Ergotamine

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Ergotamine
Ergotamine-skeletal.svg
Ergotamine ball-and-stick.png
Clinical data
Trade namesCafergot (with caffeine), Ergomar, others
Other names2'-Methyl-5'α-benzyl-12'-hydroxy-3',6',18-trioxoergotaman; 9,10α-Dihydro-12'-hydroxy-2'-methyl-5'α-(phenylmethyl)ergotaman-3',6',18-trione
AHFS/Drugs.comMonograph
Routes of
administration
Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityIntravenous: 100%,[1]
Intramuscular: 47%,[2]
Oral: <1%[3] (Enhanced by co-administration of caffeine[1])
MetabolismHepatic[2]
Elimination half-life2 hours[2]
Excretion90% biliary[2]
Identifiers
  • (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
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.003.658 Edit this at Wikidata
Chemical and physical data
FormulaC33H35N5O5
Molar mass581.673 g·mol−1
3D model (JSmol)
  • C[C@@]1(C(=O)N2[C@H](C(=O)N3CCC[C@H]3[C@@]2(O1)O)CC4=CC=CC=C4)NC(=O)[C@H]5CN([C@@H]6CC7=CNC8=CC=CC(=C78)C6=C5)C
  • 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 checkY
  • Key:XCGSFFUVFURLIX-VFGNJEKYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Ergotamine, sold under the brand names Cafergot (with caffeine) and Ergomar among others, is an ergopeptine and part of the ergot family of alkaloids; it is structurally and biochemically closely related to ergoline.[4] 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 hemorrhage (bleeding after childbirth). It was first isolated from the ergot fungus by Arthur Stoll at Sandoz in 1918 and marketed as Gynergen in 1921.[5]

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.[6] Its biosynthesis in these fungi requires the amino acid 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 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]

Medical uses[edit]

Ergotamine continues to be prescribed for migraines and cluster headaches.[8]

Availability and dosage[edit]

In the United States, ergotamine is available as a suppository, a sublingual tablet, and a tablet, sometimes in combination with caffeine. The suppository is available under the brand name Migergot, 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.[9]

This preparation may be used immediately following the aura/onset of pain to abort the migraine. For the best results, dosage should start at the first sign of an attack.[10]

Contraindications[edit]

Contraindications include: atherosclerosis, Buerger's syndrome, coronary artery disease, hepatic disease, pregnancy, pruritus, Raynaud's syndrome, and renal disease.[11] It's also contraindicated if patient is taking macrolide antibiotics (e.g., erythromycin), certain HIV protease inhibitors (e.g., ritonavir, nelfinavir, indinavir), certain azole antifungals (e.g., ketoconazole, itraconazole, voriconazole) delavirdine, efavirenz, or a 5-HT1 receptor agonist (e.g., sumatriptan). [12]

Side effects[edit]

Side effects of ergotamine include nausea and vomiting. At higher doses, it can cause raised arterial blood pressure, vasoconstriction (including coronary vasospasm) and bradycardia or tachycardia. Severe vasoconstriction may cause symptoms of intermittent claudication.[13][8]

Pharmacology[edit]

Pharmacodynamics[edit]

Ergotamine interacts with serotonin, adrenergic, and dopamine receptors.[14][15] It is an agonist of serotonin receptors including the 5-HT1 and 5-HT2 subtypes.[14] Ergotamine is an agonist of the serotonin 5-HT2B receptor and has been associated with cardiac valvulopathy.[16] Despite acting as a potent 5-HT2A receptor agonist, ergotamine is said to be non-hallucinogenic similarly to lisuride.[17][18] This is thought to be due to functional selectivity at the 5-HT2A receptor.[17][18]

