Antiepileptic Drugs (AEDs)

Classification of Seizures (ILAE)

Seizure Type Details

• Tonic-clonic (Grand mal): Loss of consciousness → sustained muscle contraction (tonic) → rhythmic jerking (clonic). Post-ictal confusion and exhaustion.
• Absence (Petit mal): Brief (3-5 sec) abrupt loss of consciousness with eye blinking. Onset at 3-5 years. Classic 3/sec spike-and-wave on EEG.
• Myoclonic: Brief jerks, usually after waking. Occur in Juvenile Myoclonic Epilepsy (JME), Dravet syndrome.
• Atonic (Drop attacks): Sudden loss of muscle tone - seen in Lennox-Gastaut syndrome.
• Tonic: Extension muscle rigidity, <60 seconds.

Mechanisms of Action of AEDs

1. Blocking voltage-gated Na⁺ channels - reduce repetitive high-frequency neuronal firing
2. Blocking voltage-gated Ca²⁺ channels (T-type) - specifically for absence seizures
3. Enhancing GABAergic inhibition - increase Cl⁻ influx or reduce GABA breakdown
4. Blocking glutamate (excitatory) transmission - AMPA or NMDA receptor antagonism

Individual Drugs

1. Phenytoin (Dilantin)

• Mechanism: Blocks voltage-gated Na⁺ channels (use-dependent/frequency-dependent block). Prolongs inactivation state.
• Uses: Focal seizures, tonic-clonic seizures, status epilepticus (IV fosphenytoin), not for absence
• Pharmacokinetics:
  • Zero-order (saturation) kinetics at therapeutic doses - small dose increase → large rise in plasma levels
  • Highly protein-bound (~90%)
  • Enzyme inducer (CYP2C9, CYP2C19, CYP3A4)
• Adverse effects:
  • Dose-related: Nystagmus (earliest), ataxia, diplopia, sedation, cognitive impairment
  • Chronic: Gingival hyperplasia, hirsutism, coarsening of facial features, peripheral neuropathy, megaloblastic anemia (folate deficiency), osteomalacia
  • Idiosyncratic: Stevens-Johnson syndrome (SJS), hypersensitivity, lupus-like syndrome
  • IV: Cardiovascular depression, hypotension - use fosphenytoin (water-soluble prodrug) to avoid this
• Teratogenicity: Fetal hydantoin syndrome (cleft palate, cardiac defects, digit abnormalities)

2. Carbamazepine (Tegretol)

• Mechanism: Blocks voltage-gated Na⁺ channels (use-dependent)
• Uses:
  • Drug of choice for focal (partial) seizures and tonic-clonic
  • Also: Trigeminal neuralgia (drug of choice), bipolar disorder
  • NOT used in absence or myoclonic (may worsen)
• Pharmacokinetics:
  • Auto-induction of its own metabolism (CYP3A4) - levels fall after 3-4 weeks
  • Active metabolite: carbamazepine-10,11-epoxide
  • Enzyme inducer - reduces levels of OCP, warfarin, other AEDs
• Adverse effects:
  • CNS: diplopia, dizziness, ataxia
  • GI: nausea
  • SIADH (hyponatremia) - common
  • Leukopenia, agranulocytosis (monitor CBC)
  • SJS/TEN - especially in HLA-B*1502 positive patients (Southeast Asian genetic screen recommended before use)
  • Aplastic anemia (rare)
• Drug of choice: Focal seizures

3. Valproic Acid / Sodium Valproate (Depakote, Epilim)

• Mechanism: Multiple - blocks Na⁺ channels, blocks T-type Ca²⁺ channels, increases GABA (inhibits GABA transaminase)
• Uses:
  • Broadest spectrum AED - effective for ALL seizure types (tonic-clonic, absence, myoclonic, focal)
  • Drug of choice: Juvenile Myoclonic Epilepsy (JME)
  • Also: Migraine prophylaxis, bipolar disorder
• Pharmacokinetics:
  • Enzyme inhibitor (opposite of carbamazepine and phenytoin) - raises levels of other AEDs (e.g., lamotrigine levels can double)
  • Highly protein-bound
  • Metabolized by glucuronidation and mitochondrial beta-oxidation
• Adverse effects:
  • GI: nausea, vomiting (give enteric-coated)
  • Weight gain
  • Hair loss (alopecia) - may regrow curly
  • Tremor
  • Hepatotoxicity - rare but fatal; highest risk in children <2 years on polytherapy
  • Pancreatitis - rare
  • Neural tube defects (spina bifida) - 1-2% risk; AVOID in pregnancy (most teratogenic AED)
  • Polycystic ovarian syndrome with long-term use
  • Hyperammonemic encephalopathy (especially with topiramate co-use)
• Contraindicated: Pregnancy, hepatic disease, urea cycle disorders

