PHENYTOIN
Clinical safety rating: avoid
Many drugs can increase or decrease phenytoin levels Can cause life-threatening dermatologic reactions like Stevens-Johnson syndrome.
Phenytoin is a hydantoin anticonvulsant that stabilizes neuronal membranes and decreases seizure activity by increasing efflux or decreasing influx of sodium ions across cell membranes in the motor cortex during generation of nerve impulses. It use-dependently blocks voltage-gated sodium channels, prolonging their inactivation phase and reducing high-frequency repetitive firing of action potentials.
| Metabolism | Phenytoin is extensively metabolized in the liver primarily by the cytochrome P450 enzyme CYP2C9, with minor contributions from CYP2C19. The major metabolite is the glucuronide conjugate of 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH). Phenytoin exhibits dose-dependent, saturable (Michaelis-Menten) pharmacokinetics. |
| Excretion | Primarily hepatic metabolism (>95%); less than 5% excreted unchanged in urine. Renal excretion of metabolites (glucuronides) accounts for ~80% of elimination; biliary/fecal excretion of metabolites ~20%. |
| Half-life | Average terminal half-life 22 hours (range 7–42 hours) in adults; dose-dependent due to saturation of metabolism at therapeutic concentrations (10–20 mg/L). Half-life increases with higher doses. |
| Protein binding | 90–95% bound, primarily to albumin; binding is saturable and decreases in hypoalbuminemia, uremia, or with other highly bound drugs. |
| Volume of Distribution | 0.6–0.8 L/kg; indicates extensive tissue distribution; crosses blood-brain barrier; Vd increases in neonates and decreases in renal failure. |
| Bioavailability | Oral: 90–100% (phenytoin sodium extended-release); IM: low and erratic (not recommended) due to precipitation and slow absorption. |
| Onset of Action | IV: 3–5 minutes for anticonvulsant effect; oral: 2–4 hours for antiepileptic effect (dose-dependent); loading dose required for rapid effect. |
| Duration of Action | Anticonvulsant effect lasts 12–24 hours with therapeutic levels; clinical duration of action is related to half-life, typically requiring twice-daily dosing for maintenance. |
| Molecular Weight | 252.27 Da |
Oral: 300-400 mg/day in 3-4 divided doses; IV: 15-20 mg/kg loading dose, then 300 mg/day maintenance.
| Dosage form | SUSPENSION |
| Renal impairment | No specific GFR-based adjustment required; use with caution in severe renal impairment (GFR < 10 mL/min) due to protein binding changes. |
| Liver impairment | Child-Pugh A: No adjustment; Child-Pugh B: Reduce dose by 25-50%; Child-Pugh C: Reduce dose by 50-75%. |
| Pediatric use | Loading dose: 15-20 mg/kg IV/PO; Maintenance: 5-10 mg/kg/day PO in 2-3 divided doses. |
| Geriatric use | Start at low end of dosing range (e.g., 3 mg/kg/day); monitor for toxicity; consider reduced protein binding and slower metabolism. |
| 1st trimester | Phenytoin is teratogenic, associated with fetal hydantoin syndrome (craniofacial defects, cardiac malformations, neurodevelopmental impairment). Use only if benefits outweigh risks; consider alternative anticonvulsants. Folic acid supplementation recommended. |
| 2nd trimester | Risk of congenital malformations persists; continue folic acid and monitor fetal growth. Avoid if possible; dose adjustments may be needed due to altered pharmacokinetics. |
| 3rd trimester | Risk of neonatal hemorrhage (due to vitamin K deficiency); maternal vitamin K supplementation recommended. Neonatal withdrawal possible at birth. |
Clinical note
Many drugs can increase or decrease phenytoin levels Can cause life-threatening dermatologic reactions like Stevens-Johnson syndrome.
| FDA category | Positive |
| Placental transfer | Phenytoin readily crosses the placenta, achieving fetal plasma concentrations similar to maternal levels (fetal-to-maternal ratio ~0.8-1.0). |
■ FDA Black Box Warning
Intravenous administration of phenytoin is associated with serious cardiovascular adverse reactions including severe hypotension and cardiac arrhythmias (e.g., bradycardia, heart block, ventricular fibrillation). These reactions can occur more frequently in patients with advanced age, known cardiac disease, or those receiving other medications that affect the cardiovascular system. Continuous monitoring of ECG and vital signs is required during IV administration, and the rate of infusion should not exceed 50 mg/min in adults.
