# Presentation: 056428

## Spotlight Case May 2007

**Antiseizure Medication Disorder **

## Source and Credits

- This presentation is based on the May 2007 AHRQ WebM&M Spotlight Case
- See the full article at _[http://](http://webmm.ahrq.gov/)__[webmm.ahrq.gov](http://webmm.ahrq.gov/)_
- CME credit is available through the Web site
- Commentary by: **Brian K. Alldredge**, **PharmD**, UCSF School of Pharmacy
- Editor, AHRQ WebM&M: Robert Wachter, MD
- Spotlight Editor: Tracy Minichiello, MD
- Managing Editor: Erin Hartman, MS

## Objectives

*	**At the conclusion of this educational activity, participants should be able to:*
- Appreciate the challenges of safe use of antiepileptic medications
- Identify phenytoin toxicity
- Understand the pharmacodynamics and pharmacokinetics of phenytoin
- List clinical scenarios when phenytoin levels may be unreliable

## Case: Antiseizure Medication Disorder 

- 	*A 76-year-old man was admitted for evaluation of increasing lethargy, confusion, and decreased appetite. The patient had a past medical history of seizure disorder with a recent admission for uncontrolled seizures, anemia, and hip arthroplasty. His medications included phenytoin 300 mg once a day, phenobarbital 30 mg three times a day, residronate 35 mg once a week, and iron supplements.*

## Case: Antiseizure Medication Disorder 

*	**On physical exam, his vital signs were unremarkable and he had no fever. By report, neurological exam revealed only confusion and diminished deep tendon reflexes.  Laboratory data was significant for a slightly elevated white blood cell count (WBC) and abnormal urinalysis, with 6-10 WBCs. A phenobarbital level was 30 (therapeutic 10-40 mcg/mL) and phenytoin level was 19 (therapeutic 10-20 mcg/mL). *

## Case: Antiseizure Medication Disorder 

*	**The rest of his electrolytes, renal function,  and liver function tests (AST, ALT, bilirubin and alkaline phosphatase) were normal. CT scan of the head was unremarkable. *
*	**The providers thought the patient’s mental status change was likely due to urinary tract infection and effects of phenobarbital. The patient was treated with antibiotics and his phenobarbital was held.*

## Epilepsy and Treatment

- Epilepsy affects approximately 2 million people in the United States
- Antiseizure medications are the primary mode of epilepsy treatment
- Medications successfully control seizures in approximately two-thirds of patients

## Antiseizure Medications

- More than 15 antiseizure medications are commonly used in the US
- Choice of agent dictated by
- Epilepsy syndrome
- Drug-drug or drug-disease state interactions
- Unique medication-related adverse effects

## Traditional Antiseizure Medications

- “Enzyme-inducing”
- Phenytoin, Carbamazepine, Phenobarbital
- “Enzyme-inhibiting”
- Valproate

**Notes:**
WILL INSERT MORE INFO ONCE GET BRIANS EDITS ON MECAHNISM OF ACTION, PERHAPS GRAPHIC?

## Newer Antiseizure Medications

- Oxcarbazepine, Lamotrigine, Topiramate, Levetiracetam
- Mostly approved for 2nd line therapy, but often used as initial therapy
- Equally effective in suppressing seizures
- Many fewer drug interactions than the older drugs

## Clinical Activity of Antiseizure Drugs for Various Types of Epileptic Seizures*

**“Standard” antiseizure drugs shown in **black**; newer antiseizure drugs shown in **red**.*

## Challenges in Safe Use of Antiseizure Medications

- 7th most common ADR in study of 1 million hospitalized patients
- Lack of standardization in dosing and monitoring of these agents

*Bond CA, Raehl CL. Pharmacotherapy. 2006;26:601-608.*

## Challenges in Safe Use of Antiseizure Medications

- Significant interpatient variability in dosages needed to reach therapeutic goals, minimal tolerable adverse effects
- Therapeutic index low
- Complex pharmacokinetics and drug interactions (particularly phenytoin, phenobarbital, carbamazepine)

**Notes:**
NOTE FOR AUTHOR:
Therapeutic index definition: (ratio between toxic dose and therapeutic dose; a measure of the relative safety of medications) 

## Initiation of Antiepileptics

- Traditional agents
- Begun at low doses and gradually titrated upward based on clinical response
- Newer agents
- Doses increased to a serum concentration or daily dose that is effective for most patients
- Poor correlation between levels and clinical activity

## Initiation of Antiepileptics

- For rapid protection from seizures
- Loading doses of select medications can be used (eg, oral or intravenous phenytoin, intravenous valproate, or intravenous phenobarbital)
- For status epilepticus, near immediate effect with IV benzodiazepines
- For bridge therapy, scheduled oral doses of  clonazepam until an effective oral maintenance dose can be attained

## Errors in Dosing Antiseizure Drugs

- Initiating therapy at too high a dose or escalating dosage too quickly
- Not considering drug interactions when devising initial dosing scheme
- Adjusting doses based solely on blood level results
- Withholding dose escalations in patients with partial response and good medication tolerability due to fear of exceeding the “usual” or “maximal” dose
- Escalating antiseizure medication doses too slowly in patients with uncontrolled seizures

