the largest scientific misconduct cases in Canada.[22]

Nitroglycerin is also used to treat acute episodes of esophageal spasms, by increasing nitric oxide (NO) levels it acts as a smooth muscle relaxant which relaxes muscle cells and lowers pressure in the lower esophageal sphincter, reducing the intense, uncoordinated contractions in the esophagus and easing chest pain.[2] It is often used to treat esophageal spasms associated with eosinophilic esophagitis and Gastroesophageal reflux disease (GERD), although it appears to be less effective at treating spasms in those with GERD.[23][24] Nitroglycerin's effect at reducing lower esophageal pressure has also been found to be effective in helping to treat esophageal food impaction and foreign body obstructions in the esophagus.[25][26][27]

Tolerance

After long-term use for chronic conditions, nitrate tolerance—tolerance to agents such as nitroglycerin—may develop in a patient, reducing its effectiveness. Tolerance is defined as the loss of symptomatic and hemodynamic effects of nitroglycerin or the need for higher doses of the drug to achieve the same effects,[28] and was first described soon after the introduction of nitroglycerin in cardiovascular therapy.[29] Studies have shown that nitrate tolerance is associated with vascular abnormalities which have the potential to worsen patients' prognosis.[30][31] These include endothelial and autonomic dysfunction.[32] The mechanisms of nitrate tolerance have been investigated over the last 30 years, and several hypotheses to explain tolerance have been offered, including:

  • 1) plasma volume expansion
  • 2) impaired transformation of nitroglycerin into NO or related species
  • 3) counteraction of nitroglycerin vasodilation by neurohormonal activation[33]
  • 4) oxidative stress[34]

Adverse events

Nitroglycerin can cause severe hypotension, reflex tachycardia, and severe headaches that necessitate analgesic intervention for pain relief, the painful nature of which can have a marked negative effect on patient compliance.[35]

Nitroglycerin also can cause severe hypotension, circulatory collapse, and death if used together with vasodilator drugs that are used for erectile dysfunction, such as sildenafil, tadalafil, and vardenafil.[36]

Nitroglycerin transdermal patches should be removed before defibrillation due to the risk of explosion or burns, but investigations have concluded that nitroglycerin patch explosions during defibrillation were due to the breakdown voltage of the metal mesh in some patches.[37][38]

Mechanism of action

Nitroglycerin is a prodrug which must be denitrated, with the nitrite anion or a related species further reduced to produce the active metabolite nitric oxide (NO). Organic nitrates that undergo these two steps within the body are called nitrovasodilators, and the denitration and reduction occur via a variety of mechanisms. The mechanism by which such nitrates produce NO is widely disputed. It has been postulated that organic nitrates produce NO by reacting with sulfhydryl groups, while others believe that enzymes such as glutathione S-transferases, cytochrome P450 (CYP), and xanthine oxidoreductase are the primary source of nitroglycerin bioactivation.[39]

The NO produced by this process is a potent activator of guanylyl cyclase (GC) by heme-dependent mechanisms; this activation results in formation of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP). Among other roles, cGMP serves as a substrate for a cGMP-dependent protein kinase that activates myosin light chain phosphatase. Thus, production of NO from exogenous sources such as nitroglycerin increases the level of cGMP within the cell, and stimulates dephosphorylation of myosin, which initiates relaxation of smooth muscle cells in blood vessels.[40]

History

It was known almost from the time of the first synthesis of nitroglycerin by Ascanio Sobrero in 1846 that handling and tasting of nitroglycerin could cause sudden intense headaches,[41][42] which suggested a vasodilation effect.[43] Constantine Hering developed a form of nitroglycerin in 1847 and advocated for its dosing as a treatment of a number of diseases; however, its use as a specific treatment for blood pressure and chest pain was not among these. This is primarily due to his deep rooted focus in homeopathy.[44][45]

Following Thomas Brunton's discovery that amyl nitrite could be used to treat chest pain, William Murrell experimented with the use of nitroglycerin to alleviate angina and reduce blood pressure, and showed that the accompanying headaches occurred as a result of overdose. Murrell began treating patients with small doses of nitroglycerin in 1878, and the substance was widely adopted after he published his results in The Lancet in 1879.[46]

The medical establishment used the name "glyceryl trinitrate" or "trinitrin" to avoid alarming patients, because of a general awareness that nitroglycerin was explosive.[47][48]

Overdoses may generate methemoglobinemia.[49]

Society and culture

Brand names

In the United States, the tablet form of nitroglycerin is marketed (brand name Nitrostat)[50] by Viatris after Upjohn was spun off from Pfizer.[51][52][53]

Nitroglycerin used for treatment of angina has multiple brand names depending on the mode of administration, such as Minitran, Nitro-Dur, Nitrolingual, Nitromist, and Nitro-Bid[54]. The brand name Nitro-bid is an ointment form of Nitroglycerin that is applied twice daily to the skin, hence the name, where "BID" indicates "twice daily" (B.I.D).[55]

