THIORIDAZINE HYDROCHLORIDE
Clinical safety rating: safe
Animal studies have demonstrated safety
Thioridazine is a typical antipsychotic of the phenothiazine class. It blocks postsynaptic dopamine D2 receptors in the mesolimbic system, and also has significant anticholinergic and alpha-adrenergic blocking activity. It exhibits a high affinity for D2, 5-HT2A, and alpha1-adrenergic receptors.
| Metabolism | Extensively metabolized in the liver via CYP2D6 to active metabolites (e.g., mesoridazine, sulforidazine). Thioridazine is also a potent inhibitor of CYP2D6. |
| Excretion | Primarily hepatic metabolism with <1% excreted unchanged in urine; metabolites are excreted renally (approximately 30% of dose as metabolites) and fecally (approximately 20-30% via bile). |
| Half-life | 24-36 hours for the parent drug; extended in hepatic impairment and elderly; steady-state reached in 4-7 days. |
| Protein binding | 95-99% bound primarily to albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | 10-20 L/kg, indicating extensive tissue binding and distribution. |
| Bioavailability | Oral: approximately 40-50% due to first-pass metabolism; not available in parenteral form. |
| Onset of Action | Oral: 30-60 minutes to onset of sedation and antipsychotic effects; peak effects at 2-4 hours. Not available parenterally. |
| Duration of Action | 6-12 hours for single oral dose; longer with chronic dosing due to accumulation; antipsychotic effects persist for days after discontinuation. |
Adults: Initial 50-100 mg orally three times daily, gradually increasing to maximum 800 mg/day in divided doses. Usual maintenance: 200-800 mg/day.
| Dosage form | CONCENTRATE |
| Renal impairment | Contraindicated in severe renal impairment (CrCl <10 mL/min). For moderate impairment (CrCl 10-50 mL/min), use 50-75% of normal dose with careful monitoring. |
| Liver impairment | Contraindicated in significant hepatic impairment. For mild impairment (Child-Pugh A), reduce dose by 50% and monitor. Avoid in Child-Pugh B or C. |
| Pediatric use | Contraindicated in children <2 years. For children ≥2 years: 0.5-3 mg/kg/day orally in divided doses, maximum 3 mg/kg/day or 200 mg/day (whichever less). |
| Geriatric use | Initial dose 10-25 mg orally once or twice daily, titrate slowly. Use lowest effective dose due to increased risk of QT prolongation and anticholinergic effects. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Strong CYP2D6 inhibitors are contraindicated due to risk of QT prolongation Can cause QT prolongation and retinopathy.
| Breastfeeding | Excreted in breast milk. M/P ratio not determined. Contraindicated due to risk of infant sedation and extrapyramidal effects. |
| Teratogenic Risk | First trimester: Limited human data, but animal studies show fetal toxicity at high doses. Second/third trimester: Risk of extrapyramidal symptoms and neonatal withdrawal. Avoid in pregnancy unless benefit outweighs risk. |
| Fetal Monitoring |
■ FDA Black Box Warning
Thioridazine has been shown to prolong the QTc interval in a dose-dependent manner, and is associated with an increased risk of sudden death. It is contraindicated in patients with congenital long QT syndrome or a history of cardiac arrhythmias. It should not be used with other drugs that prolong the QTc interval or in patients with electrolyte imbalances. Use is restricted to patients with schizophrenia who have failed to respond to at least two other antipsychotics.
| Common Effects | Extrapyramidal symptoms |
| Serious Effects |
["Known hypersensitivity to thioridazine or other phenothiazines","Congenital long QT syndrome or history of cardiac arrhythmias","QTc interval >450 ms in males or >470 ms in females","Coadministration with drugs that prolong QTc interval (e.g., quinidine, procainamide, amiodarone, sotalol, fluoxetine, pimozide, etc.)","Coadministration with fluvoxamine, fluoxetine, or paroxetine (CYP2D6 inhibitors)","Severe CNS depression or coma","Untreated hypokalemia or hypomagnesemia","Pheochromocytoma"]
| Precautions |
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| Monitor maternal ECG for QT prolongation, maternal blood pressure, liver function. Fetal: assess growth and neonatal behavior after delivery. |
| Fertility Effects | May cause hyperprolactinemia leading to menstrual irregularities and reduced fertility in women. Reversible upon discontinuation. |
| ["QT prolongation and risk of torsades de pointes; perform ECG before and during therapy","Neuroleptic malignant syndrome (NMS); hyperthermia, rigidity, autonomic instability","Tardive dyskinesia with long-term use","Anticholinergic effects: constipation, urinary retention, blurred vision","Hypotension, especially orthostatic","Seizure threshold lowering","Hepatic impairment","Coadministration with drugs that inhibit CYP2D6 or prolong QTc","Avoid in elderly with dementia-related psychosis due to increased mortality"] |