Flupenthixole

Uses

Psychoses, Depression with or without anxiety, Psychoses

Flupenthixole is also used to associated treatment for these conditions: Chronic Schizophrenia, Depression, Dysphoria, Neurasthenia

How Flupenthixole works

The mechanism of action of flupentixol is not completely understood. The antipsychotic actions are mainly thought to arise from cis(Z)-flupentixol, the active stereoisomer, acting as an antagonist at both dopamine D₁ and D₂ receptors with equal affinities. Schizophrenia is a mental illness characterized by positive (such as hallucinations and delusions) and negative (such as affect flattening and apathy) symptoms. While several neurotransmitter systems are implicated in the pathophysiologic processes leading to the development of symptoms, the dopamine and glutamate systems have been extensively studied. It is generally understood that positive symptoms of schizophrenia arise from a dysregulated striatal dopamine pathway, leading to hyperstimulation of D₂ receptors. Many antipsychotic agents work by blocking D₂ receptors as antagonists; similarly, cis(Z)-flupentixol, the active stereoisomer, is an antagonist at D₂ receptors. However, there is now evidence that antipsychotic agents can work by blocking other dopamine receptor subtypes, such as D₁, D₃, or D₄ receptors. One study showed that cis(Z)-flupentixol is an antagonist at both dopamine D₁ and D₂ receptors with equal affinities, and binds to D3 and D4 receptors with lower affinities. It also binds to alpha-1 adrenoceptors. Antidepressant effects of flupentixol are understood to be mediated by antagonism at 5-HT_2A receptors, which are commonly downregulated following repeated antidepressant treatment. Flupenthixole also binds to 5-HT_2C receptors.

Dosage

Flupenthixole dosage

Oral-Depression with or without anxiety:

• Adult: Initially, 1 mg daily increased after 1 wk to 2 mg daily and then to a max of 3 mg daily, last dose should be given not later than 4 p.m. Doses >2 mg should be given in 2 divided doses. Discontinue treatment if there is no improvement within 1 wk of using the max dose.
• Elderly: Initially, 0.5 mg daily increased after 1 wk to 1 mg daily with the last dose given not later than 4 p.m. Max: 2 mg daily in 2 divided doses.

Oral-

Psychoses:

• Adult: Initially, 3-9 mg bid, adjusted according to response. Max: 18 mg daily.
• Elderly: Initial dose: ¼ or ½ of the usual initial dose.

Intramuscular-

Psychoses:

• Adult:Initially, 20 mg (1 ml of a 2% oily solution) is given as test dose. After at least 7 days and depending on the response, subsequent doses of 20-40 mg may be given at intervals of 2-4 wk. Usual maintenance dose: 50 mg every 4 wk to 300 mg every 2 wk. Up to 400 mg wkly may be used in severe or resistant cases.
• Elderly: Initial dose: ¼ or ½ of the usual initial dose.

Side Effects

Rigidity, tremors, restlessness, tardive dyskinesia, insomnia, dryness of mouth, wt gain, sexual dysfunction, galactorrhoea and menstrual disturbances.

Potentially Fatal: Neuroleptic malignant syndrome (hyperthermia, hypertonicity of skeletal muscles, unconsciousness and autonomic nervous system instability).

Toxicity

The oral LD₅₀ is 423 mg/kg in mice and 791 mg/kg in rats. The intravenous LD₅₀ is 37 mg/kg in rats.[L31873]

Flupenthixole overdose is characterized by sedation, frequently preceded by extreme agitation, excitement, confusion, somnolence, coma, convulsions, and hyperthermia or hypothermia. Extrapyramidal symptoms or respiratory and circulatory collapse may be observed. ECG changes, QT prolongation, Torsades de Pointes, cardiac arrest and ventricular arrhythmias have been reported from the combined use of drugs known to affect the heart with large doses of flupentixol. In case of overdose, symptomatic treatment should be initiated with airway management. In case of severe hypotension, epinephrine should not be used: instead, intravenous vasopressor drugs, such as levarterenol, can be used. Antiparkinsonian medication should be administered only if extrapyramidal symptoms develop. Gastric lavage should be initiated in the case of flupentixol tablet overdose. Further injections of flupentixol should be discontinued in case of an intramuscularly-administered drug overdose until the patient shows signs of relapse, in which the dosage can subsequently be decreased.

Neuroleptic malignant syndrome is associated with neuroleptic drugs, which should be responded to with immediate discontinuation of the drug and initiation of symptomatic treatment and medical monitoring.

Precaution

Patients with convulsive disorders; advanced hepatic, renal, CV or resp disease; tasks requiring mental alertness; elderly (especially with dementia), and debilitated patients; neuroleptics with sedative effect must be withdrawn gradually; history of angle-closure glaucoma; urinary retention; prostatic hyperplasia; breast cancer, prolactin dependent tumours; parkinsonism; myasthenia gravis; pregnancy; Avoid direct sunlight.

Interaction

May potentiate the adverse effects of drugs with antimuscarinic effects e.g. TCAs. Reduced efficacy of levodopa. Increases adverse extrapyramidal symptoms with dopamine antagonists (metoclopramide and prochlorperazine).

Food Interaction

• Avoid alcohol. Flupenthixole can enhance the sedative effects of alcohol.
• Take with or without food. Food has negligible effects on drug pharmacokinetics.

Volume of Distribution

The apparent volume of distribution is about 14.1 L/kg. Following administration, the highest levels of flupentixol are found in the lungs, liver, and spleen. Lower concentrations of the drug are found in the blood and brain.

Elimination Route

Following oral administration, flupentixol is readily absorbed from the gastrointestinal tract, with oral bioavailability of about 40%. T_max ranges from three to eight hours. Steady-state plasma levels are achieved in about seven days and following once-daily oral administration of 5 mg flupentixol, the mean minimum steady-state level was about 1.7 ng/mL (3.9 nmol/L).

From the site of intramuscular injection, esterified flupentixol diffuses slowly from the oil solution and is slowly released into the extracellular fluid and the circulation to be distributed to different tissues. Peak drug concentrations are reached between four and seven days following intramuscular injection. Intramuscularly administered flupentixol is detectable in the blood three weeks after injection and reaches steady-state concentrations after about three months of repeated administration.

Half Life

The elimination half-life is about 35 hours following oral administration and three weeks following intramuscular administration.

Clearance

Following oral administration, the mean systemic clearance is about 0.29 L/min.

Elimination Route

Fecal excretion is more predominant than renal excretion. In the feces, flupentixol is recovered in the feces mainly as the unchanged form, as well as its lipophilic metabolites, such as dealkyl-flupentixol. Flupenthixole is recovered in the urine as the unchanged form as well as its hydrophilic sulfoxide and glucuronide metabolites.

Pregnancy & Breastfeeding use

Category C: Either studies in animals have revealed adverse effects on the foetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the foetus

Contraindication

Hypersensitivity. Extremely excitable and overactive patients; mania; porphyria; coma; preexisting CNS depression; bone-marrow supression; phaeochromocytoma. Lactation.

Storage Condition

Store below 25° C.

Innovators Monograph

You find simplified version here Flupenthixole