Usage
- Sertindole is an atypical antipsychotic medication primarily prescribed for the treatment of schizophrenia in adult patients who have shown intolerance to at least one other antipsychotic agent.
- Pharmacological Classification: Atypical antipsychotic.
- Mechanism of Action: Sertindole acts by antagonizing dopamine D2, alpha1-adrenergic, and serotonin 5-HT2 receptors. It has a high affinity for these receptors, contributing to its antipsychotic effects. It has less potent effects on muscarinic receptors compared to older antipsychotics.
Alternate Names
- International Nonproprietary Name (INN): Sertindole
- Brand Name: Serdolect
How It Works
- Pharmacodynamics: Sertindole primarily affects dopamine D2, serotonin 5HT2A and alpha1-adrenergic receptors. It shows negligible effects on muscarinic and histaminic H1 receptors, which explains the lower incidence of related side effects.
- Pharmacokinetics: Sertindole is well-absorbed orally, but absorption is slow. The drug is extensively metabolized in the liver primarily by CYP2D6 and CYP3A4 enzymes. The elimination half-life is long (53–102 hours) allowing once daily dosing. Excretion mainly occurs via feces.
- Mode of Action: Sertindole binds to and blocks dopamine D2 receptors in the mesolimbic and mesocortical pathways of the brain. This action helps reduce the excessive dopamine activity thought to be involved in the positive symptoms of schizophrenia (hallucinations, delusions, disorganized thoughts). It also binds to serotonin 5-HT2A receptors and alpha-1-adrenergic receptors, which may contribute to its overall therapeutic profile including improvement in negative symptoms and reduction in extrapyramidal side effects.
- Elimination pathways: Primarily hepatic metabolism by CYP2D6 and CYP3A4, followed by fecal excretion and minor urinary excretion.
Dosage
Standard Dosage
Adults:
- Initial dose: 4 mg orally once daily.
- Titration: Increase the dose in 4 mg increments every 4–5 days until the optimal maintenance dose (12-20 mg/day) is achieved.
- Maximum dose: 24 mg/day in exceptional cases only.
Children:
- Sertindole is not recommended for use in children and adolescents due to lack of data on safety and efficacy.
Special Cases:
- Elderly Patients: Slower dose titration and lower maintenance doses are recommended due to increased sensitivity to orthostatic hypotension. Thorough cardiovascular examination is required before initiating treatment.
- Patients with Renal Impairment: Dose adjustment is not generally required.
- Patients with Hepatic Dysfunction: For mild to moderate impairment, slower dose titration and lower maintenance doses are recommended. Sertindole is contraindicated in patients with severe hepatic impairment.
- Patients with Comorbid Conditions: Pre-existing cardiovascular disease (including CHF, cardiac hypertrophy, arrhythmia, bradycardia, or congenital long QT syndrome), uncorrected hypokalemia or hypomagnesemia are contraindications to Sertindole. Use with caution in patients with a history of seizures, Parkinson’s disease, conditions that may elevate core body temperature, or those at risk for aspiration pneumonia.
Clinical Use Cases
Sertindole is not indicated for the treatment of dementia-related psychosis. Dosages in situations like intubation, surgical procedures, mechanical ventilation, ICU use, and other emergencies have not been established. Its long half-life makes it unsuitable for acute management of emergency psychiatric conditions.
Dosage Adjustments
Dose adjustments are based on patient response, tolerability, and potential drug interactions. If treatment interruption exceeds one week, re-titration is necessary.
Side Effects
Common Side Effects:
- Headache
- Dizziness
- Insomnia
- Dry mouth
- Nasal congestion
- Rhinitis
- Weight gain
- Orthostatic hypotension
- Ejaculation failure
- Sexual dysfunction
Rare but Serious Side Effects:
- QT interval prolongation
- Torsade de Pointes
- Neuroleptic malignant syndrome
- Seizures
- Tardive dyskinesia
Long-Term Effects:
- Weight gain, dyslipidemia, and hyperglycemia can occur with long-term use, increasing the risk of metabolic syndrome and cardiovascular complications. Tardive dyskinesia may develop, but this side effect is less common with atypical antipsychotics such as Sertindole.
Adverse Drug Reactions (ADR):
- Any sign of QT interval prolongation or cardiac arrhythmias (palpitations, dizziness, syncope), extrapyramidal symptoms (muscle rigidity, tremor, restlessness), or neuroleptic malignant syndrome (fever, muscle rigidity, altered mental status) requires urgent medical attention.
