Levomepromazine
Encyclopedia
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 receptor
s, including adrenergic receptor
s, dopamine receptor
s, histamine receptor
s, muscarinic acetylcholine receptor
s, 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. 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.
, particular those of schizophrenia
, and manic
phases of bipolar disorder
. It should be used only with caution in the treatment of agitated depression
s, 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.
. 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.
The mode of action explains the particular pharmacological effects of levomepromazine.
s 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 seizure
s.
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.
Phenothiazine
Phenothiazine is an organic compound that occurs in various antipsychotic and antihistaminic drugs. It has the formula S2NH. This yellow tricyclic compound is soluble in acetic acid, benzene, and ether. The compound is related to the thiazine-class of heterocyclic compounds...
neuroleptic drug
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
. It is a low-potency antipsychotic (approximately half as potent as chlorpromazine
Chlorpromazine
Chlorpromazine is a typical antipsychotic...
) with strong analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
and antiemetic
Antiemetic
An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer....
properties.
Serious side effects include tardive dyskinesia
Tardive dyskinesia
Tardive dyskinesia is a difficult-to-treat form of dyskinesia that can be tardive...
, akathisia
Akathisia
Akathisia, or acathisia, is a syndrome characterized by unpleasant sensations of inner restlessness that manifests itself with an inability to sit still or remain motionless...
, and the potentially fatal neuroleptic malignant syndrome
Neuroleptic malignant syndrome
Neuroleptic malignant syndrome is a life- threatening neurological disorder most often caused by an adverse reaction to neuroleptic or antipsychotic drugs...
.
As is typical of phenothiazine antipsychotics, levomepromazine is a "dirty drug
Dirty drug
A dirty drug is an informal term used in pharmacology to describe drugs that may bind to many different molecular targets or receptors in the body, and so tend to have a wide range of effects and possibly negative side effects...
": it exerts its effects by blocking
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
a variety of receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
s, including adrenergic receptor
Adrenergic receptor
The adrenergic receptors are a class of metabotropic G protein-coupled receptors that are targets of the catecholamines, especially noradrenaline and adrenaline ....
s, dopamine receptor
Dopamine receptor
Dopamine receptors are a class of metabotropic G protein-coupled receptors that are prominent in the vertebrate central nervous system . The neurotransmitter dopamine is the primary endogenous ligand for dopamine receptors....
s, histamine receptor
Histamine receptor
The histamine receptors are a class of G protein-coupled receptors with histamine as their endogenous ligand.There are four known histamine receptors:*H1 receptor*H2 receptor*H3 receptor*H4 receptor-Comparison:...
s, muscarinic acetylcholine receptor
Muscarinic acetylcholine receptor
Muscarinic receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled in the plasma membranes of certain neurons and other cells...
s, 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. 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 psychosisPsychosis
Psychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...
, particular those of schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
, and manic
Manic
Manić is a suburban settlement of Belgrade, the capital of Serbia. It is located in the municipality of Barajevo.Manić developed on the eastern slopes of the Kosmaj mountain...
phases of bipolar disorder
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
. It should be used only with caution in the treatment of agitated depression
Clinical depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
s, as it can cause akathisia
Akathisia
Akathisia, or acathisia, is a syndrome characterized by unpleasant sensations of inner restlessness that manifests itself with an inability to sit still or remain motionless...
as a side effect, which could worsen the agitation.
Levomepromazine is also used at lower doses for the treatment of nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
and insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
.
In Europe it is approved for the treatment of chronic idiopathic pain.
Adverse effects
The most common side effect is akathisiaAkathisia
Akathisia, or acathisia, is a syndrome characterized by unpleasant sensations of inner restlessness that manifests itself with an inability to sit still or remain motionless...
. Levomepromazine has prominent sedative
Sedative
A sedative or tranquilizer is a substance that induces sedation by reducing irritability or excitement....
and anticholinergic
Anticholinergic
An anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. An example of an anticholinergic is dicycloverine, and the classic example is atropine....
/sympatholytic
Sympatholytic
A sympatholytic drug is a medication which inhibits the postganglionic functioning of the sympathetic nervous system . They are indicated for various functions, for example they may be used as antihypertensives...
effects (dry mouth, hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
, sinus tachycardia
Sinus tachycardia
Sinus tachycardia is a heart rhythm with elevated rate of impulses originating from the sinoatrial node, defined as a rate greater than 100 beats/min in an average adult. The normal heart rate in the average adult ranges from 60–100 beats/min...
