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Tuesday, July 29, 2025

Promethazine (Phenergan)


Generic Name: Promethazine
Brand Names: Phenergan, Promethegan, Phenadoz
Drug Class: First-generation antihistamine; Phenothiazine derivative
Formulations: Oral tablets, syrup, rectal suppositories, injectable solution
Route of Administration: Oral, rectal, intramuscular, intravenous (IV with extreme caution)

1. Pharmacological Classification

Promethazine is a first-generation antihistamine from the phenothiazine class. While structurally related to antipsychotics such as chlorpromazine, it exhibits predominantly antihistaminic, antiemetic, sedative, and anticholinergic properties with negligible antipsychotic effects at standard doses.

2. Mechanism of Action

Promethazine acts primarily as:

  • H1 receptor antagonist: It competitively inhibits histamine at H1 receptors in the respiratory tract, gastrointestinal tract, and blood vessels, relieving allergic symptoms and inducing sedation.

  • Anticholinergic activity: Blocks muscarinic receptors, which contributes to its anti-nausea and anti-motion sickness effects.

  • Dopamine receptor antagonist (D2 blockade): At higher doses, this effect helps in treating nausea and vomiting, but also contributes to extrapyramidal side effects.

  • Alpha-adrenergic blockade: Can cause orthostatic hypotension due to inhibition of vasoconstriction.

3. Therapeutic Uses

Promethazine is used in various clinical scenarios due to its multi-receptor effects:

a. Antiemetic

  • Management of nausea and vomiting due to motion sickness, postoperative state, chemotherapy, or general illness.

b. Sedative/Hypnotic

  • As a preoperative sedative or adjunct to anesthesia.

  • For short-term insomnia where sedation is appropriate.

c. Allergic Conditions

  • Symptomatic relief of allergic rhinitis, urticaria, contact dermatitis, angioedema, and anaphylaxis adjunct (not primary treatment).

d. Motion Sickness Prevention

  • Effective for prophylaxis and treatment of motion sickness.

e. Cough and Cold

  • Often used in combination products for cough suppression (via central sedative effect) and for drying secretions due to anticholinergic activity.

f. Adjunct in Pain Management

  • Enhances the analgesic effect of opioids and may reduce opioid dosage.

4. Dosage Guidelines

a. Allergy (Adults)

  • 25 mg at bedtime or 12.5 mg before meals and at bedtime.

b. Motion Sickness

  • 25 mg orally 30–60 minutes before travel; then 12.5–25 mg every 8–12 hours as needed.

c. Nausea and Vomiting

  • 12.5–25 mg every 4–6 hours as required.

d. Sedation

  • 25–50 mg at bedtime.

e. Children (Caution advised)

  • Typically not recommended in children <2 years due to respiratory depression risk.

  • Age 2–12 years: individualized dose (commonly 0.25–0.5 mg/kg/dose) under medical supervision.

5. Pharmacokinetics

  • Absorption: Well absorbed orally and rectally.

  • Onset: 20 minutes (oral); 5 minutes (IV).

  • Duration: 4–6 hours (up to 12 hours for sedative effects).

  • Metabolism: Hepatic via CYP2D6 enzymes.

  • Elimination: Primarily renal, excreted as metabolites.

6. Contraindications

  • Children <2 years: Risk of fatal respiratory depression

  • Comatose states

  • Known hypersensitivity to promethazine or phenothiazines

  • Severe CNS depression or respiratory depression

  • Intra-arterial or subcutaneous injection (severe tissue damage risk)

  • Glaucoma, prostatic hypertrophy, bladder obstruction (caution due to anticholinergic effects)

7. Warnings and Precautions

a. Black Box Warning

  • Children <2 years: Contraindicated due to fatal respiratory depression

  • Severe tissue injury including gangrene with IV use; deep IM preferred

b. CNS Depression

  • Potentiates effects of alcohol, sedatives, hypnotics, opioids, and tranquilizers.

c. Extrapyramidal Symptoms

  • May cause dystonia, parkinsonism, or tardive dyskinesia, especially with high doses.

d. Anticholinergic Toxicity

  • Dry mouth, constipation, urinary retention, blurred vision, confusion—especially in the elderly.

e. Orthostatic Hypotension

  • Especially in elderly and those with cardiovascular disease.

f. Photosensitivity

  • Advise patients to use sun protection.

8. Adverse Effects

Common:

  • Drowsiness

  • Dizziness

  • Dry mouth

  • Blurred vision

  • Constipation

  • Photosensitivity

Serious:

  • Respiratory depression

  • Severe tissue damage (necrosis/gangrene) from IV administration

  • Seizures

  • Extrapyramidal symptoms: Tics, tremors, dystonia

  • Neuroleptic Malignant Syndrome

  • Agranulocytosis

  • Hallucinations or delirium in elderly patients

9. Drug Interactions

a. CNS Depressants

  • Enhanced CNS and respiratory depression with opioids, benzodiazepines, alcohol, barbiturates, and general anesthetics.

b. Anticholinergics

  • Increased risk of urinary retention, constipation, and confusion when combined with atropine, tricyclic antidepressants, or antipsychotics.

c. Monoamine Oxidase Inhibitors (MAOIs)

  • May potentiate CNS depression and anticholinergic effects.

d. QT-Prolonging Drugs

  • Additive risk with antiarrhythmics (amiodarone, sotalol) or antipsychotics.

e. Serotonergic Drugs

  • May enhance serotonergic effects; caution advised.

f. CYP2D6 Inhibitors

  • May affect promethazine metabolism (e.g., fluoxetine, paroxetine).

10. Special Populations

a. Pregnancy

  • Category C (old system); limited human data, animal studies show fetal toxicity at high doses.

  • Used cautiously for nausea and vomiting when benefits outweigh risks.

b. Lactation

  • Excreted in breast milk; may cause sedation in nursing infants. Use with caution.

c. Elderly

  • Higher sensitivity to CNS effects, falls, and anticholinergic burden.

  • Use lowest effective dose; monitor closely.

d. Hepatic/Renal Impairment

  • Use caution; impaired metabolism and clearance may lead to drug accumulation and increased toxicity.

11. Toxicity and Overdose

Symptoms:

  • Extreme drowsiness

  • Confusion

  • Seizures

  • Respiratory depression

  • Coma

  • Severe extrapyramidal reactions

Management:

  • Supportive care, activated charcoal if early ingestion

  • Airway protection and ventilation

  • IV fluids, benzodiazepines for seizures

  • No specific antidote available.

12. Clinical Considerations

  • Avoid IV route unless absolutely necessary; use IM for parenteral administration.

  • Advise patients about sedation risk when driving or operating machinery.

  • Avoid use with alcohol or other sedating agents.

  • For chronic allergic conditions, second-generation antihistamines (e.g., loratadine, cetirizine) are preferred due to fewer side effects.

13. Brand Formulations and Availability

  • Phenergan tablets: 10 mg, 25 mg, 50 mg

  • Phenergan syrup: 5 mg/5 mL

  • Phenergan suppositories: 12.5 mg, 25 mg

  • Promethegan rectal suppository

  • Phenadoz (oral disintegrating tablet or rectal form)

  • Generic versions widely available in oral, rectal, and injectable forms




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