Phenytoin

Usage

• Medical Conditions: Phenytoin is an anticonvulsant primarily prescribed for the management of generalized tonic-clonic seizures, focal (partial) seizures, and status epilepticus. It is also used for seizure prophylaxis during or following neurosurgery, and occasionally for certain cardiac arrhythmias unresponsive to conventional treatments.
• Pharmacological Classification: Anticonvulsant, antiepileptic.
• Mechanism of Action: Phenytoin stabilizes neuronal membranes by modulating voltage-gated sodium channels, inhibiting the repetitive firing of action potentials and limiting the spread of seizure activity.

Alternate Names

• International/Regional Variations: Diphenylhydantoin.
• Brand Names: Dilantin, Phenytek.

How It Works

• Pharmacodynamics: Phenytoin exerts its anticonvulsant effect by reducing the sustained high-frequency repetitive firing of action potentials in neurons by promoting sodium efflux from neurons. It selectively binds to the inactive state of voltage-gated sodium channels, prolonging their inactivation and reducing neuronal excitability. It does not appear to have a direct effect on GABAergic neurotransmission.
• Pharmacokinetics:
  • Absorption: Phenytoin is well-absorbed orally, but the rate varies depending on the formulation (prompt-release, extended-release, or suspension). Intravenous administration achieves rapid therapeutic levels.
  • Metabolism: Primarily metabolized in the liver by CYP2C9 and CYP2C19 enzymes, with a small contribution from CYP3A4. Phenytoin exhibits saturable metabolism, leading to non-linear pharmacokinetics. Small dose increases can result in disproportionately large increases in serum concentrations.
  • Elimination: Mainly through hepatic metabolism, with a small portion excreted unchanged in the urine. The elimination half-life is variable (10-30 hours) and dose-dependent.
• Mode of Action: Phenytoin binds preferentially to the inactivated state of voltage-gated sodium channels, prolonging their inactivation and reducing the ability of neurons to fire repetitive action potentials. This action decreases seizure activity.
• Receptor Binding/Enzyme Inhibition: Phenytoin primarily interacts with voltage-gated sodium channels. It does not significantly bind to GABA receptors or other neurotransmitter receptors.
• Elimination Pathways: Primarily hepatic metabolism via CYP2C9, CYP2C19, and CYP3A4 enzymes, followed by renal excretion of metabolites.

Dosage

Standard Dosage

Adults:

• Initial Dose (phenytoin-naive): 100 mg orally three times a day.
• Maintenance Dose: 300-400 mg/day, adjusted according to serum levels and clinical response. Maximum: 600 mg/day. Extended-release capsules can be used for once-daily dosing in some patients after stabilization on divided doses.
• Administration: Oral or intravenous. IV infusion should not exceed 50 mg/minute.

Children:

• Initial Dose: 5 mg/kg/day orally in two to three divided doses.
• Maintenance Dose: 4-8 mg/kg/day, not to exceed 300 mg/day. Higher doses (8-10 mg/kg/day) may be necessary for infants and young children.
• Pediatric Safety: Monitor closely for adverse effects.

Special Cases:

• Elderly Patients: Lower initial and maintenance doses may be required.
• Patients with Renal Impairment: Monitor closely; dosage adjustment may be necessary based on serum concentrations and clinical response. Free phenytoin levels may be more informative in these patients.
• Patients with Hepatic Dysfunction: Reduced dosage is required due to decreased metabolism.
• Patients with Comorbid Conditions: Careful monitoring and dosage adjustment are necessary.

Clinical Use Cases:

• Intubation: Phenytoin may be used for seizure prophylaxis in intubated patients, especially those with a history of seizures or at high risk for developing seizures.
• Surgical Procedures (Neurosurgery): Prophylaxis and treatment: 100-200 mg every 4 hours during and for 48-72 hours after neurosurgery, followed by adjustment to maintenance dose based on serum levels.
• Mechanical Ventilation: Serum phenytoin levels can vary significantly in mechanically ventilated patients, and careful monitoring is essential.
• Intensive Care Unit (ICU) Use: Phenytoin levels should be monitored closely, as critically ill patients can have unpredictable drug metabolism. IV loading dose: 15-20 mg/kg, followed by 3-7 mg/kg/day maintenance. Consider PEEP interaction.
• Emergency Situations (Status Epilepticus): Loading dose: 15-20 mg/kg (adults) or 18 mg/kg (Walton Centre guidelines) IV at a rate not exceeding 50 mg/minute. Maintenance: 100 mg IV or orally every 6-8 hours. Pediatric loading dose: 15-20 mg/kg IV at 1-3 mg/kg/min (max 50 mg/min).

Dosage Adjustments:

• Close monitoring of serum phenytoin levels is essential, especially after dosage changes, and dose adjustments should be made in small increments (25-50 mg).
• Consider renal/hepatic function, albumin levels, concomitant medications, and other patient-specific factors.

