A drug with a narrow therapeutic index is being dosed in a patient who develops acute renal failure. The pharmacokinetic parameter that MOST directly determines the accumulation and toxicity risk is:

• A Volume of distribution, which expands in renal failure
• B Clearance (CL), which is reduced leading to increased half-life and steady-state plasma concentration ✓
• C Bioavailability, which is reduced due to renal tubular secretion of the prodrug form
• D Protein binding, which increases as albumin increases in renal failure

Explanation

For drugs primarily eliminated by the kidney, renal failure directly reduces total body clearance (CL). Since half-life = 0.693 x Vd / CL, a reduction in CL proportionally increases half-life. The steady-state concentration (Css = dosing rate / CL) rises as CL falls. For a narrow therapeutic index drug (e.g., digoxin, aminoglycosides, vancomycin), this accumulation leads to toxicity. Protein binding is actually decreased in renal failure (uraemia displaces drug from albumin binding sites), increasing the free fraction — the opposite of option D.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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Written and medically reviewed by the StethoPrep medical team.