Ergotamine
Encyclopedia
Ergotamine is an ergopeptine and part of the ergot
family of alkaloid
s; it is structurally and biochemically closely related to ergoline
. It possesses structural similarity to several neurotransmitter
s, and has biological activity
as a vasoconstrictor.
It is used medicinally
for treatment of acute migraine
attacks (sometimes in combination with caffeine
). Medicinal usage of ergot fungus began in the 16th century to induce childbirth
, yet dosage uncertainties discouraged the use. It has been used to prevent post-partum haemorrhage (bleeding after childbirth). It was first isolated from the ergot fungus by Arthur Stoll at Sandoz in 1918 and marketed as Gynergen in 1921.
, dopamine
, and epinephrine
and can thus bind to several receptors
acting as an agonist
. The anti-migraine effect is due to constriction of the intracranial extracerebral blood vessels through the 5-HT1B receptor
, and by inhibiting trigeminal
neurotransmission by 5-HT1D receptors. Ergotamine also has effects on the dopamine
and norepinephrine
receptors. It is its action on the D2 dopamine and 5-HT1A receptors that can cause some side effects.
(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
L-tryptophan
and dimethylallyl diphosphate. These precursor compounds are the substrates for the enzyme, dimethylallyl-tryptophan (DMAT) synthase, 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 covalently links LA to the amino acids, L-alanine
, L-proline
, and L-phenylalanine
. Enzyme-catalyzed or spontaneous cyclizations, oxygenation
s/oxidations, and isomerizations at selected residues precede, and give rise to, formation of ergotamine.
In high doses ergotamine is conducive to vascular stasis, thrombosis
and gangrene
. It can increase uterine contractivity and occasionally is used therapeutically immediately post-partum to decrease uterine bleeding. See also ergometrine.
Ergotamine continues to be prescribed for migraines.
Contraindications include: atherosclerosis
, Buerger's syndrome, coronary artery disease, hepatic disease, pregnancy, pruritus, Raynaud's syndrome, and renal disease.
Ergotamine is also a precursor of LSD.
Ergot
Ergot or ergot fungi refers to a group of fungi of the genus Claviceps. The most prominent member of this group is Claviceps purpurea. This fungus grows on rye and related plants, and produces alkaloids that can cause ergotism in humans and other mammals who consume grains contaminated with its...
family of alkaloid
Alkaloid
Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...
s; it is structurally and biochemically closely related to ergoline
Ergoline
Ergoline is a chemical compound whose structural skeleton is contained in a diverse range of alkaloids including a few psychedelic drugs . Ergoline derivatives are used clinically for the purpose of vasoconstriction and in the treatment of migraines and Parkinson's disease...
. It possesses structural similarity to several neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
s, and has biological activity
Biological activity
In pharmacology, biological activity or pharmacological activity describes the beneficial or adverse effects of a drug on living matter. When a drug is a complex chemical mixture, this activity is exerted by the substance's active ingredient or pharmacophore but can be modified by the other...
as a vasoconstrictor.
It is used medicinally
Pharmacology
Pharmacology is the branch of medicine and biology concerned with the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function...
for treatment of acute migraine
Migraine
Migraine is a chronic neurological disorder characterized by moderate to severe headaches, and nausea...
attacks (sometimes in combination with caffeine
Caffeine
Caffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...
). Medicinal usage of ergot fungus began in the 16th century to induce childbirth
Childbirth
Childbirth is the culmination of a human pregnancy or gestation period with the birth of one or more newborn infants from a woman's uterus...
, yet dosage uncertainties discouraged the use. It has been used to prevent post-partum haemorrhage (bleeding after childbirth). It was first isolated from the ergot fungus by Arthur Stoll at Sandoz in 1918 and marketed as Gynergen in 1921.
Mechanism of action
The mechanism of action of ergotamine is complex. The molecule shares structural similarity with neurotransmitters such as serotoninSerotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
, dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
, and epinephrine
Epinephrine
Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...
and can thus bind to several receptors
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
acting as an agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
. The anti-migraine effect is due to constriction of the intracranial extracerebral blood vessels through the 5-HT1B receptor
5-HT1B receptor
5-hydroxytryptamine receptor 1B also known as the 5-HT1B receptor is a protein that in humans is encoded by the HTR1B gene. The 5-HT1B receptor is a 5-HT receptor subtype.-Tissue distribution and function:...
, and by inhibiting trigeminal
Trigeminal nerve
The trigeminal nerve contains both sensory and motor fibres. It is responsible for sensation in the face and certain motor functions such as biting, chewing, and swallowing. Sensory information from the face and body is processed by parallel pathways in the central nervous system...
neurotransmission by 5-HT1D receptors. Ergotamine also has effects on the dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
and norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
receptors. It is its action on the D2 dopamine and 5-HT1A receptors that can cause some side effects.
Biosynthesis
Ergotamine is a secondary metaboliteSecondary metabolite
Secondary metabolites are organic compounds that are not directly involved in the normal growth, development, or reproduction of an organism. Unlike primary metabolites, absence of secondary metabolities does not result in immediate death, but rather in long-term impairment of the organism's...
(natural product
Natural product
A natural product is a chemical compound or substance produced by a living organism - found in nature that usually has a pharmacological or biological activity for use in pharmaceutical drug discovery and drug design...
) and the principal alkaloid produced by the ergot fungus, Claviceps purpurea
Claviceps purpurea
Claviceps purpurea is a fungus that grows on the ears of rye and related cereal and forage plants. Consumption of grains or seeds contaminated with the fruiting structure of this fungus, the ergot sclerotium, can cause ergotism in humans and other mammals.. C...
