Methylergometrine

Last updated

Methylergometrine
Methylergometrin.svg
Clinical data
Trade names Methergine
Other namesMethylergonovine; methylergobasin; Methylergobasine; Methylergobrevin; d-Lysergic acid 1-butanolamide; N-[(2S)-1-Hydroxybutan-2-yl]-6-methyl-9,10-didehydroergoline-8β-carboxamide
AHFS/Drugs.com International Drug Names
MedlinePlus a601077
Pregnancy
category
  • Contraindicated
Routes of
administration 		Oral
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Metabolism Liver
Elimination half-life 30–120 minutes
Excretion Mostly bile
Identifiers
  • (6aR,9R)-N-[(2S)-1-hydroxybutan-2-yl]-7-methyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.003.661 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C20H25N3O2
Molar mass 339.439 g·mol−1
3D model (JSmol)
Melting point 172 °C (342 °F)
Solubility in water Insoluble mg/mL (20 °C)
  • CC[C@@H](CO)NC(=O)[C@@H]2/C=C1/c3cccc4N\C=C(\C[C@H]1N(C)C2)c34
  • InChI=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 X mark.svgN
  • Key:UNBRKDKAWYKMIV-QWQRMKEZSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

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. [1] Previously thought to be an exclusively synthetic compound, it has been reported to occur naturally in Argyreia nervosa (Hawaiian baby woodrose). [2] [3] The drug is on the World Health Organization's List of Essential Medicines. [4]

Contents

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. [5] [6] [7]

Migraine

Methylergometrine is sometimes used for both prevention [8] and acute treatment [9] of migraine. It is an active metabolite of methysergide. [10] 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. [10]

Contraindications

Methylergometrine is contraindicated in patients with hypertension and pre-eclampsia. [5] It is also contraindicated in HIV positive patients taking protease inhibitors, delavirdine, and efavirenz (which is also an agonist at the 5-HT2A–mGlu2 receptor protomer and increases the chances of a patient experiencing hallucinations during methylergometrine therapy). [11]

Side effects

Adverse effects include: [5]

In excessive doses, methylergometrine can also lead to cramping, respiratory depression and coma. [5]

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. [5]

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-HT2A receptors, [12] while blood vessels are affected to a lesser extent compared to other ergot alkaloids. [5] It has been found to interact with the serotonin 5-HT1A, 5-HT1B, 5-HT1E, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT5A, and 5-HT7 receptors. [13] [14] [15] [16]

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. [17] This can be attributed to its agonistic action at the 5-HT2A–mGlu2 receptor protomers.[ citation needed ] Clinical efficacy occurs around 200 μg, ten times lower than the hallucinogenic threshold. [17]

Methylergometrine is an agonist of the serotonin 5-HT2B receptor and may be linked to cardiac valvulopathy. [18]

Activities of methylergometrine at various sites [13] [14] [19]
SiteAffinity (Ki [nM])Efficacy (Emax [%])Action
5-HT1A 1.5–2.0 ?Full agonist
5-HT1B 251 ?Full agonist
5-HT1D 0.86–2.970Partial agonist
5-HT1E 89 ?Full agonist
5-HT1F 31 ?Full agonist
5-HT2A 0.35–1.1 ?Full agonist
5-HT2B 0.46–2.2 ?Full or partial agonist
5-HT2C 4.6–43.7 ?Full agonist
5-HT3  ?––
5-HT5A  ?24.4 [16] Full agonist [16]
5-HT6  ? ?Full agonist
5-HT7 11–52 ?Full agonist
Notes: All sites are human except 5-HT1B (rat) and 5-HT7 (guinea pig). [13] [14] [19] Additional refs: [20] [21] [15] [22] [23]

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).

