Antiepileptic Drugs

• Enhanced GABAergic Inhibitory Neurotransmission: GABA is the primary inhibitory neurotransmitter in the central nervous system. Many AEDs including barbiturates (phenobarbital), benzodiazepines (diazepam, lorazepam), and gabapentin potentiate GABA-A receptor function by increasing chloride channel opening duration or frequency, thereby hyperpolarizing neuronal membranes and raising the threshold for action potential generation. Increased inhibitory tone suppresses the sustained high-frequency firing characteristic of epileptic networks. Valproic acid increases GABA synthesis via inhibition of GABA-transaminase (the enzyme that catabolizes GABA), thereby increasing synaptic GABA concentrations. This mechanism is particularly important in generalized tonic-clonic and absence seizures.

• Voltage-Gated Sodium Channel Blockade: Phenytoin, carbamazepine, lamotrigine, oxcarbazepine, and valproic acid inhibit voltage-gated sodium channels in their inactive state, preventing sodium influx and repetitive neuronal firing. By slowing the rate of rise of the action potential and prolonging the refractory period, these drugs prevent the high-frequency repetitive firing that characterizes seizure discharges. This mechanism is particularly effective for focal onset seizures and generalized tonic-clonic seizures. The selectivity for inactive channels means these drugs preferentially block hyperactive neurons while sparing normal neuronal function.

• Voltage-Gated Calcium Channel Modulation: Ethosuximide selectively blocks low-voltage-activated T-type calcium channels in thalamic neurons, disrupting the thalamocortical oscillations that generate the characteristic 3-Hz spike-and-wave pattern of absence seizures. Pregabalin and gabapentin bind to the alpha-2-delta subunit of L-type calcium channels, reducing calcium influx and neurotransmitter release. Levetiracetam binds to the synaptic vesicle protein SV2A, modulating calcium-dependent neurotransmitter release, though its precise mechanism remains incompletely understood.

• Glutamate Antagonism and Excitatory Neurotransmission Reduction: Topiramate acts as a weak AMPA/kainate receptor antagonist, reducing the effects of the excitatory neurotransmitter glutamate. Phenytoin and other sodium channel blockers indirectly reduce glutamate release through decreased neuronal depolarization. Reduction of excitatory glutamatergic drive is particularly important in symptomatic focal seizures resulting from cortical lesions (tumors, stroke, traumatic brain injury) where aberrant glutamate signaling is enhanced.

• GABA-B Receptor Modulation: Baclofen and vigabatrin enhance GABA-B receptor signaling or increase GABA availability. Vigabatrin irreversibly inhibits GABA-transaminase, producing sustained elevation of GABA levels. This is particularly effective in infantile spasms (West syndrome) and tuberous sclerosis complex-associated seizures.

• Other Molecular Mechanisms: Lacosamide selectively enhances slow sodium channel inactivation with greater specificity than other sodium channel blockers. Perampanel is a selective non-competitive AMPA receptor antagonist that reduces postsynaptic glutamate-mediated excitation. Lacosamide and perampanel represent newer mechanisms that may have improved efficacy in drug-resistant epilepsy.

• Unprovoked Seizures/Epilepsy: A single unprovoked seizure has a 40-50% recurrence risk, whereas two unprovoked seizures (meeting the definition of epilepsy) carry an 80%+ recurrence risk, warranting AED initiation. Idiopathic generalized epilepsy (childhood absence epilepsy, juvenile myoclonic epilepsy, generalized tonic-clonic seizures) and genetic focal epilepsies have variable responses to different AED classes. Primary generalized epilepsies often respond better to valproic acid, lamotrigine, and levetiracetam, while focal seizures may respond to carbamazepine, oxcarbazepine, or phenytoin.

• Provoked Seizures and Status Epilepticus: Seizures provoked by acute metabolic derangement (hypoglycemia, hyponatremia, hypocalcemia), withdrawal states (alcohol, benzodiazepines, barbiturates), or structural lesions (acute stroke, traumatic brain injury, intracranial hemorrhage) require immediate parenteral AED administration. Lorazepam or diazepam are first-line agents for status epilepticus due to rapid CNS penetration, followed by load of phenytoin, fosphenytoin, or valproic acid. These provoked seizures do not mandate long-term AED therapy once the underlying cause is corrected, though neuroprotection during the acute phase is critical.

