Hydroxyzine is a first-generation antihistamine (and anticholingeric) with a variety of uses and indications, including uses as an anxiolytic.

Hydroxyzine's predominant mechanism of action is as a potent and selective histamine (H1) receptor inverse agonist. This action is responsible for its antihistamine and sedative effects. Unlike other first-generation antihistamines like diphenhydramine (tradename: Benadryl), hydroxyzine has very low affinity for the muscarinic (acetylcholine) receptors. Therefore it is not a muscarinic receptor antagonist, which means it has very little anticholinergic side effects.

Hydroxyzine has also been shown to act as an antagonist of the serotonin 5-HT2A receptor, the dopamine D2 receptor, and the α1-adrenergic receptor. The weak anti-serotonergic effects of hydroxyzine make it useful as an anxiolytic, as other antihistamines without such properties have not been found to be effective in the treatment of anxiety.

First vs. Second Generation Antihistamines

Hydroxyzine is a first-generation antihistamine, which means it crosses the blood–brain barrier easily and exerts effects on the central nervous system (which explains it sedative and anxiolytic effects). Newer, second-generation antihistamines like cetirizine (tradename: Reactine) are less able to cross the blood–brain barrier. Thus, they are marketed as non-drowsy and have less side effects such as memory impairment.

Because of its antihistamine effects, it can be used for the treatment of severe cases of pruritus, hyperalgesia, and motion sickness-induced nausea. It has also been used in some cases to relieve the effects of opioid withdrawal.

Even though it is an effective sedative, hypnotic, and anxiolytic, it shares virtually none of the abuse, dependence, addiction, and toxicity potential of other drugs used for the same range of therapeutic reasons. Due to its antagonistic effects on several receptor systems in the brain, hydroxyzine also has anxiolytic, anti-obsessive, and antipsychotic properties.