Phenytoin

Phenytoin is a hydantoin antiseizure medicine used for focal and generalised tonic-clonic seizures and as a second-line drug in status epilepticus. It follows saturable, zero-order kinetics in the therapeutic range, binds heavily to albumin and is a strong enzyme inducer, so small dose changes can cause large level swings and many interactions.

Mechanism. Blocks voltage-gated sodium channels in a use-dependent way, limiting repetitive neuronal firing.

Pharmacokinetics. Bioavailability varies between products. Protein binding is about 90%, so free drug rises in hypoalbuminaemia, uraemia and with valproate. Metabolism is mainly by cytochrome P450 2C9 and 2C19 and saturates near the therapeutic range, with half-life rising from about 7 to over 40 hours as levels climb. Poor metaboliser genotypes need lower doses. Phenytoin sodium 100 mg contains about 92 mg of phenytoin base.

First-line use. Focal and generalised tonic-clonic seizures where cost or availability limits other options. Prevention of seizures after neurosurgery or head injury for the first 7 days.

• Adults, oral phenytoin: start 3 to 4 mg/kg daily (typically 300 mg daily), once daily or in two divided doses. Adjust in steps of 25 to 50 mg, rechecking levels after 7 to 14 days. Usual maintenance 300 to 400 mg daily. Maximum 600 mg daily.

• Children: 5 mg/kg daily in two or three doses, usual 4 to 8 mg/kg daily, maximum 300 mg daily.

• Oral loading (specialist): 1000 mg divided as 400 mg, 300 mg and 300 mg at 2-hour intervals, with monitoring.

Emergency use. Status epilepticus after a benzodiazepine, when levetiracetam or valproate are unavailable or have failed:

• Phenytoin intravenous loading 20 mg/kg (usual maximum 1500 mg) at not over 50 mg/min in adults, and 25 mg/min or slower in older adults or people with cardiac disease. In children, 20 mg/kg at not over 1 mg/kg/min and not over 50 mg/min. Use continuous ECG and blood pressure monitoring.

• Maintenance 100 mg intravenously or orally every 6 to 8 hours, starting 12 to 24 hours after the load. Do not give intramuscularly.

• In obesity, base the load on ideal body weight.

Kidney, liver, weight and age.

• Kidney and liver: free fraction rises, so a normal total level can mean toxicity. Use free level or correct the total level.

• Corrected total concentration = observed total concentration divided by (0.02 x albumin in g/L + 0.1) in normal kidney function. For example, albumin 25 g/L gives a divisor of 0.6.

• Older adults: lower maintenance doses; use free levels.

Contraindications. Sinus bradycardia, sinoatrial block, second or third degree atrioventricular block, Adams-Stokes syndrome, hypersensitivity to hydantoins, and delavirdine.

Serious adverse effects. Hypotension and arrhythmia with rapid infusion (boxed-warning-level risk), purple glove syndrome and tissue necrosis from extravasation, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, hepatitis, blood dyscrasias, cerebellar atrophy, and foetal hydantoin syndrome.

Common adverse effects. Gingival hyperplasia, hirsutism, coarse features, acne, megaloblastic anaemia, osteomalacia, peripheral neuropathy and hyperglycaemia. Toxicity by level: nystagmus over 20 mg/L, ataxia over 30 mg/L, lethargy and confusion over 40 mg/L.

Interactions.

• Raised levels: isoniazid, fluconazole, metronidazole, amiodarone, chloramphenicol, co-trimoxazole, cimetidine and omeprazole. Valproate raises the free fraction.

• Lowered levels: rifampicin, chronic alcohol, and enteral feeds, so hold feeds 1 to 2 hours around doses.

• Induction lowers warfarin (after a brief rise), direct oral anticoagulants (avoid), hormonal contraceptives, corticosteroids, dolutegravir, efavirenz, protease inhibitors, artemether-lumefantrine, praziquantel and doxycycline.

Common prescribing errors. Large dose steps near the therapeutic range. Judging by total level in hypoalbuminaemia. Running it in glucose. Intramuscular use. Fast intravenous infusion.

Special groups.

• Pregnancy: teratogenic. Free levels fall in pregnancy. Give folic acid 5 mg daily before conception and vitamin K to the newborn.

• Breastfeeding: acceptable; monitor for drowsiness and poor feeding.

• Ancestry: HLA-B*1502 raises skin reaction risk in South and Southeast Asian ancestry; cytochrome P450 2C9 poor metabolisers need lower doses.

• Regional: tuberculosis treatment with isoniazid and HIV treatment are common co-prescriptions that change levels. Phenytoin is often one of the more available antiseizure medicines.

Formulations. Capsules 25, 50, 100 and 300 mg. Chewable tablets 50 mg. Suspension 30 mg/5 mL or 125 mg/5 mL. Injection 50 mg/mL (pH about 12, irritant). Shake suspension; hold enteral feeds around doses.

Preparation. Give by syringe pump into a large vein, undiluted, or dilute in 0.9% sodium chloride only to 1 to 10 mg/mL with an in-line filter and use within 1 hour. Never use glucose. Flush the line with sodium chloride before and after.

Monitoring.

• Continuous ECG and blood pressure during infusion; stop or slow for hypotension or QRS widening.

• Trough total level 10 to 20 mg/L (free 1 to 2 mg/L); check 7 to 14 days after changes. Also monitor albumin, full blood count, liver function, calcium and vitamin D.

Stopping. Taper over at least 4 weeks. Stop immediately for severe rash.

Referral and escalation. Refer for persistent seizures, suspected toxicity, severe skin reaction, or when pregnancy is planned. Seizures continuing after phenytoin loading need escalation to anaesthetic-level care.