Farmacoquimica

Chapter 37: Antihistamines and Related Antiallergic and Antiulcer Agents
Case Study 3

It's a typically cold and wintry Thanksgiving week in Omaha, Nebraska, and CJ, an executive with the Union Pacific railroad and a single mom, is about to head out across the state with her 30-month-old daughter, KJ, to Grandma's house in Scottsbluff. KJ is actually CJ's second child, but her firstborn waslost tragically at 2 months of age to sudden infant death syndrome (SIDS). Fortunately, KJ has been a healthy child, although she did experience prolonged jaundice when she was first born.
As if the trip across the flat and seemingly endless Platte River Valley wasn't hard enough, KJ has developed a pruritic rash on her arms and legs from wearing pajamas that were exposed to perfume from the newbrand of dryer sheet that CJ used when doing yesterday's laundry. The itching kept KJ and her mom from getting a full night's sleep last night. CJ purchased a tube of 1% hydrocortisone cream in the morning and has it has helped a bit, but KJ is still scratching and acting cranky. If the weather doesn't close in, the trip to Grandma's should take a full 8 hr, and CJ is worried that her daughter willbe uncomfortable and fussy the whole time. She called the pediatrician, who has recommended that KJ be given an antihistamine and seeks your advice. The four H1-receptor antagonists shown have been mentioned as possible therapeutic alternatives.

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1. Identify the therapeutic problem(s) for which the pharmacist's intervention may benefit the patient.

KJ is very uncomfortable and wouldbenefit from systemic antihistamine therapy, particularly as she will be confined in a car for the better part of a day, unable to play or otherwise distract herself from her discomfort. Because she must ride in the back seat to avoid the airbags (the nonparental ones), she cannot easily be soothed or comforted by her mom during the car trip. Everyone's nerves and holiday spirit will benefit froma peaceful and quiet ride to Scottsbluff.

2. Identify and prioritize the patient-specific factors that must be considered to achieve the desired therapeutic outcomes.

KJ is 2.5 years old. Normally, cytochrome P34A (CYP3A4), CYP2D6, and the CYP2C family of metabolizing enzymes should be functional at this age, and children often exhibit higher drug clearance rates than do adults.
KJ wasjaundiced as a newborn, but this generally has little, if any, effect on hepatic function in young children.
A formulation that allows for flexible dosing would be advantageous.
Pills and capsules may be hard for the child to swallow.
KJ is has not been getting good sleep and needs rest.
CJ is the only adult in the car, and KJ will be in the backseat. No one besides CJ can attend to KJ'sneeds, so the more comfortable the child, the fewer the delays from pulling over to the side of the road (which can be dangerous) and the less frustration from driving a crying child to the next interstate rest stop.

3. Conduct a thorough and mechanistically oriented structure–activity analysis of all therapeutic alternatives provided in the case.

Compound 1 is a phenothiazine antihistamine,which is a specialized form of ethylenediamine. The two aromatic rings commonly found in H1-antagonist structures have been joined through a sulfur atom to form the tricyclic phenothiazine ring system. Although the system looks flat on paper, the molecule actually can fold along the S-N axis like a butterfly so that the two aromatic rings begin to face each other. The terminal nitrogen atom is byfar the more basic because its lone pair of electrons are localized (as opposed to the lone pair of electrons on the phenothiazine nitrogen, which can resonate with both aromatic rings). All marketed H1-antagonists (except one, compound 2) contain an ionizable amino nitrogen and, in cationic form, the terminal nitrogen is believed to help hold the molecule to the H1-receptor through an ion–ion...