Methylergometrine

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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]

Contents

It is on the World Health Organization's List of Essential Medicines. [2]

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. [3] [4] [5]

Migraine

Methylergometrine is sometimes used for both prevention [6] and acute treatment [7] of migraine. It is an active metabolite of methysergide. [8] 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. [8]

Contraindications

Methylergometrine is contraindicated in patients with hypertension and pre-eclampsia. [3] 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). [9]

Side effects

Adverse effects include: [3]

In excessive doses, methylergometrine can also lead to cramping, respiratory depression and coma. [3]

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. [3]

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, [10] while blood vessels are affected to a lesser extent compared to other ergot alkaloids. [3] 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. [11] [12] [13] [14]

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. [15] This can be attributed to due 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. [15]

Methylergometrine is an agonist of the serotonin 5-HT2B receptor and may be linked to cardiac valvulopathy. [16]

Activities of methylergometrine at various sites [11] [12] [17]
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 [14] Full agonist [14]
5-HT6  ? ?Full agonist
5-HT7 11–52 ?Full agonist
Notes: All sites are human except 5-HT1B (rat) and 5-HT7 (guinea pig). [11] [12] [17] Additional refs: [18] [19] [13] [20] [21]

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).

Related Research Articles

<span class="mw-page-title-main">LSD</span> Hallucinogenic drug

Lysergic acid diethylamide, commonly known as LSD, is a potent psychedelic drug that intensifies thoughts, emotions, and sensory perception. Often referred to as acid or lucy, LSD can cause mystical, spiritual, or religious experiences. At higher doses, it primarily induces visual and auditory hallucinations. LSD is not considered addictive, because it does not produce compulsive drug-seeking behavior. Using LSD can lead to adverse psychological reactions, such as anxiety, paranoia, and delusions. Additionally, it may trigger "flashbacks," also known as hallucinogen persisting perception disorder (HPPD), where individuals experience persistent visual distortions after use.

<span class="mw-page-title-main">Ergine</span> Chemical compound

Ergine, also known as lysergic acid amide and lysergamide, is an ergoline alkaloid that occurs in Clavicipitaceous fungi, which includes Convolvulaceae vines, which have a permanent bond with these fungi. The most common source of ergine for consumers is the seeds of Ipomoea tricolor, Ipomoea corymbosa, and Argyreia nervosa; isoergine and lysergic acid propanolamide have also been shown to contribute to their psychoactivity.

<span class="mw-page-title-main">Ergoline</span> Chemical compound

Ergoline is a core structure in many alkaloids and their synthetic derivatives. Ergoline alkaloids were first characterized in ergot. Some of these are implicated in the condition of ergotism, which can take a convulsive form or a gangrenous form. Even so, many ergoline alkaloids have been found to be clinically useful. Annual world production of ergot alkaloids has been estimated at 5,000–8,000 kg of all ergopeptines and 10,000–15,000 kg of lysergic acid, used primarily in the manufacture of semi-synthetic derivatives.

<span class="mw-page-title-main">Ergotamine</span> Chemical compound in the ergot family of alkaloids

Ergotamine, sold under the brand name Ergomar among others, is an ergopeptine and part of the ergot family of alkaloids; it is structurally and biochemically closely related to ergoline. It is structurally similar to several neurotransmitters, and it acts as a vasoconstrictor. It is used for acute migraines, sometimes with caffeine as the combination ergotamine/caffeine.

<span class="mw-page-title-main">Bromocriptine</span> Dopamine agonist medication

Bromocriptine, originally marketed as Parlodel and subsequently under many brand names, is an ergoline derivative and dopamine agonist that is used in the treatment of pituitary tumors, Parkinson's disease, hyperprolactinaemia, neuroleptic malignant syndrome, and, as an adjunct, type 2 diabetes.

<span class="mw-page-title-main">Pergolide</span> Dopamine agonist medication

Pergolide, sold under the brand name Permax and Prascend (veterinary) among others, is an ergoline-based dopamine receptor agonist used in some countries for the treatment of Parkinson's disease. Parkinson's disease is associated with reduced dopamine synthesis in the substantia nigra of the brain. Pergolide acts on many of the same receptors as dopamine to increase receptor activity.

<i>Argyreia nervosa</i> Species of plant

Argyreia nervosa is a perennial climbing vine native to the Indian subcontinent and introduced to numerous areas worldwide, including Hawaii, Africa, and the Caribbean. Though it can be invasive, it is often prized for its aesthetic and medicinal value. Common names include Hawaiian baby woodrose, adhoguda अधोगुडा or vidhara विधारा (Sanskrit), elephant creeper and woolly morning glory. Its seeds are known for their powerful entheogenic properties, greater or similar to those of Ipomoea species, with users reporting significant psychedelic and spiritual experiences. The two botanical varieties are Argyreia nervosa var. nervosa described here, and Argyreia nervosa var. speciosa, the roots of which are used in Ayurvedic medicine.

<span class="mw-page-title-main">Cabergoline</span> Chemical compound

Cabergoline, sold under the brand name Dostinex among others, is a dopaminergic medication used in the treatment of high prolactin levels, prolactinomas, Parkinson's disease, and for other indications. It is taken by mouth.

<span class="mw-page-title-main">Lysergamides</span> Class of chemical compounds

Amides of lysergic acid are collectively known as lysergamides or ergoamides, and include a number of compounds with potent agonist and/or antagonist activity at various serotonin and dopamine receptors. Lysergamides contain an embedded tryptamine structure, and as a result can produce similar, often psychedelic, effects to those of the true tryptamines.

