Phenytoin - A Comprehensive Drug Profile

1. Overview & History

• Katzung's Basic and Clinical Pharmacology, 16th Ed.
• Goodman & Gilman's Pharmacological Basis of Therapeutics

2. Chemical Structure & Formulations

• Phenytoin is the 5,5-diphenyl-substituted analog of hydantoin - a five-membered ring similar to barbiturates (six-membered ring)
• pKa = 8.06-8.33; the free base is poorly water-soluble
• Phenytoin sodium dissolves in water at ~17 mg/mL
• Available as:
  • Extended-release capsules (peak at 4-12 hours; can be dosed once daily)
  • Immediate-release capsules (peak at 1.5-3 hours)
  • Oral suspension and chewable tablets (free base; TID dosing)
  • IV solution (contains propylene glycol and alcohol, pH 12)
  • Fosphenytoin (water-soluble prodrug; preferred IV/IM route)

3. Mechanism of Action

1. Primary mechanism: Slows the rate of recovery of voltage-activated Na⁺ channels from inactivation. This reduces the ability of neurons to fire repetitively at high frequency - the hallmark of seizure discharges.
2. The effect is greater when the membrane is depolarized (voltage-dependent), targeting neurons that are pathologically active.
3. At therapeutic concentrations: selective Na⁺ channel effect only - no change in spontaneous activity or GABA/glutamate responses.
4. At supratherapeutic concentrations (5-10× higher): reduction of spontaneous activity + enhancement of GABA responses - this contributes to toxicity.
5. Also blocks secondary calcium influx into partially depolarized neurons, reducing their excitability and prolonging their refractory period.
6. In cardiac tissue: acts as a Class IB antiarrhythmic - slows conduction in the His-Purkinje system.

• Goodman & Gilman's, p. 411-412
• Henry's Clinical Diagnosis, p. 424
• Tietz Textbook of Laboratory Medicine, 7th Ed.

4. Pharmacokinetics

Absorption

• Oral bioavailability is highly formulation-dependent (ranges from 30-95%)
• Particle size and pharmaceutical additives significantly affect absorption rate and extent
• Time to peak: 3-12 hours (oral), 1-2 hours (IV/fosphenytoin)
• IM injection of phenytoin: NOT recommended - drug precipitates at injection site with slow, unpredictable absorption

Distribution

• ~90-95% protein-bound (primarily to albumin)
• Only free (unbound) drug is pharmacologically active and crosses membranes
• Protein binding is reduced by: hypoalbuminemia, uremia, hyperbilirubinemia, elderly state, competing drugs (valproate, salicylates, sulfonylureas)

Metabolism - THE KEY FEATURE

• Metabolized by hepatic microsomal enzymes: primarily CYP2C9/2C10, secondarily CYP2C19
• Principal metabolite: 5-(p-hydroxyphenyl)-5-phenylhydantoin - inactive, excreted as glucuronide
• SATURABLE (zero-order/Michaelis-Menten) kinetics within the therapeutic range:
  • At LOW concentrations (<5 μg/mL): first-order kinetics apply
  • As levels rise, hepatic metabolism becomes saturated → small dose increases cause disproportionately large plasma level increases
  • This explains why 300 mg/day and 400 mg/day can produce vastly different blood levels
  • Plasma t½ ranges from 6-24 hours at concentrations below 10 μg/mL

Elimination

• Only ~5% excreted unchanged in urine
• Half-life is dose-dependent: t½ = 24 ± 12 hours (standard dosing)
• Steady state: ~7-10 days of continuous dosing
• Not effectively removed by dialysis (high protein binding)

Fosphenytoin (Prodrug)

• Water-soluble phosphate ester; converted to phenytoin by plasma and RBC phosphatases
• Conversion t½: 8-15 minutes
• Protein binding: 95-99% (even higher than phenytoin)
• Can be given IM or IV; preferred over phenytoin IV due to better tolerability
• Dosed in "phenytoin equivalents" (PE)
• Katzung's Basic and Clinical Pharmacology, 16th Ed.
• Goodman & Gilman's, p. 412
• Henry's Clinical Diagnosis, p. 421

5. Therapeutic Uses & Indications

• Absence seizures (petite mal)
• May worsen absence epilepsy, juvenile myoclonic epilepsy (JME), and Dravet syndrome
• Katzung, p. 855
• Tietz Textbook of Laboratory Medicine, 7th Ed.
• Forensic Medicine and Toxicology, 36th Ed.

