Ergotamine: Difference between revisions

{{Short description|Chemical compound in the ergot family of alkaloids}}

{{Infobox drug

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 443732840

| IUPAC_name = (6a''R'',9''R'')-''N''-((2''R'',5''S'',10a''S'',10b''S'')-5-Benzyl-10b-hydroxy-2-methyl-3,6-dioxooctahydro-2''H''-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

| image = Ergotamine-skeletal.svg

| width = 250px

| image2 = Ergotamine ball-and-stick.png

| width2 =

<!--Clinical data-->

| tradename = [[Cafergot]] (with [[caffeine]]), Ergomar, others

| Drugs.com = {{drugs.com|monograph|ergomar}}

| pregnancy_US = X

| pregnancy_category =

| legal_AU = Schedule 4

| legal_BR = D1

| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-15 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=2023-04-04}}</ref>

| legal_CA = Schedule VI

| legal_UK = POM

| legal_US = Rx-only

| legal_US_comment = [[DEA list of chemicals|DEA controlled precursor]]

| routes_of_administration = [[Oral administration|Oral]]

<!--Pharmacokinetic data-->

| bioavailability = Intravenous: 100%,<ref name="kinetics1">{{cite journal | vauthors = Sanders SW, Haering N, Mosberg H, Jaeger H | title = Pharmacokinetics of ergotamine in healthy volunteers following oral and rectal dosing | journal = European Journal of Clinical Pharmacology | volume = 30 | issue = 3 | pages = 331–334 | date = 1986 | pmid = 3732370 | doi = 10.1007/BF00541538 | s2cid = 37538721 }}</ref> <br />Intramuscular: 47%,<ref name="kinetics2">{{cite book | vauthors = Tfelt-Hansen P, Johnson ES | chapter = Ergotamine | veditors = Olesen J, Tfelt-Hansen P, Welch KM | title = The Headaches | location = New York | publisher = Raven Press | date = 1993 | pages = 313–22 }}</ref><br />Oral: <1%<ref name="pmid6419759">{{cite journal | vauthors = Ibraheem JJ, Paalzow L, Tfelt-Hansen P | title = Low bioavailability of ergotamine tartrate after oral and rectal administration in migraine sufferers | journal = British Journal of Clinical Pharmacology | volume = 16 | issue = 6 | pages = 695–699 | date = December 1983 | pmid = 6419759 | pmc = 1428366 | doi = 10.1111/j.1365-2125.1983.tb02243.x }}</ref> (Enhanced by co-administration of caffeine<ref name="kinetics1" />)

| metabolism = Hepatic<ref name="kinetics2" />

| elimination_half-life = 2 hours<ref name="kinetics2" />

| excretion = 90% biliary<ref name="kinetics2" />

<!--Identifiers-->

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 113-15-5

| ATC_prefix = N02

| ATC_suffix = CA02

| PubChem = 8223

| ChEBI_Ref = {{ebicite|changed|EBI}}

| ChEBI = 64318

| IUPHAR_ligand = 149

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB00696

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 7930

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D07906

| PDB_ligand = ERM

| synonyms = 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

<!--Chemical data-->

| C=33 | H=35 | N=5 | O=5

| 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

'''Ergotamine''', sold under the brand names '''Cafergot''' (with [[caffeine]]) and '''Ergomar''' among others, is an [[ergopeptine]] and part of the [[ergot]] family of [[alkaloid]]s; it is structurally and biochemically closely related to [[ergoline]].<ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA397|year=2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=397–}}</ref> It is structurally similar to several [[neurotransmitter]]s, and it [[biological activity|acts]] as a [[vasoconstrictor]].

