Phenytoin Monitoring in the Intensive Care Unit

Abstract

Phenytoin has been used extensively in the neurological and neurosurgical settings since its introduction in 1938. Despite the fact that alternative agents exist, including a whole series of newer agents, phenytoin is still considered one of the most effective, relatively nontoxic anticonvulsant therapies currently available. Unfortunately, however, the pharmacokinetics and pharmacodynamics of this drug are complex and often confuse the pharmacist and physician team, resulting in suboptimal or unacceptably high serum concentrations. This was exactly the case in our institution up until 3 years ago, when a major pharmacy-initiated education and dosing service program was implemented. We review the basic phenytoin monitoring guidelines used in our institution, which are substantiated by the current literature and by personal experience. Copyright © 1995 by W.B. Saunders Company PHENYTOIN IS THE MAIN anticonvul-.t sant in the pharmacological class known ashydantoins. Other hydantoins, such as mephenytoin and ethotoin, are available but infrequently used. Seizure control has been successful over the years with phenytoin use and, in ambulatory epileptic patients, has been shown in a dose-dependent manner to provide up to 97% efficacy.' Seizure prophylaxis efficacy data in the head injury/neurosurgical setting are both lacking and confusing. The incidence of seizures in such patients can range from 6% to 53% depending on diagnosis or proximity to the event, and those studies that do attempt to assess efficacy have varied tremendously with regards to dosing methods and group stratification.2-13 By promoting sodium efflux from neurons within the motor cortex, hydantoins tend to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. Because phenytoin is able to inhibit rapid sodium influx, its utility as an antiarrhythmic (Class IB) is also noted; it is considered the drug of choice in patients experiencing arrhythmias secondary to digoxin toxicity. 14,15 INITIAL DOSING In initiating phenytoin therapy in a patient who has a serum concentration of zero, a bolus dose must be given. An intravenous dose of 15 mg/kg or an oral dose of 20 mg/kg should be given; these doses are based on a phenytoin volume of distribution of 0.71 /kg, the respective dosage form bioavailability, and a desired postload serum concentration of approximately 15 to 20 J,Lg/mL. The traditional 1-g load, then, for most people, serendipitously turns out to be satisfactory. However, patients who are very small (less than 60 kg) or large (more than 75 kg) do need their bolus dose tailored to their body weight to insure that they achieve an adequate, nontoxic serum concentration. In our experience, loading doses should be based on total body weight, within reason. Several patients in our ICU have been given boluses of 1.5 to 2 g loading doses without adverse sequelae, and despite the literature that supports an alternative dosing for obese patients, it has ...

Correlation of Free and Total Phenytoin Serum Concentrations in Critically Ill Patients

“…This agent exhibits nonlinear pharmacokinetics at therapeutic concentrations. 4 Hepatic metabolism predictably rises as the phenytoin serum concentration increases until liver metabolic enzyme saturation occurs. 4 Following saturation, a maximum threshold of the enzymatic metabolic capabilities is reached despite increases in doses administered.…”

“…4 Hepatic metabolism predictably rises as the phenytoin serum concentration increases until liver metabolic enzyme saturation occurs. 4 Following saturation, a maximum threshold of the enzymatic metabolic capabilities is reached despite increases in doses administered. 4 Consequently, increases in phenytoin doses result in prolonged elimination and disproportional elevation in serum drug concentrations.…”

Phenytoin Serum Concentrations in Patients With Left Ventricular Support Devices: A Case Series

“…Phenytoin is an antiepileptic medication that is often used in the intensive care unit (ICU) for the treatment and prophylaxis of seizures or status epilepticus. 1,2 Phenytoin and its prodrug fosphenytoin have complicated pharmacokinetic parameters that must be considered when utilizing these medications. Phenytoin exhibits extensive protein binding (>90%), and only the free portion of phenytoin is pharmacologically active for the treatment of or prevention of seizures.…”

“…Additionally, there are numerous drug interactions seen with phenytoin due to its induction of cytochrome P450 enzymes, including CYP3A4, CYP1A2, and CYP2B6 and potential for alterations in protein binding. 2,3 All of these parameters lead to the common practice of therapeutic drug monitoring of phenytoin, with a typical total serum concentration goal of 10 to 20 µg/mL. 2,4…”

“…2,3 All of these parameters lead to the common practice of therapeutic drug monitoring of phenytoin, with a typical total serum concentration goal of 10 to 20 µg/mL. 2,4…”