Anticonvulsant Classifications

• Decreased Na influx and prolonged Na Channel Inactivation
  • Carbamazepine (Tegretol)
  • Oxcarbazepine (Trileptal)
  • Phenytoin (Dilantin)
  • Lacosamide (Vimpat)
  • Lamotrigine
  • Valproate
• Reduction of Ca Influx
  • Ethosuximide
  • Lamotrigine
  • Valproate
• Enhanced GABA-mediated Inhibition
  • Barbiturates (GABA_A agonist)
  • Benzodiazepines (GABA_A agonist)
  • Valproate (Increases GABA Levels)
  • Gabapentin (Increases GABA Levels)
  • Vigabatrin (Inhibits GABA Transaminase)
  • Tiagabine (Inhibits GAT-1)
• Antagonism of Glutamate and Other Excitatory Neurotransmitters
  • Felbamate (NMDA Antagonist)
  • Topiramate (Kainate / AMPA Antagonist)

Na Channel Mediated MOA

Hydantoin Derivatives (Phenytoin, etc.)

MOA

Binds and stabilizes the inactivated state of Na Channels

Example Drugs

• Phenytoin
• Fosphenytoin
• Ethotoin (fewer SEs than phenytoin, but less effective)
• Mephenytoin (more toxic than phenytoin)

Phenytoin

Phenytoin has unique PK properties, as the metabolic enzymes which control phenytoin metabolism are saturated at therapeutic concentrations. This leads to non-linear pharmacokinetics. Phenytoin is also highly protein bound, and induces CYP enzymes leading to a large number of drug interactions

Iminostilbenes (Carbamazepine, etc.)

MOA

Iminostilbenes bind and stabilize the incativated state of Na channels in the brain in a similar way to hydantoins (their 3D structures are very similar); however their planar structures are tricyclic. Iminostilbenes induce hepatic CYPs leading to many drug interactions

Example Drugs

• Carbamazepine
• Oxcarbazepine

Lacosamide

MOA

Enhances the inactivation of Na channels

Ca Channel Inhibitors

Clinical Uses

Absence Szs only

Succinimides

MOA

Inhibition of T-Type Ca Channels in thalamic neurons

Example Drugs

• Ethosuximide (Zarontin)
• Methsuximide (more toxic)
• Phensuximide (less effective)

Mixed Na and Ca Inhibitors

Lamotrigine (Lamictal)

MOA

Inhibition of Ca and Na channels (has effects of both classes, and can therefore be used for more than absence Szs). Also disrupts glutamate release

Valproate (Depaken, Depakote)

MOA

Inhibition of Ca and Na channels (has effects of both classes, and can therefore be used for more than absence Szs). Increases GABA levels by stimulating glutamic acid decarboxylase or inhibiting GAt-1 or GABA-T

GABAergic Drugs

Barbiturates

MOA

PAM of GABA_A receptors increasing the duration of Cl entry into the post-synaptic neuron (an inhibitory signal). At high concentrations these drugs can also inhibit Na and Ca channels. Primidone may have more similar behaviors to phenytoin.

Example Drugs

• Phenobarbital (Luminal)
• Primidone (Mysoline)

Benzodiazepines

MOA

PAM of GABA_A receptors increasing the frequency of Cl opening events, hyperpolarizing the post-synaptic neuron.

Example Drugs

• Diazepam (Valium)
• Lorazepam (Ativan)
• Clonazepam (Klonopin)

GABA Analogs

MOA

Increases GABA release and potentially decreases presynaptic Ca influx reducing glutamate release.

Example Drugs

• Gabapentin (Neurontin)
• Pregabalin (Lyrica)

Vigabatrin (Sabrile)

MOA

Analog of GABA which irreversibly inhibits GABA transaminase, which normally degrades GABA. Mat also inhibit GAT.

Tiagabine (Gabatril)

MOA

Inhibits GAT-1 (GABA vesicular transporter)

Glutamate Antagonists

Felbamate (Felbatol)

MOA

NMDA Antagonist (NMDA Usually triggers influx of Na and Ca, along with Efflux of K) and enhanced GABA_A signaling.

Topiramate

MOA

AMPA (Na influx and K efflux) and Kainate antagonist. Inhibition of Na Channels. Enhanced GABA_A signaling.

Misc Anticonvulsants

Levetiracetam (Keppra)

MOA

Binds SV₂A (Synaptic Vesicular Protein) interfering with neurotransmitter release. May also interfere with Ca influx in presynaptic neurons

Brivaracetam (Briviact)

MOA

Analog of levetiracetem with higher affinity for SV₂A