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#separator:tab
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#notetype:Basic
#deck:Antiepileptic Drugs (AEDs)
#tags:pharmacology neurology AED antiepileptic

What are the 6 main mechanisms of action of antiepileptic drugs?	<ol><li><b>Voltage-gated Na⁺ channel blockade</b></li><li><b>T-type Ca²⁺ channel blockade</b></li><li><b>GABA enhancement</b> (receptor potentiation, reuptake block, or metabolism inhibition)</li><li><b>Glutamate receptor blockade</b> (NMDA, AMPA)</li><li><b>SV2A synaptic vesicle modulation</b></li><li><b>α2δ Ca²⁺ channel subunit blockade</b></li></ol>
Which AEDs act by blocking voltage-gated sodium channels?	<b>Phenytoin, Carbamazepine, Oxcarbazepine, Eslicarbazepine, Lamotrigine, Lacosamide, Valproate (partial), Zonisamide, Rufinamide, Felbamate (partial)</b><br><br>Mnemonic: <i>"Please Call Lola – Very Lazy, Often Eats Zucchini, Ruining Felbamate's Reputation"</i>
What is the unique mechanism of lacosamide compared to other Na⁺ channel blockers?	Lacosamide enhances <b>slow inactivation</b> of voltage-gated Na⁺ channels (not fast inactivation like phenytoin/carbamazepine).<br>This reduces repetitive neuronal firing with less effect on normal neurotransmission.
Which AEDs act via T-type calcium channel blockade?	<b>Ethosuximide</b> (primary mechanism) and <b>Valproate</b> (partial)<br><br>T-type Ca²⁺ channels drive thalamic pacemaker oscillations → responsible for <b>absence seizures</b>
What is the mechanism of action of levetiracetam?	Binds <b>SV2A</b> (synaptic vesicle glycoprotein 2A) on presynaptic vesicles → reduces vesicular neurotransmitter release<br><br>Mnemonic: <i>"racetam = race to the vesicle"</i>
What is the mechanism of action of gabapentin and pregabalin?	Bind the <b>α2δ subunit</b> of voltage-gated Ca²⁺ channels → reduce presynaptic Ca²⁺ influx → reduce neurotransmitter release<br><br>⚠️ Despite having GABA in the name, they do <b>NOT</b> act on GABA receptors
How do benzodiazepines differ from barbiturates in their GABA-A mechanism?	<b>Benzodiazepines</b>: increase <b>FREQUENCY</b> of Cl⁻ channel opening<br><b>Barbiturates</b>: increase <b>DURATION</b> of Cl⁻ channel opening<br><br>Mnemonic: <i>"Benzo = Frequency, Barb = Duration"</i> (B before D alphabetically)
What is the mechanism of vigabatrin?	<b>Irreversible inhibitor of GABA-transaminase (GABA-T)</b> → prevents GABA breakdown → increases synaptic GABA levels<br><br>Mnemonic: <i>"VIGAbatrin → Very Irrevocably Gorges on GABA-T"</i>
What is the mechanism of tiagabine?	Blocks <b>GABA reuptake transporter (GAT-1)</b> → increases synaptic GABA concentration<br><br>Think: "like an SSRI, but for GABA"
What is the mechanism of valproate?	<b>Multiple mechanisms:</b><ol><li>Na⁺ channel blockade</li><li>T-type Ca²⁺ channel blockade</li><li>Enhances GABA (increases synthesis, inhibits catabolism)</li><li>NMDA receptor inhibition</li></ol>Truly "broad spectrum" because it hits everything.