, 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
Neuroleptic malignant syndrome
Neuroleptic malignant syndrome is a life- threatening neurological disorder most often caused by an adverse reaction to neuroleptic or antipsychotic drugs...
(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 lipophilicLipophilicLipophilicity, , refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. These non-polar solvents are themselves lipophilic — the axiom that like dissolves like generally holds true...
and easily crosses the blood-brain barrierBlood-brain barrierThe blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
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 sulfoxideSulfoxideA sulfoxide is a chemical compound containing a sulfinyl functional group attached to two carbon atoms. Sulfoxides can be considered as oxidized sulfides...
, a glucuronideGlucuronideA glucuronide, also known as glucuronoside, is any substance produced by linking glucuronic acid to another substance via a glycosidic bond...
, and a demethylatedDemethylationDemethylation is the chemical process resulting in the removal a of methyl group from a molecule.A common way of demethylation is the replacement of a methyl group by a hydrogen atom, resulting in a net loss of one carbon and two hydrogen atoms....
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 : AChAcetylcholine receptorAn acetylcholine receptor is an integral membrane protein that responds to the binding of acetylcholine, a neurotransmitter.-Classification:...
, Alpha1Alpha-1 adrenergic receptorThe alpha-1 adrenergic receptor is a G protein-coupled receptor associated with the Gq heterotrimeric G-protein. It consists of three highly homologous subtypes, including α1A-, α1B-, and α1D-adrenergic...
, 5-HT2a5-HT2A receptorThe mammalian 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor . This is the main excitatory receptor subtype among the GPCRs for serotonin , although 5-HT2A may also have an inhibitory effect on certain areas such... - moderate : H1
- weak : D2Dopamine receptorDopamine receptors are a class of metabotropic G protein-coupled receptors that are prominent in the vertebrate central nervous system . The neurotransmitter dopamine is the primary endogenous ligand for dopamine receptors....
/D3Dopamine receptorDopamine receptors are a class of metabotropic G protein-coupled receptors that are prominent in the vertebrate central nervous system . The neurotransmitter dopamine is the primary endogenous ligand for dopamine receptors.... - unknown : D4Dopamine receptorDopamine receptors are a class of metabotropic G protein-coupled receptors that are prominent in the vertebrate central nervous system . The neurotransmitter dopamine is the primary endogenous ligand for dopamine receptors....
, Alpha2Alpha-2 adrenergic receptorThe alpha-2 adrenergic receptor is a G protein-coupled receptor associated with the Gi heterotrimeric G-protein. It consists of three highly homologous subtypes, including α2A-, α2B-, and α2C-adrenergic. Some species other than humans express a fourth α2D-adrenergic receptor as well...
, 5-HT1a5-HT receptorThe serotonin receptors, also known as 5-hydroxytryptamine receptors or 5-HT receptors, are a group of G protein-coupled receptors and ligand-gated ion channels found in the central and peripheral nervous systems. They mediate both excitatory and inhibitory neurotransmission...
- strong : ACh
The mode of action explains the particular pharmacological effects of levomepromazine.
Interactions
Dosages of concomitantly administered opioidOpioid
An opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...
s should be reduced by approximately half, because levomepromazine amplifies the therapeutic actions and side-effects of opioids. Combination with tramadol
Tramadol
Tramadol hydrochloride is a centrally acting synthetic opioid analgesic used in treating moderate pain. The drug has a wide range of applications, including treatment for restless legs syndrome and fibromyalgia...
(Ultram) is associated with increased risk of seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s.
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
Ileus
Ileus is a disruption of the normal propulsive ability of the gastrointestinal tract.Ileus is commonly defined simply as bowel obstruction. However, authoritative sources define it as decreased motor activity of the GI tract due to non-mechanical causes...
and glaucoma
Glaucoma
Glaucoma is an eye disorder in which the optic nerve suffers damage, permanently damaging vision in the affected eye and progressing to complete blindness if untreated. It is often, but not always, associated with increased pressure of the fluid in the eye...
. 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.