It is used for acute [[migraine]]s, sometimes with [[caffeine]]. [[Pharmacology|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|ergot fungus]] by [[Arthur Stoll]], at [[Sandoz]] in 1918, and was marketed as Gynergen in 1921.<ref>A. J. Giannini, A. E. Slaby. ''Drugs of Abuse''. Oradell, New Jersey: Medical Economics Books, 1989.</ref>

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]].<ref>{{cite web|url=http://pharmaxchange.info/press/2011/12/pharmacognosy-of-ergot-argot-or-st-anthonys-fire/ |title=Pharmacognosy of Ergot (Argot or St. Anthony's Fire) |date=30 December 2011|website=pharmaxchange.info |url-status=live |archive-url=https://web.archive.org/web/20120717232322/http://pharmaxchange.info/press/2011/12/pharmacognosy-of-ergot-argot-or-st-anthonys-fire/ |archive-date= 17 July 2012 }}</ref> Its biosynthesis in these fungi requires the [[amino acid]] <small>L</small>-[[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 <small>L</small>-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|nonribosomal peptide synthetase]], which [[covalent]]ly links LA to the amino acids, <small>L</small>-[[alanine]], <small>L</small>-[[proline]], and <small>L</small>-[[phenylalanine]]. Enzyme-catalyzed or spontaneous cyclizations, [[Oxygenation (medicine)|oxygenations]]/[[oxidation]]s, and [[isomerization]]s at selected residues precede, and give rise to, formation of ergotamine.<ref name="Schardl">{{cite journal | vauthors = Schardl CL, Panaccione DG, Tudzynski P | title = Ergot alkaloids--biology and molecular biology | journal = The Alkaloids. Chemistry and Biology | volume = 63 | pages = 45–86 | year = 2006 | pmid = 17133714 | doi = 10.1016/S1099-4831(06)63002-2 | isbn = 978-0-12-469563-4 }}</ref>

==Medical uses==

Ergotamine continues to be prescribed for migraines and cluster headaches.<ref name="myths">{{cite journal | vauthors = Zajdel P, Bednarski M, Sapa J, Nowak G | title = Ergotamine and nicergoline - facts and myths | journal = Pharmacological Reports | volume = 67 | issue = 2 | pages = 360–363 | date = April 2015 | pmid = 25712664 | doi = 10.1016/j.pharep.2014.10.010 | s2cid = 22768662 }}</ref>

===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&nbsp;mg of ergotamine with 100&nbsp;mg caffeine. The sublingual tablet is available under the brand name Ergomar and contains 2&nbsp;mg of ergotamine. The combination tablet in combination with caffeine called [[Cafergot]] contains 1&nbsp;mg of ergotamine and 100&nbsp;mg of caffeine.<ref>{{cite web | url = https://www.fda.gov/media/71474/download | title = Approved Drug Products | work = FDA Orange Book | publisher = U.S. Food and Drug Administration | edition = 40th | date = 2020 }}</ref>

This preparation may be used immediately following the [[Aura (symptom)|aura]]/onset of pain to abort the migraine. For the best results, dosage should start at the first sign of an attack.<ref>{{cite web|url=http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=b4a06de6-f837-43a8-ae7a-aadb38dd2a7d#DA|title= CAFERGOT- ergotamine tartrate and caffeine tablet, film coated| work = DailyMed | publisher = U.S. National Library of Medicine|url-status=live|archive-url= https://web.archive.org/web/20140116115705/http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=b4a06de6-f837-43a8-ae7a-aadb38dd2a7d#DA |archive-date=2014-01-16}}</ref>

===Contraindications===

Contraindications include: [[atherosclerosis]], [[Buerger's syndrome]], [[coronary artery disease]], hepatic disease, pregnancy, [[pruritus]], [[Raynaud's syndrome]], and renal disease.<ref>{{cite book | vauthors = Giannini AJ | title = Biological Foundations of Clinical Psychiatry | location = Oradell, NJ | publisher = Medical Economics Publishing Co. | date = 1986 }}</ref>

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 agonist|5-HT₁ receptor agonist]] (e.g., [[sumatriptan]]).

