Pharmacology CNS Epilepsy Flashcards
What are seizures due to?
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
Describe seizures that remain in one place:
Focal seizures
Localised structural abnormality (lesion)
Describe seizures that spread from one place:
Waves of activity spread from the focal centre
Generalised seizure (all of brain affected)
Chain reaction of depolarisation and synaptic activity
Describe the areas of the brain a seizure can occur and what are the symptoms of this?
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
Name the 2 types of seizures:
Focal
Generalised
What is an aura in relation to a seizure?
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
How can GABA have an affect on seizures?
Decrease in inhibitory activity (inhibitory stops neuronal activation)
GABA antagonists causes convulsions
Describe how excitatory activity can affect seizures:
Increase in excitatory activity can cause excitotoxicity
How can a seizure start?
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
Describe what are absence seizures?
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
Describe the genetic component of epilepsy:
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
What are the most common drug mechanisms of drugs used to treat epilepsy?
Enhanced GABA transmission
Inhibition of Na+ channels
Inhibition of Ca2+ channels
What are the areas of the GABAergic synapse that are affected to increase the amount of GABA?
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
Name drugs that act at the GABAa receptors to enhance transmission:
Benzodiazepines e.g clobazam, lorazepam
Barbiturates e.g phenobarbital
How do benzodiazepines work at GABAa r to enhance transmission?
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
How do barbiturates work at the GABAa r to enhance transmission?
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
How does Gabapentin work for epilepsy?
Designed as a GABAa agonist but doesn’t work like this
It is an anticonvulsant acting at P/Q type Ca2+ channels
Name drugs that modulate GABA metabolism for epilepsy and how:
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
Name drugs that inhibit GABA re-uptake for epilepsy and how:
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
What is the effect of inhibiting the VG Na+ channel for a treatment in epilepsy?
Stops the AP and therefore the spread of neuronal activity across the brain
Name drugs that can inhibit the VG Na+ channel in epilepsy:
Valproate
Phenytoin
Carbamazepine
Lamotrigine
Rufinamide
Lacosamide
Why is it important for anti-epileptic drugs to exhibit use-dependency?
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
What is the effect of Ca2+ channels in the brain?
Important in NT release, therefore signalling from one neurone to another
Name examples of drugs that block T type Ca2+ channels for absence seizures:
Ethosuximide
Valproate
Clonazepam
Name examples of drugs that block P/Q type Ca2+ channels in epilepsy:
Gabapentin
Describe Levetiracetam MoA:
Binds to the synaptic vesicle protein SV2A
Modulation of NT release- exact MoA unknown
Are there drugs in the treatment of epilepsy that inhibit the NMDAr?
No, not proved to be effective
Name drugs that inhibit the glutamate receptor for epilepsy:
Phenobarbital
Topiramate
Perampanel
How does phenobarbital work in epilepsy?
Inhibits glutamate r as well as enhancing GABAr and blocking Na+ channels
How does topiramate work in epilepsy?
Blocks the AMPAr as well as blocking Na+ and Ca2+ channels and enhancing action of GABA
How does perampernal work in epilepsy?
Was designed as an AMPA antagonist and is one of the most recently introduced drugs
