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Nitroglycerin (medication)

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For the undiluted form used as an explosive, see Nitroglycerin.

Nitroglycerin
Clinical data
Trade namesNitrol, others
AHFS/Drugs.comMonograph
MedlinePlusa601086
Routes of
administration		Sublingual, transdermal, by mouth, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability<1%
Metabolismliver (rapid), red blood cells, vascular wall
Elimination half-life3 minutes
ExcretionIn urine, in bile
Identifiers
  • 1,3-dinitrooxypropan-2-yl nitrate; [3-(nitrooxy)-2-[(nitrooxy)methyl]propyl] nitrate; 1,2,3-trinitroxy propane
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
ChEBI
ChEMBL
Chemical and physical data
FormulaC3H5N3O9
Molar mass227.085 g·mol−1
3D model (JSmol)
  • C(C(CO[N+](=O)[O-])O[N+](=O)[O-])O[N+](=O)[O-]
  • InChI=1S/C3H5N3O9/c7-4(8)13-1-3(15-6(11)12)2-14-5(9)10/h3H,1-2H2 checkY
  • Key:SNIOPGDIGTZGOP-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Nitroglycerin, also known as glyceryl trinitrate (GTN), is a vasodilator used for heart failure, high blood pressure (hypertension), anal fissures, painful periods, 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.[1] It is taken by mouth, under the tongue, applied to the skin, or by injection into a vein.[1]

Common side effects include headache and low blood pressure.[1] The low blood pressure can be severe.[1] It is unclear if use in pregnancy is safe for the fetus.[1] It should not be used together with medications within the PDE5 inhibitor family such as sildenafil due to the risk of low blood pressure.[1] Nitroglycerin is in the nitrate family of medications.[1] While it is not entirely clear how it works, it is believed to function by dilating blood vessels.[1]

Nitroglycerin was written about as early as 1846[5][6] and came into medical use in 1878.[7][8][9] The drug nitroglycerin is a dilute form of the same chemical used as the explosive, nitroglycerin.[9] Dilution makes it non-explosive.[9] In 2022, it was the 196th most commonly prescribed medication in the United States, with more than 2 million prescriptions.[10][11]

Medical uses

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Three different forms of nitroglycerin: intravenous, sublingual spray, and the nitroglycerin patch.

Nitroglycerin is used for the treatment of angina, acute myocardial infarction, severe hypertension, and acute coronary artery spasms.[1][12] It may be administered intravenously, as a sublingual spray, or as a patch applied to the skin.

Angina

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Glyceryl trinitrate 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 glyceryl trinitrate, providing 24-hour release.[13] However, the effectiveness of glyceryl trinitrate 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, glyceryl trinitrate works best when used only in short-term, pulse dosing. Glyceryl trinitrate is useful for myocardial infarction (heart attack) and pulmonary edema, again working best if used quickly, within a few minutes of symptom onset, as a pulse dose. [citation needed]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.[14]

Other uses

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Tentative evidence indicates efficacy of glyceryl trinitrate in the treatment of various tendinopathies, both in pain management and acceleration of soft tissue repair.[15][16][17][18][19]

Glyceryl trinitrate is also used in the treatment of anal fissures, though usually at a much lower concentration than that used for angina treatment.[2]

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

Glyceryl trinitrate 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.[20]

Tolerance

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After long-term use for chronic conditions, nitrate tolerance—tolerance to agents such as glyceryl trinitrate— may develop in a patient, reducing its effectiveness. Tolerance is defined as the loss of symptomatic and hemodynamic effects of glyceryl trinitrate and/or the need for higher doses of the drug to achieve the same effects,[citation needed] and was first described soon after the introduction of glyceryl trinitrate in cardiovascular therapy. Studies have shown[citation needed] that nitrate tolerance is associated with vascular abnormalities which have the potential to worsen patients' prognosis.[21][full citation needed] These include endothelial and autonomic dysfunction.[22][full citation needed]

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 glyceryl trinitrate into NO or related species
  3. counteraction of glyceryl trinitrate vasodilation by neurohormonal activation[23]
  4. oxidative stress[24][full citation needed]

Adverse events

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Glyceryl trinitrate 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.

