Methylergometrine: Difference between revisions

{{Short description|Chemical compound}}

{{cs1 config|name-list-style=vanc}}

{{Drugbox

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 403104775

| IUPAC_name = (6''aR'',9''R'')-''N''-[(2''S'')-1-hydroxybutan-2-yl]-7-methyl-6,6a,8,9-tetrahydro-4''H''-indolo[4,3-fg]quinoline-9-carboxamide

| image = Methylergometrin.svg

| width = 150px

<!--Clinical data-->

| tradename = Methergine

| Drugs.com = {{drugs.com|international|methylergometrine}}

| MedlinePlus = a601077

| pregnancy_AU =

| pregnancy_US =

| pregnancy_category = Contraindicated

| legal_AU =

| legal_CA =

| legal_UK =

| legal_US =

| legal_status = Rx-only

| routes_of_administration = [[Oral administration|Oral]]

<!--Pharmacokinetic data-->

| bioavailability =

| protein_bound =

| metabolism = Liver

| elimination_half-life = 30–120 minutes

| excretion = Mostly bile

<!--Identifiers-->

| IUPHAR_ligand = 150

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

| KEGG = D08207

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

| ChemSpiderID = 7933

| UNII_Ref = {{fdacite|changed|FDA}}

| UNII = W53L6FE61V

| ChEMBL_Ref = {{ebicite|changed|EBI}}

| ChEMBL = 1201356

| synonyms = Methylergonovine; methylergobasin; Methylergobasine; Methylergobrevin; ''d''-Lysergic acid 1-butanolamide; ''N''-[(2''S'')-1-Hydroxybutan-2-yl]-6-methyl-9,10-didehydroergoline-8β-carboxamide

<!--Chemical data-->

| SMILES = CC[C@@H](CO)NC(=O)[C@@H]2/C=C1/c3cccc4N\C=C(\C[C@H]1N(C)C2)c34

| StdInChI_Ref = {{stdinchicite|changed|chemspider}}

| StdInChI = 1S/C20H25N3O2/c1-3-14(11-24)22-20(25)13-7-16-15-5-4-6-17-19(15)12(9-21-17)8-18(16)23(2)10-13/h4-7,9,13-14,18,21,24H,3,8,10-11H2,1-2H3,(H,22,25)/t13-,14+,18-/m1/s1

| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}

| StdInChIKey = UNBRKDKAWYKMIV-QWQRMKEZSA-N

<!--Physical data-->

| solubility = Insoluble

'''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.{{Citation needed|date=December 2022}}

It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO22nd">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 22nd list (2021) | year = 2021 | hdl = 10665/345533 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2021.02 | hdl-access=free }}</ref>

==Medical uses==

===Obstetric use===

Methylergometrine is a smooth muscle constrictor that mostly acts on the [[uterus]]. It is most commonly used to prevent or control excessive bleeding following childbirth and spontaneous or elective abortion, and also to aid in expulsion of retained products of conception after a missed abortion (miscarriage in which all or part of the fetus remains in the uterus) and to help deliver the placenta after childbirth. It is available as tablets or injection ([[intramuscular injection|IM]] or [[intravenous therapy|IV]]) or in liquid form to be taken orally.<ref name="Austria-Codex">{{cite book |title=Austria-Codex| veditors = Jasek W |publisher=Österreichischer Apothekerverlag |location=Vienna |year=2007 |edition=62nd |isbn=978-3-85200-181-4 |pages=5193–5 |language=German }}</ref><ref>{{cite book | vauthors = Mutschler E, Schäfer-Korting M |title= Arzneimittelwirkungen |language=German |location=Stuttgart |publisher=Wissenschaftliche Verlagsgesellschaft |year=2001 |edition=8th |page=447 |isbn=3-8047-1763-2 }}</ref><ref>{{cite book | title = Fachinformation des Arzneimittel-Kompendium der Schweiz | chapter-url = http://www.kompendium.ch/Monographie.aspx?Id=c2bb9f2c-77a5-46c6-b9e5-dfd5b50e7c89&lang=de&MonType=fi | chapter = Methergin | language = German }}{{Dead link|date=March 2024 |bot=InternetArchiveBot |fix-attempted=yes }}</ref>

