Nitroglycerin

For the undiluted form used as an explosive, see Nitroglycerin (chemical).
Nitroglycerin
Names
Trade namesNitrol, others
IUPAC name
  • 1,3-dinitrooxypropan-2-yl nitrate; [3-(nitrooxy)-2-[(nitrooxy)methyl]propyl] nitrate; 1,2,3-trinitroxy propane
Clinical data
Main usesAngina[1]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • US: C (Risk not ruled out)
    Routes of
    use    		sublingual, transdermal, by mouth, intravenous
    Onset of actionUnder tongue: 2 min[2]
    Ointment: 30 min[2]
    Duration of actionUnder tongue: 30 min[2]
    Ointment: 3 hrs[2]
    Defined daily dose2.5 to 5 mg[3]
    External links
    AHFS/Drugs.comSystemic: Monograph
    Topical: Monograph
    MedlinePlusa601086
    Legal
    Legal status
    Pharmacokinetics
    Bioavailability<1%
    Metabolismliver (rapid), red blood cells, vascular wall
    Elimination half-life3 minutes
    ExcretionIn urine, in bile
    Chemical and physical data
    FormulaC3H5N3O9
    Molar mass227.085 g·mol−1
    3D model (JSmol)
    SMILES
    • C(C(CO[N+](=O)[O-])O[N+](=O)[O-])O[N+](=O)[O-]
    InChI
    • 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

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

    Common side effects include headache and low blood pressure.[2] The low blood pressure can be severe.[2] It is unclear if use in pregnancy is safe for the baby.[2] It should not be used together with medications within the sildenafil (PDE5 inhibitor) family due to the risk of low blood pressure.[2] Nitroglycerin is in the nitrate family of medications.[2] While it is not entirely clear how it works, it is believed to function by dilating blood vessels.[2]

    Nitroglycerin was written about as early as 1846 and came into medical use in 1878.[7][8] It is on the World Health Organization's List of Essential Medicines.[9] The wholesale cost in the developing world as of 2014, was US$0.06–0.22 per dose by mouth.[10] The drug nitroglycerin (GTN) is a dilute form of the same chemical used as the explosive, nitroglycerin (chemical).[8] Dilution makes it non-explosive.[8] In 2017, it was the 143rd most commonly prescribed medication in the United States, with more than four million prescriptions.[11][12]

    Medical uses

    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.[2][13]

    Angina

    GTN 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.[14] 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 acute myocardial infarction (heart attack) and pulmonary edema, again working best if used quickly, within a few minutes of symptom onset, as a pulse dose. 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.[15]

    Other uses

    Topical nitroglycerine- resolving ischemia of the fingers, 5 days after the ischemic event.

    Tentative evidence indicates efficacy of glyceryl trinitrate in the treatment of various tendinopathies, both in pain management and acceleration of soft tissue repair.[16][17][18][19][20]

    GTN is also used in the treatment of anal fissures, though usually at a much lower concentration than that used for angina treatment.[4]

    GTN has been used to decrease pain associated with dysmenorrhea.[5]

    Tolerance

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

    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 GTN into NO or related species
    3. counteraction of GTN vasodilation by neurohormonal activation[23]
    4. oxidative stress[24]

    Recent evidence suggests that deleterious GTN-induced production of oxygen free radicals might induce a number of abnormalities, include those described above, so that the oxidative stress hypothesis might represent a unifying principle.

    Dosage

    The defined daily dose is 5 mg by mouth or as a skin patch and 2.5 mg as a spray or dissolved under the tongue.[25][3] To treat angina it is generally used at a dose of 0.5 to 1 mg by mouth and repeated up to three times every three minutes.[1] For prevention of angina 0.5 to 1 mg may be taken before an event that could potentially result in angina.[1]

    Side events

    Glyceryl trinitrate can cause severe low blood pressure, reflex tachycardia, and headaches that necessitate intervention for pain relief.

