Nitroglycerin, also known as glyceryl trinitrate (GTN), is a

vasodilator Vasodilation, also known as vasorelaxation, 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. Blood vessel wal ...

used for

heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome caused by an impairment in the heart's ability to Cardiac cycle, fill with and pump blood. Although symptoms vary based on which side of the heart is affected, HF ...

high blood pressure Hypertension, also known as high blood pressure, 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 itself. It is, however, a major ri ...

, anal fissures, painful periods, and to treat and prevent

chest pain Chest pain is pain or discomfort in the chest, typically the front of the chest. It may be described as sharp, dull, pressure, heaviness or squeezing. Associated symptoms may include pain in the shoulder, arm, upper abdomen, or jaw, along with n ...

caused by decreased blood flow to the heart (

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 parti ...

) or due to the recreational use of

cocaine Cocaine is a tropane alkaloid and central nervous system stimulant, derived primarily from the leaves of two South American coca plants, ''Erythroxylum coca'' and ''Erythroxylum novogranatense, E. novogranatense'', which are cultivated a ...

. This includes chest pain from a

heart attack A myocardial infarction (MI), commonly known as a heart attack, occurs when Ischemia, blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom ...

. It is taken

by mouth Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

, under the tongue, applied to the skin, or by injection into a vein. Common side effects include

headache A headache, also known as cephalalgia, 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 (mood), depression in those with severe ...

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 gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...

is safe for the fetus. It should not be used together with medications within the

PDE5 inhibitor A phosphodiesterase type 5 inhibitor (PDE5 inhibitor) is a vasodilating medication, 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 vess ...

family such as

sildenafil Sildenafil, sold under the brand name Viagra among others, is a medication used to treat erectile dysfunction and pulmonary hypertension, pulmonary arterial hypertension. It is also sometimes used off-label for the treatment of certain sym ...

due to the risk of low blood pressure. Nitroglycerin is in the

nitrate Nitrate is a polyatomic ion with the chemical formula . salt (chemistry), Salts containing this ion are called nitrates. Nitrates are common components of fertilizers and explosives. Almost all inorganic nitrates are solubility, soluble in wa ...

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. The drug nitroglycerin is a dilute form of the same chemical used as the explosive,

nitroglycerin Nitroglycerin (NG) (alternative spelling nitroglycerine), also known as trinitroglycerol (TNG), nitro, glyceryl trinitrate (GTN), or 1,2,3-trinitroxypropane, is a dense, colorless or pale yellow, oily, explosive liquid most commonly produced by ...

. Dilution makes it non-explosive. In 2022, it was the 196th most commonly prescribed medication in the United States, with more than 2million prescriptions.

Medical uses

Nitroglycerin is used for the treatment of angina, acute myocardial infarction, severe

hypertension Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...

, and acute coronary artery spasms. 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 nutr ...

, as a sublingual spray/tablet, or as a patch applied to the skin.

Angina

Nitroglycerin is useful in decreasing

attacks, perhaps more so than reversing angina once started, by supplementing blood concentrations of NO, also called

endothelium-derived relaxing factor The Endothelium-derived relaxing factor (EDRF) is a strong Vasodilation, vasodilator produced by Endothelial cells, cardiac endothelial cells in response to stress signals such as high levels of ADP-ribosylation, ADP accumulation or Hypoxia (medic ...

, before the structure of NO as the responsible agent was known. This led to the development of transdermal patches of nitroglycerin, providing 24-hour release. However, the effectiveness of nitroglycerin 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, nitroglycerin works best when used only in short-term, pulse dosing. Nitroglycerin is useful for

myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when Ischemia, blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom ...

(heart attack) and

pulmonary edema Pulmonary edema (British English: oedema), also known as pulmonary congestion, is excessive fluid accumulation in the tissue or air spaces (usually alveoli) of the lungs. This leads to impaired gas exchange, most often leading to shortness ...

, 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 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 nitroglycerin in the treatment of various tendinopathies, both in pain management and acceleration of soft tissue repair. Nitroglycerin is also used in the treatment of anal fissures, though usually at a much lower concentration than that used for angina treatment. Nitroglycerin 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 ...

. Nitroglycerin 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 more porous bone, and consequent increase in Bone fracture, fracture risk. It is the most common reason f ...

; however, the researcher Sophie Jamal 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 method, scholarly conduct and ethics, ethical behavior in the publication of professional science, scientific research. It is the violation of scientific integrity: violati ...

cases in Canada.

