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Sunday, July 27, 2025

Haloperidol


Haloperidol is a first-generation (typical) antipsychotic medication belonging to the butyrophenone chemical class. It has potent dopamine D₂ receptor antagonist activity in the central nervous system and is primarily used to manage schizophrenia, acute psychosis, and tics in Tourette’s syndrome. It is also employed in acute agitation, mania, and as adjunctive therapy in delirium and nausea/vomiting (off-label). Its use is associated with a high risk of extrapyramidal symptoms (EPS) due to strong dopaminergic blockade in the nigrostriatal pathway.


Brand Names

  • Haldol®

  • Serenace®

  • Dozic® (varies by region)

  • Halol®

  • Haloperidol Decanoate (Depot formulation)

Pharmacological Class

  • Therapeutic class: Antipsychotic

  • Pharmacological class: Butyrophenone derivative

  • Generation: First-generation (typical) antipsychotic

  • ATC code: N05AD01

Mechanism of Action

Haloperidol functions mainly by antagonizing dopamine D2 receptors in the mesolimbic and mesocortical pathways of the brain. This results in:

  • Reduction of positive psychotic symptoms such as hallucinations and delusions.

  • Dopamine blockade in the nigrostriatal pathway, which is associated with extrapyramidal symptoms.

  • It also has antagonist activity at alpha-1 adrenergic receptors and minimal anticholinergic activity.

  • Minimal to moderate antagonism of 5-HT2 (serotonin) receptors and H1 histaminergic receptors.

In depot (long-acting) formulations, haloperidol decanoate is slowly released and converted into the active form over several weeks, providing prolonged therapeutic effects.

Therapeutic Indications

FDA-Approved Uses

  • Schizophrenia (acute and chronic)

  • Acute psychotic states

  • Control of tics and vocal utterances in Tourette’s disorder

  • Severe behavioral problems in children (e.g., combative hyperactivity)

  • Severe agitation and psychosis in elderly patients

  • Hyperactive delirium (short-term, off-label use)

Off-Label Uses

  • Acute mania (as part of bipolar management)

  • Delirium-associated agitation

  • Severe nausea and vomiting (especially chemotherapy-induced)

  • Postoperative nausea (in refractory cases)

  • Huntington’s chorea

  • Alcoholic hallucinosis

Dosage and Administration

Oral Tablets

  • Adults (Schizophrenia/Psychosis): Initial 0.5–5 mg two to three times daily; adjusted up to 20 mg/day based on response.

  • Elderly: Start low (0.5–1 mg/day), increase cautiously.

  • Children (>3 years): 0.05–0.15 mg/kg/day in divided doses.

Intramuscular Injection (Acute Agitation)

  • 2–10 mg IM, repeated every 4 to 8 hours as needed.

  • Maximum: 20 mg/day in most settings.

IV Administration (Caution: Off-label; risk of QT prolongation)

  • For severe agitation/delirium: 0.5–5 mg IV, titrated slowly under cardiac monitoring.

Depot Injection (Haloperidol Decanoate)

  • 25–100 mg IM every 4 weeks.

  • May increase to 200 mg monthly as needed.

  • Overlap with oral haloperidol for the first 2–3 weeks after the first injection.

Contraindications

  • Known hypersensitivity to haloperidol or butyrophenones

  • Parkinson’s disease

  • Severe CNS depression or comatose states

  • Dementia-related psychosis (increased risk of death)

  • QT interval prolongation or history of torsades de pointes

  • Concurrent use with medications that significantly prolong the QT interval

  • Pheochromocytoma (risk of hypertensive crisis)

Adverse Effects

Neurological (dopaminergic blockade)

  • Extrapyramidal symptoms (EPS): dystonia, parkinsonism, akathisia

  • Tardive dyskinesia (long-term use)

  • Neuroleptic malignant syndrome (NMS)

  • Sedation

  • Seizures (rare)

  • Headache, insomnia

Cardiovascular

  • QT prolongation

  • Torsades de pointes

  • Orthostatic hypotension

  • Tachycardia

Endocrine / Metabolic

  • Hyperprolactinemia → galactorrhea, amenorrhea, gynecomastia

  • Weight gain

  • Impaired glucose tolerance

Gastrointestinal

  • Constipation

  • Dry mouth

  • Nausea/vomiting

Other

  • Skin rash, photosensitivity

  • Urinary retention

  • Visual disturbances

  • Risk of falls in elderly patients

Boxed Warning

Increased mortality in elderly patients with dementia-related psychosis
Haloperidol and other antipsychotic drugs increase the risk of death in elderly patients with dementia-related psychosis. Not approved for dementia-related psychotic disorders.

