Phenytoin combined with sulfamethoxazole-trimethoprim is associated with which risk?

• A. Decreased seizure control
• B. No interaction
• C. Increased risk of phenytoin toxicity
• D. Increased risk of kidney stones

Answer: (C)

Phenytoin has a narrow therapeutic window, and its blood levels can be pushed up quickly by drug interactions. When sulfamethoxazole-trimethoprim is added, phenytoin levels can rise due to two effects: it displaces phenytoin from albumin, increasing the free, active fraction, and it inhibits hepatic enzymes (especially CYP2C9) that metabolize phenytoin. Because phenytoin shows saturable, nonlinear (zero-order) kinetics, even small interactions can cause disproportionately large increases in level, leading to toxicity. In older adults, this risk is even higher due to age-related changes in metabolism and protein binding.

Toxicity from phenytoin can manifest as ataxia, nystagmus, diplopia, confusion, sedation, or even seizures in severe cases, which is why this combination is a red flag. The pairing does not improve seizure control and does not cause kidney stones, so the other options don’t fit.