Subacute Care Forum

Guidelines for Monitoring Phenytoin

Phenytoin (Dilantin, Parke-Davis) is used for various indications including treatment of grand mal and psychomotor seizures, prevention and treatment of seizures following neurosurgery, and the treatment of trigeminal neuralgia. The intravenous dosage form is used in status epilepticus and digitalis-induced arrhythmias.

Phenytoin is 90 percent bound to albumin, and the remaining 10 percent reaches the tissues and produces the pharmacologic and adverse effects. Several factors may alter the protein binding of phenytoin (i.e., hypoalbuminemia, end-stage renal disease, and various medications). Most current nursing home residents do not have extensive renal disease. However, as subacute care begins to play a more important role in facilities, these types of residents will be encountered more frequently, along with the typical nursing home residents with low serum albumin.

I conducted a review of phenytoin dosing in nursing home residents. The results are presented in this column.

Methods

Twenty-seven residents in seven skilled-nursing facilities were reviewed as part of the monthly drug-regimen review (DRR). Assessed were total serum phenytoin concentrations, albumin concentrations, and estimated creatinine clearances; the serum phenytoin concentrations were adjusted according to these factors when necessary.

FIGURE 1.

DATE:_________ RESIDENT:_____________________________________

PHENYTOIN DOSE:_____________________PHYSICIAN:______________

FACILITY:____________________________________________________

AGE:______ HEIGHT:_______ WEIGHT:_______ (KG) KG= LB/2.2

LBW:_______________

LBW MALES = 50 + (2.3 X INCHES OVER 5 FEET)

LBW FEMALES= 45 + (2.3 X INCHES OVER 5 FEET)

IF LBW > THAN ACTUAL WEIGHT, USE ACTUAL

IF OBESE, WEIGHT = ( ACTUAL- LBW ) X 0.4 + LBW

SERUM CREATININE (SCR) = ______________________________MG/DL

CREATININE CLEARANCE = ______________________________ML/MIN

MALES= ((140- AGE) X WEIGHT)/(72 X SCR)

FEMALES = MALES X 0.85

ALBUMIN :___________ G/DL

phenytoin LEVEL:___________________µG/ML

I also devised a data collection form (Figure 1) for use during the monthly DRR. Data collected included age, height, weight, phenytoin dose, serum creatinine, albumin, and serum phenytoin concentration. Hypoalbuminemia was defined as less than 4.4 g/dL and therapeutic phenytoin concentrations were defined as 10-20 µg/mL.

TABLE 1. Adjusted Phenytoin Level for Hypoalbuminemia

Measured Total Phenytoin Concentration	Patients Serum Albumin (g/dL)
	3.5	3	2.5	2
	Adjusted Total Phenytoin Concentration (µg/mL) *
(µg/mL)
5	6	7	8	10
10	13	14	17	20
15	19	21	25	30

* Adjusted concentration= measured total concentration ÷ ((0.2 x albumin)+ 0.1)
Adjusted phenytoin concentrations were calculated if albumin levels were < 4.4 g/dL. Adjusted phenytoin concentrations (Table 1) were calculated as follows³:
Adjusted phenytoin concentration = Measured total concentration ÷ ((0.2 x albumin) + 0.1 )

TABLE 2. Adjusted Dilantin Level for Hypoalbuminemia and CLCR< 10 Ml/Min

Measured Total Phenytoin Concentration	Patients Serum Albumin (g/dL)
	4.0	3.5	3	2.5	2
	Adjusted Total Phenytoin Concentration (µg/mL)a
(µg/mL)
5	10	11	13	14	17
10	20	22	25	29	33
15	30	33	38	43	50

a Adjusted concentration= measured total concentration ÷ ((0.1 x albumin) + 0.1)
*Adjusted phenytoin level _____________ µg/mL

If serum albumin was < 4.4 g/dL and estimated creatinine clearance < 10 mL/min the following equation was used (Table 2):³

Adjusted concentration= Measured concentration +((0.1 x albumin) ÷ 0.1)

Physicians and members of the nursing staff were notified of residents for whom the serum phenytoin concentration was adjusted secondary to hypoalbuminemia or creatinine clearance < 10 mL/min.

