Phenytoin has a narrow therapeutic index and exhibits capacity-limited (Michaelis-Menten) pharmacokinetics. At concentrations approaching therapeutic range (10-20 mg/L), which is the most appropriate clinical guidance for dose adjustments?

• A Large dose increments (e.g., 50-100 mg) are safe as proportionate increases in plasma levels are expected
• B Twice-daily dosing should be switched to once-daily to improve adherence and reduce peak fluctuations
• C Only small dose increments (e.g., 25-50 mg) should be made, as plasma levels can rise disproportionately due to enzyme saturation at therapeutic concentrations ✓
• D Dose adjustments should be based on renal clearance because phenytoin is primarily renally excreted unchanged

Explanation

Phenytoin's metabolism by CYP2C9/CYP2C19 follows Michaelis-Menten kinetics, and the Km for phenytoin is within or near the therapeutic concentration range (10–20 mg/L). As concentrations approach and exceed Km, hepatic enzymes approach saturation and phenytoin shifts from near-first-order to zero-order elimination. Small increases in dose can therefore produce markedly disproportionate increases in steady-state plasma levels, precipitating toxicity (nystagmus, ataxia, encephalopathy). Clinical practice mandates very small dose increments (25 mg) when phenytoin levels are already therapeutic. Phenytoin is primarily hepatically metabolised (not renally excreted).

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

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Written and medically reviewed by the StethoPrep medical team.