Epilepsy

Healthy human brain exists in balance between

excitatory and inhibitory factors

What causes a seizure?

• abnormal function of ion channels and neural networks leading to rapid, synchronous, and uncontrolled spread of electrical activity

  • caused by domoate toxin ingestion, penicillin injection (GABA_A antagonist)

Convulsion

symptom of epileptic seizure

series of extreme jerky movements of the muscles that repeatedly contract and relax

Seizure

the clinical manifestation of an abnormal and excessive excitation of a population of cortical neurons

symptom of epilepsy (symptoms vary according to location of seizure activity)

Epilepsy

disorder characterized by recurring seizures

The duration and frequency of action potential is limited by

• Sodium channel

• impose limit on frequency of firing and help prevent repetitive firing

• repetitive firing = seizures

Focal seizure

activity begins in seizure focus and spreads to adjacent areas via diffuse neuronal connections

ex. shaking of hand and progress to arm and leg

caused by decreases in GABA-mediated inhibition

Secondary generalized seizure

• activity begins in focus but then spreads to subcortical areas

Primary Generalized Seizures

• absence seizure (petit mal): characterized by sudden interruption in consciousness

Main goals of AEDs

• cellular level: Na+ channel inactivation

• network level: GABA-mediated inhibition

5 main categories of AEDs

1. drugs that enhance Na+ channel-mediated inhibition

2. drugs that enhance K+ channel-mediated inhibition

3. drugs that inhibit calcium channels

4. drugs that enhance GABA-mediated inhibition

5. drugs that inhibit glutamate receptors

What drug is used for all types of seizures

Valproate

What drug can be used for all except one type of seizure?

Lamotrigine

the one seizure that it cannot treat: myoclonic

MOA of AEDs

block seizures through one of 3 general mechs:

1. reducing electrical excitability of membrane (inhibit sodium channels)

2. enhance GABA-mediated synaptic inhibition

   1. inhibit GABA-T, or GABA agonists

3. modification of ion channel conductance

   1. Inhibit glutamate synaptic function

AEDs that inhibit sodium channels

• phenytoin

• carbamazepine

• valproic acid

• oxcarbamazepine

• lamotrigine

• lacosamide

Classes of Calcium channel inhibitors

1. inhibit T-type calcium channels

2. inhibit high-voltage-activated calcium channel

Calcium channel inhibitors

• Ethusuximide

• Valproic acid

• Gabapentin

• Pregabalin

Potassium channel inhibitors

• Ezogabine (Retigabine)

  • adverse effects:

    • urinary retention

    • blue skin discoloration

    • retinal abnormalities

Drugs that enhance GABA-mediated inhibition

• Barbiturates (Phenobarbital)

• Benzodiazepines (Diazepam, Clonzapam, Lorazapam)

• BZPs and BBTs increase Cl- influx through GABA_A channels

• Vigabatrin

  • irreversibly inhibit GABA-T, increase GABA levels

Glutamate Receptor inhibitors

• glutamate: excitatory NT

• inhibition of NMDA and AMPA receptors can inhibit generation of seizure activity and protect neurons from seizure-induced injury

• serious adverse effects

• Felbamate: inhibit NMDA

  • potent AED, lacks sedative effects

• Perampanel: non-competitive antagonist of AMPA