What is the drug of choice for absence seizures?	<b>Ethosuximide</b> (first-line)<br><b>Valproate</b> (second-line, or if mixed seizure types)<br><br>⚠️ Carbamazepine and phenytoin can <b>WORSEN</b> absence seizures
What is the drug of choice for juvenile myoclonic epilepsy (JME)?	<b>Valproate</b> (first-line in males and non-pregnant females)<br><b>Levetiracetam</b> or <b>Lamotrigine</b> (if valproate not suitable, e.g., women of childbearing age)
What is the treatment sequence for status epilepticus?	<b>1st line:</b> <b>Lorazepam</b> IV (or diazepam)<br><b>2nd line:</b> <b>Phenytoin/Fosphenytoin</b> or <b>Levetiracetam</b> or Valproate IV<br><b>3rd line (refractory):</b> Propofol, midazolam infusion, or phenobarbital<br><br>Mnemonic: <i>"LAPSE" – Lorazepam Always Precedes Second-line Emergency</i>
What is the drug of choice for infantile spasms (West syndrome)?	<b>Vigabatrin</b> + <b>ACTH</b> (adrenocorticotropic hormone)<br><br>Mnemonic: <i>"VIGorous ACTHion for infantile spasms"</i>
Which AED is the drug of choice for trigeminal neuralgia?	<b>Carbamazepine</b><br><br>Also used for: bipolar disorder (mood stabilizer), focal seizures
Which AEDs are "broad spectrum" (effective for both focal AND generalized seizures)?	<b>Valproate, Lamotrigine, Levetiracetam, Topiramate, Zonisamide, Lacosamide</b><br><br>Mnemonic: <i>"VaLe, LeVeL, ToZ, LaCo"</i>
Which AEDs are "narrow spectrum" and can WORSEN absence/myoclonic seizures?	<b>Carbamazepine, Phenytoin, Oxcarbazepine, Gabapentin, Pregabalin, Tiagabine</b><br><br>⚠️ Never use narrow-spectrum AEDs as monotherapy when absence or JME is suspected
What are the unique (signature) side effects of phenytoin?	<ul><li><b>Gingival hyperplasia</b></li><li><b>Hirsutism</b></li><li>Coarsening of facial features</li><li>Nystagmus, ataxia, diplopia (toxicity)</li><li>Peripheral neuropathy (long-term)</li><li>Osteoporosis</li><li>Nonlinear (saturable) pharmacokinetics</li></ul>Mnemonic: <i>"PHENYToin = PHYsically ugly"</i>
What is the unique pharmacokinetics of phenytoin?	<b>Zero-order (nonlinear/saturable) kinetics</b> at therapeutic levels<br>→ Once plasma levels exceed ~10 µg/mL, small dose increases cause <b>disproportionately large</b> rises in levels and toxicity<br>→ Half-life increases as levels rise (12–36 h)
What are the unique (signature) side effects of carbamazepine?	<ul><li><b>SIADH → Hyponatremia</b></li><li><b>Stevens-Johnson Syndrome (SJS)</b> – especially HLA-B*1502 (South/East Asian patients)</li><li>Aplastic anemia (rare)</li><li>Diplopia, ataxia</li><li>Autoinduction of own metabolism</li></ul>Mnemonic: <i>"Carba-WATER-zepine" (dilutes sodium)</i>
What is autoinduction and which AED is famous for it?	<b>Carbamazepine</b> induces its own metabolism (CYP3A4)<br>→ Doses adequate at start of therapy become subtherapeutic after <b>weeks</b> as enzyme activity builds up<br>→ Requires dose increases after initial stabilization
What are the unique (signature) side effects of valproate?	<ul><li><b>Teratogenicity</b> (neural tube defects, cognitive impairment in offspring)</li><li><b>Hepatotoxicity</b> (especially children under 2 on polytherapy)</li><li>Weight gain</li><li>Tremor</li><li>Hair loss (alopecia)</li><li>Pancreatitis</li><li>Thrombocytopenia</li></ul>Mnemonic: <i>"Valpro = Valuable but FAT, HAIRY-less, and DANGEROUS in pregnancy"</i>
What are the teratogenic risks of valproate specifically?	<ul><li><b>Neural tube defects</b> (spina bifida) – ~1–2%</li><li><b>Cognitive impairment</b> in offspring (IQ reduction)</li><li>Major malformation rate: <b>6–11%</b> (highest of all AEDs)</li><li>Fetal valproate syndrome: midface hypoplasia, limb defects</li></ul>⚠️ Avoid in women of childbearing age if possible; use folate 4–5 mg/day if must use