<ref>{{cite web|title=Ergotamine: Indications, Side Effects, Warnings |url= https://www.drugs.com/cdi/ergotamine.html | work = Drugs.com | access-date=25 March 2017 |url-status=live|archive-url= https://web.archive.org/web/20170325202114/https://www.drugs.com/cdi/ergotamine.html|archive-date=25 March 2017}}</ref>

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]].<ref>{{cite web|url=https://www.drugs.com/pro/medihaler-ergotamine.html|title=Medihaler Ergotamine|website=[[drugs.com]]|access-date=2016-05-20|url-status=live|archive-url=https://web.archive.org/web/20160401081841/http://www.drugs.com/pro/medihaler-ergotamine.html|archive-date=2016-04-01}}</ref><ref name="myths"/>

==Pharmacology==

===Pharmacodynamics===

Ergotamine interacts with [[serotonin receptor|serotonin]], [[adrenergic receptor|adrenergic]], and [[dopamine receptor]]s.<ref name="pmid23815106">{{cite journal | vauthors = Ramírez Rosas MB, Labruijere S, Villalón CM, Maassen Vandenbrink A | title = Activation of 5-hydroxytryptamine1B/1D/1F receptors as a mechanism of action of antimigraine drugs | journal = Expert Opinion on Pharmacotherapy | volume = 14 | issue = 12 | pages = 1599–1610 | date = August 2013 | pmid = 23815106 | doi = 10.1517/14656566.2013.806487 | s2cid = 22721405 }}</ref><ref name="PDSPKiDatabase" /> It is an [[agonist]] of serotonin receptors including the [[5-HT1 receptor|5-HT₁]] and [[5-HT2 receptor|5-HT₂ subtype]]s.<ref name="pmid23815106" /> Ergotamine is an agonist of the serotonin [[5-HT2B receptor|5-HT_2B receptor]] and has been associated with [[cardiac valvulopathy]].<ref name="pmid24361689">{{cite journal | vauthors = Cavero I, Guillon JM | title = Safety Pharmacology assessment of drugs with biased 5-HT(2B) receptor agonism mediating cardiac valvulopathy | journal = Journal of Pharmacological and Toxicological Methods | volume = 69 | issue = 2 | pages = 150–161 | date = 2014 | pmid = 24361689 | doi = 10.1016/j.vascn.2013.12.004 }}</ref> Despite acting as a [[potency (pharmacology)|potent]] [[5-HT2A receptor|5-HT_2A receptor]] agonist, ergotamine is said to be non-[[hallucinogenic]] similarly to [[lisuride]].<ref name="pmid24637012">{{cite journal | vauthors = Karaki S, Becamel C, Murat S, Mannoury la Cour C, Millan MJ, Prézeau L, Bockaert J, Marin P, Vandermoere F | display-authors = 6 | title = Quantitative phosphoproteomics unravels biased phosphorylation of serotonin 2A receptor at Ser280 by hallucinogenic versus nonhallucinogenic agonists | journal = Molecular & Cellular Proteomics | volume = 13 | issue = 5 | pages = 1273–1285 | date = May 2014 | pmid = 24637012 | pmc = 4014284 | doi = 10.1074/mcp.M113.036558 |doi-access=free }}</ref><ref name="HanksGonzález-Maeso2016">{{cite book | vauthors = Hanks J, González-Maeso J |chapter= Molecular and Cellular Basis of Hallucinogen Action | veditors = Preedy VR |title=Neuropathology of Drug Addictions and Substance Misuse |volume=2: Stimulants, Club and Dissociative Drugs, Hallucinogens, Steroids, Inhalants and International Aspects |year=2016 |pages=803–812 |doi=10.1016/B978-0-12-800212-4.00075-3 |isbn=978-0-12-800212-4}}</ref> This is thought to be due to [[functional selectivity]] at the 5-HT_2A receptor.<ref name="pmid24637012" /><ref name="HanksGonzález-Maeso2016" />

