Welcome to the video tutorial on the pharmacology of epilepsy.
Epilepsy is characterised by a high risk of recurrent seizures and affects over 50 million
people worldwide. Epilepsy can be controlled by medication,
but usually not cured. When examining the pharmacology of epilepsy
there are a number of receptors and channels we will be concerned with: the NMDA receptor
-NMDA stands for N-methyl D Aspartic Acid The AMPA receptor: AMPA stands for Alpha-Amino-3-Hydroxy-5-Methyl-4-Isoxazole
Propionic Acid The GABA receptor: GABA stands for Gamma Amino
Butyric Acid As well as Sodium and Calcium channels
Here we have a representation of a post synaptic neuron with NMDA, AMPA and GABA receptors
and sodium and t-type calcium channels. Each receptor has a number of sites on it,
upon which neurotransmitters and drugs may act
such as the glycine site on the NMDA receptor, glutamate sites present both on NMDA and AMPA
receptors And the Barbiturate site,
GABA site, And benzodiazepine site present on GABA receptors
To begin with we will focus on the glutamate site of the NMDA receptor.
An epileptic focus generates an action potential which travels to pre-synaptic glutaminergic
neurons. This causes vesicles containing the neurotransmitter
glutamate to move towards the pre-synaptic membrane, eventually fusing with it.
Glutamate is an excitatory neurotransmitter which will cause the action potentials from
the epileptic focus to advance If Lamotrigine, an anti-epileptic medication,
is administered it will stop glutamate from being released from glutaminergic neurons,
stopping the epileptic action potentials from spreading, reducing the likelihood of seizures
occurring In the absence of lamotrigine, glutamate is
released into synaptic cleft and binds to the glutamate site of the NMDA receptor.
This causes the opening of the ion channel leading to an influx of sodium ions
In turn this causes depolarisation and excitation, propagating the action potential which started
from the epileptic focus. This will cause generalised excitation, resulting
in the characteristic seizures seen in epilepsy. The NMDA receptor also contains a glycine
site, to which the antiepileptic Felbamate binds.
The binding of Felbamate to the glycine site closes the ion channel stopping sodium from
entering. The end result is that the action potential
from the epileptic focus is not propagated, avoiding a seizure.
Next we will look at the AMPA receptor. Again when an action potential leaves the
epileptic focus and reaches the glutaminergic neuron, glutamate is released.
As mentioned before the antiepileptic lamotrigine stops glutamate release from glutaminergic
neurons In the absence of lamotrigine, glutamate is
released and binds to the glutamate site of the AMPA receptor opening the channel
Sodium ions enter the post-synaptic neuron through the channel causing depolarisation,
excitation and spread of the epileptic action potentials causing seizures
Topiramate binds to the glutamate site of the AMPA receptor, without causing the channel
to open. When glutamate is released from glutaminergic
neurons after stimulation by epileptic focus action potentials,
It travels across the synaptic cleft but cannot bind to the glutamate site on the AMPA receptor
as it is blocked by Topiramate Therefore the action potential from the epileptic
focus cannot advance stopping a seizure from developing
Let’s look at the GABA receptor. The GABA receptor has three sites: the barbiturate
site, the GABA site and the benzodiazepine site.
GABA is taken up by GABA-ergic neurons and packaged into vesicles.
Some is metabolised by GABA transaminase or GABA- T to produce succinic semialdehyde
The remainder is released into the synaptic cleft. Here it binds to the GABA site of the
GABA receptor and causes the channel to open.
Chlorine ions enter the post synaptic neuron causing hyperpolarisation and inhibition
This reduces the likelihood of an action potential being propagated, reducing the chances of
seizures occurring There are two other sites on the GABA receptor:
the barbiturate site and the benzodiazepine site.
Phenobarbital acts on the barbiturate site, and Diazepam acts on the benzodiazepine site
These act to allow more chlorine ions to move throughout the channel and into the post synaptic
neuron causing greater hyperpolarisation and inhibition and further reducing the chances
of seizures occurring. As mentioned, GABA is taken up into GABA-ergic
neurons but the anti-epileptic drug Tiagabine can prevent this from happening.
This allows more GABA to reach the GABA site on the GABA receptor, bypassing breakdown
by GABA-T into succinic semi aldehyde. The amount of GABA broken down to succinic
semi aldehyde can also be reduced by the addition of the anti-epileptic medicines: Valproate
and Vigabatrine Valproate and vigabatrine are GABA-T inhibitors.
By blocking the action of GABA-T, Valproate and Vigabatrine cause more GABA to be released
from GABA-ergic neurons to travel across the synaptic cleft and bind with GABA sites on
the GABA receptor. As mentioned this causes the associated channel
to open, allowing chlorine ions to enter the post synaptic neuron, causing hyperpolarisation
and inhibition of action potentials which could lead to seizures.
The post synaptic neuron also has a number of sodium channels present.
When sodium channels are open, sodium ions move into the post synaptic neuron causing
depolarisation and excitation which can lead to proliferation of any action potentials
from an epileptic focus. Phenytoin and Carbamazapine block these sodium
channels, stopping sodium from entering and reducing the likelihood of epileptic focus
action potential propagation. This reduces the risk of seizures occurring.
In a similar way, open T-Type calcium channels allow calcium to enter the post synaptic neuron
causing depolarisation and excitation This allows the epileptic focus action potentials
to spread further. However, Ethosuximide blocks T –Type calcium
channels, stopping calcium from entering the post synaptic neuron and therefore reducing
the chances of seizures occurring.