    GTN 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.[26]

    GTN transdermal patches should be removed before defibrillation due to the risk of explosion and/or burns,[27] but investigations have concluded that GTN patch explosions during defibrillation were due to voltage breakdown involving the metal mesh in some patches.[28]

    Mechanism of action

    GTN 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 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 GTN bioactivation. In recent years, a great deal of evidence has been produced that supports the conclusion that GTN'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. Thus, production of NO from exogenous sources such as GTN increases the level of cGMP within the cell, and stimulates dephosphorylation of myosin, which initiates relaxation of smooth muscle cells in blood vessels.

    History

    It was known almost from the time of the first synthesis of GTN by Ascanio Sobrero in 1846 that handling and tasting of nitroglycerin could cause sudden intense headaches,[29][30] which suggested a vasodilation effect (as suggested by Sobrero).[31] 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.[32][33]

    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 pectoris and reduce blood pressure, and showed that the accompanying headaches occurred as a result of overdose. Murrell began treating patients with small doses of GTN in 1878, and the substance was widely adopted after he published his results in The Lancet in 1879.[34]

    The medical establishment used the name "glyceryl trinitrate" or "trinitrin" to avoid alarming patients, because of a general awareness that nitroglycerin was explosive.[35]

    Overdoses may generate methemoglobinemia.[36]

    Society and culture

    Cost

    The wholesale cost in the developing world as of 2014, was US$0.06–0.22 per dose by mouth.[10] In 2017, it was the 143rd most commonly prescribed medication in the United States, with more than four million prescriptions.[11][12] In the UK, GTN costs the NHS just over a penny per dose by spray and nearly 3 pence per dose by a tablet under the tongue.[37]

    • Nitroglycerin costs (US)
      Nitroglycerin costs (US)
    • Nitroglycerin prescriptions (US)
      Nitroglycerin prescriptions (US)

