Flupenthixol

Usage

Flupenthixol is prescribed for the maintenance therapy of chronic schizophrenia in patients whose primary symptoms do not include prominent excitement, agitation, or hyperactivity. It can also be used in the treatment of depressive illness (with or without anxiety), and as a short-term adjunctive treatment for severe anxiety. Its pharmacological classification is as a thioxanthene antipsychotic. Flupenthixol’s mechanism of action involves dopamine D1 and D2 receptor antagonism, although the precise mechanism underlying its antipsychotic effects remains unclear. It’s less sedating and hypotensive compared to some other antipsychotics but carries a higher risk of extrapyramidal side effects.

Alternate Names

Flupenthixol is also known as flupentixol decanoate (depot formulation). Brand names include Depixol, Fluanxol, and Emergil.

How It Works

Pharmacodynamics: Flupenthixol primarily acts as a dopamine D1 and D2 receptor antagonist. It shares similarities with the phenothiazine fluphenazine. Its antipsychotic effect likely stems from its action on dopaminergic pathways in the brain.

Pharmacokinetics:

• Absorption: Flupenthixol decanoate, administered intramuscularly, forms a depot at the injection site, allowing slow release and prolonged action. Peak plasma concentrations are typically reached between 4 and 7 days post-injection.
• Metabolism: While specific metabolic pathways haven’t been fully elucidated, it’s known that flupenthixol is metabolized in the liver, with metabolites considered largely inactive.
• Elimination: The elimination half-life varies significantly between individuals, contributing to the necessity for individualized dosing.

Mode of Action/Receptor Binding: Flupenthixol primarily blocks dopamine D1 and D2 receptors, though it can affect other receptors to a lesser degree. This blockade is thought to be the basis for its therapeutic effects in schizophrenia.

Elimination Pathways: While precise details on elimination haven’t been fully described, it’s likely to involve a combination of hepatic metabolism and renal excretion.

Dosage

Standard Dosage

Adults:

• Oral: Initial dose is typically 1 mg daily, increasing as needed up to a maximum of 3 mg daily. Doses above 2 mg should be divided.
• Intramuscular (Depot): An initial test dose of 20 mg is common, followed by 20-40 mg every 2-4 weeks. Dosage is adjusted based on patient response. Some patients may require doses up to 400 mg weekly.

Children: Flupenthixol is not recommended for use in children due to a lack of clinical data establishing safety and efficacy in this population.

Special Cases:

• Elderly Patients: Start with a lower dose (e.g., 0.5 mg orally or a reduced initial depot dose) and titrate cautiously due to increased sensitivity and potential for age-related organ dysfunction.
• Patients with Renal Impairment: Flupenthixol has not been extensively studied in patients with renal impairment, but increased cerebral sensitivity should be considered. Dose adjustments may be necessary.
• Patients with Hepatic Dysfunction: Flupenthixol has not been studied in patients with hepatic impairment, therefore dosage adjustments based on close monitoring of side effects or drug levels may be required.
• Patients with Comorbid Conditions: Caution is necessary in patients with epilepsy, diabetes, Parkinson’s disease, glaucoma, or cardiovascular, liver, kidney, thyroid, or prostate problems.

Clinical Use Cases

Flupenthixol’s primary indication is for maintenance therapy in chronic schizophrenia, not for acute management of conditions like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations.

Dosage Adjustments

Dosage adjustments are based on individual patient response and tolerability. Monitor closely for adverse effects, particularly extrapyramidal symptoms. Renal or hepatic dysfunction may necessitate further adjustments, but specific guidelines are limited due to insufficient study in these populations.

Side Effects

Common Side Effects

Constipation, dizziness, drowsiness, increased appetite/weight gain, dry mouth, extrapyramidal symptoms (muscle stiffness, tremors, restlessness), and injection site pain.

Rare but Serious Side Effects

Neuroleptic malignant syndrome (NMS), tardive dyskinesia, seizures, QTc prolongation and arrhythmias, liver damage, blood dyscrasias (agranulocytosis, neutropenia, thrombocytopenia), hyperprolactinemia, and allergic reactions.

Long-Term Effects

Tardive dyskinesia can be a persistent and potentially irreversible movement disorder with long-term flupenthixol use. Hyperprolactinemia can lead to decreased bone mineral density with prolonged exposure.

Adverse Drug Reactions (ADR)

NMS, severe extrapyramidal reactions, and significant QTc prolongation require immediate medical attention.

Contraindications

Hypersensitivity to thioxanthenes, CNS depression from any cause, circulatory collapse, coma, subcortical brain damage, blood dyscrasias, pheochromocytoma, and concurrent use with drugs known to prolong the QTc interval.

