Phenytoin: An In-Depth Analysis

Phenytoin, a hydantoin derivative, is one of the most extensively utilised antiepileptic drugs (AEDs). It was first synthesised in 1908 and has been in clinical use since the 1930s. Despite the advent of newer-generation anticonvulsants, phenytoin remains a cornerstone in the management of seizure disorders due to its efficacy, cost-effectiveness, and broad therapeutic index. By modulating voltage-gated sodium channels, phenytoin stabilises neuronal membranes and attenuates excessive excitatory activity, making it a vital agent in controlling epileptic seizures and related neurological conditions.

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Therapeutic Indications

Phenytoin has a broad spectrum of clinical applications, including:

Generalised tonic-clonic seizures: A primary agent in managing generalised seizures that involve loss of consciousness and convulsive activity.
Focal (partial) seizures: Used to control focal seizures, both with and without secondary generalisation.
Status epilepticus: Intravenous phenytoin is an essential treatment in managing prolonged seizure episodes.
Post-traumatic seizure prophylaxis: Commonly employed in neurosurgical settings to mitigate seizure risk following brain trauma.
Trigeminal neuralgia: In refractory cases, phenytoin may be used when conventional treatments fail.
Off-label indications: Investigated for its efficacy in bipolar disorder, neuropathic pain, and certain psychiatric conditions.

Dosage and Administration

Phenytoin dosing is patient-specific, requiring therapeutic drug monitoring (TDM) to maintain optimal plasma concentrations (10–20 µg/mL).

Oral administration:
- Initial dose: 3–5 mg/kg/day (typically 300 mg daily in divided doses).
- Maintenance dose: Adjusted based on serum levels and clinical response.
Intravenous (IV) administration:
- Loading dose: 15–20 mg/kg at a maximum infusion rate of 50 mg/min in adults (to avoid cardiovascular complications).
- Maintenance dose: 4–7 mg/kg/day.

Dose Adjustments in Special Populations

Renal Impairment

Phenytoin is highly protein-bound, and in patients with renal dysfunction, the free (active) drug concentration may increase, leading to toxicity.

Total phenytoin levels may be misleading; free phenytoin monitoring is recommended.
Dose adjustment is guided by corrected phenytoin levels using the Sheiner-Tozer equation.

Hepatic Impairment

As phenytoin is primarily metabolised by hepatic enzymes (CYP2C9, CYP2C19), hepatic insufficiency may result in drug accumulation and toxicity.

Recommendations: Initiate at a lower dose, with frequent plasma level monitoring.
Additional monitoring: Liver function tests should be conducted periodically.

Pregnancy

Phenytoin is a recognised teratogen, linked to foetal hydantoin syndrome.

Recommendations:
- The lowest effective dose should be administered.
- Folic acid supplementation is strongly advised (5 mg daily).
- TDM is critical as pregnancy increases drug clearance.
- Neonatal vitamin K supplementation is recommended to prevent haemorrhagic disease of the newborn.

Pharmacokinetics and Pharmacodynamics

Absorption: Variable, with dose-dependent bioavailability.
Distribution: Highly protein-bound (~90%).
Metabolism: Non-linear kinetics via hepatic CYP2C9 and CYP2C19 pathways.
Elimination: Primarily renal excretion as inactive metabolites.
Mechanism of action: Phenytoin stabilises excitable membranes by blocking sodium channels, preventing seizure propagation.

Adverse Effects and Toxicity

Common Side Effects

Neurological: Nystagmus, ataxia, dizziness, cognitive impairment.
Gastrointestinal: Nausea, vomiting, hepatotoxicity.
Dermatological: Rash, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN).
Haematological: Agranulocytosis, megaloblastic anaemia.
Chronic Use Effects: Gingival hyperplasia, hirsutism, osteoporosis.

Toxicity and Overdose Management

Clinical signs: Ataxia, nystagmus, confusion, hypotension, coma.
Treatment: Supportive care, haemodialysis for severe toxicity.
Antidote: There is no specific antidote, but activated charcoal may be beneficial in acute overdose.

Drug Interactions

Phenytoin is a potent inducer of cytochrome P450 enzymes, leading to numerous drug interactions:

Reduces efficacy of: Warfarin, oral contraceptives, antifungals.
Affected by: Valproate (inhibits phenytoin metabolism, increasing toxicity risk), carbamazepine (induces metabolism, reducing efficacy).
Alcohol interaction: Acute alcohol intake increases phenytoin toxicity, while chronic alcohol use induces metabolism, lowering plasma levels.

Formulations and Presentation

Formulation	Strength
Tablets	50 mg, 100 mg
Capsules	30 mg, 100 mg, 200 mg, 300 mg
Suspension	30 mg/5mL, 125 mg/5mL
Injectable	50 mg/mL

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Clinical Comparison with Other AEDs

Drug	Mechanism	Metabolism	Half-life	Adverse Effects
Phenytoin	Na+ channel blocker	Hepatic	10–22 hrs	Gingival hyperplasia, ataxia
Carbamazepine	Na+ channel blocker	Hepatic	12–17 hrs	Hepatotoxicity, hyponatraemia
Valproate	GABA enhancer	Hepatic	9–16 hrs	Hepatotoxicity, weight gain
Levetiracetam	Unknown	Renal	7–8 hrs	Behavioural changes, sedation

Infusion Considerations

Dilution: Only in normal saline (NS); incompatible with dextrose.
Infusion rate: Should not exceed 50 mg/min to prevent hypotension and arrhythmias.
Monitoring: Continuous ECG monitoring is essential.
Extravasation risk: Can cause tissue necrosis (purple glove syndrome).

Recent Updates (2025 Guidelines)

Revised recommendations on therapeutic drug monitoring in pregnancy.
Enhanced safety warnings regarding cardiovascular risks with IV phenytoin.
Alternative AEDs recommended for individuals at risk of hypersensitivity reactions.

Key Facts About Phenytoin

Administer IV slowly to prevent cardiovascular events.
Highly protein-bound, requiring correction in hypoalbuminaemia.
Long-term therapy necessitates monitoring for bone health (risk of osteoporosis).
Notoriously associated with teratogenicity; extreme caution is needed in pregnancy.