Answer: Some antihistamines nonselectively block the histamine receptors, which can lead to sleepiness.
Histamine is an important neurotransmitter for regulation of the sleep-wake cycle. It is produced mainly by the tuberomammillary nucleus in the hypothalamus, and these projections are sent broadly across the entire brain. It is also produced by mast cells when fighting an infection or during an allergic response. It is also important for causing the sensation of itch at the skin.
The first generation antihistamines, such as Benadryl, are antagonists at the histamine receptor. They block the symptoms of allergies by preventing signaling at the histamine receptors. However, they did so indiscriminately: all classes of histamine receptors were blocked.
When histamine is released, overall, there is an increase in wakefulness. Histamine acts on 4 different classes of receptors.
- The H1 receptor is widely expressed in the brain. Antagonists of H1 lead to drowsiness.
- The H2 receptor is not expressed in areas that regulate wakefulness. Therefore, H2 antagonists generally do not cause a change in sleepiness. H2 receptors are heavily expressed in the gut - drugs such as Zantac (ranitidine) are very popular drugs.
- The H3 receptor is an autoreceptor expressed on the cell terminals of histaminergic neurons in the tuberomammillary nucleus. They are part of a negative feedback loop that decreases the release of more histamine when activated.
- H4 receptors are not expressed in the central nervous system, and likely do not play a role in wakefulness.