Tolerance

After long-term use for chronic conditions, nitrate tolerance—tolerance to agents such as nitroglycerin—may develop in a patient, reducing its effectiveness. Tolerance is defined as the loss of symptomatic and hemodynamic effects of nitroglycerin or the need for higher doses of the drug to achieve the same effects, and was first described soon after the introduction of nitroglycerin 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 nitroglycerin into NO or related species # counteraction of nitroglycerin vasodilation by neurohormonal activation # oxidative stress

Adverse events

Nitroglycerin can cause severe

hypotension Hypotension, also known as low blood pressure, is a cardiovascular condition characterized by abnormally reduced blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood and is ...

, reflex tachycardia, and severe headaches that necessitate

analgesic An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in s ...

intervention for pain relief, the painful nature of which can have a marked negative effect on patient compliance. Nitroglycerin also can cause severe hypotension, circulatory collapse, and death if used together with

drugs that are used for

erectile dysfunction Erectile dysfunction (ED), also referred to as impotence, is a form of sexual dysfunction in males characterized by the persistent or recurring inability to achieve or maintain a Human penis, penile erection with sufficient rigidity and durat ...

, such as

, tadalafil, and vardenafil. Nitroglycerin 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). Defibrillation delivers a dose of electric current (often called a ''count ...

due to the risk of explosion or burns, but investigations have concluded that nitroglycerin patch explosions during defibrillation were due to the

breakdown voltage The breakdown voltage of an insulator (electrical), insulator is the minimum voltage that causes a portion of an insulator to experience electrical breakdown and become electrically Conductor (material), conductive. For diodes, the breakdown vo ...

of the metal mesh in some patches.

Mechanism of action

Nitroglycerin is a

prodrug A prodrug is a pharmacologically inactive 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 ...

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, nitrogen monooxide, 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 den ...

(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 insol ...

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 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 grou ...

groups, while others believe that enzymes such as glutathione ''S''-transferases,

cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...

(CYP), and

xanthine oxidoreductase Xanthine oxidase (XO or 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 xanthine to u ...

are the primary source of nitroglycerin bioactivation. The NO produced by this process is a potent activator of

guanylyl cyclase Guanosine monophosphate (GMP), also known as 5′-guanidylic acid or guanylic acid ( conjugate base guanylate), is a nucleotide that is used as a monomer in RNA. It is an ester of phosphoric acid with the nucleoside guanosine. GMP consists of th ...

(GC) by

heme Heme (American English), or haem (Commonwealth English, both pronounced /Help:IPA/English, hi:m/ ), is a ring-shaped iron-containing molecule that commonly serves as a Ligand (biochemistry), ligand of various proteins, more notably as a Prostheti ...

-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 ...

(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 di ...

(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 nitroglycerin increases the level of

cGMP CGMP is an initialism. It can refer to: *cyclic guanosine monophosphate (cGMP) * current good manufacturing practice (cGMP) *CGMP, Cisco Group Management Protocol, the Cisco version of Internet Group Management Protocol The Internet Group Manag ...

within the cell, and stimulates

dephosphorylation In biochemistry, dephosphorylation is the removal of a phosphate () group from an organic compound by hydrolysis. It is a reversible post-translational modification. Dephosphorylation and its counterpart, phosphorylation, activate and deactivate e ...

myosin Myosins () are a Protein family, family of motor proteins (though most often protein complexes) best known for their roles in muscle contraction and in a wide range of other motility processes in eukaryotes. They are adenosine triphosphate, ATP- ...

, which initiates relaxation of smooth muscle cells in blood vessels.

History

It was known almost from the time of the first synthesis of nitroglycerin by

Ascanio Sobrero Ascanio Sobrero (12 October 1812 – 26 May 1888) was an Italian chemist, born in Casale Monferrato. He studied under Théophile-Jules Pelouze at the University of Turin, who had worked with the explosive material guncotton. Education and ca ...

in 1846 that handling and tasting of

could cause sudden intense

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, also known as vasorelaxation, 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. Blood vessel wa ...

effect. 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 Homeopathy or homoeopathy is a pseudoscientific system of alternative medicine. It was conceived in 1796 by the German physician Samuel Hahnemann. Its practitioners, called homeopaths or homeopathic physicians, believe that a substance that ...

. 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 Blood pressure (BP) is the pressure of Circulatory system, 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 ...

, 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. Retrieved on September 20, 2014.

. Murrell began treating patients with small doses of nitroglycerin 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, founded in England in 1823. It is one of the world's highest-impact academic journals and also one of the oldest medical journals still in publication. The journal publishes ...

'' 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 ma ...

Society and culture

Brand names

In the United States, Nitrostat is marketed by Viatris after Upjohn was spun off from

Pfizer Pfizer Inc. ( ) is an American Multinational corporation, multinational Pharmaceutical industry, pharmaceutical and biotechnology corporation headquartered at The Spiral (New York City), The Spiral in Manhattan, New York City. Founded in 184 ...