Thorazine

Thorazine (chlorpromazine hydrochloride) is a first-generation typical antipsychotic medication belonging to the phenothiazine class. It represents a foundational agent in psychopharmacology, primarily indicated for the management of manifestations of psychotic disorders, severe behavioral problems in children, and as an adjunctive treatment for intractable hiccups, nausea, and vomiting. Its mechanism of action is primarily through antagonism of postsynaptic mesolimbic dopaminergic D1 and D2 receptors in the brain, though it also exhibits significant antagonism at adrenergic, cholinergic, and histaminergic receptors, contributing to both its therapeutic effects and its side effect profile. This broad receptor activity underpins its use across a spectrum of conditions, establishing it as a versatile, though potent, therapeutic tool in both psychiatric and general medical practice.

Features

• Active Ingredient: Chlorpromazine Hydrochloride.
• Drug Class: First-generation (typical) antipsychotic; Phenothiazine derivative.
• Available Formulations: Oral tablets, oral concentrate solution, and injectable forms (IM/IV).
• Mechanism of Action: Potent antagonist of dopamine D2 receptors in the mesolimbic pathway. Also acts as an antagonist at alpha-1 adrenergic receptors, muscarinic (M1) cholinergic receptors, and histamine (H1) receptors.
• Bioavailability: Oral bioavailability is significant but variable and subject to extensive first-pass metabolism.
• Half-life: Approximately 30 hours, allowing for once or twice-daily dosing in maintenance therapy.
• Metabolism: Hepatically metabolized via the cytochrome P450 system, primarily by CYP2D6, into multiple active and inactive metabolites.

Benefits

• Provides rapid control of acute psychotic agitation and positive symptoms of schizophrenia, such as hallucinations and delusions.
• Offers a reliable therapeutic option for treatment-resistant nausea, vomiting, and persistent hiccups (singultus) where conventional therapies have failed.
• Serves as an effective agent for the preoperative relief of restlessness and apprehension.
• Can be utilized as adjunctive therapy in the treatment of tetanus, acute intermittent porphyria, and severe behavioral problems in pediatric patients.
• Its long history of use provides a well-understood efficacy and safety profile for clinicians.
• Available in multiple formulations (tablet, liquid, injectable) allows for flexible dosing strategies across different clinical settings, from outpatient management to acute inpatient care.

Common use

Thorazine is indicated for a range of psychiatric and non-psychiatric conditions. Its primary use is in the management of psychotic disorders, including schizophrenia, to control psychomotor agitation, aggressiveness, impulsivity, and mood lability. It is effective in mitigating the positive symptoms of psychosis. Beyond psychiatry, it is a potent antiemetic used to manage severe nausea and vomiting associated with conditions like uremia, radiation sickness, cancer chemotherapy, and surgery. It is also FDA-approved for the treatment of intractable hiccups. Furthermore, it is used as an adjunct in the treatment of tetanus and for the short-term treatment of hyperactive children who show excessive motor activity with conduct disorders.

Dosage and direction

Dosage must be highly individualized based on diagnosis, severity of symptoms, patient response, and tolerance to side effects. Therapy should be initiated at the lowest effective dose.

• Psychotic Disorders (Adults): Oral: Initial dose is typically 25 mg to 50 mg two to four times daily, titrated upward by 25 mg to 50 mg every other day as tolerated. The usual maintenance dose ranges from 200 mg to 800 mg daily in divided doses, though some patients may require higher doses. IM: For rapid control of acute agitation, 25 mg to 50 mg is administered. Subsequent doses of 25 mg to 50 mg may be given in 1 to 4 hours, gradually increasing to a maximum of 400 mg every 4 to 6 hours until symptom control is achieved.
• Nausea and Vomiting (Adults): Oral: 10 mg to 25 mg every 4 to 6 hours as needed. IM: 25 mg to 50 mg, repeated every 3 to 4 hours as necessary.
• Intractable Hiccups (Adults): Oral/IM: 25 mg to 50 mg three to four times daily.
• Geriatric or Debilitated Patients: Initiate at lower doses (10 mg to 25 mg once or twice daily) and titrate more slowly due to increased susceptibility to side effects, particularly hypotension and sedation.
• Pediatric Patients (for severe behavioral problems or nausea/vomiting): Dosing is based on body weight (0.5 mg/kg per dose every 4 to 6 hours orally or IM). The total daily dose should not exceed 40 mg for children under 5 years or 75 mg for children aged 5 to 12 years.

