Download Chapter 24 Review Question Answers

Chapter 24 Review Question Answers
1. The suspected heroin overdose has caused respiratory depression in this patient. The
addition of an antihistamine may cause further respiratory depression necessitating
assisted ventilation.1 Treating the rash can wait.
2. You suspect that the mother is a rapid metabolizer or an ultrarapid metabolizer of
codeine, resulting in increased morphine levels in the mother and in her breast milk. This
would imply a genetic variant in the CYP2D6 gene or multiple copies of the gene,
leading to ultrarapid metabolism of CYP2D6-metabolized drugs. A review of the
literature shows that deaths of breastfed infants have occurred when mothers with this
genotype are prescribed normal doses of codeine. Postmortem blood levels have
confirmed that the infants died from morphine overdoses. 2,3
3. If dispensed as written, the prescription would put the patient in jeopardy of an
acetaminophen overdose. Vicodin ES contains 7.5 mg hydrocodone and 750 mg
acetaminophen per tablet. Thus, this prescription would call for 6,000 mg of
acetaminophen per day, which is over the recommended maximum of 4,000 mg per day.
4. Loperamide does not usually have any CNS side effects because it is pumped out of the
brain via the p-glycoprotein transporter. Quinidine is an inhibitor of this transporter and
poses at least a theoretical risk of allowing loperamide concentrations in the brain to rise,
resulting in toxic CNS effects.4
5. The salicylic acid ring binds to the ∆5–∆8 double-binding region of the enzyme with
which the carboxylic group interacts, via an ionic interaction, with an Arg 120 residue on
the active site of the enzyme. The fluorine-containing ring binds to the ∆11 doublebinding region of the enzyme, thereby enhancing its binding affinity and its potency.
Diflunisal is eliminated from the body primarily via the ether-type glucuronides of the
phenolic OH group of the salicylic acid moiety. The ester-type glucuronides undergo
hepatic recirculation to their parent drug molecule, thus providing long duration of action.
6. Acetaminophen lacks anti-inflammatory activity because of the higher levels of peroxides
in the synovial fluids of the inflammatory cells as a consequence of the induction of the
COX isozymes, which rapidly degrade acetaminophen into its inactive glutathione
conjugates via its N-acetyliminoquinone intermediate.
7. In the presence of a CYP3A4 inhibitor, diclofenac is degraded by the CYP2C9 isozymes
to give the expected 5-hydroxylated diclofenac as its major inactive metabolites. Thus, an
inhibitor of either CYP3A4 or CYP2C9 has little or no effect on its pharmacokinetic
profile. However, an inducer of CYP3A4 isozymes definitely increases the formation of
the 4’-hydroxylated metabolites, therefore enhancing renal clearance of diclofenac.
8. Sulindac is an NSAID prodrug that contains a chiral sulfoxide moiety that must undergo
in vivo reduction by the hepatic enzymes into its active, achiral methyl sulfide metabolite
before it has any inhibitory action toward COX isozymes. Thus, unlike indomethacin, it
has lower risk of stomach bleeding because it does not inhibit PGE2 synthesis in the
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parietal cells, which is needed to regulate stomach acid release. However, it does cause
some stomach irritation due to the acidity of its free carboxylic acid group. Sulindac also
lacks nephrotoxicity because its active methyl sulfide metabolite is rapidly oxidized in
the renal tubules back to its sulfoxide prodrug. Thus, it has no inhibitory action on the
prostaglandin synthesis, which regulates renal blood flow.
9. Frovatriptan has a much lower CNS toxicity than eletriptan because of the greater water
solubility of its N-demethylated active metabolite, which prevents it from entering the
brain, whereas desmethyleletriptan is an active metabolite of eletriptan that accounts for
approximately 10 to 20% of the parent drug.
Chapter 24 Review Question Answer References
1. Anwari, J. S., and Iqbal, S.: Anaesthesia 58:494–495, 2003.
2. Koren, G., Cairns, J., Chitayat, D., et al.: Lancet 368:704, 2006.
3. Madadi, P., Koren, G., Cairns, J., et al.: Can. Fam. Physician 53:33–35, 2007.
4. Sadeque, A. J., Wandel, C., He, H., et al.: Clin. Pharmacol. Ther. 68:231–237, 2000.
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