Narrow therapeutic index drugs like phenytoin and warfarin show non-linear (Michaelis-Menten) pharmacokinetics at therapeutic concentrations. The clinical consequence is:

• A Steady state is reached faster than predicted by standard first-order calculations
• B The half-life is constant across all plasma concentrations, allowing simple dose-proportional adjustments
• C The volume of distribution decreases at higher concentrations, preventing toxicity
• D Small dose increases can cause disproportionately large rises in plasma concentration as metabolic enzymes become saturated, dramatically raising toxicity risk ✓

Explanation

When metabolic enzymes (e.g., CYP2C9 for phenytoin) become saturated (Vmax reached), any additional dose cannot be cleared proportionally — it shifts from first-order to zero-order kinetics. A small dose increment (e.g., from 300 to 350 mg phenytoin) can cause plasma levels to double or triple rather than increase by the same proportion. This capacity-limited kinetics explains why dose adjustments in the toxic range must be made in very small increments, and why inter-patient variability in Km and Vmax creates wide therapeutic range variation.

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

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Written and medically reviewed by the StethoPrep medical team.