, and related fungi in the family Clavicipitaceae
Clavicipitaceae
Clavicipitaceae is a family of fungi within the order Hypocreales. It consists of 43 genera, and 321 species.-Phylogeny:Molecular phylogenetic analysis of multigene DNA sequence data indicates that the taxon, Clavicipitaceae, is paraphyletic, and consists of three well-defined clades, at least one...
. Its biosynthesis in these fungi requires the amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
L-tryptophan
Tryptophan
Tryptophan is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in the standard genetic code as the codon UGG...
and dimethylallyl diphosphate. These precursor compounds are the substrates for the enzyme, dimethylallyl-tryptophan (DMAT) synthase, catalyzing the first step in ergot alkaloid biosynthesis, i.e., the prenylation
Prenylation
Prenylation, or isoprenylation, or lipidation is the addition of hydrophobic molecules to a protein. It is usually assumed that prenyl groups facilitate attachment to cell membranes, similar to lipid anchor like the GPI anchor, though direct evidence is missing...
of L-tryptophan. Further reactions, involving methyltransferase
Methyltransferase
A methyltransferase is a type of transferase enzyme that transfers a methyl group from a donor to an acceptor.Methylation often occurs on nucleic bases in DNA or amino acids in protein structures...
and oxygenase
Oxygenase
An oxygenase is any enzyme that oxidizes a substrate by transferring the oxygen from molecular oxygen O2 to it. The oxygenases form a class of oxidoreductases; their EC number is EC 1.13 or EC 1.14....
enzymes, yield the ergoline
Ergoline
Ergoline is a chemical compound whose structural skeleton is contained in a diverse range of alkaloids including a few psychedelic drugs . Ergoline derivatives are used clinically for the purpose of vasoconstriction and in the treatment of migraines and Parkinson's disease...
, lysergic acid
Lysergic acid
Lysergic acid, also known as D-lysergic acid and -lysergic acid, is a precursor for a wide range of ergoline alkaloids that are produced by the ergot fungus and some plants. Amides of lysergic acid, lysergamides, are widely used as pharmaceuticals and as psychedelic drugs...
. Lysergic acid (LA) is the substrate of lysergyl peptide synthetase, a nonribosomal peptide synthetase
Nonribosomal peptide
Nonribosomal peptides are a class of peptide secondary metabolites, usually produced by microorganisms like bacteria and fungi. Nonribosomal peptides are also found in higher organisms, such as nudibranchs, but are thought to be made by bacteria inside these organisms...
, which covalently links LA to the amino acids, L-alanine
Alanine
Alanine is an α-amino acid with the chemical formula CH3CHCOOH. The L-isomer is one of the 20 amino acids encoded by the genetic code. Its codons are GCU, GCC, GCA, and GCG. It is classified as a nonpolar amino acid...
, L-proline
Proline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
, and L-phenylalanine
Phenylalanine
Phenylalanine is an α-amino acid with the formula C6H5CH2CHCOOH. This essential amino acid is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. L-Phenylalanine is an electrically neutral amino acid, one of the twenty common amino acids used to biochemically form...
. Enzyme-catalyzed or spontaneous cyclizations, oxygenation
Oxygenation
Oxygenation may refer to:* Oxygenation , a measurement of dissolved oxygen concentration in soil or water* Oxygenation , the process by which concentrations of oxygen increase within a tissue...
s/oxidations, and isomerizations at selected residues precede, and give rise to, formation of ergotamine.
Drug uses
Ergotamine produces vasoconstriction peripherally as well as damages the peripheral epithelium.In high doses ergotamine is conducive to vascular stasis, thrombosis
Thrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...
and gangrene
Gangrene
Gangrene is a serious and potentially life-threatening condition that arises when a considerable mass of body tissue dies . This may occur after an injury or infection, or in people suffering from any chronic health problem affecting blood circulation. The primary cause of gangrene is reduced blood...
. It can increase uterine contractivity and occasionally is used therapeutically immediately post-partum to decrease uterine bleeding. See also ergometrine.
Ergotamine continues to be prescribed for migraines.
Contraindications include: atherosclerosis
Atherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
, Buerger's syndrome, coronary artery disease, hepatic disease, pregnancy, pruritus, Raynaud's syndrome, and renal disease.
Ergotamine is also a precursor of LSD.
Side effects
Ergotamine is associated with adverse effects that are significantly more severe than the effects of the triptans. These side effects, along with a decreased effectiveness compared to the triptans, explain why ergotamine is a rarely used abortive drug for the treatment of migraines. The side effects include GI tract irritation, tingling, angina, contraction of the uterus, damage to the endothelium, vasoconstriction, drowsiness, dizziness and rebound headache. The risk of ergotamine's side effects becomes greater when taken with other drugs that inhibit its metabolism.See also
- CafergotCafergotCafergot is the proprietary name of a medication consisting of ergotamine tartrate and caffeine. This combination is used for the treatment of vascular headaches, such as migraine headache.-Use:...
, an abortive migraine treatment with ergotamine and caffeineCaffeineCaffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants... - DihydroergotamineDihydroergotamineDihydroergotamine is an ergot alkaloid used to treat migraines. It is a derivative of ergotamine. It is administered as a nasal spray or injection and has an efficacy similar to that of sumatriptan...
, a semi-synthetic form used as an abortive migraine treatment - ErgotismErgotismErgotism is the effect of long-term ergot poisoning, traditionally due to the ingestion of the alkaloids produced by the Claviceps purpurea fungus which infects rye and other cereals, and more recently by the action of a number of ergoline-based drugs. It is also known as ergotoxicosis, ergot...
- Ergometrine