Phenytoin

1. Drug Name

• Generic Name: Phenytoin

• Brand Names: Dilantin, Phenytek

2. Drug Classification

• Class: Anticonvulsant

• Subclass: Hydantoin derivative

3. Mechanism of Action

• Phenytoin stabilizes neuronal membranes and reduces seizure activity by inhibiting voltage-gated sodium channels in the brain.

• It prolongs the inactivation state of sodium channels, thereby preventing the spread of abnormal electrical activity in the brain.

• At the cellular level, it decreases the excitability of neurons, reducing the likelihood of repetitive firing, which helps in controlling seizures.

4. Pharmacokinetics

• Absorption:

  • Bioavailability: Oral bioavailability is around 90–100%; however, absorption is dose-dependent.

  • Peak Plasma Concentration (Tmax): Achieved within 3–12 hours after oral administration, depending on the dosage form.

• Distribution:

  • Volume of Distribution (Vd): Approximately 0.6–0.8 L/kg.

  • Protein Binding: Highly bound to plasma proteins (90–95%), primarily albumin. Reduced binding in hypoalbuminemia or uremia can increase free (active) drug levels.

• Metabolism:

  • Primary Site: Metabolized in the liver primarily via the CYP2C9 and CYP2C19 enzymes.

  • Kinetics: Displays non-linear (zero-order) kinetics at higher doses, where a small increase in dose may lead to a disproportionate increase in blood concentration.

• Excretion:

  • Half-life (t½): Ranges from 12 to 36 hours and varies based on dose and metabolic capacity.

  • Routes: Primarily eliminated as inactive metabolites in the urine.

• Special Considerations:

  • Hepatic Impairment: Reduced clearance in liver disease, requiring dose adjustments.

  • Age: Adjustments may be necessary in the elderly and in neonates due to slower metabolism.

5. Indications

• Primary Indications:

  • Epilepsy: Management of generalized tonic-clonic and complex partial seizures.

  • Status Epilepticus: Used intravenously for emergency management of status epilepticus after benzodiazepines.

• Off-label Uses:

  • Trigeminal Neuralgia: Sometimes used in patients who are unresponsive to other treatments.

• Special Populations:

  • Useful in adults with epilepsy; less often used as first-line therapy in children due to adverse effects.

6. Dosage and Administration

• Adult Dosing:

  • Epilepsy (oral): Initial dose of 300 mg/day, typically divided into 2–3 doses. Maintenance dose ranges between 300–400 mg/day.

  • Status Epilepticus (IV): 10–15 mg/kg administered slowly (not exceeding 50 mg/min) due to risk of cardiovascular side effects.

• Pediatric Dosing:

  • Loading dose for status epilepticus: 15–20 mg/kg IV.

  • Maintenance dose: 5–8 mg/kg/day divided into 2–3 doses.

• Dose Adjustments:

  • In patients with renal or hepatic impairment, careful monitoring and potential dose reduction are recommended.

  • Elderly patients may require lower doses due to altered pharmacokinetics.

7. Contraindications

• Absolute Contraindications:

  • Hypersensitivity to phenytoin or other hydantoins.

  • Sinus bradycardia, sinoatrial block, or 2nd/3rd degree heart block (when used intravenously).

• Relative Contraindications:

  • Hepatic Dysfunction: Use with caution due to impaired metabolism.

  • Pregnancy: May increase risk of congenital malformations (e.g., fetal hydantoin syndrome).

8. Warnings and Precautions

• Black Box Warning:

  • IV Administration: Rapid IV administration (especially >50 mg/min) can cause severe cardiovascular reactions, including arrhythmias and hypotension. Close monitoring is necessary.

• Other Warnings:

  • Teratogenic Risk: Phenytoin is associated with fetal hydantoin syndrome; pregnant patients should be counseled on risks.

  • Gingival Hyperplasia: Common in long-term therapy, especially in children.

