Nitroglycerin (medication)

Nitroglycerin, also known as glyceryl trinitrate (GTN), is a vasodilator used for heart failure, high blood pressure, anal fissures, painful periods, treating the pain from esophageal spasm, 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. It is taken by mouth, under the tongue, applied to the skin by cream or a patch, as a spray, or by injection into a vein.[5][6]

Common side effects include headache and low blood pressure.[5] The low blood pressure can be severe.[5] It is unclear if use in pregnancy is safe for the fetus.[5] It should not be used together with medications within the PDE5 inhibitor family such as sildenafil due to the risk of low blood pressure.[5] Nitroglycerin is in the nitrate family of medications.[5] While it is not entirely clear how it works, it is believed to function by dilating blood vessels.[5]

Nitroglycerin was written about as early as 1846 and came into medical use in 1878.[7][8] The drug nitroglycerin is a dilute form of the same chemical used as the explosive, nitroglycerin.[8] Dilution makes it non-explosive.[8] In 2023, it was the 207th most commonly prescribed medication in the United States, with more than 2million prescriptions.[9][10]

Medical uses

Nitroglycerin is used for the treatment of angina, acute myocardial infarction, severe hypertension, and acute coronary artery spasms.[5][11] It may be administered intravenously, as a sublingual spray/tablet, or as a patch applied to the skin.

Adverse events

Nitroglycerin 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.[35]

Nitroglycerin 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.[36]

Nitroglycerin transdermal patches should be removed before defibrillation due to the risk of explosion or burns, but investigations have concluded that nitroglycerin patch explosions during defibrillation were due to the breakdown voltage of the metal mesh in some patches.[37][38]

Mechanism of action

Nitroglycerin 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. It has been postulated 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 nitroglycerin bioactivation.[39]

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 nitroglycerin increases the level of cGMP within the cell, and stimulates dephosphorylation of myosin, which initiates relaxation of smooth muscle cells in blood vessels.[40]

History

It was known almost from the time of the first synthesis of nitroglycerin by Ascanio Sobrero in 1846 that handling and tasting of nitroglycerin could cause sudden intense headaches,[41][42] which suggested a vasodilation effect.[43] 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.[44][45]

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

Society and culture

Further reading