Flupenthixol + Nortriptyline

Usage

• Flupenthixol + Nortriptyline is prescribed for the treatment of schizophrenia and depression, particularly in cases where anxiety is a prominent feature. It’s also used in patients who have difficulty complying with oral medication regimens.
• Pharmacological Classification: This combination drug falls under two classifications:
  • Flupenthixol: Thioxanthene antipsychotic
  • Nortriptyline: Tricyclic antidepressant (TCA)
• Mechanism of Action: Flupenthixol primarily acts as a dopamine antagonist, blocking dopamine D1 and D2 receptors in the brain. This action helps manage the psychotic symptoms associated with schizophrenia. Nortriptyline, on the other hand, is a TCA that inhibits the reuptake of serotonin and norepinephrine, increasing their levels in the synaptic cleft. This contributes to the antidepressant and anxiolytic effects of the combination.

Alternate Names

While the generic name is Flupenthixol + Nortriptyline, several brand names exist depending on the region and manufacturer. Some examples of brand names are:

• Fluxip N
• Cilapam FN
• Fpx N
• No Anxit
• Delexit-N
• Zoly

How It Works

• Pharmacodynamics: Flupenthixol primarily affects dopaminergic pathways, exhibiting a high affinity for dopamine D1 and D2 receptors, and to a lesser extent, α1-adrenergic, 5-HT2, and histamine H1 receptors. Nortriptyline primarily inhibits the reuptake of serotonin and norepinephrine, increasing their availability in the synapses. Both drugs exert their effects on the central nervous system, contributing to mood regulation.

• Pharmacokinetics: Both drugs are absorbed orally. Flupenthixol is metabolized hepatically and has an elimination half-life of approximately 35 hours. Nortriptyline undergoes extensive hepatic metabolism, primarily via CYP2D6, with a half-life ranging from 18 to 90 hours. Both are excreted in the urine and feces.

• Mode of Action: Flupenthixol is a dopamine antagonist, while nortriptyline is a TCA inhibiting serotonin and norepinephrine reuptake. Flupenthixol blocks dopamine from binding to its receptors, reducing dopaminergic neurotransmission. Nortriptyline enhances serotonergic and noradrenergic signaling by increasing the availability of serotonin and norepinephrine in the synapse. Flupenthixol has a relatively high affinity for D1 and D2 receptors, as well as affinity for alpha-1 adrenergic, serotonin 5-HT2, and histamine H1 receptors.

• Elimination Pathways: Both drugs are subject to hepatic metabolism. Flupenthixol undergoes hepatic metabolism and has an elimination half-life of around 35 hours. Nortriptyline is primarily metabolized by CYP2D6 and has a variable half-life from 18 to 90 hours.

Dosage

Standard Dosage

Adults:

• Starting dose: Usually 1 mg flupenthixol and 10 mg nortriptyline in the morning.
• Maintenance dose: Can be increased up to 3 mg flupenthixol and a maximum of 150mg nortriptyline, distributed throughout the day. Titration should be gradual based on patient response.

Children:

• Not recommended for use in children.

Special Cases:

• Elderly Patients: Start with lower doses (0.5 mg flupenthixol and 10 mg nortriptyline) and titrate cautiously due to age-related changes in metabolism and increased sensitivity to side effects.
• Patients with Renal Impairment: Dose reduction is necessary for both flupenthixol and nortriptyline. For flupenthixol, consider half the usual adult dose or less. For nortriptyline, dosage adjustments are needed based on creatinine clearance.
• Patients with Hepatic Dysfunction: Dose reduction is required for both medications due to impaired metabolism.
• Patients with Comorbid Conditions: Close monitoring and dose adjustments may be necessary, especially for patients with cardiovascular disease, diabetes, glaucoma, epilepsy, or seizure disorders.

Clinical Use Cases

The combination of Flupenthixol + Nortriptyline is not typically indicated for acute medical settings such as intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. Its primary use is in the management of chronic conditions like schizophrenia and depression.

Dosage Adjustments

Dose modifications should be made based on individual patient factors such as renal or hepatic impairment, age, other medical conditions, and concurrent medications. Therapeutic drug monitoring (TDM) may be useful, especially for nortriptyline, to ensure optimal plasma levels and minimize side effects.

Side Effects

Common Side Effects:

Dry mouth, constipation, weight gain, sleepiness, orthostatic hypotension, urinary retention, blurred vision, increased heart rate, muscle stiffness, restlessness, tremors, nausea, dizziness, headache, insomnia, and extrapyramidal symptoms.

Rare but Serious Side Effects:

Neuroleptic malignant syndrome (NMS), seizures, severe allergic reactions, cardiac arrhythmias, tardive dyskinesia, and prolonged QT interval.

Long-Term Effects:

Tardive dyskinesia, weight gain, metabolic disturbances, and sexual dysfunction.

Adverse Drug Reactions (ADR):

NMS, agranulocytosis, serotonin syndrome, and severe allergic reactions require immediate medical intervention.

