Chemistry:Ergotamine

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Ergotamine, sold under the brand name Ergomar among others, is an ergopeptine and part of the ergot family of alkaloids; it is structurally and biochemically closely related to ergoline.[1] It is structurally similar to several neurotransmitters, and it acts as a vasoconstrictor. It is used for acute migraines, sometimes with caffeine as the combination ergotamine/caffeine.[2][3]

The drug is a non-selective modulator or agonist of serotonin receptors and other receptors.[4][5][6] It is peripherally selective and crosses into the brain in minimal amounts.[6]

Medicinal use of ergot fungus began in the 16th century, for the induction of childbirth; but dosage uncertainty discouraged its 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 was marketed as Gynergen in 1921.[7]

Medical uses

Ergotamine is indicated as therapy to abort or prevent vascular headache.[8][9]

Available forms

Ergotamine is available as a suppository and as a tablet, sometimes in combination with caffeine.[8][10][2][3]

Contraindications

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

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][9]

Pharmacology

Pharmacodynamics

Ergotamine interacts with serotonin, adrenergic, and dopamine receptors.[4][5][6] It is an agonist of serotonin receptors including the serotonin 5-HT1 and 5-HT2 subtypes.[4][6][14] Ergotamine is an agonist of the serotonin 5-HT2B receptor and has been associated with cardiac valvulopathy.[15] Despite acting as a potent serotonin 5-HT2A receptor agonist, ergotamine is said to be non-hallucinogenic similarly to lisuride.[6][16][17] This has been posited to be due to functional selectivity at the serotonin 5-HT2A receptor.[16][17] However, ergotamine is also peripherally selective, which may instead account for its lack of psychedelic effects.[6][18][19]

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 ? Agonist
5-HT1F 170–171 ? Agonist
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).[5] No affinity for histamine H1 or H2, cannabinoid CB1, GABA, glutamate, or nicotinic acetylcholine receptors, nor the monoamine transporters (all >10,000 nM).[5]

Pharmacokinetics

The bioavailability of ergotamine is around 2% orally, 6% rectally, and 100% by intramuscular or intravenous injection.[4] The low oral and rectal bioavailability is due to low gastrointestinal absorption and high first-pass metabolism.[4]

However, ergotamine does not readily cross the blood–brain barrier and hence is peripherally selective.[6][18][19] This is due to it being an avid substrate for P-glycoprotein and breast cancer resistance protein (BCRP).[6] Only minimal amounts of the drug (~1%) cross into the brain.[6]

Natural occurrence

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.[20][unreliable medical source?] 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.[21]

Society and culture

Ergotamine is a List I regulated chemical in the United States.[22]

