Antihistamines vary significantly in how they affect the brain, with older medicines causing more drowsiness and cognitive impairment than newer options.
First-generation antihistamines such as chlorphenamine, diphenhydramine and promethazine, developed in the 1940s, easily cross the blood-brain barrier and block histamine receptors that maintain alertness. Brain imaging studies show these older drugs block more brain histamine receptors than newer antihistamines, leading to greater sleepiness, slower reaction times and reduced concentration.
Second-generation antihistamines introduced in the 1980s and 1990s, including loratadine, cetirizine and fexofenadine, were designed to cause fewer side-effects. One study found fexofenadine occupied around 2% of brain histamine receptors, compared with 24% for cetirizine and 50 to 60% for chlorpheniramine. This variation explains why some "non-drowsy" antihistamines may still cause sleepiness in certain people.
Researchers increasingly view antihistamines as existing on a spectrum rather than falling into two distinct groups. Some older antihistamines have strong effects on alertness while some newer medicines have mild or very little effect on the brain.
Beyond drowsiness, older antihistamines also block acetylcholine, a chemical messenger involved in memory, learning and attention. These anticholinergic effects can cause dry mouth, blurred vision, constipation, dizziness and confusion, with potentially more serious consequences in older people. While research has not proved these medicines directly cause dementia, findings have strengthened advice to avoid unnecessary anticholinergic use in older populations.
Dipa Kamdar, Associate Professor in Pharmacy Practice at Kingston University, notes that people who drive, study or take multiple medicines may benefit from antihistamines less likely to cause sleepiness.