Glyceryl trinitrate 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.[25]

Glyceryl trinitrate transdermal patches should be removed before defibrillation due to the risk of explosion and/or burns,[26][verification needed][better source needed] but investigations have concluded that glyceryl trinitrate patch explosions during defibrillation were due to the breakdown voltage of the metal mesh in some patches.[27][non-primary source needed]

Mechanism of action

[edit]

Glyceryl trinitrate 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. Some believe[weasel words] 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 glyceryl trinitrate bioactivation. In recent years,[when?] a great deal of evidence has been produced[citation needed] that supports the conclusion that glyceryl trinitrate's clinically relevant denitration and reduction produce 1,2-glyceryl dinitrate (GDN) and NO, and that this reaction is catalysed by mitochondrial aldehyde dehydrogenase (ALDH2 or mtALDH).

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.[clarification needed] Thus, production of NO from exogenous sources such as glyceryl trinitrate increases the level of cGMP within the cell, and stimulates dephosphorylation of myosin, which initiates relaxation of smooth muscle cells in blood vessels.

History

[edit]

It was known almost from the time of the first synthesis of glyceryl trinitrate by Ascanio Sobrero in 1846 that handling and tasting of nitroglycerin could cause sudden intense headaches,[5][6] which suggested a vasodilation effect (as suggested by Sobrero).[28] 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.[29][30]

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 glyceryl trinitrate in 1878, and the substance was widely adopted after he published his results in The Lancet in 1879.[7]

The medical establishment used the name "glyceryl trinitrate" or "trinitrin" to avoid alarming patients, because of a general awareness that nitroglycerin was explosive.[31][verification needed]

Overdoses may generate methemoglobinemia.[32]

Society and culture

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Brand names

[edit]

In the US, Nitrostat is marketed by Viatris after Upjohn was spun off from Pfizer.[33][34][35]