===Migraine===

Methylergometrine is sometimes used for both prevention<ref>{{cite journal | vauthors = Koehler PJ, Tfelt-Hansen PC | title = History of methysergide in migraine | journal = Cephalalgia | volume = 28 | issue = 11 | pages = 1126–1135 | date = November 2008 | pmid = 18644039 | doi = 10.1111/j.1468-2982.2008.01648.x | s2cid = 22433355 }}</ref> and acute treatment<ref>{{cite journal | vauthors = Niño-Maldonado AI, Caballero-García G, Mercado-Bochero W, Rico-Villademoros F, Calandre EP | title = Efficacy and tolerability of intravenous methylergonovine in migraine female patients attending the emergency department: a pilot open-label study | journal = Head & Face Medicine | volume = 5 | issue = 21 | pages = 21 | date = November 2009 | pmid = 19895705 | pmc = 2780385 | doi = 10.1186/1746-160X-5-21 | doi-access = free }}</ref> of migraine. It is an [[active metabolite]] of [[methysergide]].<ref name="pmid21271306">{{cite journal | vauthors = Lambru G, Matharu M | title = Serotonergic agents in the management of cluster headache | journal = Current Pain and Headache Reports | volume = 15 | issue = 2 | pages = 108–117 | date = April 2011 | pmid = 21271306 | doi = 10.1007/s11916-011-0176-4 | s2cid = 34063682 }}</ref> In the treatment of [[cluster headache]]s, methylergometrine has been initiated at a dose of 0.2&nbsp;mg/day, rapidly increased to 0.2&nbsp;mg three times per day, and increased to a maximum of 0.4&nbsp;mg three times per day.<ref name="pmid21271306" />

==Contraindications==

Methylergometrine is contraindicated in patients with [[hypertension]] and [[pre-eclampsia]].<ref name="Austria-Codex" /> It is also contraindicated in [[HIV]] positive patients taking [[protease inhibitors]], [[delavirdine]], and [[efavirenz]] (which is also an agonist at the 5-HT_2A–mGlu2 receptor protomer and increases the chances of a patient experiencing hallucinations during methylergometrine therapy).<ref>{{cite web|url=https://www.drugs.com/monograph/methylergonovine-maleate.html|title=Methylergonovine Maleate Monograph for Professionals - Drugs.com|website=drugs.com|url-status=live|archive-url=https://web.archive.org/web/20160920031804/https://www.drugs.com/monograph/methylergonovine-maleate.html|archive-date=2016-09-20}}</ref>

Adverse effects include:<ref name="Austria-Codex" />

* Nausea, vomiting, and diarrhea

* Pulmonary hypertension{{citation needed|date=July 2012}}

* Severe systemic hypertension (especially in patients with [[pre-eclampsia]])

* Convulsions

In excessive doses, methylergometrine can also lead to cramping, [[respiratory depression]] and coma.<ref name="Austria-Codex" />

== Interactions ==

Methylergometrine likely interacts with drugs that inhibit the liver enzyme [[CYP3A4]], such as [[azole antifungal]]s, [[macrolide antibiotic]]s and many HIV drugs. It can also increase constriction of blood vessels caused by [[sympathomimetic]] drugs and other ergot alkaloids.<ref name="Austria-Codex" />

