Haloperidol

1. Drug Name

• Generic Name: Haloperidol

• Brand Names: Haldol, Haldol Decanoate (long-acting formulation), Serenace

2. Drug Classification

• Class: Antipsychotic Agent

• Subclass: First-generation antipsychotic (FGA), also known as a typical antipsychotic

3. Mechanism of Action

Haloperidol is a typical antipsychotic that primarily works by antagonizing dopamine receptors in the brain, specifically the D2 dopamine receptor. It has a high affinity for these receptors, leading to a reduction in dopaminergic neurotransmission.

• Dopamine Antagonism: By blocking D2 receptors in the mesolimbic and mesocortical pathways, haloperidol reduces the symptoms of psychosis such as delusions and hallucinations. The D2 receptor antagonism in the nigrostriatal pathway is thought to contribute to movement disorders like extrapyramidal symptoms (EPS), which are common side effects of haloperidol.

• Serotonin and Other Receptor Interactions: Haloperidol also weakly antagonizes serotonin (5-HT2A) receptors, which may contribute to its effects on mood and psychotic symptoms. Additionally, it has some affinity for α1-adrenergic receptors, contributing to its sedative effects, as well as H1 histamine receptors, which contribute to drowsiness and sedation.

4. Pharmacokinetics

• Absorption: Haloperidol is well absorbed from the gastrointestinal tract after oral administration, though bioavailability is reduced by first-pass metabolism. The bioavailability is approximately 60–70%.

• Distribution: Haloperidol is widely distributed throughout the body, including in the central nervous system (CNS). It has a large volume of distribution (Vd), and it is highly protein-bound in plasma (approximately 92–98%).

• Metabolism: Haloperidol is extensively metabolized in the liver by the cytochrome P450 system, particularly CYP3A4, CYP2D6, and CYP1A2 enzymes. The primary metabolic products are inactive metabolites.

• Excretion: The drug and its metabolites are mainly excreted in the urine (approximately 60%) and feces (about 40%). The half-life of haloperidol varies from 14 to 26 hours for the oral formulation, but the long-acting injectable form (haloperidol decanoate) has a much longer half-life (approximately 3 weeks).

• Half-life: Oral haloperidol has a half-life of 14 to 26 hours, and haloperidol decanoate has a prolonged half-life of 3–4 weeks due to its depot formulation.

• Special Considerations: Haloperidol's metabolism can be affected by liver dysfunction, and dose adjustments may be needed for patients with hepatic impairment. It should also be used cautiously in the elderly due to the risk of extrapyramidal symptoms (EPS).

5. Indications

• Primary Indications:

  • Schizophrenia: Haloperidol is used for the treatment of acute and chronic psychosis, particularly schizophrenia, where it helps to reduce symptoms such as hallucinations and delusions.

  • Acute Psychosis and Mania: It is used for managing acute psychosis, including manic episodes in bipolar disorder.

  • Tourette Syndrome: Haloperidol is used for managing severe symptoms of Tourette syndrome, such as motor and vocal tics.

  • Severe Behavioral Problems: It may be used off-label in cases of severe behavioral disturbances, especially in pediatric or geriatric populations.

• Off-label Uses:

  • Delirium: Haloperidol is sometimes used off-label to manage delirium in hospitalized patients.

  • Nausea and Vomiting: In some cases, haloperidol is used off-label for severe nausea and vomiting, particularly when other antiemetics have failed.

6. Dosage and Administration

• Adult Dosing:

  • Schizophrenia (oral): The initial dose is typically 2 to 5 mg once or twice daily, which can be increased gradually to 10 to 15 mg per day depending on the patient’s response. The maximum dose should not exceed 100 mg per day.

  • Acute Psychosis (IV or IM): 5 to 10 mg may be given, and the dose can be repeated every 4 to 8 hours as needed.

  • Long-acting (Haloperidol Decanoate): The typical starting dose is 10 to 15 times the patient's daily oral dose, administered as an intramuscular injection every 4 weeks.

• Pediatric Dosing:

  • Tourette Syndrome: Starting dose is 0.25 mg per day for children aged 3 to 12 years, and it can be increased based on tolerance and response, with a maximum of 0.5 mg/kg/day.

• Elderly Dosing: Start at lower doses due to an increased sensitivity to the drug and the risk of side effects like sedation and extrapyramidal symptoms. Typically, 1–2 mg daily is recommended.

• Renal and Hepatic Impairment Dosing: Reduce the dose in patients with significant renal or hepatic impairment due to altered drug metabolism.

7. Contraindications

• Absolute Contraindications:

  • Hypersensitivity to haloperidol or any of its components.

  • Severe CNS depression or coma.

  • Parkinson's disease (due to the risk of worsening motor symptoms).

• Relative Contraindications:

  • Cardiac arrhythmias: Haloperidol may prolong the QT interval and increase the risk of arrhythmias. Caution should be used in patients with a history of arrhythmias, electrolyte imbalances, or those on other QT-prolonging drugs.

  • Elderly: Use with caution due to an increased risk of extrapyramidal symptoms and sedation.

