anti-epileptic

**Mechanisms of action** - **Na+ channel blockers** (prolong the inactivated state; use-dependent): phenytoin, carbamazepine, oxcarbazepine, lamotrigine, lacosamide (enhances slow inactivation), zonisamide, topiramate (also GABA-A potentiation and AMPA/kainate block). - **GABA enhancers:** - Benzodiazepines (lorazepam, diazepam, clonazepam) increase the *frequency* of Cl- channel opening. - Barbiturates (phenobarbital, primidone) increase the *duration* of opening. - Vigabatrin irreversibly inhibits GABA transaminase. - Tiagabine inhibits GAT-1 (GABA reuptake). - Valproate increases GABA and blocks Na+ and T-type Ca2+ channels. - **T-type Ca2+ channel blockers (thalamic):** ethosuximide (first-line for absence seizures); valproate also acts here. - **α2δ subunit of voltage-gated Ca2+ channels:** gabapentin and pregabalin. These are also used for neuropathic pain. - **SV2A binding (synaptic vesicle protein):** levetiracetam, brivaracetam. - **AMPA antagonist:** perampanel. - **Others:** felbamate (NMDA antagonist), cenobamate (Na+ channel blocker and GABA-A modulator).

**Drug selection by seizure type (high-yield)** - **Focal (partial):** carbamazepine, oxcarbazepine, lamotrigine, or levetiracetam. - **Generalized tonic-clonic:** valproate, lamotrigine, or levetiracetam. Carbamazepine and phenytoin are alternatives. - **Absence:** ethosuximide is first-line. Valproate is preferred if the patient also has generalized tonic-clonic seizures. Carbamazepine and phenytoin can *worsen* absence and myoclonic seizures. - **Myoclonic / juvenile myoclonic epilepsy:** valproate, levetiracetam, or lamotrigine. Valproate is avoided in women of childbearing potential. - **Status epilepticus:** IV benzodiazepine (lorazepam) first, then IV fosphenytoin, valproate, or levetiracetam. Phenobarbital is a further option. - **Infantile spasms (West syndrome):** ACTH or corticosteroids. Vigabatrin is first-line in tuberous sclerosis. - **Eclampsia:** magnesium sulfate. - **Trigeminal neuralgia:** carbamazepine.

**Classic adverse effects** - **Phenytoin:** gingival hyperplasia, hirsutism, nystagmus and ataxia, peripheral neuropathy, megaloblastic anemia (folate deficiency), osteomalacia, and fetal hydantoin syndrome. IV infusion can cause cardiac arrhythmias and hypotension (purple glove syndrome with extravasation). Shows zero-order (saturable) kinetics at higher doses. - **Carbamazepine:** SJS/TEN (HLA-B*1502 in Asian patients), agranulocytosis and aplastic anemia, hyponatremia (SIADH), hepatotoxicity, diplopia, and teratogenicity (neural tube defects). Strong CYP450 inducer, including autoinduction. - **Valproate:** hepatotoxicity (especially in children under 2 and in mitochondrial disease such as POLG mutations), pancreatitis, tremor, weight gain, alopecia, thrombocytopenia, hyperammonemia, and neural tube defects. It is the **most teratogenic** AED. It inhibits CYP450. - **Lamotrigine:** SJS/TEN. Risk rises with rapid titration and with co-administration of valproate, which inhibits lamotrigine metabolism. - **Phenobarbital:** sedation, cognitive slowing, and respiratory depression. It induces CYP450 and is addictive, with withdrawal risk. - **Ethosuximide:** GI upset, headache, and urticaria/SJS. - **Topiramate:** weight loss, cognitive slowing (word-finding difficulty), kidney stones and metabolic acidosis (carbonic anhydrase inhibition), paresthesias, and angle-closure glaucoma. - **Levetiracetam:** irritability and mood or behavioral changes, somnolence. - **Gabapentin/pregabalin:** sedation, ataxia, and peripheral edema. - **Vigabatrin:** irreversible peripheral visual field loss. - **Felbamate:** aplastic anemia and hepatic failure. - **Benzodiazepines:** sedation, respiratory depression, tolerance, and dependence.

**Key associations / board pearls** - **CYP450 inducers:** carbamazepine, phenytoin, phenobarbital. They *decrease* levels of OCPs, warfarin, and other drugs, so OCPs may fail. Use alternative contraception. - **CYP450 inhibitor:** valproate. - **Teratogenicity:** Most AEDs carry risk. Valproate carries the highest risk of neural tube defects and neurodevelopmental effects. Phenytoin causes fetal hydantoin syndrome. Carbamazepine causes neural tube defects. Lamotrigine and levetiracetam have the lowest risk. Give folic acid to women of childbearing potential on AEDs. - **Vitamin K:** Enzyme-inducing AEDs can cause neonatal coagulopathy due to vitamin K deficiency. Give vitamin K to the newborn. - **Bone health:** Enzyme-inducing AEDs increase vitamin D catabolism, leading to osteomalacia and osteoporosis. - **Abrupt withdrawal** can precipitate seizures or status epilepticus. Taper gradually. - **Narrow therapeutic index:** phenytoin, carbamazepine, valproate, and phenobarbital need therapeutic drug monitoring. - **HLA-B*1502 screening** before carbamazepine in patients of Asian ancestry. - **Pregnancy and AED levels:** Lamotrigine clearance rises during pregnancy, so monitor levels. - **Mood stabilizers:** valproate, carbamazepine, and lamotrigine are also used in bipolar disorder. - **Migraine prophylaxis:** topiramate and valproate.