Introduction
Haloperidol is a first-generation (typical) antipsychotic medication belonging to the butyrophenone class. Initially synthesized in 1958 by Paul Janssen, it has been widely used for decades in the management of psychiatric disorders. Haloperidol remains a cornerstone in acute agitation management and maintenance therapy for chronic psychotic conditions due to its potent dopamine receptor blockade and generally favorable side effect profile compared to other typical antipsychotics.
Mechanism of Action
Haloperidol exerts its therapeutic effects primarily through potent antagonism of dopamine D2 receptors in the mesolimbic pathway of the brain. The drug also exhibits affinity for sigma receptors and weak antagonism at alpha-1 adrenergic receptors, serotonin 5-HT2 receptors, and muscarinic cholinergic receptors. Its antipsychotic efficacy correlates strongly with D2 receptor occupancy (approximately 70-80% for therapeutic effect), while higher occupancy levels (>80%) are associated with increased risk of extrapyramidal symptoms.
Indications
FDA-approved indications:- Treatment of schizophrenia
- Management of tics and vocal utterances in Tourette's syndrome
- Treatment of severe behavioral problems in children
- Acute agitation and psychosis in emergency settings
- Delirium management in hospitalized patients
- Adjunctive treatment in bipolar disorder
- Nausea and vomiting refractory to conventional antiemetics
Dosage and Administration
Oral administration:- Initial dose: 0.5-5 mg 2-3 times daily for psychosis
- Maintenance: 2-20 mg daily (maximum 100 mg daily)
- Elderly/debilitated patients: Start with 0.5-1 mg daily
- IM (acute agitation): 2-5 mg, repeat every 60 minutes as needed
- IM decanoate (long-acting): Initial 10-15 times daily oral dose, monthly injections
- Hepatic impairment: Reduce dose by 30-50%
- Renal impairment: No significant adjustment needed
- Pediatrics: 0.05-0.15 mg/kg/day for Tourette's syndrome
Pharmacokinetics
Absorption: Well absorbed orally (60-70% bioavailability), peak concentrations in 2-6 hours Distribution: Vd: 10-35 L/kg, highly protein bound (90%), crosses blood-brain barrier and placenta Metabolism: Extensive hepatic metabolism via CYP3A4 and CYP2D6 to inactive metabolites Elimination: Half-life: 12-36 hours (oral), 21 days (decanoate); excreted primarily in urine (40%) and feces (15%)Contraindications
- Hypersensitivity to haloperidol or components
- Parkinson's disease
- Comatose or severely depressed states
- Dementia with Lewy bodies
- Known QT prolongation or significant cardiac disease
- Concurrent use with other QT-prolonging agents when unavoidable
Warnings and Precautions
Black Box Warnings:- Increased mortality in elderly patients with dementia-related psychosis
- Not approved for dementia-related behavioral disturbances
- Risk of QT prolongation and torsades de pointes
- Neuroleptic malignant syndrome (NMS)
- Tardive dyskinesia (risk increases with duration and cumulative dose)
- Seizure threshold lowering
- Orthostatic hypotension
- Cognitive and motor impairment
- Temperature regulation dysfunction
- Esophageal dysmotility and aspiration risk
Drug Interactions
Major interactions:- CYP3A4 inhibitors (ketoconazole, clarithromycin): Increase haloperidol levels
- CYP3A4 inducers (carbamazepine, rifampin): Decrease haloperidol levels
- Other CNS depressants: Additive sedation
- QT-prolonging agents: Increased arrhythmia risk
- Lithium: Increased neurotoxicity risk
- Anticholinergic agents: Increased side effects
Adverse Effects
Common (>10%):- Extrapyramidal symptoms (dystonia, akathisia, parkinsonism)
- Sedation
- Dry mouth
- Constipation
- Blurred vision
- Tardive dyskinesia
- Neuroleptic malignant syndrome
- QT prolongation and cardiac arrhythmias
- Seizures
- Blood dyscrasias (agranulocytosis)
- Hyperprolactinemia
- Sudden cardiac death
Monitoring Parameters
Baseline assessment:- Complete medical and psychiatric history
- ECG (QTc interval)
- CBC with differential
- Liver function tests
- Renal function
- Prolactin level if symptomatic
- Mental status and symptom response
- Extrapyramidal symptoms (AIMS assessment every 6 months)
- Weight and metabolic parameters (quarterly)
- ECG (annually or with dose changes)
- TD assessment every 3-6 months
Patient Education
- Take medication exactly as prescribed; do not stop abruptly
- Avoid alcohol and other CNS depressants
- Rise slowly from sitting/lying position to prevent dizziness
- Report any muscle stiffness, tremors, or restlessness immediately
- Use caution when driving or operating machinery
- Maintain regular follow-up appointments
- Report any palpitations, dizziness, or fainting
- Use sun protection due to photosensitivity risk
- Notify all healthcare providers of haloperidol use
References
1. FDA Prescribing Information: Haloperidol Tablets 2. Lehne, R. A. (2013). Pharmacology for Nursing Care (8th ed.) 3. Stahl, S. M. (2021). Stahl's Essential Psychopharmacology (5th ed.) 4. Miller, D. D. (2004). "Atypical antipsychotics: sleep, sedation, and rebound psychosis." Journal of Clinical Psychiatry 5. Marder, S. R., et al. (2004). "Physical health monitoring of patients with schizophrenia." American Journal of Psychiatry 6. Kane, J. M., et al. (2019). "Clinical guidance on the identification and management of treatment-resistant schizophrenia." Journal of Clinical Psychiatry 7. Clinical Pharmacokinetics of Haloperidol (2020). Therapeutic Drug Monitoring Journal