==Pharmacology==

===Pharmacodynamics===

Methylergometrine is an [[partial agonist|agonist]] or [[receptor antagonist|antagonist]] to [[serotonin]], [[dopamine]], and [[α-adrenergic receptor]]s. Its specific binding and activation pattern on these receptors leads to a highly, if not completely, specific contraction of smooth uterus muscle via serotonin [[5-HT2A|5-HT_2A receptor]]s,<ref>{{cite book | vauthors = Pertz H, Eich E | chapter = Ergot Alkaloids and their Derivatives as Ligands for Serotoninergic, Dopaminergic, and Adrenergic Receptors | veditors = Křen V, Cvak L |title=Ergot: the genus Claviceps |year=1999 |publisher=CRC Press |isbn=978-905702375-0 |pages=411–440 }}</ref> while blood vessels are affected to a lesser extent compared to other ergot alkaloids.<ref name="Austria-Codex" /> It has been found to interact with the serotonin [[5-HT1A receptor|5-HT_1A]], [[5-HT1B receptor|5-HT_1B]], [[5-HT1E receptor|5-HT_1E]], [[5-HT1F receptor|5-HT_1F]], [[5-HT2A receptor|5-HT_2A]], [[5-HT2B receptor|5-HT_2B]], [[5-HT2C receptor|5-HT_2C]], [[5-HT5A receptor|5-HT_5A]], and [[5-HT7 receptor|5-HT₇ receptor]]s.<ref name="PDSPKiDatabase" /><ref name="PDSPKiDatabase2" /><ref name="OlivierWijngaarden1997" /><ref name=":0">{{cite journal | vauthors = Zhang S, Chen H, Zhang C, Yang Y, Popov P, Liu J, Krumm BE, Cao C, Kim K, Xiong Y, Katritch V, Shoichet BK, Jin J, Fay JF, Roth BL | display-authors = 6 | title = Inactive and active state structures template selective tools for the human 5-HT_5A receptor | journal = Nature Structural & Molecular Biology | volume = 29 | issue = 7 | pages = 677–687 | date = July 2022 | pmid = 35835867 | pmc = 9299520 | doi = 10.1038/s41594-022-00796-6 }}</ref>

Methylergometrine is a [[chemical synthesis|synthetic]] [[analog (chemistry)|analogue]] of [[ergometrine]], a [[Psychedelic drug|psychedelic]] [[alkaloid]] found in [[ergot]], and many species of [[morning glory]]. Methylergometrine is a member of the [[ergoline]] family and chemically similar to [[LSD]], [[ergine]], [[ergometrine]], and [[lysergic acid]]. According to [[Jonathan Ott]], methylergometrine produces LSD-like [[psychedelic]] effects at doses of 2&nbsp;mg and above.<ref name="pmid7420432">{{cite journal | vauthors = Ott J, Neely P | title = Entheogenic (hallucinogenic) effects of methylergonovine | journal = Journal of Psychedelic Drugs | volume = 12 | issue = 2 | pages = 165–166 | date = 1980 | pmid = 7420432 | doi = 10.1080/02791072.1980.10471568 }}</ref> This can be attributed to due to its agonistic action at the 5-HT_2A–[[Metabotropic glutamate receptor 2|mGlu2]] receptor [[Protomer (structural biology)|protomer]]s.{{Citation needed|date=April 2021}} Clinical efficacy occurs around 200&nbsp;μg, ten times lower than the hallucinogenic threshold.<ref name="pmid7420432" />

Methylergometrine is an agonist of the serotonin 5-HT_2B receptor and is maybe linked to [[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>

{| class="wikitable"

