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