MPharm Master of Pharmacy Master of Pharmacy: Pharmacology and Therapeutics 5 — Questions and Answers
Question 1: A patient with rheumatoid arthritis on methotrexate and naproxen develops toxicity. Which pharmacokinetic interaction is responsible?
- NSAIDs induce CYP3A4, increasing methotrexate metabolism
- NSAIDs reduce renal blood flow and tubular secretion, impairing methotrexate clearance (Correct answer)
- Naproxen displaces methotrexate from DHFR binding sites
- NSAIDs increase methotrexate absorption via gut inflammation
Correct answer: NSAIDs reduce renal blood flow and tubular secretion, impairing methotrexate clearance
NSAIDs reduce renal prostaglandin synthesis, decreasing GFR and inhibiting organic anion transporters, impairing methotrexate excretion and causing toxicity.
Question 2: Which mechanism distinguishes selective COX-2 inhibitors (coxibs) from non-selective NSAIDs regarding cardiovascular risk?
- COX-2 inhibitors increase thromboxane A2 production in platelets
- COX-2 inhibition reduces prostacyclin without reducing platelet thromboxane A2, shifting balance toward thrombosis (Correct answer)
- COX-2 inhibitors directly activate platelet aggregation receptors
- COX-2 inhibitors increase blood pressure via direct vasoconstriction
Correct answer: COX-2 inhibition reduces prostacyclin without reducing platelet thromboxane A2, shifting balance toward thrombosis
COX-2 in vascular endothelium produces antithrombotic prostacyclin; selective COX-2 inhibition reduces prostacyclin but spares platelet COX-1-derived thromboxane A2, promoting thrombosis.
Question 3: A patient with treatment-resistant depression fails SSRIs and SNRIs. Ketamine is considered. What is its proposed antidepressant mechanism?
- Inhibition of serotonin reuptake transporter
- NMDA receptor antagonism promoting rapid BDNF-mediated synaptogenesis (Correct answer)
- MAO inhibition increasing monoamine availability
- GABA-A receptor positive allosteric modulation reducing anxiety
Correct answer: NMDA receptor antagonism promoting rapid BDNF-mediated synaptogenesis
Ketamine blocks NMDA receptors, leading to a glutamate surge that activates AMPA receptors, promoting BDNF release and rapid synaptogenesis in the prefrontal cortex.
Question 4: A patient on amiodarone develops hypothyroidism after 18 months. Which mechanism is primarily responsible?
- Amiodarone directly destroys thyroid follicular cells via oxidative damage
- Amiodarone's high iodine content causes Wolff-Chaikoff effect blocking thyroid hormone synthesis (Correct answer)
- Amiodarone inhibits TSH release from the pituitary
- Amiodarone accelerates thyroid hormone metabolism via CYP450 induction
Correct answer: Amiodarone's high iodine content causes Wolff-Chaikoff effect blocking thyroid hormone synthesis
Amiodarone contains ~37% iodine by weight; the iodine load triggers the Wolff-Chaikoff effect, suppressing thyroid hormone synthesis and causing hypothyroidism in susceptible patients.
Question 5: In a patient with chronic kidney disease, why does the dosing interval for aminoglycosides need to be extended rather than reducing individual doses?
- Reduced renal clearance extends half-life; maintaining peak concentrations preserves concentration-dependent killing (Correct answer)
- Lower doses would fall below the MIC, causing therapeutic failure
- Extended intervals allow accumulation to therapeutic troughs needed for efficacy
- CKD increases volume of distribution, requiring larger individual doses
Correct answer: Reduced renal clearance extends half-life; maintaining peak concentrations preserves concentration-dependent killing
Aminoglycosides are concentration-dependent antibiotics; high peak/MIC ratios drive efficacy, so maintaining peak concentrations while extending intervals accommodates reduced clearance in CKD.
Question 6: Which drug interaction occurs when P-glycoprotein (P-gp) inhibitors are combined with digoxin?
- Decreased digoxin absorption due to increased gut motility
- Increased digoxin plasma levels due to reduced P-gp-mediated efflux and renal secretion (Correct answer)
- Increased digoxin metabolism via intestinal CYP3A4 induction
- Decreased digoxin protein binding leading to increased free fraction toxicity
Correct answer: Increased digoxin plasma levels due to reduced P-gp-mediated efflux and renal secretion
P-gp normally limits digoxin absorption in the gut and facilitates renal tubular secretion; P-gp inhibitors (e.g., amiodarone, verapamil) increase digoxin bioavailability and reduce its elimination.
Question 7: A patient develops pseudomembranous colitis after clindamycin therapy. What is the pathophysiological mechanism?
- Direct mucosal damage from clindamycin's metabolites
- C. difficile overgrowth producing toxins A and B that disrupt colonic epithelial tight junctions (Correct answer)
- Clindamycin-induced ischemic colitis via vasoconstriction
- Immune-mediated colitis from clindamycin acting as a hapten
Correct answer: C. difficile overgrowth producing toxins A and B that disrupt colonic epithelial tight junctions
Antibiotic disruption of normal gut flora allows C. difficile overgrowth; its toxins A and B cause glucosylation of Rho GTPases, disrupting tight junctions and triggering colitis.
MPharm Master of Pharmacy Master of Pharmacy: Pharmacology and Therapeutics 5
A patient with rheumatoid arthritis on methotrexate and naproxen develops toxicity.
Which pharmacokinetic interaction is responsible?