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Ergotamine
Systematic (IUPAC) name
(6aR,9R)-N-((2 R,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
Identifiers
CAS number 113-15-5
ATC code N02CA02
PubChem 8223
ChemSpider 7930
Chemical data
Formula C 33H35N5O5  
Mol. mass 581.66 g/mol
Pharmacokinetic data
Bioavailability  ?
Metabolism hepatic
Half life  ?
Excretion renal
Therapeutic considerations
Pregnancy cat. X(US)
Legal status Prescription Only (S4) (AU) POM (UK) -only (US)
Routes Oral
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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), and to induce childbirth and prevent post-partum haemorrhage. It was first isolated from the ergot fungus by Arthur Stoll at Sandoz in 1918 and marketed as Gynergen in 1921. [1]

Contents

Mechanism of action

The mechanism of action of ergotamine is complex.[2] 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-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. [3]

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.[4]

Drug uses

Ergotamine is a precursor of LSD and 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.

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. [5]

See also

References

  1. ^ AJ Giannini, AE Slaby. Drugs of Abuse. Oradell, NJ, Medical Economics Books, 1989.
  2. ^ Walkembach J, Brüss M, Urban BW, Barann M (October 2005). "Interactions of metoclopramide and ergotamine with human 5-HT(3A) receptors and human 5-HT reuptake carriers". Br. J. Pharmacol. 146 (4): 543–52. doi:10.1038/sj.bjp.0706351. PMID 16041395.  
  3. ^ 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.  
  4. ^ Schardl CL, Panaccione DG, Tudzynski P (2006). "Ergot alkaloids--biology and molecular biology". Alkaloids Chem. Biol. 63: 45–86. doi:10.1016/S1099-4831(06)63002-2. PMID 17133714.  
  5. ^ AJ Giannini. Biological Foundations of Clinical Psychiatry. Oradell, NJ. Medical Economics Puclishing Co., 1986.







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