Snapshot A 17-year-old man presents with myoclonic seizures followed by generalized a tonic-clonic seizure after awakening. He denies any recent head trauma or substance abuse. He reports to being sleep deprived for the past week due to final examinations. Routine EEG testing is significant for 5-Hz bilateral polyspike and slow wave discharges. Valproic acid is prescribed. (Juvenile myoclonic epilepsy) Introduction Antiepileptic drugs (AED) can be separated by mechanism of action (MOA) affecting the following voltage-gated Na+ channels Ca2+ channels GABA activity Choice of AED is dependent on seizure type, patient, cost, and side-effect profile Affecting Voltage-Gated Na+ Channels Phenytoin uses parital (simple and complex) generalized (tonic-clonic) prophylaxis for status epilepticus mechanism blocks voltage-gated Na+ channels stops seizure propogation kinetics induction of P450 zero-order kinetics with saturation of degradative liver enzymes toxicity nystagmus/ataxia/diplopia sedation/CNS depression SLE-like syndrome gingival hyperplasia peripheral neuropathy osteopenia megaloblastic anemia (↓ folate absorption) tetratogenic fetal hydantoin syndrome cleft lip and palate notes fosphenytoin for parenteral use Carbamazepine uses partial (simple and complex) generalized (tonic-clonic) mechanism ↑ refractory period of voltage-gated Na+ channels likely binds to the inactivated state, inhibiting action potential generation kinetics induction of P450 reduces its own levels toxicity diplopia/ataxia agranulocytosis aplastic anemia hepatotoxicity SIADH Stevens-Johnson syndrome teratogenic cleft lip and palate spina bifida notes first-line for trigeminal neuralgia also used for bipolar disorders Lamotrigine uses partial (simple and complex) generalized (tonic-clonic) absence mechanism blocks voltage-gated Na+ channels and glutamate receptors toxicity Stevens-Johnson syndrome Affecting Calcium Channels Ethosuximide uses absence seizures mechanism blocks thalamic T-type Ca2+ channels toxicity GI distress fatigue headache Stevens-Johnson syndrome Affecting GABA Activity Phenobarbital uses partial (simple and complex) in pregnant women and children generalized (tonic-clonic) in pregnant women and children mechanism ↑ GABAA action kinetics induction of P450 tolerance/dependence toxicity sedation Benzodiazepines uses acute treatment for status epilepticus alcohol withdrawal syndrome mechanism ↑ GABAA action notes also used for seizures of eclampsia 1st-line is MgSO4 Tiagabine uses partial (simple and complex) mechanism inhibition of GABA reuptake Vigabatrin uses partial (simple and complex) mechanism irreversible inhibition of GABA transaminase Multiple Mechanisms of Action Valproic acid uses partial (simple and complex) generalized (tonic-clonic and absence) mechanism ↑ refractory period of voltage-gated Na+ channels ↑ GABA concentration via inhibition of GABA transaminase inhibition of thalamic T-type Ca2+ channels toxicity pancreatitis hepatoxicity accumulation of toxic metabolite tetratogenic neural tube defects tremor hyperammonemia thrombocytopenia anemia myelodysplasia notes first-line for myoclonic seizures first-line for juvenile myoclonic epilepsy can be used as prophylactic treatment for migraines Topiramate uses partial (simple and complex) generalized (tonic-clonic) migraine prophylaxis mechanism blocks voltage-gated Na+ channels ↑ GABA action toxicity sedation/mental dulling renal stones weight loss Other Levetiracetam uses partial (simple and complex) complex (tonic-clonic) mechanism unknown, but does bind to synaptic vesicle protein SV2A, which may modulate synaptic transmission through alteration of vesicle fusion, and may indirectly modulate GABA Gabepentin uses partial (simple and complex) mechanims inhibit voltage-gated Ca2+ channel via α2δ subunit structurally similar to GABA toxicity sedation ataxia notes also used for peripheral neuropathy/neuropathic pain