Ergotamine Explained

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.^[9] 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.^{[10] [11]}

The drug is a non-selective modulator or agonist of serotonin receptors and other receptors. It is peripherally selective and crosses into the brain in minimal amounts.^[12]

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.^[13]

Medical uses

Ergotamine is indicated as therapy to abort or prevent vascular headache.^[14]

Available forms

Ergotamine is available as a suppository and as a tablet, sometimes in combination with caffeine.

Contraindications

Contraindications include: atherosclerosis, Buerger's syndrome, coronary artery disease, hepatic disease, pregnancy, pruritus, Raynaud's syndrome, and renal disease.^[15] 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).^[16]

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.^{[17] [14]}

Pharmacology

Pharmacodynamics

Ergotamine interacts with serotonin, adrenergic, and dopamine receptors.^[18] It is an agonist of serotonin receptors including the serotonin 5-HT₁ and 5-HT₂ subtypes.^[19] Ergotamine is an agonist of the serotonin 5-HT_2B receptor and has been associated with cardiac valvulopathy.^[20] Despite acting as a potent serotonin 5-HT_2A receptor agonist, ergotamine is said to be non-hallucinogenic similarly to lisuride.^{[21] [22]} This has been posited to be due to functional selectivity at the serotonin 5-HT_2A receptor. However, ergotamine is also peripherally selective, which may instead account for its lack of psychedelic effects.

! Site! Affinity (K_i/IC₅₀ [nM])! Efficacy (E_max [%])! 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). No affinity for histamine H1 or H2, cannabinoid CB1, GABA, glutamate, or nicotinic acetylcholine receptors, nor the monoamine transporters (all >10,000 nM).

Pharmacokinetics

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

However, ergotamine does not readily cross the blood–brain barrier and hence is peripherally selective.^{[23] [24]} This is due to it being an avid substrate for P-glycoprotein and breast cancer resistance protein (BCRP). Only minimal amounts of the drug (~1%) cross into the brain.

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.^[25] 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.^[26]

Society and culture

Legal status

United States

Ergotamine is a List I regulated chemical in the United States.^[27]

See also

• Substituted ergoline
• Non-hallucinogenic 5-HT_2A receptor agonist

External links

• Web site: Ergotamine and caffeine . MedlinePlus .