|+ {{Nowrap|Activities of methylergometrine at various sites<ref name="PDSPKiDatabase">{{cite web |url=https://pdsp.unc.edu/databases/pdsp.php?testFreeRadio=testFreeRadio&testLigand=Methylergonovine&doQuery=Submit+Query |title=PDSP Database - UNC |website=pdsp.unc.edu |access-date=15 January 2022 |archive-url=https://web.archive.org/web/20210416001542/https://pdsp.unc.edu/databases/pdsp.php?testFreeRadio=testFreeRadio&testLigand=Methylergonovine&doQuery=Submit+Query |archive-date=16 April 2021 |url-status=dead}}</ref><ref name="PDSPKiDatabase2">{{cite web |url=https://pdsp.unc.edu/databases/pdsp.php?testFreeRadio=testFreeRadio&testLigand=Methergine&doQuery=Submit+Query |title=PDSP Database - UNC |website=pdsp.unc.edu |access-date=15 January 2022 |archive-url=https://web.archive.org/web/20210416011555/https://pdsp.unc.edu/databases/pdsp.php?testFreeRadio=testFreeRadio&testLigand=Methergine&doQuery=Submit+Query |archive-date=16 April 2021 |url-status=dead}}</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="GuzmanArmer2020">{{cite journal | vauthors = Guzman M, Armer T, Borland S, Fishman R, Leyden M | title = Novel Receptor Activity Mapping of Methysergide and its Metabolite, Methylergometrine, Provides a Mechanistic Rationale for both the Clinically Observed Efficacy and Risk of Fibrosis in Patients with Migraine | id = 2663 | journal = Neurology | volume = 94 | issue = 15 Supplement | date = April 2020 | doi = 10.1212/WNL.94.15_supplement.2663 | s2cid = 266103427 | url = https://www.xocpharma.com/file.cfm/7/docs/AHS_2019_Poster_1_XocPharma_Final.pdf }}</ref><ref name="OlivierWijngaarden1997">{{cite book| vauthors = Olivier B, van Wijngaarden I, Soudijn W |title=Serotonin Receptors and their Ligands|url=https://books.google.com/books?id=lfo0hGqIex0C&pg=PA149|date=10 July 1997|publisher=Elsevier|isbn=978-0-08-054111-2|pages=149–}}</ref><ref name="Leff1998">{{cite book| vauthors = Leff P |title=Receptor - Based Drug Design|url=https://books.google.com/books?id=YYk04RMvSSUC&pg=PA181|date=10 April 1998|publisher=CRC Press|isbn=978-1-4200-0113-6|pages=181–182}}</ref><ref name="PertzHeich1999">{{cite book|vauthors=Pertz H, Eich E|title=Ergot|chapter=Ergot Alkaloids and their Derivatives as Ligands for Serotoninergic, Dopaminergic, and Adrenergic Receptors|year=1999|pages=432–462|doi=10.1201/9780203304198-21|isbn=9780429219764|chapter-url=http://chemistry.mdma.ch/hiveboard/palladium/pdf/Ergot%20-%20The%20Genus%20Claviceps%20%281999%29/TF3168ch14.pdf|archive-url=https://web.archive.org/web/20210416003930/http://chemistry.mdma.ch/hiveboard/palladium/pdf/Ergot%20-%20The%20Genus%20Claviceps%20%281999%29/TF3168ch14.pdf|archive-date=2021-04-16}}</ref>}}

! Site

! Affinity (K_i [nM])

! Efficacy (E_max [%])

! Action

|-

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

| 1.5–2.0

| ?

| Full agonist

|-

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

| 251

| ?

| Full agonist

|-

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

| 0.86–2.9

| 70

| Partial agonist

|-

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

| 89

| ?

| Full agonist

|-

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

| 31

| ?

| Full agonist

|-

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

| 0.35–1.1

| ?

| Full agonist

|-

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

| 0.46–2.2

| ?

| Full or partial agonist

|-

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

| 4.6–43.7

| ?

| Full agonist

|-

| [[5-HT3 receptor|5-HT₃]]

| ?

| –

| –

|-

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

| ?

| 24.4<ref name=":0" />

| Full agonist<ref name=":0" />

|-

| [[5-HT6 receptor|5-HT₆]]

| ?

| ?

| Full agonist

|-

| [[5-HT7 receptor|5-HT₇]]

| 11–52

| ?

| Full agonist

|- class="sortbottom"

| colspan="4" style="width: 1px; background-color:#eaecf0; text-align: center;" | '''Notes:''' All sites are human except 5-HT_1B (rat) and 5-HT₇ (guinea pig).<ref name="PDSPKiDatabase" /><ref name="PDSPKiDatabase2" />

|}

==Chemistry==

Methylergometrine, also known as ''d''-lysergic acid 1-butanolamide, is a [[chemical derivative|derivative]] of the [[ergoline]] and [[lysergamide]] classes and is structurally related to [[ergometrine]] (''d''-lysergic acid β-propanolamide) and [[lysergic acid diethylamide]].

== References ==

{{Reflist}}

{{Navboxes

| title = [[Medical use]]s

| titlestyle = background:#ccccff

| list1 =

{{Oxytocics}}

{{Antimigraine preparations}}

{{Hallucinogens}}

}}

{{Navboxes

| title = [[Pharmacodynamics]]

| titlestyle = background:#ccccff

| list1 =

{{Adrenergic receptor modulators}}

{{Dopamine receptor modulators}}

{{Serotonin receptor modulators}}

}}

{{Ergolines}}

{{Uterotonics}}

[[Category:Antimigraine drugs]]

[[Category:Human drug metabolites]]

[[Category:Lysergamides]]

[[Category:Uterotonics]]

[[Category:Serotonin receptor agonists]]