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Tuesday, July 29, 2025

Phenytoin


Generic Name: Phenytoin
Brand Names: Dilantin, Epanutin, Phenytek, Dilantin Infatabs, Dilantin-125, Phenytoin Sodium


Drug Class: Anticonvulsant (Hydantoin derivative)
Pharmaceutical Category: Antiepileptic drug (AED); Voltage-gated sodium channel blocker
Formulations:
– Oral: Extended-release capsules, chewable tablets, oral suspension
– Parenteral: IV solution (Phenytoin Sodium); Fosphenytoin (prodrug for IV/IM use)
Route of Administration: Oral, Intravenous, rarely intramuscular

1. Pharmacological Classification

Phenytoin is a first-generation antiepileptic drug and belongs to the hydantoin class. It is primarily used to manage tonic-clonic seizures, focal seizures, and status epilepticus, with additional off-label uses in neuropathic pain and cardiac arrhythmias. It is among the oldest antiepileptic medications in clinical use.

2. Mechanism of Action

Phenytoin stabilizes neuronal membranes and limits repetitive firing of action potentials by:

  • Blocking voltage-gated sodium channels in the inactivated state

  • Inhibiting sustained high-frequency neuronal discharges by delaying recovery of sodium channels

It has no direct GABAergic or glutamatergic effects but indirectly reduces neuronal excitability.

3. Therapeutic Indications

A. FDA-Approved Uses

  • Generalized tonic-clonic seizures (grand mal epilepsy)

  • Focal (partial) seizures with or without secondary generalization

  • Status epilepticus (IV formulation)

  • **Prevention and treatment of seizures following neurosurgery or severe head trauma

B. Off-label Uses

  • Trigeminal neuralgia

  • Neuropathic pain (e.g., diabetic neuropathy)

  • Paroxysmal neurological symptoms in multiple sclerosis

  • Cardiac arrhythmias (especially digoxin-induced, Class IB effect on myocardium)

4. Dosage and Administration

Adults (Oral Maintenance)

  • Initial dose: 100 mg three times daily

  • Maintenance dose: 300–400 mg/day in divided doses

  • Maximum dose: Up to 600 mg/day (based on serum levels and clinical response)

Loading Dose (IV for Status Epilepticus)

  • 15–20 mg/kg at 50 mg/min (maximum rate)

  • Monitoring required for hypotension and cardiac arrhythmias

Children

  • 5–8 mg/kg/day in 2–3 divided doses

  • Pediatric dosing must be weight-based and individualized

Therapeutic Serum Levels

  • Total phenytoin: 10–20 mcg/mL

  • Free phenytoin: 1–2 mcg/mL (important in hypoalbuminemia or renal failure)

5. Pharmacokinetics

  • Absorption: Oral absorption is variable and formulation-dependent

  • Bioavailability: ~90% for oral formulations

  • Protein Binding: ~90% (mainly to albumin); clinically important in liver/kidney disease

  • Metabolism: Hepatic via CYP2C9 and CYP2C19, saturable (zero-order kinetics at therapeutic doses)

  • Half-life: ~22 hours (varies with dose)

  • Elimination: Hepatic metabolism; minimal renal clearance

  • Nonlinear kinetics: Small dose changes may cause disproportionate increases in blood levels

6. Contraindications

  • Hypersensitivity to phenytoin or hydantoin derivatives

  • Sinus bradycardia, sinoatrial block, 2nd/3rd-degree AV block

  • Adams-Stokes syndrome

  • History of prior phenytoin-induced hepatotoxicity

  • Intramuscular use of phenytoin sodium (due to local tissue necrosis risk—use fosphenytoin instead)

7. Warnings and Precautions

A. Cardiovascular Risk (IV use)

  • Rapid infusion → risk of hypotension and arrhythmias

  • Monitor ECG and BP during infusion

B. Dermatologic Reactions

  • Severe rash, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)

  • Risk increased in HLA-B*1502 allele carriers (common in Asian populations)