• Structural Brain Lesions: Post-traumatic seizures, seizures associated with brain tumors, arteriovenous malformations, cortical dysplasia, or stroke are common indications for prophylactic or therapeutic AED use. Levetiracetam and phenytoin are frequently used in post-traumatic settings, though evidence supports levetiracetam's superior tolerability profile. In tumor-associated seizures, levetiracetam, carbamazepine, and valproic acid are commonly selected.

• Special Populations: Pregnant women with epilepsy represent a unique challenge due to teratogenic risks (discussed in Complications). Women planning pregnancy should transition to monotherapy with agents carrying lower teratogenic risk (lamotrigine, levetiracetam, oxcarbazepine) if seizure control permits. Neonatal seizures due to hypoxic-ischemic encephalopathy, metabolic disorders, or infection require specialized AED selection; phenobarbital and phenytoin remain standards despite newer agents being studied.

• Generalized Tonic-Clonic Seizures: Characterized by sudden loss of consciousness, sustained muscle rigidity (tonic phase, 10-20 seconds), followed by rhythmic jerking (clonic phase, 20-60 seconds), and postictal confusion. First-line AEDs include valproic acid, lamotrigine, levetiracetam, and topiramate. Older agents like phenytoin remain effective but have less favorable pharmacokinetics and more drug interactions.

• Focal Onset Seizures with Aware vs. Impaired Awareness: Focal seizures may manifest with retained consciousness (motor automatisms, sensory phenomena, or autonomic features) or progress to impaired awareness with behavioral arrest and automatisms. Carbamazepine and oxcarbazepine are particularly effective for focal seizures, though lamotrigine, levetiracetam, and topiramate are also first-line options. Recognition of focal seizure semiology determines whether antiepileptic monotherapy is appropriate or whether neuroimaging to identify structural lesions is needed.

• Absence Seizures (Petit Mal): Brief episodes (5-10 seconds) of behavioral arrest with staring and loss of awareness, often multiple times daily. Ethosuximide is the drug of choice for childhood absence epilepsy due to its selective T-type calcium channel blockade and efficacy specifically in absence seizures. Valproic acid and lamotrigine are alternative first-line agents. Notably, sodium channel blockers like phenytoin may exacerbate absence seizures and should be avoided.

• Myoclonic Seizures: Sudden, brief, jerking movements of limbs or trunk. Valproic acid is the gold-standard treatment for juvenile myoclonic epilepsy, with levetiracetam and topiramate as alternatives. Lamotrigine may exacerbate myoclonic seizures in some patients and should be used cautiously.

• Atonic Seizures (Drop Attacks): Sudden loss of muscle tone causing falls without loss of consciousness (in Lennox-Gastaut syndrome). Valproic acid remains most effective, with lamotrigine and topiramate as alternatives. These seizures carry high injury risk, and successful seizure control is paramount.

• Infantile Spasms (West Syndrome): Clusters of flexor or extensor spasms in infants aged 3-12 months. Adrenocorticotropic hormone (ACTH) is first-line, but vigabatrin is highly effective, particularly in tuberous sclerosis complex. Conventional AEDs like phenytoin are ineffective, highlighting the importance of recognizing this specific syndrome.

• Clinical History: A detailed witness account of ictal and postictal features is essential. Key questions include prodrome presence, consciousness level, lateralization of motor signs, speech preservation, and postictal confusion duration. The history often provides more diagnostic value than any objective test. A single unprovoked seizure requires evaluation, while a seizure provoked by known precipitant (alcohol withdrawal, sleep deprivation, intercurrent illness) may warrant watchful waiting rather than chronic AED therapy.

• Electroencephalography (EEG): Interictal EEG shows characteristic abnormalities depending on seizure type: generalized 3-Hz spike-and-wave discharges in absence seizures, focal sharp waves or spike-and-wave patterns in focal seizures, and polyspike-and-wave patterns in myoclonic seizures. Sensitivity varies by syndrome (90%+ in juvenile myoclonic epilepsy, 60-70% in generalized tonic-clonic seizures). Ictal EEG during a recorded seizure provides the highest diagnostic specificity but is impractical in most settings. Absence of EEG abnormality does not exclude epilepsy, as up to 40% of patients with untreated generalized tonic-clonic epilepsy have normal initial EEGs.

