A 50-year-old man on phenytoin for epilepsy develops symptoms of cerebellar ataxia, nystagmus, and confusion. His plasma phenytoin level is 32 mcg/mL. The treating physician reduces the dose. This toxicity occurs at a sub-lethal level primarily because phenytoin exhibits:
- A First-order elimination kinetics with constant clearance irrespective of drug levels
- B Induction of its own metabolism leading to accumulation at high doses
- C Zero-order (saturation) kinetics at therapeutic levels, so small dose increments cause disproportionate concentration rises ✓
- D Renal tubular secretion that is inhibited by the drug's own acidic metabolites
Correct answer: C. Zero-order (saturation) kinetics at therapeutic levels, so small dose increments cause disproportionate concentration rises
Explanation
Phenytoin undergoes Michaelis-Menten (saturable, zero-order) kinetics at therapeutic concentrations because hepatic hydroxylation enzymes become saturated around 10-20 mcg/mL. At this point, even a small dose increase results in a disproportionately large increase in plasma concentration (non-linear kinetics), making toxicity easy to precipitate. This differentiates phenytoin from most drugs that follow first-order kinetics. Phenytoin induces CYP enzymes for other drugs, not autoinduction of its own elimination.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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