8. Warnings and Precautions

• Extrapyramidal Symptoms (EPS): Haloperidol is associated with an increased risk of EPS, including tardive dyskinesia (TD), dystonia, and parkinsonism. These effects are more common in high doses or long-term therapy.

• Neuroleptic Malignant Syndrome (NMS): Haloperidol can cause NMS, a life-threatening condition that includes fever, muscle rigidity, autonomic dysregulation, and altered mental status. Immediate discontinuation of the drug is required in such cases.

• QT Prolongation: Haloperidol can prolong the QT interval and should be used with caution in patients with a history of arrhythmias or electrolyte abnormalities.

• Hypotension: Haloperidol may cause orthostatic hypotension, especially in the elderly.

• Tardive Dyskinesia: Prolonged use of haloperidol can cause irreversible movement disorders, including tardive dyskinesia, characterized by involuntary, repetitive movements, especially of the face and tongue.

9. Adverse Effects

• Common Adverse Effects:

  • Sedation and drowsiness are common, especially in the early stages of treatment.

  • Extrapyramidal Symptoms (EPS): Including tremors, rigidity, bradykinesia, and tardive dyskinesia with prolonged use.

  • Hypotension: Orthostatic hypotension and dizziness may occur, especially in elderly patients.

• Less Common but Clinically Significant Side Effects:

  • QT Prolongation and potential arrhythmias.

  • Neuroleptic Malignant Syndrome (NMS): A rare but severe condition that presents with high fever, muscle rigidity, and autonomic dysfunction.

• Serious Adverse Effects:

  • Tardive Dyskinesia: An irreversible movement disorder that is a significant concern with long-term use.

  • Severe Sedation or Cognitive Impairment: Especially in the elderly or those with high doses.

  • Liver Dysfunction: Elevated liver enzymes, jaundice, or hepatic failure in rare cases.

10. Drug Interactions

• Major Drug Interactions:

  • CNS Depressants: Concomitant use with other CNS depressants (e.g., alcohol, benzodiazepines) may increase sedation and the risk of respiratory depression.

  • QT-Prolonging Drugs: Combining haloperidol with other medications that prolong the QT interval (e.g., amiodarone, tricyclic antidepressants) increases the risk of arrhythmias.

  • CYP450 Inhibitors/Inducers: Drugs that inhibit CYP3A4 (e.g., ketoconazole) or CYP2D6 (e.g., fluoxetine) can increase haloperidol levels, while CYP inducers can reduce its efficacy.

• Food-Drug Interactions: No significant food-drug interactions; however, alcohol should be avoided due to the risk of potentiating CNS depressant effects.

• Lab Test Interactions: Haloperidol may alter the results of liver function tests and electrolyte measurements due to its effects on the liver and renal systems.

11. Clinical Pharmacology

• Pharmacodynamics: Haloperidol is a dopamine antagonist, primarily acting on D2 receptors in the mesolimbic and mesocortical areas of the brain to reduce symptoms of psychosis.

• Pharmacological Effects: It also has sedative effects, which may help in acutely calming agitated patients. Haloperidol’s sedative properties are partly due to its antagonism of histamine and α1-adrenergic receptors.

12. Special Populations

• Pregnancy Category: Category C, as haloperidol may cause fetal harm in animal studies but its safety during pregnancy is not well-established.

• Lactation: Haloperidol is excreted in breast milk, and its use is not recommended in breastfeeding mothers unless the benefits outweigh the risks.

• Geriatrics: Elderly patients are more sensitive to the sedative and extrapyramidal side effects of haloperidol and may require dose adjustments.

• Renal and Hepatic Impairment: Dosing adjustments are necessary in patients with severe renal or hepatic dysfunction.

13. Therapeutic Uses

• Schizophrenia: Often used for acute exacerbations and maintenance therapy.

• Acute Psychotic States: Including manic episodes and agitation.

• Tourette Syndrome: Used to reduce the frequency and severity of tics.

• Severe Behavioral Disorders: In some cases, haloperidol may be used in the management of severe behavioral problems, particularly in non-psychotic patients.

14. Monitoring and Follow-Up

• EKG Monitoring: For QT prolongation in high-risk patients.

• Extrapyramidal Symptoms: Regular assessment for signs of EPS, particularly during dose escalation.

• Liver and Renal Function: Monitor liver enzymes and renal function in patients with preexisting conditions or during prolonged therapy.

15. Overdose Management

• Symptoms of Overdose: Severe sedation, hypotension, extrapyramidal symptoms, and respiratory depression.

• Treatment Protocols: Overdose management involves supportive care, including maintaining airway patency, cardiovascular monitoring, and administering antidotes for EPS (e.g., diphenhydramine for dystonic reactions).

• Supportive Measures: Maintain adequate hydration, treat symptoms of hypotension, and monitor respiratory function.

16. Patient Counseling Information

• Key Points:

  • Take haloperidol as prescribed, and do not stop abruptly to avoid withdrawal symptoms.

  • Be aware of possible side effects like sedation, dizziness, and movement problems.

  • Report any unusual movements (e.g., tongue or facial grimacing) to your doctor.

  • Avoid alcohol and other CNS depressants while taking this medication.

  • Regular follow-ups are needed to monitor for side effects like tardive dyskinesia, and liver function should be checked periodically.

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