What is the most teratogenic AED? What is the safest?	<b>Most teratogenic: Valproate</b> (6–11% major malformation rate)<br><b>Relatively safest: Lamotrigine and Levetiracetam</b><br><br>⚠️ No AED is entirely safe in pregnancy. All patients should take <b>folate 4–5 mg/day</b>
What are the unique (signature) side effects of lamotrigine?	<ul><li><b>Stevens-Johnson Syndrome (SJS) / Toxic Epidermal Necrolysis (TEN)</b><br>→ Risk increased by: rapid dose titration + valproate co-administration</li><li>Headache, dizziness</li></ul>Mnemonic: <i>"LAMOtrigine = LAMEntable skin"</i><br><br>⚠️ Always titrate SLOWLY, especially with valproate
What are the unique (signature) side effects of levetiracetam?	<ul><li><b>Irritability, mood disturbance</b></li><li><b>Depression, psychosis</b> (rare)</li><li>Behavioral changes ("levetiracetam rage")</li></ul>Mnemonic: <i>"LEVEtiracetam = LEVEl your rage"</i><br>Advantage: virtually no pharmacokinetic interactions
What are the unique (signature) side effects of topiramate?	<ul><li><b>Cognitive slowing</b> – word-finding difficulty ("Dopamax")</li><li><b>Nephrolithiasis</b> (kidney stones) – carbonic anhydrase inhibition</li><li><b>Weight loss</b></li><li>Metabolic acidosis</li><li>Paraesthesias</li></ul>Mnemonic: <i>"Topiramate = TOP stupidity + kidney TOPaz stones + TOPpling weight"</i>
What are the unique (signature) side effects of vigabatrin?	<b>Irreversible, concentric visual field constriction</b> (retinal toxicity/peripheral vision loss)<br><br>→ Up to 30–40% of patients develop visual field defects<br>→ Must monitor with perimetry regularly<br><br>Mnemonic: <i>"VIGAbatrin → VIsion Gone"</i>
What are the side effects of gabapentin and pregabalin?	<ul><li>Sedation, dizziness</li><li><b>Weight gain</b></li><li>Peripheral edema</li><li>Ataxia</li></ul>Both require dose reduction in <b>renal impairment</b> (renally excreted)
Which AEDs are hepatic enzyme INDUCERS?	<b>Carbamazepine, Phenytoin, Phenobarbital, Primidone</b> (also oxcarbazepine – mild)<br><br>Mnemonic: <i>"Carb Please Permit Barb to Induce"</i><br><br>Consequence: reduce levels of OCP, warfarin, other drugs
Which AED is a hepatic enzyme INHIBITOR?	<b>Valproate</b> (only classic AED that inhibits enzymes)<br><br>→ Increases levels of: phenytoin, phenobarbital, lamotrigine (doubles lamotrigine t½!)<br><br>Mnemonic: <i>"VALproate = VALidly INhibits"</i>
Which AEDs have minimal/no pharmacokinetic drug interactions?	<b>Levetiracetam</b> (drug of choice for polypharmacy patients)<br><b>Gabapentin, Pregabalin, Lacosamide</b> also minimal interactions<br><br>Why levetiracetam? Minimal protein binding, minimal hepatic metabolism, renal excretion unchanged
How does valproate interact with lamotrigine?	Valproate <b>inhibits glucuronidation</b> of lamotrigine → <b>doubles</b> lamotrigine half-life<br>→ Risk of <b>SJS</b> increases greatly<br>→ Must start lamotrigine at <b>half the normal dose</b> and titrate even more slowly
How does valproate interact with phenytoin?	Valproate <b>displaces phenytoin from plasma proteins</b> → increased free (active) phenytoin<br>→ <b>Phenytoin toxicity</b> despite normal total levels<br>→ Measure <b>free phenytoin</b> levels if co-administering
Which AEDs require dose reduction in renal impairment (CKD)?	<b>Levetiracetam, Gabapentin, Pregabalin, Topiramate (partial)</b><br><br>Mnemonic: <i>"LEGS need adjustment in renal failure"</i><br>L=Levetiracetam, E=Everything gabapentinoid, G=Gabapentin, S=Some topiramate
