Phenytoin exhibits Michaelis-Menten (zero-order/saturable/nonlinear) kinetics at therapeutic concentrations. The clinical consequence is:
- A Dose increases produce proportional plasma level increases, simplifying dose titration
- B Small dose increments above the therapeutic range cause disproportionately large plasma level rises, dramatically increasing toxicity risk ✓
- C The half-life shortens as plasma concentration rises, auto-limiting toxicity
- D Phenytoin clearance is constant regardless of plasma concentration, enabling steady-state prediction from a single blood level
Correct answer: B. Small dose increments above the therapeutic range cause disproportionately large plasma level rises, dramatically increasing toxicity risk
Explanation
At phenytoin doses that saturate CYP2C9/CYP2C19 enzymes, elimination switches from first-order (proportional to concentration) to zero-order (constant rate). Once saturation occurs, even small dose increments produce large, unpredictable plasma level increases because the elimination pathway cannot increase to match the higher input. This makes phenytoin dangerous to titrate above the mid-therapeutic range (10–20 mg/L); doubling the dose may increase levels 5–10 fold. The apparent half-life increases (not decreases) as levels rise — the opposite of option C.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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Written and medically reviewed by the StethoPrep medical team.