CNS 32: Mechanism of Antiepileptic Drugs

In this discussion, we will go over the mechanisms of antiepileptic medications

Characteristics of Antiepileptic Drugs (AEDs)

These are medications that decrease the frequency and/or severity of seizures in people with epilepsy. It is important to note that these medications do not prevent epilepsy development.

The goal is to maximize the quality of life by eliminating seizures or diminishing frequency.

The Generations of AEDs

First-generation: These are carbamazepine, ethosuximide, phenobarbital, phenytoin, primidone, and valproic acid.

Newer generation: gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, rufinamide, stiripentol, tiagabine, topiramate, vigabatrin, zonisamide.

Mechanisms

There are four major categories:

  • Cation channels: The modulation of cation channels (Na, K, Ca), leads to a prolongation of inactivated state, positive modulation of K, or inhibition of Ca.
  • GABA; Enhance GABA through GABA-A, modulation of GABA metabolism, or inhibition of GABA reuptake.
  • Synaptic Release: The actions on SV2A or Ca channels with alpha-2-delta subunit
  • Reduce excitation – By ionotropic glutamate (AMPA)

Barbiturates

These bind to GABA-A receptors as well as kainate receptors.

Primidone

Primidone has two active metabolites, which are phenobarbital and phenylethylmalonamide PEMA, both of which have antiseizure effects.

Carbamazepine and Phenytoin

Carbamazepine blocks Na channels that are firing at high speed, reducing repetitive action potentials by slowing the rate of recovery and stabilizing the channel in the inactive state. This lengthens the refractory period and keeps neurons from depolarizing again.

These medications have antiseizure activity without CNS depression.

Oxcarbazepine

Oxcarbazepine is an analog of carbamazepine. It acts as prodrug, and metabolized to eslicarbazepine (active metabolite). Exlicarbazepine is also a prodrug.

Benzodiazepines

These medications bind to GABA-A at the alpha-1 subunit and open the Cl channel of the GABA-A and allow Cl to enter neurons. (Positive allosteric modulator of GABA-A)

Felbamate

Felbamate blocks Na, Ca, and NMDA, and enhances the GABA response.

Gabapentin and Pregabalin

These medications block the alpha-2-delta subunit of the Ca channel. Despite their names, they do not mimic or enhance GABA. They are only structurally related to GABA. They reduce the influx of calcium into neurons and decrease the synaptic release of neurotransmitters, such as glutamate, NE, and substance P.

Lamotrigine

This is a Na channel blocker that can also modulate the kainate receptor.

Zonisamide

This is another medication that blocks the Na channel, but can also act on the T-type Ca channels.

Topiramate

This medication blocks Na and Ca channels. It increases the frequency at which GABA opens its Cl channel. It also antagonizes glutamate at AMPA and kainate.

Tiagabine

This medication blocks GABA re-uptake and increases synaptic concentration of GABA. This prevents synchronous neuronal firing and seizures.

Valproic Acid

This is a GABA-transaminase (an enzyme that metabolizes GABA) inhibitor. It also blocks Na channels and modulates the T-type calcium channel.

Vigabatrin

This medication irreversibly inhibits GABA-transaminase, increasing GABA concentration as well.

Ethosuximide

This is a partial antagonist of low threshold T-type calcium. It decreases the burst firing and stabilizes nerve activity in the cortex.

Levetiracetam

This is a unique medication that binds to a protein on synaptic vesicle SV2a protein. This is a reversible binding, which reduces the rate of vesicle fusion to the presynaptic nerve terminal and reduces neurotransmitter release.

Keppra also modulates the kainate receptor and has a reverse inhibition of GABA and glycine by negative allosteric modulations.

Lacosamide (Vimpat)

Lacosamide slows the inactivation of voltage-gated sodium channels

Rufinamide (Banzel) and Oxcarbazepine

Both stabilize Na channels. Oxcarbazepine also exerts an effect on k channels.

Adverse Effects of AEDs

Neurologic and psychiatric (most common)

  • Sedation
  • Fatigue
  • Dizziness
  • Tremor
  • paresthesia
  • Eiplopia
  • Mental impairment
  • mood changes
  • Sexual dysfunction

GI

  • Mild to moderate: hyponatremia, ALT/AST increase, leukopenia, thrombocytopenia
  • Weight gain or weight loss

Hematologic

  • Marrow aplasias, such as abnormal bleeding, acute fever, and anemia

SJS and TEN can also happen. This is more common with a combination of lamotrigine and VPA.

Gingival Hyperplasia with phenytoin

Long-term ADR:

  • osteomalacia, osteoporosis
  • Teratogenesis
  • Altered connective tissue metabolism
  • Cerebellar degeneration
  • Sexual Dysfunction

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