Further reading

References

  1. 0.4% nitroglycerin ointment : in the treatment of chronic anal fissure pain Drugs, 2006^
  2. Clinical and manometric effects of nitroglycerin in diffuse esophageal spasm The New England Journal of Medicine, Massachusetts Medical Society, July 1973^
  3. Nitroglycerin as a uterine relaxant: a systematic review Journal of Obstetrics and Gynaecology Canada, May 2002^
  4. Role of voltage-gated sodium, potassium and calcium channels in the development of cocaine-associated cardiac arrhythmias British Journal of Clinical Pharmacology, May 2010^
  5. Nitroglycerin The American Society of Health-System Pharmacists, retrieved 8 December 2016^
  6. How and when to take glyceryl trinitrate (GTN) nhs.uk, 2023-04-18, retrieved 2025-11-17^
  7. Analogue-based Drug Discovery John Wiley & Sons, 2006^
  8. The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs John Wiley & Sons, 2011^
  9. The Top 300 of 2023 ClinCalc, retrieved 12 August 2025^
  10. Nitroglycerin Drug Usage Statistics, United States, 2013 - 2023 ClinCalc, retrieved 20 August 2025^
  11. Coronary artery spasm--clinical features, diagnosis, pathogenesis, and treatment Journal of Cardiology, February 2008^
  12. Nitro-Dur - FDA prescribing information, side effects and uses drugs.com, retrieved 31 March 2017^
  13. DailyMed - NITRO-DUR- nitroglycerin patch dailymed.nlm.nih.gov, retrieved 2025-11-17^
  14. DailyMed - NITROLINGUAL- nitroglycerin spray dailymed.nlm.nih.gov, retrieved 2025-11-17^
  15. Managing Your Angina Symptoms With Nitroglycerin Circulation, American Heart Association, 4 June 2013, retrieved 30 December 2025^
  16. Nitroclycerin Oral Route and Sublingual Route www.mayoclinic.org^
  17. Tendinopathy: a review of the pathophysiology and evidence for treatment The Physician and Sportsmedicine, September 2013^
  18. Treatment of tendinopathy: what works, what does not, and what is on the horizon Clinical Orthopaedics and Related Research, July 2008^
  19. Glyceryl trinitrate patches-An alternative treatment for shoulder impingement syndrome Journal of Orthopaedic Translation, January 2015^
  20. The role of nitric oxide in tendon healing Journal of Shoulder and Elbow Surgery, February 2012^
  21. Evidence on the effectiveness of topical nitroglycerin in the treatment of tendinopathies: a systematic review and meta-analysis Archives of Physical Medicine and Rehabilitation, August 2010^
  22. Misconduct saga rattles bone scientists CMAJ, September 2016^
  23. Esophageal spasm: clinical and manometric response to nitroglycerine and long acting nitrites Gastroenterology, Elsevier Inc., January 1977^
  24. Effect of sublingual nitroglycerin and long-acting nitrate preparations on esophageal motility Gastroenterology, Elsevier Inc., October 1980^
  25. Oral Nitroglycerin Solution May Be Effective for Esophageal Food Impaction The Journal of Emergency Medicine, Elsevier Inc., May 2018^
  26. Sublingual Nitroglycerine for Esophageal Meat Impaction American Journal of Gastroenterology, © The American College of Gastroenterology, October 2009^
  27. The Use of Intravenous Nitroglycerin During Endoscopic Removal of Sharp Esophageal Foreign Body: A Case Report Journal of Iranian Medical Council, 12 December 2022^
  28. Nitrate tolerance The American Journal of Cardiology, Elsevier Inc., December 1985^
  29. Explaining the phenomenon of nitrate tolerance Circulation Research, September 2005^
  30. New insights into mechanisms underlying nitrate tolerance The American Journal of Cardiology, Elsevier Inc., May 1996^
  31. Early vascular abnormalities and de novo nitrate tolerance in diabetes mellitus Diabetes, Obesity & Metabolism, Wiley Online, September 2002^
  32. Nitrate tolerance and the links with endothelial dysfunction and oxidative stress British Journal of Clinical Pharmacology, December 2003^
  33. Such activation is suggested to cause sympathetic activation, and release of vasoconstrictors such as endothelin and angiotensin II.^
  34. Nitrate tolerance, oxidative stress, and mitochondrial function: another worrisome chapter on the effects of organic nitrates The Journal of Clinical Investigation, American Society for Clinical Investigation, February 2004^
  35. Adverse events after prehospital nitroglycerin administration in a nationwide registry analysis The American Journal of Emergency Medicine, December 2021^
  36. Phosphodiesterase Inhibitors CV Pharmacology, retrieved 3 April 2017^
  37. The hazards of defibrillation through nitroglycerin patches Annals of Emergency Medicine, November 1990^