Activities of ergotamine at various sites[15][19][20][21][22]
Site Affinity (Ki/IC50 [nM]) Efficacy (Emax [%]) Action
5-HT1A 0.17–0.3 ? Full agonist
5-HT1B 0.3–4.7 ? Agonist
5-HT1D 0.3–6.0 ? Agonist
5-HT1E 19–840 ? ?
5-HT1F 170–171 ? ?
5-HT2A 0.64–0.97 ? Full agonist
5-HT2B 1.3–45 ? Partial agonist
5-HT2C 1.9–9.8 ? Partial agonist
5-HT3 >10,000
5-HT4 65 ? ?
5-HT5A 14 ? Agonist
5-HT5B 3.2–16 ? ?
5-HT6 12 ? ?
5-HT7 1,291 ? Agonist
α1A 15–>10,000
α1B 12–>10,000
α1D ? ? ?
α2A 106 ? ?
α2B 88 ? ?
α2C >10,000
β1 >10,000
β2 >10,000
D1 >10,000
D2 4.0–>10,000 Agonist
D3 3.2–>10,000
D4 12–>10,000
D5 170 ? ?
H1 >10,000
H2 >10,000
M1 862 ? ?
M2 911 ? ?
M3 >10,000
M4 >10,000
M5 >10,000
Notes: All receptors are human except 5-HT5A (mouse/rat) and 5-HT5B (mouse/rat—no human counterpart).[15] No affinity for histamine H1 or H2, cannabinoid CB1, GABA, glutamate, or nicotinic acetylcholine receptors, nor the monoamine transporters (all >10,000 nM).[15]

Pharmacokinetics[edit]

The bioavailability of ergotamine is around 2% orally, 6% rectally, and 100% by intramuscular or intravenous injection.[14] The low oral and rectal bioavailability is due to low gastrointestinal absorption and high first-pass metabolism.[14]

Legal status[edit]

Ergotamine is a controlled substance in the United States as it is a commonly used precursor for the production of LSD.[23]

