Phenytoin (Dilantin, Phenytek, generics) was approved by the FDA in 1953 for the management of seizures in children and adults, and it is still relevant today. It is often our go-to agent for adults requiring critical care for status epilepticus. Fosphenytoin, the water-soluble prodrug of phenytoin, was approved in 1996. It offers faster infusion times and an improved administration safety profi le. The two agents are indicated for tonic-clonic and complex partial seizures and for seizure prevention in both head injury and neurosurgery. Although phenytoin is one of the oldest agents in our current anticonvulsant arsenal, it has several unique pharmacokinetic properties that make it more complicated to properly manage than other drugs. It is still one of the medications most misunderstood by practitioners.
Phenytoin is highly lipophilic, distributing readily into adipose tissue. Normal adult loading doses are 15 to 20 mg/kg based on total body weight. However, because of the lipophilic nature of phenytoin, clinicians should consider giving higher loading doses in obese patients (up to 25 mg/kg) because it will take a higher initial dose to obtain adequate plasma concentrations of free drug.1,2 This is somewhat counterintuitive because with many other drugs, we adjust doses down for obesity, using an adjusted body weight or even a lean (ideal) weight. The impact of obesity on subsequent maintenance dosing is not as significant because the loading dose has "filled the tank" and now one needs only to maintain the level with a continuing dose. There is a paucity of primary literature that evaluates optimal maintenance dosing in obese patients, but using an ideal or an adjusted weight and monitoring levels is reasonable.2
Phenytoin is also highly protein-bound (90-95% in healthy adults), making the amount of active or free drug only about 10% of the total level in the blood. Some institutions monitor free phenytoin levels, which are easy to interpret because no correction for protein status is required (usual therapeutic range, 1-2 µg/mL). However, if your institution uses total levels (usual range, 10-20 µg/mL), then the patient's protein status (generally measured by albumin) will need to be accounted for.1,3 Interpretation of total levels is tricky. A phenytoin level of 7 µg/mL may look low on its face, but when a patient's albumin is also low, the reported level will need to be adjusted to make up for higher amounts of free drug resulting from less available protein for binding. For example, a patient with a total phenytoin level of 7 µg/mL, an albumin level of 2 g/dL, and normal renal function would have a corrected phenytoin level of 14 µg/mL. This is equivalent to a free active drug level of approximately 1.4 µg/mL. Thus, a phenytoin level of 7 µg/mL in this patient is actually therapeutic. In patients with renal failure, higher levels of uremia essentially kick phenytoin off its protein-binding sites, making the ratio of free to total drug even more pronounced.4 This same patient with renal failure would have a corrected total level of 23 µg/mL, making the measured total level of 7 µg/mL slightly supratherapeutic. Calculators are available online to correct for phenytoin levels in patients with hypoalbuminemia or renal failure.
Another fact to consider is that phenytoin at therapeutic levels undergoes capacity-limited pharmacokinetics. In most drugs for which levels are regularly monitored, we often observe that a doubling of dose will lead (roughly) to a doubling of level in the blood. However, because of its unique kinetics, doubling a phenytoin maintenance dose may lead to a quadrupling or more of the level in the blood. Therefore, the recommendation is that changes in maintenance dose based on blood levels be no more than 50 to 100 mg/day. For example, you may increase the phenytoin dose from 300 to 400 mg/day and see the total level jump from 6 to 18 µg/mL. Also keep in mind that reaching steady-state levels may take several weeks, so frequent monitoring of blood levels and changes to dosing may only convolute your dosing strategy.
Lastly, phenytoin has many drug interactions that require serious consideration in complicated inpatient drug regimens. Most come from inhibition or induction of hepatic metabolism of phenytoin (eg, ciprofloxacin, fluconazole) or its effect on the metabolism of other drugs. However, some drugs may compete for protein-binding sites, resulting in a greater amount of free phenytoin (eg, valproic acid). Reevaluation is crucial whenever these medications are stopped or started during an inpatient stay. JAAPA
Kristen Bamberg, PharmD, MS, BCPS, is a lead critical care pharmacist at Flagstaff Medical Center in
Flagstaff, Arizona, and a board-certifi ed pharmacotherapy specialist.
REFERENCES
1. Winter ME. Phenytoin and fosphenytoin. In: Murphy J, ed. Clinical Pharmacokinetics. 3rd ed. Bethesda, MD:American Society of Health System Pharmacists; 2005: chap 14.
2. Erstad, BL. Dosing of medications in morbidly obese patients in the intensive care unit setting. Intensive Care Med. 2004;30(1):18-32.
3. Lindow J, Wijdicks EF. Phenytoin toxicity associated with hypoalbuminemia in critically ill patients. Chest. 1994;
105(2):602-604.
4. Dasgupta A, Abu-Alfa A. Increased free phenytoin concentrations in predialysis serum compared to postdialysis serum in patients with uremia treated with hemodialysis. Role of uremic compounds. Am J Clin Pathol. 1992;98(1):19-25.