Ergotamine

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Ergotamine
Ergotamine-skeletal.svg
Ergotamine ball-and-stick.png
Clinical data
Trade names Cafergot (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.com Monograph
Routes of
administration 		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability Intravenous: 100%, [2]
Intramuscular: 47%, [3]
Oral: <1% [4] (Enhanced by co-administration of caffeine [2] )
Metabolism Hepatic [3]
Elimination half-life 2 hours [3]
Excretion 90% biliary [3]
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 InfoCard 100.003.658 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C33H35N5O5
Molar mass 581.673 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 Yes check.svgY
  • Key:XCGSFFUVFURLIX-VFGNJEKYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (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. [5] It is structurally similar to several neurotransmitters, and it acts as a vasoconstrictor.

Contents

It is used for acute migraines, sometimes with caffeine. 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. [6]

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. [7] 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. [8]

Medical uses

Ergotamine continues to be prescribed for migraines and cluster headaches. [9]

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. [10]

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. [11]

Contraindications

Contraindications include: atherosclerosis, Buerger's syndrome, coronary artery disease, hepatic disease, pregnancy, pruritus, Raynaud's syndrome, and renal disease. [12] 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). [13]

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. [14] [9]

Pharmacology

Pharmacodynamics

Ergotamine interacts with serotonin, adrenergic, and dopamine receptors. [15] [16] It is an agonist of serotonin receptors including the 5-HT1 and 5-HT2 subtypes. [15] Ergotamine is an agonist of the serotonin 5-HT2B receptor and has been associated with cardiac valvulopathy. [17] Despite acting as a potent 5-HT2A receptor agonist, ergotamine is said to be non-hallucinogenic similarly to lisuride. [18] [19] This is thought to be due to functional selectivity at the 5-HT2A receptor. [18] [19]

Activities of ergotamine at various sites [16] [20] [21] [22] [23]
SiteAffinity (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). [16] No affinity for histamine H1 or H2, cannabinoid CB1, GABA, glutamate, or nicotinic acetylcholine receptors, nor the monoamine transporters (all >10,000 nM). [16]

Pharmacokinetics

The bioavailability of ergotamine is around 2% orally, 6% rectally, and 100% by intramuscular or intravenous injection. [15] The low oral and rectal bioavailability is due to low gastrointestinal absorption and high first-pass metabolism. [15]

Ergotamine is included as a List I precursor in the United States, as it is a commonly used precursor for the production of LSD. [24]

See also

Related Research Articles

<span class="mw-page-title-main">Ergoline</span> Chemical compound

Ergoline is a chemical compound whose structural skeleton is contained in a variety of alkaloids, referred to as ergoline derivatives or ergoline alkaloids. Ergoline alkaloids, one being ergine, were initially characterized in ergot. Some of these are implicated in the condition ergotism, which can take a convulsive form or a gangrenous form. Even so, many ergoline alkaloids have been found to be clinically useful. Annual world production of ergot alkaloids has been estimated at 5,000–8,000 kg of all ergopeptines and 10,000–15,000 kg of lysergic acid, used primarily in the manufacture of semi-synthetic derivatives.

<span class="mw-page-title-main">Bromocriptine</span> Organic Chemical Compound

Bromocriptine, originally marketed as Parlodel and subsequently under many brand names, is an ergoline derivative and dopamine agonist that is used in the treatment of pituitary tumors, Parkinson's disease, hyperprolactinaemia, neuroleptic malignant syndrome, and, as an adjunct, type 2 diabetes.

<span class="mw-page-title-main">Pergolide</span> Chemical compound

Pergolide, sold under the brand name Permax and Prascend (veterinary) among others, is an ergoline-based dopamine receptor agonist used in some countries for the treatment of Parkinson's disease. Parkinson's disease is associated with reduced dopamine activity in the substantia nigra of the brain. Pergolide acts on many of the same receptors as dopamine to increase receptor activity.

<span class="mw-page-title-main">Triptan</span> Class of pharmaceutical drugs

Triptans are a family of tryptamine-based drugs used as abortive medication in the treatment of migraines and cluster headaches. This drug class was first commercially introduced in the 1990s. While effective at treating individual headaches, they do not provide preventive treatment and are not considered a cure. They are not effective for the treatment of tension–type headache, except in persons who also experience migraines. Triptans do not relieve other kinds of pain.

<span class="mw-page-title-main">Ergoloid</span> Chemical compound

Ergoloid mesylates (USAN), co-dergocrine mesilate (BAN) or dihydroergotoxine mesylate, trade name Hydergine, is a mixture of the methanesulfonate salts of three dihydrogenated ergot alkaloids.