References

  1. ↑ Ott J, Neely P (April 1980). "Entheogenic (hallucinogenic) effects of methylergonovine". Journal of Psychedelic Drugs. 12 (2): 165–166. doi:10.1080/02791072.1980.10471568. PMID   7420432.
  2. ↑ Chen W, De Wit-Bos L (2020). Risk assessment of Argyreia nervosa (PDF) (Report). doi:10.21945/rivm-2019-0210.
  3. ↑ Paulke A, Kremer C, Wunder C, Wurglics M, Schubert-Zsilavecz M, Toennes SW (April 2015). "Studies on the alkaloid composition of the Hawaiian Baby Woodrose Argyreia nervosa, a common legal high". Forensic Sci Int. 249: 281–293. doi:10.1016/j.forsciint.2015.02.011. PMID   25747328.
  4. ↑ World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl: 10665/345533 . WHO/MHP/HPS/EML/2021.02.
  5. 1 2 3 4 5 6 Jasek W, ed. (2007). Austria-Codex (in German) (62nd ed.). Vienna: Österreichischer Apothekerverlag. pp. 5193–5. ISBN   978-3-85200-181-4.
  6. ↑ Mutschler E, Schäfer-Korting M (2001). Arzneimittelwirkungen (in German) (8th ed.). Stuttgart: Wissenschaftliche Verlagsgesellschaft. p. 447. ISBN   3-8047-1763-2.
  7. ↑ "Methergin". Fachinformation des Arzneimittel-Kompendium der Schweiz (in German).[ permanent dead link ]
  8. ↑ Koehler PJ, Tfelt-Hansen PC (November 2008). "History of methysergide in migraine". Cephalalgia. 28 (11): 1126–1135. doi:10.1111/j.1468-2982.2008.01648.x. PMID   18644039. S2CID   22433355.
  9. ↑ Niño-Maldonado AI, Caballero-García G, Mercado-Bochero W, Rico-Villademoros F, Calandre EP (November 2009). "Efficacy and tolerability of intravenous methylergonovine in migraine female patients attending the emergency department: a pilot open-label study". Head & Face Medicine. 5 (21): 21. doi: 10.1186/1746-160X-5-21 . PMC   2780385 . PMID   19895705.
  10. 1 2 Lambru G, Matharu M (April 2011). "Serotonergic agents in the management of cluster headache". Current Pain and Headache Reports. 15 (2): 108–117. doi:10.1007/s11916-011-0176-4. PMID   21271306. S2CID   34063682.
  11. ↑ "Methylergonovine Maleate Monograph for Professionals". Drugs.com. Archived from the original on 2016-09-20.
  12. ↑ Pertz H, Eich E (1999). "Ergot Alkaloids and their Derivatives as Ligands for Serotoninergic, Dopaminergic, and Adrenergic Receptors". In Křen V, Cvak L (eds.). Ergot: the genus Claviceps. CRC Press. pp. 411–440. ISBN   978-905702375-0.
  13. 1 2 3 "PDSP Database - UNC". pdsp.unc.edu. Archived from the original on 16 April 2021. Retrieved 15 January 2022.
  14. 1 2 3 "PDSP Database - UNC". pdsp.unc.edu. Archived from the original on 16 April 2021. Retrieved 15 January 2022.
  15. 1 2 Olivier B, van Wijngaarden I, Soudijn W (10 July 1997). Serotonin Receptors and their Ligands. Elsevier. pp. 149–. ISBN   978-0-08-054111-2.
  16. 1 2 3 Zhang S, Chen H, Zhang C, Yang Y, Popov P, Liu J, et al. (July 2022). "Inactive and active state structures template selective tools for the human 5-HT5A receptor". Nature Structural & Molecular Biology. 29 (7): 677–687. doi:10.1038/s41594-022-00796-6. PMC   9299520 . PMID   35835867.
  17. 1 2 Ott J, Neely P (1980). "Entheogenic (hallucinogenic) effects of methylergonovine". Journal of Psychedelic Drugs. 12 (2): 165–166. doi:10.1080/02791072.1980.10471568. PMID   7420432.
  18. ↑ Cavero I, Guillon JM (2014). "Safety Pharmacology assessment of drugs with biased 5-HT(2B) receptor agonism mediating cardiac valvulopathy". Journal of Pharmacological and Toxicological Methods. 69 (2): 150–161. doi:10.1016/j.vascn.2013.12.004. PMID   24361689.
  19. 1 2 Liu T. "BindingDB BDBM50330860 CHEMBL1201356::METHYLERGONOVINE::Methylergometrine". BindingDB. Retrieved 1 November 2024.
  20. ↑ Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A, Hufeisen SJ, et al. (December 2000). "Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications". Circulation. 102 (23): 2836–2841. doi: 10.1161/01.cir.102.23.2836 . PMID   11104741.
  21. ↑ Guzman M, Armer T, Borland S, Fishman R, Leyden M (April 2020). "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" (PDF). Neurology. 94 (15 Supplement). doi:10.1212/WNL.94.15_supplement.2663. S2CID   266103427. 2663. Archived from the original (PDF) on 2023-05-29. Retrieved 2021-04-16.
  22. ↑ Leff P (10 April 1998). Receptor - Based Drug Design. CRC Press. pp. 181–182. ISBN   978-1-4200-0113-6.
  23. ↑ Pertz H, Eich E (1999). "Ergot Alkaloids and their Derivatives as Ligands for Serotoninergic, Dopaminergic, and Adrenergic Receptors" (PDF). Ergot. pp. 432–462. doi:10.1201/9780203304198-21. ISBN   9780429219764. Archived from the original (PDF) on 2021-04-16.
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