Adverse drug reactions from - anticonvulsants

Reaction spectrum

Reaction spectrum spans idiosyncratic hypersensitivity, teratogenicity, and drug-specific organ toxicity
Aromatic anticonvulsants (carbamazepine, phenytoin, lamotrigine, phenobarbital) - highest risk of SJS/TEN and DRESS, cross-reactive with each other
Valproate - teratogenicity (highest risk of any anticonvulsant), hepatotoxicity, hyperammonaemia, thrombocytopenia, weight gain
Carbamazepine - hyponatraemia (SIADH), agranulocytosis/aplastic anaemia (rare), enzyme induction
Phenytoin - gingival hyperplasia, cerebellar toxicity (ataxia, nystagmus) at high levels, purple glove syndrome (IV extravasation)

*HLA-B15:02** - strongly associated with carbamazepine-induced SJS/TEN, esp. in patients of Han Chinese/South-East Asian ancestry - screen before starting
*HLA-A31:01** - associated with carbamazepine hypersensitivity across broader ancestries
Valproate teratogenicity - dose-dependent, highest of all anticonvulsants for neural tube defects and neurodevelopmental impairment

SJS/TEN/DRESS: T-cell mediated hypersensitivity, HLA-restricted presentation of drug/metabolite to cytotoxic T-cells
Valproate hepatotoxicity: mitochondrial beta-oxidation impairment -> microvesicular steatosis, higher risk in young children and mitochondrial disease
Valproate hyperammonaemia: impaired urea cycle (carbamoyl phosphate synthetase inhibition) -> can occur with normal LFTs
Carbamazepine SIADH: direct effect on ADH release/renal tubular sensitivity to ADH
Enzyme induction (carbamazepine, phenytoin, phenobarbital) -> reduces efficacy of oral contraceptives, warfarin, other anticonvulsants

*HLA-B15:02 testing before carbamazepine in at-risk ancestry**
Rash within first 8 weeks of a new anticonvulsant - assess for SJS/TEN/DRESS features (mucosal involvement, eosinophilia, facial oedema, fever, lymphadenopathy)
Valproate: LFTs + ammonia if encephalopathic (even with normal LFTs); FBE for thrombocytopenia
Phenytoin level if ataxia/nystagmus/confusion - correlate with free (unbound) level if hypoalbuminaemic

Any suspected SJS/TEN/DRESS - stop immediately, do not rechallenge, avoid cross-reactive aromatic anticonvulsants
Valproate hyperammonaemic encephalopathy - stop the drug, L-carnitine, supportive care
Avoid valproate in women of childbearing potential unless no suitable alternative and on a pregnancy prevention program
Correct hyponatraemia/monitor sodium periodically on carbamazepine
Phenytoin toxicity - reduce/withhold dose, supportive care, levels fall over days given zero-order kinetics at high concentration

Enzyme induction reduces efficacy of hormonal contraception - use non-hormonal or higher-dose/alternative contraception
Valproate + lamotrigine - valproate inhibits lamotrigine metabolism, dose reduction needed to avoid rash/toxicity
Chronic phenytoin - osteomalacia, peripheral neuropathy, coarsening facial features

SJS/TEN mortality significant (higher with TEN than SJS); survivors risk long-term ocular/mucosal scarring
Most idiosyncratic rashes without systemic features resolve on stopping the drug
Teratogenic effects are irreversible once exposure has occurred in pregnancy - prevention (planning, alternative agents) is the only mitigation

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