Contraindications

• Hypersensitivity to flupenthixol, nortriptyline, or any component of the formulation.
• Coma, circulatory collapse, subcortical brain damage, blood dyscrasias, Parkinson’s disease, dementia with Lewy bodies, pheochromocytoma, prolactin-dependent tumors, Long QT syndrome.
• Recent myocardial infarction.
• Concurrent use of MAO inhibitors.

Drug Interactions

• CNS depressants (e.g., alcohol, opioids, barbiturates): Increased sedation and respiratory depression.
• Anticholinergics: Additive anticholinergic effects.
• QT prolonging agents (e.g., certain antiarrhythmics, some antibiotics): Increased risk of Torsades de Pointes.
• CYP2D6 inhibitors or inducers: Alter nortriptyline levels.
• Antihypertensives: Enhanced hypotensive effects.
• CNS stimulants (e.g., amphetamines): Decreased efficacy of Flupenthixol.
• Other antidepressants (e.g., SSRIs, SNRIs): Increased risk of serotonin syndrome.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: Flupenthixol + Nortriptyline is generally avoided during pregnancy, especially in the first trimester, due to the potential for adverse effects on the developing fetus. Use only if the benefits outweigh the risks. Neonatal withdrawal symptoms may occur in newborns exposed to the drug in the third trimester.
• Breastfeeding: Flupenthixol and nortriptyline are excreted in breast milk. Although limited data suggest low levels in breastfed infants with maternal use of up to 4 mg flupenthixol, it is generally recommended to use caution and monitor the infant for potential side effects. Alternatives may be considered if necessary.

Drug Profile Summary

• Mechanism of Action: Flupenthixol: Dopamine antagonist; Nortriptyline: Serotonin and norepinephrine reuptake inhibitor.
• Side Effects: Dry mouth, constipation, drowsiness, orthostatic hypotension, extrapyramidal symptoms, NMS, seizures, tardive dyskinesia.
• Contraindications: Hypersensitivity, coma, circulatory collapse, recent MI, concurrent MAOI use.
• Drug Interactions: CNS depressants, anticholinergics, QT prolonging agents, CYP2D6 inhibitors/inducers.
• Pregnancy & Breastfeeding: Generally avoided during pregnancy and used with caution during breastfeeding.
• Dosage: Adults: Flupenthixol 1-3 mg/day, Nortriptyline 10-150 mg/day; elderly and patients with renal/hepatic impairment: lower doses.
• Monitoring Parameters: Mental status, blood pressure, heart rate, ECG, weight, liver enzymes, CBC, serum sodium (in at-risk populations), and extrapyramidal symptoms. TDM for nortriptyline may be considered.

Popular Combinations

Flupenthixol + Nortriptyline is itself a combination. Adding other medications should be done cautiously and with careful monitoring due to the potential for drug interactions.

Precautions

• Baseline ECG and cardiac evaluation are recommended, especially for patients with pre-existing cardiac conditions.
• Monitor for extrapyramidal symptoms and tardive dyskinesia.
• Patients should be cautioned about potential orthostatic hypotension and advised to change positions slowly.
• Avoid alcohol and other CNS depressants.
• Caution should be exercised in patients with epilepsy, glaucoma, prostatic hypertrophy, and urinary retention.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Flupenthixol + Nortriptyline?

A: The starting dose is typically 1 mg flupenthixol and 10 mg nortriptyline, with titration up to 3 mg flupenthixol and 150 mg nortriptyline based on clinical response. Lower doses are recommended for elderly patients and those with renal or hepatic impairment.

Q2: What are the most common side effects?

A: Common side effects include dry mouth, constipation, drowsiness, orthostatic hypotension, blurred vision, increased heart rate, and extrapyramidal symptoms.

Q3: What are the serious side effects to watch out for?

A: Serious side effects include neuroleptic malignant syndrome, seizures, cardiac arrhythmias, and tardive dyskinesia.

Q4: Can this combination be used during pregnancy or breastfeeding?

A: It is generally avoided during pregnancy, especially in the first trimester, and used with caution during breastfeeding.

Q5: What are the key drug interactions?

A: Important drug interactions occur with CNS depressants, anticholinergics, QT prolonging agents, CYP2D6 inhibitors/inducers, and other antidepressants.

Q6: What pre-existing conditions should be carefully considered before prescribing this drug?

A: Caution is needed in patients with cardiovascular disease, epilepsy, glaucoma, prostatic hypertrophy, urinary retention, renal or hepatic impairment, and a history of blood dyscrasias.

Q7: How should I monitor patients on Flupenthixol + Nortriptyline?

A: Monitor vital signs, mental status, ECG, weight, liver enzymes, CBC, and for extrapyramidal symptoms. TDM may be considered for nortriptyline.

Q8: How does Flupenthixol + Nortriptyline compare to other antipsychotic/antidepressant combinations?

A: This combination offers the combined benefits of a dopamine antagonist and a TCA, making it potentially suitable for patients with psychotic symptoms and prominent anxiety or depression. However, individual patient response and tolerability vary, and other combinations may be more appropriate for some individuals.

Q9: What patient education is important for this medication?

A: Patients should be advised about common side effects, serious adverse reactions, drug interactions, and the importance of adherence to the prescribed regimen. They should also be cautioned about activities requiring alertness, such as driving, until the effects of the medication are known.