References

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  1. ^ a b c d e f g h i j "Nitroglycerin". The American Society of Health-System Pharmacists. Archived from the original on 21 December 2016. Retrieved 8 December 2016.
  2. ^ a b Fenton C, Wellington K, Easthope SE (2006). "0.4% nitroglycerin ointment: in the treatment of chronic anal fissure pain". Drugs. 66 (3): 343–9. doi:10.2165/00003495-200666030-00006. PMID 16526822. S2CID 46984485.
  3. ^ a b Morgan PJ, Kung R, Tarshis J (May 2002). "Nitroglycerin as a uterine relaxant: a systematic review". Journal of Obstetrics and Gynaecology Canada. 24 (5): 403–9. doi:10.1016/S1701-2163(16)30403-0. PMID 12196860.
  4. ^ O'Leary ME, Hancox JC (May 2010). "Role of voltage-gated sodium, potassium and calcium channels in the development of cocaine-associated cardiac arrhythmias". British Journal of Clinical Pharmacology. 69 (5): 427–42. doi:10.1111/j.1365-2125.2010.03629.x. PMC 2856043. PMID 20573078.
  5. ^ a b Sobrero A (1847). "Sur plusieur composés détonants produits avec l'acide nitrique et le sucre, la dextrine, la lactine, la mannite et la glycérine" [On several detonating compounds produced with nitric acid and sugar, dextrin, lactose, mannitol, and glycerine]. Comptes Rendus (in French). 24: 247–248. 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.)
  6. ^ a b Sobrero A (1849). "Sopra alcuni nuovi composti fulminanti ottenuti col mezzo dell'azione dell'acido nitrico sulle sostante organiche vegetali" [On some new explosive products obtained by the action of nitric acid on some vegetable organic substances]. Memorie della Reale Accademia delle Scienze di Torino. 2nd series (in Italian). 10: 195–201. 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.)
  7. ^ a b Murrell W (1879). "Nitro-glycerine as a remedy for angina pectoris". The Lancet. 113 (2894): 80–81, 113–115, 151–152, 225–227. doi:10.1016/s0140-6736(02)42404-x. hdl:2027/uc1.b5295238. PMC 5901592.
  8. ^ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 454. ISBN 9783527607495. Archived from the original on 20 December 2016.
  9. ^ a b c Ravina E (2011). The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs. John Wiley & Sons. p. 153. ISBN 9783527326693. Archived from the original on 20 December 2016.
  10. ^ "The Top 300 of 2022". ClinCalc. Archived from the original on 30 August 2024. Retrieved 30 August 2024.
  11. ^ "Nitroglycerin Drug Usage Statistics, United States, 2013 - 2022". ClinCalc. Retrieved 30 August 2024.
  12. ^ Yasue H, Nakagawa H, Itoh T, Harada E, Mizuno Y (February 2008). "Coronary artery spasm--clinical features, diagnosis, pathogenesis, and treatment". Journal of Cardiology. 51 (1): 2–17. doi:10.1016/j.jjcc.2008.01.001. PMID 18522770. Retrieved 23 November 2016.
  13. ^ "Nitro-Dur - FDA prescribing information, side effects and uses". drugs.com. Archived from the original on 1 April 2017. Retrieved 31 March 2017.
  14. ^ "Nitroclycerin Oral Route and Sublingual Route". www.mayoclinic.org.
  15. ^ Goldin M, Malanga GA (September 2013). "Tendinopathy: a review of the pathophysiology and evidence for treatment". The Physician and Sportsmedicine. 41 (3): 36–49. doi:10.3810/psm.2013.09.2019. PMID 24113701. S2CID 26907571.
  16. ^ Andres BM, Murrell GA (July 2008). "Treatment of tendinopathy: what works, what does not, and what is on the horizon". Clinical Orthopaedics and Related Research. 466 (7): 1539–54. doi:10.1007/s11999-008-0260-1. PMC 2505250. PMID 18446422.
  17. ^ Assem Y, Arora M (January 2015). "Glyceryl trinitrate patches-An alternative treatment for shoulder impingement syndrome". Journal of Orthopaedic Translation. 3 (1): 12–20. doi:10.1016/j.jot.2014.11.001. PMC 5982354. PMID 30035035.
  18. ^ Bokhari AR, Murrell GA (February 2012). "The role of nitric oxide in tendon healing". Journal of Shoulder and Elbow Surgery. 21 (2): 238–44. doi:10.1016/j.jse.2011.11.001. PMID 22244067.
  19. ^ Gambito ED, Gonzalez-Suarez CB, Oquiñena TI, Agbayani RB (August 2010). "Evidence on the effectiveness of topical nitroglycerin in the treatment of tendinopathies: a systematic review and meta-analysis". Archives of Physical Medicine and Rehabilitation. 91 (8): 1291–305. doi:10.1016/j.apmr.2010.02.008. PMID 20684913.
  20. ^ Shuchman M (20 September 2016). "Misconduct saga rattles bone scientists". Canadian Medical Association Journal. 188 (13): 938–939. doi:10.1503/cmaj.109-5314. PMC 5026510. PMID 27551032.
  21. ^ Nakamura et al.[full citation needed]
  22. ^ Gori et al.[full citation needed]
  23. ^ Such activation is suggested to cause sympathetic activation, and release of vasoconstrictors such as endothelin and angiotensin II.
  24. ^ Hypothesis of Munzel et al. (1995).[full citation needed]
  25. ^ "Phosphodiesterase Inhibitors". CV Pharmacology. Archived from the original on 13 June 2017. Retrieved 3 April 2017.
  26. ^ Scientific Committee on Occupational Exposure Limits (May 2008). Recommendation From the Scientific Committee on Occupational Exposure Limits for Glycerol Trinitrate (Nitroglycerin) [SCOEL/SUM/147] (Report). The Hague, NDL: Sociaal-Economische Raad. Archived from the original on 3 March 2016. Retrieved 30 March 2017.
  27. ^ Liddle R, Richmond W (June 1998). "Investigation into voltage breakdown in glyceryl trinitrate patches". Resuscitation. 37 (3): 145–8. doi:10.1016/S0300-9572(98)00059-8. PMID 9715773.
  28. ^ (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 breath. 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.
  29. ^ Hering C (1849). "Glonoine, a new medicine for headache, &c". American Journal of Homoeopathy. 4 (1): 3–5. Note: Hering renamed nitroglycerine "glonoine".
  30. ^ Fye WB (January 1986). "Nitroglycerin: a homeopathic remedy". Circulation. 73 (1): 21–9. doi:10.1161/01.cir.73.1.21. PMID 2866851. See pp. 22–23.
  31. ^ Sneader W (2005). Drug Discovery: A History. New York, NY: John Wiley & Sons. p. 433. ISBN 978-0471899808. Archived from the original on 8 September 2017.[verification needed]
  32. ^ Kaplan KJ, Taber M, Teagarden JR, Parker M, Davison R (January 1985). "Association of methemoglobinemia and intravenous nitroglycerin administration". The American Journal of Cardiology. 55 (1): 181–3. doi:10.1016/0002-9149(85)90324-8. PMID 3917597.
  33. ^ "Pfizer Completes Transaction to Combine Its Upjohn Business with Mylan". Pfizer. 16 November 2020. Retrieved 17 June 2024 – via Business Wire.
  34. ^ "Nitrostat". Pfizer. Retrieved 17 June 2024.
  35. ^ "Brands". Viatris. 16 November 2020. Retrieved 17 June 2024.

Further reading

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