  38. Investigation into voltage breakdown in glyceryl trinitrate patches Resuscitation, June 1998^
  39. Organic nitrate metabolism and action: toward a unifying hypothesis and the future-a dedication to Professor Leslie Z. Benet Journal of Pharmaceutical Sciences, September 2013^
  40. Nitroglycerin StatPearls, StatPearls Publishing, 31 July 2023, retrieved 30 December 2025^
  41. From p. 248: "Il faut toutefois être sur ses gardes en faissant cet essai, car il suffit d'en tenir une très-petite quantité (ce qu'on peut en prendre en y mouillant légèrement le bout du petit doigt) sur la langue pour en éprouver une migraine assez forte pendant pleusieurs heures. Cette action sur le corps humain a été constatée par plusieurs personnes dans mon laboratoire, et je l'ai éprouvée plusieurs fois sur moi-même avant que je fusse certain qu'elle a des propriétés toxiques." (It is always necessary to be on one's guard when making this test, for it suffices to take a very small quantity of it (which one can take by lightly wetting, in it, the tip of the little finger) on [one's] tongue in order to feel a quite strong headache for several hours. This action on the human body has been confirmed by several persons in my laboratory, and I tested it several times on myself before I was certain that it has toxic properties.) Sur plusieur composés détonants produits avec l'acide nitrique et le sucre, la dextrine, la lactine, la mannite et la glycérine Comptes Rendus, 1847^
  42. From p. 198: " … basta il tenere una gocciolina di Piroglicerina sulla lingua, senza inghiottirla, perchè si provi tosto un violento dolore di capo, quale è quello di una forte emicrania, accompagnato da pulsazioni interne assai penose: nello stesso tempo provasi debolezza alle estremità inferiori. Questo effetto sentii io più volte, ed il provarono il signor prof. Valerico Cauda prepartore della mia scuola, ed altre persone ehe tentarono l'esperimento." ( … it suffices to hold a droplet of Piroglicerina [i.e., Sabrero's name for nitroglycerin] on [one's] tongue, without swallowing it, because one soon feels a violent pain in the head, which is a strong headache, accompanied by very painful internal throbbings; at the same time one would feel weakness in the lower extremities. This effect I felt many times, and it was felt by Prof. Valerico Cauda, who prepares lecture demonstrations at my school, and [by] other people who tried the experiment.) Sopra alcuni nuovi composti fulminanti ottenuti col mezzo dell'azione dell'acido nitrico sulle sostante organiche vegetali Memorie della Reale Accademia delle Scienze di Torino, 1849^
  43. (Sobrero, 1849), pp. 198–199. On pages 198–199, Sobrero describes the results of administering nitroglycerin to a puppy, a mouse, and a guinea pig. After giving (orally) several centigrams of nitroglycerin to a puppy, the animal vomited, and within 7-8 minutes, it ceased to breathe. Sobrero managed to revive it, but it convulsed. "L'apertura del suo corpo non diede a scorgere alterazione veruna al ventricolo. I vasi de cervello erano pieni di sangue, come rigonfii di sangue erano l'orocchietta destra de cuore e specialmente la vena cava superiore." (The opening of its body did not reveal any deterioration of the ventricle. The vessels of the brain were full of blood; similarly swollen with blood were the right auricle of the heart and especially the superior vena cava.) Administering nitroglycerin to a mouse and a guinea pig produced similar results.^
  44. Note: Hering renamed nitroglycerine "glonoine". Glonoine, a new medicine for headache, &c. American Journal of Homoeopathy, 1849^
  45. See pp. 22–23. Nitroglycerin: a homeopathic remedy Circulation, January 1986^
  46. Nitro-glycerine as a remedy for angina pectoris. The Lancet, 1879^
  47. Drug Discovery: A History John Wiley & Sons, 2005^
  48. Glyceryl Trinitrate: History, Mystery, and Alcohol Intolerance Molecules, October 2021^
  49. Association of methemoglobinemia and intravenous nitroglycerin administration The American Journal of Cardiology, January 1985^
  50. DailyMed - NITROSTAT- nitroglycerin tablet dailymed.nlm.nih.gov, retrieved 2025-11-17^
  51. Pfizer Completes Transaction to Combine Its Upjohn Business with Mylan Pfizer, 16 November 2020, retrieved 17 June 2024^
  52. Nitrostat Pfizer, retrieved 17 June 2024^
  53. Brands Viatris, 16 November 2020, retrieved 17 June 2024^
  54. Nitroglycerin for angina patient.info, retrieved 2025-11-17^
  55. ISMP's List of Products with Drug Name Suffixes Institute for Safe Medication Practices^