Ergotamine

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Ergotamine
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Clinical data
Trade namesErgomar, 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.comMonograph
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Pregnancy
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Routes of
administration		Oral
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Legal status
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Pharmacokinetic data
BioavailabilityIntravenous: 100%,[6]
Intramuscular: 47%,[7]
Oral: <1%[8] (Enhanced by co-administration of caffeine[6])
MetabolismLiver[7]
Elimination half-life2 hours[7]
Excretion90% Bile duct[7]
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
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Chemical and physical data
FormulaC33H35N5O5
Molar mass581.673 g·mol−1
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  • 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 checkY
  • Key:XCGSFFUVFURLIX-VFGNJEKYSA-N checkY
Data page
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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.[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.[12][13][14] It is peripherally selective and crosses into the brain in minimal amounts.[14]

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.[15]

Medical uses

Ergotamine is indicated as therapy to abort or prevent vascular headache.[2][16]

Available forms

Ergotamine is available as a suppository and as a tablet, sometimes in combination with caffeine.[2][5][10][11]

Contraindications

Contraindications include: atherosclerosis, Buerger's syndrome, coronary artery disease, hepatic disease, pregnancy, pruritus, Raynaud's syndrome, and renal disease.[17] 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).[18]

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.[19][16]

Pharmacology

Pharmacodynamics

Ergotamine interacts with serotonin, adrenergic, and dopamine receptors.[12][13][14] It is an agonist of serotonin receptors including the serotonin 5-HT1 and 5-HT2 subtypes.[12][14][20] Ergotamine is an agonist of the serotonin 5-HT2B receptor and has been associated with cardiac valvulopathy.[21] Despite acting as a potent serotonin 5-HT2A receptor agonist, ergotamine is said to be non-hallucinogenic similarly to lisuride.[14][22][23] This has been posited to be due to functional selectivity at the serotonin 5-HT2A receptor.[22][23] However, ergotamine is also peripherally selective, which may instead account for its lack of psychedelic effects.[14][24][25]

Activities of ergotamine at various sites[13][26][27][28][29][20]
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).[13] No affinity for histamine H1 or H2, cannabinoid CB1, GABA, glutamate, or nicotinic acetylcholine receptors, nor the monoamine transporters (all >10,000 nM).[13]

Pharmacokinetics

The bioavailability of ergotamine is around 2% orally, 6% rectally, and 100% by intramuscular or intravenous injection.[12] The low oral and rectal bioavailability is due to low gastrointestinal absorption and high first-pass metabolism.[12]

However, ergotamine does not readily cross the blood–brain barrier and hence is peripherally selective.[14][24][25] This is due to it being an avid substrate for P-glycoprotein and breast cancer resistance protein (BCRP).[14] Only minimal amounts of the drug (~1%) cross into the brain.[14]

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.[30][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.[31]

Society and culture

United States

Ergotamine is a List I regulated chemical in the United States.[32]

See also

References

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  2. ^ a b c d Page Module:Citation/CS1/styles.css has no content."Ergomar- ergotamine tartrate tablet, orally disintegrating". DailyMed. 8 September 2012. Retrieved 20 May 2024.
  3. ^ Page Module:Citation/CS1/styles.css has no content."Ergotamine (Ergomar) Use During Pregnancy". Drugs.com. 6 May 2024. Retrieved 20 May 2024.
  4. ^ Page Module:Citation/CS1/styles.css has no content.Anvisa (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] (in português do Brasil). Diário Oficial da União (published 4 April 2023). Archived from the original on 3 August 2023. Retrieved 15 August 2023.
  5. ^ a b Page Module:Citation/CS1/styles.css has no content."Ergomar sublingual- ergotamine tartrate tablet". DailyMed. 25 October 2022. Retrieved 18 May 2024.
  6. ^ a b Page Module:Citation/CS1/styles.css has no content.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.
  7. ^ a b c d Page Module:Citation/CS1/styles.css has no content.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.
  8. ^ Page Module:Citation/CS1/styles.css has no content.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.
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