C. Hepatic Effects

  • Rare but serious hepatotoxicity

  • Monitor liver enzymes if symptoms suggest hepatic injury

D. Hematologic Toxicity

  • Agranulocytosis, leukopenia, thrombocytopenia, aplastic anemia

E. Endocrine and Bone Health

  • Long-term use may cause osteomalacia, vitamin D deficiency, and hyperglycemia

F. Teratogenicity

  • Known teratogen: fetal hydantoin syndrome, associated with cleft palate, cardiac defects, and developmental delay

  • Pregnancy category D (old classification)

8. Adverse Effects

Dose-Related (Common)

  • Nystagmus

  • Ataxia

  • Slurred speech

  • Dizziness

  • Fatigue

  • Cognitive slowing

  • Blurred vision

Chronic Use

  • Gingival hyperplasia (50% incidence, especially in children)

  • Hirsutism

  • Coarsening of facial features

  • Peripheral neuropathy

  • Folate deficiency → megaloblastic anemia

  • Acne and rash

Idiosyncratic (Rare but Serious)

  • Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN)

  • Lupus-like syndrome

  • Liver failure

  • Hypersensitivity syndrome with fever, rash, eosinophilia

  • Aplastic anemia

9. Drug Interactions

Phenytoin is a potent enzyme inducer (mainly CYP3A4, CYP2C9, CYP2C19, UGT), resulting in reduced plasma levels of many drugs, including:

Induces metabolism of:

  • Oral contraceptives → ↓ efficacy → contraceptive failure

  • Warfarin → ↓ INR (requires dose adjustment)

  • Corticosteroids → ↓ therapeutic effect

  • Antivirals, antifungals, and other AEDs (lamotrigine, valproate)

Interacts with other enzyme inducers/inhibitors:

  • Cimetidine, isoniazid, valproic acid → ↑ phenytoin levels

  • Carbamazepine, phenobarbital, rifampin → ↓ phenytoin levels

Alcohol

  • Acute use inhibits phenytoin metabolism

  • Chronic use induces metabolism → ↓ plasma levels

10. Pregnancy and Lactation

Pregnancy

  • Category D: Positive evidence of human fetal risk

  • Associated with fetal hydantoin syndrome: craniofacial abnormalities, limb defects, neurodevelopmental delays

  • Use only if benefit outweighs risk

  • Folic acid supplementation recommended (≥4 mg/day)

Lactation

  • Excreted in breast milk

  • Generally considered compatible with breastfeeding

  • Monitor infants for sedation or poor feeding

11. Toxicity and Overdose

Symptoms

  • Nystagmus, ataxia

  • Lethargy → coma

  • Hypotension (IV form)

  • Cardiac arrhythmias

  • Respiratory depression

Management

  • Supportive care

  • Gastric lavage (if recent ingestion)

  • No specific antidote

  • Monitor serum levels and vital signs

  • Hemodialysis may help in severe toxicity

12. Monitoring Parameters

  • Serum phenytoin level: Total (10–20 mcg/mL); free (1–2 mcg/mL)

  • Liver function tests (LFTs)

  • Complete blood count (CBC)

  • ECG and BP (during IV administration)

  • Oral hygiene (gingival hyperplasia risk)

  • Serum albumin (for accurate level interpretation)

  • Vitamin D and bone mineral density in long-term users

13. Formulations and Brand Availability

Oral

  • Extended-release capsules: 30 mg, 100 mg

  • Chewable tablets: 50 mg

  • Suspension: 125 mg/5 mL

  • Dilantin Kapseals, Phenytek, Epanutin (UK)

IV

  • Phenytoin sodium injection (pH ~12; risk of vein irritation)

  • Fosphenytoin (Cerebyx): water-soluble prodrug, preferred for IV/IM use due to lower infusion site risk

14. Clinical Notes and Pearls

  • Nonlinear (zero-order) pharmacokinetics: Dose adjustments must be cautious

  • Fosphenytoin preferred in emergencies (less risk of tissue damage, safer infusion)

  • Avoid switching between brands/formulations without monitoring serum levels

  • Patient education critical: adherence, oral hygiene, drug interactions

  • Periodic review is essential in elderly and polypharmacy cases




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