Dr Christina Abdel Shaheed

BPharm PhD (University of Sydney)

Lecturer Medical Education (School of Medicine, Western Sydney
University)
OUTLINE
• Basic physiology/anatomy and
• Pharmacology
 ACTION POTENTIAL AND NEURONS

http://bealbio.wikispaces.com/On+Line+and+Upload+Period+4+Nervous+System?showComments=1
LETS LOOK AT A REPRESENTATION OF A
POSTSYNAPTIC NEURON
In epilepsy the important receptors are:
• NMDA receptor
• AMPA receptor
• GABA receptor

In epilepsy the important ion channels

we will focus on are:

• Na+ channels
• T-Type Ca2+ channels
NOTICE THE SITES ON THE RECEPTORS
Notice how each receptor has
various sites on it – these
sites are the targets for
neurotransmitters and drugs

A basic understanding of this

will help us to understand the
pharmacological
management of epilepsy
NOTICE HOW MANY DRUG/NEUROTRANSMITTER TARGETS
ON EACH RECEPTOR
Key target sites in Epilepsy

NMDA receptor – 2 target sites

• Glycine site
• Glutamate site

AMPA receptor – 1 target site

• Glutamate site

GABA receptor – 3 target sites

• Barbiturate site
• GABA site
• Benzodiazepine site
NMDA RECEPTOR - PRIMARY RECEPTOR FOR GLUTAMATE
1. An Epileptic focus (EF) generates an action
potential.

2. EF travels down to presynaptic glutaminergic

neurons.

3. As a result, vesicles containing glutamate

(excitatory neurotransimtter) move towards the
presynaptic membrane and eventually fuse with the
membrane.
• Note: Glutamate = excitatory
neurotransmitter. It will cause the
action potential (that originated from
the EF) to advance to postsynaptic
neurons and propagate
Ordinarily what would happen is:

1. Glutamate released into the

synaptic cleft
2. Glutamate binds to glutamate
site of the NMDA receptor
3. This causes ion channel to open
4. As a result there is an influx of
Na+ ions
5. Entry of Na+ ions causes
depolarisation and excitation
6. The action potential which
started from the EF spreads.
NMDA RECEPTOR CONT’D
• Some people with epilepsy may have faster or longer activation of the NMDA
receptors

• The receptor may be affected by an underling genetic cause but may also be
affected by brain tumour, brain injury or infection
LAMOTRIGINE
1. Lamotrigine prevents the
release of glutamate from
glutaminergic neurons
2. This in turn prevents the
spread of the epileiptic action
potential  risk of seizure
alleviated
DRUGS THAT BIND TO GLYCINE SITE ON NMDA
• The NMDA receptor’s glycine site
is the target site for some anti-
epileptic medications such as
felbamate.

• When felbamate binds to the

glycine site on the NMDA
receptor, the ion channel closes
therefore preventing sodium from
entering.

• This ultimately stops the

propagation of the action potential
from the epileptic focus.

Note however: felbamate is not

available in Australia and it is not
listed on the PBS.
AMPA RECEPTOR
AMPA RECEPTOR CONT’D
1. Action potential leaves the EF and
reaches the glutaminergic neuron
2. Glutamate is released
3. Glutamate binds to the glutamate
site of the AMPA receptor
4. As a result the ion channel opens
to allow Na+ to enter the post-
synaptic neuron
5. This in turn causes depolarisation
and excitation  spread of action
potential is prevented  seizure
avoided.
TOPIRAMATE

1. Topiramate binds to the AMPA receptor’s glutamate binding site receptor without
causing the ion channel to open.
2. When glutamate is released from glutaminergic neurons (due to stimulation by
an EF) it travels across the synaptic cleft but won’t be able to bind to the
glutamate site on the AMPA receptor as it is occupied and blocked by
topiramate.
This stops the propagation of the action potential from the EF and a seizure is
avoided.
GLUTAMATE TO GABA??
• GABA is synthesized from glutamate using the enzyme glutamate decarboxylase (GAD)
and pyridoxal phosphate (which is the active form of vitamin B6) as a cofactor.

• This process converts glutamate, the principal excitatory neurotransmitter, into the
principal inhibitory neurotransmitter (GABA).
GABA RECEPTOR

GABA receptor has 3 target sites:

• Barbiturate site – this is where

phenobarbital binds

• GABA site – this is where a

number of anti-epileptic drugs
binds

• Benzodiazepine site – this is

where diazepam binds
GABA
EXPLANATION
• Steps 1-2: GABA is taken up by GABAergic neurons
• 3: GABA is packaged into vesicles
• 4: Some GABA is metabollised by the enzyme, GABA Transaminase (GABA-T) to
produce succinic semialdehyde (SSA)
• 5: The remaining GABA is released into the synaptic cleft
• 6: The GABA released into the synaptic cleft binds to the GABA site of the GABA receptor
• 7: As a result the ion channel opens
• 8: Chloride ions enter the postsynaptic neuron
• 9: This in turn causes hyperpolarisation and inhibition and so a seizure is avoided.
DRUGS THAT ACT ON GABA RECEPTOR

Phenobarbital (a barbiturate) acts on the barbiturate site of the GABA receptor whereas
diazepam (a benzodiazepine) acts on the benzodiazepine site of this receptor. Both of
these drugs allow influx of chloride ions into the postsynaptic neuron 
hyperpolarisation and inhibition  seizure avoided
TIAGABINE

