Chlorpromazine

1. Drug Name

• Generic Name: Chlorpromazine

• Brand Names: Thorazine, Largactil, Chlorprom, and others.

2. Drug Classification

• Class: Antipsychotic Agent

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

3. Mechanism of Action

Chlorpromazine is a first-generation antipsychotic that exerts its therapeutic effects primarily through the dopamine D2 receptor antagonism. By blocking D2 receptors, particularly in the mesolimbic and mesocortical pathways, it reduces the symptoms of psychosis, such as delusions and hallucinations. Additionally, chlorpromazine has the following properties:

• Dopamine Antagonism: Chlorpromazine reduces dopaminergic activity in the brain, specifically in regions like the mesolimbic pathway, which is involved in the manifestation of psychotic symptoms. Its antagonism of D2 receptors is believed to alleviate symptoms of schizophrenia and other psychotic disorders.

• Receptor Affinity: Chlorpromazine also antagonizes other neurotransmitter receptors, including alpha-1 adrenergic receptors, histamine H1 receptors, and serotonin 5-HT2A receptors. These interactions contribute to its sedative, antiemetic, and other side effects.

• Anticholinergic Effects: Chlorpromazine has anticholinergic properties, which may contribute to side effects such as dry mouth, blurred vision, constipation, and urinary retention.

4. Pharmacokinetics

• Absorption: Chlorpromazine is well absorbed following oral administration, but it undergoes extensive first-pass metabolism, which reduces its bioavailability to approximately 25-30%.

• Distribution: Chlorpromazine is widely distributed throughout the body, including the central nervous system (CNS), and is highly protein-bound (90%) in plasma. Its volume of distribution (Vd) is high, indicating that it is extensively distributed in tissues.

• Metabolism: Chlorpromazine is metabolized extensively in the liver, primarily through CYP450 enzymes (mainly CYP2D6, CYP3A4), producing several metabolites, including active ones like chlorpromazine sulfoxide. The liver plays a central role in its metabolism, and hepatic dysfunction can affect its clearance.

• Excretion: The drug and its metabolites are primarily excreted via the urine, although a small amount is excreted in the feces. Chlorpromazine has a half-life of about 30 hours, though this can be prolonged in elderly patients or those with liver impairment.

• Special Considerations: In patients with liver impairment, dose adjustments may be necessary, as chlorpromazine is heavily metabolized by the liver. Elderly patients are particularly sensitive to the sedative effects and hypotension.

5. Indications

• Primary Indications:

  • Schizophrenia: Chlorpromazine is used to manage both acute and chronic psychotic disorders, including schizophrenia. It helps in reducing positive symptoms such as hallucinations, delusions, and agitation.

  • Bipolar Disorder: It is used in the acute management of manic episodes in bipolar disorder.

  • Severe Nausea and Vomiting: Chlorpromazine is effective as an antiemetic, particularly in patients who have not responded to other antiemetics.

  • Behavioral Disorders: It may be used off-label to manage severe behavioral problems, especially in children or individuals with developmental disabilities.

  • Acute Psychosis: Chlorpromazine is often used in the short-term management of acute psychotic episodes in both inpatient and outpatient settings.

• Off-label Uses:

  • Acute Agitation and Severe Anxiety: In some cases, chlorpromazine is used to help manage severe agitation and anxiety in patients with psychiatric conditions.

  • Intractable Hiccups: It is sometimes used off-label to treat persistent or severe hiccups that have not responded to other therapies.

6. Dosage and Administration

• Adult Dosing:

  • Schizophrenia (oral): The usual starting dose is 25–50 mg 2–3 times daily, which may be gradually increased to 200–800 mg/day, depending on the patient's response. Maintenance doses range between 100 to 400 mg per day.

  • Acute Psychosis (IV or IM): A typical initial dose for an acute episode is 25–50 mg, which can be repeated every 4–6 hours if needed.

  • Nausea and Vomiting (oral or IM): 10–25 mg 3–4 times daily, depending on the severity.

• Pediatric Dosing:

  • For behavioral problems: Dosing starts at 0.5–1 mg/kg per day, which can be increased depending on response, with a maximum of 6 mg/kg/day.

• Elderly Dosing: In elderly patients, initial doses should be lower (e.g., 12.5 mg–25 mg daily), with gradual increases, as they are more sensitive to the side effects like sedation and hypotension.

• Renal and Hepatic Impairment Dosing: Dose reductions may be necessary in patients with hepatic impairment due to reduced drug metabolism.

7. Contraindications

• Absolute Contraindications:

  • Known hypersensitivity to chlorpromazine or other phenothiazines.

  • Comatose patients or those in a state of CNS depression.

  • Severe hepatic dysfunction or bone marrow suppression.

• Relative Contraindications:

  • Cardiovascular disease: Use with caution in patients with cardiovascular disease, as chlorpromazine can cause hypotension and prolong the QT interval.

  • Parkinson’s disease: May worsen motor symptoms in patients with Parkinson’s disease due to its dopaminergic antagonism.

