Phenytoin

Mechanism

Chemical and Commercial Profile

Common trade names: Neosidantoin, Dilantin, Phenytoin Sodium.
Group: First generation antiepileptic, hydantoin derivative.

Mechanism of Action

Phenytoin acts by selectively blocking voltage-gated sodium channels (Na_v 1.2 and Na_v 1.6) in their inactive state, preventing recovery of the channel after cellular depolarization. This limits the repetitive high-frequency discharge of action potentials at the epileptogenic focus without altering the normal physiological low-frequency discharges.

Pharmacokinetics

Pharmacokinetics

• Routes of administration: Oral (tablets, capsules), Intramuscular (not recommended due to local tissue crystallization) and Intravenous (slow IV).
• Absorption: Slow but complete orally, with a bioavailability of 90-95%. The plasma peak (C_max) occurs at 4-12 hours.
• Distribution: Highly lipophilic. Binding to plasma proteins (mainly albumin) of 90%. The volume of distribution (V_d) is 0.6-0.8 L/kg. In states of hypoalbuminemia or uremia, the free active fraction of the drug increases drastically.
• Metabolism: Hepatic through oxidation by the isoenzymes CYP2C9 (90%) and CYP2C19 (10%) to its main inactive metabolite HPPH (5-(p-hydroxyphenyl)-5-phenylhydantoin). This metabolism has a capacity for enzymatic saturation within the usual therapeutic range.
• Excretion: Renal in the form of HPPH-glucuronide (>95%).
• Half-life (t_1/2): Very variable due to non-linear kinetics; It ranges between 12 and 36 hours depending on the serum concentration.

Saturable Elimination Equation (Michaelis-Menten Kinetics) -\frac{dC}{dt} = \frac{V_{max} \cdot C}{K_m + C} Where V_{max} is the maximum elimination rate and K_m is the Michaelis constant (serum concentration at which the rate is half maximum, typically ~4-6 mcg/mL). At concentrations above K_m, the elimination rate becomes zero-order (independent of concentration), meaning that small dose increments can cause massive and dangerous increases in plasma levels.

Indicators and dose

Indications

• Focal motor and non-motor seizures (with or without evolution to bilateral tonic-clonic).
• Generalized tonic-clonic seizures.
• Second-line treatment in **Status Epilepticus** by slow intravenous route (after failure of benzodiazepines).
• Trigeminal neuralgia (second choice).

Dosage and Settings

• Clinical Focus or Loading Dose (Status Epilepticus IV): 15-20 mg/kg administered at a maximum rate of 50 mg/minute by direct IV infusion in physiological solution (never in glucose serum by immediate chemical precipitation of the drug). Requires continuous monitoring of ECG and blood pressure.
• Maintenance Dose (Oral): 300-400 mg/day divided into two or three doses (or a single prolonged-release nighttime dose). Slow adjustments of 25-50 mg after plasma monitoring.
• Target Therapeutic Range: 10-20 mcg/mL total concentration; 1-2 mcg/mL free serum phenytoin.
• Kidney Failure / Hypoalbuminemia: Sheiner-Tozer Adjustment Equation (for altered albumin levels) C_{ajustada} = \frac{C_{medida}}{(0.2 \cdot \text{Albúmina}) + 0.1} Where albumin is measured in g/dL. In case of creatinine clearance <10 mL/min, the factor 0.2 of the equation is replaced by 0.1 due to the lower affinity of albumin for the drug in uremia.

Security

Contraindications

• Sinoatrial block, second or third degree atrioventricular block, or Stokes-Adams syndrome (due to cardiac membrane stabilizing effect that can aggravate nodal conduction).
• Concomitant use with delavirdine.
• Generalized absence seizures and myoclonic seizures (can exacerbate them in a paradoxical way).

Adverse Effects (ADR)

Clinical Interactions

• Potent enzyme inducer: Robustly stimulates the transcription of the enzymes CYP3A4, CYP2C9, CYP2C19 and UGT. It drastically reduces the levels of oral contraceptives, oral anticoagulants (warfarin), antiretrovirals, and immunosuppressants (cyclosporine).
• Drugs that inhibit its metabolism: Valproic acid, amiodarone, fluconazole and isoniazid inhibit the CYP2C9 enzyme, which can cause a sudden and severe increase in phenytoin concentration to levels of neurological toxicity (ataxia, stupor).

Pregnancy and Breastfeeding

FDA Category: D. High risk of teratogenicity known as Fetal Hydantoin Syndrome (characterized by cleft lip, cleft palate, digital and nail hypoplasia, microcephaly and delayed motor development). If prescribed, supplementation with folic acid at high doses (5 mg/day) should be associated. Breastfeeding: Compatible with caution; It is excreted in breast milk at low levels (infant dose fraction ~2-5%). Monitor sedation in the infant.