Ergotamine

Ergotamine
Names
Trade namesAlone: Ergomar, others
With caffeine: Cafergot, 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
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
Main usesMigraines, cluster headaches[1]
Side effectsNausea, abdominal pain, tingling extremities[1]
InteractionsCYP3A4 inhibitors[1]
Pregnancy
category
    Routes of
    use    		By mouth, under the tongue[1]
    External links
    AHFS/Drugs.comMonograph
    Legal
    Legal status
    Pharmacokinetics
    BioavailabilityIntravenous: 100%,[3]
    Intramuscular: 47%,[4]
    By mouth: <1%[5] (Enhanced by co-administration of caffeine[3])
    MetabolismLiver[4]
    Elimination half-life2 hours[4]
    Excretion90% biliary[4]
    Chemical and physical data
    FormulaC33H35N5O5
    Molar mass581.673 g·mol−1
    3D model (JSmol)
    SMILES
    • 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
    • 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

    Ergotamine, sold under the brand names Ergomar among others, is a medication used to treat migraines, cluster headaches, and post partum bleeding.[1][6] It is not effective for tension headaches.[1] It is taken by mouth, under the tongue, or rectally.[1][7] Onset of effects is generally between 30 minutes and 2 hours.[8]

    Common side effects include nausea, abdominal pain, and tingling extremities.[1] Other side effects may include medication overuse headaches, pulmonary fibrosis, and ergotism.[9][1] Use in pregnancy or when breastfeeding may harm the baby.[2] It is not recommended in people with vascular disease, liver, or kidney problems.[9] It is in the ergot family of medications and acts on serotonin among other receptors.[9][8]

    Ergotamine was first isolated by Arthur Stoll in 1918 from ergot fungus.[10] The fungus had been used medicinally since at least the 16th century to induce childbirth, treat bleeding after childbirth, or bring about an abortion.[11] In the United States it is generally only used if triptans are not effective; though remains commonly used in some parts of the world.[9] It is also available with caffeine under the brand Cafergot among others.[1]

    Medical uses

    Ergotamine continues to be prescribed for migraines and cluster headaches.[12]

    Availability and dosage

    In the United States, ergotamine is available as a suppository, a sublingual tablet, and a tablet, sometimes in combination with caffeine. A suppository is available which contains 2 mg of ergotamine with 100 mg caffeine. A sublingual tablet is available that contains 2 mg of ergotamine. The combination tablet in combination with caffeine called Cafergot contains 1 mg of ergotamine and 100 mg of caffeine.[13]

    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.[14]

    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 people are 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][12]

    Pharmacology

    Pharmacodynamics

    Ergotamine interacts with serotonin, adrenergic, and dopamine receptors.[18][19] It is an agonist of serotonin receptors including the 5-HT1 and 5-HT2 subtypes.[18] Ergotamine is an agonist of the serotonin 5-HT2B receptor and has been associated with cardiac valvulopathy.[20] Despite acting as a potent 5-HT2A receptor agonist, ergotamine is said to be non-hallucinogenic similarly to lisuride.[21][22] This is thought to be due to functional selectivity at the 5-HT2A receptor.[21][22]

    Activities of ergotamine at various sites[19][23][24][25][26]
    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).[19] No affinity for histamine H1 or H2, cannabinoid CB1, GABA, glutamate, or nicotinic acetylcholine receptors, nor the monoamine transporters (all >10,000 nM).[19]

    Pharmacokinetics

    The bioavailability of ergotamine is around 2% orally, 6% rectally, and 100% by intramuscular or intravenous injection.[18] The low oral and rectal bioavailability is due to low gastrointestinal absorption and high first-pass metabolism.[18]

    Society and culture

    Cost

    In the United States the 2 mg tablets for under the tongue cost about 63 USD each as of 2021.[27] The version with caffeine on the other hand is about 3 USD per tablet.[28]

    Ergotamine is a controlled substance in the United States as it is a commonly used precursor for the production of LSD.[29]

    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.[30] 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.[31]

