Usage
- Medical Conditions: Thioridazine is prescribed for the treatment of schizophrenia in patients who have not responded to other antipsychotic medications. It may also be used for severe behavioral problems in children marked by combativeness and/or explosive hyperexcitable behavior.
- Pharmacological Classification: Thioridazine is classified as a first-generation antipsychotic (FGA) or neuroleptic, specifically a piperidine phenothiazine.
- Mechanism of Action: Thioridazine primarily acts as a dopamine D2 receptor antagonist, blocking the action of dopamine in the brain. This action helps reduce the positive symptoms of schizophrenia, such as hallucinations and delusions. It also affects other neurotransmitter systems including alpha-adrenergic, muscarinic, and histaminergic receptors.
Alternate Names
- International/Regional Variations: There are no widely used international variations of the name “Thioridazine.”
- Brand Names: Mellaril (withdrawn in several countries due to safety concerns)
How It Works
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Pharmacodynamics: Thioridazine primarily blocks dopamine D2 receptors in the mesolimbic and mesocortical pathways of the brain, leading to a reduction in psychotic symptoms. Its effects on alpha-adrenergic, muscarinic, and histaminergic receptors contribute to its sedative and hypotensive effects.
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Pharmacokinetics:
- Absorption: Thioridazine is well-absorbed orally.
- Metabolism: Extensively metabolized in the liver, primarily by CYP2D6. Poor metabolizers of CYP2D6 may experience increased drug levels and effects.
- Elimination: Excreted in urine and feces.
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Mode of Action: Binds to and blocks dopamine D2 receptors, reducing dopaminergic neurotransmission.
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Receptor Binding/Enzyme Inhibition: Antagonist at dopamine D2 receptors; may inhibit CYP2D6.
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Elimination Pathways: Primarily hepatic metabolism via CYP2D6, followed by renal and biliary excretion.
Dosage
Standard Dosage
Adults:
- Initial: 50–100 mg three times a day.
- Maintenance: 200–800 mg/day divided into two to four doses. Dosages above 200 mg should be prescribed by a specialist with ECG monitoring. Maximum dose: 800 mg/day. Once control is attained, the dose should be gradually lowered to the minimum effective maintenance dose.
Children (2-12 years):
- Initial: 0.5 mg/kg/day orally, divided into doses.
- Maximum: 3 mg/kg/day, divided into doses. Increase the dose gradually until therapeutic effects are observed or the maximum dose is reached.
Special Cases:
- Elderly Patients: Initiate at a lower dose and titrate cautiously, monitoring for adverse effects.
- Patients with Renal Impairment: Dose adjustment may not be necessary, but caution is advised.
- Patients with Hepatic Dysfunction: Start with a lower dose and titrate slowly, carefully monitoring liver function.
- Patients with Comorbid Conditions: Careful monitoring and dose adjustment may be necessary for patients with cardiovascular disease or other relevant conditions.
Clinical Use Cases
Thioridazine is not typically recommended for use in intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations due to its potential for serious side effects, including cardiac arrhythmias and QTc prolongation. Other agents are generally preferred in these settings.
Dosage Adjustments
Dose adjustments should be made based on individual patient response, tolerability, and the presence of any comorbid conditions or drug interactions. Patients with long QT syndrome, a history of cardiac arrhythmias, or those taking medications that prolong the QT interval should avoid thioridazine. Patients who are poor metabolizers of CYP2D6 require careful monitoring and dose adjustment.
Side Effects
Common Side Effects:
- Drowsiness, sedation
- Dry mouth, constipation
- Blurred vision, dizziness
- Extrapyramidal symptoms (EPS), such as tremors and muscle rigidity
- Headache
- Prolactin elevation (leading to sexual side effects, amenorrhea, galactorrhea)
- Weight gain
- Skin rash
Rare but Serious Side Effects:
- QTc prolongation, torsades de pointes (potentially fatal cardiac arrhythmia)
- Neuroleptic malignant syndrome (NMS)
- Tardive dyskinesia
- Ocular pigmentation and retinopathy
- Agranulocytosis
Long-Term Effects:
- Tardive dyskinesia
- Irreversible retinal pigmentation
Adverse Drug Reactions (ADR):
- Agranulocytosis
- Torsades de pointes
- Neuroleptic malignant syndrome
Contraindications
- Hypersensitivity to thioridazine
- Severe cardiovascular disease
- Pre-existing long QT syndrome or history of cardiac arrhythmias
- Concurrent use of drugs known to prolong the QTc interval
- Severe CNS depression or comatose states
- Patients with decreased CYP2D6 activity
Drug Interactions
- Drugs that prolong the QT interval (e.g., certain antibiotics, antifungals, antiarrhythmics)
- CYP2D6 inhibitors (e.g., fluoxetine, paroxetine)
- Anticholinergic drugs
- Alcohol
- CNS depressants
Pregnancy and Breastfeeding
- Pregnancy Safety Category: While not assigned a formal FDA category, thioridazine is generally considered to have some risk in pregnancy and should be used only if the potential benefit justifies the potential risk to the fetus.
