Pharmacology and Toxicology Flashcards

A patient on warfarin is started on fluconazole for a fungal infection. Three days later, their INR has risen dangerously. Which mechanism best explains this interaction?

Answer: Fluconazole inhibits CYP2C9, reducing warfarin S-enantiomer metabolism

Warfarin's S-enantiomer (the more potent form) is primarily metabolized by CYP2C9. Fluconazole is a potent CYP2C9 inhibitor, which dramatically reduces S-warfarin clearance, leading to elevated plasma concentrations and supratherapeutic anticoagulation. The R-enantiomer is less affected (it is metabolized mainly by CYP3A4/1A2). Albumin displacement is clinically insignificant for warfarin in practice, and fluconazole does not directly inhibit VKOR.

A researcher studying drug tolerance finds that prolonged morphine administration leads to receptor desensitization. Which intracellular event is MOST directly responsible for the rapid (minutes-to-hours) phase of μ-opioid receptor desensitization?

Answer: GRK-mediated phosphorylation of the receptor C-terminal tail promoting β-arrestin recruitment

The rapid phase of μ-opioid receptor (MOR) desensitization is initiated by G protein-coupled receptor kinases (GRKs), particularly GRK2/3, which phosphorylate serine/threonine residues on the receptor's intracellular C-terminal tail. This phosphorylation recruits β-arrestin, which sterically uncouples the receptor from its Gi/Go protein and simultaneously triggers clathrin-mediated internalization. cAMP superactivation (adenylyl cyclase upregulation) is a longer-term compensatory mechanism underlying aspects of physical dependence, not the rapid desensitization phase.

A 4-year-old child ingests an unknown quantity of a grandparent's iron supplement tablets. In the emergency department, the child develops metabolic acidosis, coagulopathy, and elevated serum ferritin. Which mechanism accounts for the metabolic acidosis seen in acute iron toxicity?

Answer: Free ferric iron catalyzes the Fenton reaction generating hydroxyl radicals that disrupt mitochondrial oxidative phosphorylation, causing lactic acidosis

In acute iron toxicity, excess free iron (Fe²⁺/Fe³⁺) catalyzes the Fenton reaction (Fe²⁺ + H₂O₂ → Fe³⁺ + OH⁻ + ·OH), generating highly reactive hydroxyl radicals. These radicals cause lipid peroxidation of mitochondrial membranes, uncoupling oxidative phosphorylation and shifting cellular metabolism to anaerobic glycolysis. The resultant lactate accumulation produces an elevated anion gap metabolic acidosis. This is compounded by direct cellular toxicity to hepatocytes and GI epithelium.

Which of the following correctly describes the pharmacodynamic concept of 'insurmountable antagonism' and distinguishes it from competitive antagonism?

Answer: Insurmountable antagonists bind covalently or with extremely high affinity to the receptor, depressing the maximum agonist response regardless of agonist concentration, whereas competitive antagonists shift the curve rightward while preserving Emax

Insurmountable (non-competitive or pseudo-irreversible) antagonism occurs when an antagonist binds with such high affinity (effectively irreversibly, e.g., covalently) that increasing agonist concentration cannot restore the full maximum response—Emax is depressed. This contrasts with surmountable (competitive) antagonism, where the antagonist is reversible and an agonist at sufficiently high concentrations can outcompete it, restoring Emax while shifting the EC50 rightward (parallel shift). Note that an insurmountable antagonist doesn't need to act allosterically—some orthosteric antagonists are insurmountable if their binding is effectively irreversible.

A patient with chronic kidney disease (GFR 18 mL/min) requires analgesia. They are prescribed tramadol. Which pharmacokinetic and pharmacodynamic concern makes this combination particularly dangerous?

Answer: Active O-desmethyltramadol (M1 metabolite, a μ-opioid agonist) and the parent compound accumulate due to impaired renal clearance, increasing seizure and opioid toxicity risk

Tramadol is partially converted by CYP2D6 to O-desmethyltramadol (M1), which has ~200-fold higher μ-opioid receptor affinity than the parent drug. Both tramadol and M1 are renally excreted. In CKD (especially GFR <30), their half-lives are prolonged dramatically, leading to accumulation. This raises risk of two distinct toxicities: (1) opioid toxicity from M1 accumulation (respiratory depression, CNS depression), and (2) seizures, since tramadol itself lowers seizure threshold via GABA modulation and norepinephrine/serotonin reuptake inhibition. Tramadol is generally contraindicated or used with extreme caution at GFR <30.

A toxicology fellow reviews a case of suspected digoxin toxicity. The patient's ECG shows frequent PVCs in a bigeminal pattern, and serum potassium is 2.9 mEq/L. Why does hypokalemia exacerbate digoxin toxicity at the molecular level?

Answer: Potassium and digoxin compete for the same extracellular binding site on the α-subunit of Na⁺/K⁺-ATPase; hypokalemia increases digoxin binding affinity to the pump

Digoxin exerts its effect by binding to the extracellular face of the α-subunit of Na⁺/K⁺-ATPase at the same site where K⁺ binds during normal pump cycling. K⁺ and digoxin are competitive at this binding site—when extracellular K⁺ is low (hypokalemia), there is less competition, and digoxin binds the pump more avidly and for longer periods, dramatically enhancing Na⁺/K⁺-ATPase inhibition. This leads to greater intracellular Na⁺ accumulation, reduced Ca²⁺ extrusion via NCX, elevated intracellular Ca²⁺, and increased risk of delayed afterdepolarizations and triggered arrhythmias. This is why potassium repletion is a cornerstone of digoxin toxicity management.