Page 163 - Medicinal Chemistry Self Assessment

152 Medicinal Chemistry Self Assessment

NOTE: When activated, the histamine receptor in the brain is responsible for wakefulness. When
hydroxyzine interacts with this receptor, it prevents histamine from binding to and activating its
receptor. As a result, the feeling of wakefulness is very limited, and the patient feels sleepy.
Cetirizine contains a carboxylic acid instead of the primary alcohol found in hydroxyzine. The carbox-
ylic acid significantly increases the water solubility of cetirizine as compared to hydroxyzine. The
carboxylic acid is also predominantly ionized at physiological pH. Although there is an equilibrium
between the ionized and unionized forms of the tertiary amine and of the carboxylic acid, the overall
percent of cetirizine in which both functional groups are unionized is especially small. As a result,
very, very little of a cetirizine dose can cross the blood–brain barrier and interact with the histamine
receptors. Because the central histamine receptors can still be activated, the feeling of wakefulness
remains, and the patient does not feel sleepy.