The perils of antiepileptic toxicity

• Published in: Australian prescriber Vol. 43; no. 2; pp. 61 - 63
• Main Authors: Madan, Arushi, Risetto, Tracy, Ad, Queensland Medicines, Ser, Information, Trenerry, Helen, Donovan, Peter
• Format: Journal Article
• Language: English
• Published: Australia Therapeutic Guidelines Limited 01.04.2020; NPS MedicineWise
• Subjects: Anticonvulsants; Ataxia; Bone marrow; Case Study; Coma; Convulsions & seizures; Drug dosages; Drug interactions; Information services; Metabolism; Nervous system; Patients; Pharmacokinetics; Queensland Australia; Australia; anticonvulsive drugs; phenytoin; valproate
• ISSN: 0312-8008; 1839-3942
• DOI: 10.18773/austprescr.2020.012

Phenytoin and valproate are both highly protein-bound drugs (>90%) with non-linear pharmacokinetics, saturable protein binding and complex drug interactions.2 The free unbound component of the drugs is responsible for their antiepileptic activity and neurological and systemic toxicity. With both antiepileptics, toxicity may present as central nervous system depression, cerebellar dysfunction, seizures, hepatotoxicity and bone marrow abnormalities (Table).3,4 Table - Correlation of total plasma concentration and clinical features of toxicity for phenytoin and valproate Clinical features of toxicity Phenytoin 10–20 mg/L Therapeutic range >20 mg/L Nystagmus and ataxia >30 mg/L Severe ataxia, dysarthria, hyperreflexia, drowsiness, nausea and vomiting >50 mg/L Extreme lethargy, coma, paradoxical seizures Cardiac conduction abnormalities with intravenous administration only Valproate 40–100 mg/L Therapeutic range >100 mg/L Mild drowsiness and ataxia Variable central nervous system depression >500 mg/L Usually coma and metabolic abnormalities >1000 mg/L Life-threatening multiorgan dysfunction – metabolic abnormalities, cerebral oedema, bone marrow suppression >2000 mg/L Death expected without urgent haemodialysis Source: reference 4 Valproate inhibits phenytoin metabolism and causes displacement of phenytoin from albumin, so it increases free phenytoin concentrations. Monitoring is especially important for individuals with altered pharmacokinetics including patients with hypoalbuminaemia, underlying organ dysfunction and those at extremes of age or during pregnancy.3 Plasma concentrations of antiepileptic drugs correlate with adverse effects and for hypoalbuminaemic patients, free drug concentrations correlate better than total concentrations.