Notes and References

1. Web site: Prescribing medicines in pregnancy database . Therapeutic Goods Administration (TGA) . 21 June 2022 . 20 May 2024.
2. Web site: Ergotamine (Ergomar) Use During Pregnancy . Drugs.com . 6 May 2024 . 20 May 2024.
3. Web site: Anvisa . Brazilian Health Regulatory Agency . 31 March 2023 . RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial . Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control. live . https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 . 3 August 2023 . 15 August 2023 . . pt-BR . 4 April 2023.
4. Web site: Ergomar- ergotamine tartrate tablet, orally disintegrating . DailyMed . 8 September 2012 . 20 May 2024.
5. Web site: Ergomar sublingual- ergotamine tartrate tablet . DailyMed . 25 October 2022 . 18 May 2024.
6. Sanders SW, Haering N, Mosberg H, Jaeger H . Pharmacokinetics of ergotamine in healthy volunteers following oral and rectal dosing . European Journal of Clinical Pharmacology . 30 . 3 . 331–334 . 1986 . 3732370 . 10.1007/BF00541538 . 37538721 .
7. Book: Tfelt-Hansen P, Johnson ES . Ergotamine . Olesen J, Tfelt-Hansen P, Welch KM . The Headaches . New York . Raven Press . 1993 . 313–22 .
8. Ibraheem JJ, Paalzow L, Tfelt-Hansen P . Low bioavailability of ergotamine tartrate after oral and rectal administration in migraine sufferers . British Journal of Clinical Pharmacology . 16 . 6 . 695–699 . December 1983 . 6419759 . 1428366 . 10.1111/j.1365-2125.1983.tb02243.x .
9. Book: Index Nominum 2000: International Drug Directory. 2000. Taylor & Francis. 978-3-88763-075-1. 397–.
10. Web site: Cafergot- ergotamine tartrate and caffeine tablet, film coated. DailyMed . U.S. National Library of Medicine. live. https://web.archive.org/web/20140116115705/http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=b4a06de6-f837-43a8-ae7a-aadb38dd2a7d#DA . 16 January 2014.
11. Web site: Migergot- ergotamine tartrate and caffeine suppository . DailyMed . 29 November 2022 . 18 May 2024.
12. Kehler J, Lindskov MS . Are the LSD-analogs lisuride and ergotamine examples of non-hallucinogenic serotonin 5-HT2A receptor agonists? . Journal of Psychopharmacology . 889–895 . May 2025 . 39 . 9 . 40322975 . 10.1177/02698811251330741 .
13. A. J. Giannini, A. E. Slaby. Drugs of Abuse. Oradell, New Jersey: Medical Economics Books, 1989.
14. Zajdel P, Bednarski M, Sapa J, Nowak G . Ergotamine and nicergoline - facts and myths . Pharmacological Reports . 67 . 2 . 360–363 . April 2015 . 25712664 . 10.1016/j.pharep.2014.10.010 . 22768662 .
15. Book: Giannini AJ . Biological Foundations of Clinical Psychiatry . Oradell, NJ . Medical Economics Publishing Co. . 1986 .
16. Web site: Ergotamine: Indications, Side Effects, Warnings . Drugs.com . 25 March 2017 . live. https://web.archive.org/web/20170325202114/https://www.drugs.com/cdi/ergotamine.html. 25 March 2017.
17. Web site: Medihaler Ergotamine. drugs.com. 20 May 2016. live. https://web.archive.org/web/20160401081841/http://www.drugs.com/pro/medihaler-ergotamine.html. 1 April 2016.
18. Ramírez Rosas MB, Labruijere S, Villalón CM, Maassen Vandenbrink A . 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 . 23815106 . 10.1517/14656566.2013.806487 . 22721405 .
19. 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 . Characterization of binding, functional activity, and contractile responses of the selective 5-HT_1F receptor agonist lasmiditan . British Journal of Pharmacology . 176 . 24 . 4681–4695 . December 2019 . 31418454 . 6965684 . 10.1111/bph.14832 . 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 [...] .
20. Cavero I, Guillon JM . 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 . 24361689 . 10.1016/j.vascn.2013.12.004 .
21. Karaki S, Becamel C, Murat S, Mannoury la Cour C, Millan MJ, Prézeau L, Bockaert J, Marin P, Vandermoere F . 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 . 24637012 . 4014284 . 10.1074/mcp.M113.036558 . free .
22. Book: Hanks J, González-Maeso J . Molecular and Cellular Basis of Hallucinogen Action . Preedy VR . Neuropathology of Drug Addictions and Substance Misuse . 2: Stimulants, Club and Dissociative Drugs, Hallucinogens, Steroids, Inhalants and International Aspects . 2016 . 803–812 . 10.1016/B978-0-12-800212-4.00075-3 . 978-0-12-800212-4.
23. Canal CE . Serotonergic Psychedelics: Experimental Approaches for Assessing Mechanisms of Action . Handb Exp Pharmacol . Handbook of Experimental Pharmacology . 252 . 227–260 . 2018 . 29532180 . 6136989 . 10.1007/164_2018_107 . 978-3-030-10560-0 .
24. Verhoeff NP, Visser WH, Ferrari MD, Saxena PR, van Royen EA . 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 . 8242725 . 10.1046/j.1468-2982.1993.1305325.x .
25. Web site: Pharmacognosy of Ergot (Argot or St. Anthony's Fire) . 30 December 2011. pharmaxchange.info . live . https://web.archive.org/web/20120717232322/http://pharmaxchange.info/press/2011/12/pharmacognosy-of-ergot-argot-or-st-anthonys-fire/ . 17 July 2012 .
26. Book: Schardl CL, Panaccione DG, Tudzynski P . The Alkaloids: Chemistry and Biology . Chapter 2 Ergot Alkaloids – Biology and Molecular Biology . 63 . 45–86 . 2006 . 17133714 . 10.1016/S1099-4831(06)63002-2 . 978-0-12-469563-4 .
27. Web site: Lists of: Scheduling Actions, Controlled Substances, Regulated Chemicals . U.S. Department of Justice . Drug Enforcement Administration, Diversion Control Division, Drug & Chemical Evaluation Section . February 2020 .