Ergotamine, sold under the brand name Ergomar among others, is an ergopeptine and part of the ergot family of

alkaloid Alkaloids are a broad class of natural product, naturally occurring organic compounds that contain at least one nitrogen atom. Some synthetic compounds of similar structure may also be termed alkaloids. Alkaloids are produced by a large varie ...

s; it is structurally and biochemically closely related to ergoline. It is structurally similar to several

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...

s, and it acts as a vasoconstrictor. It is used for acute migraines, sometimes with

caffeine Caffeine is a central nervous system (CNS) stimulant of the methylxanthine chemical classification, class and is the most commonly consumed Psychoactive drug, psychoactive substance globally. It is mainly used for its eugeroic (wakefulness pr ...

as the combination ergotamine/caffeine. The drug is a non-selective modulator or

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

of serotonin receptors and other

receptor Receptor may refer to: * Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and respond ...

s. It is peripherally selective and crosses into the

brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...

in minimal amounts. Medicinal use of ergot fungus began in the 16th century, for the induction of

childbirth Childbirth, also known as labour, parturition and delivery, is the completion of pregnancy, where one or more Fetus, fetuses exits the Womb, internal environment of the mother via vaginal delivery or caesarean section and becomes a newborn to ...

; but dosage uncertainty discouraged its use. It has been used to prevent post-partum

hemorrhage Bleeding, hemorrhage, haemorrhage or blood loss, is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur internally, or externally either through a natural opening such as the mouth, nose, ear, urethra, ...

(bleeding after childbirth). It was first isolated from the ergot fungus by Arthur Stoll, at Sandoz in 1918, and was marketed as Gynergen in 1921.

Medical uses

Ergotamine is indicated as therapy to abort or prevent vascular headache.

Available forms

Ergotamine is available as a suppository and as a tablet, sometimes in combination with

Contraindications

Contraindications include:

atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...

, Buerger's syndrome,

coronary artery disease Coronary artery disease (CAD), also called coronary heart disease (CHD), or ischemic heart disease (IHD), is a type of cardiovascular disease, heart disease involving Ischemia, the reduction of blood flow to the cardiac muscle due to a build-up ...

, hepatic disease, pregnancy, pruritus, Raynaud's syndrome, and renal disease. It's also contraindicated if patient is taking macrolide antibiotics (e.g., erythromycin), certain HIV protease inhibitors (e.g., ritonavir,

nelfinavir Nelfinavir, sold under the brand name Viracept, is an antiretroviral medication used in the treatment of HIV/AIDS. Nelfinavir belongs to the class of drugs known as protease inhibitor (pharmacology), protease inhibitors (PIs) and like other PIs ...

, indinavir), certain azole antifungals (e.g.,

ketoconazole Ketoconazole, sold under the brand name Nizoral, among others, is an antiandrogen, antifungal drug, antifungal, and antiglucocorticoid medication used to treat a number of fungal infections. Applied to the skin it is used for fungal skin inf ...

itraconazole Itraconazole, sometimes abbreviated ITZ, is an antifungal medication used to treat a number of fungal infections. This includes aspergillosis, blastomycosis, coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis. It may be given ...

, voriconazole) delavirdine, efavirenz, or a 5-HT₁ receptor agonist (e.g., sumatriptan).

Side effects

Side effects of ergotamine include nausea and vomiting. At higher doses, it can cause raised arterial

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 ...

, vasoconstriction (including coronary vasospasm) and

bradycardia Bradycardia, also called bradyarrhythmia, is a resting heart rate under 60 beats per minute (BPM). While bradycardia can result from various pathological processes, it is commonly a physiological response to cardiovascular conditioning or due ...

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 ...

. Severe vasoconstriction may cause symptoms of intermittent claudication.

Pharmacology

Pharmacodynamics

Ergotamine interacts with

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

, adrenergic, and dopamine receptors. It is an

of serotonin receptors including the

5-HT₁ and 5-HT₂ subtypes. Ergotamine is an agonist of the serotonin 5-HT_2B receptor and has been associated with cardiac valvulopathy. Despite acting as a potent serotonin 5-HT_2A receptor agonist, ergotamine is said to be non- hallucinogenic similarly to lisuride. This has been posited to be due to functional selectivity at the serotonin 5-HT_2A receptor. However, ergotamine is also peripherally selective, which may instead account for its lack of psychedelic effects.

Pharmacokinetics

The bioavailability of ergotamine is around 2% orally, 6% rectally, and 100% by intramuscular or intravenous injection. The low oral and rectal bioavailability is due to low

gastrointestinal The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascular system. ...

absorption and high first-pass metabolism. However, ergotamine does not readily cross the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...

and hence is peripherally selective. This is due to it being an avid substrate for P-glycoprotein and breast cancer resistance protein (BCRP). Only minimal amounts of the drug (~1%) cross into the

Biosynthesis

Ergotamine is a secondary metabolite ( natural product) and the principal alkaloid produced by the ergot fungus, '' Claviceps purpurea'', and related fungi in the family Clavicipitaceae. Its biosynthesis in these fungi requires the

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

L- tryptophan and dimethylallyl pyrophosphate. These precursor compounds are the substrates for the enzyme, tryptophan dimethylallyltransferase, catalyzing the first step in ergot alkaloid biosynthesis, i.e., the prenylation of L-tryptophan. Further reactions, involving methyltransferase and oxygenase enzymes, yield the ergoline, lysergic acid. Lysergic acid (LA) is the substrate of ''lysergyl peptide synthetase'', a nonribosomal peptide synthetase, which

covalent A covalent bond is a chemical bond that involves the sharing of electrons to form electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs. The stable balance of attractive and repulsive forces between atom ...

ly links LA to the amino acids, L-

alanine Alanine (symbol Ala or A), or α-alanine, is an α-amino acid that is used in the biosynthesis of proteins. It contains an amine group and a carboxylic acid group, both attached to the central carbon atom which also carries a methyl group sid ...

, L- proline, and L-

phenylalanine Phenylalanine (symbol Phe or F) is an essential α-amino acid with the chemical formula, formula . It can be viewed as a benzyl group substituent, substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of ...

. Enzyme-catalyzed or spontaneous cyclizations, oxygenations/

oxidation Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is ...

s, and isomerizations at selected residues precede, and give rise to, formation of ergotamine.

Society and culture

Legal status

Ergotamine is a List I regulated chemical in the United States.

References

External links

* {{Authority control Alpha-1 blockers Alpha-2 adrenergic receptor agonists Antimigraine drugs Biased ligands Cardiotoxins Ergopeptines Ergot alkaloids Lactams Non-hallucinogenic 5-HT2A receptor agonists Oxazolopyrrolopyrazines Peripherally selective drugs Serotonin receptor agonists Vasoconstrictors