What causes elevated phenytoin (Dilantin) levels in patients with a history of seizure disorders, such as epilepsy?

Causes of Elevated Phenytoin (Dilantin) Levels

Elevated phenytoin levels result primarily from the drug's saturation kinetics, drug interactions that inhibit metabolism or displace protein binding, impaired hepatic function, and medication non-adherence leading to dose accumulation.

Primary Mechanisms of Phenytoin Elevation

Saturation Kinetics and Dose-Related Accumulation

• Phenytoin exhibits non-linear (saturable) pharmacokinetics, meaning small dose increases can cause disproportionately large increases in serum levels 1
• The half-life of phenytoin is dose-dependent: less than 20 hours at low doses but becomes prolonged at higher doses, leading to accumulation 1
• Approximately 75% of phenytoin is metabolized by the liver, making hepatic metabolism the rate-limiting step 1

Drug Interactions That Increase Phenytoin Levels

Enzyme Inhibitors:

• Drugs that inhibit hepatic metabolism can dramatically increase phenytoin levels by reducing clearance 1
• Common culprits include certain antibiotics, antifungals, and other anticonvulsants that compete for the same metabolic pathways 1

Protein Binding Displacement:

• Phenytoin is normally 90-95% protein-bound in plasma 1
• Drugs that displace phenytoin from plasma proteins increase the level of unbound (active) phenytoin, leading to toxicity even when total levels appear therapeutic 1
• This mechanism is particularly dangerous because standard lab tests measure total phenytoin, not the free (active) fraction 1

Hepatic Dysfunction

• Severe liver disease reduces phenytoin clearance by approximately 50%, leading to accumulation 1
• Patients with chronic liver disease or cirrhosis require dose adjustments to prevent toxicity 2
• Phenytoin is recommended as the primary anticonvulsant in hepatic encephalopathy, but dosing must be carefully monitored 2

Patient-Specific Factors

Age-Related Changes:

• Elderly patients have prolonged phenytoin half-life, increasing risk of accumulation 1
• Newborn infants also demonstrate prolonged half-life 1

Rapid Intravenous Administration:

• Rapid IV infusion can cause sudden elevation in serum levels, potentially triggering paradoxical seizures and blood dyscrasias 3
• The recommended maximum infusion rate is 50 mg/min to prevent acute toxicity 4

Clinical Consequences of Elevated Levels

Phenytoin Encephalopathy

• High phenytoin levels cause cognitive impairment and cerebellar syndrome (ataxia, nystagmus, balance disturbances) 1
• This is particularly problematic in patients with intellectual disability who are already susceptible to balance and cognitive dysfunction 1

Paradoxical Seizures

• At very high concentrations (>70-93 mcg/mL), phenytoin can paradoxically exacerbate seizures or precipitate status epilepticus in epileptic patients 5
• This occurs in approximately 2% of toxic epileptic patients, though most tolerate levels up to 85 mcg/mL without seizure exacerbation 5
• The mechanism involves decreased seizure threshold at toxic concentrations 3, 5

Hematologic Toxicity

• Elevated levels can cause blood dyscrasias including unusual bruising, bleeding, and bone marrow suppression 6, 3

Common Pitfalls and Prevention Strategies

Monitoring Failures:

• Failure to monitor both total and free phenytoin levels in patients on multiple medications or with hypoalbuminemia leads to unrecognized toxicity 1
• Steady-state levels are typically reached within 1-2 weeks, but this is prolonged with enzyme inhibitors 1

Treating Numbers Instead of Patients:

• Some patients require "supratherapeutic" levels (>80 micromol/L or even twice the normal therapeutic range) for seizure control without toxicity 7
• Clinicians must balance serum concentrations against clinical response and adverse effects rather than rigidly adhering to reference ranges 7

Drug Interaction Oversights:

• Concomitant enzyme-inducing drugs (phenobarbital, carbamazepine) shorten phenytoin half-life, but their discontinuation can cause sudden phenytoin accumulation 1
• Adding enzyme inhibitors without dose adjustment predictably causes toxicity 1

Special Population Considerations:

• Pregnancy decreases phenytoin levels due to increased metabolism and volume of distribution, but postpartum levels rise rapidly 6
• Patients with intellectual disability require particularly careful monitoring due to increased susceptibility to cognitive and cerebellar adverse effects 1