Antihistamine
The vast majority of marketed H-antihistamines are receptor antagonists and only a minority of marketed compounds are inverse agonists at the receptor. Clinically, H-antihistamines are used to treat allergic reactions and mast cell-related disorders. Sedation is a common side effect of H-antihistamines that readily cross the blood–brain barrier; some of these drugs, such as diphenhydramine and doxylamine, are therefore used to treat insomnia. H-antihistamines can also reduce inflammation, since the expression of NF-κB, the transcription factor the regulates inflammatory processes, is promoted by both the receptor's constitutive activity and agonist (i.e., histamine) binding at the H receptor.
Histamine
First-generation H antihistamines (i.e., antagonists of histamine receptor H) are capable of crossing the blood–brain barrier and produce drowsiness by antagonizing histamine H receptors in the tuberomammillary nucleus. The newer class of second-generation H antihistamines do not readily permeate the blood–brain barrier and thus are less likely to cause sedation, although individual reactions, concomitant medications and dosage may increase the likelihood of a sedating effect. In contrast, histamine H receptor antagonists increase wakefulness. Similar to the sedative effect of first-generation H antihistamines, an inability to maintain vigilance can occur from the inhibition of histamine biosynthesis or the loss (i.e., degeneration or destruction) of histamine-releasing neurons in the TMN.