Drug Interactions

Flupenthixol can interact with a wide array of drugs, including other antipsychotics, antidepressants (especially tricyclics and SSRIs), antiarrhythmics (e.g., quinidine, amiodarone), antibiotics (e.g., erythromycin, moxifloxacin), levodopa, antihypertensives like guanethidine, CNS depressants (e.g., alcohol, barbiturates, opioids), and drugs with anticholinergic effects. These interactions can lead to increased side effects, decreased efficacy, or potentially life-threatening complications.

Pregnancy and Breastfeeding

Flupenthixol is generally avoided during pregnancy due to potential risks to the fetus, especially in the third trimester (extrapyramidal and withdrawal symptoms in newborns). Its use should only be considered if the potential benefit outweighs the risk. Flupenthixol is excreted in breast milk. Although limited data suggest relatively low levels with maternal use, breastfeeding is generally not recommended due to potential adverse effects on the infant.

Drug Profile Summary

• Mechanism of Action: Dopamine D1 and D2 receptor antagonist.
• Side Effects: Extrapyramidal symptoms, drowsiness, dry mouth, constipation, weight gain, tardive dyskinesia, NMS.
• Contraindications: Hypersensitivity, CNS depression, coma, subcortical brain damage, blood dyscrasias, pheochromocytoma, concomitant use with QTc-prolonging drugs.
• Drug Interactions: Numerous interactions with other medications (see Drug Interactions section).
• Pregnancy & Breastfeeding: Generally avoided.
• Dosage: Individualized, starting low and titrating. See detailed dosage section above.
• Monitoring Parameters: Extrapyramidal symptoms, prolactin levels, QTc interval, liver function tests, complete blood count.

Popular Combinations

Flupenthixol is not typically used in combination with other antipsychotics. Adjunctive use of anticholinergics or benzodiazepines may be necessary for managing extrapyramidal symptoms or severe agitation, respectively. However, these should be used cautiously.

Precautions

• General Precautions: Screen for pre-existing medical conditions, including cardiovascular, liver, and renal disease.
• Specific Populations: Avoid in pregnancy and breastfeeding if possible. Exercise caution in the elderly and children.
• Lifestyle Considerations: Advise patients against alcohol consumption during treatment, as this may exacerbate side effects.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Flupenthixol?

A: Dosage is highly individualized. Oral: Adults initially 1 mg daily, increased up to a maximum of 3 mg/day. Elderly initially 0.5 mg daily, max 1.5 mg/day. Intramuscular (Depot): Adults initially 20 mg test dose, then 20-40 mg every 2-4 weeks, adjustable up to a maximum of 400 mg per week. Dosage in the elderly should be lower and initiated cautiously. Not recommended for children.

Q2: What are the most common side effects of Flupenthixol?

A: Extrapyramidal symptoms, drowsiness, dry mouth, constipation, weight gain, and injection site pain (depot formulation).

Q3: What are the serious side effects of Flupenthixol that require urgent medical attention?

A: Neuroleptic malignant syndrome (NMS), tardive dyskinesia, severe extrapyramidal reactions, and significant QTc prolongation.

Q4: What are the contraindications for Flupenthixol?

A: Hypersensitivity to thioxanthenes, CNS depression, coma, subcortical brain damage, blood dyscrasias, pheochromocytoma, concomitant use with QTc-prolonging drugs.

Q5: Can Flupenthixol be used during pregnancy or breastfeeding?

A: Generally avoided due to potential fetal risks (especially in the third trimester) and excretion in breast milk. Use only if benefits outweigh the risks.

Q6: What are the important drug interactions to be aware of with Flupenthixol?

A: Numerous, including interactions with other antipsychotics, antidepressants, antiarrhythmics, antibiotics, levodopa, antihypertensives, and CNS depressants (including alcohol). Consult a comprehensive drug interaction resource for details.

Q7: What is the mechanism of action of Flupenthixol?

A: Primarily acts as a dopamine D1 and D2 receptor antagonist.

Q8: How should Flupenthixol be administered?

A: Available in oral tablets and as a long-acting intramuscular (depot) injection.

Q9: What monitoring parameters are important for patients on Flupenthixol?

A: Extrapyramidal symptoms, prolactin levels, QTc interval, liver function tests, and complete blood count.

Q10: What is the difference between flupenthixol and flupenthixol decanoate?

A: Flupenthixol refers to the active ingredient. Flupenthixol decanoate is the ester form used in the depot injection formulation, which provides slow release and prolonged action.