What are the pharmacokinetics and pharmacodynamics of phenytoin in a typical adult patient with a history of seizures?

Pharmacokinetics and Pharmacodynamics of Phenytoin

Pharmacodynamics

Phenytoin exerts its antiepileptic effect primarily by stabilizing neuronal membranes through blockade of voltage-gated sodium channels, preventing the spread of seizure activity from cortical foci and reducing maximal activity of brain stem centers responsible for tonic-clonic seizures. 1

• The drug promotes sodium efflux from neurons, stabilizing the threshold against hyperexcitability caused by excessive stimulation 1
• It reduces posttetanic potentiation at synapses, preventing cortical seizure foci from activating adjacent cortical areas 1
• The primary site of action is the motor cortex where spread of seizure activity is inhibited 1
• Phenytoin is effective for generalized tonic-clonic seizures, partial seizures with or without generalization, and convulsive status epilepticus 2

Pharmacokinetics

Absorption and Distribution

• After oral administration, phenytoin achieves therapeutic levels within 3-8 hours, with 48-55% of patients reaching therapeutic concentrations by 3-10 hours post-ingestion 3
• The drug is rapidly distributed from blood to tissues after absorption 2
• Phenytoin is 90-95% protein-bound under normal conditions 2
• Free phenytoin levels may be altered in patients whose protein binding characteristics differ from normal 1

Metabolism and Elimination

• Phenytoin exhibits saturable (Michaelis-Menten) kinetics, meaning the liver enzyme system becomes saturated at high plasma levels, causing small dose increases to produce disproportionately large increases in serum concentrations 1
• The drug is almost completely metabolized in the liver 2
• Most of the drug is excreted in bile as inactive metabolites, which are reabsorbed from the intestinal tract and excreted in urine 1
• Urinary excretion occurs partly through glomerular filtration but more importantly by tubular secretion 1

Half-Life and Steady-State

• The plasma half-life averages 22 hours (range 7-42 hours) after oral administration 1
• Steady-state therapeutic levels are achieved in 7-10 days (5-7 half-lives) after initiation of therapy with recommended doses of 300 mg/day 1
• The half-life is less than 20 hours at low doses but is prolonged with high doses 2
• Half-life is shortened when phenytoin is given with enzyme-inducing drugs such as phenobarbital or carbamazepine 2
• Half-life is prolonged in newborn infants and elderly people 2

Therapeutic Range and Monitoring

• The therapeutic serum concentration range is 10-20 mcg/mL (40-80 micromol/L), though some patients achieve seizure control below 10 mcg/mL while others require concentrations at the upper end or above 15 mcg/mL 3, 1
• Optimum control without clinical signs of toxicity occurs most often with serum levels between 10-20 mcg/mL 1
• When serum level determinations are necessary, they should be obtained at least 5-7 half-lives after treatment initiation, dosage change, or addition/subtraction of another drug 1
• Trough levels should be obtained just prior to the patient's next scheduled dose 1
• Peak levels for Dilantin capsules occur 4-12 hours after administration 1

Route-Specific Kinetics

IV Administration:

• Therapeutic levels are reached within 10 minutes of rapid IV loading completion, though the 2-4 hour timepoint confirms sustained therapeutic concentrations 3
• With an 18 mg/kg IV dose, 97% of patients achieve therapeutic levels (>10 μg/mL) immediately after infusion 4
• Approximately 50% of patients may have subtherapeutic levels at 12 hours after loading 3
• Most patients (approximately 83%) maintain therapeutic levels at 24 hours after appropriate loading 3

Oral Administration:

• Oral loading achieves therapeutic levels generally within 3-8 hours after administration 3
• Regular oral maintenance dosing without a loading dose may take 3-7 days to achieve therapeutic levels 3
• Oral loading takes more than 5 hours to reach therapeutic levels 5

Loading Dose Pharmacokinetics

• The recommended IV loading dose is 18-20 mg/kg at a maximum infusion rate of 50 mg/min in adults 5, 4
• Oral loading dose is 20 mg/kg divided in maximum doses of 400 mg every 2 hours 5
• For status epilepticus that doesn't respond to initial treatment, up to 30 mg/kg may be administered before using another antiepileptic drug 4

Maintenance Dosing

• Typical maintenance range is 200-700 mg daily depending on individual patient factors 3, 1
• The standard starting dose is 300 mg daily, which can be administered as a single daily dose or divided (100 mg three times daily) 3, 1
• In pediatric patients, initial dosing is 5 mg/kg/day in two or three equally divided doses, with recommended daily maintenance of 4-8 mg/kg 1

Special Pharmacokinetic Considerations

Common Pitfall: Because of saturable kinetics, small incremental doses (10% or more) may produce very substantial increases in serum levels when concentrations are in the upper therapeutic range, potentially causing intoxication 1. This is the most critical pharmacokinetic property to understand when dosing phenytoin.

• Wide interpatient variability exists in phenytoin serum levels with equivalent dosages 1
• Unusually low levels may indicate noncompliance or hypermetabolism of phenytoin 1
• Unusually high levels result from liver disease, congenital enzyme deficiency, or drug interactions causing metabolic interference 1
• Patients with hepatic or renal impairment require more frequent monitoring 3