Antiepileptic Drugs

Question 1

What is a seizure?

Answer 1

A sudden burst of uncontrolled electrical activity in the brain that occurs when neurons become excessively active
Seizure can be seen as an imbalance between inhibitory and excitory processes in the brain

Question 2

What classifications of seizures are there?

Answer 2

Two types:

Focal
Affect a portion of the brain, typically one hemisphere
Can occur with or without impairment of awareness (consciousness)

Generalised
Affect both sides of the brain at the same time
Cause loss of consciousness

Question 3

Properties of a simple excitatory neuron

Answer 3

Inside is more negative than outside

Question 4

How does an AP start/work at excitatory neurons?

Answer 4

Voltage gated sodium channels open > sodium ions flow in > membrane depolarisation (inside is now more positive than the outside) > high voltage activated calcium channels open > calcium ions enter > glutamate vesicles are stimulated to bind to membrane > glutamate released by exocytosis into synapse > glutamate binds to AMPA on postsynaptic neurons > sodium ions enter postsynaptic neuron > glutamate binds to NMDA receptors on post-synaptic membrane > Ca ions enter > Ca can also enter through low-voltage-activated (T-type) Ca channels (open bc small depolarisations) > postsynaptic neuron is depolarised

Too much glutamate > hyperexcitable neuron

Question 5

What is the effect of inhibitory neurons? How do they work?

Answer 5

GABA binds to GABAa Receptors on excitatory neurons > GABAaRs open > chloride enters > neuron hyperpolarises > membrane potential is lower on the inside than outside > no longer excitable

GABA dissociates from GABAaR > GABA-transporter-1 (GAT1) reuptakes GABA from synaptic cleft > GABA degraded by GABA-aminotransferase (GABA-T)

Question 6

What is the main goal of antiepileptic drugs? How is this achieved?

Answer 6

Reduce seizures by either reducing neuronal excitability or increasing neuronal inhibition

Can be achieved by:
- Blocking voltage-gated sodium channels
Examples: carbamazepine, oxcarbazepine, lamotrigine, phenytoin, topiramate, valproic acid, zonisamide
- Blocking high-voltage-activated calcium channels
Examples: lamotrigine, topiramate
- Blocking T-type calcium channels
Examples: valproic acid, zonisamide
- Blocking AMPA (post-synaptic sodium channel)
Example: topiramate
- Blocking high-voltage-activated calcium channels by binding to the alpha-2-delta-1 accessory subunit (channels with this subunit appear to modulate the release of glutamate)
Example: gabapentin, pregabalin
- Binds to SV2A protein found in walls of the glutamate-carrying vesicles which is responsible for the synaptic release of glutamate
Example: levetiracetam
- Blocking NMDA receptors
Example: Felbamate

• Binding to GABAaRs and prologing the opening of the channel
  Example: benzodiazepines, barbiturates
• Blocking the reuptake of GABA by blocking GAT1
  Example: tiagabine
• Irreversibly inhibiting GABA-T
  Example: vigabatrin

Question 7

What are the side effects of antiepileptic drugs?

Answer 7

All: sedation and dizziness

Hyponatremia: carbamazepine, oxcarbazepine
Loss of vision: vigabatrin
Double vision: lamotrigine, phenytoin
Gingival hyperplasia (enlarged gums): phenytoin
Hirutism (excessive hairgrowth): phenytoin
Cognitive problems: topiramate, zonisamide
Weight loss: zonisamide
Weight gain: valproic acid, gabapentin, pregabalin
Peripheral oedema: gabapentin, pregabalin
Liver toxicity: valproic acid, felbamate
Aplastic anaemia (rare): felbamate