Chemistry:Ergotamine
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| Trade names | Cafergot (with caffeine), Ergomar, others |
| Other names | 2'-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.com | Monograph |
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| Routes of administration | Oral |
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| Bioavailability | Intravenous: 100%,[1] Intramuscular: 47%,[2] Oral: <1%[3] (Enhanced by co-administration of caffeine[1]) |
| Metabolism | Hepatic[2] |
| Elimination half-life | 2 hours[2] |
| Excretion | 90% biliary[2] |
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| Formula | C33H35N5O5 |
| Molar mass | 581.673 g·mol−1 |
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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
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
Ergotamine continues to be prescribed for migraines and cluster headaches.[8]
Availability and dosage
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
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][8]
Pharmacology
Pharmacodynamics
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]
| 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
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
Ergotamine is included as a List I precursor in the United States, as it is a commonly used precursor for the production of LSD.[19]
See also
References
- ↑ 1.0 1.1 "Pharmacokinetics of ergotamine in healthy volunteers following oral and rectal dosing". European Journal of Clinical Pharmacology 30 (3): 331–334. 1986. doi:10.1007/BF00541538. PMID 3732370.
- ↑ 2.0 2.1 2.2 2.3 "Ergotamine". The Headaches. New York: Raven Press. 1993. pp. 313–22.
- ↑ "Low bioavailability of ergotamine tartrate after oral and rectal administration in migraine sufferers". British Journal of Clinical Pharmacology 16 (6): 695–699. December 1983. doi:10.1111/j.1365-2125.1983.tb02243.x. PMID 6419759.
- ↑ 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.
- ↑ AJ Giannini, AE Slaby. Drugs of Abuse. Oradell, NJ, Medical Economics Books, 1989.
- ↑ "Pharmacognosy of Ergot (Argot or St. Anthony's Fire)". 30 December 2011. http://pharmaxchange.info/press/2011/12/pharmacognosy-of-ergot-argot-or-st-anthonys-fire/.
- ↑ "Ergot alkaloids--biology and molecular biology". The Alkaloids. Chemistry and Biology 63: 45–86. 2006. doi:10.1016/S1099-4831(06)63002-2. ISBN 978-0-12-469563-4. PMID 17133714.
- ↑ 8.0 8.1 "Ergotamine and nicergoline - facts and myths". Pharmacological Reports 67 (2): 360–363. April 2015. doi:10.1016/j.pharep.2014.10.010. PMID 25712664.
- ↑ "Approved Drug Products". FDA Orange Book. U.S. Food and Drug Administration. 2020. https://www.fda.gov/media/71474/download.
- ↑ "CAFERGOT- ergotamine tartrate and caffeine tablet, film coated". DailyMed. U.S. National Library of Medicine. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=b4a06de6-f837-43a8-ae7a-aadb38dd2a7d#DA.
- ↑ Biological Foundations of Clinical Psychiatry. Oradell, NJ: Medical Economics Publishing Co.. 1986.
- ↑ "Ergotamine: Indications, Side Effects, Warnings". Drugs.com. https://www.drugs.com/cdi/ergotamine.html.
- ↑ "Medihaler Ergotamine". https://www.drugs.com/pro/medihaler-ergotamine.html.
- ↑ 14.0 14.1 14.2 14.3 "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.
- ↑ 15.0 15.1 15.2 Cite error: Invalid
<ref>tag; no text was provided for refs namedPDSPKiDatabase - ↑ "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.
- ↑ 17.0 17.1 "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.
- ↑ 18.0 18.1 "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.
- ↑ "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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