What effect do enzyme-inducing AEDs have on oral contraceptives?	Reduce OCP plasma levels via CYP450 induction → <b>contraceptive failure</b><br><br>Affected drugs: Carbamazepine, Phenytoin, Phenobarbital, Primidone<br><br>→ Use higher-dose OCP or alternative contraception (IUD preferred)
What effect do AEDs have on bone health?	Most AEDs (especially enzyme inducers) increase risk of <b>osteoporosis and fracture</b><br><br>Mechanism: CYP450 induction → increased vitamin D degradation → reduced Ca²⁺ absorption<br><br>Management: Calcium + Vitamin D supplementation; periodic DEXA scan
What is the class-wide FDA warning for all AEDs?	All AEDs carry an <b>FDA black-box warning for increased risk of suicidality</b> (suicidal ideation and behavior)<br><br>Applies to patients with epilepsy AND psychiatric conditions
What are the pharmacokinetics of levetiracetam?	<ul><li>Oral bioavailability: &gt;95%</li><li>Minimal protein binding (&lt;10%)</li><li>Minimal hepatic metabolism (hydrolysed in blood)</li><li>Excreted <b>unchanged</b> in urine (~66%)</li><li>t½: 6–11 h</li><li>No significant drug interactions</li></ul>
What is the half-life of phenobarbital and what does this mean clinically?	t½ = <b>80–120 hours</b> (very long)<br>→ Once-daily dosing<br>→ Takes <b>weeks</b> to reach steady state<br>→ Also takes weeks to clear after stopping (useful in neonatal seizures, longer time window)<br>→ Slow titration needed
What is the role of carbamazepine epoxide and why does it matter clinically?	Carbamazepine is metabolized to <b>carbamazepine-10,11-epoxide</b>, which is pharmacologically active and contributes to toxicity<br><br>Valproate inhibits epoxide hydrolase → <b>epoxide accumulates</b> → toxicity even with normal carbamazepine levels<br>→ Measure epoxide separately if unexplained toxicity
What is the mechanism and use of ethosuximide?	<b>Mechanism:</b> T-type Ca²⁺ channel blocker (reduces thalamic pacemaker bursting)<br><b>Use:</b> <b>Absence seizures ONLY</b><br><b>Not effective for</b> focal or tonic-clonic seizures<br><br>Mnemonic: <i>"Ethosux... absence only, other seizures suck for it"</i>
What is the mechanism, use, and key side effect of perampanel?	<b>Mechanism:</b> Selective non-competitive antagonist at postsynaptic <b>AMPA receptors</b> (blocks glutamate excitation)<br><b>Use:</b> Adjunctive therapy for focal and primary generalized tonic-clonic seizures<br><b>Side effects:</b> Dizziness, somnolence, behavioral/psychiatric effects<br><b>Dosing:</b> Once daily (long t½ ~105 h)
What are the indications for topiramate beyond epilepsy?	<ol><li><b>Migraine prophylaxis</b></li><li><b>Weight loss</b> (combined with phentermine as Qsymia)</li><li>Binge eating disorder</li></ol>
What are the indications for valproate beyond epilepsy?	<ol><li><b>Bipolar disorder</b> (mood stabilizer)</li><li><b>Migraine prophylaxis</b></li><li>Schizoaffective disorder (adjunctive)</li></ol>
What are the indications for gabapentin and pregabalin beyond epilepsy?	<b>Gabapentin:</b><ol><li>Neuropathic pain (diabetic neuropathy, post-herpetic neuralgia)</li><li>Restless legs syndrome</li></ol><b>Pregabalin:</b><ol><li>Neuropathic pain</li><li>Generalized anxiety disorder (GAD)</li><li>Fibromyalgia</li></ol>
What is the mechanism behind AED-associated SJS/TEN and which drugs most commonly cause it?	Mechanism: Immune-mediated (T-cell) reaction to drug-protein hapten complexes → keratinocyte apoptosis<br><br><b>Most common AED causes:</b> Carbamazepine, Lamotrigine, Phenytoin, Oxcarbazepine<br><br>Risk factors: HLA-B*1502 (carbamazepine in South/East Asian patients) — mandatory genetic screening before prescribing carbamazepine in these populations
