Editing Ergotamine (section)

==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" /><ref name="KehlerLindskov2025" /> It is an [[agonist]] of serotonin receptors including the [[serotonin]] [[5-HT1 receptor|5-HT<sub>1</sub>]] and [[5-HT2 receptor|5-HT<sub>2</sub> subtype]]s.<ref name="pmid23815106" /><ref name="KehlerLindskov2025" /> Ergotamine is an agonist of the serotonin [[5-HT2B receptor|5-HT<sub>2B</sub> 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]] serotonin [[5-HT2A receptor|5-HT<sub>2A</sub> receptor]] agonist, ergotamine is said to be non-[[hallucinogenic]] similarly to [[lisuride]].<ref name="KehlerLindskov2025" /><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 | 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 has been posited to be due to [[functional selectivity]] at the serotonin 5-HT<sub>2A</sub> receptor.<ref name="pmid24637012" /><ref name="HanksGonzález-Maeso2016" /> However, ergotamine is also [[peripheral selectivity|peripherally selective]], which may instead account for its lack of psychedelic effects.<ref name="KehlerLindskov2025" /><ref name="Canal2018" /><ref name="VerhoeffVisserFerrari1993" />

{| 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 | title = Characterization of binding, functional activity, and contractile responses of the selective 5-HT<sub>1F</sub> 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<sub>i</sub>/IC<sub>50</sub> [nM])
! Efficacy (E<sub>max</sub> [%])
! Action
|-
| [[5-HT1A receptor|5-HT<sub>1A</sub>]]
| 0.17–0.3
| ?
| Full agonist
|-
| [[5-HT1B receptor|5-HT<sub>1B</sub>]]
| 0.3–4.7
| ?
| Agonist
|-
| [[5-HT1D receptor|5-HT<sub>1D</sub>]]
| 0.3–6.0
| ?
| Agonist
|-
| [[5-HT1E receptor|5-HT<sub>1E</sub>]]
| 19–840
| ?
| ?
|-
| [[5-HT1F receptor|5-HT<sub>1F</sub>]]
| 170–171
| ?
| ?
|-
| [[5-HT2A receptor|5-HT<sub>2A</sub>]]
| 0.64–0.97
| ?
| Full agonist
|-
| [[5-HT2B receptor|5-HT<sub>2B</sub>]]
| 1.3–45
| ?
| Partial agonist
|-
| [[5-HT2C receptor|5-HT<sub>2C</sub>]]
| 1.9–9.8
| ?
| Partial agonist
|-
| [[5-HT3 receptor|5-HT<sub>3</sub>]]
| >10,000
| –
| –
|-
| [[5-HT4 receptor|5-HT<sub>4</sub>]]
| 65
| ?
| ?
|-
| [[5-HT5A receptor|5-HT<sub>5A</sub>]]
| 14
| ?
| Agonist
|-
| [[5-HT5B receptor|5-HT<sub>5B</sub>]]
| 3.2–16
| ?
| ?
|-
| [[5-HT6 receptor|5-HT<sub>6</sub>]]
| 12
| ?
| ?
|-
| [[5-HT7 receptor|5-HT<sub>7</sub>]]
| 1,291
| ?
| Agonist
|-
| [[α1A-Adrenergic receptor|α<sub>1A</sub>]]
| 15–>10,000
| –
| –
|-
| [[α1B-Adrenergic receptor|α<sub>1B</sub>]]
| 12–>10,000
| –
| –
|-
| [[α1D-Adrenergic receptor|α<sub>1D</sub>]]
| ?
| ?
| ?
|-
| [[α2A-Adrenergic receptor|α<sub>2A</sub>]]
| 106
| ?
| ?
|-
| [[α2B-Adrenergic receptor|α<sub>2B</sub>]]
| 88
| ?
| ?
|-
| [[α2C-Adrenergic receptor|α<sub>2C</sub>]]
| >10,000
| –
| –
|-
| [[β1-Adrenergic receptor|β<sub>1</sub>]]
| >10,000
| –
| –
|-
| [[β2-Adrenergic receptor|β<sub>2</sub>]]
| >10,000
| –
| –
|-
| [[D1 receptor|D<sub>1</sub>]]
| >10,000
| –
| –
|-
| [[D2 receptor|D<sub>2</sub>]]
| 4.0–>10,000
| –
| Agonist
|-
| [[D3 receptor|D<sub>3</sub>]]
| 3.2–>10,000
| –
| –
|-
| [[D4 receptor|D<sub>4</sub>]]
| 12–>10,000
| –
| –
|-
| [[D5 receptor|D<sub>5</sub>]]
| 170
| ?
| ?
|-
| [[H1 receptor|H<sub>1</sub>]]
| >10,000
| –
| –
|-
| [[H2 receptor|H<sub>2</sub>]]
| >10,000
| –
| –
|-
| [[Muscarinic acetylcholine receptor M1|M<sub>1</sub>]]
| 862
| ?
| ?
|-
| [[Muscarinic acetylcholine receptor M2|M<sub>2</sub>]]
| 911
| ?
| ?
|-
| [[Muscarinic acetylcholine receptor M3|M<sub>3</sub>]]
| >10,000
| –
| –
|-
| [[Muscarinic acetylcholine receptor M4|M<sub>4</sub>]]
| >10,000
| –
| –
|-
| [[Muscarinic acetylcholine receptor M5|M<sub>5</sub>]]
| >10,000
| –
| –
|- class="sortbottom"
| colspan="4" style="width: 1px; background-color:#eaecf0; text-align: center;" | '''Notes:''' All receptors are human except 5-HT<sub>5A</sub> (mouse/rat) and 5-HT<sub>5B</sub> (mouse/rat—no human counterpart).<ref name="PDSPKiDatabase" /> No affinity for [[histamine]] [[H1 receptor|H<sub>1</sub>]] or [[H2 receptor|H<sub>2</sub>]], [[cannabinoid receptor|cannabinoid]] [[CB1 receptor|CB<sub>1</sub>]], [[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" />

However, ergotamine does not readily cross the [[blood–brain barrier]] and hence is [[peripheral selectivity|peripherally selective]].<ref name="KehlerLindskov2025" /><ref name="Canal2018">{{cite journal | vauthors = Canal CE | title = Serotonergic Psychedelics: Experimental Approaches for Assessing Mechanisms of Action | journal = Handb Exp Pharmacol | series = Handbook of Experimental Pharmacology | volume = 252 | issue = | pages = 227–260 | date = 2018 | pmid = 29532180 | pmc = 6136989 | doi = 10.1007/164_2018_107 | isbn = 978-3-030-10560-0 | url = }}</ref><ref name="VerhoeffVisserFerrari1993">{{cite journal | vauthors = Verhoeff NP, Visser WH, Ferrari MD, Saxena PR, van Royen EA | title = Dopamine D2-receptor imaging with 123I-iodobenzamide SPECT in migraine patients abusing ergotamine: does ergotamine cross the blood brain barrier? | journal = Cephalalgia | volume = 13 | issue = 5 | pages = 325–329 | date = October 1993 | pmid = 8242725 | doi = 10.1046/j.1468-2982.1993.1305325.x | url = }}</ref> This is due to it being an avid [[substrate (biochemistry)|substrate]] for [[P-glycoprotein]] and [[breast cancer resistance protein]] (BCRP).<ref name="KehlerLindskov2025" /> Only minimal amounts of the drug (~1%) cross into the [[brain]].<ref name="KehlerLindskov2025" />