Are antimuscarinic effects common in hydroxyzine overdose? A cohort analysis of antimuscarinic effects in hydroxyzine and diphenhydramine-poisoned patients

IntroductionExposures to hydroxyzine, a first-generation H1 antihistamine, have increased rapidly over the last two decades. Many assumptions about hydroxyzine poisoning are based on other antihistamines, like diphenhydramine. However, the receptor affinities of hydroxazine suggest that there should be fewer antimuscarinic findings than diphenhydramine.MethodsThis was a cohort study that compared hydroxyzine and diphenhydramine exposures reported to the National Poison Data System between January 1, 2000, and December 31, 2020, and the Toxicologic Investigators Consortium Core Registry between January 1, 2010, and December 31, 2020. The primary outcome was to assess for antimuscarinic findings in hydroxyzine-poisoned patients, using diphenhydramine-poisoned patients as a comparison group. The secondary outcomes were to assess for markers of overall toxicity. Inclusion criteria were single-substance exposures with known outcomes. Exclusion criteria for National Poison Data System exposures were chronic exposures, unintentional exposures, and patients younger than 12 years old. There were no exclusion criteria for exposures reported to the Toxicologic Investigators Consortium Core Registry.ResultsThere were 17,265 hydroxyzine and 102,354 diphenhydramine exposures reported to the National Poison Data System and 134 hydroxyzine and 1,484 diphenhydramine exposures reported to the Toxicologic Investigators Consortium Core Registry that met inclusion criteria. In both datasets, hydroxyzine-poisoned patients had lower rates and relative risk of developing antimuscarinic findings or receiving physostigmine, with the exception of hyperthermia in the Toxicologic Investigators Consortium Core Registry dataset. Coma/central nervous system depression (major), respiratory depression, seizures, ventricular dysrhythmias, intubation, and benzodiazepine administration were less likely in hydroxyzine-poisoned patients, but central nervous system depression (mild) was more likely in exposures reported to the National Poison Data System. The mortality in hydroxyzine-poisoned patients was rare: 0.02% and 0.8% of exposures reported to the National Poison Data System and Toxicologic Investigators Consortium Core Registry, respectively.DiscussionThe clinical manifestations of hydroxyzine exposures are consistent with the pharmacology of hydroxazine. The clinical effects were consistent across two United States national datasets. Clinicians should not generalize the illness script of diphenhydramine exposures to hydroxyzine exposures.ConclusionsHydroxyzine-poisoned patients were less likely to develop antimuscarinic findings than diphenhydramine-poisoned patients. Hydroxyzine-poisoned patients were more likely to have mild central nervous system depression than an antimuscarinic toxidrome.