Monitoring albumin levels in phenytoin therapy

Nurse Practitioner, Apr 2000 by Crowder, Karen M

Extensive research has been conducted on the treatment of epileptic patients. Many studies have focused on monitoring free serum phenytoin (Dilantin) levels (unbound) versus total serum phenytoin levels (bound and unbound). Researchers have studied how to properly monitor phenytoin therapy using methods such as monitoring free serum phenytoin levels or serum albumin/total serum phenytoin ratio (see Table 1). Research has also focused on the pharmacokinetics of protein binding and drug interactions that cause competition for receptor sites on the protein.

In the emergency department, patients are examined by health care providers who are often unaware of the patient's complete medication regimen. For example, ibuprofen has a high affinity to bind with protein and will displace phenytoin from the protein receptor sites.' Patients who use over-the-counter ibuprofen may not disclose this information to their health care provider or in the emergency department.

Phenytoin is the oldest of the ef fective major antiepileptic drugs and one of the most potent drugs for preventing major tonic-clonic and other types of seizures.z It has a narrow therapeutic range that is responsible for the consequences of subtherapeutic or toxic serum phenytoin levels. Determining the specific pharmacokinetic parameters that warrant the monitoring of serum phenytoin levels for each patient may be difficult.'

A relationship between albumin and phenytoin levels exists, based on the clinical pharmacokinetics of the protein-binding mechanism (see Table 2). One principle of plasma protein is the affinity of certain drugs, such as phenytoin, to bind with it 4 Albumin is the major source of protein binding in the plasma.5

The second principle of plasma protein is the number of binding sites available for the drug at any given time. The final principle of pharmacokinetics is drug distribution. Many drugs compete for the same protein-binding sites, and this competition may increase the unbound or free serum concentration of the drug. The resulting uneven distribution will increase the drug response in the body

A total serum level is the amount of unbound and bound phenytoin in the blood. Only the free serum or unbound phenytoin is available for use by the body.

Marked toxic reactions to phenytoin can occur in critically ill patients with hypoalbuminemia or in patients with liver or kidney dysfunction in whom excretion of the unbound drug is inhibited.6 In many cases, therapeutic monitoring may only be achieved by directly measuring free phenytoin levels because there is a strong relationship between increased free serum concentration of phenytoin and phenytoin toxicity (see Figures 1 and 2).''8

When phenytoin levels are too high, symptoms of a toxic reaction such as drowsiness and ataxia are apparent. However, if phenytoin levels are too low, epileptic control is inadequate.9 Checking blood levels is imperative when treating a seizure patient. The optimal method for checking blood levels is by obtaining a sample just before the morning dose and then 2 hours after the morning dose has been taken.

The frequency of blood monitoring depends on epileptic control. If seizures are well controlled, sampling every 6 or even 12 months is adequate. If seizures are poorly controlled, blood samples may be taken daily or many times a day in a hospital setting. 10

Conscientiously investigating the total serum phenytoin and serum albumin ratio in epileptic patients is necessary to ensure therapeutic levels of phenytoin."

REFERENCES

1. Dasgupta A, Timmerman TG: In vitro displacement of phenytoin from protein binding by nonsteroidal anti-inflammatory drugs tolmetin, ibuprofen, and naproxen in normal and uremic sera. Therapeutic Drug Monitoring 1996;18(1): 97-99.

2. Downs T: The Epicentre (electronic data tape). Westmead, Australia: The Neurological Centre, 1997.

3. Bohenek W: 1995. Phenytoin (Dilantin): Helpful hints for dosing and monitoring in adult patients. Available: http://dacc.bsd.uchicago.edu/ drug/Bulletins/NI 95.html

4. Young LY, Koda-Kimble MA: Applied therapeutics: The clinical use of drugs. Vancouver, Wash.: Applied Therapeutics, Inc, 1995. Chpt 2:1-4.

5. Marcowsky SJ, Skaar DJ, Christie JM, et al.: Phenytoin protein binding and dosage requirements during acute and convalescent phases following brain injury. Ann Pharmaco Therapy

1996;30(5):443-48.

6. Fedler DJ, Stewart MJ: Plasma total pheny

toin: A possibly misleading test in developing countries. Therapeutic Drug Monitoring 1999;21(2):155-60.

7. Lindow J, Wijdicks EF: Phenytoin toxicity associated with hypoalbuminemia in critically ill patients. Chest 1994;105(2):602-04.

8. Peterson GM, Khoo BH, Von Witt RJ: Clinical response in epilepsy in relation to total and free serum levels of phenytoin. Therapeutic Drug Monitoring 1991;13(5):415-19.

9. Profeta LM, Bradbury K, Mehl B: Pharmacotherapy: Preventing overdoses and underdoses. Mt. Sinai J Med 1995;62(4):312-14.

10. Evans WE, Shentag JJ, Jusko WJ: Applied pharmacokinetics: Principles of therapeutic drug monitoring. Vancouver, Wash.: Applied Therapeutics, Inc., 1992.