Summarize the AED drug of choice for each seizure type in one line each.	<table><tr><th>Seizure Type</th><th>Drug of Choice</th></tr><tr><td>Absence</td><td>Ethosuximide</td></tr><tr><td>JME</td><td>Valproate / Levetiracetam</td></tr><tr><td>Focal</td><td>Carbamazepine / Levetiracetam</td></tr><tr><td>Generalized TC</td><td>Valproate / Lamotrigine / LEV</td></tr><tr><td>Status epilepticus</td><td>Lorazepam → Phenytoin/LEV</td></tr><tr><td>Infantile spasms</td><td>Vigabatrin + ACTH</td></tr><tr><td>Trigeminal neuralgia</td><td>Carbamazepine</td></tr><tr><td>Neuropathic pain</td><td>Gabapentin / Pregabalin</td></tr><tr><td>Migraine prophylaxis</td><td>Valproate / Topiramate</td></tr></table>
What is the first drug to use in a patient with epilepsy on multiple medications (polytherapy) where drug interactions are a concern?	<b>Levetiracetam</b><br><br>Reasons:<ul><li>No hepatic enzyme induction or inhibition</li><li>Minimal protein binding</li><li>No significant interactions with chemotherapy, anticoagulants, or other AEDs</li></ul>
What AED should be AVOIDED in young women of childbearing age, and why?	<b>Valproate</b><br><br>Reasons:<ul><li>Highest teratogenic risk (6–11% malformation rate)</li><li>Neural tube defects</li><li>Cognitive impairment in offspring</li></ul>Alternatives: Lamotrigine, Levetiracetam (if monotherapy needed)
Name the AED associated with each mnemonic: (1) "Dopamax" (2) "Carba-WATER-zepine" (3) "VIsion Gone" (4) "PHYsically ugly"	<ol><li>"Dopamax" = <b>Topiramate</b> (cognitive slowing)</li><li>"Carba-WATER-zepine" = <b>Carbamazepine</b> (hyponatremia/SIADH)</li><li>"VIsion Gone" = <b>Vigabatrin</b> (retinal toxicity)</li><li>"PHYsically ugly" = <b>Phenytoin</b> (gingival hyperplasia, hirsutism, coarse features)</li></ol>
What is the mechanism of action of phenobarbital? What seizures is it used for?	<b>Mechanism:</b> Enhances GABA-A receptor function by increasing duration of Cl⁻ channel opening; at high doses, directly opens Cl⁻ channels<br><b>Indications:</b> Focal + generalized tonic-clonic seizures; neonatal seizures; status epilepticus (2nd/3rd line)<br><b>Side effects:</b> Sedation, cognitive dulling, paradoxical hyperactivity in children, tolerance, dependence
What is fosphenytoin and when is it used?	<b>Fosphenytoin</b> is a water-soluble <b>prodrug of phenytoin</b><br>→ Rapidly converted to phenytoin in vivo<br><b>Advantages over IV phenytoin:</b><ul><li>Can be given IM</li><li>Faster IV administration (less cardiovascular risk)</li><li>No propylene glycol vehicle → less hypotension/arrhythmia</li></ul><b>Used for:</b> Status epilepticus (IV/IM), acute seizure management
How is AED blood level monitoring used clinically?	<b>Useful for:</b> Phenytoin (narrow TI, nonlinear kinetics), carbamazepine, phenobarbital, valproate<br><br><b>Free drug levels</b> should be measured in:<ul><li>Hypoalbuminemia</li><li>Renal failure (uremia alters protein binding)</li><li>Suspected drug interactions displacing from proteins</li></ul><br>Levetiracetam, gabapentin, lamotrigine: levels less routinely monitored
What is the monitoring required for patients on vigabatrin?	Regular <b>visual field testing (perimetry)</b><br>→ Due to risk of irreversible concentric visual field constriction (peripheral vision loss)<br>→ Monitoring frequency: every 3–6 months during treatment<br>→ The visual toxicity is dose-related and usually irreversible
