methylergometrine

{{Drugbox

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 403104775

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

| image = Methylergometrin.svg

| width = 150px

| 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

| bioavailability =

| protein_bound =

| metabolism = Liver

| elimination_half-life = 30–120 minutes

| excretion = Mostly bile

| IUPHAR_ligand = 150

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

| CAS_number = 113-42-8

| DrugBank = DB00353

| ATC_prefix = G02

| ATC_suffix = AB01

| PubChem = 8226

| 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-[(2S)-1-Hydroxybutan-2-yl]-6-methyl-9,10-didehydroergoline-8β-carboxamide

| C=20 | H=25 | N=3 | O=2

| 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

| melting_point = 172

| melting_high =

| 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 as an antimigraine agent in the treatment of migraine headaches. It reportedly produces psychedelic effects similar to those of lysergic acid diethylamide (LSD) at high doses.{{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 = April 1980 | pmid = 7420432 | doi = 10.1080/02791072.1980.10471568 }} Previously thought to be an exclusively synthetic compound, it has been reported to occur naturally in Argyreia nervosa (Hawaiian baby woodrose).{{cite report | vauthors = Chen W, De Wit-Bos L | title=Risk assessment of Argyreia nervosa | date=2020 | doi=10.21945/rivm-2019-0210 | url = https://www.rivm.nl/bibliotheek/rapporten/2019-0210.pdf}}{{cite journal | vauthors = Paulke A, Kremer C, Wunder C, Wurglics M, Schubert-Zsilavecz M, Toennes SW | title = Studies on the alkaloid composition of the Hawaiian Baby Woodrose Argyreia nervosa, a common legal high | journal = Forensic Sci Int | volume = 249 | issue = | pages = 281–293 | date = April 2015 | pmid = 25747328 | doi = 10.1016/j.forsciint.2015.02.011 | url = }} The drug is on the World Health Organization's List of Essential Medicines.{{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 }}

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 (IM or IV) or in liquid form to be taken orally.{{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 }}{{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 }}{{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 }}

=Migraine=

Methylergometrine is sometimes used for both prevention{{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 }} and acute treatment{{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 }} of migraine. It is an active metabolite of methysergide.{{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 }} In the treatment of cluster headaches, methylergometrine has been initiated at a dose of 0.2 mg/day, rapidly increased to 0.2 mg three times per day, and increased to a maximum of 0.4 mg three times per day.

Contraindications

Methylergometrine is contraindicated in patients with hypertension and pre-eclampsia. 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).{{cite web|url=https://www.drugs.com/monograph/methylergonovine-maleate.html|title=Methylergonovine Maleate Monograph for Professionals | work = 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}}

Side effects

Adverse effects include:

Nausea, vomiting, and diarrhea
Dizziness
Pulmonary hypertension{{citation needed|date=July 2012}}
Coronary artery vasoconstriction
Severe systemic hypertension (especially in patients with pre-eclampsia)
Convulsions

In excessive doses, methylergometrine can also lead to cramping, respiratory depression and coma.

Interactions

Methylergometrine likely interacts with drugs that inhibit the liver enzyme CYP3A4, such as azole antifungals, macrolide antibiotics and many HIV drugs. It can also increase constriction of blood vessels caused by sympathomimetic drugs and other ergot alkaloids.

Pharmacology

=Pharmacodynamics=

Methylergometrine is an agonist or antagonist to serotonin, dopamine, and α-adrenergic receptors. 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-HT_2A receptors,{{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 }} while blood vessels are affected to a lesser extent compared to other ergot alkaloids. It has been found to interact with the serotonin 5-HT_1A, 5-HT_1B, 5-HT_1E, 5-HT_1F, 5-HT_2A, 5-HT_2B, 5-HT_2C, 5-HT_5A, and 5-HT₇ receptors.{{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 | 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 }}

Methylergometrine is a synthetic analogue of ergometrine, a 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 mg and above.{{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 }} This can be attributed to its agonistic action at the 5-HT_2A–mGlu2 receptor protomers.{{Citation needed|date=April 2021}} Clinical efficacy occurs around 200 μg, ten times lower than the hallucinogenic threshold.

Methylergometrine is an agonist of the serotonin 5-HT_2B receptor and may be linked to cardiac valvulopathy.{{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 }}

class="wikitable"

|+ {{Nowrap|Activities of methylergometrine at various sites{{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}}{{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}}{{cite web | last=Liu | first=Tiqing | title=BindingDB BDBM50330860 CHEMBL1201356::METHYLERGONOVINE::Methylergometrine | website=BindingDB | url=https://www.bindingdb.org/rwd/bind/chemsearch/marvin/MolStructure.jsp?monomerid=50330860 | access-date=1 November 2024}}}}

! Site

! Affinity (K_i [nM])

! Efficacy (E_max [%])

! Action

5-HT_1A

| 1.5–2.0

| ?

| Full agonist

5-HT_1B

| 251

| ?

| Full agonist

5-HT_1D

| 0.86–2.9

| 70

| Partial agonist

5-HT_1E

| 89

| ?

| Full agonist

5-HT_1F

| 31

| ?

| Full agonist

5-HT_2A

| 0.35–1.1

| ?

| Full agonist

5-HT_2B

| 0.46–2.2

| ?

| Full or partial agonist

5-HT_2C

| 4.6–43.7

| ?

| Full agonist

5-HT₃

| ?

| –

5-HT_5A

| ?

| 24.4

| Full agonist

5-HT₆

| ?

| Full agonist

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). Additional refs: {{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 }}{{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 | archive-date = 2023-05-29 | access-date = 2021-04-16 | archive-url = https://web.archive.org/web/20230529232959/https://www.xocpharma.com/file.cfm/7/docs/AHS_2019_Poster_1_XocPharma_Final.pdf | url-status = dead }}{{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–}}{{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}}{{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}}

Chemistry

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