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Nitroglycerin, also known as glyceryl trinitrate (GTN), is a medication used for
heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, ...
,
high blood pressure Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...
,
anal fissures An anal fissure is a break or tear in the skin of the anal canal. Anal fissures may be noticed by bright red anal bleeding on toilet paper and undergarments, or sometimes in the toilet. If acute they are painful after defecation, but with chronic ...
, 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 Cocaine (from , from , ultimately from Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly used recreationally for its euphoric effects. It is primarily obtained from the leaves of two Coca species native to South Am ...
. This includes chest pain from a
heart attack A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which ma ...
. It is taken by mouth, under the tongue, applied to the skin, or by
injection into a vein Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...
. Common side effects include
headache Headache is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of depression in those with severe headaches. Headaches can occur as a result ...
and low blood pressure. The low blood pressure can be severe. It is unclear if use in
pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ...
is safe for the baby. It should not be used together with medications within the PDE5 inhibitor family such as
sildenafil Sildenafil, sold under the brand name Viagra, among others, is a medication used to treat erectile dysfunction and pulmonary arterial hypertension. It is unclear if it is effective for treating sexual dysfunction in women. It is taken by ...
due to the risk of low blood pressure. Nitroglycerin is in the
nitrate Nitrate is a polyatomic ion with the chemical formula . Salts containing this ion are called nitrates. Nitrates are common components of fertilizers and explosives. Almost all inorganic nitrates are soluble in water. An example of an insolu ...
family of medications. While it is not entirely clear how it works, it is believed to function by dilating blood vessels. Nitroglycerin was written about as early as 1846 and came into medical use in 1878. It is on the World Health Organization's List of Essential Medicines. The drug nitroglycerin (GTN) is a dilute form of the same chemical used as the explosive,
nitroglycerin Nitroglycerin (NG), (alternative spelling of nitroglycerine) also known as trinitroglycerin (TNG), nitro, glyceryl trinitrate (GTN), or 1,2,3-trinitroxypropane, is a dense, colorless, oily, explosive liquid most commonly produced by nitrating g ...
. Dilution makes it non-explosive. In 2020, it was the 165th most commonly prescribed medication in the United States, with more than 3million prescriptions.


Medical uses

Nitroglycerin is used for the treatment of
angina Angina, also known as angina pectoris, is chest pain or pressure, usually caused by insufficient blood flow to the heart muscle (myocardium). It is most commonly a symptom of coronary artery disease. Angina is typically the result of obstr ...
,
acute myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may t ...
, severe
hypertension Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high b ...
, and acute
coronary artery spasm Coronary vasospasm refers to when a coronary artery suddenly undergoes either complete or sub-total temporary occlusion. In 1959, Prinzmetal et al. described a type of chest pain resulting from coronary vasospasm, referring to it as a variant form ...
s. It may be administered intravenously, as a sublingual spray, or as a patch applied to the skin.


Angina

GTN is useful in decreasing
angina Angina, also known as angina pectoris, is chest pain or pressure, usually caused by insufficient blood flow to the heart muscle (myocardium). It is most commonly a symptom of coronary artery disease. Angina is typically the result of obstr ...
attacks, perhaps more so than reversing angina once started, by supplementing blood concentrations of NO, also called
endothelium-derived relaxing factor Endothelium-derived relaxing factor (EDRF) is a name for a substance that Robert F. Furchgott discovered had the eponymous properties. Today, it is firmly established this substance is nitric oxide (NO). Endothelium produces NO which then diffuse ...
, 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. 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 A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which ma ...
(heart attack) and
pulmonary edema Pulmonary edema, also known as pulmonary congestion, is excessive liquid accumulation in the tissue and air spaces (usually alveoli) of the lungs. It leads to impaired gas exchange and may cause hypoxemia and respiratory failure. It is due ...
, 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 Sublingual (abbreviated SL), from the Latin for "under the tongue", refers to the pharmacological route of administration by which substances diffuse into the blood through tissues under the tongue. The sublingual glands receive their primary ...
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.


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. GTN is also used in the treatment of
anal fissure An anal fissure is a break or tear in the skin of the anal canal. Anal fissures may be noticed by bright red anal bleeding on toilet paper and undergarments, or sometimes in the toilet. If acute they are painful after defecation, but with chronic ...
s, though usually at a much lower concentration than that used for angina treatment. GTN has been used to decrease pain associated with
dysmenorrhea Dysmenorrhea, also known as period pain, painful periods or menstrual cramps, is pain during menstruation. Its usual onset occurs around the time that menstruation begins. Symptoms typically last less than three days. The pain is usually in th ...
. GTN was once researched for the prevention and treatment of
osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone a ...
; however, the researcher Sophie Jamal was found to have falsified the findings, sparking one of the largest scientific misconduct cases in Canada.


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. These include endothelial and autonomic dysfunction. 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 GTN into NO or related species # counteraction of GTN vasodilation by neurohormonal activation # oxidative stress 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.