    References

    1. 1 2 3 "GLYCERYL TRINITRATE = NITROGLYCERIN = TRINITRIN oral - Essential drugs". medicalguidelines.msf.org. Archived from the original on 28 August 2021. Retrieved 30 August 2020.
    2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 "Nitroglycerin". The American Society of Health-System Pharmacists. Archived from the original on 21 December 2016. Retrieved 8 December 2016.
    3. 1 2 "WHOCC - ATC/DDD Index". www.whocc.no. Archived from the original on 20 September 2020. Retrieved 30 August 2020.
    4. 1 2 Fenton, Caroline; Wellington, Keri; Easthope, Stephanie E. (2006). "0.4% nitroglycerin ointment : in the treatment of chronic anal fissure pain". Drugs. 66 (3): 343–349. doi:10.2165/00003495-200666030-00006. ISSN 0012-6667. PMID 16526822.
    5. 1 2 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.
    6. ↑ 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.
    7. ↑ Fischer, Janos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 454. ISBN 9783527607495. Archived from the original on 2016-12-20.
    8. 1 2 3 Ravina, Enrique (2011). The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs. John Wiley & Sons. p. 153. ISBN 9783527326693. Archived from the original on 2016-12-20.
    9. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
    10. 1 2 IDPIG Staff (2014). "Glyceryl Trinitrate". International Medical Products Price Guide: International Drug Price Indicator Guide (IDPIG). Archived from the original on 15 December 2019. Retrieved 8 December 2016 – via ERC.MSH.org.
    11. 1 2 "The Top 300 of 2020". ClinCalc. Archived from the original on 12 February 2021. Retrieved 11 April 2020.
    12. 1 2 "Nitroglycerin - Drug Usage Statistics". ClinCalc. Archived from the original on 8 July 2020. Retrieved 11 April 2020.
    13. ↑ Yasue H, Nakagawa H, Itoh T, Harada E, Mizuno Y (February 2008). "Coronary artery spasm--clinical features, diagnosis, pathogenesis, and treatment". J Cardiol. 51 (1): 2–17. doi:10.1016/j.jjcc.2008.01.001. PMID 18522770. Archived from the original on 16 December 2019. Retrieved 23 November 2016.
    14. ↑ "Nitro-Dur - FDA prescribing information, side effects and uses". drugs.com. Archived from the original on 1 April 2017. Retrieved 31 March 2017.
    15. ↑ "Nitroclycerin Oral Route and Sublingual Route". www.mayoclinic.org. Archived from the original on 2020-07-10. Retrieved 2020-07-10.
    16. ↑ 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.
    17. ↑ Andres, BM; Murrell, GA (2008). "Treatment of Tendinopathy: What Works, What Does Not, and What is on the Horizon". Clin. Orthop. Relat. Res. 466 (7): 1539–54. doi:10.1007/s11999-008-0260-1. PMC 2505250. PMID 18446422.
    18. ↑ Assem, Yusuf; Arora, Manit (1 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.
    19. ↑ Bokhari, Ali R.; Murrell, George A. C. (1 February 2012). "The role of nitric oxide in tendon healing". Journal of Shoulder and Elbow Surgery. 21 (2): 238–244. doi:10.1016/j.jse.2011.11.001. PMID 22244067.
    20. ↑ Gambito, ED; Gonzalez-Suarez, CB; Oquiñena, TI; Agbayani, RB (2010). "Evidence on the effectiveness of topical nitroglycerin in the treatment of tendinopathies: a systematic review and meta-analysis. syndrome". Arch Phys Med Rehabil. 91 (8): 1291–305. doi:10.1016/j.apmr.2010.02.008. PMID 20684913.
    21. ↑ Nakamura et al.
    22. ↑ Gori et al.
    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).
    25. ↑ "Single Drug Information – International Medical Products Price Guide". mshpriceguide. Archived from the original on 28 August 2021. Retrieved 13 August 2020.
    26. ↑ "Phosphodiesterase Inhibitors". CV Pharmacology. CV Pharmacology. Archived from the original on 13 June 2017. Retrieved 3 April 2017.
    27. ↑ 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.
    28. ↑ Liddle, R.; Richmond, W. (1998). "Investigation into voltage breakdown in glyceryl trinitrate patches". Resuscitation. 37 (3): 145–148. doi:10.1016/S0300-9572(98)00059-8. PMID 9715773.
    29. ↑ Sobrero, Ascagne (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. Archived from the original on 2020-01-23. Retrieved 2017-09-28.{{cite journal}}: CS1 maint: unrecognized language (link) 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.)
    30. ↑ Sobrero, Ascanio (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. Archived from the original on 2021-08-28. Retrieved 2017-09-28.{{cite journal}}: CS1 maint: unrecognized language (link) 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.)
    31. ↑ (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.
    32. ↑ Hering, Constantine (1849). "Glonoine, a new medicine for headache, &c". American Journal of Homoeopathy. 4 (1): 3–5. Archived from the original on 2021-08-28. Retrieved 2017-09-29. Note: Hering renamed nitroglycerine "glonoine".
    33. ↑ Fye, W. Bruce (January 1986). "Nitroglycerin: a homeopathic remedy". Circulation. 73 (1): 21–29. doi:10.1161/01.cir.73.1.21. PMID 2866851. See pp. 22–23.
    34. ↑ Murrell, William (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. Archived from the original on 2020-01-03. Retrieved 2017-09-28.
    35. ↑ Sneader, Walter (2005). Drug Discovery: A History. New York, NY: John Wiley & Sons. p. 433. ISBN 978-0471899808. Archived from the original on 2017-09-08.
    36. ↑ Kaplan, KJ; Taber, M; Teagarden, JR; Parker, M; Davison, R (1985). "Association of methemoglobinemia and intravenous nitroglycerin administration". Am J Cardiol. 55 (1): 181–3. doi:10.1016/0002-9149(85)90324-8. PMID 3917597.
    37. ↑ BNF (80 ed.). BMJ Group and the Pharmaceutical Press. September 2020 – March 2021. pp. 232–233. ISBN 978-0-85711-369-6.{{cite book}}: CS1 maint: date format (link)

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