Antiepileptic Drugs: Mechanisms & Toxicities
Every antiseizure drug has a target and a signature toxicity: learn the pairs
How antiseizure drugs work
Three main levers. Seizures arise when neurons fire in excessive, synchronized bursts. Antiseizure drugs restore balance in a few ways: stabilizing the inactivated state of voltage-gated Na+ channels (phenytoin, carbamazepine, oxcarbazepine, lamotrigine, lacosamide), blocking T-type Ca2+ channels in thalamic relay neurons (ethosuximide, valproate), or enhancing GABA inhibition (benzodiazepines, barbiturates, vigabatrin, tiagabine). Other drugs act on synaptic vesicle protein SV2A (levetiracetam), the α2δ subunit of presynaptic Ca2+ channels (gabapentin, pregabalin), or glutamate receptors (topiramate at AMPA/kainate, felbamate at NMDA).
Use-dependent block. Na+ channel blockers bind preferentially to channels in the inactivated state and slow their return to rest. A seizure focus firing at high frequency keeps channels cycling through inactivation, so it is suppressed selectively, while normal low-frequency firing is largely spared.
Sodium channel blockers
Phenytoin kinetics. Phenytoin is metabolized by CYP2C9 and CYP2C19, enzymes that saturate near the therapeutic range (10–20 μg/mL total). Elimination then becomes zero-order, so a small dose increase can produce a disproportionate rise in level. Phenytoin is highly albumin-bound; in hypoalbuminemia or uremia the free fraction rises, so the free level is measured. It is a potent CYP inducer that lowers levels of oral contraceptives, warfarin, and many other drugs.
Phenytoin toxicity. Acute toxicity is dose-related and cerebellar–vestibular: horizontal nystagmus above about 20 μg/mL, then ataxia, diplopia, and dysarthria above 30, then lethargy and confusion above 40. Rapid IV infusion causes hypotension and arrhythmias (limit 50 mg/min) and soft-tissue injury with limb discoloration and swelling (purple glove syndrome). Fosphenytoin, a water-soluble prodrug, infuses more safely and can be given IM. Chronic use causes gingival hyperplasia, hirsutism, coarse facial features, osteomalacia (from accelerated vitamin D catabolism), megaloblastic anemia (impaired folate absorption), peripheral neuropathy, cerebellar atrophy, drug-induced lupus, and lymphadenopathy (pseudolymphoma).
Carbamazepine. Carbamazepine blocks Na+ channels and strongly induces CYP3A4, including its own metabolism (autoinduction), so levels fall over the first weeks and the dose must be raised. It is first-line for trigeminal neuralgia and is used for focal seizures and bipolar mania. Toxicities include diplopia and ataxia, agranulocytosis and aplastic anemia (monitor the CBC), SIADH with hyponatremia, hepatotoxicity, and teratogenicity (neural tube defects, cleft lip).
Carbamazepine, oxcarbazepine, and phenytoin can worsen absence and myoclonic seizures, so they are avoided in generalized epilepsies with those seizure types.
Oxcarbazepine and lacosamide. Oxcarbazepine, a carbamazepine analog, induces CYP enzymes less and rarely harms the marrow, but causes hyponatremia more often. Lacosamide enhances the slow inactivation of Na+ channels, is available orally and IV for focal seizures, and prolongs the PR interval, so it is avoided in AV block; dizziness and diplopia are common.
Lamotrigine. Lamotrigine blocks Na+ channels and reduces glutamate release. It is broad-spectrum (focal, generalized tonic-clonic, and absence seizures) and a maintenance drug that delays depressive episodes in bipolar disorder. Its danger is SJS/TEN, whose risk rises with fast titration, high starting doses, young age, and valproate co-therapy: valproate inhibits lamotrigine glucuronidation and roughly doubles its level. Start low, titrate slowly, and stop at the first rash. Lamotrigine clearance rises in pregnancy and with estrogen-containing contraceptives, so levels fall and need monitoring.
Aromatic Na+ blockers (carbamazepine, phenytoin, oxcarbazepine, lamotrigine) can cause SJS/TEN or DRESS, usually within the first 2 months. Carriers of HLA-B*15:02, common in Han Chinese, Thai, and other Southeast Asian ancestries, have a markedly higher risk with carbamazepine and phenytoin; genotype before starting.
| Drug | Kinetic hallmark | Signature toxicities |
|---|---|---|
| Phenytoin | Zero-order at therapeutic levels; CYP inducer | Nystagmus, ataxia, gingival hyperplasia, hirsutism, osteomalacia, megaloblastic anemia, fetal hydantoin syndrome |
| Carbamazepine | CYP3A4 inducer and autoinducer | Agranulocytosis/aplastic anemia, SIADH, SJS (HLA-B*15:02), hepatotoxicity, neural tube defects |
| Oxcarbazepine | Weaker inducer | Hyponatremia |
| Lamotrigine | Level doubled by valproate; falls in pregnancy | SJS/TEN with rapid titration |
| Lacosamide | Enhances slow inactivation | PR prolongation, dizziness, diplopia |
Valproate and ethosuximide
Valproate mechanism and uses. Valproate blocks Na+ channels and T-type Ca2+ channels and raises brain GABA by inhibiting GABA transaminase and boosting GABA synthesis. It covers generalized tonic-clonic, myoclonic, and absence seizures and is also used for bipolar mania and migraine prophylaxis. Unlike the inducers, valproate inhibits drug metabolism (CYP2C9, UGT), raising lamotrigine and phenobarbital levels.
