A 32-year-old woman with generalized tonic-clonic seizures is being counseled about antiepileptic drugs (AEDs). Regarding the pharmacology and clinical use of first-line AEDs, all of the following are correct EXCEPT:

Explanation

## Analysis of First-Line Antiepileptic Drugs ### Pharmacokinetic Profiles | AED | Protein Binding | Metabolism | TDM Required | Key Interaction | |-----|-----------------|------------|--------------|------------------| | Valproate | 90% | Hepatic (β-oxidation) | Yes | Inhibits CYP450; displaces other drugs | | Levetiracetam | <10% | Renal + non-hepatic | No | Minimal CYP interactions | | Lamotrigine | 55% | Hepatic glucuronidation | No | Affected by valproate (↑ levels) | | Phenytoin | 90% | Hepatic | Yes | Induces CYP450; saturable kinetics | ### Why Option 3 (Phenytoin) is INCORRECT **Key Point:** Phenytoin exhibits **Michaelis-Menten (saturable) kinetics** at therapeutic doses, NOT zero-order kinetics. This means: - At low doses: first-order kinetics (linear increase in serum level with dose increase) - At therapeutic doses: saturable enzyme metabolism → small dose increases cause disproportionate serum level rises - This **non-linear relationship** makes dose prediction unpredictable, but the kinetics are Michaelis-Menten, not zero-order **High-Yield:** Zero-order kinetics (constant amount eliminated per unit time, independent of concentration) occurs with alcohol and aspirin at high doses. Phenytoin's saturable metabolism is the classic example of **dose-dependent kinetics** in clinical practice. ### Why the Other Options Are Correct **Option 1 (Valproate):** ✓ Correct - 90% protein-bound → displaces other highly protein-bound drugs (warfarin, phenytoin) - Hepatic metabolism via β-oxidation → inhibits CYP2C9, CYP2C19 → significant interactions **Option 2 (Levetiracetam):** ✓ Correct - <10% protein binding → minimal displacement interactions - 66% renal excretion unchanged; 34% non-hepatic metabolism → no CYP450 involvement - No TDM needed; linear kinetics **Option 4 (Lamotrigine):** ✓ Correct - Slow titration required to reduce risk of Stevens-Johnson syndrome / toxic epidermal necrolysis (SJS/TEN) - Risk is highest in first 2–8 weeks; 1 in 1000 in children, 1 in 3000 in adults - Valproate co-administration doubles lamotrigine levels (inhibits glucuronidation) **Clinical Pearl:** Phenytoin's saturable kinetics explain why a patient stable on 300 mg/day may develop toxicity if the dose is increased to 400 mg/day — the serum level may jump from 15 μg/mL to 35 μg/mL due to enzyme saturation. [cite:Harrison 21e Ch 369]