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 2million prescriptions.[10][11]
Medical uses
Three different forms of nitroglycerin: intravenous, sublingual spray, and the nitroglycerin patch.
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
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
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:
plasma volume expansion
impaired transformation of glyceryl trinitrate into NO or related species
counteraction of glyceryl trinitrate vasodilation by neurohormonal activation[23]
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 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).
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]
In the US, Nitrostat is marketed by Viatris after Upjohn was spun off from Pfizer.[33][34][35]
References
^ abcdefghij"Nitroglycerin". The American Society of Health-System Pharmacists. Archived from the original on 21 December 2016. Retrieved 8 December 2016.
^ abMorgan 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. PMID12196860.
^ abSobrero 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.)
^ abSobrero 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.)
^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. PMID24113701. S2CID26907571.
^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. PMID22244067.
^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. PMID20684913.
^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. PMID9715773.
^(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.
^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. PMID3917597.
Lundberg JO, Weitzberg E, Gladwin MT (February 2008). "The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics". Nature Reviews. Drug Discovery. 7 (2): 156–67. doi:10.1038/nrd2466. PMID18167491. S2CID5141850.
Marsh N, Marsh A (April 2000). "A short history of nitroglycerine and nitric oxide in pharmacology and physiology". Clinical and Experimental Pharmacology & Physiology. 27 (4): 313–9. doi:10.1046/j.1440-1681.2000.03240.x. PMID10779131. S2CID12897126.
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