Valproate toxicity. Hepatotoxicity can be fatal; risk is highest in children under 2 years on multiple antiseizure drugs and in POLG mitochondrial disease, so liver tests are monitored. Other effects include pancreatitis, hyperammonemia (it is contraindicated in urea cycle disorders), thrombocytopenia, tremor, weight gain, and hair loss. It is the most teratogenic antiseizure drug: neural tube defects (spina bifida), cardiac and limb defects, and lower IQ and higher autism risk in exposed children.
Ethosuximide. Ethosuximide blocks T-type Ca2+ channels in thalamic relay neurons, which generate the 3-Hz spike-and-wave rhythm of absence seizures. It is first-line for childhood absence epilepsy but does nothing for tonic-clonic seizures; when both coexist, a broad-spectrum drug such as valproate or lamotrigine is chosen. Adverse effects are GI upset (nausea, abdominal pain), fatigue, headache, and dizziness, with rare SJS and blood dyscrasias.
GABAergic drugs and status epilepticus
Benzodiazepines. Benzodiazepines increase the frequency of GABA-A chloride channel opening and are first-line for status epilepticus: a seizure lasting 5 minutes or longer, or repeated seizures without recovery in between. Their main risks are sedation and respiratory depression.
- 0–5 minutesStabilize airway, breathing, and circulation; check glucose.
- 5–20 minutesBenzodiazepine: IV lorazepam, or IM midazolam or rectal/intranasal diazepam without IV access.
- 20–40 minutesIV fosphenytoin, valproate, or levetiracetam.
- Beyond 40 minutesRefractory status: anesthetic infusion (midazolam, propofol, pentobarbital) with continuous EEG.
Phenobarbital. Barbiturates prolong the duration of chloride channel opening and, at high doses, open the channel directly without GABA, which makes them far more lethal in overdose than benzodiazepines. Phenobarbital is first-line for neonatal seizures. It is a strong CYP inducer, causes sedation, respiratory depression, and cognitive and behavioral effects in children, and is contraindicated in acute porphyria because it induces ALA synthase.
Vigabatrin and tiagabine. Vigabatrin irreversibly inhibits GABA transaminase, raising GABA. It is used for infantile spasms, particularly with tuberous sclerosis, and refractory focal seizures, but causes permanent bilateral concentric visual field loss, so vision is monitored. Tiagabine blocks the GAT-1 GABA reuptake transporter and is used for focal seizures.
Other mechanisms
Levetiracetam. Binds synaptic vesicle glycoprotein 2A and modulates transmitter release. It is broad-spectrum, renally cleared (dose reduced in renal failure), has few drug interactions, and comes in an IV form, making it a go-to in liver disease, the ICU, and pregnancy. Its main adverse effects are behavioral: irritability, aggression, depression, and rarely psychosis, plus somnolence and fatigue.
Gabapentin and pregabalin. Although designed as GABA analogs, they bind the α2δ subunit of presynaptic voltage-gated Ca2+ channels and reduce excitatory transmitter release. They treat focal seizures, neuropathic pain (diabetic neuropathy, postherpetic neuralgia), and fibromyalgia (pregabalin). Both are renally cleared and cause sedation, dizziness, ataxia, peripheral edema, weight gain, and misuse.
Topiramate. Blocks Na+ channels and AMPA/kainate receptors, enhances GABA-A, and weakly inhibits carbonic anhydrase, which explains calcium phosphate kidney stones, non-anion-gap metabolic acidosis, and paresthesias. It also causes weight loss, cognitive slowing with word-finding difficulty, acute angle-closure glaucoma, and oligohidrosis. It is used for epilepsy and migraine prophylaxis.
Felbamate. Blocks NMDA receptors and enhances GABA-A. Because it can cause aplastic anemia and hepatic failure, it is reserved for refractory epilepsy such as Lennox-Gastaut syndrome. Felbamate and carbamazepine are the antiseizure drugs classically linked to aplastic anemia.
Choosing a drug: seizure type and pregnancy
| Seizure type | Preferred drugs | Avoid or note |
|---|---|---|
| Focal | Lamotrigine, levetiracetam | Carbamazepine, oxcarbazepine are alternatives |
| Generalized tonic-clonic | Valproate, lamotrigine, levetiracetam | Avoid valproate if pregnancy is possible |
| Absence | Ethosuximide | Valproate or lamotrigine if tonic-clonic seizures coexist |
| Myoclonic | Valproate, levetiracetam | Avoid carbamazepine, phenytoin |
| Status epilepticus | Benzodiazepine, then fosphenytoin, valproate, or levetiracetam | Anesthetic infusion if refractory |
| Neonatal seizures | Phenobarbital | — |
| Infantile spasms | ACTH or vigabatrin | Vigabatrin favored in tuberous sclerosis |
Pregnancy. Lamotrigine and levetiracetam carry the lowest malformation risk and are preferred. Valproate is the worst offender and should be avoided in anyone who may become pregnant. Phenytoin causes fetal hydantoin syndrome: cleft lip and palate, hypoplasia of the distal phalanges and nails, microcephaly, and growth and developmental delay. Carbamazepine, phenobarbital, and topiramate also raise malformation risk, and enzyme inducers can cause vitamin K–deficiency bleeding in the newborn. Folic acid is started before conception, and lamotrigine levels are monitored because clearance rises during pregnancy.