Adverse events

Glyceryl trinitrate can cause severe
hypotension Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the di ...
, 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 Compliance can mean: Healthcare * Compliance (medicine), a patient's (or doctor's) adherence to a recommended course of treatment * Compliance (physiology), the tendency of a hollow organ to resist recoil toward its original dimensions (this is a ...
. GTN also can cause severe hypotension, circulatory collapse, and death if used together with vasodilator drugs that are used for
erectile dysfunction Erectile dysfunction (ED), also called impotence, is the type of sexual dysfunction in which the penis fails to become or stay erect during sexual activity. It is the most common sexual problem in men.Cunningham GR, Rosen RC. Overview of ma ...
, such as
sildenafil Sildenafil, sold under the brand name Viagra, among others, is a medication used to treat erectile dysfunction and pulmonary arterial hypertension. It is unclear if it is effective for treating sexual dysfunction in women. It is taken by ...
, tadalafil, and vardenafil. GTN transdermal patches should be removed before
defibrillation Defibrillation is a treatment for life-threatening cardiac arrhythmias, specifically ventricular fibrillation (V-Fib) and non-perfusing ventricular tachycardia (V-Tach). A defibrillator delivers a dose of electric current (often called a ''coun ...
due to the risk of explosion and/or burns, but investigations have concluded that GTN patch explosions during defibrillation were due to voltage breakdown involving the metal mesh in some patches.


Mechanism of action

GTN is a
prodrug A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the dru ...
which must be denitrated, with the
nitrite The nitrite ion has the chemical formula . Nitrite (mostly sodium nitrite) is widely used throughout chemical and pharmaceutical industries. The nitrite anion is a pervasive intermediate in the nitrogen cycle in nature. The name nitrite also ...
anion or a related species further reduced to produce the active metabolite
nitric oxide Nitric oxide (nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes denoted by a dot in its ...
(NO). Organic
nitrates Nitrate is a polyatomic ion with the chemical formula . Salts containing this ion are called nitrates. Nitrates are common components of fertilizers and explosives. Almost all inorganic nitrates are soluble in water. An example of an insolu ...
that undergo these two steps within the body are called
nitrovasodilators A nitrovasodilator is a pharmaceutical agent that causes vasodilation (widening of blood vessels) by donation of nitric oxide (NO), and is mostly used for the treatment and prevention of angina pectoris. This group of drugs includes nitrates ( e ...
, 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 In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl gro ...
groups, while others believe that enzymes such as
glutathione S-transferase Glutathione ''S''-transferases (GSTs), previously known as ligandins, are a family of eukaryotic and prokaryotic phase II metabolic isozymes best known for their ability to catalyze the conjugation of the reduced form of glutathione (GSH) ...
s,
cytochrome P450 Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...
(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 Cyclic guanosine monophosphate (cGMP) is a cyclic nucleotide derived from guanosine triphosphate (GTP). cGMP acts as a second messenger much like cyclic AMP. Its most likely mechanism of action is activation of intracellular protein kinases ...
(cGMP) from
guanosine triphosphate Guanosine-5'-triphosphate (GTP) is a purine nucleoside triphosphate. It is one of the building blocks needed for the synthesis of RNA during the transcription process. Its structure is similar to that of the guanosine nucleoside, the only ...
(GTP). Among other roles, cGMP serves as a substrate for a
cGMP-dependent protein kinase cGMP-dependent protein kinase or protein kinase G (PKG) is a serine/threonine-specific protein kinase that is activated by cGMP. It phosphorylates a number of biologically important targets and is implicated in the regulation of smooth muscle ...
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 Myosins () are a superfamily of motor proteins best known for their roles in muscle contraction and in a wide range of other motility processes in eukaryotes. They are ATP-dependent and responsible for actin-based motility. The first myosin (M ...
, 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 Ascanio Sobrero (12 October 1812 – 26 May 1888) was an Italian chemist, born in Casale Monferrato. He was studying under Théophile-Jules Pelouze at the University of Turin, who had worked with the explosive material guncotton. He studied med ...
in 1846 that handling and tasting of
nitroglycerin Nitroglycerin (NG), (alternative spelling of nitroglycerine) also known as trinitroglycerin (TNG), nitro, glyceryl trinitrate (GTN), or 1,2,3-trinitroxypropane, is a dense, colorless, oily, explosive liquid most commonly produced by nitrating g ...
could cause sudden intense
headache Headache is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of depression in those with severe headaches. Headaches can occur as a result ...
s, 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 ne'stongue 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.) 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'' .e., Sabrero's name for nitroglycerinon ne'stongue, 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 yother people who tried the experiment.) which suggested a vasodilation effect (as suggested by Sobrero).
Constantine Hering Constantine J. Hering (January 1, 1800 – July 23, 1880) was a physician who was an early pioneer of homeopathy in the United States. Biography Hering was born in Oschatz, and studied medicine at the University of Leipzig where his interest ...
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. 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 Blood pressure (BP) is the pressure of circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term "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 ''The Lancet'' is a weekly peer-reviewed general medical journal and one of the oldest of its kind. It is also the world's highest-impact academic journal. It was founded in England in 1823. The journal publishes original research articles ...
'' in 1879. The medical establishment used the name "glyceryl trinitrate" or "trinitrin" to avoid alarming patients, because of a general awareness that nitroglycerin was explosive. Overdoses may generate
methemoglobinemia Methemoglobinemia, or methaemoglobinaemia, is a condition of elevated methemoglobin in the blood. Symptoms may include headache, dizziness, shortness of breath, nausea, poor muscle coordination, and blue-colored skin (cyanosis). Complications ...
.


References


Further reading

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