See also

References

  1. ↑ Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 397–. ISBN 978-3-88763-075-1. https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA397. 
  2. ↑ 2.0 2.1 "Cafergot- ergotamine tartrate and caffeine tablet, film coated". DailyMed. U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=b4a06de6-f837-43a8-ae7a-aadb38dd2a7d. 
  3. ↑ 3.0 3.1 "Migergot- ergotamine tartrate and caffeine suppository". 29 November 2022. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3a31ad0c-7bdd-544b-f5df-a99d04cf541c. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 "Activation of 5-hydroxytryptamine1B/1D/1F receptors as a mechanism of action of antimigraine drugs". Expert Opinion on Pharmacotherapy 14 (12): 1599–1610. August 2013. doi:10.1517/14656566.2013.806487. PMID 23815106. 
  5. ↑ 5.0 5.1 5.2 5.3 Cite error: Invalid <ref> tag; no text was provided for refs named PDSPKiDatabase
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8 "Are the LSD-analogs lisuride and ergotamine examples of non-hallucinogenic serotonin 5-HT2A receptor agonists?". Journal of Psychopharmacology 39 (9): 889–895. May 2025. doi:10.1177/02698811251330741. PMID 40322975. 
  7. ↑ A. J. Giannini, A. E. Slaby. Drugs of Abuse. Oradell, New Jersey: Medical Economics Books, 1989.
  8. ↑ 8.0 8.1 Cite error: Invalid <ref> tag; no text was provided for refs named Ergomar FDA label
  9. ↑ 9.0 9.1 "Ergotamine and nicergoline - facts and myths". Pharmacological Reports 67 (2): 360–363. April 2015. doi:10.1016/j.pharep.2014.10.010. PMID 25712664. https://ruj.uj.edu.pl/xmlui/handle/item/106887. 
  10. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Ergomar sublingual FDA label
  11. ↑ Biological Foundations of Clinical Psychiatry. Oradell, NJ: Medical Economics Publishing Co.. 1986. 
  12. ↑ "Ergotamine: Indications, Side Effects, Warnings". Drugs.com. https://www.drugs.com/cdi/ergotamine.html. 
  13. ↑ "Medihaler Ergotamine". https://www.drugs.com/pro/medihaler-ergotamine.html. 
  14. ↑ "Characterization of binding, functional activity, and contractile responses of the selective 5-HT1F receptor agonist lasmiditan". British Journal of Pharmacology 176 (24): 4681–4695. December 2019. doi:10.1111/bph.14832. PMID 31418454. "TABLE 1 Summary of pIC50 (negative logarithm of the molar concentration of these compounds at which 50% of the radioligand is displaced) and pKi (negative logarithm of the molar concentration of the Ki ) values of individual antimigraine drugs at 5‐HT receptors [...] TABLE 2 Summary of pEC50 values of cAMP (5‐HT1A/B/E/F and 5‐HT7), GTPγS (5‐HT1A/B/D/E/F), and IP (5‐HT2) assays of individual antimigraine drugs at 5‐HT receptors [...]". 
  15. ↑ "Safety Pharmacology assessment of drugs with biased 5-HT(2B) receptor agonism mediating cardiac valvulopathy". Journal of Pharmacological and Toxicological Methods 69 (2): 150–161. 2014. doi:10.1016/j.vascn.2013.12.004. PMID 24361689. 
  16. ↑ 16.0 16.1 "Quantitative phosphoproteomics unravels biased phosphorylation of serotonin 2A receptor at Ser280 by hallucinogenic versus nonhallucinogenic agonists". Molecular & Cellular Proteomics 13 (5): 1273–1285. May 2014. doi:10.1074/mcp.M113.036558. PMID 24637012. 
  17. ↑ 17.0 17.1 "Molecular and Cellular Basis of Hallucinogen Action". Neuropathology of Drug Addictions and Substance Misuse. 2: Stimulants, Club and Dissociative Drugs, Hallucinogens, Steroids, Inhalants and International Aspects. 2016. pp. 803–812. doi:10.1016/B978-0-12-800212-4.00075-3. ISBN 978-0-12-800212-4. 
  18. ↑ 18.0 18.1 "Serotonergic Psychedelics: Experimental Approaches for Assessing Mechanisms of Action". Handb Exp Pharmacol. Handbook of Experimental Pharmacology 252: 227–260. 2018. doi:10.1007/164_2018_107. ISBN 978-3-030-10560-0. PMID 29532180. 
  19. ↑ 19.0 19.1 "Dopamine D2-receptor imaging with 123I-iodobenzamide SPECT in migraine patients abusing ergotamine: does ergotamine cross the blood brain barrier?". Cephalalgia 13 (5): 325–329. October 1993. doi:10.1046/j.1468-2982.1993.1305325.x. PMID 8242725. 
  20. ↑ "Pharmacognosy of Ergot (Argot or St. Anthony's Fire)". 30 December 2011. https://pharmaxchange.info/2011/12/pharmacognosy-of-ergot-argot-or-st-anthonys-fire/. 
  21. ↑ "Chapter 2 Ergot Alkaloids – Biology and Molecular Biology". The Alkaloids: Chemistry and Biology. 63. 2006. pp. 45–86. doi:10.1016/S1099-4831(06)63002-2. ISBN 978-0-12-469563-4. 
  22. ↑ "Lists of: Scheduling Actions, Controlled Substances, Regulated Chemicals". Drug Enforcement Administration, Diversion Control Division, Drug & Chemical Evaluation Section. U.S. Department of Justice. February 2020. https://www.deadiversion.usdoj.gov/schedules/orangebook/orangebook.pdf. 



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