2.7 - Epilepsy

Question 1

What is the physiology of an inhibitory and excitatory input to a post-synaptic neuron in the temporal lobe?

Answer 1

• excitatory neurone - voltage gated sodium channel, voltage gated calcium channel, synaptic vesicle protein, glutamate vesicle
• inhibitory neurone - GABA reuptake transporter, GABA transaminase, succinic semi-aldehyde, GABA vesicle
• postsynaptic neurone - NMDA receptor, AMPA receptor, GABAa receptor

Question 2

What are the four classical drug target sites for epilepsy synapses?

Answer 2

• receptors - GABAa receptor, AMPA receptor, NMDA receptor
• enzymes - GABA transaminase
• ion channels - VGSC, VGCC
• transport proteins - GABA reuptake transporter

Question 3

How does diazepam work?

Answer 3

• binds to GABAa receptor (alpha subunit) on the post-synaptic membrane in the temporal lobe
• treats for complex, partial focal seizures
• end result - diazepam binds and increases the effectiveness of GABA activation of this receptor (doesn’t activate receptor itself)
• leads to Cl- influx in the presence of GABA, which hyperpolarises the temporal lobe neurone and decreases febrile seizures

Question 4

How does lamotrigine work?

Answer 4

• wants to reduce glutamate release
• binds to and blocks VGSCs on glutamatergic neurones in temporal lobe
• this reduces neuronal depolarisation which would eventually lead to glutamate NT release
• therefore, glutamate neurotransmission is decreased and there is less excitatory stimulation of the post-synaptic neurone
• produces anti-epileptic effect

Question 5

How does pregabalin work?

Answer 5

• wants to reduce glutamate release
• binds to and blocks VGCCs on glutamergic neurones in temporal lobe
• prevents Ca2+ influx which is required to promote vesicle exocytosis and NT release
• therefore, glutamate neurotransmission is decreased and there is less excitatory stimulation of the post-synaptic neurone
• produces anti-epileptic effect

Question 6

How does levetiracetam work?

Answer 6

• binds to synaptic vesicle protein SV2A in glutamatergic neurones in the temporal lobe
• the drug interferes with vesicle fusion and therefore reduces exocytosis of glutamate, thus decreasing the excitatory activation of the post-synaptic neurone

Question 7

Sodium valproate has low selectivity and isn’t prescribed to women with childbearing potential - what does this mean?

Answer 7

• non-selective drug - acts on multiple targets e.g. VGSCs, GABA transaminase, VGCCs, NMDA receptor blockade and enhances GABA production
• this means it can have a large number of side effects due to hitting so many targets
• it is teratogenic so not given to females of childbearing age - mechanism of this is unknown but may involve inhibition of folate receptors