    References

    1. 1 2 3 4 5 6 7 8 9 10 "Ergotamine Monograph for Professionals". Drugs.com. Archived from the original on 27 January 2021. Retrieved 23 July 2021.
    2. 1 2 "Ergotamine (Ergomar) Use During Pregnancy". Drugs.com. Archived from the original on 25 November 2020. Retrieved 23 July 2021.
    3. 1 2 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.
    4. 1 2 3 4 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.
    5. ↑ 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.
    6. ↑ Weeks, A (January 2015). "The prevention and treatment of postpartum haemorrhage: what do we know, and where do we go to next?". BJOG : An International Journal of Obstetrics and Gynaecology. 122 (2): 202–10. doi:10.1111/1471-0528.13098. PMID 25289730.
    7. ↑ BNF (80 ed.). BMJ Group and the Pharmaceutical Press. September 2020 – March 2021. p. 500. ISBN 978-0-85711-369-6.{{cite book}}: CS1 maint: date format (link)
    8. 1 2 Aschenbrenner, Diane S.; Venable, Samantha J. (2009). Drug Therapy in Nursing. Lippincott Williams & Wilkins. p. 423. ISBN 978-0-7817-6587-9. Archived from the original on 2021-08-28. Retrieved 2021-07-23.
    9. 1 2 3 4 Levin, Morris (8 May 2008). Comprehensive Review of Headache Medicine. Oxford University Press, USA. p. 217. ISBN 978-0-19-536673-0. Archived from the original on 28 August 2021. Retrieved 23 July 2021.
    10. ↑ Silberstein, Stephen D. (8 May 2018). Headache in Clinical Practice. Routledge. p. PT19. ISBN 978-1-351-44131-5. Archived from the original on 28 August 2021. Retrieved 23 July 2021.
    11. ↑ Nielsch, Ulrich; Fuhrmann, Ulrike; Jaroch, Stefan (30 March 2016). New Approaches to Drug Discovery. Springer. p. PA6. ISBN 978-3-319-28914-4. Archived from the original on 28 August 2021. Retrieved 23 July 2021.
    12. 1 2 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.{{cite journal}}: CS1 maint: uses authors parameter (link)
    13. ↑ "Approved Drug Products". FDA Orange Book (40th ed.). U.S. Food and Drug Administration. 2020. Archived from the original on 2021-07-05. Retrieved 2021-06-18.
    14. ↑ "CAFERGOT- ergotamine tartrate and caffeine tablet, film coated". DailyMed. U.S. National Library of Medicine. Archived from the original on 2014-01-16.
    15. ↑ Giannini AJ (1986). Biological Foundations of Clinical Psychiatry. Oradell, NJ: Medical Economics Puclishing Co.
    16. ↑ "Ergotamine: Indications, Side Effects, Warnings". Drugs.com. Archived from the original on 25 March 2017. Retrieved 25 March 2017.
    17. ↑ "Medihaler Ergotamine". drugs.com. Archived from the original on 2016-04-01. Retrieved 2016-05-20.
    18. 1 2 3 4 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.
    19. 1 2 3 4 https://web.archive.org/web/20210413101932/https://pdsp.unc.edu/databases/pdsp.php?testFreeRadio=testFreeRadio&testLigand=Ergotamine&doQuery=Submit+Query
    20. ↑ 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.
    21. 1 2 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.
    22. 1 2 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. Vol. 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.
    23. ↑ 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.
    24. ↑ 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.
    25. ↑ 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.
    26. ↑ 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.
    27. ↑ "Ergomar Prices, Coupons & Savings Tips - GoodRx". GoodRx. Retrieved 23 July 2021.
    28. ↑ "Cafergot Prices, Coupons & Savings Tips - GoodRx". GoodRx. Archived from the original on 9 November 2016. Retrieved 23 July 2021.
    29. ↑ "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. Archived (PDF) from the original on 2021-07-05. Retrieved 2021-06-18.
    30. ↑ "Pharmacognosy of Ergot (Argot or St. Anthony's Fire)". pharmaxchange.info. 30 December 2011. Archived from the original on 17 July 2012.
    31. ↑ 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.
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