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". European Journal of Clinical Pharmacology. 30 (3): 331–4. doi:10.1007/BF00541538. PMID 3732370. S2CID 37538721.
  2. ^ a b c d Tfelt-Hansen P, Johnson ES (1993). "Ergotamine". In Olesen J, Tfelt-Hansen P, Welch KM (eds.). The Headaches. New York: Raven Press. pp. 313–22.
  3. ^ Ibraheem JJ, Paalzow L, Tfelt-Hansen P (December 1983). "Low bioavailability of ergotamine tartrate after oral and rectal administration in migraine sufferers". British Journal of Clinical Pharmacology. 16 (6): 695–9. doi:10.1111/j.1365-2125.1983.tb02243.x. PMC 1428366. PMID 6419759.
  4. ^ Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 397–. ISBN 978-3-88763-075-1.
  5. ^ AJ Giannini, AE Slaby. Drugs of Abuse. Oradell, NJ, Medical Economics Books, 1989.
  6. ^ "Pharmacognosy of Ergot (Argot or St. Anthony's Fire)". pharmaxchange.info. 30 December 2011. Archived from the original on 17 July 2012.
  7. ^ Schardl CL, Panaccione DG, Tudzynski P (2006). "Ergot alkaloids--biology and molecular biology". The Alkaloids. Chemistry and Biology. 63: 45–86. doi:10.1016/S1099-4831(06)63002-2. ISBN 978-0-12-469563-4. PMID 17133714.
  8. ^ a b Zajdel P, Bednarski M, Sapa J, Nowak G (2015). "Ergotamine and nicergoline - facts and myths". Pharmacol Rep. 67 (2): 360–363. doi:10.1016/j.pharep.2014.10.010. PMID 25712664.CS1 maint: uses authors parameter (link)
  9. ^ "Approved Drug Products". FDA Orange Book (40th ed.). U.S. Food and Drug Administration. 2020.
  10. ^ "CAFERGOT- ergotamine tartrate and caffeine tablet, film coated". DailyMed. U.S. National Library of Medicine. Archived from the original on 2014-01-16.
  11. ^ Giannini AJ (1986). Biological Foundations of Clinical Psychiatry. Oradell, NJ: Medical Economics Puclishing Co.
  12. ^ "Ergotamine: Indications, Side Effects, Warnings". Drugs.com. Archived from the original on 25 March 2017. Retrieved 25 March 2017.
  13. ^ "Medihaler Ergotamine". drugs.com. Archived from the original on 2016-04-01. Retrieved 2016-05-20.
  14. ^ a b c d Ramírez Rosas MB, Labruijere S, Villalón CM, Maassen Vandenbrink A (August 2013). "Activation of 5-hydroxytryptamine1B/1D/1F receptors as a mechanism of action of antimigraine drugs". Expert Opin Pharmacother. 14 (12): 1599–610. doi:10.1517/14656566.2013.806487. PMID 23815106.
  15. ^ a b c d https://web.archive.org/web/20210413101932/https://pdsp.unc.edu/databases/pdsp.php?testFreeRadio=testFreeRadio&testLigand=Ergotamine&doQuery=Submit+Query
  16. ^ Cavero I, Guillon JM (2014). "Safety Pharmacology assessment of drugs with biased 5-HT(2B) receptor agonism mediating cardiac valvulopathy". J Pharmacol Toxicol Methods. 69 (2): 150–61. doi:10.1016/j.vascn.2013.12.004. PMID 24361689.
  17. ^ a b Karaki S, Becamel C, Murat S, Mannoury la Cour C, Millan MJ, Prézeau L, Bockaert J, Marin P, Vandermoere F (May 2014). "Quantitative phosphoproteomics unravels biased phosphorylation of serotonin 2A receptor at Ser280 by hallucinogenic versus nonhallucinogenic agonists". Mol Cell Proteomics. 13 (5): 1273–85. doi:10.1074/mcp.M113.036558. PMC 4014284. PMID 24637012.
  18. ^ a b Hanks, James B.; González-Maeso, Javier (2016). "Molecular and Cellular Basis of Hallucinogen Action". In Victor R. Preedy (ed.). Neuropathology of Drug Addictions and Substance Misuse. 2: Stimulants, Club and Dissociative Drugs, Hallucinogens, Steroids, Inhalants and International Aspects. pp. 803–812. doi:10.1016/B978-0-12-800212-4.00075-3. ISBN 978-0-12-800212-4.
  19. ^ Silberstein SD, McCrory DC (February 2003). "Ergotamine and dihydroergotamine: history, pharmacology, and efficacy". Headache. 43 (2): 144–66. doi:10.1046/j.1526-4610.2003.03034.x. PMID 12558771.
  20. ^ Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A, Hufeisen SJ, Roth BL (December 2000). "Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications". Circulation. 102 (23): 2836–41. doi:10.1161/01.cir.102.23.2836. PMID 11104741.
  21. ^ Rubio-Beltrán E, Labastida-Ramírez A, Haanes KA, van den Bogaerdt A, Bogers AJ, Zanelli E, Meeus L, Danser AH, Gralinski MR, Senese PB, Johnson KW, Kovalchin J, Villalón CM, MaassenVanDenBrink A (December 2019). "Characterization of binding, functional activity, and contractile responses of the selective 5-HT1F receptor agonist lasmiditan". Br J Pharmacol. 176 (24): 4681–4695. doi:10.1111/bph.14832. PMC 6965684. PMID 31418454.
  22. ^ Pytliak M, Vargová V, Mechírová V, Felšöci M (2011). "Serotonin receptors - from molecular biology to clinical applications". Physiol Res. 60 (1): 15–25. doi:10.33549/physiolres.931903. PMID 20945968.
  23. ^ "Lists of: Scheduling Actions, Controlled Substances, Regulated Chemicals" (PDF). Drug Enforcement Administration, Diversion Control Division, Drug & Chemical Evaluation Section. U.S. Department of Justice. February 2020.