The oral concentrate must be diluted just prior to administration in at least 60 mL (2 fl oz) of a suitable liquid (e.g., water, juice, milk). Administration with food or milk can help minimize gastrointestinal upset.

Precautions

• Neurologic Effects: Use with extreme caution in patients with a history of seizures or conditions that may lower the seizure threshold. Parkinsonian-like symptoms, akathisia, and dystonia can occur.
• Cardiovascular Effects: Orthostatic hypotension is common, especially with initial dosing and parenteral administration. Use cautiously in patients with cardiovascular disease, noting that the drug can cause ECG changes (e.g., prolonged QT interval, T-wave blunting).
• Hematologic Effects: There is a risk of agranulocytosis and leukopenia. Patients should report any signs of infection (e.g., fever, sore throat) immediately.
• Hepatic Impairment: Metabolized by the liver; use with caution and potentially at reduced doses in patients with hepatic disease.
• Ocular Effects: Long-term use is associated with pigmentary retinopathy and corneal deposits. Regular ophthalmological examinations are recommended.
• Temperature Regulation: Can impair the body’s ability to reduce core temperature, leading to hyperthermia or heat stroke, particularly in elderly patients and in hot weather.
• Sedation: Marked sedation can impair mental and/or physical abilities required for hazardous tasks like driving or operating machinery.
• Abrupt Discontinuation: Sudden cessation after long-term, high-dose therapy should be avoided to prevent withdrawal symptoms or rapid recurrence of psychotic symptoms.

Contraindications

Thorazine is contraindicated in patients with known hypersensitivity to chlorpromazine or any phenothiazine. Its use is also contraindicated in patients with significant CNS depression (e.g., comatose states) due to alcohol, barbiturates, opioids, etc., or in the presence of bone marrow suppression. It should not be used in patients with suspected or established subcortical brain damage, as it can worsen the condition. Due to its hypotensive effects, it is contraindicated in patients with severe hypotension or hypertension.

Possible side effect

Side effects are common and are often dose-related, stemming from its antagonism of various neurotransmitter receptors.

• Common: Drowsiness/sedation, dizziness, orthostatic hypotension, dry mouth, blurred vision, constipation, nausea, weight gain, photosensitivity.
• Neurologic (Extrapyramidal Symptoms - EPS): Parkinsonism (tremor, rigidity, bradykinesia), akathisia (motor restlessness), acute dystonic reactions (muscle spasms, torticollis, oculogyric crisis). Tardive dyskinesia (involuntary, repetitive movements) is a risk with long-term therapy.
• Endocrine: Galactorrhea, amenorrhea, gynecomastia, impotence, due to hyperprolactinemia.
• Cardiovascular: Tachycardia, ECG changes (QT prolongation, T-wave abnormalities), syncope.
• Dermatologic: Skin rashes, contact dermatitis, photosensitivity reactions.
• Hematologic: Agranulocytosis, leukopenia, eosinophilia, thrombocytopenic purpura (rare but serious).
• Ocular: Pigmentary retinopathy, corneal and lens deposits.
• Other: Neuroleptic malignant syndrome (NMS—a medical emergency characterized by fever, muscle rigidity, altered mental status, and autonomic dysfunction), cholestatic jaundice.

Drug interaction

Thorazine has a significant potential for drug interactions due to its metabolism and pharmacodynamic effects.

