Nitroglycerin (medication)
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]
For the undiluted form used as an explosive, see Nitroglycerin.Clinical data
Nitrol, others
- AU: S3 (Pharmacist only)
- UK: P (Pharmacy medicines)
- US: ℞-only
<1%
liver (rapid), red blood cells, vascular wall
3 minutes
In urine, in bile
C3H5N3O9
227.085 g·mol−1
Side effects and mechanism[edit]
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[edit]
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 2021, it was the 174th most commonly prescribed medication in the United States, with more than 2 million prescriptions.[10][11]
Adverse events[edit]
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] 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]
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 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, a great deal of evidence has been produced 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. 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]
Overdoses may generate methemoglobinemia.[32]