KAPS Pharmacology and Therapeutics 2 — Questions and Answers
Question 1: A patient taking warfarin is started on fluconazole. What is the most likely pharmacokinetic mechanism behind the increased bleeding risk?
- Inhibition of CYP2C9, reducing warfarin metabolism (Correct answer)
- Induction of CYP3A4, increasing warfarin clearance
- Displacement of warfarin from plasma proteins
- Increased renal excretion of warfarin
Correct answer: Inhibition of CYP2C9, reducing warfarin metabolism
Fluconazole inhibits CYP2C9, the primary enzyme responsible for S-warfarin metabolism, leading to elevated warfarin levels and increased anticoagulation.
Question 2: Which receptor mechanism is responsible for the therapeutic effect of beta-2 agonists in asthma?
- Gq-coupled receptor activation causing smooth muscle contraction
- Gs-coupled receptor activation increasing cAMP and causing bronchodilation (Correct answer)
- Gi-coupled receptor reducing airway inflammation
- Ion channel activation causing membrane hyperpolarization
Correct answer: Gs-coupled receptor activation increasing cAMP and causing bronchodilation
Beta-2 agonists activate Gs-coupled receptors, elevating intracellular cAMP, which activates protein kinase A and relaxes bronchial smooth muscle.
Question 3: A patient with stage 3 chronic kidney disease is prescribed metformin. What is the primary concern?
- Hypoglycemia due to decreased renal glucose excretion
- Lactic acidosis due to metformin accumulation (Correct answer)
- Nephrotoxicity from metformin's direct renal tubular toxicity
- Increased risk of diabetic ketoacidosis
Correct answer: Lactic acidosis due to metformin accumulation
Metformin is renally cleared, and accumulation in CKD increases the risk of lactic acidosis, especially when eGFR falls below 30 mL/min/1.73m².
Question 4: Which pharmacodynamic principle explains why combining two opioid agonists rarely doubles the analgesic effect?
- Competitive antagonism between the two opioids
- Receptor saturation at the mu-opioid receptor (Correct answer)
- Pharmacokinetic induction of opioid metabolism
- Tachyphylaxis developing only to the first opioid
Correct answer: Receptor saturation at the mu-opioid receptor
Once mu-opioid receptors are saturated, adding a second full agonist produces little additional effect because the maximum receptor occupancy has been reached.
Question 5: A 70-year-old patient receives gentamicin for a gram-negative infection. Which dosing strategy best reduces nephrotoxicity?
- Continuous infusion to maintain steady plasma levels
- Once-daily extended-interval dosing exploiting concentration-dependent killing (Correct answer)
- Dosing every 4 hours to minimize peak concentrations
- Using the lowest dose that achieves minimum inhibitory concentration
Correct answer: Once-daily extended-interval dosing exploiting concentration-dependent killing
Extended-interval (once-daily) dosing achieves high bactericidal peaks while allowing trough levels to fall, reducing aminoglycoside accumulation in renal tubular cells.
Question 6: Which mechanism best explains the hepatotoxicity seen with acetaminophen overdose?
- Direct inhibition of mitochondrial cytochrome c oxidase
- Accumulation of NAPQI depleting glutathione and binding hepatic proteins (Correct answer)
- Competitive inhibition of hepatic bile acid transporters
- Immune-mediated hepatitis triggered by acetaminophen metabolites
Correct answer: Accumulation of NAPQI depleting glutathione and binding hepatic proteins
CYP2E1 converts excess acetaminophen to the reactive metabolite NAPQI; when glutathione stores are depleted, NAPQI covalently binds hepatic macromolecules, causing necrosis.
Question 7: A patient on phenytoin for epilepsy is also prescribed rifampin for tuberculosis. What dosing adjustment is expected?
- Decrease phenytoin dose to prevent toxicity from rifampin-mediated CYP inhibition
- Increase phenytoin dose to compensate for rifampin-induced CYP3A4/2C9 induction (Correct answer)
- No adjustment needed as rifampin does not affect phenytoin metabolism
- Discontinue phenytoin because combination is absolutely contraindicated
Correct answer: Increase phenytoin dose to compensate for rifampin-induced CYP3A4/2C9 induction
Rifampin is a potent inducer of multiple CYP enzymes including CYP2C9 and CYP3A4, accelerating phenytoin metabolism and requiring higher doses to maintain therapeutic levels.
KAPS Pharmacology and Therapeutics 2
A patient taking warfarin is started on fluconazole.
What is the most likely pharmacokinetic mechanism behind the increased bleeding risk?