A drug follows zero-order kinetics at therapeutic doses. Which clinical implication is most important?

• A Small increases in dose can produce disproportionately large increases in plasma concentration, with unpredictable toxicity risk ✓
• B The drug reaches steady state after exactly 4-5 half-lives like any other drug
• C Doubling the dose will double the plasma concentration proportionally and safely
• D The drug's half-life is constant and independent of plasma concentration

Explanation

In zero-order (saturable, dose-independent) kinetics, the elimination pathway is saturated at therapeutic concentrations, so a fixed amount of drug is eliminated per unit time regardless of plasma concentration. Phenytoin (and ethanol, salicylates at high doses) exhibits this pattern above certain concentrations. Because elimination rate is constant and not proportional to concentration, small dose increments can cause disproportionately large rises in steady-state plasma concentration, quickly crossing into the toxic range. For phenytoin: increasing dose from 300 to 400 mg/day may barely raise levels, but going from 350 to 400 mg/day at higher baseline concentrations can double the plasma level. This makes dose titration hazardous and requires careful therapeutic drug monitoring.

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

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Written and medically reviewed by the StethoPrep medical team.