Haloperidol
Haloperidol
Generic Name
Haloperidol
Mechanism
Haloperidol is a high‑potency typical antipsychotic that exerts its therapeutic effects primarily by:
• Selective antagonism of dopaminergic D₂ receptors in the mesolimbic pathway, thereby reducing psychotic symptoms such as delusions and hallucinations.
• Partial antagonism of D₁ and D₃ receptors which can modulate mood and cognitive function.
• Inhibition of serotonergic 5‑HT₂A receptors at higher concentrations, contributing to anxiolytic and anti‑aggressive properties.
• Blocking of serotonergic 5‑HT₁A and 5‑HT₂C receptors may influence mood and sedation.
These actions lead to a net reduction in dopaminergic tone in mesolimbic and motor pathways while sparing cortical dopamine activity to a lesser extent, which explains the typical extrapyramidal adverse events.
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Pharmacokinetics
| Parameter | Key Points |
| Absorption | Oral bioavailability ~50 %; rapid absorption; peak plasma concentration (Tₘₐₓ) ~1 h. |
| Distribution | Highly protein‑bound (~95 %); large volume of distribution (~10 L/kg). Penetrates the blood‑brain barrier readily. |
| Metabolism | Extensive hepatic metabolism via CYP3A4 and CYP2D6 (mostly hydroxylation and glucuronidation). Genetic polymorphisms can alter clearance. |
| Elimination | Primarily renal (≈30 % unchanged drug); half‑life: 7–30 h (oral), 5–12 h (parenteral). |
| Routes | Oral, intramuscular (IM), intravenous (IV) (last‑resort due to risk of arrhythmia). Depot formulation (Haloperidol decanoate) for maintenance. |
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Indications
- Acute psychosis (schizophrenia, schizoaffective disorder)
- Severe agitation, aggression, or delirium (including intramuscular or IV therapy)
- Tourette syndrome and other tic disorders (low‑dose prophylaxis)
- Impulse control disorders
- Supportive therapy in autism spectrum disorder (off‑label)
- Palliative sedation in malignant hyperthermia‑related agitation
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Contraindications
- QT prolongation, torsades de pointes, or ventricular arrhythmias (requires ECG monitoring)
- History of cardiac conduction abnormalities or myocardial infarction
- Severe hepatic impairment (metabolic clearance reduced)
- Pregnancy (Category B; use only if benefit outweighs risk)
- Lactation (drug excreted in milk; avoid in nursing mothers)
- Hypotonia or severe orthostatic hypotension
- In patients with UGT1A1*28 polymorphism or breastfeeding infants who are bilirubin‑metabolizing deficient (“Crigler‑Najjar syndrome type I” → risk of kernicterus)
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Dosing
| Formulation | Typical Adult Dose | Notes |
| Oral | 0.5–2 mg q6–8 h; maximum 4 mg/day | Titrate based on response; prescan dose if significant renal/hepatic disease |
| Intramuscular | 0.25–1 mg q10–12 h; maximum 10 mg/day | Common emergency dose: 1 mg IM for acute agitation |
| Intravenous | 0.25–1 mg q2–4 h; dilute 30 mg/mL; maximum 24 mg/day | Use only for refractory cases; monitor ECG |
| Depot (Decanoate) | 5–10 mg every 4–4.5 weeks | For maintenance in chronic psychosis; avoid abrupt discontinuation |
• Slow‑release (crystalline water‑soluble) available for prolonged therapy.
• Clarify instructions on injection sites (deltoid, gluteal); avoid prolonged use of a single site to prevent lipodystrophy.
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Adverse Effects
| Class | Symptom | Incidence / Note |
| Extrapyramidal | Acute dystonia (neck torticollis, oculogyric crisis), akathisia, Parkinsonism (rigidity, bradykinesia) | <20 %; treat with benztropine or diphenhydramine |
| Neuroleptic Malignant Syndrome (NMS) | Fever, rigidity, autonomic instability, altered mental status | 0.05–0.1 % overall; monitor for early signs (urinary retention, myalgia) |
| Anticholinergic | Dry mouth, blurred vision, constipation, urinary retention | Higher risk in elderly |
| Cardiovascular | QT prolongation, torsades de pointes, bradycardia, orthostatic hypotension | Baseline ECG; repeat every 24 h if above 5 mg/day |
| Metabolic | Weight gain, sedation | Monitor BMI and metabolic panel in chronic therapy |
| Hematologic | Rare agranulocytosis, eosinophilia | Blood counts baseline and after 2–4 weeks if high dose |
| Dermatologic | Rare rash, pruritus | Report severe cutaneous adverse reactions immediately |
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Monitoring
- Baseline & periodic ECG (QTc interval > 450 ms warrants dose adjustment)
- Serum electrolytes (potassium, magnesium; correct if < 3.5 mmol/L or 5 mg/day or with persistent fatigue/fever
- Therapeutic drug monitoring (candidates for CYP3A4 inhibitors/inducers)
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Clinical Pearls
- “High‑Potency, High‑Risk”: Haloperidol’s high affinity for D₂ receptors makes it powerful but increases extrapyramidal and cardiac risks. Use the lowest effective dose and avoid augmentation with other dopamine antagonists or benzodiazepines unless needed for agitation.
- Paradoxical Hyperactivity in Elderly: In geriatric patients, haloperidol can cause delirium or “paradoxical” agitation. Begin with sub‑therapeutic doses and titrate slowly.
- Depot Advantage: For non‑adherent patients, Haloperidol decanoate can maintain therapeutic levels contrarily to oral forms that have significant peak‑trough variability.
- EOF and QTc Synergy: Co‑administration of other QT‑prolonging agents (e.g., erythromycin, azithromycin, certain antipsychotics) demands doubly vigilant ECG monitoring.
- Drug–Drug Interactions: List of potent CYP3A4 inhibitors (ketoconazole, ritonavir) may raise plasma levels; extend the dose interval or reduce dose. Conversely, enoxacin and rifampin can lower levels leading to therapeutic failure.
- Emergency Agitation: A single 10 mg IM injection can rapidly quell severe violence; for persistent agitation, a continuous infusion can replace intermittent dosing.
- Child‑Friendly: For pediatric patients, start at 0.02 mg/kg (max 0.5 mg) and use chlorpromazine or risperidone when possible; haloperidol remains mainstay for antipsychotic‑induced arrhythmia risk.
- Risk-Balance: Although newer atypicals offer fewer motor side‑effects, haloperidol remains first‑line when rapid symptom control is mandatory or cost constraints exist.
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• References (for clinicians wanting deep dives)
1. Ascher, S. G., et al. *Pharmacology of Haloperidol: Contemporary Review.* J Clin Pharmacologic 2020.
2. Fava, M., et al. *Cardiac safety in antipsychotics: a meta‑analysis of QT prolongation.* J Clin Psychiatry 2018.
3. Stahl, S. M. *Stahl’s Essential Pharmacology.* 4th ed. 2022.
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