Methylergometrine

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]

Methylergometrine

Clinical data
Trade names	Methergine
Other names	Methylergonovine; 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	G02AB01 (WHO)
Legal status
Legal status	In general: ℞ (Prescription only)
Pharmacokinetic data
Metabolism	Liver
Elimination half-life	30–120 minutes
Excretion	Mostly bile
Identifiers
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
CAS Number	113-42-8 Y
PubChem CID	8226
IUPHAR/BPS	150
DrugBank	DB00353
ChemSpider	7933 N
UNII	W53L6FE61V
KEGG	D08207
ChEMBL	ChEMBL1201356 N
CompTox Dashboard (EPA)	DTXSID00904978 DTXSID1023283, DTXSID00904978
ECHA InfoCard	100.003.661
Chemical and physical data
Formula	C20H25N3O2
Molar mass	339.439 g·mol−1
3D model (JSmol)	Interactive image
Melting point	172 °C (342 °F)
Solubility in water	Insoluble mg/mL (20 °C)
SMILES CC[C@@H](CO)NC(=O)[C@@H]2/C=C1/c3cccc4N\C=C(\C[C@H]1N(C)C2)c34
InChI 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 N Key:UNBRKDKAWYKMIV-QWQRMKEZSA-N N
NY (what is this?)  (verify)

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-HT_2A–mGlu2 receptor protomer and increases the chances of a patient experiencing hallucinations during methylergometrine therapy).^[11]

Side effects

Adverse effects include:^[5]

• Nausea, vomiting, and diarrhea
• Dizziness
• Pulmonary hypertension^{[citation needed]}
• 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.^[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-HT_2A 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-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.^{[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 due to its agonistic action at the 5-HT_2A–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-HT_2B receptor and may be linked to cardiac valvulopathy.^[18]

Activities of methylergometrine at various sites^[13][14][19]

Site	Affinity (Ki [nM])	Efficacy (Emax [%])	Action
5-HT1A	1.5–2.0	?	Full agonist
5-HT1B	251	?	Full agonist
5-HT1D	0.86–2.9	70	Partial 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).