  • Severe respiratory diseases: Caution is required in patients with respiratory disorders, as chlorpromazine may depress respiratory function.

8. Warnings and Precautions

• Extrapyramidal Symptoms (EPS): Chlorpromazine is associated with the development of EPS, including tremors, rigidity, bradykinesia, and tardive dyskinesia, especially with long-term use. Early recognition and intervention are important.

• Neuroleptic Malignant Syndrome (NMS): Chlorpromazine can lead to NMS, a rare but life-threatening condition characterized by high fever, muscle rigidity, altered mental status, and autonomic instability. Immediate discontinuation of the drug is necessary.

• QT Prolongation: Chlorpromazine can prolong the QT interval, which may increase the risk of arrhythmias, particularly in patients with existing heart disease or electrolyte imbalances.

• Hypotension: Chlorpromazine can cause orthostatic hypotension, especially in the elderly or those receiving high doses.

• Blood Dyscrasias: Chlorpromazine may cause agranulocytosis or leukopenia, necessitating regular monitoring of blood counts during treatment.

9. Adverse Effects

• Common Adverse Effects:

  • Sedation and drowsiness are frequently reported, especially during the initiation of therapy.

  • Extrapyramidal Symptoms (EPS): Includes symptoms like tremors, rigidity, bradykinesia, and tardive dyskinesia with long-term use.

  • Anticholinergic Effects: Dry mouth, blurred vision, constipation, urinary retention.

  • Hypotension: Orthostatic hypotension is common, especially during the initial stages of treatment.

• Less Common but Clinically Significant Side Effects:

  • QT Prolongation: Risk of arrhythmias, particularly when used with other drugs that prolong the QT interval.

  • Neuroleptic Malignant Syndrome (NMS): Life-threatening condition requiring immediate cessation of the drug.

  • Liver Dysfunction: Can cause elevated liver enzymes or jaundice, indicating hepatic toxicity.

• Serious Adverse Effects:

  • Agranulocytosis and other blood disorders (e.g., leukopenia, thrombocytopenia).

  • Severe sedation and confusion, particularly in the elderly.

  • Tardive Dyskinesia: An irreversible condition that results in involuntary movements, especially of the face and tongue.

10. Drug Interactions

• Major Drug Interactions:

  • CNS Depressants: Concomitant use with alcohol, benzodiazepines, or other CNS depressants may potentiate sedation and respiratory depression.

  • QT-Prolonging Drugs: Use of chlorpromazine with other QT-prolonging medications (e.g., amiodarone, tricyclic antidepressants) increases the risk of arrhythmias.

  • Antihypertensive Medications: Chlorpromazine may enhance the hypotensive effects of other antihypertensive drugs.

  • CYP450 Inhibitors: Chlorpromazine is metabolized by CYP3A4 and CYP2D6, and drugs that inhibit these enzymes (e.g., fluoxetine, ketoconazole) can increase its plasma concentration.

• Food-Drug Interactions: No significant food-drug interactions, but alcohol should be avoided as it increases CNS depression.

11. Clinical Pharmacology

Chlorpromazine is a potent dopamine antagonist that provides both antipsychotic effects and additional sedative and antiemetic properties. It has a broad range of activity across various neurotransmitter systems, which accounts for both its therapeutic effects and its side-effect profile.

12. Special Populations

• Pregnancy Category: Category C; it should only be used during pregnancy if the benefits outweigh the risks.

• Lactation: Excreted in breast milk; not recommended unless necessary.

• Geriatrics and Pediatrics: Dose reduction may be necessary for elderly patients, as they are more prone to side effects. In pediatric populations, chlorpromazine is used with caution, particularly in the long-term management of behavioral disorders.

13. Therapeutic Uses

Chlorpromazine is primarily used for managing schizophrenia, acute psychosis, severe agitation, bipolar disorder, and severe nausea and vomiting. It is part of the treatment regimen for both acute exacerbations and long-term maintenance of psychiatric conditions.

14. Monitoring and Follow-Up

Regular monitoring is necessary for:

• Electrolyte levels (for patients on other medications that affect the heart or cause QT prolongation).

• Liver function tests, as chlorpromazine may cause hepatic dysfunction.

• Blood cell counts, especially during prolonged therapy to monitor for blood dyscrasias.

15. Overdose Management

• Symptoms of Overdose: Symptoms include severe sedation, hypotension, extrapyramidal symptoms, and coma.

• Treatment: Overdose management is largely symptomatic, with supportive care for respiratory and cardiovascular function. Antidotes for EPS may include diphenhydramine.

16. Patient Counseling Information

• Key Points:

  • Patients should take chlorpromazine as prescribed and not discontinue it abruptly.

  • Patients should avoid alcohol and sedatives during treatment.

  • Report any symptoms of abnormal movements, such as tremors or facial grimacing, to the healthcare provider.

  • Regular follow-up appointments are necessary to monitor for side effects, especially in long-term use.