<span class="mw-page-title-main">Ergonovine</span> Lysergamide

Ergonovine, also known as ergometrine and lysergic acid propanolamide is a medication used to cause contractions of the uterus to treat heavy vaginal bleeding after childbirth. It can be used either by mouth, by injection into a muscle, or injection into a vein. It begins working within 15 minutes when taken by mouth and is faster in onset when used by injection. Effects last between 45 and 180 minutes.

<span class="mw-page-title-main">Dihydroergotamine</span> Chemical used to treat migraines

Dihydroergotamine (DHE), sold under the brand names D.H.E. 45 and Migranal among others, is an ergot alkaloid used to treat migraines. It is a derivative of ergotamine. It is administered as a nasal spray or injection and has an efficacy similar to that of sumatriptan. Nausea is a common side effect.

<span class="mw-page-title-main">Lysergic acid hydroxyethylamide</span> Chemical compound

ᴅ-Lysergic acid α-hydroxyethylamide, also known as ᴅ-lysergic acid methyl carbinolamide, is an ergoamide and an ergoline. It is perhaps the main constituent of the parasitic fungus, Claviceps paspali; and found in trace amounts in Claviceps Purpurea. C. paspali and C. purpurea are ergot-spreading fungi. Periglandula, Clavicipitacepus fungi, are permanently symbiotically connected to an estimated 450 species of Convolvulaceae and thus generate LAH in some of them. The most well-known ones are Ipomoea tricolor, Turbina corymbosa (coaxihuitl), and Argyreia nervosa.

<span class="mw-page-title-main">Methysergide</span> Chemical compound

Methysergide, sold under the brand names Deseril and Sansert, is a monoaminergic medication of the ergoline and lysergamide groups which is used in the prophylaxis and treatment of migraine and cluster headaches. It has been withdrawn from the market in the United States and Canada due to safety concerns. It is taken by mouth.

<span class="mw-page-title-main">Lisuride</span> Chemical compound

Lisuride, sold under the brand name Dopergin among others, is a monoaminergic medication of the ergoline class which is used in the treatment of Parkinson's disease, migraine, and high prolactin levels. It is taken by mouth.

<span class="mw-page-title-main">Indole alkaloid</span> Class of alkaloids

Indole alkaloids are a class of alkaloids containing a structural moiety of indole; many indole alkaloids also include isoprene groups and are thus called terpene indole or secologanin tryptamine alkaloids. Containing more than 4100 known different compounds, it is one of the largest classes of alkaloids. Many of them possess significant physiological activity and some of them are used in medicine. The amino acid tryptophan is the biochemical precursor of indole alkaloids.

<span class="mw-page-title-main">Pizotifen</span> Drug used to reduce frequency of headaches

Pizotifen, also known as pizotyline and sold under the brand names Sandomigran and Mosegor among others, is an antimigraine agent of the tricyclic group which is used primarily as a preventative to reduce the frequency of recurrent migraine headaches.

<span class="mw-page-title-main">Serotonin receptor agonist</span> Neurotransmission-modulating substance

A serotonin receptor agonist is an agonist of one or more serotonin receptors. They activate serotonin receptors in a manner similar to that of serotonin, a neurotransmitter and hormone and the endogenous ligand of the serotonin receptors.

<span class="mw-page-title-main">2-Bromo-LSD</span> Chemical compound

2-Bromo-LSD, also known as BOL-148 or as bromolysergide, is a derivative of lysergic acid invented by Albert Hofmann, as part of the original research from which the closely related compound LSD was also derived. It is a non-hallucinogenic serotonin 5-HT2A receptor partial agonist, as well as acting at other targets, with psychoplastogenic and antidepressant-like effects in animals.

<span class="mw-page-title-main">Amesergide</span> Chemical compound

Amesergide is a serotonin receptor antagonist of the ergoline and lysergamide families related to methysergide which was under development by Eli Lilly and Company for the treatment of a variety of conditions including depression, anxiety, schizophrenia, male sexual dysfunction, migraine, and thrombosis but was never marketed. It reached phase II clinical trials for the treatment of depression, erectile dysfunction, and premature ejaculation prior to the discontinuation of its development.

<span class="mw-page-title-main">Lysergine</span> Ergot alkaloid and serotonin receptor agonist

Lysergine, also known as 9,10-didehydro-6,8β-dimethylergoline, is an ergot alkaloid and serotonin receptor agonist of the ergoline family. It is a minor constituent of ergot.

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. ↑ 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.
  3. 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.
  4. ↑ Mutschler E, Schäfer-Korting M (2001). Arzneimittelwirkungen (in German) (8th ed.). Stuttgart: Wissenschaftliche Verlagsgesellschaft. p. 447. ISBN   3-8047-1763-2.
  5. ↑ "Methergin". Fachinformation des Arzneimittel-Kompendium der Schweiz (in German).[ permanent dead link ]
  6. ↑ 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.
  7. ↑ 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.
  8. 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.
  9. ↑ "Methylergonovine Maleate Monograph for Professionals". Drugs.com. Archived from the original on 2016-09-20.
  10. ↑ 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.
  11. 1 2 3 "PDSP Database - UNC". pdsp.unc.edu. Archived from the original on 16 April 2021. Retrieved 15 January 2022.
  12. 1 2 3 "PDSP Database - UNC". pdsp.unc.edu. Archived from the original on 16 April 2021. Retrieved 15 January 2022.
  13. 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.
  14. 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.
  15. 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.
  16. ↑ 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.
  17. 1 2 Liu T. "BindingDB BDBM50330860 CHEMBL1201356::METHYLERGONOVINE::Methylergometrine". BindingDB. Retrieved 1 November 2024.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ Leff P (10 April 1998). Receptor - Based Drug Design. CRC Press. pp. 181–182. ISBN   978-1-4200-0113-6.
  21. ↑ 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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