{| class="wikitable"

|+ {{Nowrap|Activities of ergotamine at various sites<ref name="PDSPKiDatabase">[https://web.archive.org/web/20210413101932/https://pdsp.unc.edu/databases/pdsp.php?testFreeRadio=testFreeRadio&testLigand=Ergotamine&doQuery=Submit+Query PDSP Database – UNC<!-- Bot generated title -->]</ref><ref name="pmid12558771">{{cite journal | vauthors = Silberstein SD, McCrory DC | title = Ergotamine and dihydroergotamine: history, pharmacology, and efficacy | journal = Headache | volume = 43 | issue = 2 | pages = 144–166 | date = February 2003 | pmid = 12558771 | doi = 10.1046/j.1526-4610.2003.03034.x | s2cid = 21356727 }}</ref><ref name="pmid11104741">{{cite journal | vauthors = Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A, Hufeisen SJ, Roth BL | title = Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications | journal = Circulation | volume = 102 | issue = 23 | pages = 2836–2841 | date = December 2000 | pmid = 11104741 | doi = 10.1161/01.cir.102.23.2836 | doi-access = free | author7-link = Bryan Roth }}</ref><ref name="pmid31418454">{{cite journal | vauthors = 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 | display-authors = 6 | title = Characterization of binding, functional activity, and contractile responses of the selective 5-HT_1F receptor agonist lasmiditan | journal = British Journal of Pharmacology | volume = 176 | issue = 24 | pages = 4681–4695 | date = December 2019 | pmid = 31418454 | pmc = 6965684 | doi = 10.1111/bph.14832 }}</ref><ref name="pmid20945968">{{cite journal | vauthors = Pytliak M, Vargová V, Mechírová V, Felšöci M | title = Serotonin receptors - from molecular biology to clinical applications | journal = Physiological Research | volume = 60 | issue = 1 | pages = 15–25 | date = 2011 | pmid = 20945968 | doi = 10.33549/physiolres.931903 | doi-access = free }}</ref>}}

! Site

! Affinity (K_i/IC₅₀ [nM])

! Efficacy (E_max [%])

! Action

|-

| [[5-HT1A receptor|5-HT_1A]]

| 0.17–0.3

| ?

| Full agonist

|-

| [[5-HT1B receptor|5-HT_1B]]

| 0.3–4.7

| ?

| Agonist

|-

| [[5-HT1D receptor|5-HT_1D]]

| 0.3–6.0

| ?

| Agonist

|-

| [[5-HT1E receptor|5-HT_1E]]

| 19–840

| ?

| ?

|-

| [[5-HT1F receptor|5-HT_1F]]

| 170–171

| ?

| ?

|-

| [[5-HT2A receptor|5-HT_2A]]

| 0.64–0.97

| ?

| Full agonist

|-

| [[5-HT2B receptor|5-HT_2B]]

| 1.3–45

| ?

| Partial agonist

|-

| [[5-HT2C receptor|5-HT_2C]]

| 1.9–9.8

| ?

| Partial agonist

|-

| [[5-HT3 receptor|5-HT₃]]

| >10,000

| –

| –

|-

| [[5-HT4 receptor|5-HT₄]]

| 65

| ?

| ?

|-

| [[5-HT5A receptor|5-HT_5A]]

| 14

| ?

| Agonist

|-

| [[5-HT5B receptor|5-HT_5B]]

| 3.2–16

| ?

| ?

|-

| [[5-HT6 receptor|5-HT₆]]

| 12

| ?

| ?

|-

| [[5-HT7 receptor|5-HT₇]]

| 1,291

| ?

| Agonist

|-

| [[α1A-Adrenergic receptor|α_1A]]

| 15–>10,000

| –

| –

|-

| [[α1B-Adrenergic receptor|α_1B]]

| 12–>10,000

| –

| –

|-

| [[α1D-Adrenergic receptor|α_1D]]

| ?