• CNS Depressants: Concomitant use with alcohol, benzodiazepines, opioids, sedative-hypnotics, or general anesthetics can result in additive CNS depression.
• Antihypertensives: May potentiate the effects of other antihypertensive drugs, leading to severe hypotension.
• QT-Prolonging Agents: Concurrent use with other drugs known to prolong the QT interval (e.g., Class IA/III antiarrhythmics, certain antibiotics, other antipsychotics) may increase the risk of life-threatening cardiac arrhythmias, including torsades de pointes.
• Anticholinergics: May potentiate the anticholinergic effects of other drugs (e.g., dry mouth, constipation, urinary retention, blurred vision).
• Levodopa: May antagonize the effects of levodopa in Parkinson’s disease.
• Enzyme Inhibitors/Inducers: CYP2D6 inhibitors (e.g., fluoxetine, paroxetine) can increase chlorpromazine plasma levels. CYP inducers (e.g., carbamazepine, rifampin) can decrease its levels and efficacy.

Missed dose

If a dose is missed, it should be taken as soon as it is remembered. However, if it is almost time for the next scheduled dose, the missed dose should be skipped, and the regular dosing schedule resumed. Patients should not double the next dose to make up for a missed one, as this increases the risk of adverse effects.

Overdose

Overdose is primarily an extension of its pharmacological actions, manifesting as profound CNS depression (ranging from sedation to coma), hypotension, extrapyramidal symptoms, agitation, restlessness, convulsions, hypothermia, and autonomic reactions (e.g., dry mouth, ileus). ECG changes, including QT prolongation, are likely. Cardiac arrhythmias and respiratory depression are serious, potentially fatal complications. There is no specific antidote. Management is supportive and symptomatic, focusing on securing the airway, ensuring ventilation, and managing hypotension with IV fluids and vasopressors (avoiding epinephrine). Gastric lavage may be considered if presentation is early. ECG monitoring is essential. Forced diuresis is not effective.

Storage

Store at controlled room temperature, 20°C to 25°C (68°F to 77°F). Protect from light and moisture. Keep the oral concentrate in its original, light-resistant container. Keep all medications out of the reach of children and pets. Do not freeze the liquid formulation. Properly discard any unused medication after the expiration date.

Disclaimer

This information is for educational and professional medical reference purposes only and is not a substitute for the professional judgment of a qualified healthcare provider in diagnosing and treating patients. The content does not cover all possible uses, directions, precautions, interactions, or adverse effects. The author and publisher disclaim any responsibility for any liability, loss, or risk, personal or otherwise, which is incurred as a consequence, directly or indirectly, of the use and application of any of the material presented. Dosing and treatment decisions must be made by a licensed medical professional based on individual patient circumstances.

Reviews

• Clinical Efficacy (Psychosis): “Thorazine remains a cornerstone for managing acute psychotic agitation. Its rapid onset of action, particularly with IM administration, is invaluable in the emergency setting for de-escalation. While the side effect profile is more pronounced than with SGAs, its efficacy and cost-effectiveness for certain patient populations are undeniable.” – Board-Certified Psychiatrist
• Utility in Treatment-Resistant Hiccups: “As a gastroenterologist, I have found chlorpromazine to be remarkably effective for intractable singultus that has failed all other pharmacological interventions. It is often a last-resort option, but its success rate in this specific indication is impressive.” – Gastroenterologist
• Side Effect Management: “The challenge with chlorpromazine is balancing its potent antiemetic or antipsychotic effects with the significant risk of extrapyramidal symptoms and sedation. It requires vigilant monitoring, especially during dose titration. Patient education on orthostatic hypotension is crucial.” – Clinical Pharmacist
• Historical Context: “While newer agents are often first-line today, understanding the pharmacology and clinical use of chlorpromazine is fundamental. It defined an era of psychiatric treatment and its applications in medicine are a testament to its powerful receptor activity.” – Professor of Pharmacology