Chemistry:Nitroglycerin (medication)

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Short description: Medication
Nitroglycerin
Nitroglycerin.svg
Nitrogylcerin (3D ball-and-stick model).png
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
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)
 ☒N☑Y (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]

Side effects and mechanism

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]

History, society and culture

Nitroglycerin was written about as early as 1846[5][6] and came into medical use in 1878.[7][8][9] The drug nitroglycerin (GTN) is a dilute form of the same chemical used as the explosive, nitroglycerin.[9] Dilution makes it non-explosive.[9] In 2020, it was the 165th most commonly prescribed medication in the United States, with more than 3 million prescriptions.[10][11]

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.[1][12] It may be administered intravenously, as a sublingual spray, or as a patch applied to the skin.

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.[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

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]

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

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

GTN 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

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,[citation needed] and was first described soon after the introduction of GTN 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 GTN into NO or related species
  3. counteraction of GTN vasodilation by neurohormonal activation[23]
  4. oxidative stress[24][full citation needed]

Recent evidence suggests[weasel words] 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.

Adverse events

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.

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.[25]

GTN 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 GTN 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

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[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 GTN bioactivation. In recent years,[when?] a great deal of evidence has been produced[citation needed] 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.[clarification needed] 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,[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 GTN 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]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 "Nitroglycerin". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/nitroglycerin.html. 
  2. ↑ 2.0 2.1 "0.4% nitroglycerin ointment: in the treatment of chronic anal fissure pain". Drugs 66 (3): 343–9. 2006. doi:10.2165/00003495-200666030-00006. PMID 16526822. 
  3. ↑ 3.0 3.1 "Nitroglycerin as a uterine relaxant: a systematic review". Journal of Obstetrics and Gynaecology Canada 24 (5): 403–9. May 2002. doi:10.1016/S1701-2163(16)30403-0. PMID 12196860. 
  4. ↑ "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. May 2010. doi:10.1111/j.1365-2125.2010.03629.x. PMID 20573078. 
  5. ↑ 5.0 5.1 "Sur plusieur composés détonants produits avec l'acide nitrique et le sucre, la dextrine, la lactine, la mannite et la glycérine" (in fr). Comptes Rendus 24: 247–248. 1847. https://babel.hathitrust.org/cgi/pt?id=mdp.39015035450777;view=1up;seq=259.  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. ↑ 6.0 6.1 "Sopra alcuni nuovi composti fulminanti ottenuti col mezzo dell'azione dell'acido nitrico sulle sostante organiche vegetali" (in it). Memorie della Reale Accademia delle Scienze di Torino. 2nd series 10: 195–201. 1849. https://babel.hathitrust.org/cgi/pt?id=iau.31858045931643;view=1up;seq=281.  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. ↑ 7.0 7.1 "Nitro-glycerine as a remedy for angina pectoris.". The Lancet 113 (2894): 80–81, 113–115, 151–152, 225–227. 1879. doi:10.1016/s0140-6736(02)42404-x. PMC 5901592. https://babel.hathitrust.org/cgi/pt?id=uc1.d0000772988;view=1up;seq=78. 
  8. ↑ (in en) Analogue-based Drug Discovery. John Wiley & Sons. 2006. p. 454. ISBN 9783527607495. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA454. 
  9. ↑ 9.0 9.1 9.2 (in en) The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs. John Wiley & Sons. 2011. p. 153. ISBN 9783527326693. https://books.google.com/books?id=iDNy0XxGqT8C&pg=PA153. 
  10. ↑ "The Top 300 of 2020". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  11. ↑ "Nitroglycerin - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Nitroglycerin. 
  12. ↑ "Coronary artery spasm--clinical features, diagnosis, pathogenesis, and treatment". Journal of Cardiology 51 (1): 2–17. February 2008. doi:10.1016/j.jjcc.2008.01.001. PMID 18522770. http://www.journal-of-cardiology.com/article/S0914-5087(08)00002-6/fulltext. Retrieved 23 November 2016. 
  13. ↑ "Nitro-Dur - FDA prescribing information, side effects and uses". drugs.com. https://www.drugs.com/pro/nitro-dur.html. 
  14. ↑ "Nitroclycerin Oral Route and Sublingual Route". https://www.mayoclinic.org/drugs-supplements/nitroglycerin-oral-route-sublingual-route/proper-use/drg-20072863. 
  15. ↑ "Tendinopathy: a review of the pathophysiology and evidence for treatment". The Physician and Sportsmedicine 41 (3): 36–49. September 2013. doi:10.3810/psm.2013.09.2019. PMID 24113701. 
  16. ↑ "Treatment of tendinopathy: what works, what does not, and what is on the horizon". Clinical Orthopaedics and Related Research 466 (7): 1539–54. July 2008. doi:10.1007/s11999-008-0260-1. PMID 18446422. 
  17. ↑ "Glyceryl trinitrate patches-An alternative treatment for shoulder impingement syndrome". Journal of Orthopaedic Translation 3 (1): 12–20. January 2015. doi:10.1016/j.jot.2014.11.001. PMID 30035035. 
  18. ↑ "The role of nitric oxide in tendon healing". Journal of Shoulder and Elbow Surgery 21 (2): 238–44. February 2012. doi:10.1016/j.jse.2011.11.001. PMID 22244067. 
  19. ↑ "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. August 2010. doi:10.1016/j.apmr.2010.02.008. PMID 20684913. 
  20. ↑ Shuchman, Miriam (20 September 2016). "Misconduct saga rattles bone scientists". Canadian Medical Association Journal 188 (13): 938–939. doi:10.1503/cmaj.109-5314. 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". http://www.cvpharmacology.com/vasodilator/PDEI. 
  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. http://www.ser.nl/nl/grenswaarden/~/media/Files/Internet/Grenswaarden/SCOEL/GSW524_SCOEL_Prov147Nitroglycerine.ashx. Retrieved 30 March 2017. 
  27. ↑ "Investigation into voltage breakdown in glyceryl trinitrate patches". Resuscitation 37 (3): 145–8. June 1998. 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. ↑ "Glonoine, a new medicine for headache, &c.". American Journal of Homoeopathy 4 (1): 3–5. 1849. https://babel.hathitrust.org/cgi/pt?id=mdp.39015009544423;view=1up;seq=171.  Note: Hering renamed nitroglycerine "glonoine".
  30. ↑ "Nitroglycerin: a homeopathic remedy". Circulation 73 (1): 21–9. January 1986. doi:10.1161/01.cir.73.1.21. PMID 2866851.  See pp. 22–23.
  31. ↑ Drug Discovery: A History. New York, NY: John Wiley & Sons. 2005. p. 433. ISBN 978-0471899808. https://books.google.com/books?id=mYQxRY9umjcC. [verification needed]
  32. ↑ "Association of methemoglobinemia and intravenous nitroglycerin administration". The American Journal of Cardiology 55 (1): 181–3. January 1985. doi:10.1016/0002-9149(85)90324-8. PMID 3917597. 

Further reading




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