Epileptic Drugs

Snapshot

• A 17-year-old man presents with myoclonic seizures followed by generalized a tonic-clonic seizure after awakening. He denies any recent head trauma or substance abuse. He reports to being sleep deprived for the past week due to final examinations. Routine EEG testing is significant for 5-Hz bilateral polyspike and slow wave discharges. Valproic acid is prescribed. (Juvenile myoclonic epilepsy)

Introduction

• Antiepileptic drugs (AED) can be separated by mechanism of action (MOA) affecting the following
  • voltage-gated Na⁺ channels
  • Ca²⁺ channels
  • GABA activity
• Choice of AED is dependent on seizure type, patient, cost, and side-effect profile

Affecting Voltage-Gated Na⁺ Channels

• Phenytoin
  • uses
    • parital (simple and complex)
    • generalized (tonic-clonic)
    • prophylaxis for status epilepticus
  • mechanism
    • blocks voltage-gated Na⁺ channels
      • stops seizure propogation
  • kinetics
    • induction of P450
    • zero-order kinetics with saturation of degradative liver enzymes
  • toxicity
    • nystagmus/ataxia/diplopia
    • sedation/CNS depression
    • SLE-like syndrome
    • gingival hyperplasia   
    • peripheral neuropathy
    • osteopenia
    • megaloblastic anemia (↓ folate absorption)
    • tetratogenic
      • fetal hydantoin syndrome
        • cleft lip and palate
  • notes
    • fosphenytoin for parenteral use
• Carbamazepine
  • uses
    • partial (simple and complex)
    • generalized (tonic-clonic)
  • mechanism
    • ↑ refractory period of voltage-gated Na⁺ channels
      • likely binds to the inactivated state, inhibiting action potential generation
  • kinetics
    • induction of P450
      • reduces its own levels
  • toxicity
    • diplopia/ataxia
    • agranulocytosis
    • aplastic anemia
    • hepatotoxicity
    • SIADH
    • Stevens-Johnson syndrome
    • teratogenic
      • cleft lip and palate
      • spina bifida
  • notes
    • first-line for trigeminal neuralgia
    • also used for bipolar disorders
• Lamotrigine
  • uses
    • partial (simple and complex)
    • generalized (tonic-clonic)
    • absence
  • mechanism
    • blocks voltage-gated Na⁺ channels and glutamate receptors
  • toxicity
• Stevens-Johnson syndrome 
  

Affecting Calcium Channels

• Ethosuximide 
  • uses
    • absence seizures 
  • mechanism
    • blocks thalamic T-type Ca²⁺ channels 
  • toxicity
    • GI distress
    • fatigue
    • headache
• Stevens-Johnson syndrome

Affecting GABA Activity

• Phenobarbital
  • uses
    • partial (simple and complex) in pregnant women and children
    • generalized (tonic-clonic) in pregnant women and children
  • mechanism
    • ↑ GABAA action
  • kinetics
    • induction of P450
    • tolerance/dependence
  • toxicity
    • sedation
• Benzodiazepines
  • uses
    • acute treatment for status epilepticus 
    • alcohol withdrawal syndrome
  • mechanism ↑ GABAA action
  • notes
    • also used for seizures of eclampsia
      • 1st-line is MgSO4
• Tiagabine
  • uses
    • partial (simple and complex)
  • mechanism
    • inhibition of GABA reuptake
• Vigabatrin
  • uses
    • partial (simple and complex)
  • mechanism
• irreversible inhibition of GABA transaminase

Multiple Mechanisms of Action

• Valproic acid
  • uses
    • partial (simple and complex)
    • generalized (tonic-clonic and absence) 
  • mechanism
    • ↑ refractory period of voltage-gated Na⁺ channels
    • ↑ GABA concentration via inhibition of GABA transaminase
    • inhibition of thalamic T-type Ca²⁺ channels
  • toxicity
    • pancreatitis
    • hepatoxicity
      • accumulation of toxic metabolite
    • tetratogenic
      • neural tube defects
    • tremor
    • hyperammonemia
    • thrombocytopenia
    • anemia
    • myelodysplasia
  • notes
    • first-line for myoclonic seizures
    • first-line for juvenile myoclonic epilepsy 
    • can be used as prophylactic treatment for migraines
• Topiramate
  • uses
    • partial (simple and complex)
    • generalized (tonic-clonic)
    • migraine prophylaxis
  • mechanism
    • blocks voltage-gated Na⁺ channels
    • ↑ GABA action
  • toxicity
    • sedation/mental dulling
    • renal stones
• weight loss

Other

• Levetiracetam
  • uses
    • partial (simple and complex)
    • complex (tonic-clonic)
  • mechanism
    • unknown, but does bind to synaptic vesicle protein SV2A, which may modulate synaptic transmission through alteration of vesicle fusion, and may indirectly modulate GABA
• Gabepentin
  • uses
    • partial (simple and complex)
  • mechanims
    • inhibit voltage-gated Ca²⁺ channel via α2δ subunit
    • structurally similar to GABA
  • toxicity
    • sedation
    • ataxia
  • notes
    • also used for peripheral neuropathy/neuropathic pain