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, a ...
,
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,
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 Quechuan languages, Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly recreational drug use, used recreationally for its euphoria, euphoric effects. It is primarily obtained from t ...
.
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 may tr ...
.[ It is taken ]by mouth
Oral administration is a route of administration where a substance is taken through the mouth. Per os abbreviated to P.O. is sometimes used as a direction for medication to be taken orally. Many medications are taken orally because they are i ...
, 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
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 dia ...
.[ 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 ca ...
is safe for the baby.[ It should not be used together with medications within the ]PDE5 inhibitor
A phosphodiesterase type 5 inhibitor (PDE5 inhibitor) is a vasodilating drug that works by blocking the degradative action of cGMP-specific phosphodiesterase type 5 (PDE5) on cyclic GMP in the smooth muscle cells lining the blood vessels supplyi ...
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
A polyatomic ion, also known as a molecular ion, is a covalent bonded set of two or more atoms, or of a metal complex, that can be considered to behave as a single unit and that has a net charge that is not zer ...
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 WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health ...
. 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 ischemia, insufficient blood flow to the Cardiac muscle, heart muscle (myocardium). It is most commonly a symptom of coronary artery disease.
Angina is typical ...
, 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 tr ...
, 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 bl ...
, 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
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 ...
, 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 ischemia, insufficient blood flow to the Cardiac muscle, heart muscle (myocardium). It is most commonly a symptom of coronary artery disease.
Angina is typical ...
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 Chemical substance, substance that Robert F. Furchgott discovered had the eponymous properties. Today, it is firmly established this substance is nitric oxide (NO). Endothelium produces NO ...
, 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 Tachyphylaxis (Greek ταχύς, ''tachys'', "rapid", and φύλαξις, ''phylaxis'', "protection") is a medical term describing an acute, sudden decrease in response to a drug after its administration; i.e. a rapid and short-term onset of drug to ...
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 may ...
(heart attack) and pulmonary edema
Pulmonary edema, also known as pulmonary congestion, is excessive edema, liquid accumulation in the parenchyma, tissue and pulmonary alveolus, air spaces (usually alveoli) of the lungs. It leads to impaired gas exchange and may cause hypoxemia an ...
, 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 prima ...
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 the ...
.[
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 ...
; however, the researcher Sophie Jamal
Sophie Jamal (born on 6 June 1966) is a Canadian endocrinologist and former osteoporosis researcher who was at the centre of a scientific misconduct case in the mid-to-late 2010s. Jamal published a high-profile paper suggesting that the heart ...
was found to have falsified the findings, sparking one of the largest scientific misconduct
Scientific misconduct is the violation of the standard codes of scholarly conduct and ethical behavior in the publication of professional scientific research. A '' Lancet'' review on ''Handling of Scientific Misconduct in Scandinavian countrie ...
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 dias ...
, reflex tachycardia
Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal (su ...
, 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
Vasodilation is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. The process is the opposite of vasoconstriction, ...
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 male ...
, 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
Tadalafil, sold under the brand name Cialis among others, is a medication used to treat erectile dysfunction (ED), benign prostatic hyperplasia (BPH), and pulmonary arterial hypertension. It is taken by mouth. Onset is typically within half ...
, and vardenafil
Vardenafil is a PDE5 inhibitor used for treating erectile dysfunction that is sold under the brand name Levitra among others.
Medical use
Vardenafil's indications and contraindications are the same as with other PDE5 inhibitors; it is closel ...
.
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 ''cou ...
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 drug ...
which must be denitrated, with the nitrite
The nitrite polyatomic ion, 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 ...
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 che ...
(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 insoluble ...
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-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) to x ...
s, cytochrome P450
Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...
(CYP), and xanthine oxidoreductase
Xanthine oxidase (XO, sometimes XAO) is a form of xanthine oxidoreductase, a type of enzyme that generates reactive oxygen species. These enzymes catalyze the oxidation of hypoxanthine to xanthine and can further catalyze the oxidation of xanthin ...
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
Aldehyde dehydrogenases () are a group of enzymes that catalyse the oxidation of aldehydes. They convert aldehydes (R–C(=O)) to carboxylic acids (R–C(=O)). The oxygen comes from a water molecule. To date, nineteen ALDH genes have b ...
(ALDH2 or mtALDH).
The NO produced by this process is a potent activator of guanylyl cyclase
Guanylate cyclase (EC 4.6.1.2, also known as guanyl cyclase, guanylyl cyclase, or GC; systematic name GTP diphosphate-lyase (cyclizing; 3′,5′-cyclic-GMP-forming)) is a lyase enzyme that converts guanosine triphosphate (GTP) to cyclic guanos ...
(GC) by heme
Heme, or haem (pronounced / hi:m/ ), is a precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver.
In biochemical terms, heme is a coordination complex "consisti ...
-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 in re ...
(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 diffe ...
(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
Myosin light-chain phosphatase, also called myosin phosphatase (EC 3.1.3.53; systematic name yosin-light-chainphosphate phosphohydrolase), is an enzyme (specifically a Protein serine/threonine phosphatase, serine/threonine-specific protein pho ...
. Thus, production of NO from exogenous sources such as GTN increases the level of cGMP within the cell, and stimulates dephosphorylation
In biochemistry, dephosphorylation is the removal of a phosphate (PO43−) group from an organic compound by hydrolysis. It is a reversible post-translational modification. Dephosphorylation and its counterpart, phosphorylation, activate and deac ...
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 ...
, 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 me ...
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
Vasodilation is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. The process is the opposite of vasoconstriction, ...
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
Sir Thomas Lauder Brunton, 1st Baronet, (14 March 1844 – 16 September 1916) was a British physician who is most-closely associated with the use of amyl nitrite to treat angina pectoris.
Early life
Brunton was born on 14 March 1844 in Roxburgh ...
's discovery that amyl nitrite
Amyl nitrite is a chemical compound with the formula C5H11ONO. A variety of isomers are known, but they all feature an amyl group attached to the nitrite functional group. The alkyl group is unreactive and the chemical and biological propertie ...
could be used to treat chest pain, William Murrell experimented with the use of nitroglycerin to alleviate angina pectoris
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 obstru ...
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" r ...
, and showed that the accompanying headaches occurred as a result of overdose
A drug overdose (overdose or OD) is the ingestion or application of a drug or other substance in quantities much greater than are recommended. . 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 m ...
.
References
Further reading
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