Epilepsy pharmacology and pathophysiology Flashcards
What causes seizures?
An unregulated neuronal discharge in the brain. Action potentials are firing in an uncontrolled manner.
What are focal and generalised seizures?
Focal:
- remain in 1 place
- usually due to a localised structural abnormality
Generalised:
- waves of activity spread from the focal centre and then affect the whole brain
- chain reaction of depolarisation and synaptic activity- everything brain controls is affected.
What does the manifestation of a seizure depend on with examples?
the area of the brain affected= the seizure mediats the areas normal responses but in an uncontrolled way.
e.g.
- if in motor cortex: skeletal muscle contraction
- If in hypothalamus: autonomic NS response such as loss of bladder control
- Reticular system: loss of consciousness
What imbalances causes seizures?
Imbalance of:
- Inhibitory- mainly via GABA
- Excitatory- mainly via Glutamate
= is lost
- Normally: inhibitory activity stops excitatory neurones from firing all the time and only when we want them to.
But if decreased inhibitory activity = convulsions- unregulation of excitatory neurones - increased excitatory activity can cause excitotoxicity
How do seizures begin?
Neurones in a focal area display sudden depolarisation for a few seconds- about 30mV
This leads to a paroxysmal depolarisation shift (PDS) = this leads to a burst of action potentials
this leads to synchronous activity in networks of neurones = seizures
What happens in absence seizures?
Oscillatory feedback between cortisol and thalamic neurones = APs going back and forth
- This involved T-type voltage gates Ca2+ channels
What are the common mechanisms of drugs used in epilepsy?
- Enhanced GABA transmission
- Inhibition of Na+ channels
- Inhibition of Ca2+ channels
Role of GABA in epilepsy
GABA is the major excitatory neurotransmitter in the CNS = stops excitatory activity in the brain.
- if inhibitory neurones are inhibited = activation of excitatory pathways = convulsions
What are the mechanisms of enhancing GABA signalling?
- Block degradation in presynaptic terminal = increased GABA
- postsynaptic receptors to enhance signalling
- Inhibit Gaba transporters in presynaptic terminal = increase GABA in synapse
How do epilepsy drugs act at GABAa receptors?
GABAa is a ligand-gated ion channel.
Normally GABA binds and activates this channel = opens.
- Therefore, Cl- ions can move down their gradient into the neurone leading to hyperpolarisation of membrane potential. This causes decreases excitability of the post-synaptic neurone.
- AEDs enhance the activity of this receptor. There are 2 classes:
- Benzodiazepines
- Barbituates
BENZODIAZEPINES:
- Act at a modulatory site on the GABA receptor. Binding potentiates the opening of the ion channel.
GABA still needs to be present for this to happen but GABA and benzodiazepine increases channel opening time = increased Cl- ions go through = increased inhibitory GABA action
e.g. Lorazepam, Clobazepam
BARBITUATES:
- These act at a channel modulator site and binding increases the opening time of the channel = increased Cl- ions through
e.g. Phenobarbitol
What are examples of AEDs that modulate GABA metabolism?
- Vigabatran- is a GABA transaminase inhibitor: increases GABA available for release. Normally, GABA transaminase breaks down GABA into glutamate, but if this is blocked there is an increase in GABA in the pre-synaptic terminal for release.
- Valproate: Increased GABA in brain- exact MOA is unknown
What is an examples of a GABA reuptake inhibitor and how do these drugs work?
Usually GABA action is inhibited by re-uptake into the pre-synaptic neurone via the GAT-1 transporter.
If this GAT-1 transporter is blocked, then the GABA remains in the synapse for longer = continue to have inhibitory action on the post-synaptic cell.
e.g. Tiagabine
What are examples of drugs that act at voltage-gated Na+ channels and how do these drugs work?
These drugs inhibit voltage gated Na+ channels and stop action potentials and therefore spread of neuronal activity across the membrane.
The initial depolarisation phase of ap propagation is mediated by Na+ channels.
- Examples: Valproate, phenytoin, carbamazepine, lamotrigine
What is important about the drugs that act at voltage-gated Na+ channel e.g, Valproate, phenytoin, carbamazepine, lamotrigine/
They exhibit use-dependency- meaning they act preferably at cells that are repetitively fire.
- They block the inactivated state of the voltage gated sodium channels = the channels is closed = drugs bind so channels remain closed for longer = slow recovery from inactivated state.
What are examples of AEDs that act at voltage gated Ca2+ channels?
T-type Ca2+ channel blockers (used in absence seizures):
- E.g.
Ethosuximide
Valproate
Clonazepam
Drugs decrease the activity of P/Q type calcium channels e.g. Gabapentin