Side Effects

Common Side Effects:

• Nystagmus, ataxia, dizziness, drowsiness, headache, nausea, vomiting, gingival hyperplasia, rash, and hirsutism.

Rare but Serious Side Effects:

• Stevens-Johnson syndrome, toxic epidermal necrolysis, hepatic failure, agranulocytosis, aplastic anemia, and cardiac arrhythmias.

Long-Term Effects:

• Osteomalacia, peripheral neuropathy, and cognitive impairment.

Adverse Drug Reactions (ADR):

• Severe skin reactions (SJS/TEN), blood dyscrasias, and hepatotoxicity.

Contraindications:

• Hypersensitivity to phenytoin or other hydantoins.
• Sinus bradycardia, sinoatrial block, or atrioventricular block.

Drug Interactions:

• Numerous drug interactions; consult a comprehensive drug interaction resource. Some key examples include:
  • CYP450 Interactions: Phenytoin is metabolized by and can induce or inhibit CYP450 enzymes, affecting the levels of other drugs metabolized by these enzymes.
  • Common Medications: Warfarin, amiodarone, carbamazepine, valproic acid, and many others.
  • OTC Drugs/Supplements: Antacids, calcium supplements.
  • Food/Lifestyle: Alcohol, grapefruit juice.

Pregnancy and Breastfeeding:

• Pregnancy Safety Category: D.
• Fetal Risks: Congenital malformations (fetal hydantoin syndrome), growth retardation, and developmental delays.
• Breastfeeding: Phenytoin is excreted in breast milk. Weigh the benefits versus risks for the infant.
• Safer Alternatives: Consider alternative anticonvulsants if possible.

Drug Profile Summary

• Mechanism of Action: Stabilizes neuronal membranes by modulating voltage-gated sodium channels.
• Side Effects: Nystagmus, ataxia, dizziness, drowsiness, gingival hyperplasia, rash, Stevens-Johnson syndrome, blood dyscrasias, hepatotoxicity.
• Contraindications: Hypersensitivity to phenytoin or other hydantoins; sinus bradycardia, SA block, or AV block.
• Drug Interactions: Numerous; consult a drug interaction resource.
• Pregnancy & Breastfeeding: Category D; fetal risks; excreted in breast milk.
• Dosage: Adults: 300-400 mg/day; children: 4-8 mg/kg/day. Adjust based on serum levels.
• Monitoring Parameters: Serum phenytoin levels, complete blood count, liver function tests.

Popular Combinations:

• Often combined with other anticonvulsants for refractory epilepsy.

Precautions:

• Monitor for hypersensitivity reactions, blood dyscrasias, and hepatotoxicity.
• Closely monitor serum levels, especially during dosage adjustments.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Phenytoin?

A: Adults: Initial dose is 100mg TID, maintenance dose 300-400mg/day divided TID/QID. Adjust as per serum levels and clinical response. Children: 5 mg/kg/day in 2-3 divided doses initially, maintenance 4-8 mg/kg/day, maximum 300 mg/day. Elderly and patients with hepatic/renal impairment may require lower doses.

Q2: How is Phenytoin administered?

A: Phenytoin can be given orally (tablets, capsules, suspension) or intravenously. IV administration should be slow, not exceeding 50mg/minute.

Q3: What are the common side effects of Phenytoin?

A: Common side effects include nystagmus, ataxia, dizziness, drowsiness, nausea, vomiting, gingival hyperplasia, and rash.

Q4: What are the serious side effects of Phenytoin?

A: Rare but serious side effects include Stevens-Johnson syndrome, toxic epidermal necrolysis, hepatic failure, agranulocytosis, and aplastic anemia.

Q5: What are the key drug interactions with Phenytoin?

A: Phenytoin interacts with numerous drugs, including warfarin, amiodarone, carbamazepine, and valproic acid. Always consult a drug interaction resource for a complete list.

Q6: Can Phenytoin be used during pregnancy?

A: Phenytoin is a pregnancy category D drug and carries a risk of fetal hydantoin syndrome. It should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.

Q7: What is the therapeutic range for serum Phenytoin levels?

A: The generally accepted therapeutic range for total phenytoin levels is 10-20 mcg/mL and 1-2 mcg/mL for free phenytoin. However, some patients may achieve seizure control with lower levels.

Q8: What should be monitored in patients taking Phenytoin?

A: Serum phenytoin levels, complete blood count (CBC), liver function tests (LFTs) should be regularly monitored.

Q9: What are the symptoms of Phenytoin toxicity?

A: Symptoms of phenytoin toxicity can include ataxia, nystagmus, slurred speech, confusion, dizziness, nausea, and vomiting. Severe toxicity can manifest as seizures, coma, and cardiovascular collapse.

Q10: How should Phenytoin be loaded in status epilepticus?

A: In status epilepticus, a loading dose of 15-20 mg/kg IV (or 18 mg/kg as per some guidelines) at a rate not exceeding 50 mg/minute is recommended, followed by a maintenance dose of 100 mg IV/PO every 6-8 hours.