PENTIXOL 40

Indications

• Psychoses
• Schizophrenia
• Depressive illness
• Accommodation disorder
• Palliative care

Dosage

Children: Refer to

Adults: Initially, 1 mg once daily, to be taken in the morning. The dose may be increased to 2 mg after one week. Doses above 2 mg should be given in divided doses, with the last dose taken before 4 pm. Discontinue if there is no response after one week at maximum dosage. Maximum daily dose is 3 mg.

Mechanism of action

The mechanism of action of flupentixol is not completely understood, but it is mainly thought to involve its active stereoisomer, cis(Z)-flupentixol, acting as an antagonist at both dopamine D1 and D2 receptors with equal affinities. This action helps mitigate the positive symptoms of schizophrenia, such as hallucinations and delusions, which are linked to dopamine dysregulation. Additionally, flupentixol may exert antidepressant effects through 5-HT receptor antagonism.

Pharmacodynamics

Flupentixol has anxiolytic and mild sedative effects, along with weak anticholinergic and adrenergic properties. It serves as an antiemetic and can cause extrapyramidal side effects, especially at higher doses. The intramuscular formulation allows for slow release and prolonged action. Its rapid antidepressant effects may be observed within two to three days of administration, though it also carries risks of QTc prolongation and cardiovascular events.

Pharmacokinetics

Flupentixol is absorbed following oral administration with a bioavailability that may vary. The drug undergoes hepatic metabolism, and its plasma half-life allows for once-daily dosing in many cases. Monitoring for serum concentrations is advised, particularly in patients with hepatic impairment, as metabolism can be affected. Its effects can be prolonged due to the depot formulation in intramuscular use.

Contra-indications

• Circulatory collapse
• Severe hepatic failure
• Severe renal failure
• Acute dystonic reactions

Adverse effects

• Appetite abnormality
• Asthenia
• Concentration impaired
• Depression
• Diarrhea
• Dyspnea
• Gastrointestinal discomfort
• Headache
• Hyperhidrosis
• Hypersalivation
• Myalgia
• Nervousness
• Palpitations
• Sexual dysfunction
• Skin reactions
• Urinary disorder
• Thrombocytopenia
• Jaundice
• QT-interval prolongation
• Suicidal behaviours

Interactions

• Flupentixol + dopaminereceptor agonists: Severe (decreases effects)
• Clozapine + flupentixol: Unknown (additive effect)
• Second-generation antipsychotics + flupentixol: Unknown (additive effect)
• Flupentixol + levodopa: Unknown (decreases effects)

Precautions

• Caution in patients with hepatic impairment
• Caution in patients with renal impairment
• Monitor serum drug concentration
• Risk of extrapyramidal side effects at higher doses
• May cause QTc prolongation

Pregnancy

Avoid unless potential benefit outweighs risk.

Breast-feeding

Use with caution; potential for adverse effects in nursing infants.

Storage

Store in a cool, dry place, away from direct sunlight. Handle with care to avoid contact.

Formulations

• Tablet
• Oral solution
• Intramuscular injection
• Suppository

Mechanism of action

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. Flupentixol also binds to 5-HT_2C receptors.

Pharmacodynamics

Flupentixol is an antipsychotic agent with anxiolytic and mild sedative actions. It exerts weak anticholinergic and adrenergic effects. It possesses antiemetic actions. As flupentixol works by antagonizing dopamine actions, it can cause extrapyramidal effects, mostly at doses greater than 10 mg. In clinical trials, flupentixol-induced extrapyramidal effects have been managed with anti-Parkinsonian drugs. Drug esterification in the intramuscular formulation of the drug results in slow release of the drug from the injection site and a prolonged duration of action. Flupentixol has been investigated for use in mild to moderate depression: compared to other antidepressant agents, flupentixol has a rapid onset of action, where antidepressive effects were observed within the first two to three days after administration. As with other antipsychotic agents, flupentixol can cause QTc prolongation and increase the risk of arrhythmias. In clinical trials, flupentixol was associated with the risk of cardiovascular disease, cerebrovascular adverse events, stroke, and venous thromboembolism. Flupentixol can elevate the levels of prolactin; however, the clinical significance of hyperprolactinemia caused by neuroleptic drugs is unclear. Long-term hyperprolactinemia, when associated with hypogonadism, may lead to decreased bone mineral density in both female and male subjects. Interestingly, recent studies show that flupentixol exhibits anti-tumour properties alone or synergistically with other anticancer drugs like gefitinib. One study demonstrated that _in vitro_, flupentixol docks to the ATP binding pocket of phosphatidylinositol 3-kinase (PI3K), a lipid kinase that activates signalling pathways that are often hyperactivated in some cancers. Flupentixol inhibited the PI3K/AKT pathway and survival of lung cancer cells _in vitro_ and _in vivo_.