Shortly after their introduction in the 1940s, the potential for severe adverse effects associated with their use was reported [11,12,13]. These older AHs have poor receptor selectivity and non-specifically bind muscarinic, serotonin, and α-adrenergic receptors, as well as cardiac potassium ion channels, leading to several intolerable and potentially life-threatening adverse effects . They also cross the blood–brain barrier and may lead to significant CNS suppression and toxicity resulting in psychomotor impairment, coma, and even death . Because of safety concerns, in 2009 Health Canada recommended that 1st Generation antihistamines not be sold in combination with other drugs to children under 6 for coughs and colds .
CNS suppression: sedation, poor sleep quality and decreased cognitive performance
Older, first-generation AHs are commonly used as sleep aids because of their strong sedative qualities. Surprisingly, the dose utilized for sleep induction is the same dose used for rhinitis symptoms. Despite their sedative effects, these older medications do not result in quality sleep [16, 17]. After a night-time dose of chlorpheniramine (1st generation), next-day “hang-over” effects like impaired vigilance, divided attention, working memory, sensory-motor performance, and reduced latency to daytime sleep has been observed .
In addition to poor sleep quality and increased sedation, older AHs have also been associated with decreased school performance measures . Walker et al. found that students with symptoms of allergic rhinitis were 40% more likely to drop a grade from practice tests to final examinations and 70% more likely to drop a grade if they reported taking older sedating AHs .
CNS impairment and accidents
First-generation AHs have been associated with injuries and fatalities due to car, plane, and boating accidents . A randomized controlled trial comparing fexofenadine 60 mg, diphenhydramine 50 mg, alcohol (0.1% blood alcohol concentration), and placebo found that driving performance was the poorest after diphenhydramine use and that drowsiness ratings were not predictive of the level of impairment . Despite warnings that diphenhydramine may cause drowsiness and should not be taken when operating machinery it is not specified that this includes driving .
In a review of 484 fatalities in Ontario, drivers who were killed in car accidents and found to be at fault were 1.5 times more likely to have been under the influence of first-generation AHs . The European Union has labelled diphenhydramine a Category III drug indicating that it is likely to produce severe effects on fitness to drive . This carries their highest warning level and the recommendation: “Do not drive. Seek medical advice before driving again.” .
In a recent review of toxicology testing profiles from 6677 fatally injured civil aviation pilots in the United States from 1990 to 2012, diphenhydramine was the drug most commonly found on autopsy that was capable of causing impairment (7.3%) . Due to the increased risk, first-generation AHs are banned for use by commercial and military airline pilots before or during flights [2, 5].
Overdose and toxicity
Diphenhydramine and other first-generation AHs are documented drugs of abuse, and overdose can result in significant anti-cholinergic effects including fever, flushing, pupillary dilatation, urinary retention, tachycardia, hypotension and coma . Infants and children who experience accidental or intentional overdose may present with paradoxical excitation including irritability, hallucinations, and seizures followed by drowsiness, delirium, respiratory depression and coma [14, 23, 24]. In 2003, 28,092 exposures to diphenhydramine were reported to poison control centres in the United States—11,355 (40.4%) of these cases were in children under the age of six, resulting in at least six fatalities .
Risk of QT prolongation and torsade de pointes
Cardiac toxicity is an increasing concern with use of first-generation AHs, especially amongst older patients with significant comorbidities and polypharmacy via drug interactions.
The cardiac safety of first generation antihistamines was never studied as this was an unknown risk when introduced. In June 2016, Health Canada released a safety recall regarding hydroxyzine and issued a “black box” warning hydroxyzine can increase the risk of QT prolongation and torsade de pointes. Hydroxyzine has the potential to cause dizziness, palpitations, syncope, seizures, or sudden cardiac death [25, 26]. Furthermore, the new maximum daily dose has been reduced to 100 mg in adults and 50 mg in the elderly, if the medication cannot be entirely avoided.