6. Therapeutic Drug Monitoring (TDM)

• At 10 μg/mL: ~50% seizure response rate
• At 15 μg/mL: ~86% seizure suppression
• Correction for hypoalbuminemia is mandatory: use the Winter-Tozer equation
  • Corrected phenytoin = measured total / [(0.2 × albumin) + 0.1]
• Monitor free phenytoin in: hypoalbuminemia, renal insufficiency, hepatic disease, pregnancy, elderly
• Sampling: trough level (within 30 min before next dose) for routine monitoring; 1 hr post-IV for peak

7. Adverse Effects

Concentration-Dependent (Dose-Related)

Chronic/Long-Term Adverse Effects

• Peripheral neuropathy (long-term)
• Cerebellar atrophy (with chronic high doses)
• Cognitive impairment, behavioral changes

• Gingival hyperplasia - occurs in ~20% of patients on chronic therapy; due to altered collagen turnover; NOT plasma-level dependent; worse in children/adolescents; managed by good oral hygiene; may require gingivoplasty

• Hirsutism - particularly problematic in females
• Coarsening of facial features

• Osteomalacia (hypocalcemia + elevated alkaline phosphatase): due to accelerated vitamin D metabolism AND impaired intestinal calcium absorption AND increased metabolism of vitamin K-dependent Ca²⁺ proteins in bone
• Hyperglycemia / glycosuria: inhibition of insulin secretion
• Hyponatremia: inhibition of ADH release
• Macrocytic/megaloblastic anemia (folate antagonism)
• Autoimmune thyroiditis

• Neutropenia, leukopenia
• Thrombocytopenia
• Red cell aplasia (rare)
• Agranulocytosis (rare)

• Transient elevation of hepatic transaminases
• Hepatic necrosis (rare, hypersensitivity-related)

Idiosyncratic/Hypersensitivity Reactions

• Morbilliform rash: 2-5% of patients
• Stevens-Johnson syndrome (SJS) - rare but life-threatening
• Toxic epidermal necrolysis (TEN) - rare
• Drug reaction with eosinophilia and systemic symptoms (DRESS / Phenytoin Hypersensitivity Syndrome): fever + rash + lymphadenopathy + hepatosplenomegaly; appears 3 weeks to 3 months after initiation

• Purple Glove Syndrome: purplish-black discoloration + edema + pain distal to injection site; may progress to skin necrosis; related to propylene glycol vehicle; less common with fosphenytoin
• Cardiovascular collapse with rapid IV infusion: bradycardia, heart block, ventricular fibrillation, hypotension - particularly in elderly and those with cardiac disease

8. Drug Interactions

Drugs that INCREASE Phenytoin Levels (inhibit CYP2C9/2C19)

• Isoniazid (especially in slow acetylators)
• Fluoxetine, fluvoxamine
• Metronidazole, miconazole
• Fluorouracil
• Chloramphenicol, cimetidine, disulfiram
• Dicumarol (warfarin)
• Valproate (dual mechanism: displaces from protein binding AND inhibits metabolism - sustained increase in free phenytoin)

Drugs that DECREASE Phenytoin Levels (induce CYP)

• Alcohol (chronic), barbiturates, carbamazepine: enzyme induction → increased metabolism
• Rifampin: potent inducer

Drugs that Displace Phenytoin from Protein Binding (increase free fraction temporarily)

• Salicylates, valproate, phenylbutazone, sulfonamides, sulfonylureas
• Note: total phenytoin level decreases but free fraction stays similar (until re-equilibration)

Drugs whose Levels are DECREASED by Phenytoin (phenytoin induces CYP3A4, 2C9, and others)

• Oral contraceptives (risk of unplanned pregnancy - clinically significant given teratogenicity)
• Warfarin (risk of bleeding disorder - bidirectional interaction)
• Corticosteroids
• Carbamazepine, cyclosporine, itraconazole
• Methadone, methotrexate, doxycycline
• Thyroid hormones (decreases T3 and T4 without causing clinical hypothyroidism usually)
• Goodman & Gilman's, p. 423
• Tietz Textbook, p. 1518-1519
• Katzung, p. 880-881

