Haloperidol

Haloperidol is a potent first-generation antipsychotic (FGA) belonging to the butyrophenone class, primarily employed in the management of schizophrenia, acute psychotic disorders, and neuropsychiatric conditions. Initially synthesised in the late 1950s, Haloperidol exerts its pharmacological action predominantly through high-affinity antagonism of dopamine D2 receptors within the mesolimbic and mesocortical pathways, thereby mitigating positive psychotic symptoms. However, its robust dopaminergic blockade in the nigrostriatal pathway accounts for its notable extrapyramidal side effect (EPS) burden, necessitating judicious therapeutic use.

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Therapeutic Indications

Haloperidol is clinically indicated for various psychiatric and neurological conditions:

• Schizophrenia and schizoaffective disorders – Effective in mitigating delusions, hallucinations, and formal thought disorders.
• Acute psychotic agitation – Commonly administered in emergency settings for rapid tranquillisation.
• Tourette syndrome – Modulates severe motor and vocal tics.
• Bipolar disorder – Utilised for acute manic episodes, often in conjunction with mood stabilisers.
• Delirium – Short-term use in ICU settings for hyperactive delirium.
• Huntington’s disease and choreiform movement disorders – Exerts symptomatic relief by attenuating dopaminergic overactivity.

Dosage and Administration

Haloperidol is available in multiple formulations, including oral tablets, liquid suspensions, and parenteral solutions.

• Oral dosing: Typically initiated at 0.5–2 mg two to three times daily, with a maximum dose of 20 mg/day for severe cases.
• Intramuscular (IM) administration: Utilised for acute agitation, with doses ranging from 2 to 10 mg, repeated as necessary.
• Long-acting depot formulations: Administered via IM injection at 4-week intervals, often for chronic schizophrenia.

Dose Modulation in Organ Dysfunction

Haloperidol undergoes extensive hepatic metabolism via CYP3A4 and CYP2D6, necessitating dose adjustments in certain patient populations:

• Renal impairment: Though primarily hepatically metabolised, renal dysfunction can prolong elimination half-life; dose reduction and extended dosing intervals are advisable in severe renal impairment.
• Hepatic impairment: Patients with compromised hepatic function require careful titration due to the risk of drug accumulation and enhanced neurotoxicity.
• Geriatric considerations: Due to heightened sensitivity to EPS and cardiovascular risks, lower initial doses (0.25–0.5 mg) with gradual up-titration are preferred.

Adverse Effects and Tolerability

Common Adverse Effects

• Extrapyramidal symptoms (EPS) – Bradykinesia, dystonia, and rigidity due to nigrostriatal dopamine blockade.
• Sedation – Frequently observed, particularly at higher doses.
• Anticholinergic effects – Xerostomia, constipation, urinary retention.
• Hyperprolactinaemia – Induces galactorrhoea, amenorrhoea, and gynecomastia.

Serious Adverse Effects

• Tardive dyskinesia (TD) – Chronic exposure may lead to irreversible involuntary movements.
• Neuroleptic malignant syndrome (NMS) – Characterised by hyperthermia, autonomic instability, and altered mental status; mandates immediate drug discontinuation.
• QT prolongation and arrhythmias – Particularly concerning in high-risk individuals.

Combination Therapy and Drug Synergies

• Adjunctive benzodiazepines (e.g., lorazepam) – Enhances sedation in acute agitation.
• Anticholinergics (e.g., benztropine) – Mitigates EPS.
• Mood stabilisers (e.g., lithium, valproate) – Augments efficacy in bipolar disorder.

Pharmacokinetics and Pharmacodynamics

• Absorption: Oral bioavailability approximates 60%, with significant first-pass metabolism.
• Metabolism: Hepatic oxidation predominantly via CYP3A4 and CYP2D6.
• Elimination half-life: Ranges from 10 to 37 hours, justifying once- or twice-daily dosing.
• Mechanism of action: Potent D2 receptor blockade within the mesolimbic pathway accounts for its antipsychotic efficacy; however, interactions with other neurotransmitter systems, including serotonergic and adrenergic receptors, contribute to its diverse side effect profile.

Drug Interactions

Haloperidol exhibits significant pharmacokinetic and pharmacodynamic interactions:

• Central nervous system depressants (e.g., alcohol, opioids) – Heightens sedation and respiratory depression.
• QT-prolonging agents (e.g., macrolides, antiarrhythmics) – Elevates arrhythmogenic risk.
• CYP3A4/CYP2D6 inhibitors (e.g., fluoxetine, ketoconazole) – May potentiate Haloperidol toxicity.

Comparative Efficacy with Other Antipsychotics

Drug	Generation	Dopamine D2 Affinity	Key Adverse Effects
Haloperidol	First	High	EPS, tardive dyskinesia
Chlorpromazine	First	Moderate	Sedation, hypotension
Risperidone	Second	Moderate	Hyperprolactinaemia, metabolic syndrome
Olanzapine	Second	Moderate	Significant weight gain, sedation

Clinical Precautions and Risk Mitigation

• ECG monitoring is imperative in patients with predisposing cardiac conditions.
• Avoidance in Parkinson’s disease due to exacerbation of motor symptoms.
• Increased mortality risk in dementia-related psychosis, necessitating cautious prescribing.

Toxicity, Overdose Management, and Antidote

• Overdose manifestations: Severe EPS, profound sedation, hypotension, and potential cardiovascular collapse.
• Therapeutic approach: Supportive management with IV fluids, airway stabilisation, and symptom-directed pharmacotherapy.
• No specific antidote; however, benzodiazepines may mitigate severe agitation and muscle rigidity.

Latest Guidelines and Emerging Trends

• Revised NICE (2025) guidance: Advocates for minimised dosage regimens to curtail EPS risk.
• Advancements in long-acting formulations: Novel depot preparations exhibit improved pharmacokinetic profiles with enhanced patient adherence.
• Expanded research on neuroprotective adjuncts: Investigations into antioxidant co-therapy to mitigate Haloperidol-induced neurotoxicity.

Key Takeaways

• Haloperidol remains a mainstay in psychiatric practice due to its robust efficacy in psychotic disorders.
• Its high D2 receptor affinity is responsible for both its therapeutic and adverse effects.
• Dose adjustments are essential in hepatic and renal impairment, as well as in geriatric populations.
• Rigorous monitoring is required to prevent tardive dyskinesia, neuroleptic malignant syndrome, and cardiac arrhythmias.

References

1. National Institute for Health and Care Excellence (NICE) Guidelines, 2025.
2. British National Formulary (BNF), 2025 Edition.
3. World Health Organization (WHO) – Antipsychotic Medication Use.
4. Royal College of Psychiatrists – Haloperidol Prescribing Information.
5. Journal of Clinical Psychopharmacology, 2025 Issue.