Mechanism of Action of Promethazine (Phenergan)
Promethazine primarily works through multiple mechanisms including histamine H1-receptor antagonism, dopamine receptor blockade, and anticholinergic effects, making it effective as an antihistamine, antiemetic, and sedative agent.
Primary Mechanisms of Action
Histamine H1-receptor antagonism: Promethazine competitively blocks H1 receptors, inhibiting most (but not all) pharmacologic effects of histamine mediated at these receptors 1, 2
Dopaminergic blockade: It blocks postsynaptic dopaminergic receptors in the brain, contributing to its antiemetic properties 1
Strong alpha-adrenergic inhibitory effect: This contributes to its sedative properties and potential hypotensive side effects 1
Anticholinergic effects: Promethazine possesses significant anticholinergic properties that contribute to its clinical effects and side effect profile 1
Pharmacokinetics
Onset of action: Clinical effects are evident within 5 minutes of intravenous administration and within 20 minutes after oral administration 1, 2
Duration of action: 4-6 hours, although effects may persist for up to 12 hours 1, 2
Half-life: Plasma half-life is 9-16 hours 1
Metabolism: Promethazine is metabolized by the liver to various compounds, with sulfoxides of promethazine and N-demethylpromethazine being the predominant metabolites appearing in the urine 2
Absorption: Well absorbed from the gastrointestinal tract when administered orally 2
Clinical Applications
Antiemetic effects: Used for management of postoperative nausea and vomiting 1
Antihistaminic effects: Effective for management of allergic reactions and anaphylaxis 1
Sedative properties: Used as an adjuvant for postoperative pain and sedation 1
Anticholinergic effects: Contributes to its overall clinical profile 1
Important Considerations and Adverse Effects
Respiratory effects: Can cause respiratory depression, particularly when combined with other central nervous system depressants 1
Cardiovascular effects: May cause hypotension, particularly when administered intravenously at rapid rates 1
Neurological effects: Can cause extrapyramidal effects ranging from restlessness to oculogyric crises, as well as neuroleptic malignant syndrome 1
Administration cautions: The FDA has added warnings regarding parenteral administration due to risks of tissue injury with incorrect administration 1, 3
Autonomic effects: Despite its anticholinergic properties, research suggests minimal effects on autonomic cardiovascular mechanisms 4
Clinical Pearls
Dosing: The usual dose of promethazine is 12.5-25 mg intravenously, infused slowly (25 mg/min) to minimize hypotension risk 1
Administration safety: Intravenous administration should be performed with caution due to risks of extravasation, tissue necrosis, and inadvertent intra-arterial injection 1, 5
Drug interactions: Exhibits enhanced sedative effects when combined with other CNS depressants such as benzodiazepines and opioids 1
Pediatric considerations: Use in children under 2 years of age has been associated with significant risks including sedation, agitation, hallucinations, and potentially life-threatening events 6