Results

A total of 19 residents were women, 8 were men; and the median age of 70 (range 36-86 years). The mean albumin concentration was 3.7 g/dL (range 3.1-4.6) and the median estimated creatinine clearance was 57 mL/min, according to the Cockroft and Gault equation. Twenty five residents had hypoalbuminemia. Of these, six had corrected phenytoin concentrations > 20 mcg/ml. In summary, eleven patients (41%) had serum phenytoin concentrations in excess of the therapeutic range. No residents had phenytoin concentrations adjusted because of creatinine clearance < 10 mL/min.

Discussion and Conclusion

Protein binding is an important concern in all residents receiving phenytoin. Although the fraction of unbound drug is increased in hypoalbuminemia, the total serum concentration may remain unchanged or even be reduced. Unfortunately, most laboratories still measure total serum phenytoin concentrations, and free phenytoin concentrations are not commonly available. Because of the unavailability of these laboratory tests, the consultant pharmacist must interpret the total serum phenytoin concentrations in consideration of the serum albumin level.

This study showed that 93 percent of the residents required adjustment of their serum phenytoin concentrations secondary to hypoalbuminemia, with 22 percent having a blood level above the therapeutic range after corrections were made. Factors that may alert the consultant pharmacist to hypoalbuminemia are liver disease, burns, and malnutrition. In addition, medications that may cause protein-binding displacement include salicylates, warfarin, fluoxetine, sertraline, and valproic acid. Unfortunately, estimation of the extent of drug displacement from albumin is very complex when these medications are administered concomitantly.

This study showed that none of the residents had to have phenytoin concentrations adjusted based on creatinine clearance. Most of these nursing home residents did not have extensive renal disease. Subacute care is playing an increasingly important role in our facilities, and these types of residents will be encountered more frequently.

The elderly residents studied here generally required smaller doses of antiepileptic medications. Adequate monitoring is essential to promote efficacy and avoid potential toxicity.

Recommendations

Based on these study results, the following recommendations can be made:

1. Trough serum phenytoin concentrations should be assessed 10 to 14 days after initiation of therapy, and if a dosage change has been made, every 6 to 12, months during long-term therapy, or when seizure activity is observed or toxicity is suspected.

2. Serum albumin concentrations should be drawn upon initiation of phenytoin therapy (if not drawn within the last 6 to 12 months). If previous albumin was normal and there is no reason to suspect a decrease, no other levels are needed. Albumin levels should be drawn along with phenytoin levels every 6 to 12 months in residents with a history of hypoalbuminemia.

Pamela Walker-Renard, Pharm. D., BCPS, FASCP
Consultant Pharmacist
Pharmacy Corporation of America
101 N. Union #108
Kennewick, WA 99336
509-783-7272

References

1. Samulak KM, Kaufman MB. Phenytoin toxicity. US Pharm 1995: H3-11.

2. American hospital formulary service. Bethesda, MD: American Society of Health-System Pharmacists, 1994: 1358-61.

3. Winter M. Phenytoin. In: Koda-Kimble MA, Young LY, ed. Basic clinical pharmacokinetics. Vancouver, WA: Applied Therapeutics, 1988: 235-64.

The Subacute Care Forum is published monthly. This column contains practice tips, news, and other information that can help consultant pharmacists provide pharmaceutical care to those increasingly common long-term care patients needing a higher level of care and more complex therapies. Contributions, always welcome, should be sent to Academics Editor L. Michael Posey, P. O. Box 6565, Athens, GA 30604; 706/613-0100, 706/613-0200 (fax), mposey@aol.com (e-mail).