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.