Contraindications
- Congenital long QT syndrome
- Acquired QT interval prolongation
- Clinically significant cardiovascular disease
- Severe hepatic impairment
- Uncorrected hypokalemia or hypomagnesemia
- Concomitant use with potent CYP3A4 inhibitors or drugs known to prolong the QT interval
- Hypersensitivity to sertindole
Drug Interactions
- CYP450 Interactions: Sertindole is primarily metabolized by CYP2D6 and CYP3A4. Avoid concomitant use with strong CYP3A4 inhibitors (e.g., ketoconazole, erythromycin, clarithromycin). Concomitant use with CYP2D6 inhibitors (e.g., fluoxetine, paroxetine) requires caution and possible dose reduction of Sertindole.
- Other Interactions: Drugs that prolong the QT interval (e.g., certain antibiotics, antifungals, antipsychotics) should be avoided. Anticholinergics may reduce the efficacy of Sertindole, while antihypertensives might enhance its hypotensive effects.
- Food/Lifestyle: Alcohol and smoking can alter Sertindole levels. Grapefruit juice can inhibit CYP3A4 and increase the risk of adverse effects.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: C (No controlled studies in pregnant women. Use only if the potential benefit justifies the potential risk to the fetus). Animal studies have not demonstrated teratogenic effects.
- Fetal Risks: Potential but poorly characterized risks to the developing fetus. Close monitoring of newborns is recommended if exposure occurs during pregnancy.
- Breastfeeding: Sertindole is present in breast milk. Consider risks and benefits for the infant and offer alternatives if necessary.
Drug Profile Summary
- Mechanism of Action: Dopamine D2, serotonin 5HT2A and alpha1-adrenergic receptor antagonist.
- Side Effects: Headache, dizziness, insomnia, dry mouth, nasal congestion, weight gain, QT prolongation, orthostatic hypotension, ejaculatory dysfunction.
- Contraindications: Long QT syndrome, cardiovascular disease, severe hepatic impairment, uncorrected hypokalemia or hypomagnesemia.
- Drug Interactions: CYP3A4 and CYP2D6 inhibitors, QT prolonging drugs.
- Pregnancy & Breastfeeding: Category C; present in breast milk.
- Dosage: Adults: 4 mg initially, titrated to 12-20 mg/day (max 24 mg/day). Not recommended for children.
- Monitoring Parameters: ECG (QT interval), blood pressure, weight, blood glucose, and lipids.
Popular Combinations
Limited information is available on commonly used combinations with Sertindole. Combined use with other antipsychotics and agents altering QT interval should be approached with caution.
Precautions
- General Precautions: Cardiovascular evaluation, ECG before and during treatment, electrolyte monitoring (potassium, magnesium). Monitor for extrapyramidal symptoms, metabolic changes (weight, glucose, lipids), and neuroleptic malignant syndrome.
- Specific Populations: Caution in elderly and patients with hepatic impairment. Avoid in severe liver disease and during pregnancy or breastfeeding unless absolutely necessary.
- Lifestyle Considerations: Limit alcohol. Advise against driving and operating machinery until response to therapy is clear.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Sertindole?
A: Adults: Initial 4mg/day, titrate up to 12-20mg/day; max 24 mg/day. Not recommended for children.
Q2: What is the primary indication for Sertindole?
A: Schizophrenia in adults intolerant to other antipsychotics.
Q3: What are the most serious side effects of Sertindole?
A: QT prolongation, Torsade de Pointes, neuroleptic malignant syndrome.
Q4: What are the common side effects of Sertindole?
A: Headache, dizziness, insomnia, dry mouth, nasal congestion, rhinitis, sexual dysfunction.
Q5: What are the key drug interactions to be aware of with Sertindole?
A: CYP3A4 inhibitors (ketoconazole, erythromycin), CYP2D6 inhibitors (fluoxetine, paroxetine), QT prolonging drugs.
Q6: Can Sertindole be used during pregnancy or breastfeeding?
A: Pregnancy Category C. Use only if potential benefit outweighs risk. Present in breast milk. Use with caution or consider alternative if available.
Q7: What pre-treatment evaluations are essential before starting Sertindole?
A: ECG, electrolyte levels (potassium, magnesium), cardiovascular assessment.
Q8: What is the mechanism of action of Sertindole?
A: Antagonism of dopamine D2, serotonin 5-HT2A, and alpha1-adrenergic receptors.
Q9: How should Sertindole be administered?
A: Orally, once daily.