  • Hematologic Effects: Rarely, it can cause leukopenia, thrombocytopenia, or agranulocytosis. Periodic blood counts are recommended.

  • Osteomalacia: Prolonged use may lead to vitamin D deficiency and osteomalacia.

  • Dermatologic Reactions: Serious skin reactions like Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are possible, especially in patients with the HLA-B*1502 allele.

9. Adverse Effects

• Common Adverse Effects:

  • CNS Effects: Dizziness, drowsiness, ataxia, nystagmus, and diplopia.

  • Gingival Hyperplasia: Especially in children and long-term use.

  • Hirsutism: Increased body hair, particularly in females.

• Less Common but Clinically Significant:

  • Acne and Coarsening of Facial Features: Seen in some long-term users.

  • Hematologic Abnormalities: Leukopenia, thrombocytopenia.

• Rare/Serious:

  • Severe Cutaneous Reactions: SJS and TEN, particularly in Asian populations with the HLA-B*1502 allele.

  • Liver Toxicity: Rare cases of hepatotoxicity may occur.

  • Arrhythmias: Particularly with IV administration or high plasma levels.

10. Drug Interactions

• Inducer of CYP450: Phenytoin is a strong CYP3A4 and CYP2C9 inducer, leading to decreased efficacy of drugs metabolized by these pathways (e.g., oral contraceptives, warfarin, corticosteroids).

• Interference with Other Antiepileptics: May increase or decrease plasma concentrations of other antiepileptic drugs (e.g., valproate, carbamazepine).

• Reduced Absorption with Enteral Feeding: Administer separately from enteral feeding to avoid reduced absorption.

• Other: Can interfere with certain lab tests (e.g., glucose and protein-bound iodine tests).

11. Clinical Pharmacology

• Pharmacodynamics: Phenytoin’s primary action is on the sodium channels in the neuronal membrane, leading to a reduction in high-frequency repetitive firing of action potentials.

• Therapeutic Range: Therapeutic plasma concentration is typically 10–20 μg/mL.

12. Special Populations

• Pregnancy: Category D due to risk of fetal hydantoin syndrome. Alternative treatments are preferred if possible.

• Lactation: Phenytoin is present in breast milk, but at low levels. Benefits of breastfeeding should be weighed against potential risks.

• Geriatrics: More sensitive to adverse effects; typically require lower dosages.

• Renal/Hepatic Impairment: Reduced clearance; dose adjustment and close monitoring are recommended.

13. Therapeutic Uses

• First-Line: For generalized tonic-clonic seizures and complex partial seizures.

• Second-Line: For status epilepticus after benzodiazepines.

• Not Recommended: For absence seizures, as it may worsen them.

14. Monitoring and Follow-Up

• Blood Levels: Regular monitoring of phenytoin serum levels to ensure therapeutic range (10–20 μg/mL).

• Liver Function: Periodic liver function tests, especially in long-term therapy.

• Blood Counts: Monitor for potential blood dyscrasias.

• Bone Health: Monitor bone density in long-term use due to risk of osteomalacia.

15. Overdose Management

• Symptoms of Overdose: Ataxia, dysarthria, nystagmus, and severe cases can lead to coma and respiratory depression.

• Treatment:

  • Supportive care and symptomatic management.

  • Activated charcoal may be used if overdose is recent.

  • Hemodialysis may be considered in severe cases, though phenytoin is only moderately dialyzable.

16. Patient Counseling Information

• Key Points:

  • Take phenytoin exactly as prescribed and avoid missed doses.

  • Report any unusual symptoms, particularly skin rash, to a healthcare provider immediately.

  • Practice good dental hygiene to prevent gingival hyperplasia.

• Signs to Watch For:

  • Signs of toxicity (e.g., unsteady gait, slurred speech).

  • Skin rash or allergic reactions, which could indicate a severe reaction.

• Lifestyle: Avoid alcohol and limit caffeine intake, as they can affect phenytoin levels and seizure control.