SPEX Exam SPEX Pharmacology 6

Question 1

A patient on warfarin is started on fluconazole for a vaginal yeast infection. Three days later, her INR rises from 2.4 to 5.8. Which mechanism best explains this interaction?

Accepted Answer

Fluconazole inhibits CYP2C9, reducing warfarin S-enantiomer metabolism

Answer

Fluconazole is a potent inhibitor of CYP2C9, which is the primary enzyme responsible for metabolizing the pharmacologically active S-enantiomer of warfarin. The S-enantiomer is approximately 3–5 times more potent as an anticoagulant than the R-enantiomer. By reducing S-warfarin clearance, fluconazole dramatically elevates anticoagulant effect and INR. While CYP1A2 handles the R-enantiomer, this pathway contributes far less to overall anticoagulant activity.

Question 2

A patient with renal failure (CrCl 18 mL/min) requires analgesia. Which opioid requires the MOST caution due to accumulation of a neurotoxic active metabolite?

Accepted Answer

Morphine

Answer

Morphine is metabolized to morphine-6-glucuronide (M6G, active analgesic) and morphine-3-glucuronide (M3G). M3G is neuroexcitatory and can cause myoclonus, hyperalgesia, and seizures. Both M6G and M3G are renally cleared and accumulate significantly in renal failure, creating a narrow therapeutic window with serious neurotoxic risk. Hydromorphone also has a neuroexcitatory metabolite (hydromorphone-3-glucuronide) but accumulates less dramatically. Fentanyl and buprenorphine have no clinically significant active metabolites and are safer in renal impairment.

Question 3

A patient taking phenelzine for depression presents to the ER after self-administering dextromethorphan (DXM) from an OTC cough syrup. Which syndrome is the primary concern and what is its mechanism?

Accepted Answer

Serotonin syndrome via excess serotonergic activity from MAO inhibition plus DXM's serotonin reuptake inhibition

Answer

DXM is a sigma-1 receptor agonist and a weak serotonin reuptake inhibitor (SERT inhibitor). When combined with an irreversible MAO inhibitor like phenelzine, which prevents serotonin degradation, the two mechanisms converge to cause serotonin syndrome: hyperthermia, clonus, hyperreflexia, diaphoresis, and agitation. This combination is absolutely contraindicated. DXM does have weak mu-opioid activity, but this is not the dominant clinical concern with MAOI co-administration.

Question 4

Which pharmacokinetic parameter, when doubled, will produce the greatest reduction in peak plasma concentration (Cmax) for a drug given as a single IV bolus dose?

Accepted Answer

Volume of distribution (Vd)

Answer

For an IV bolus, Cmax = Dose / Vd. Doubling Vd directly halves Cmax because the drug distributes into a larger apparent space immediately after administration. Elimination half-life affects how long drug remains in plasma but does not affect the initial Cmax after an IV bolus. Protein binding changes free drug fraction but total plasma concentration (which Cmax measures) is determined by Vd. Renal clearance affects elimination rate and AUC, not the initial peak after a single bolus.

Question 5

A pharmacist notes a patient on methotrexate (MTX) 15 mg/week for rheumatoid arthritis is prescribed trimethoprim-sulfamethoxazole (TMP-SMX) for a UTI. Beyond folate antagonism, which additional mechanism most significantly elevates MTX toxicity risk?

Accepted Answer

TMP-SMX inhibits renal tubular secretion of MTX via OAT1/OAT3 competition, raising MTX levels

Answer

MTX relies heavily on active renal tubular secretion via organic anion transporters (OAT1 and OAT3) for elimination. TMP-SMX, particularly the sulfamethoxazole component, competes for these transporters, significantly reducing MTX clearance and raising plasma concentrations to toxic levels. This is additive to the shared folate antagonism (both drugs inhibit dihydrofolate reductase to varying degrees), making this combination dangerous and generally contraindicated. While protein displacement is possible with sulfonamides, the transporter competition is the mechanistically dominant interaction.

SPEX Exam Practice Test

SPEX Exam Practice Test

SPEX Exam SPEX Pharmacology 6