Pharmacology and Toxicology Flashcards

A patient receiving warfarin for atrial fibrillation is started on fluconazole for a systemic fungal infection. Three days later, his INR has risen from 2.4 to 6.1 despite no change in warfarin dose. Which mechanism best explains this interaction?

Answer: Fluconazole inhibits CYP2C9, reducing S-warfarin metabolism and elevating plasma levels

S-warfarin (the more potent enantiomer) is primarily metabolized by CYP2C9. Fluconazole is a potent CYP2C9 inhibitor (as well as CYP3A4), which dramatically reduces warfarin clearance, elevating plasma concentrations and anticoagulant effect. This interaction is well-documented and clinically significant, often requiring a 25–50% dose reduction in warfarin.

A 45-year-old man presents with tremor, rigidity, hyperthermia, diaphoresis, and confusion after his psychiatrist added linezolid for a resistant MRSA infection while he was already on phenelzine. Which receptor mechanism is primarily responsible for his life-threatening syndrome?

Answer: Excess serotonergic activity in the CNS due to dual MAO inhibition

Linezolid possesses weak but clinically significant monoamine oxidase inhibitory activity. Combined with phenelzine (a non-selective irreversible MAOI), the result is profound inhibition of serotonin breakdown, triggering serotonin syndrome. The triad of cognitive changes, autonomic instability, and neuromuscular abnormalities (especially clonus and hyperreflexia) distinguishes serotonin syndrome from neuroleptic malignant syndrome.

Which of the following correctly pairs a toxin with its specific antidote mechanism?

Answer: Methanol poisoning → Fomepizole competitively inhibits alcohol dehydrogenase, preventing formate accumulation

Fomepizole (4-methylpyrazole) is a competitive inhibitor of alcohol dehydrogenase (ADH). In methanol poisoning, ADH converts methanol to formaldehyde and then formate, which causes the metabolic acidosis and optic nerve toxicity. By blocking ADH, fomepizole prevents this conversion. Glucagon bypasses β-blockade, not digoxin toxicity (that uses Fab fragments). Pralidoxime, not N-acetylcysteine, reactivates acetylcholinesterase. Cyanide poisoning is treated with hydroxocobalamin or nitrites/thiosulfate, not deferoxamine (which is used for iron toxicity).

A researcher studies a novel drug that exhibits the following kinetics: doubling the dose quadruples the AUC, and the drug's clearance decreases as plasma concentration increases. This drug most likely exhibits which property?

Answer: Zero-order (saturation) kinetics due to a capacity-limited elimination process

When doubling the dose more than doubles AUC (here it quadruples it), and clearance decreases with increasing concentration, this is characteristic of saturation (Michaelis-Menten or zero-order) kinetics. The eliminating enzyme or transporter becomes saturated, so a larger fraction of the drug accumulates with each dose increase. Classic examples include phenytoin and ethanol. In pure first-order kinetics, AUC would double proportionally with dose and clearance remains constant.

A patient with chronic kidney disease (eGFR 15 mL/min) requires pain management. She is already on lisinopril and spironolactone. Which analgesic choice presents the greatest risk for an acute, life-threatening electrolyte disturbance?

Answer: Ketorolac 15 mg IV every 6 hours

Ketorolac (an NSAID) inhibits prostaglandin synthesis, which is critical for maintaining renal afferent arteriolar dilation in a patient with CKD. This further reduces GFR in an already compromised kidney. More critically, reduced renal perfusion and prostaglandin inhibition decrease aldosterone effect and potassium excretion. Combined with lisinopril (ACE inhibitor, which reduces aldosterone) and spironolactone (aldosterone antagonist), the patient faces a 'triple whammy' nephrotoxic combination with severe risk of life-threatening hyperkalemia and acute kidney injury. NSAIDs are contraindicated in this scenario.

A pharmacokineticist notes that Drug X has a hepatic extraction ratio of 0.95. A patient with hepatic cirrhosis and portosystemic shunting starts this drug orally. Compared to a healthy subject receiving the same dose, what is the primary pharmacokinetic change expected?

Answer: Markedly increased oral bioavailability due to bypassed first-pass hepatic metabolism

A hepatic extraction ratio of 0.95 means 95% of an orally administered drug is removed during first-pass hepatic metabolism in a healthy individual, leaving only ~5% bioavailable. In cirrhosis with portosystemic shunts, portal blood bypasses the liver entirely and enters systemic circulation directly. This eliminates first-pass metabolism for that shunted fraction, dramatically increasing bioavailability. Classic high-extraction drugs include propranolol, lidocaine, morphine, and labetalol — their oral doses must be significantly reduced in cirrhotic patients to avoid toxicity.