| Common Effects | Gingival hyperplasia |
| Serious Effects |
Hypersensitivity to phenytoin or hydantoinsSinus bradycardiaSinoatrial blockSecond- or third-degree AV blockAdams-Stokes syndrome
| Precautions | Cardiovascular risk during IV administration (see black box warning), Hypersensitivity reactions: Angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), Hepatic injury: Acute hepatotoxicity, including elevated liver enzymes and hepatitis, Hematologic effects: Agranulocytosis, thrombocytopenia, leukopenia, pancytopenia, Central nervous system effects: Nystagmus, ataxia, slurred speech, mental confusion, dizziness, drowsiness, Hyperglycemia: May elevate blood glucose levels, Osteomalacia and hypocalcemia due to altered vitamin D metabolism, Teratogenicity: Fetal hydantoin syndrome (craniofacial abnormalities, growth deficiency, intellectual disability), Birth defects: Increased risk of cardiovascular malformations and neural tube defects, Carcinogenicity: Long-term use associated with increased risk of malignancies (lymphoma, hepatocellular carcinoma) |
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| Breastfeeding | Phenytoin is excreted into breast milk in low concentrations (milk-to-plasma ratio ~0.18-0.45). Risk of infant toxicity is low with maternal therapeutic doses. Monitor infant for sedation, poor feeding, and rash. Generally considered compatible with breastfeeding, but caution advised with high maternal doses. |
| Lactation Rating | L3 - Moderately Safe |
| Teratogenic Risk | Phenytoin is associated with fetal hydantoin syndrome, including craniofacial dysmorphisms, cardiac defects, neural tube defects, and cognitive impairment. Risk is highest during first trimester (organogenesis). Second and third trimester exposure may cause impaired fetal growth, microcephaly, and neurodevelopmental delay. Risk of major malformations is dose-dependent and increases with polytherapy. |
| Fetal Monitoring | Monitor maternal serum phenytoin concentrations (total and free) monthly; adjust dose to maintain therapeutic range (10-20 mcg/mL total, 1-2 mcg/mL free). Perform fetal ultrasound for structural anomalies at 18-20 weeks; consider serial growth scans. Assess maternal signs of toxicity: nystagmus, ataxia, drowsiness. Evaluate for folate deficiency and supplement with folic acid 4-5 mg/day. Monitor clotting factors in neonate due to vitamin K deficiency risk. |
| Fertility Effects | Phenytoin may cause reversible decreases in sperm count and motility in males; in females, phenytoin can induce hepatic enzymes affecting sex hormone metabolism, potentially leading to menstrual irregularities, anovulation, and reduced fertility. Use contraception if not planning pregnancy. |
| Food/Dietary | Enteral tube feedings can decrease phenytoin absorption; hold feeds 1-2 hours before and after administration. High-fat meals may increase absorption consistency. Folic acid supplementation may lower phenytoin levels. Calcium supplements and antacids can impair absorption; separate by 2-3 hours. |
| Clinical Pearls | Phenytoin exhibits zero-order kinetics at therapeutic levels; small dose increases can cause toxicity. Monitor free phenytoin levels in hypoalbuminemia or uremia. Fosphenytoin is a prodrug used for IV loading with fewer infusion-site reactions. Caution in CYP2C9 poor metabolizers; consider genetic testing. May cause folate deficiency, peripheral neuropathy, and osteomalacia with long-term use. Co-administration with valproate displaces phenytoin from protein binding, increasing free fraction. |
| Patient Advice | Take exactly as prescribed; do not skip doses or change brands without consulting your doctor. · Do not stop taking suddenly as this may cause withdrawal seizures. · Avoid alcohol as it can affect drug levels and increase side effects. · Report any rash, fever, swollen glands, or mouth sores immediately (risk of Stevens-Johnson syndrome). · Use reliable contraception if sexually active; phenytoin reduces effectiveness of hormonal contraceptives. · Maintain good dental hygiene and see dentist regularly; may cause gum overgrowth. · Take with food if stomach upset occurs, but avoid high-fat meals if consistent timing is needed. · May cause dizziness, drowsiness, or blurred vision; avoid driving until you know how it affects you. |