4. Phenobarbital

• Mechanism: Enhances GABA_A receptor activity - prolongs Cl⁻ channel opening duration (vs. benzodiazepines which increase frequency)
• Uses:
  • Tonic-clonic, focal seizures
  • Status epilepticus (IV/IM)
  • Neonatal seizures
  • Febrile convulsions (prophylaxis - though no longer recommended routinely)
• Pharmacokinetics:
  • Long half-life (~80-100 hours) - once daily dosing
  • Major enzyme inducer (CYP1A2, CYP2C9, CYP3A4)
• Adverse effects:
  • Sedation, cognitive impairment (limits use)
  • Dependence and tolerance
  • Hyperactivity in children (paradoxical)
  • Megaloblastic anemia (folate deficiency)
  • Osteomalacia (Vitamin D deficiency via enzyme induction)
  • Respiratory depression in overdose

5. Ethosuximide (Zarontin)

• Mechanism: Blocks T-type Ca²⁺ channels in thalamic neurons - interrupts the oscillatory firing underlying absence seizures
• Uses:
  • Drug of choice for absence seizures (petit mal) in children
  • Effective ONLY for absence - no effect on tonic-clonic
• Adverse effects:
  • GI: nausea, vomiting, anorexia (most common - take with food)
  • CNS: headache, dizziness, hiccups
  • Lupus-like syndrome
  • Blood dyscrasias (leukopenia, aplastic anemia - rare)
• Note: If a patient has BOTH absence + tonic-clonic seizures, use valproate (not ethosuximide) - Lippincott, Ch. 19

6. Benzodiazepines (Diazepam, Lorazepam, Clonazepam, Clobazam)

• Mechanism: Enhance GABA_A receptor activity - increase frequency of Cl⁻ channel opening (vs. barbiturates which increase duration)
• Uses:

• Adverse effects: Sedation, tolerance, dependence, respiratory depression
• Tolerance develops rapidly to antiepileptic effect of clonazepam - limits long-term use

7. Lamotrigine (Lamictal)

• Mechanism: Blocks voltage-gated Na⁺ channels; also blocks Ca²⁺ channels; reduces glutamate release
• Uses: Broad spectrum - focal seizures, generalized tonic-clonic, absence, Lennox-Gastaut, bipolar disorder
• Pharmacokinetics:
  • Metabolized by glucuronidation
  • Half-life affected greatly by co-medications: Valproate doubles lamotrigine levels (inhibits glucuronidation) → start very low; Enzyme inducers (carbamazepine, phenytoin) halve levels
• Adverse effects:
  • Steven-Johnson Syndrome (SJS) - serious risk especially if dose escalated too fast or used with valproate (titrate slowly!)
  • Dizziness, diplopia, headache, ataxia
  • Generally well-tolerated; weight-neutral
  • Relatively safer in pregnancy compared to valproate

8. Gabapentin (Neurontin) & Pregabalin (Lyrica)

• Mechanism: Bind to α2-δ subunit of voltage-gated Ca²⁺ channels → reduce Ca²⁺ influx → reduce neurotransmitter release (NOT related to GABA despite the name)
• Uses:
  • Gabapentin: Adjunctive for focal seizures; neuropathic pain, postherpetic neuralgia, restless legs syndrome
  • Pregabalin: Same as gabapentin + generalized anxiety disorder, fibromyalgia
• Pharmacokinetics: Not metabolized, excreted unchanged by kidney - dose adjust in renal failure; no drug interactions (no enzyme effects)
• Adverse effects: Sedation, dizziness, ataxia, weight gain, peripheral edema

