Pharmacology · Year 2 · from Pharmacology
Case 2: Phenytoin Toxicity Due to Enzyme Saturation
Clinical Scenario
A 45-year-old male with epilepsy presents with ataxia, nystagmus, and slurred speech after his neurologist increased his phenytoin dose.
Patient Demographics
- Age: 45 years
- Sex: Male
- Weight: 70 kg
Chief Complaint
Unsteady gait, double vision, and difficulty speaking for 3 days
History of Present Illness
The patient has had well-controlled epilepsy on phenytoin 300 mg daily for 10 years. Due to breakthrough seizure activity, his dose was increased to 400 mg daily one week ago. Since then, he has developed progressive unsteadiness, difficulty speaking, and feeling "drunk without drinking."
Physical Examination
- Vital Signs: BP 125/80 mmHg, HR 78 bpm, RR 14, T 37.0C
- General: Alert but appears intoxicated
- Neurological:
- Horizontal nystagmus on lateral gaze bilaterally
- Dysarthria (slurred speech)
- Ataxic gait (unable to tandem walk)
- Finger-to-nose dysmetria
- Deep tendon reflexes normal
Workup and Results
| Test | Result | Reference Range |
|---|---|---|
| Total phenytoin level | 35 mcg/mL | 10-20 mcg/mL |
| Free phenytoin level | 4.2 mcg/mL | 1-2 mcg/mL |
| Albumin | 3.8 g/dL | 3.5-5.0 g/dL |
| ALT | 45 U/L | 7-56 U/L |
| AST | 38 U/L | 10-40 U/L |
Diagnosis
Phenytoin toxicity due to saturation kinetics (zero-order elimination)
Pharmacokinetic Principles Illustrated
- Non-linear (saturation) kinetics: Phenytoin follows Michaelis-Menten kinetics. At therapeutic doses, the hepatic enzymes become saturated, converting first-order to zero-order elimination.
- Disproportionate concentration increases: Small dose increases (33% in this case) can lead to disproportionately large increases in plasma concentration (75% increase).
- Narrow therapeutic index: Therapeutic range 10-20 mcg/mL; toxicity occurs at levels only slightly above.
- Protein binding considerations: Phenytoin is highly protein-bound (90%). Free drug levels are more clinically relevant.
Treatment
- Hold phenytoin until levels decrease to therapeutic range
- Supportive care for ataxia (fall precautions)
- Seizure precautions
- No antidote needed; allow drug clearance
- Resume phenytoin at lower dose (350 mg) once level <20 mcg/mL
- Consider free phenytoin level monitoring
Clinical Image
Chemical structure of phenytoin (5,5-diphenylhydantoin), an anticonvulsant with saturable hepatic metabolism leading to non-linear pharmacokinetics.
Image Source: Wikimedia Commons License: Public Domain URL: https://commons.wikimedia.org/wiki/File:Phenytoin_structure.svg