Precautions

  • Cardiac monitoring: ECG prior to IV or high-dose use due to QT prolongation risk.

  • Elderly: Increased risk of sedation, falls, and extrapyramidal symptoms.

  • Seizure disorders: Lower seizure threshold.

  • Liver dysfunction: Dose adjustment may be needed.

  • Abrupt discontinuation: May lead to withdrawal dyskinesia or relapse.

  • Pregnancy: Category C – potential risks vs. benefits should be considered.

Drug Interactions

QT Prolongation Risk

  • Macrolides (e.g., erythromycin)

  • Fluoroquinolones (e.g., ciprofloxacin)

  • Azole antifungals (e.g., ketoconazole)

  • Other antipsychotics (e.g., ziprasidone, thioridazine)

  • Methadone

CNS Depressants

  • Benzodiazepines, opioids, antihistamines → additive sedation, respiratory depression

Anticholinergics

  • Increased risk of urinary retention, dry mouth, constipation

Carbamazepine

  • Reduces haloperidol plasma concentration via CYP3A4 induction

SSRIs

  • May increase haloperidol plasma levels (fluoxetine, paroxetine inhibit CYP2D6)

Levodopa

  • Haloperidol antagonizes the effect of levodopa; should not be used in Parkinson's patients

Pharmacokinetics

  • Absorption: Oral bioavailability ~60%

  • Peak plasma: 2–6 hours after oral dose

  • Distribution: Highly lipophilic, crosses blood-brain barrier

  • Protein binding: ~90%

  • Metabolism: Hepatic (CYP3A4, CYP2D6, CYP1A2)

  • Elimination half-life: Oral: 14–36 hours; Depot: ~3 weeks

  • Excretion: Urine and feces

Use in Special Populations

Pregnancy

  • Category C (FDA)

  • Some studies report teratogenicity in animals; limited human data.

  • Risk-benefit assessment required.

Lactation

  • Excreted in breast milk.

  • Monitor infants for sedation and extrapyramidal symptoms.

Elderly

  • Increased risk of cerebrovascular events and mortality in dementia.

  • Initiate at lower doses and monitor closely.

Monitoring Parameters

  • ECG: Baseline and periodic QT interval monitoring

  • Electrolytes: Especially potassium and magnesium

  • Liver function tests

  • Extrapyramidal symptoms: AIMS or SAS scales

  • Prolactin levels: If symptomatic

  • Signs of tardive dyskinesia or neuroleptic malignant syndrome

Poisoning and Overdose

Symptoms:

  • Severe EPS

  • Hypotension

  • Respiratory depression

  • QT prolongation, ventricular arrhythmias

  • Coma

Treatment:

  • Supportive care

  • Activated charcoal (if early)

  • Benzodiazepines for agitation

  • IV fluids for hypotension

  • Monitor ECG continuously

No specific antidote is available.

Comparative Notes

FeatureHaloperidolRisperidone (atypical)Olanzapine (atypical)
EPS riskHighModerateLow to moderate
SedationModerateLowHigh
Prolactin elevationHighHighModerate
Weight gainLowModerateHigh
Anticholinergic effectMinimalMinimalModerate



Clinical Pearls

  • Haloperidol remains a key agent in rapid tranquilization protocols due to its parenteral forms.

  • Depot formulation is useful for long-term maintenance in non-adherent patients.

  • Close monitoring of movement disorders is essential, especially in long-term use.

  • Caution is warranted in QT-prolongation risk patients and polypharmacy cases




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