SPEX Pharmacology Flashcards

A 58-year-old patient on warfarin for atrial fibrillation is started on fluconazole for a fungal infection. His INR rises from 2.4 to 5.8 within 5 days. Which mechanism best explains this interaction?

Answer: Fluconazole inhibits CYP2C9, reducing S-warfarin metabolism and raising free drug levels

Fluconazole is a potent inhibitor of CYP2C9, the primary enzyme responsible for metabolizing the more pharmacologically active S-enantiomer of warfarin. This inhibition decreases warfarin clearance, elevating plasma levels and significantly potentiating anticoagulation. The other mechanisms either do not apply to fluconazole or are not clinically relevant contributors to this interaction.

A patient with end-stage renal disease (CRRT-dependent) requires sedation in the ICU. Which opioid analgesic poses the greatest risk of accumulation of an active, neuroexcitatory metabolite in this patient?

Answer: Morphine

Morphine is metabolized to morphine-6-glucuronide (M6G), an active opioid agonist, and morphine-3-glucuronide (M3G), a neuroexcitatory metabolite. Both glucuronide metabolites accumulate significantly in renal failure and are poorly cleared by CRRT. M3G accumulation can cause myoclonus, hyperalgesia, and seizures. Fentanyl and methadone have no renally-cleared active metabolites of concern; hydromorphone's metabolite (hydromorphone-3-glucuronide) also accumulates but is less extensively studied than morphine's metabolites.

A physician prescribes linezolid for a VRE infection in a patient already taking phenelzine for refractory depression. Three days later the patient develops hyperthermia, agitation, clonus, and diaphoresis. What is the most accurate explanation for this presentation?

Answer: Phenelzine inhibits MAO-A and MAO-B; linezolid also weakly inhibits MAO, causing serotonin syndrome through additive serotonergic excess

Linezolid is a weak, reversible inhibitor of monoamine oxidase. When combined with an irreversible MAO inhibitor like phenelzine, there is additive MAO inhibition leading to accumulation of serotonin, norepinephrine, and dopamine. The clinical picture—hyperthermia, agitation, clonus, and diaphoresis—is classic serotonin syndrome. This combination is contraindicated. The other options incorrectly describe mechanisms not associated with either drug.

Which of the following correctly describes the pharmacokinetic basis for why amiodarone requires a loading dose strategy and has an extremely long half-life (40–55 days)?

Answer: Amiodarone is highly lipophilic with an enormous volume of distribution (~60 L/kg), requiring extensive tissue redistribution before steady-state is achieved

Amiodarone is extremely lipophilic and accumulates extensively in adipose tissue, lungs, liver, and other tissues, giving it a volume of distribution of approximately 60 L/kg. Because the drug must saturate these deep tissue compartments before achieving therapeutic plasma levels, loading doses are required. Elimination is slow because the drug must redistribute back from tissues into plasma for hepatic metabolism. Amiodarone is not renally eliminated and does not follow zero-order kinetics at therapeutic doses.

A patient taking carbamazepine for trigeminal neuralgia develops progressively worsening hyponatremia (Na⁺ 126 mEq/L) without edema, normal thyroid function, and normal cortisol levels. Urine osmolality is inappropriately elevated. What is the mechanism of this adverse effect?

Answer: Carbamazepine potentiates the effect of ADH at V2 receptors in the renal collecting duct, causing SIADH-like water retention

Carbamazepine causes SIADH (syndrome of inappropriate antidiuretic hormone secretion) by potentiating the action of ADH (vasopressin) at V2 receptors in the renal collecting duct, increasing water reabsorption. This leads to dilutional hyponatremia with inappropriately concentrated urine. This is a well-recognized adverse effect, particularly in elderly patients. The other options describe incorrect mechanisms—carbamazepine does not inhibit Na-K-ATPase, does not block aquaporin-2, and CYP3A4 induction does not cause hyponatremia.

A patient with HIV on a stable antiretroviral regimen including ritonavir-boosted atazanavir develops an acute gout flare and is prescribed colchicine. Forty-eight hours later he presents with severe myopathy and pancytopenia. Which pharmacokinetic interaction best explains this toxicity?

Answer: Ritonavir potently inhibits CYP3A4 and P-glycoprotein, dramatically increasing colchicine bioavailability and systemic exposure

Colchicine is a substrate of both CYP3A4 and P-glycoprotein (P-gp). Ritonavir is among the most potent inhibitors of both CYP3A4 and P-gp. This dual inhibition dramatically increases colchicine bioavailability and reduces its clearance, causing profound elevation of plasma colchicine concentrations. The result is colchicine toxicity—myopathy, bone marrow suppression, and potentially multi-organ failure. This interaction is so dangerous that colchicine is contraindicated in patients on ritonavir-containing regimens. Standard colchicine doses that are safe in other patients become potentially lethal in this context.