9. Toxicology & Overdose Management

Toxicological Thresholds

• Therapeutic: up to 20 μg/mL
• Toxic effects: typically >30 μg/mL
• Paradoxical seizures: >35 μg/mL
• Lethal dose: not clearly defined; death usually results from ventricular fibrillation or cardiac arrest (especially with rapid IV administration)

Features of Overdose

1. Early: horizontal gaze nystagmus, gait ataxia, drowsiness
2. Progressive: vertical nystagmus, oscillopsia, slurred speech, coarse tremors, confusion
3. Severe: coma (rare), paradoxical increase in seizures, encephalopathy
4. Cardiac: hypotension (dose/concentration-dependent), bradycardia, heart block, VF/cardiac arrest (especially IV route)

Management

1. Decontamination: gastric lavage (within a few hours), activated charcoal
2. Supportive care + continuous cardiovascular monitoring
3. Hypotension: Trendelenburg positioning, IV fluids, vasopressors (dopamine, norepinephrine)
4. Heart block: atropine or temporary cardiac pacing
5. Paradoxical seizures: diazepam first-line, phenobarbitone second-line
6. Hypersensitivity reactions: systemic corticosteroids

• Forensic Medicine and Toxicology, 36th Ed., p. 6774-6788
• Washington Manual of Medical Therapeutics

10. Use in Special Populations

Pregnancy

• Category D teratogen
• Causes Fetal Hydantoin Syndrome: neural tube defects, orofacial clefts, cardiovascular malformations, urogenital anomalies, limb deformities, digit/nail hypoplasia
• Risk of neonatal hemorrhage (inhibits vitamin K-dependent clotting factors) - give maternal vitamin K before delivery
• Recent 2023 Cochrane systematic review (PMID 37647086) confirmed elevated congenital malformation risk with phenytoin monotherapy in pregnancy
• A 2024 systematic review in Neurology (PMID 38531021) found adverse neurodevelopmental outcomes in children exposed in utero
• Use only when benefit outweighs risk; newer agents preferred
• Oral contraceptive failure: phenytoin induces CYP3A4, reducing OC efficacy

Renal Disease

• No significant renal clearance (only 5% excreted unchanged)
• But: uremia reduces albumin binding → higher free fraction → toxicity at seemingly therapeutic total levels
• Monitor free phenytoin in renal patients

Hepatic Disease

• Reduced CYP-mediated metabolism → drug accumulation
• Hypoalbuminemia (cirrhosis) → higher free fraction

Elderly

• Reduced albumin → increased free fraction
• Decreased CYP activity → slower metabolism
• Increased CNS sensitivity
• Higher risk of osteomalacia

Pediatric Dosing (Harriet Lane)

• Oral: extended release capsules (BID); chewable tablets and suspension (TID)
• IV push rate: ≤0.5 mg/kg/min in neonates; ≤1 mg/kg/min in infants/children/adults (max 50 mg/min)
• Ideal body weight for dosing calculations
• Therapeutic levels: 10-20 mg/L (total) or 1-2 mg/L (free)
• Oral absorption reduced in neonates; t½ is variable (7-42 hours)

Pharmacogenomics

• CYP2C9 intermediate metabolizer: 25% dose reduction + TDM
• CYP2C9 poor metabolizer: 50% dose reduction + TDM
• HLA-B*1502 carriers: associated with increased risk of SJS/TEN (especially in Asian populations); some guidelines recommend avoiding phenytoin in these patients
• HLA-B1502 or CYP2C93 carriers: consider avoiding phenytoin

11. Cardiac Uses (Antiarrhythmic)

• Stabilizes cardiac sodium channels in the His-Purkinje system
• Most useful for digitalis-induced arrhythmias (including digoxin toxicity causing atrial/ventricular arrhythmias)
• Therapeutic concentration range for antiarrhythmic effect mirrors the antiseizure range: 10-20 μg/mL
• IV use is associated with significant risk (bradycardia, hypotension, VF); requires ECG monitoring
• Rarely used today for this purpose given safer alternatives

12. Seizure Prophylaxis in Brain Injury (Current Guidelines)

13. Summary Reference Table