<span class="mw-page-title-main">Zolmitriptan</span> Medication used in treatment of migraines

Zolmitriptan, sold under the brand name Zomig among others, is a triptan used in the acute treatment of migraine attacks with or without aura and cluster headaches. It is a selective serotonin receptor agonist of the 1B and 1D subtypes.

<span class="mw-page-title-main">Cabergoline</span> Chemical compound

Cabergoline, sold under the brand name Dostinex among others, is a dopaminergic medication used in the treatment of high prolactin levels, prolactinomas, Parkinson's disease, and for other indications. It is taken by mouth.

<span class="mw-page-title-main">Ergometrine</span> Lysergamide

Ergometrine, also known as ergonovine and sold under the brand names Ergotrate, Ergostat, and Syntometrine among others, is a medication used to cause contractions of the uterus to treat heavy vaginal bleeding after childbirth. It can be used either by mouth, by injection into a muscle, or injection into a vein. It begins working within 15 minutes when taken by mouth and is faster in onset when used by injection. Effects last between 45 and 180 minutes.

<span class="mw-page-title-main">Dihydroergotamine</span> An ergot alkaloid used to treat migraines

Dihydroergotamine (DHE), sold under the brand names D.H.E. 45 and Migranal among others, is an ergot alkaloid used to treat migraines. It is a derivative of ergotamine. It is administered as a nasal spray or injection and has an efficacy similar to that of sumatriptan. Nausea is a common side effect.

Caffeine/ergotamine is the proprietary name of a medication consisting of ergotamine tartrate and caffeine. This combination is used for the treatment of headaches, such as migraine headache.

<span class="mw-page-title-main">Methylergometrine</span> Chemical compound

Methylergometrine, also known as methylergonovine and sold under the brand name Methergine, is a medication of the ergoline and lysergamide groups which is used as an oxytocic in obstetrics and in the treatment of migraine. It reportedly produces psychedelic effects similar to those of lysergic acid diethylamide (LSD) at high doses.

<span class="mw-page-title-main">Methysergide</span> Chemical compound

Methysergide, sold under the brand names Deseril and Sansert, is a monoaminergic medication of the ergoline and lysergamide groups which is used in the prophylaxis and treatment of migraine and cluster headaches. It has been withdrawn from the market in the United States and Canada due to adverse effects. It is taken by mouth.

<span class="mw-page-title-main">Eletriptan</span> Chemical compound

Eletriptan, sold under the brand name Relpax and used in the form of eletriptan hydrobromide, is a second-generation triptan medication intended for treatment of migraine headaches. It is used as an abortive medication, blocking a migraine attack which is already in progress. Eletriptan is marketed and manufactured by Pfizer Inc.

<span class="mw-page-title-main">Lisuride</span> Chemical compound

Lisuride, sold under the brand name Dopergin among others, is a monoaminergic medication of the ergoline class which is used in the treatment of Parkinson's disease, migraine, and high prolactin levels. It is taken by mouth.

<span class="mw-page-title-main">Indole alkaloid</span> Class of alkaloids

Indole alkaloids are a class of alkaloids containing a structural moiety of indole; many indole alkaloids also include isoprene groups and are thus called terpene indole or secologanin tryptamine alkaloids. Containing more than 4100 known different compounds, it is one of the largest classes of alkaloids. Many of them possess significant physiological activity and some of them are used in medicine. The amino acid tryptophan is the biochemical precursor of indole alkaloids.

<span class="mw-page-title-main">Nicergoline</span> Chemical compound

Nicergoline, sold under the brand name Sermion among others, is an ergot derivative used to treat senile dementia and other disorders with vascular origins. Internationally it has been used for frontotemporal dementia as well as early onset in Lewy body dementia and Parkinson's dementia. It decreases vascular resistance and increases arterial blood flow in the brain, improving the utilization of oxygen and glucose by brain cells. It has similar vasoactive properties in other areas of the body, particularly the lungs. Unlike many other ergolines, such as ergotamine, nicergoline is not associated with cardiac fibrosis.

<span class="mw-page-title-main">Antimigraine drug</span> Medication intended to reduce the effects or intensity of migraine headache

Antimigraine drugs are medications intended to reduce the effects or intensity of migraine headache. They include drugs for the treatment of acute migraine symptoms as well as drugs for the prevention of migraine attacks.

5-HT<sub>1D</sub> receptor Serotonin receptor which affects locomotion and anxiety in humans

5-hydroxytryptamine (serotonin) receptor 1D, also known as HTR1D, is a 5-HT receptor, but also denotes the human gene encoding it. 5-HT1D acts on the central nervous system, and affects locomotion and anxiety. It also induces vasoconstriction in the brain.

