Although promethazine is classified as a phenothiazine, its ability to antagonize dopamine is approximately one-tenth that of chlorpromazine. For this reason, promethazine is not used as a neuroleptic. Like other antihistamines, promethazine does not prevent the release of histamine, as do cromolyn and nedocromil, but competes with free histamine for binding at HA-receptor sites. Histamine receptors in the GI tract, uterus, large blood vessels, and bronchial muscle are blocked. Other CNS receptor sites can also be affected, since promethazine is believed to indirectly reduce stimuli to the brain stem reticular system.
Sedation is significant at concentrations achieved from therapeutic dosages.
Antitussive activity has been attributed to promethazine, but this effect probably results from anticholinergic and sedative actions. Local anesthetic activity requires higher concentrations than those required to antagonize histamine receptors. Onset of action occurs within 15-60 minutes after oral or rectal administration and within 20 minutes after intramuscular administration. Following intravenous administration, onset of action occurs within 3-5 minutes. Promethazine is highly protein-bound.