1: Tiagabine primarily acts to prevent the uptake of GABA into GABAergic neurons
2: This means more GABA is available to reach the GABA site on the GABA receptor
bypassing the breakdown of GABA by GABA-T into SSA
3: When more GABA is available to bind to the GABA site on the GABA receptor, the ion
channel opens allowing the flow of chloride ions into the postsynaptic neuron. This in
turn causes greater hyperpolarisation and inhibition.
GABA-T INHIBITORS – VALPROATE AND VIGABATRIN
1.Valproate and Vigabatrin inhibit
GAB-T

2: by inhibiting GABA-T these

drugs cause more GABA to be
released from the GABAergic
neuron to travel across the
synaptic cleft

3: The free GABA bind to the

GABA site on the GABA receptor

4: this causes opening of the ion

channel and the influx of chloride
ions into the postsynaptic neuron
 hyperpolarisation and
inhibition of action potentials 
spread of seizure prevented
DRUGS WHICH TARGET THE SODIUM CHANNELS

1. There are a number of sodium channels present on the postsynaptic neuron. When the
sodium ion channels open, the influx of Na+ into the postsynaptic neuron causes
depolarisation and excitation. This in turn can lead to proliferation of any action potentials
from an EF and propagate the spread of seizure.
2. Phenytoin and carbamazapine act to block these sodium channels
3. By blocking the sodium channels, sodium is prevented from entering  reduces
depolarisation and excitation  reduces risk of seizure.
DRUGS THAT TARGET CALCIUM CHANNELS

1. The postsynaptic neuron also has a number of open t-type calcium channels.
These allow calcium to enter the post-synaptic neuron. As a result you get
depolarisation and excitation  spread of seizure
2. Ethosuxamide acts to blocks these t-type calcium channels
3. This will prevent the influx of calcium into the post-synaptic neuron  reduces
chance of seizures
SPECIAL MENTION TO SODIUM VALPROATE
• Has several mechanisms of action
• It targets the voltage gated channels AND stimulates GABA activity
• It is also a GABA-T inhibitor
SUMMARY: DRUGS TO TREAT EPILEPSY
1. Drugs that inhibit voltage gated sodium and calcium ion channels responsible for the propagation of the impulse
• Carbamazepine
• Phenytoin
• Ethosuxamide
• Lamotrigine

2. Drugs that enhance synaptic inhibition – stopping the impulse by increasing GABA activity (GABA is the inhibitory
neurotransmitter in the CNS)
• Benzodiazepines e.g. diazepam – stimulate GABA receptor activity and therefore inhibit depolarisation
(stop the excitement)
• Barbiturates e.g. phenobarbital
• Vigabatrin – inhibits GABA-T (the enzyme that converts GABA to SSA and result in more GABA being
available in the synaptic cleft
• Tiagibine – inhibits the reuptake of GABA resulting in more GABA activity in the synaptic cleft
 EXERCISE
For each of the following anti-epileptic drugs (AEDs) indicate what ADEC category (A, B1, B2, B3, C, D, X)
they are in pregnancy
To revisit ADEC categories see: http://esa.act.gov.au/wp-content/uploads/Pregnancy-Categories.pdf

AED Category in Pregnancy

Sodium Valproate
Lamotrigine
Phenytoin
Ethosuximide
Phenobarbital
Tiagabine
Vigabatrin
Carabamazapine
 EXERCISE - ANSWERS
For each of the following anti-epileptic drugs (AEDs) indicate what ADEC category they are in pregnancy

AED Category in Pregnancy

Sodium Valproate D
Lamotrigine C
Phenytoin D
Ethosuximide C
Phenobarbital D
Tiagabine C
Vigabatrin C
Carabamazapine D
EXERCISE - PHARMACEUTICAL BENEFITS
SCHEME (PBS) AND MANDATORY CO-PAYMENT
• Some AED’s like vigabatrin require an authority prescription in Australia. This would allow
the patient to obtain the medicine under the Pharmaceutical Benefits Scheme (i.e.
concession card holder would pay a mandatory co-payment of $6.20 and a non-
concession card holder would pay a mandatory co-payment of $38.30 (surcharges may
apply, 2016 figures). Without a special authority script the medicine would be much more
expensive and the government would not subsidise any cost to the patient .
• 1. Have a look at the following website:
• http://www.pbs.gov.au/pbs/home;jsessionid=19dn5txw48ee818m3kbvmi7son
• 2. In the search tab (top right hand corner) type in vigabatrin
• 3. Click on any of the options that come up
• 4. what criteria must a person meet in order to obtain an authority prescription for
vigabatrin?

Note: DPMQ gives you an idea of the cost of drug – amount remaining after the patient has
paid the mandatory co-payment is subsidised by the government.
END OF SECTION TWO: MCQ
• Which of these drugs blocks t-type calcium channels:
• Ethosuxamide
• Methotrexate
• Amitryptiline
• Vigabatrin

• True or False: Valproate and Vigabatrin prevent the breakdown of GABA by GABA-T?

• What is the by-product of the breakdown of GABA by GABA-T

• MSA
• SFA
• SSA
• FDA
END OF SECTION TWO: MCQ
• Which of the following drugs is thought to target voltage gated ion channels, stimulates
GABA activity and inhibit GABA-T?
• Carbamazepine
• Topiramate
• Sodium valproate
• Ethosuxamide