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| Trade names | 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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| Pharmacokinetic data | |
| Bioavailability | Intravenous: 100%,[6] Intramuscular: 47%,[7] Oral: <1%[8] (Enhanced by co-administration of caffeine[6]) |
| Metabolism | Liver[7] |
| Eliminationhalf-life | 2 hours[7] |
| Excretion | 90%Bile duct[7] |
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| ECHA InfoCard | 100.003.658 |
| Chemical and physical data | |
| Formula | C33H35N5O5 |
| Molar mass | 581.673 g·mol−1 |
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Ergotamine, sold under the brand nameErgomar among others, is anergopeptine and part of theergot family ofalkaloids; it is structurally and biochemically closely related toergoline.[9] It is structurally similar to severalneurotransmitters, and itacts as avasoconstrictor. It is used for acutemigraines, sometimes withcaffeine as the combinationergotamine/caffeine.[10][11]
The drug is anon-selectivemodulator oragonist ofserotonin receptors and otherreceptors.[12][13][14] It isperipherally selective and crosses into thebrain in minimal amounts.[14]
Medicinal use of ergot fungus began in the 16th century, for the induction ofchildbirth; but dosage uncertainty discouraged its use. It has been used to preventpost-partumhemorrhage (bleeding after childbirth). It was first isolated from theergot fungus byArthur Stoll, atSandoz in 1918, and was marketed as Gynergen in 1921.[15]
Ergotamine isindicated as therapy to abort or prevent vascular headache.[2][16]
Ergotamine is available as asuppository and as atablet, sometimes incombination withcaffeine.[2][5][10][11]
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 takingmacrolide antibiotics (e.g.,erythromycin), certain HIVprotease inhibitors (e.g.,ritonavir,nelfinavir,indinavir), certain azole antifungals (e.g.,ketoconazole,itraconazole,voriconazole)delavirdine,efavirenz, or a5-HT1 receptor agonist (e.g.,sumatriptan).[18]
Side effects of ergotamine include nausea and vomiting. At higher doses, it can cause raised arterialblood pressure,vasoconstriction (includingcoronary vasospasm) andbradycardia ortachycardia. Severe vasoconstriction may cause symptoms ofintermittent claudication.[19][16]
Ergotamine interacts withserotonin,adrenergic, anddopamine receptors.[12][13][14] It is anagonist of serotonin receptors including theserotonin5-HT1 and5-HT2 subtypes.[12][14][20] Ergotamine is an agonist of the serotonin5-HT2B receptor and has been associated withcardiac valvulopathy.[21] Despite acting as apotent serotonin5-HT2A receptor agonist, ergotamine is said to be non-hallucinogenic similarly tolisuride.[14][22][23] This has been posited to be due tofunctional selectivity at the serotonin 5-HT2A receptor.[22][23] However, ergotamine is alsoperipherally selective, which may instead account for its lack of psychedelic effects.[14][24][25]
| 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 forhistamineH1 orH2,cannabinoidCB1,GABA,glutamate, ornicotinic acetylcholine receptors, nor themonoamine transporters (all >10,000 nM).[13] | |||
Thebioavailability of ergotamine is around 2%orally, 6%rectally, and 100% byintramuscular orintravenous injection.[12] The low oral and rectal bioavailability is due to lowgastrointestinalabsorption and highfirst-pass metabolism.[12]
However, ergotamine does not readily cross theblood–brain barrier and hence isperipherally selective.[14][24][25] This is due to it being an avidsubstrate forP-glycoprotein andbreast cancer resistance protein (BCRP).[14] Only minimal amounts of the drug (~1%) cross into thebrain.[14]
Ergotamine is asecondary metabolite (natural product) and the principal alkaloid produced by the ergot fungus,Claviceps purpurea, and related fungi in the familyClavicipitaceae.[30][unreliable medical source?] Its biosynthesis in these fungi requires theamino acidL-tryptophan anddimethylallyl pyrophosphate. These precursor compounds are the substrates for the enzyme,tryptophan dimethylallyltransferase, catalyzing the first step in ergot alkaloid biosynthesis, i.e., theprenylation ofL-tryptophan. Further reactions, involvingmethyltransferase andoxygenase enzymes, yield theergoline,lysergic acid. Lysergic acid (LA) is the substrate oflysergyl peptide synthetase, anonribosomal peptide synthetase, whichcovalently links LA to the amino acids,L-alanine,L-proline, andL-phenylalanine. Enzyme-catalyzed or spontaneous cyclizations,oxygenations/oxidations, andisomerizations at selected residues precede, and give rise to, formation of ergotamine.[31]
Ergotamine is a List I regulated chemical in the United States.[32]
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 [...]
