Promethazine

• Nausea and vomiting prevention and treatment
• Allergic rhinitis and other allergic conditions
• Motion sickness prevention
• Sedation (preoperative and postoperative)
• Adjunct in anaphylaxis treatment

Promethazine is a first-generation antihistamine with additional antiemetic, sedative, and anticholinergic properties. Originally developed as an antihistamine, it has found widespread use for prevention and treatment of nausea and vomiting, as a sedative, and as an adjunct in pain management. Its versatility makes it valuable in multiple clinical settings, though safety considerations limit its use in certain populations.

Mechanism of Action

Promethazine exerts its effects through multiple receptor interactions. As a histamine H1 receptor antagonist, it blocks the effects of histamine on capillaries, bronchial smooth muscle, and the gastrointestinal tract. Its antiemetic effect results primarily from blocking H1 receptors and muscarinic receptors in the vomiting center and chemoreceptor trigger zone. The sedative effects are mediated through central H1 blockade. Promethazine also has significant anticholinergic activity and weak antidopaminergic properties, contributing to both therapeutic effects and side effects.

The medication has local anesthetic properties due to its membrane-stabilizing effects, which may contribute to its ability to relieve itching and irritation associated with allergic reactions.

Available Formulations

Promethazine (Phenergan) is available in multiple formulations including oral tablets (12.5 mg, 25 mg, 50 mg), oral solution (6.25 mg/5 mL), suppositories (12.5 mg, 25 mg, 50 mg), and injectable solution (25 mg/mL, 50 mg/mL) for deep intramuscular or intravenous use. The variety of formulations allows administration even when nausea prevents oral intake. Combination products with codeine (Phenergan with Codeine) are available for cough suppression.

FDA-Approved Indications

Promethazine is FDA-approved for allergic conditions (perennial and seasonal allergic rhinitis, allergic conjunctivitis, uncomplicated allergic skin manifestations of urticaria and angioedema), prevention and control of nausea and vomiting associated with certain types of anesthesia and surgery, therapy adjunct in anaphylactic reactions (after acute symptoms controlled with epinephrine), preoperative, postoperative, or obstetric sedation, and prevention and treatment of motion sickness.

Dosing Guidelines

For allergic conditions, the typical adult dose is 25 mg orally at bedtime, or 12.5 mg before meals and at bedtime. For nausea and vomiting, 12.5-25 mg every 4-6 hours as needed is typical. For sedation, 25-50 mg at bedtime or preoperatively. For motion sickness, 25 mg 30-60 minutes before travel, repeated every 8-12 hours as needed. Doses should be reduced in elderly patients and those with hepatic impairment.

Boxed Warning for Respiratory Depression in Children

Promethazine carries a boxed warning contraindicated in children less than 2 years of age due to the potential for fatal respiratory depression. In children 2 years and older, use the lowest effective dose and avoid combination with other respiratory depressants. Promethazine should not be used for treatment of uncomplicated vomiting in children; use should be limited to prolonged vomiting of known etiology.

Important Safety Considerations

Beyond the pediatric concerns, promethazine causes significant sedation and impairs mental and physical abilities required for tasks such as driving. Anticholinergic effects include dry mouth, urinary retention, constipation, and blurred vision. The medication can lower the seizure threshold and should be used cautiously in patients with seizure disorders. Neuroleptic malignant syndrome has been reported. Avoid concurrent use with other CNS depressants including opioids, sedatives, and alcohol.

Injection Site Concerns

Intravenous administration of promethazine has been associated with severe tissue injury including gangrene requiring amputation. The preferred route is deep intramuscular injection. If IV administration is necessary, it should be given through a running IV line at the port furthest from the patient's vein, at a concentration no greater than 25 mg/mL, at a rate not exceeding 25 mg/minute. Subcutaneous and intra-arterial injection are contraindicated.

Drug Interactions

CNS depressants (opioids, benzodiazepines, alcohol) have additive effects and may cause profound sedation or respiratory depression. Anticholinergic drugs increase the risk of adverse effects. MAO inhibitors may prolong and intensify anticholinergic effects. Promethazine may enhance the hypotensive effects of antihypertensive agents. It may interfere with pregnancy tests and glucose tolerance tests.

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