## Case (cont.)

*	**Despite these interventions, the patient continued to be confused. A neurology consult was obtained. Review of the laboratory data revealed a serum albumin of 2.4 g/dL. This led to the calculation of a corrected phenytoin level: it was 33 (therapeutic 10-20 mcg/mL). Phenytoin was held and the patient's mental status returned to baseline in 72 hours.*

## Phenytoin Toxicity

- Phenytoin is one of the drugs most commonly associated with preventable clinically significant adverse events
- Requires careful monitoring and dosage adjustment, particularly in the elderly

*Winterstein AG, et a;. Am J Health Syst Pharm. 2002;59:1742-1749.*

## Phenytoin Toxicity Symptoms

- Early symptoms
- Dizziness, drowsiness, lethargy, and visual disturbances
- At higher levels
- Ataxia and confusion
- Less common
- Increase in the frequency or severity of seizures

## If Phenytoin Toxicity Suspected...Note:

- Recent dosage adjustments
- Changes in product appearance
- Phenytoin blood level
- Alterations in concomitant drug therapies, such as:
- Addition of phenytoin metabolism inhibitor (e.g., cimetidine)
- Removal of phenytoin metabolism inducer (e.g., rifampin)

## Avoiding Phenytoin Toxicity

- CYP2C9 and CYP2C19 enzymes responsible for phenytoin metabolism are saturable at drug concentrations near those used in clinical care
- Dosage changes result in disproportionate changes in phenytoin blood levels and pharmacologic response
- Limit dosage increases to no more than 30 to 50 mg per day, and increase dosages no more frequently than once every 1 or 2 weeks

## Understanding Phenytoin Levels

- 90% bound to plasma proteins, primarily albumin
- Therapeutic range of 10-20 mcg/mL represents the total of both protein-bound and free drug in serum
- Only unbound phenytoin has access to tissue sites responsible for efficacy and toxicity

*Soldin SJ. Arch Pathol Lab Med. 1999;123:822-823.*

## Understanding Phenytoin Levels

- A total (bound + unbound) phenytoin concentration value – which is the result reported by most clinical laboratories when a “phenytoin level” is requested – is an _indirect_ measure of the pharmacologically active (unbound) concentration

*Soldin SJ. Arch Pathol Lab Med. 1999;123:822-823.*

## Factors That Can Alter Phenytoin Protein Binding 

- Hypoalbuminemia
- End-stage renal disease (creatinine clearance < 25 mL/min)
- Presence of displacing drugs (eg, aspirin, valproic acid)

*Winter ME. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:321-363. *

**Notes:**
Winter ME. Phenytoin. In: Winter ME, ed. Basic Clinical Pharmacokinetics. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:321-363. 

## Determining Free Phenytoin Levels 

- Order an unbound phenytoin level and assess it in the context of an unbound therapeutic range of 1-2 mcg/mL
- Use calculation methods to adjust the reported total phenytoin serum level to the value that would be expected if protein binding were not perturbed

*Winter ME. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:321-363. *

**Notes:**
Winter ME. Phenytoin. In: Winter ME, ed. Basic Clinical Pharmacokinetics. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:321-363. 

## Phenytoin Half-life

- When unbound phenytoin levels are unusually high, the rate of decline in phenytoin concentrations is often slower than expected
- Due to saturable metabolism, at high serum levels, phenytoin half-life is much longer than it is at lower drug levels
- Varies between individuals and within an individual depending on serum concentration at any given time

*Soldin SJ. Arch Pathol Lab Med. 1999;123:822-823.*

## System Improvements

- Replace total serum concentration monitoring with assays to measure only the unbound (“free”) concentration of phenytoin
- unbound phenytoin concentrations more closely correlate with clinical status
- Require that unbound phenytoin levels be reported in patients with hypoalbuminemia or end-stage renal failure

*Kilpatrick CJ, et al. Br J Clin Pharmacol. 1984;17:539-546.**Burt M, et al. Clin Chem. 2000;46:1132-1135.*

## The Role of the Pharmacist

- Pharmacist monitoring improves both economic and clinical outcomes with antiseizure drug therapy
- By 2003, most states had enacted laws or amendments to permit enhanced pharmacist involvement in direct drug therapy
- Pharmacist-managed drug therapy is fastest growing clinical pharmacy service in US hospitals

*See notes for complete references.*

## Take-Home Points

- Dosing and monitoring of antiseizure drugs are challenging due to the need to individualize therapy, the low therapeutic index of these agents, and complex pharmacokinetics
- Due to ease of use, newer antiseizure drugs are being used more commonly as initial therapy for epilepsy

## Take-Home Points

- Phenytoin dosing and monitoring are complex due to saturable metabolism and the potential for displacement from albumin binding sites
- In patients with low serum albumin or end-stage renal disease, total (bound + unbound) phenytoin levels can be misleading and must be interpreted with caution

## Take-Home Points

- Unbound (free) phenytoin concentrations more closely correlate with clinical status of patients and are less likely to be misinterpreted than total phenytoin concentrations
- Pharmacist involvement in management of antiseizure drug therapy can improve economic and patient outcomes