| ?

| ?

|-

| [[α2A-Adrenergic receptor|α_2A]]

| 106

| ?

| ?

|-

| [[α2B-Adrenergic receptor|α_2B]]

| 88

| ?

| ?

|-

| [[α2C-Adrenergic receptor|α_2C]]

| >10,000

| –

| –

|-

| [[β1-Adrenergic receptor|β₁]]

| >10,000

| –

| –

|-

| [[β2-Adrenergic receptor|β₂]]

| >10,000

| –

| –

|-

| [[D1 receptor|D₁]]

| >10,000

| –

| –

|-

| [[D2 receptor|D₂]]

| 4.0–>10,000

| –

| Agonist

|-

| [[D3 receptor|D₃]]

| 3.2–>10,000

| –

| –

|-

| [[D4 receptor|D₄]]

| 12–>10,000

| –

| –

|-

| [[D5 receptor|D₅]]

| 170

| ?

| ?

|-

| [[H1 receptor|H₁]]

| >10,000

| –

| –

|-

| [[H2 receptor|H₂]]

| >10,000

| –

| –

|-

| [[Muscarinic acetylcholine receptor M1|M₁]]

| 862

| ?

| ?

|-

| [[Muscarinic acetylcholine receptor M2|M₂]]

| 911

| ?

| ?

|-

| [[Muscarinic acetylcholine receptor M3|M₃]]

| >10,000

| –

| –

|-

| [[Muscarinic acetylcholine receptor M4|M₄]]

| >10,000

| –

| –

|-

| [[Muscarinic acetylcholine receptor M5|M₅]]

| >10,000

| –

| –

|- class="sortbottom"

| colspan="4" style="width: 1px; background-color:#eaecf0; text-align: center;" | '''Notes:''' All receptors are human except 5-HT_5A (mouse/rat) and 5-HT_5B (mouse/rat—no human counterpart).<ref name="PDSPKiDatabase" /> No affinity for [[histamine]] [[H1 receptor|H₁]] or [[H2 receptor|H₂]], [[cannabinoid receptor|cannabinoid]] [[CB1 receptor|CB₁]], [[GABA receptor|GABA]], [[glutamate receptor|glutamate]], or [[nicotinic acetylcholine receptor]]s, nor the [[monoamine transporter]]s (all >10,000&nbsp;nM).<ref name="PDSPKiDatabase" />

|}

===Pharmacokinetics===

The [[bioavailability]] of ergotamine is around 2% [[oral administration|orally]], 6% [[rectal administration|rectally]], and 100% by [[intramuscular injection|intramuscular]] or [[intravenous injection]].<ref name="pmid23815106" /> The low oral and rectal bioavailability is due to low [[gastrointestinal tract|gastrointestinal]] [[absorption (pharmacokinetics)|absorption]] and high [[first-pass metabolism]].<ref name="pmid23815106" />

==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]].<ref>{{cite web | title = Lists of: Scheduling Actions, Controlled Substances, Regulated Chemicals | url = https://www.deadiversion.usdoj.gov/schedules/orangebook/orangebook.pdf | publisher = U.S. Department of Justice | work = Drug Enforcement Administration, Diversion Control Division, Drug & Chemical Evaluation Section | date = February 2020 }}</ref>

== References ==

{{Reflist}}

{{Navboxes

| title = [[Pharmacodynamics]]

| titlestyle = background:#ccccff

| list1 =

{{Adrenergic receptor modulators}}

{{Dopamine receptor modulators}}

{{Serotonin receptor modulators}}

}}

{{Ergolines}}

[[Category:Alpha-1 blockers]]

[[Category:Alpha-2 adrenergic receptor agonists]]

[[Category:Biased ligands]]

[[Category:Lysergamides]]

[[Category:Serotonin receptor agonists]]

[[Category:Vasoconstrictors]]