9. Topiramate (Topamax)

• Mechanism: Multiple - blocks Na⁺ channels, enhances GABA_A, blocks AMPA/kainate glutamate receptors, inhibits carbonic anhydrase
• Uses: Focal seizures, tonic-clonic, Lennox-Gastaut, migraine prophylaxis (second-line)
• Adverse effects:
  • Cognitive impairment/word-finding difficulty ("Dope-a-max") - most troublesome
  • Weight loss (unlike most AEDs)
  • Kidney stones (carbonic anhydrase inhibition → metabolic acidosis → hypocitraturia)
  • Glaucoma (acute angle-closure)
  • Teratogenic (oral cleft risk)

10. Levetiracetam (Keppra)

• Mechanism: Binds SV2A (synaptic vesicle protein 2A) → modulates neurotransmitter release
• Uses: Focal seizures, myoclonic seizures (JME), generalized tonic-clonic; increasingly used as first-line due to favorable profile
• Pharmacokinetics: Minimal protein binding, mostly renally excreted, minimal drug interactions
• Adverse effects: Sedation, dizziness; behavioral/psychiatric effects - irritability, aggression, depression (most notable)

11. Oxcarbazepine (Trileptal) & Eslicarbazepine

• Mechanism: Blocks voltage-gated Na⁺ channels (similar to carbamazepine but no auto-induction)
• Uses: Focal seizures (preferred over carbamazepine in many centers due to better tolerability)
• Advantages over carbamazepine: Less enzyme induction, no auto-induction, no active epoxide metabolite
• Adverse effects: Dizziness, diplopia; hyponatremia (SIADH) - more prominent than carbamazepine; rash

12. Lacosamide (Vimpat)

• Mechanism: Enhances slow inactivation of voltage-gated Na⁺ channels (unique mechanism among Na⁺ channel blockers)
• Uses: Focal seizures (adjunctive and monotherapy)
• Adverse effects: Dizziness, diplopia, nausea, PR interval prolongation (cardiac monitoring needed)

13. Vigabatrin (Sabril)

• Mechanism: Irreversible inhibitor of GABA transaminase → increases GABA levels
• Uses: Infantile spasms (West syndrome) - drug of choice; adjunctive for refractory focal seizures
• Major ADR: Permanent visual field defects (concentric peripheral vision loss due to retinal toxicity) - mandatory visual field monitoring

14. Zonisamide (Zonegran)

• Mechanism: Blocks Na⁺ and T-type Ca²⁺ channels; also carbonic anhydrase inhibitor
• Uses: Focal seizures (adjunctive); Dravet syndrome, myoclonic
• Adverse effects: Kidney stones, cognitive effects, weight loss, anhydrosis (no sweating - especially in children)

Drug of Choice Summary

Teratogenicity of AEDs

• All pregnant women on AEDs should receive folic acid 5 mg/day (high dose)
• Vitamin K supplementation for mother before delivery (enzyme inducers deplete Vit K → neonatal hemorrhage)

Drug Interactions (Key)

• Enzyme Inducers (increase metabolism of other drugs): Phenytoin, Carbamazepine, Phenobarbital, Primidone → reduce levels of OCP, warfarin, other AEDs
• Enzyme Inhibitors: Valproate → increases lamotrigine levels (double), inhibits phenobarbital metabolism
• Valproate + Lamotrigine = highest SJS risk; start lamotrigine at 25 mg alternate days and titrate slowly

Status Epilepticus Management (Stepwise)

1. Immediate (0-5 min): IV Lorazepam 0.1 mg/kg (or Diazepam 0.1-0.2 mg/kg IV/rectal)
2. 5-30 min (if seizure continues): IV Fosphenytoin 20 mg PE/kg OR IV Valproate OR IV Levetiracetam
3. Refractory (>30 min): IV Phenobarbital; consider ICU with IV Midazolam/Propofol infusion

Special Notes from Padmaja Udaykumar's Approach

Note: Padmaja Udaykumar's Clinical Pharmacology textbook is not available in the current library, but the content above is compiled from Lippincott Illustrated Reviews: Pharmacology (Ch. 19 - Drugs for Epilepsy) and Katzung's Basic & Clinical Pharmacology (16e), which cover identical content and are standard references for the same examinations.