Ergotamine

From Wikipedia, the free encyclopedia - View original article

Ergotamine
Ergotamine-skeletal.svg
Ergotamine ball-and-stick.png
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 namesCafergot, Ergomar
AHFS/Drugs.commonograph
Pregnancy cat.
Legal status
RoutesOral
Pharmacokinetic data
BioavailabilityIntravenous: 100%,[1]
Intramuscular: 47%,[2]
Oral: <1% [3] (Enhanced by co-administration of caffeine [1])
MetabolismHepatic [2]
Half-life2 hours [2]
Excretion90% biliary [2]
Identifiers
CAS number113-15-5 YesY
ATC codeN02CA02
PubChemCID 8223
IUPHAR ligand149
DrugBankDB00696
ChemSpider7930 YesY
UNIIPR834Q503T YesY
KEGGD07906 YesY
ChEBICHEBI:64318 N
ChEMBLCHEMBL442 YesY
Chemical data
FormulaC33H35N5O5 
Mol. mass581.66 g/mol
 N (what is this?)  (verify)
 
Jump to: navigation, search
Ergotamine
Ergotamine-skeletal.svg
Ergotamine ball-and-stick.png
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 namesCafergot, Ergomar
AHFS/Drugs.commonograph
Pregnancy cat.
Legal status
RoutesOral
Pharmacokinetic data
BioavailabilityIntravenous: 100%,[1]
Intramuscular: 47%,[2]
Oral: <1% [3] (Enhanced by co-administration of caffeine [1])
MetabolismHepatic [2]
Half-life2 hours [2]
Excretion90% biliary [2]
Identifiers
CAS number113-15-5 YesY
ATC codeN02CA02
PubChemCID 8223
IUPHAR ligand149
DrugBankDB00696
ChemSpider7930 YesY
UNIIPR834Q503T YesY
KEGGD07906 YesY
ChEBICHEBI:64318 N
ChEMBLCHEMBL442 YesY
Chemical data
FormulaC33H35N5O5 
Mol. mass581.66 g/mol
 N (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[edit]

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-HT1B receptor, and by inhibiting trigeminal neurotransmission by 5-HT1D receptors. Ergotamine also has effects on the dopamine and norepinephrine receptors. Its side effects are due mainly to its action at the D2 dopamine and 5-HT1A receptors.[6]

Biosynthesis[edit]

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.[7] 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.[8]

Drug uses[edit]

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.[9]

Availability and dosage[edit]

In the United States, ergotamine is available as a suppository, a sublingual tablet, and a tablet in combination with caffeine. The suppository is available under the brand name Miegerot, which contains 2 mg of ergotamine with 100 mg caffeine. The sublingual tablet is available under the brand name Ergomar and contains 2 mg of ergotamine. The combination tablet in combination with caffeine called Cafergot contains 1 mg of ergotamine and 100 mg of caffeine.[10]

This preparation may be used immediately following the aura/onset of pain to abort the migraine. Procedure: For the best results, dosage should start at the first sign of an attack.[11]

Cafergot is no longer commercially available.

See also[edit]

References[edit]

  1. ^ a b Sanders, SW; Haering N; Mosberg H; Jaeger H (1986). "Pharmacokinetics of ergotamine in healthy volunteers following oral and rectal dosing". Eur J Clin Pharmacol 30 (3): 331–4. doi:10.1007/BF00541538. PMID 3732370. 
  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. 
  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. ^ Pharmacognosy of Ergot
  8. ^ 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 978-0-12-469563-4. PMID 17133714. 
  9. ^ AJ Giannini. Biological Foundations of Clinical Psychiatry. Oradell, NJ. Medical Economics Puclishing Co., 1986.
  10. ^ FDA Orange Book http://www.accessdata.fda.gov/scripts/cder/ob/docs/tempai.cfm
  11. ^ http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=b4a06de6-f837-43a8-ae7a-aadb38dd2a7d#DA