Ergotamine

Ergotamine

Systematic (IUPAC) name
(6aR,9R)-N-((2R,5S,10aS,10bS)- 5-benzyl-10b-hydroxy-2-methyl- 3,6-dioxooctahydro-2H-oxazolo[3,2-a] pyrrolo[2,1-c]pyrazin-2-yl) -7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg] quinoline-9-carboxamide
Clinical data
Trade names	Ergomar
AHFS/Drugs.com	monograph
Pregnancy cat.	X(US)
Legal status	Prescription Only (S4) (AU) POM (UK) ℞-only (US)
Routes	Oral
Pharmacokinetic data
Bioavailability	Intravenous: 100%,[1] Intramuscular: 47%,[2] Oral: <1% [3] (Enhanced by co-administration of caffeine [1])
Metabolism	Hepatic [2]
Half-life	2 hours [2]
Excretion	90% biliary [2]
Identifiers
CAS number	113-15-5
ATC code	N02CA02
PubChem	CID 8223
IUPHAR ligand	149
DrugBank	DB00696
ChemSpider	7930 Y
UNII	PR834Q503T Y
KEGG	D07906 Y
ChEMBL	CHEMBL442 Y
Chemical data
Formula	C33H35N5O5
Mol. mass	581.66 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C33H35N5O5/c1-32(35-29(39)21-15-23-22-10-6-11-24-28(22)20(17-34-24)16-25(23)36(2)18-21)31(41)38-26(14-19-8-4-3-5-9-19)30(40)37-13-7-12-27(37)33(38,42)43-32/h3-6,8-11,15,17,21,25-27,34,42H,7,12-14,16,18H2,1-2H3,(H,35,39)/t21-,25-,26+,27+,32-,33+/m1/s1 Y Key:XCGSFFUVFURLIX-VFGNJEKYSA-N Y
Y(what is this?)  (verify)

Ergotamine is an ergopeptine and part of the ergot family of alkaloids; it is structurally and biochemically closely related to ergoline. It possesses structural similarity to several neurotransmitters, 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.^[4]

Mechanism of action

The mechanism of action of ergotamine is complex.^[5] The molecule shares structural similarity with neurotransmitters such as serotonin, 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-HT_1B receptor, and by inhibiting trigeminal neurotransmission by 5-HT_1D receptors. Ergotamine also has effects on the dopamine and norepinephrine receptors. It is its action on the D2 dopamine and 5-HT_1A receptors that can cause some side effects.^[6]

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 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, oxygenations/oxidations, and isomerizations at selected residues precede, and give rise to, formation of ergotamine.^[7]

Drug uses

Ergotamine produces vasoconstriction peripherally as well as damages the peripheral epithelium. 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.^[8]

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

• Cafergot, an abortive migraine treatment with ergotamine and caffeine
• Dihydroergotamine, a semi-synthetic form used as an abortive migraine treatment
• Ergotism
• Ergometrine

References

1. ^ ^{a b} Sanders SW, Haering N, Mosberg H, Jaeger H. Pharmacokinetics of ergotamine in healthy volunteers following oral and rectal dosing. Eur J Clin Pharmacol 1983; 30: 331–4.
2. ^ ^{a b c d} Tfelt-Hansen P, Johnson ES. Ergotamine. In: Olesen J, Tfelt-Hansen P, Welch KM, editors. The headaches. New York: Raven Press; 1993. p. 313–22.
3. ^ Ibraheem JJ, Paalzow L, Tfelt-Hansen P. Low bioavailability of ergotamine tartrate after oral and rectal administration in migraine sufferers. Br J Clin Pharmacol 1983; 16: 695–9.
4. ^ AJ Giannini, AE Slaby. Drugs of Abuse. Oradell, NJ, Medical Economics Books, 1989.
5. ^ Walkembach J, Brüss M, Urban BW, Barann M (October 2005). "Interactions of metoclopramide and ergotamine with human 5-HT3A receptors and human 5-HT reuptake carriers". Br. J. Pharmacol. 146 (4): 543–52. doi:10.1038/sj.bjp.0706351. PMC 1751187. PMID 16041395. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1751187. 
6. ^ Tfelt-Hansen P, Saxena PR, Dahlof C, Pascual J, Lainez M, Henry P, Diener H, Schoenen J, Ferrari MD, Goadsby PJ (2000). "Ergotamine in the acute treatment of migraine: a review and European consensus". Brain 123: 9–18. doi:10.1093/brain/123.1.9. PMID 10611116. 
7. ^ Schardl CL, Panaccione DG, Tudzynski P (2006). "Ergot alkaloids--biology and molecular biology". Alkaloids Chem. Biol.. The Alkaloids: Chemistry and Biology 63: 45–86. doi:10.1016/S1099-4831(06)63002-2. ISBN 9780124695634. PMID 17133714. 
8. ^ AJ Giannini. Biological Foundations of Clinical Psychiatry. Oradell, NJ. Medical Economics Puclishing Co., 1986.