Levomepromazine

Methotrimeprazine

Systematic (IUPAC) name
(2R)-3-(2-Methoxyphenothiazine-10-yl-)-N,N,2-trimethylpropanamine
Clinical data
AHFS/Drugs.com	Micromedex Detailed Consumer Information
Pregnancy cat.	Only if clearly needed
Legal status	Rx-only (n.a. in the USA)
Routes	Oral, seldom intramuscular
Pharmacokinetic data
Bioavailability	approx. 50 to 60%
Metabolism	Hepatic
Half-life	~ 20 hours
Excretion	In feces and urine (metabolites), unchanged drug only 1%
Identifiers
CAS number	60-99-1 Y 7104-38-3 (maleate), 1236-99-3 HCl)
ATC code	N05AA02
PubChem	CID 72287
DrugBank	DB01403
ChemSpider	65239 Y
UNII	9G0LAW7ATQ Y
KEGG	D00403 Y
ChEBI	CHEBI:6838 N
ChEMBL	CHEMBL1764 Y
Chemical data
Formula	C19H24N2OS
Mol. mass	328.47 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C19H24N2OS/c1-14(12-20(2)3)13-21-16-7-5-6-8-18(16)23-19-10-9-15(22-4)11-17(19)21/h5-11,14H,12-13H2,1-4H3/t14-/m1/s1 Y Key:VRQVVMDWGGWHTJ-CQSZACIVSA-N Y
N(what is this?)  (verify)

Levomepromazine in Germany and Methotrimeprazine in America (Sold as Nosinan Nozinan, Levoprome) is an aliphatic phenothiazine neuroleptic drug. It is a low-potency antipsychotic (approximately half as potent as chlorpromazine) with strong analgesic and antiemetic properties.

Serious side effects include tardive dyskinesia, akathisia, and the potentially fatal neuroleptic malignant syndrome. As is typical of phenothiazine antipsychotics, levomepromazine is a "dirty drug": it exerts its effects by blocking a variety of receptors, including adrenergic receptors, dopamine receptors, histamine receptors, muscarinic acetylcholine receptors, and serotonin receptors.

Currently, levomepromazine is not registered in the USA, although some American physicians are conducting studies regarding the strong analgesic effect of levomepromazine.^{[citation needed]} In Europe it has been marketed for decades as Neurocil and Nozinan (manufactured by Sanofi-Avensis). Nozinan is also available in Canada. Nozinan is available in round tablets of 5, 25 or 100 mg.

Indications

Levomepromazine is used for the treatment of psychosis, particular those of schizophrenia, and manic phases of bipolar disorder. It should be used only with caution in the treatment of agitated depressions, as it can cause akathisia as a side effect, which could worsen the agitation.

Levomepromazine is also used at lower doses for the treatment of nausea and insomnia.

In Europe it is approved for the treatment of chronic idiopathic pain.

Adverse effects

The most common side effect is akathisia.^{[citation needed]} Levomepromazine has prominent sedative and anticholinergic/sympatholytic effects (dry mouth, hypotension, sinus tachycardia, night sweats) and may cause weight gain. These side effects normally preclude prescribing the drug in doses needed for full remission of schizophrenia, so it has to be combined with a more potent antipsychotic. In any case, blood pressure and EKG should be monitored regularly.

A rare but life-threatening side effect is neuroleptic malignant syndrome (NMS). The symptoms of NMS include muscle stiffness, convulsions and fever.

Pharmacokinetics

• Absorption, and other characteristics : Levomepromazine has an incomplete oral bioavailability, because it undergoes considerable first-pass-metabolism in the liver. It has a half-life of approximately 20 hours (15 to 30 hours). Maximum plasma levels are reached 1 to 4 hours after oral dosing. After i.m.-doses maximum plasma levels are seen after 30 to 90 minutes.
• Distribution : The approximate distribution volume is 30 l/kg. Levomepromazine is lipophilic and easily crosses the blood-brain barrier and the placenta, and can also be found in the milk of breast-feeding mothers. Liquor concentration usually exceeds the plasma concentrations.
• Metabolism : Levomepromazine is metabolized in the liver to a sulfoxide, a glucuronide, and a demethylated metabolite.
• Elimination : Drug elimination (as metabolites, only 1% of unchanged levomepromazine is recovered) is relatively slow. The metabolites are found in feces and urine.

Mechanism of action

Levomepromazine blocks the following postsynaptic receptors:

• • strong : ACh, Alpha₁, 5-HT_2a
  • moderate : H₁
  • weak : D₂/D₃
  • unknown : D₄, Alpha₂, 5-HT_1a

The mode of action explains the particular pharmacological effects of levomepromazine.

Interactions

Dosages of concomitantly administered opioids should be reduced by approximately half, because levomepromazine amplifies the therapeutic actions and side-effects of opioids. Combination with tramadol (Ultram) is associated with increased risk of seizures.

Additive sedative effects and confusional states may emerge if levomepromazine is given with benzodiazepines or barbiturates. This may be avoided by using the lowest dose possible with the substances in question.

Exert particular caution in combining levomepromazine with other anticholinergic drugs (tricyclic antidepressants and antiparkinsonian-agents): Particularly the elderly may develop delirium, high fever, severe obstipation, even ileus and glaucoma. Reduce both the dose of levomepromazine and the dose of the other drug. If possible, avoid such combinations.

Caffeine and/or stimulants of the ephedrine/amphetamine type may counteract the specific actions of levomepromazine. Concomitant use of these substances should be avoided.

Coffee and black tea should be avoided because they decrease the absorption of levomepromazine considerably. The same is true for antacids; these should be given 1 to 2 hours before or after oral administration of levomepromazine.

References

• PubChem Substance Summary: Levomepromazine National Center for Biotechnology Information.
• NOZINAN - Lévomépromazine Doctissimo Guides des Medicaments