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Phenytoin

Anticonvulsants

Drug Overview

Phenytoin (brand name Dilantin) is a widely used anticonvulsant medication prescribed to prevent and control seizures in patients with epilepsy and related disorders.

It works by stabilizing neuronal membranes and reducing excitability through selective inhibition of voltage-gated sodium channels in the brain, thereby decreasing abnormal electrical activity that leads to seizures.

Because of its nonlinear pharmacokinetics and narrow therapeutic index, phenytoin dosing typically requires careful monitoring of blood levels to optimize treatment and minimize toxicity.

Relevant Genes and Their Roles

The key genes influencing phenytoin response are CYP2C9, a liver enzyme responsible for metabolizing phenytoin into inactive compounds, and HLA-B, a human leukocyte antigen involved in immune recognition and drug‐induced hypersensitivity.

Variants in CYP2C9 can alter the enzyme’s activity, affecting drug clearance and blood levels. The HLA-B*15:02 allele is associated with an increased risk of serious cutaneous adverse reactions, such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), in certain populations.

Impact of Genetics on Drug Response

Genetic differences in CYP2C9 define metabolizer phenotypes (poor, intermediate, normal) that directly influence phenytoin blood concentrations and therapeutic risk, while the presence of HLA-B*15:02 carries an immune-mediated risk of severe cutaneous adverse reactions independent of drug levels.

Expected Clinical Effects of Genetic Variation

Normal Metabolizer

  • Effect on drug levels: Expected to metabolize phenytoin at typical rates, maintaining standard blood concentrations.
  • Clinical consequence: Standard seizure control with usual dosing regimens.
  • Side effects: Typical risk of dizziness or ataxia; severity and frequency align with general population rates.

Intermediate Metabolizer

  • Effect on drug levels: Slower clearance leading to moderately increased blood concentrations.
  • Clinical consequence: Slightly higher risk of dose-dependent toxicity; therapeutic levels should be monitored.
  • Side effects: Mild to moderate central nervous system side effects (e.g., nystagmus, drowsiness); may occur somewhat more frequently.

Poor Metabolizer

  • Effect on drug levels: Significantly reduced clearance causing substantially elevated blood concentrations.
  • Clinical consequence: High risk of toxicity; dose reduction necessary to maintain safe levels.
  • Side effects: Severe CNS toxicity such as ataxia and cognitive impairment; increased severity and frequency if unadjusted.

Indeterminate/Not Available

  • Effect on drug levels: Unknown due to insufficient genetic information.
  • Clinical consequence: No specific guidance; follow standard dosing with clinical monitoring.
  • Side effects: Uncertain; monitor for any signs of toxicity as per routine practice.

Dosing Guidelines

The following dosing guidelines are based on the available recommendations for CYP2C9 and HLA-B from CPIC and FDA.

CYP2C9 Dosing Guideline (CPIC)

Phenotype Clinical Consequence Guideline Recommendation
Normal Metabolizer Normal phenytoin metabolism No adjustments needed from typical dosing strategies. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects.
Intermediate Metabolizer (activity score 1.5) Slightly reduced metabolism without increased toxicity No adjustments needed from typical dosing strategies. Monitor response and side effects.
Intermediate Metabolizer (activity score 1.0) Reduced metabolism; higher probability of toxicity For first dose, use typical initial or loading dose. For subsequent doses, use ~25% less than typical maintenance dose and monitor closely.
Poor Metabolizer Significantly reduced metabolism with high toxicity risk For first dose, use typical initial or loading dose. For subsequent doses, use ~50% less than typical maintenance dose and adjust based on monitoring.
Indeterminate / Not available Unknown impact Initiate therapy with recommended starting dose and monitor clinically.

HLA-B Dosing Guideline (CPIC)

Phenotype Clinical Consequence Guideline Recommendation
HLA-B*15:02 Positive Increased risk of severe cutaneous adverse reactions (SJS/TEN) Avoid phenytoin; consider alternative anticonvulsants.
HLA-B*15:02 Negative Standard risk Standard dosing with clinical monitoring as per CYP2C9 phenotype and usual practice.
Indeterminate / Not available Unknown risk Initiate therapy with recommended starting dose and monitor for adverse reactions.

Alternative Treatment Options

In patients who are HLA-B*15:02 positive, alternative anticonvulsant medications such as levetiracetam or valproate may be considered. These examples are drawn from guideline recommendations and are provided for informational purposes only.

Sources and References

Disclaimer: This document is for informational purposes only and is not a substitute for medical advice. Clinical decisions should be made by a qualified healthcare professional.

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