Why do older antihistamines make people drowsy while newer ones do not? · Grey Matter

In the brain, histamine from the tuberomammillary nucleus of the hypothalamus helps sustain wakefulness, largely by exciting its targets through H1 receptors.

Why do older antihistamines make people drowsy while newer ones do not?

In the brain, histamine from the tuberomammillary nucleus of the hypothalamus helps sustain wakefulness, largely by exciting its targets through H1 receptors. First-generation H1 blockers such as diphenhydramine and doxylamine are fat-soluble and cross the blood-brain barrier, so besides calming an allergy they block that waking signal, which is why they are sold as sleep aids too. Second-generation drugs such as loratadine and fexofenadine are less fat-soluble and are pumped back out by the barrier's efflux transporters, so they block H1 receptors in the body and leave the brain's mostly untouched. The difference between the two generations is a difference in crossing the barrier.