Levomepromazine

Levomepromazine

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File:Levomepromazine3d.png
Clinical data
Pregnancy category	Only if clearly needed
Routes of administration	oral, seldom i.m.
ATC code	N05AA02 (WHO)
Legal status
Legal status	Rx-only (n.a. in the USA)
Pharmacokinetic data
Bioavailability	approx. 50 to 60%
Metabolism	Hepatic
Elimination half-life	~ 20 hours
Excretion	feces and urine (metabolites), unchanged drug only 1%
Identifiers
IUPAC name (2R)-3-(2-Methoxyphenothiazine-10-yl-)-N,N,2-trimethylpropanamine
CAS Number	60-99-1 (7104-38-3 [maleate], 1236-99-3 [HCl])
PubChem CID	72287
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}
Chemical and physical data
Formula	C19H24N2OS
Molar mass	328.473 g/mol

General Remarks and Pharmacology

Levomepromazine in Germany and Methotrimeprazine in America (Sold as Nosinan® Nozinan®, Levoprome®) is an aliphatic phenothiazine neuroleptic drug. It is a low potent antipsychotic (approximately half as potent as chlorpromazine). It has strong analgesic and also strong antiemetic properties. Serious side effects include tardive dyskinesia and the potentially fatal neuroleptic malignant syndrome. Patient willingness to take this drug is low because of the agonizing side effect of akathisia. It is an aliphatic compound combined with phenothiazine which was introduced by Dupont as an insecticide in 1935. It exerts its actions through a central adrenergic-blocking, a dopamine-blocking, a serotonin-blocking, and a anticholinergic blocking.

• Absorption, and other characteristics : Levomepromazine has an incomplete oral bioavailability, because it undergoes considerable first-pass-metabolism in the liver. It has a halflife 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. Levomepromazin is lipophilic and crosses easily 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 and degraded to a Sulfoxid-, a Glucuronid- and a Demethyl-moiety.
• Elimination : Drug elimination (as metabolites, only 1% of unchanged levomepromazin is recovered) is relatively slow. The metabolites are found in feces and urine.
• Mode of Action : Levomepromazine blocks the following postsynaptic receptors:
  • strong : ACh, Alpha1, 5-HT2a
  • moderate : H1
  • weak : D2/D3
  • unknown : D4, Alpha2, 5-HT1a

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

Currently, levomepromazine is not registered in the USA. In Europe it has been marketed for decades as Neurocil® and Nozinan®. Nozinan® is also available in Canada.

Some American physicians are currently conducting studies regarding the strong analgesic effect of levomepromazine.

Indications

Levomepromazine is used for the treatment of psychosis, particular those of schizophrenia, and manic phases of bipolar disorder. It should never be used in the treatment of agitated depressions because this drug increases agitation through the side effect of akathisia.

Side effects

The most commonly complained about side effect is the agonizing akathisia. Levomepromazine has prominent sedative and anticholinergic/sympatholytic effects (dry mouth, hypotension, sinus tachycardia, extreme night sweats) and causes massive 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.

Other symptoms include muscle stiffness, fever and neuroleptic malignant syndrome.

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 stimulantes 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 leveomepromazine.

References

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