Phenytoin

Phenytoin is approximately 90% protein bound. Plasma levels are based on total phenytoin (bound plus free) and dosage must be adjusted when serum albumin is reduced (see equation below). Hypoalbuminaemia will lead to an increased fraction of unbound drug.The free fraction is responsible for the pharmacological action of the drug. Phenytoin demonstrates zero-order kinetics and does not demonstrate a proportional relationship between drug levels and dose. Maintenance dosage should not be increased by increments of more than 50–100 mg.

Uses
Status epilepticus
Anticonvulsant prophylaxis in post-neurosurgical operations
Anti-arrhythmic – particularly for arrhythmias associated with digoxin toxicity

Contraindications
Do not use IV phenytoin in sino-atrial block, or second- and thirddegree
AV block

Administration
• Status epilepticus:
IV: 15 mg/kg, give at a rate not >50 mg/min (20–30 min), followed by 100 mg every 8 hourly for maintenance

• Anticonvulsant prophylaxis:
PO/IV: 200–600 mg/day

• Anti-arrhythmic:
IV: 100mg every 15 min until arrhythmia stops. Maximum
15 mg/kg/day

Monitor:
ECG and BP
Serum phenytoin level
Recommended therapeutic range 40–80 μmol/l or 10–20 mg/l Hypoalbuminaemia will lead to an increased fraction of unbound active
drug.The reported total phenytoin (bound + free) levels are open to misinterpretation because an apparently ‘normal’ level in a hypoalbuminaemic patient may hide a toxic level of free phenytoin.A conceptual corrected level can be determined, which reflects what the total phenytoin level would be if the patient had normal protein levels.To adjust for
a low albumin:
Adjusted phenytoin level = reported level divide [(0.02 x serum albumin) + 0.1]

However, this equation depends on the accurate measurement of serum albumin. Some albumin assays are not reliable below 15 g/l. If available, free phenytoin levels are preferable if the albumin is low.
If the patient is fitting and levels are low:

• Consider repeating a loading dose:
Loading dose (mg) = 0.67 x weight (kg) x change in plasma concentration required (in mg/l)

• Increase maintenance dose as follows:
<7 mg/l level, increase daily dose by 100 mg daily
7–12 mg/l level, increase daily dose by 50 mg daily
12–16 mg/l level, increase daily dose by 25 mg daily

NG administration and IV to oral/NG conversion: theoretically one should take account of the different salts of the IV and liquid preparation but in practice one can use a 1-to-1 conversion, but give the oral/NG as a single daily dose. Note that enteral feed reduces the absorption of phenytoin liquid so stop feed for 1 hour before and 2 hours after phenytoin administration. In practice, conversion from IV to NG phenytoin at the same total daily dose often results in reduced levels.

How not to use phenytoin
Rapid IV bolus not recommended (hypotension, arrhythmias, CNS depression)
Do not dissolve in solutions containing glucose (precipitation)
IM injection not recommended (absorption slow and erratic)
Do not give into an artery (gangrene)
Do not prescribe NG phenytoin three times daily, as feed will be turned off for 9 hours per day

Adverse effects
Nystagmus, ataxia and slurred speech
Drowsiness and confusion
Hypotension (rapid IV)
Prolonged QT interval and arrhythmias (rapid IV)
Gingival hyperplasia (long-term)
Rashes
Aplastic anaemia
Agranulocytosis
Folate deficiency
Megaloblastic anaemia
Thrombocytopenia

Cautions
Severe liver disease (reduce dose)
Metabolism subject to other enzyme inducers and inhibitors
Additive CNS depression with other CNS depressants

Organ failure
CNS: enhanced sedation
Hepatic: increased serum level