• Neuroimaging: MRI is superior to CT and should be performed in all new-onset focal seizures to identify structural lesions (tumors, cortical dysplasia, mesial temporal sclerosis, vascular malformations). High-resolution brain MRI with epilepsy protocol (thin-section coronal and axial T1, T2, FLAIR sequences) can identify subtle cortical abnormalities in 30-40% of drug-resistant focal epilepsy cases. Neuroimaging is less critical in genetic generalized epilepsies but remains important to exclude structural mimics.

• Seizure Diagnosis Criteria: The International League Against Epilepsy (ILAE) classification distinguishes generalized-onset seizures (bilateral, symmetric thalamic involvement), focal-onset seizures (unilateral, single region of origin), and unknown-onset seizures. This classification guides AED selection: generalized seizures respond differently than focal seizures to the same medications.

• Diagnostic Certainty: Establishing that events are actually seizures rather than syncope, psychogenic non-epileptic seizures, or other mimickers is critical before initiating long-term AED therapy. Syncope is brief (<30 seconds), with rapid recovery, whereas seizures typically last 1-2 minutes with prolonged postictal confusion. Psychogenic non-epileptic seizures often have features inconsistent with physiologic seizures (variable duration, resistance to AEDs, frequent falls without injuries).

First-Line Monotherapy Selection by Seizure Type

Generalized Tonic-Clonic Seizures

• Valproic Acid (Divalproex, Depakote): Loading dose 15 mg/kg IV/oral, maintenance 10-60 mg/kg/day divided BID-TID (serum levels 50-100 mcg/mL). Broad spectrum efficacy, highly effective for generalized seizures. Metabolism by hepatic glucuronidation with metabolites having anticonvulsant activity. Half-life 8-16 hours. Major limitation: Teratogenicity (neural tube defects 10-20% risk), hyperammonemia, hepatotoxicity, pancreatitis, weight gain, tremor. Regular monitoring of serum levels, LFTs, and ammonia required. Contraindicated in pregnancy (relative contraindication with FDA Pregnancy Category D) and urea cycle disorders. Cost-effective and well-established efficacy.

• Lamotrigine (Lamictal): Maintenance 100-400 mg/day divided BID (serum levels not routinely monitored). Mechanism involves sodium channel blockade and weak glutamate antagonism. Slow titration required due to severe rash risk (Stevens-Johnson syndrome/toxic epidermal necrolysis in 0.3%, benign maculopapular rash in 10%). Initiate 25 mg daily, increase by 25-50 mg weekly. Half-life 24-35 hours. Metabolism via hepatic glucuronidation with reduced clearance in hepatic or renal disease. Advantages: Favorable cognitive profile, weight-neutral, safe in pregnancy (FDA Pregnancy Category C, lower teratogenic risk), effective for mood stabilization. Disadvantages: Complex titration schedule, drug interactions requiring dose adjustment (oral contraceptives reduce lamotrigine levels by 40-60%), phenytoin/phenobarbital induce lamotrigine metabolism.

• Levetiracetam (Keppra): Loading 500 mg BID × 3 days, maintenance 1000-3000 mg/day divided BID. Mechanism involves SV2A binding and modulation of neuronal excitability. Minimal metabolism (90% renal excretion unchanged), no hepatic drug interactions, linear pharmacokinetics allowing flexible dosing without level monitoring. Advantages: Rapid titration (can load acutely in status epilepticus), no drug interactions, no teratogenicity concern (FDA Pregnancy Category C), minimal cognitive effects at therapeutic doses. Disadvantages: Behavioral/psychiatric adverse effects (agitation, suicidality, mood changes) in 10-15% of patients (often reversible upon dose reduction), must monitor for suicidal ideation, contraindicated in severe behavioral disorders.

• Topiramate (Topamax): Maintenance 200-400 mg/day divided BID. Mechanism includes sodium channel blockade, AMPA/kainate receptor antagonism, carbonic anhydrase inhibition, and GABA potentiation. Slow titration 25 mg daily increased by 25-50 mg weekly to minimize cognitive and renal stone risk. Metabolism via hepatic glucuronidation and renal excretion. Advantages: Effective for both focal and generalized seizures, weight loss (unlike valproate), not teratogenic (Category C). Disadvantages: Cognitive dulling (especially at doses >400 mg/day), renal stone risk (1-4%, monitor hydration and electrolytes), hyperchloremic metabolic acidosis, paresthesias common initially. Carbonic anhydrase inhibition explains renal complications; caution in patients with history of

