## Zero-Order Kinetics of Phenytoin **Key Point:** Phenytoin exhibits zero-order (saturation) kinetics at therapeutic doses because the hepatic enzyme system (CYP2C9, CYP2C19) becomes saturated. At saturation, the rate of elimination is constant and independent of serum concentration. ## Mathematical Basis At zero-order kinetics: - Elimination rate = constant (e.g., 5 mg/day) - Half-life increases as concentration increases - Small dose increments cause large concentration increases $$\text{Clearance} = \frac{V_{max}}{K_m + [C]}$$ When [C] >> K_m, clearance approaches zero, and small increases in dose produce disproportionate increases in steady-state concentration. ## Clinical Consequences **High-Yield:** Phenytoin has a **narrow therapeutic window** (10–20 μg/mL). Doses must be increased in small increments (25–50 mg) because: 1. A 100 mg increase may cause toxicity 2. Therapeutic drug monitoring is mandatory 3. Steady-state is reached slowly (5–7 days) 4. Individual variation is large **Warning:** Clinicians often make the mistake of increasing phenytoin dose aggressively, leading to acute toxicity (ataxia, nystagmus, confusion). **Clinical Pearl:** This is why phenytoin is being phased out in favor of newer antiepileptics with linear (first-order) kinetics (e.g., levetiracetam, lamotrigine), which have more predictable dosing. **Mnemonic:** **ZERO = Zero-order = Enzyme saturation = Risky dose escalation = Obligatory TDM** [cite:KD Tripathi 8e Ch 12]
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