Promethazine - Drug Monograph

Introduction

Promethazine is a first-generation phenothiazine derivative with antihistaminic, antiemetic, anticholinergic, and sedative properties. First introduced in the 1940s, it remains widely used in clinical practice despite the development of newer agents. Promethazine is available in various formulations including oral tablets, syrups, suppositories, and injectable solutions.

Mechanism of Action

Promethazine exerts its therapeutic effects through multiple mechanisms:

• Histamine H₁ receptor antagonism: Competitive inhibition at peripheral H₁ receptors mediates its antihistaminic effects
• Dopamine D₂ receptor antagonism: Blocks dopamine receptors in the chemoreceptor trigger zone, providing antiemetic effects
• Muscarinic acetylcholine receptor antagonism: Contributes to its anticholinergic and anti-motion sickness properties
• Alpha-adrenergic receptor blockade: May contribute to sedative and hypotensive effects
• Local anesthetic effects: Sodium channel blockade contributes to its efficacy in pain management when combined with opioids

Indications

• Allergic conditions (allergic rhinitis, urticaria, angioedema)
• Motion sickness prevention and treatment
• Nausea and vomiting management
• Postoperative sedation and analgesia adjunct
• Nighttime sedation

• Acute migraine treatment (often combined with analgesics)
• Anxiety management (short-term)
• Insomnia treatment
• Symptomatic treatment of upper respiratory infections

Dosage and Administration

• Allergic conditions: 25 mg orally at bedtime or 12.5 mg before meals and at bedtime
• Motion sickness: 25 mg orally twice daily
• Nausea/vomiting: 12.5-25 mg orally/rectally/IM every 4-6 hours as needed
• Sedation: 25-50 mg orally/IM at bedtime

• Allergic conditions: 0.1 mg/kg/dose (max 12.5 mg) orally tid or 0.5 mg/kg/dose (max 25 mg) at bedtime
• Motion sickness: 0.5 mg/kg orally divided bid (max 25 mg bid)
• Nausea/vomiting: 0.25-0.5 mg/kg orally/rectally/IM every 4-6 hours (max 25 mg)

• Geriatric: Use lower doses due to increased sensitivity
• Hepatic impairment: Dose reduction recommended
• Renal impairment: Caution advised; consider dose reduction

• Avoid intravenous administration (risk of severe tissue injury)
• Deep intramuscular injection preferred
• Oral administration with food may reduce GI upset

Pharmacokinetics

Contraindications

• Known hypersensitivity to promethazine or other phenothiazines
• Comatose states
• CNS depression from alcohol, barbiturates, opioids, or other agents
• Neonates and infants younger than 2 years
• Intravenous administration (boxed warning)
• Concomitant use with MAO inhibitors (within 14 days)

Warnings and Precautions

• Tissue injury, gangrene, and amputation with intravenous administration
• Respiratory depression in children (avoid use in children <2 years)

• CNS depression: May impair mental/physical abilities; caution with hazardous activities
• Respiratory depression: Especially in children, elderly, and those with respiratory conditions
• Seizures: May lower seizure threshold
• Neuroleptic malignant syndrome: Rare but potentially fatal
• Extrapyramidal symptoms: Particularly in children and young adults
• Bone marrow suppression: Agranulocytosis and other blood dyscrasias reported
• Anticholinergic effects: Use caution in patients with glaucoma, prostate hypertrophy, GI obstruction
• QT prolongation: May occur at high doses
• Paradoxical reactions: Excitement, nightmares, hallucinations (especially in children)

Drug Interactions

• CNS depressants (alcohol, benzodiazepines, opioids): Additive CNS depression
• MAO inhibitors: Risk of hypertensive crisis and severe anticholinergic effects
• Anticholinergic agents: Enhanced anticholinergic effects
• QT-prolonging agents: Increased risk of torsades de pointes
• CYP2D6 inhibitors: May increase promethazine levels

• Epinephrine: Reversed pressor effect due to alpha-blockade
• Guanethidine: Inhibited antihypertensive effect
• Lithium: Possible neurotoxicity
• SSRIs/SNRIs: Increased risk of serotonin syndrome

Adverse Effects

• Sedation/drowsiness
• Dry mouth
• Blurred vision
• Dizziness
• GI disturbances

• Respiratory depression
• Neuroleptic malignant syndrome
• Severe extrapyramidal reactions
• Blood dyscrasias (agranulocytosis, leukopenia)
• Seizures
• Jaundice
• Cardiovascular effects (hypotension, tachycardia, QT prolongation)
• Tissue necrosis with extravasation
• Anaphylaxis

Monitoring Parameters

• Respiratory status, especially in high-risk populations
• Mental status and sedation level
• Signs of extrapyramidal symptoms
• Blood pressure and heart rate
• Complete blood count with prolonged use
• Signs of tissue injury at injection site
• Therapeutic efficacy for indicated condition
• Signs of anticholinergic toxicity

Patient Education

• This medication may cause significant drowsiness; avoid driving or operating machinery
• Avoid alcohol and other CNS depressants while taking promethazine
• Rise slowly from sitting/lying position to prevent dizziness
• Report any difficulty breathing, muscle stiffness, or unusual movements
• Use sugar-free formulations if diabetic
• Notify healthcare provider of all medications being taken
• Keep out of reach of children
• Do not use in children under 2 years due to risk of serious breathing problems
• Report any pain, swelling, or redness at injection site immediately

References

1. FDA Prescribing Information: Promethazine Hydrochloride Injection 2. Lexicomp Drug Information: Promethazine 3. Thiopurine S-methyltransferase pharmacogenetics: variant allele functional and comparative genomics. Pharmacogenet Genomics. 2005 4. Phenothiazines and sudden infant death syndrome. Pediatrics. 2009 5. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2017 6. Clinical Pharmacology of Promethazine: A Systematic Review. Clin Pharmacokinet. 2020 7. Drug-induced QT interval prolongation: mechanisms and clinical management. Ther Adv Drug Saf. 2012 8. Practice guideline for the treatment of patients with delirium. Am J Psychiatry. 1999