Histamine acts at four GPCRs: H1 (Gq, allergic + bronchoconstriction + CNS arousal — H1-i causes sedation), H2 (Gs, gastric acid — covered in GI-1), H3 (presynaptic autoreceptor in CNS), H4 (immune cells, chemotaxis). First-gen H1 blockers cross BBB → sedation (diphenhydramine, hydroxyzine, doxylamine, chlorpheniramine, brompheniramine, meclizine, dimenhydrinate, promethazine). Second-gen H1 blockers minimize BBB penetration → non-sedating (loratadine, cetirizine, desloratadine, fexofenadine, levocetirizine, ketotifen, olopatadine — last two also have mast-cell-stabilizer activity for ophthalmic use). Inverse agonism at H1 + strong anticholinergic side effects characterize the first-generation class. Cetirizine + levocetirizine retain mild BBB penetration → some sedation.
Organ Systems
immune-hematologic
nervous
Pathway Steps
histamine → h1-mediated-allergic-symptoms — via H1/Gq → smooth muscle contraction + endothelial permeability + sensory nerve activation → itch/sneezing/wheal. Histamine released from mast cells and basophils acts on H1 receptors (Gq) to cause the wheal-and-flare of allergy — vasodilation, increased permeability (edema), itch, and bronchoconstriction. H1-antihistamines (cetirizine, loratadine) are inverse agonists here; older sedating ones also cross into the brain.
histamine → tmn-arousal — via H1 on cortical + tuberomammillary nucleus → wakefulness; cross-link: orexin_arousal_axis. Histamine from tuberomammillary nucleus (TMN) neurons acts as a wakefulness-promoting neurotransmitter in the brain. This is why first-generation (CNS-penetrant) H1-antihistamines cause sedation, and why the H3 autoreceptor controlling histamine release is a target for wake-promoting drugs (pitolisant).