Common indications for the use of phenytoin are:
Control of generalized tonic-clonic and complex partial (psychomotor, temporal lobe) seizures
Prevention and treatment of seizures occurring during or following neurosurgery
Prevention of early (within 1 week) post-traumatic seizures following traumatic brain injury
The initial dose of phenytoin is a loading dose of 15-20 mg/kg, followed by a maintenance dose of 5-6mg/kg/day.
How can I tell if the phenytoin concentration is therapeutic?
To determine if a patient has a therapeutic phenytoin level, I look at 4 things in the following order:
– Are seizures controlled?
– Are side effects present?
– Is the drug at steady-state?
– What is the phenytoin level?
As with all drugs, it is important to treat the patient and not the number. For most patients the therapeutic range of phenytoin is 10-20 mcg/mL. However if seizures are controlled at 9 mcg/mL or side effects are present at 12 mcg/mL, a patient specific therapeutic range should be considered.
Phenytoin is highly protein bound. In the setting of hypoalbuminemia, either a corrected phenytoin level should be estimated or a free phenytoin level should be checked.
Formulas for adjusting the measured phenytoin level for hypoalbuminemia are population-based and may not be accurate in any given patient. A large number of conditions including burns, sepsis, uremia, liver disease (and many more!) can alter the serum binding of phenytoin.
My preference is always to measure the free phenytoin if the patient has hypoalbuminemia because this is a patient-specific result.
The average half-life of phenytoin in adults is about 24 hours, so any level taken within the first 5 days of initiation or dose change should not be considered a steady-state level.
I’ll check a level 2-3 days after initiation to make sure phenytoin metabolism is not significantly abnormal, and again 5 days after initiation or any dose change to assess the steady-state concentration. After that, I’ll monitor the phenytoin level weekly while the patient is still in the hospital.
Monitoring & dose adjustments
I remember my pharmacokinetics class being split into two parts:
– Phenytoin kinetics
– All other drugs
The body’s capacity to metabolize phenytoin is fixed and saturable. This is referred to as zero-order or Michaelis-Menten kinetics.
The mnemonic “Peas & WHEATS” has been used to remember all the drugs that have saturable metabolism:
What makes phenytoin unique from these other medications is that the saturation point can overlap with the normal therapeutic dose range. A small change in dose can result in a massive change in plasma concentration if the saturation point is unknowingly exceeded. Even the 8% increase in bioavailability between the phenytoin base (oral suspension and chewable tablets) compared to phenytoin sodium (oral capsules and IV formulation) could be enough to surpass the saturation point and cause toxicity.
Adjustments to the maintenance dose of phenytoin should be made in small increments. A fantastic guideline for maintenance dose adjustment is used by the University of Michigan Medical School:
A rough guide to making an adjustment to the daily dose that should increase a serum level without leading to supratherapeutic / toxic levels is:
If the phenytoin concentration is < 7 mcg/mL, the dose may be increased by 100 mg/day.
If the phenytoin concentration is 7-12 mcg/mL, the dose may be increased by 50 mg/day.
If the phenytoin concentration is >12 mcg/mL, the dose may be increased by 30 mg/day.
If the phenytoin concentration is >16 mcg/mL, any change may result in a significant increase in serum level and should be done very carefully.
If the phenytoin level is subtherapeutic, and seizures are not controlled, it is best to re-load the patient to quickly obtain a therapeutic level rather than make a large change to the daily dose. The University of Michigan Medical School also gives a nice rule of thumb for re-loading a patient with phenytoin to achieve a therapeutic level:
loading dose = (goal total phenytoin level – current total phenytoin level) x weight in kilograms
Cardiac toxicity may occur with phenytoin administration, even at normal infusion rates. Because of this the FDA has added a warning to the prescribing information for phenytoin that suggests cardiac monitoring occur during and after IV phenytoin administration.
At supratherapeutic levels, phenytoin can be extremely toxic. The expected toxicities according to the plasma level are:
20 and 30 mcg/mL – Nystagmus
30 and 40 mcg/mL – Ataxia, slurred speech, nausea, and vomiting
40 and 50 mcg/mL – Lethargy and confusion
> 50 mcg/mL – Coma and seizures
The treatment of chronic phenytoin toxicity involves supportive care. Multiple dose activated charcoal may help enhance elimination. Lidocaine use should be avoided as the two drugs are both Vaughan Williams Class IB antiarrhythmic agents.
Phenytoin is a complex medication to use safely. If you are not already familiar with phenyotin, you can expand your understanding beyond this podcast by reading an excellent review article found in Pharmacotherapy here.
Do you have your own preference for dosing phenytoin? Post it in the comment section below!
If you like this post, check out my book – A Pharmacist’s Guide to Inpatient Medical Emergencies: How to respond to code blue, rapid response calls, and other medical emergencies.