Phenytoin Level

Phenytoin is used as both an abortive and preventive medication in seizure management. ^{[1, 2, 3]}

The total phenytoin reference range varies by age, as follows:

• Children and adults: 10-20 µg/mL ^[4]

• Neonates: 8-15 µg/mL

Toxic phenytoin levels are defined as greater than 30 µg/mL. ^[4]

Lethal levels are defined as greater than 100 µg/mL.

The reference range of free phenytoin is 1-2.5 µg/mL.

In patients with renal failure associated with hypoalbuminemia, free phenytoin levels may be more accurate than total phenytoin levels. ^{[5, 6]} However, the Sheiner-Tozer formula (below) can be used to correct the phenytoin level. ^{[5, 7]}

Adjusted concentration = measured total concentration / [(0.2 x albumin) + 0.1]

Administration of phenytoin and interpretation of serum phenytoin levels vary depending on the clinical scenario. Loading doses to achieve rapid therapeutic levels should be checked 1 hour after an intravenous loading dose and 24 hours after an oral loading dose. ^[5]

Patients who are on long-term phenytoin therapy generally do not need to be monitored at intervals less than 3-12 months after a steady state has been reached unless clinically indicated, for example in patients who may have intentionally or unintentionally taken a toxic dose. ^[5]

Although the reference range is between 10 and 20 µg/mL, about half of patients’ seizures are controlled at values lower and higher than the therapeutic range. ^[7]

Some adverse effects of phenytoin are related to specific serum levels. Nystagmus is frequently observed at levels greater than 20 µg/mL. ^{[6, 7]} At greater than 30 µg/mL, patients may exhibit slurring of speech, ataxia, and movement disorders such as tremor, choreoathetosis, and orofacial dyskinesia. ^{[6, 7]} At serum levels that exceed 40 µg/mL, patients are often lethargic, stuporous, and confused and may require aggressive supportive measures. ^[6]

Phenytoin has been associated with adverse effects on the cerebellum. A literature review by Ferner et al found that out of 81 cases with signs of cerebellar impact from phenytoin, 96% had one or more clinical signs of ataxia; 63%, of dysarthria; and 70%, of nystagmus. Out of 76 cases with signs of cerebellar effects, 13% experienced recovery within a year, 72% had residual disability, and 14% died. The report indicated that in most phenytoin patients with cerebellar dysfunction, the serum phenytoin concentrations are above the reference range. ^[8]

Specimen: Blood

Container: Red-top tube

Collection method: Routine venipuncture

Loading doses to achieve rapid therapeutic levels should be checked 1 hour after an intravenous loading dose and 24 hours after an oral loading dose. ^[5]

Description

Phenytoin is an antiepileptic drug with several pharmacologic actions, including ion conductance, Na-K ATPase activity, synaptic transmission, and neurotransmitter release; the antiepileptic effects of phenytoin are thought to be primarily related to its action at the sodium channels during depolarization, preventing repetitive neuronal firing. ^[7]

Assessing phenytoin levels is useful in prophylaxis of seizures in patients with intracranial pathology, management of epileptic patients, and evaluation of patients with potential phenytoin overdose/toxicity.

Indications/Applications

Phenytoin is used as both an abortive and preventive medication in seizure management. Intravenous administration of phenytoin ceased seizure activity in 60%-80% of patients in status epilepticus within 20 minutes. Prophylactic indications include pregnancy-induced hypertension, postneurosurgery, cerebrovascular accidents, and traumatic brain injury. Of these, there is inconsistent evidence to support the routine use of phenytoin in patients who have undergone craniectomy.

Less-common uses of phenytoin include the treatment of neuropathic pain, motion sickness, muscular dystrophy, and arrhythmia. ^[7]

Phenytoin levels are helpful in determining therapeutic dosing in patients with epilepsy and in managing adverse effects and toxicity in accidental or intentional overdoses.

Considerations

Phenytoin is available in many formulations, including extended-release capsules. When managing patients receiving extended-release capsules, a random serum level will suffice given the prolonged half-life. ^[5]

Total phenytoin levels reflect both bound and unbound drug; because protein-bound phenytoin cannot cross the blood-brain barrier, only free phenytoin is active. In healthy adults, approximately 90% of phenytoin is bound to albumin. Corrected levels can be calculated using the Sheiner-Tozer method. ^{[5, 7]} Correction should be used in patients with uremia, hepatic disease, and AIDS. ^[7]

Concomitant use of valproic acid alters free phenytoin levels by competitively binding to serum albumin. ^[7]

Because hepatic metabolism is saturable, elimination of phenytoin may be delayed in patients with large ingestions. ^[6]

In addition to monitoring renal function, hepatic function, and albumin levels, physicians should be aware of antifolate and anti–vitamin K properties of phenytoin in pregnant women. Folate levels and abnormal bleeding profiles should be considered in pregnant women and newborns, with supplementation as indicated. ^[9]