What folate supplementation is recommended for pregnant women on AEDs?	<b>4–5 mg/day</b> of folic acid (high-dose)<br><br>Rationale: Enzyme-inducing AEDs (carbamazepine, phenytoin, phenobarbital) reduce folate levels → increased risk of neural tube defects<br><br>⚠️ Start BEFORE conception ideally
What is the significance of HLA-B*1502 in AED prescribing?	<b>HLA-B*1502</b> allele is associated with <b>carbamazepine-induced SJS/TEN</b><br>→ Predominantly in <b>South and Southeast Asian</b> populations (Han Chinese, Thai, Malaysian)<br><b>Clinical implication:</b> Screen for HLA-B*1502 before prescribing carbamazepine in Asian patients<br>Also relevant: HLA-A*3101 (carbamazepine hypersensitivity in Europeans/Japanese)
Which AEDs are safe to use as monotherapy in absence epilepsy and which are contraindicated?	<b>Safe (first-line):</b> Ethosuximide, Valproate, Lamotrigine<br><br><b>Contraindicated/worsen absence:</b> Carbamazepine, Phenytoin, Oxcarbazepine, Gabapentin, Tiagabine, Vigabatrin<br><br>⚠️ These drugs can precipitate or worsen absence and myoclonic seizures
What AED can be used for both epilepsy AND bipolar disorder AND migraine?	<b>Valproate (Valproic acid / Divalproex sodium)</b><br><br>Triple role:<ul><li>Broad-spectrum AED</li><li>Mood stabilizer in bipolar disorder</li><li>Migraine prophylaxis</li></ul>
What is the mechanism of action of rufinamide?	<b>Na⁺ channel blocker</b> (limits sustained firing) with additional mechanisms<br><b>Use:</b> Adjunctive therapy for <b>Lennox-Gastaut syndrome</b> (drop attacks)<br><b>Pharmacokinetics:</b> t½ 6–10 h; well absorbed (&gt;85%); minimal protein binding (35%)
What drugs are used for Lennox-Gastaut syndrome?	<ul><li><b>Valproate</b></li><li><b>Topiramate</b></li><li><b>Rufinamide</b></li><li><b>Clobazam</b></li><li><b>Lamotrigine</b> (reduces drop attacks)</li><li><b>Felbamate</b> (reserved – hepatotoxicity/aplastic anemia risk)</li></ul>
What is the clinical significance of carbamazepine-induced SIADH?	Carbamazepine stimulates ADH secretion → <b>syndrome of inappropriate ADH (SIADH)</b> → dilutional <b>hyponatremia</b><br><br>→ Can cause confusion, seizures, nausea, coma if severe<br>→ Monitor serum sodium (Na⁺), especially in elderly<br>→ Oxcarbazepine causes hyponatremia more frequently than carbamazepine
Compare levetiracetam and brivaracetam.	Both are <b>SV2A ligands</b> with similar mechanisms<br><br><b>Brivaracetam advantages:</b><ul><li>Higher affinity for SV2A</li><li>Less behavioral/psychiatric side effects than levetiracetam</li><li>Fewer drug interactions</li></ul><b>Levetiracetam:</b> More widely used, well-established efficacy data
What is the general principle for starting antiepileptic therapy?	<ul><li>Start with <b>monotherapy</b> at a low dose</li><li>Titrate up slowly</li><li>Prefer <b>once or twice daily dosing</b> for adherence</li><li>70% patients controlled with medications</li><li>~50% respond to first agent</li><li>3rd+ agent adds very little benefit</li><li>Combination of some newer drugs may be more successful than older polytherapy</li></ul>
When is it appropriate to discontinue AEDs?	After <b>2–5 seizure-free years</b> (depending on epilepsy type/syndrome)<br><br>Factors favoring discontinuation: single seizure type, normal EEG, normal MRI, seizure-free &gt;2 years<br><br>Factors against: JME (high relapse rate ~90%), abnormal MRI, abnormal EEG, symptomatic epilepsy<br><br>Taper slowly over <b>months</b> to avoid withdrawal seizures

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