- Fetal Risks: Potential for extrapyramidal and/or withdrawal symptoms in neonates exposed to antipsychotic drugs during the third trimester.
- Breastfeeding: Thioridazine is present in breast milk. The risks and benefits should be carefully weighed before using thioridazine during breastfeeding.
Drug Profile Summary
- Mechanism of Action: Dopamine D2 receptor antagonist.
- Side Effects: Drowsiness, dry mouth, EPS, QTc prolongation, tardive dyskinesia, retinopathy.
- Contraindications: Long QT syndrome, severe cardiovascular disease, concurrent use of QT-prolonging drugs.
- Drug Interactions: CYP2D6 inhibitors, QT-prolonging drugs.
- Pregnancy & Breastfeeding: Use with caution; weigh risks and benefits.
- Dosage: Adults: 200-800 mg/day; Children: 0.5-3 mg/kg/day. Special adjustments needed for specific populations.
- Monitoring Parameters: ECG, serum potassium, liver function tests, complete blood counts, eye exams.
Popular Combinations
Thioridazine is not commonly combined with other medications due to its potential for drug interactions and significant adverse effects. If used, combinations should be carefully monitored.
Precautions
- General Precautions: Baseline ECG, monitor for QTc prolongation, assess for risk factors for arrhythmias.
- Specific Populations: See “Dosage - Special Cases” and “Pregnancy and Breastfeeding.”
- Lifestyle Considerations: Avoid alcohol and other CNS depressants. May impair alertness; avoid driving or operating machinery.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Thioridazine?
A: Adults: Initial 50-100 mg three times daily, maintenance 200-800 mg/day divided into two to four doses (max 800 mg/day, doses over 200mg daily need specialist supervision). Children (2-12 years): Initial 0.5 mg/kg/day divided into doses, maximum 3 mg/kg/day divided into doses.
Q2: What are the most serious side effects of Thioridazine?
A: QTc prolongation, torsades de pointes, tardive dyskinesia, neuroleptic malignant syndrome, retinopathy, and agranulocytosis.
Q3: Is Thioridazine safe to use during pregnancy?
A: Thioridazine carries potential risks during pregnancy. It should only be used if the potential benefits outweigh the risks to the fetus. Consult with a specialist.
Q4: What other medications interact with Thioridazine?
A: QT prolonging medications (e.g. certain antibiotics, antifungals, antiarrhythmics), CYP2D6 inhibitors (e.g., fluoxetine, paroxetine), and other drugs that cause CNS depression.
Q5: Can Thioridazine be used in patients with liver disease?
A: Use with caution in patients with hepatic impairment. Start with a lower dose and titrate slowly, monitoring liver function tests.
Q6: What is the mechanism of action of Thioridazine?
A: Thioridazine primarily acts as a dopamine D2 receptor antagonist.
Q7: Why is Thioridazine considered a second-line treatment for schizophrenia?
A: Due to its potential for serious side effects, particularly QTc prolongation and cardiac arrhythmias, Thioridazine is reserved for patients who haven’t responded to other antipsychotic medications.
Q8: What monitoring parameters are important when prescribing Thioridazine?
A: ECG, serum potassium, complete blood counts, liver function tests, and ophthalmologic evaluations.
Q9: What patient education should be provided regarding Thioridazine?
A: Patients should be informed about potential side effects, including drowsiness, dry mouth, EPS, and the signs and symptoms of serious adverse effects like cardiac arrhythmias. They should be advised to avoid alcohol and other CNS depressants, as well as activities requiring alertness. They should also understand the importance of regular monitoring and follow-up appointments.