Organ toxicities and their mechanisms

• Phenytoin: gingival hyperplasia (fibroblast proliferation), hirsutism, coarsened facies, and megaloblastic anemia from impaired folate absorption/metabolism. Chronic CYP450 induction accelerates vitamin D catabolism → osteomalacia/osteopenia. Dose-related cerebellar toxicity produces nystagmus → ataxia → dysarthria → sedation as levels rise; zero-order (saturable) kinetics means small dose increases cause disproportionate level jumps. IV phenytoin causes hypotension and bradyarrhythmia (propylene glycol diluent) and purple glove syndrome — fosphenytoin, a water-soluble prodrug, avoids this.
• Carbamazepine: agranulocytosis and aplastic anemia, plus SIADH with hyponatremia (enhanced ADH effect at the collecting duct); oxcarbazepine causes hyponatremia even more often. Potent CYP3A4 inducer with autoinduction of its own metabolism.
• Valproate: idiosyncratic hepatotoxicity (highest risk in children under 2 on polytherapy), pancreatitis, thrombocytopenia, tremor, weight gain, alopecia, and hyperammonemic encephalopathy from carnitine depletion and urea-cycle inhibition — L-carnitine is the specific reversal agent. Contraindicated in pregnancy, urea cycle disorders, and POLG (Alpers) mitochondrial disease.
• Topiramate/zonisamide: carbonic anhydrase inhibition → nephrolithiasis, hyperchloremic non-anion-gap acidosis, oligohidrosis with hyperthermia; topiramate also causes acute angle-closure glaucoma.
• Vigabatrin: irreversible concentric peripheral visual field constriction, mandating an FDA REMS program with periodic perimetry.
• Others: perampanel carries an FDA boxed warning for aggression/homicidal ideation; lacosamide prolongs PR (avoid in high-grade AV block); felbamate causes aplastic anemia and hepatic failure.

Monitoring and reversal

• Required labs: valproate — LFTs, CBC, ammonia; carbamazepine — CBC and sodium; phenytoin — free level when albumin is low or in uremia, since only unbound drug is active.
• Pharmacogenomics: FDA labeling advises *HLA-B\*1502* testing before carbamazepine in patients of Asian ancestry (SJS/TEN risk).
• Class effects: all AEDs carry an FDA warning for suicidal ideation; abrupt withdrawal can precipitate status epilepticus. No antidote exists for most AEDs — care is supportive, with urinary alkalinization for phenobarbital. Flumazenil reverses benzodiazepines but may provoke seizures and is avoided in AED-treated patients.

• Absence seizures: ethosuximide is first-line (T-type calcium channel blockade in thalamic neurons); valproate is preferred only when generalized tonic-clonic seizures coexist. The classic distractor is carbamazepine, phenytoin, gabapentin, or tiagabine — all can worsen absence and myoclonic seizures.
• Phenytoin's zero-order kinetics is the single most tested pharmacokinetic fact: once hepatic hydroxylation saturates, a modest dose increase produces toxicity. A stem with a patient on stable phenytoin who develops nystagmus and ataxia after a small dose increase — or after adding a CYP inhibitor — is testing this.
• Hyponatremia + new anticonvulsant = carbamazepine or oxcarbazepine (SIADH-like effect). Check a sodium before blaming the seizure disorder.
• Rash on lamotrigine: stop the drug immediately; risk of SJS/TEN rises with rapid titration and with concurrent valproate, which inhibits glucuronidation and roughly doubles lamotrigine levels. The best next step in a stem where valproate is added to lamotrigine is to reduce the lamotrigine dose.
• Status epilepticus sequence (American Epilepsy Society guideline): IV benzodiazepine first (lorazepam, or IM midazolam without IV access), then a second-line agent — fosphenytoin, valproate, or levetiracetam, shown to be essentially equivalent in the ESETT trial. Do not skip the benzodiazepine.
• Pregnancy: valproate has the highest risk of neural tube defects and impaired neurodevelopment and should be avoided in people who may become pregnant; lamotrigine and levetiracetam are the preferred alternatives. Supplement folic acid preconception per ACOG. Lamotrigine clearance rises markedly in pregnancy and with estrogen-containing contraceptives — levels fall and seizures may break through.
• Behavioral change on a "clean" drug = levetiracetam (irritability, aggression, depression); pyridoxine supplementation or a switch to brivaracetam is often used.
• Vigabatrin for infantile spasms, especially with tuberous sclerosis — the tested association is irreversible peripheral visual field loss requiring formal perimetry monitoring.