Pharmacology and Toxicology Flashcards

A patient on warfarin is started on fluconazole for a fungal infection. Four days later, his INR is critically elevated. Which mechanism best explains this interaction?

Answer: Fluconazole inhibits CYP2C9, reducing S-warfarin metabolism and increasing its anticoagulant effect

Fluconazole is a potent inhibitor of CYP2C9, the primary enzyme responsible for metabolizing the pharmacologically active S-enantiomer of warfarin. Inhibition of this pathway leads to markedly elevated S-warfarin plasma levels, dramatically potentiating anticoagulation and raising the INR. While protein displacement was historically proposed as a mechanism for drug interactions, it rarely causes sustained clinical effects because the displaced drug is also more rapidly cleared.

A 72-year-old woman with chronic kidney disease (GFR 18 mL/min) is prescribed metformin by an urgent care provider. Three days later she presents obtunded with an arterial pH of 7.08, lactate of 14 mmol/L, and normal glucose. What is the pathophysiologic mechanism of her toxicity?

Answer: Accumulated metformin inhibits mitochondrial complex I, impairing oxidative phosphorylation and forcing anaerobic lactate production

Metformin-associated lactic acidosis (MALA) occurs primarily through inhibition of mitochondrial complex I (NADH dehydrogenase) of the electron transport chain. This impairs oxidative phosphorylation, forces cells into anaerobic glycolysis, and generates excess lactate. In renal impairment, metformin accumulates to toxic concentrations because it is cleared almost entirely by glomerular filtration. Metformin does inhibit hepatic gluconeogenesis (its therapeutic mechanism), but MALA's root cause is mitochondrial respiratory chain dysfunction.

Which of the following correctly pairs a drug with its mechanism of causing QT prolongation via cardiac ion channel blockade?

Answer: Dofetilide — blockade of the rapid delayed rectifier potassium current (IKr encoded by hERG)

Dofetilide is a selective IKr blocker — it specifically targets the rapid component of the delayed rectifier potassium current, which is encoded by the hERG (KCNH2) gene. Blocking IKr delays ventricular repolarization, prolonging the QT interval and increasing the risk of torsades de pointes. Amiodarone broadly blocks multiple ion channels (IKr, IKs, INa, ICaL) rather than selectively IKs. Sotalol also primarily blocks IKr, not IK1. Ibutilide's primary mechanism is activation of a slow inward sodium current, not direct ICaL blockade.

A researcher finds that a novel drug has a volume of distribution (Vd) of 450 L in a 70 kg patient and a plasma protein binding of 95%. Which of the following conclusions is most pharmacokinetically accurate?

Answer: The drug extensively distributes into peripheral tissues, likely via lipophilicity or tissue binding, and plasma concentration reflects only a small fraction of total body drug

Vd of 450 L far exceeds total body water (~42 L) and plasma volume (~3 L), indicating extensive sequestration into peripheral tissues — typically driven by lipophilicity, intracellular binding, or high tissue affinity. High plasma protein binding (95%) actually works against tissue distribution by retaining drug in plasma; the large Vd despite high binding means the drug's affinity for tissue sites overwhelms its affinity for plasma proteins. Vd is a mathematical construct and does not directly inform about hepatic extraction or renal clearance kinetics.

A patient presents with bradycardia, miosis, salivation, bronchospasm, and urinary incontinence after occupational pesticide exposure. Atropine is administered. Which receptor phenomenon explains why extremely large doses of atropine may be required in severe organophosphate poisoning?

Answer: Organophosphates irreversibly inhibit acetylcholinesterase, causing massive ACh accumulation that must be competitively overcome by high-dose atropine at muscarinic receptors

Organophosphates irreversibly (or near-irreversibly) phosphorylate and inactivate acetylcholinesterase, causing ACh to accumulate continuously at synapses. Atropine is a competitive antagonist at muscarinic receptors; because ACh accumulation is ongoing and massive, extremely large doses of atropine are required to competitively displace ACh and occupy enough muscarinic receptors to reverse the cholinergic crisis. Doses 10–20× the normal maximum may be needed. Atropine does not effectively block nicotinic receptors at clinically achievable doses, and oximes (pralidoxime) are used to address the nicotinic/neuromuscular component.

A 34-year-old woman with bipolar disorder stabilized on lithium (serum level 0.9 mEq/L) is prescribed ibuprofen for knee pain. Two weeks later she develops coarse tremor, ataxia, and confusion. Her lithium level is now 2.6 mEq/L. What is the primary pharmacokinetic mechanism of this toxicity?

Answer: NSAIDs reduce renal prostaglandin synthesis, decreasing GFR and reducing lithium clearance, causing accumulation

Lithium is eliminated almost entirely by the kidney via glomerular filtration and is reabsorbed in the proximal tubule alongside sodium. NSAIDs, including ibuprofen, inhibit renal prostaglandin (PGE2) synthesis, which reduces afferent arteriolar dilation and decreases GFR. Additionally, reduced prostaglandins enhance sodium (and lithium) reabsorption in the proximal tubule. Both effects markedly reduce lithium clearance, causing accumulation to toxic levels. Lithium is not metabolized by CYP450 enzymes — it has no hepatic metabolism — making option B impossible.