Pharmacodynamics 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. In addition to its antihistamine activity, hydroxyzine has also been shown to act more weakly as an
antagonist of the
serotonin 5-HT2A receptor, the
dopamine D2 receptor, and the
α1-adrenergic receptor. Other antihistamines without such properties have not been found to be effective in the treatment of
anxiety. Hydroxyzine crosses the
blood–brain barrier easily and exerts effects in the
central nervous system. In addition, subjective sleepiness correlated well with the brain H1 receptor occupancy. Hydroxyzine also acts as a functional inhibitor of
acid sphingomyelinase.
Pharmacokinetics Hydroxyzine can be administered orally or via intramuscular injection. In both cases it is rapidly absorbed and distributed. It is metabolized in the liver and the main metabolite (45%),
cetirizine is formed through oxidation of the alcohol moiety to a carboxylic acid by
alcohol dehydrogenase. Overall effects are observed within one hour of administration. Higher concentrations are found in the skin than in the plasma. Cetirizine, although less sedating, is non-
dialyzable and possesses similar antihistamine properties. Metabolites identified include an
N-dealkylated metabolite and an
O-dealkylated 1/16 metabolite with a plasma half-life of 59 hours. These pathways are mediated principally by
CYP3A4 and
CYP3A5. The N-dealykylated metabolite, norchlorcyclizine, bears some structural similarities to
trazodone, but it has not been established whether it is pharmacologically active. In animals, hydroxyzine and its metabolites are excreted in feces primarily through biliary elimination. In rats, less than 2% of the drug is excreted unchanged. Its elimination half-life is shorter in children compared to adults. One study found that the elimination half-life of hydroxyzine in adults was as short as 3 hours, but this may have just been due to methodological limitations. Although hydroxyzine has a long elimination half-life and acts, in-vivo, as an antihistamine for as long as 24 hours, the predominant CNS effects of hydroxyzine and other antihistamines with long half-lives seem to diminish after 8 hours. Administration in geriatrics differs from the administration of hydroxyzine in younger patients; according to the FDA, there have not been significant studies made (2004), which include population groups over 65, which provide a distinction between elderly aged patients and other younger groups. Hydroxyzine should be administered carefully in the elderly with consideration given to possible reduced elimination. ==Chemistry==