Lecture: Pharmacology of Antiepileptic Drugs

Introduction

• Primary use of antiepileptic drugs is to prevent or control epilepsy (seizures).
• Seizures: Sudden burst of uncontrolled electrical activity in the brain due to excessive neuronal activity.
• Types of Seizures:
  • Focal Seizures: Begin in one hemisphere, may or may not impair awareness.
  • Generalized Seizures: Affect both hemispheres, usually cause loss of consciousness.

Basic Mechanisms of Seizures

• Imbalance: Result from too little inhibition or too much excitation.
• Neuron Communication: Occurs through action potentials, involving ion channels.
  • Action Potential: Triggered by voltage-gated sodium channels allowing Na+ influx.
  • Calcium Channels: High-voltage-activated channels allow Ca2+ entry, triggering glutamate release.
  • Glutamate Receptors: AMPA (Na+ entry) and NMDA (Ca2+ entry) receptors on postsynaptic neurons.
  • Inhibitory Neurons: Release GABA, bind to GABA-A receptors to allow Cl- entry, causing hyperpolarization (inhibition).
  • GABA Reuptake and Degradation: Involves GAT-1 reuptake and GABA-T degradation.

Pharmacology of Antiepileptic Drugs

Goals

• Lower neuronal excitability.
• Enhance neuronal inhibition.

Mechanisms and Drugs

1. Sodium Channel Blockers
   • Drugs: Carbamazepine, Oxcarbazepine, Lamotrigine, Phenytoin, Topiramate, Valproic acid, Zonisamide.
2. Calcium Channel Blockers
   • High-voltage: Lamotrigine, Topiramate.
   • Low-voltage (T-type): Valproic acid, Zonisamide.
   • Additional Actions: Some drugs block sodium channels and AMPA receptors.
3. Unique Mechanisms
   • Gabapentin & Pregabalin: Bind to alpha-2-delta-1 subunit, reducing neurotransmitter release.
   • Levetiracetam: Binds SV2A protein, impairing glutamate release.
   • Felbamate: Blocks NMDA receptors.
4. GABA System Modulators
   • Benzodiazepines & Barbiturates: Bind to GABA-A receptors, enhancing Cl- influx.
   • Tiagabine: Inhibits GABA reuptake.
   • Vigabatrin: Inhibits GABA-T, increasing GABA levels.

Side Effects

• General: Sedation, dizziness.
• Specific Drugs:
  • Carbamazepine, Oxcarbazepine: Hyponatremia.
  • Vigabatrin: Visual field loss.
  • Lamotrigine, Phenytoin: Double vision.
  • Phenytoin: Gingival hyperplasia, hirsutism.
  • Topiramate, Zonisamide: Cognitive problems.
  • Topiramate: Weight loss.
  • Valproic acid, Gabapentin, Pregabalin: Weight gain, peripheral edema.
  • Valproic acid, Felbamate: Liver toxicity.
  • Felbamate: Risk of aplastic anemia.

Conclusion

• Antiepileptic drugs have diverse mechanisms and side effects.
• Important to match drug choice to individual patient needs and side effect profiles.