Pharmacology CNS Epilepsy

Question 1

What are seizures due to?

Answer 1

An unregulated neuronal discharge in the brain
APs firing within the neurons in an uncontrolled manner
Arises as a result of imbalance of inhibitory (mainly GABA) and excitatory (mainly glutamate) activity

Question 2

Describe seizures that remain in one place:

Answer 2

Focal seizures
Localised structural abnormality (lesion)

Question 3

Describe seizures that spread from one place:

Answer 3

Waves of activity spread from the focal centre
Generalised seizure (all of brain affected)
Chain reaction of depolarisation and synaptic activity

Question 4

Describe the areas of the brain a seizure can occur and what are the symptoms of this?

Answer 4

Motor cortex- contraction of skeletal muscle
Somatosensory cortex- feels sensations that the cortex is usually detecting
Hypothalamus- autonomous NS control, loss of bladder control
Reticular system- loss of consciousness

Question 4

Name the 2 types of seizures:

Answer 4

Focal
Generalised

Question 5

What is an aura in relation to a seizure?

Answer 5

Usually in generalised seizures, when a pt knows they are about to have a seizure e.g twitching of a particular muscle, certain smell- depends where focus of seizure is in the brain

Question 6

How can GABA have an affect on seizures?

Answer 6

Decrease in inhibitory activity (inhibitory stops neuronal activation)
GABA antagonists causes convulsions

Question 7

Describe how excitatory activity can affect seizures:

Answer 7

Increase in excitatory activity can cause excitotoxicity

Question 8

How can a seizure start?

Answer 8

Neurons in the focal area have been shown to display sudden depolarisation (30mV for a few seconds)
-depolarisation called paroxysmal depolarisation shift (PDS)
-leads to burst of AP in those neurons
-NMDAr are believed to play a role in this
-synchronous activity in network of neurons (seizures)
-hyperexcitability in regions surrounding the focal area- so can’t surgically remove specific area

Question 9

Describe what are absence seizures?

Answer 9

Oscillatory feedback between cortical and thalamic neurons
AP going backwards and forward within these regions then manifest as absence seizures
Involve activity of T-type VG Ca2+ channels- important in treatment

Question 10

Describe the genetic component of epilepsy:

Answer 10

FH- high concordance in MZ twins
Around 2% of cases due to specific mutations
Many mutations identified:
*ion channels
-enzymes
-GPCRs
-NTs
More than 150 mutations to the VG Na+ channel have been associated with epilepsy

Question 11

What are the most common drug mechanisms of drugs used to treat epilepsy?

Answer 11

Enhanced GABA transmission
Inhibition of Na+ channels
Inhibition of Ca2+ channels

Question 12

What are the areas of the GABAergic synapse that are affected to increase the amount of GABA?

Answer 12

Block degradation within the presynaptic terminal to enhance amount of GABA
Act at the synaptic receptors which enhance signalling at receptors
Act at GABA transports ion presynaptic terminal and non neuronal cells (inhibits these processes) so more GABA within synapse to have down stream post synaptic effects

Question 13

Name drugs that act at the GABAa receptors to enhance transmission:

Answer 13

Benzodiazepines e.g clobazam, lorazepam
Barbiturates e.g phenobarbital

Question 14

How do benzodiazepines work at GABAa r to enhance transmission?

Answer 14

Potentiate the action of GABA at the GABAa r by action of the modulatory site
They potentiate the opinion got the channel so still need GABA present, so increase amount of time channel open so increase amount of Cl- entering, enhancing hyperpolarisation

Question 15

How do barbiturates work at the GABAa r to enhance transmission?

Answer 15

Potentiate the action of GABA at GABAa r by action at the channel modulator site
They potentiate the opinion got the channel so still need GABA present, so increase amount of time channel open so increase amount of Cl- entering, enhancing hyperpolarisation

Question 16

How does Gabapentin work for epilepsy?

Answer 16

Designed as a GABAa agonist but doesn’t work like this
It is an anticonvulsant acting at P/Q type Ca2+ channels

Question 17

Name drugs that modulate GABA metabolism for epilepsy and how:

Answer 17

Vigabatrin is a GABA transaminase inhibitor, it increase the amount of GABA available for release (less succinic semialdehyde)
Valproate (amongst other things) increase the amount of GABA in the brain, MoA unclear

Question 18

Name drugs that inhibit GABA re-uptake for epilepsy and how:

Answer 18

Tiagabine is a GABA uptake (GAT1) inhibitor
GAT1 is found in pre-synaptic and non-neuronal cells (astrocytes)
It increases the amount of GABA following synaptic release so can continue to have inhibitory effects in post synaptic cell

Question 19

What is the effect of inhibiting the VG Na+ channel for a treatment in epilepsy?

Answer 19

Stops the AP and therefore the spread of neuronal activity across the brain

Question 20

Name drugs that can inhibit the VG Na+ channel in epilepsy:

Answer 20

Valproate
Phenytoin
Carbamazepine
Lamotrigine
Rufinamide
Lacosamide

Question 21

Why is it important for anti-epileptic drugs to exhibit use-dependency?

Answer 21

Means they act preferentially at cells that are receptively firing, so still have normal AP, just block high freq AP during seizures
Block the inactivated state
Slows recovery from inactivation

Question 22

What is the effect of Ca2+ channels in the brain?

Answer 22

Important in NT release, therefore signalling from one neurone to another

Question 23

Name examples of drugs that block T type Ca2+ channels for absence seizures:

Answer 23

Ethosuximide
Valproate
Conazepam

Question 24

Name examples of drugs that block P/Q type Ca2+ channels in epilepsy:

Answer 24

Gabapentin

Question 25

Describe Levetiracetam MoA:

Answer 25

Binds to the synaptic vesicle protein SV2A
Modulation of NT release- exact MoA unknown

Question 26

Are there drugs in the treatment of epilepsy that inhibit the NMDAr?

Answer 26

No, not proved to be effective

Question 27

Name drugs that inhibit the glutamate receptor for epilepsy:

Answer 27

Phenobarbital
Topiramate
Perampanel

Question 28

How does phenobarbital work in epilepsy?

Answer 28

Inhibits glutamate r as well as enhancing GABAr and blocking Na+ channels

Question 29

How does topiramate work in epilepsy?

Answer 29

Blocks the AMPAr as well as blocking Na+ and Ca2+ channels and enhancing action of GABA

Question 30

How does phenobarbital work in epilepsy?

Answer 30

Was designed as an AMPA antagonist and is one of the most recently introduced drugs