Haloperidol

Haloperidol is a potent antipsychotic medication primarily used in the management of schizophrenia, acute psychosis, and severe agitation. It belongs to the butyrophenone class of drugs and is valued for its strong dopamine receptor antagonism and rapid onset of action in acute settings.

Chemical and Pharmacological Profile

Chemical Structure

Haloperidol is a butyrophenone derivative with the molecular formula C₂₁H₂₃FNO₂ and a molecular weight of 375.45 g/mol. Its structure consists of a fluorobutyrophenone moiety linked to a piperidine ring, which contributes to its pharmacological properties.

Pharmacodynamics

Haloperidol exerts its therapeutic effects primarily through antagonism of dopamine D2 receptors in the central nervous system:

• Reduces dopaminergic neurotransmission in the mesolimbic pathway, decreasing positive symptoms of psychosis.
• Antagonism at D2 receptors in the nigrostriatal pathway can lead to extrapyramidal symptoms.
• Modulates other neurotransmitter systems, including minor effects on serotonin, adrenergic, and histaminergic receptors.

Pharmacokinetics

• Absorption: Well absorbed orally with a bioavailability of approximately 60-70%.
• Distribution: Highly protein-bound (90%), with wide distribution in body tissues including the brain.
• Metabolism: Extensively metabolized in the liver via CYP3A4 and CYP2D6 enzymes into active and inactive metabolites.
• Excretion: Primarily excreted in urine and feces, with a half-life ranging from 14 to 36 hours depending on individual factors.

Indications

Haloperidol is used in the management of a variety of psychiatric and neurological conditions due to its potent antipsychotic effects:

• Schizophrenia and Other Psychotic Disorders: Effective for controlling positive symptoms such as hallucinations, delusions, and thought disorder.
• Acute Agitation or Delirium: Rapid onset of action makes it suitable for managing severe agitation or delirious states in hospital settings.
• Tourette Syndrome: Helps reduce the frequency and severity of motor and vocal tics.
• Nausea and Vomiting: Sometimes used off-label in palliative care or chemotherapy-induced nausea due to its dopaminergic antagonism.

Dosage and Administration

Oral Formulations

• Typical starting doses for adults range from 0.5 mg to 5 mg two to three times daily, adjusted based on clinical response.
• Doses are titrated gradually to achieve optimal symptom control while minimizing adverse effects.

Parenteral Formulations

• Intramuscular Administration: Used for rapid control of acute agitation; doses typically range from 2 mg to 10 mg, repeated every 4 to 8 hours as needed.
• Intravenous Use: Less commonly used due to risk of cardiovascular effects; requires careful monitoring of heart rate and blood pressure.

Special Populations

• Pediatric Dosing: Lower doses are recommended, with careful monitoring for adverse effects.
• Geriatric Adjustments: Reduced doses may be necessary due to increased sensitivity and risk of sedation or orthostatic hypotension.
• Renal and Hepatic Impairment: Dose adjustments are advised in patients with significant organ dysfunction to avoid accumulation and toxicity.

Contraindications and Precautions

• Absolute Contraindications: Known hypersensitivity to haloperidol or other butyrophenone derivatives, and severe CNS depression.
• Use in Pregnancy and Lactation: Generally avoided unless benefits outweigh risks; may cause extrapyramidal symptoms or withdrawal in neonates.
• Cardiovascular Disease: Caution in patients with arrhythmias, prolonged QT interval, or heart failure due to risk of cardiac adverse effects.
• Neurological Disorders: Use with care in Parkinson’s disease, seizure disorders, or dementia, as haloperidol may worsen symptoms or increase fall risk.

Adverse Effects

Common Adverse Effects

• Extrapyramidal symptoms including dystonia, akathisia, and parkinsonism.
• Sedation, drowsiness, and cognitive slowing.
• Weight gain, dry mouth, constipation, and other anticholinergic effects.

Serious Adverse Effects

• Tardive dyskinesia, which may be irreversible with long-term use.
• Neuroleptic malignant syndrome, characterized by hyperthermia, rigidity, autonomic instability, and altered mental status.
• Cardiovascular effects such as QT interval prolongation, arrhythmias, and hypotension.

Drug Interactions

• Other Antipsychotics: Concurrent use may increase the risk of additive central nervous system depression and extrapyramidal symptoms.
• CYP450 Enzyme Interactions: Haloperidol is metabolized by CYP3A4 and CYP2D6; inhibitors or inducers of these enzymes can alter plasma concentrations, affecting efficacy and toxicity.
• CNS Depressants: Alcohol, benzodiazepines, and opioids may enhance sedation and respiratory depression.
• Antihypertensives: Combined use may increase the risk of hypotension.

Monitoring and Safety

• Clinical Response: Regular assessment of psychotic symptoms and behavioral changes to adjust dosage appropriately.
• Laboratory and ECG Monitoring: Baseline and periodic ECG for QT prolongation, and routine metabolic labs if long-term therapy is planned.
• Extrapyramidal Symptoms and Neuroleptic Malignant Syndrome: Vigilant observation for early signs to initiate prompt management.

Special Considerations

• Use in Elderly Patients with Dementia: Increased risk of cerebrovascular events and mortality; haloperidol should be used only when clearly necessary and at the lowest effective dose.
• Long-Acting Injectable Formulations: Available for maintenance therapy in chronic psychotic disorders; useful for patients with poor adherence to oral medication.
• Management of Overdose: Symptoms may include severe sedation, hypotension, extrapyramidal effects, and cardiac arrhythmias. Treatment involves supportive care, monitoring, and, in severe cases, administration of antidotes such as benzodiazepines for agitation or anticholinergics for dystonia.

References

1. Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 5th ed. Cambridge: Cambridge University Press; 2013.
2. Kaplan HI, Sadock BJ, Ruiz P. Kaplan and Sadock’s Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry. 12th ed. Philadelphia: Wolters Kluwer; 2020.
3. Cutler NR, Sramek JJ, Doraiswamy PM. Clinical Handbook of Psychotropic Drugs. 23rd ed. North Tonawanda: Hogrefe Publishing; 2021.
4. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman’s: The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill; 2021.
5. Mauri MC, Paletta S, Di Pace C, et al. Clinical pharmacology of haloperidol. CNS Drugs. 2018;32(2):107-123.
6. van der Heijden FMMA, et al. Haloperidol in the treatment of acute psychosis: efficacy and safety considerations. Expert Opin Drug Saf. 2019;18(7):595-607.
7. American Psychiatric Association. Practice Guideline for the Treatment of Patients With Schizophrenia. 3rd ed. Washington, DC: APA; 2021.