5-HT<sub>2B</sub> receptor Mammalian protein found in Homo sapiens

5-Hydroxytryptamine receptor 2B (5-HT2B) also known as serotonin receptor 2B is a protein that in humans is encoded by the HTR2B gene. 5-HT2B is a member of the 5-HT2 receptor family that binds the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT). Like all 5-HT2 receptors, the 5-HT2B receptor is Gq/G11-protein coupled, leading to downstream activation of phospholipase C.

Triptans is a word commonly used for a class of anti-migraine drugs that are selective 5-hydroxytryptamine/serotonin1B/1D (5-HT1B/1D) agonists. Migraine is a complex disease which affects about 15% of the population and can be highly disabling. Triptans have advantages over ergotamine and dihydroergotamine, such as selective pharmacology, well established safety record and evidence-based prescribing instructions. Triptans are therefore often preferred treatment in migraine.

References

  1. ↑ Anvisa (2023-03-31). "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] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-15.
  2. 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): 331–334. doi:10.1007/BF00541538. PMID   3732370. S2CID   37538721.
  3. 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.
  4. ↑ 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): 695–699. doi:10.1111/j.1365-2125.1983.tb02243.x. PMC   1428366 . PMID   6419759.
  5. ↑ Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 397–. ISBN   978-3-88763-075-1.
  6. ↑ A. J. Giannini, A. E. Slaby. Drugs of Abuse. Oradell, New Jersey: Medical Economics Books, 1989.
  7. ↑ "Pharmacognosy of Ergot (Argot or St. Anthony's Fire)". pharmaxchange.info. 30 December 2011. Archived from the original on 17 July 2012.
  8. ↑ 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.
  9. 1 2 Zajdel P, Bednarski M, Sapa J, Nowak G (April 2015). "Ergotamine and nicergoline - facts and myths". Pharmacological Reports. 67 (2): 360–363. doi:10.1016/j.pharep.2014.10.010. PMID   25712664. S2CID   22768662.
  10. ↑ "Approved Drug Products". FDA Orange Book (40th ed.). U.S. Food and Drug Administration. 2020.
  11. ↑ "CAFERGOT- ergotamine tartrate and caffeine tablet, film coated". DailyMed. U.S. National Library of Medicine. Archived from the original on 2014-01-16.
  12. ↑ Giannini AJ (1986). Biological Foundations of Clinical Psychiatry. Oradell, NJ: Medical Economics Publishing Co.
  13. ↑ "Ergotamine: Indications, Side Effects, Warnings". Drugs.com. Archived from the original on 25 March 2017. Retrieved 25 March 2017.
  14. ↑ "Medihaler Ergotamine". drugs.com . Archived from the original on 2016-04-01. Retrieved 2016-05-20.
  15. 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 Opinion on Pharmacotherapy. 14 (12): 1599–1610. doi:10.1517/14656566.2013.806487. PMID   23815106. S2CID   22721405.
  16. 1 2 3 4 PDSP Database – UNC
  17. ↑ Cavero I, Guillon JM (2014). "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. doi:10.1016/j.vascn.2013.12.004. PMID   24361689.
  18. 1 2 Karaki S, Becamel C, Murat S, Mannoury la Cour C, Millan MJ, Prézeau L, et al. (May 2014). "Quantitative phosphoproteomics unravels biased phosphorylation of serotonin 2A receptor at Ser280 by hallucinogenic versus nonhallucinogenic agonists". Molecular & Cellular Proteomics. 13 (5): 1273–1285. doi: 10.1074/mcp.M113.036558 . PMC   4014284 . PMID   24637012.
  19. 1 2 Hanks J, González-Maeso J (2016). "Molecular and Cellular Basis of Hallucinogen Action". In Preedy VR (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.
  20. ↑ Silberstein SD, McCrory DC (February 2003). "Ergotamine and dihydroergotamine: history, pharmacology, and efficacy". Headache. 43 (2): 144–166. doi:10.1046/j.1526-4610.2003.03034.x. PMID   12558771. S2CID   21356727.
  21. ↑ 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): 2836–2841. doi: 10.1161/01.cir.102.23.2836 . PMID   11104741.
  22. ↑ Rubio-Beltrán E, Labastida-Ramírez A, Haanes KA, van den Bogaerdt A, Bogers AJ, Zanelli E, et al. (December 2019). "Characterization of binding, functional activity, and contractile responses of the selective 5-HT1F receptor agonist lasmiditan". British Journal of Pharmacology. 176 (24): 4681–4695. doi:10.1111/bph.14832. PMC   6965684 . PMID   31418454.
  23. ↑ Pytliak M, Vargová V, Mechírová V, Felšöci M (2011). "Serotonin receptors - from molecular biology to clinical applications". Physiological Research. 60 (1): 15–25. doi: 10.33549/physiolres.931903 . PMID   20945968.
  24. ↑ "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.
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