Epilepsy: how seizures occur and how drugs work Flashcards
What are non gated ion channels responsible for
Resting membrane potential
What are voltage gated ion channels responsible for
Na+, K+, Ca++, Cl-
Dendrite information
Action potential and depolarisation
What does glutamate do to neurones
Excites them
What does GABA do to neurones
inhibits them
What does burst firing look like
What is burst firing like in some forms of epilepsy
Spikes in quick succession
Burst firing in an abnormal amount is seen in some forms of epilepsy
What are Epileptiform discharges due to
Neuronal bursting
Increased synaptic effets (both glutamate and GABA)
Glia effects
Non-synaptic effects
what happens in the initiation and early seizure
Excitatory burst overcome inhibition
What happens in the synchronisation of the epileptic activity (middle phase of seizure)
Local and long-range synaptic connections make neurons fire together
What happens in the Termination of a seizure
Synaptic inhibition
Hyperpolarization due to opening of K channels
Activation of Adenosine, opioids, endocannabinoids and other effects
What do generalised seizures often reflect a disturbance of
Normal thalami-cortical circuits
What drugs are effective in generalised seizures
Ethosuximide, benzodiazepines
Both target receptors involved in thalamo-cortical circuits
What is Epileptogenesis
The process following an injury that leads to the first of a series of spontaneous and recurring seizures
What structural changes can occur in epileptogenesis
Cell loss inhibitory - (if there’s less inhibition, then there’s an excess of excitatory circuits)
Axonal sprouting- (extra excitatory circuits)
Neurogenesis
Gliosis (glial reaction)
Neuro- inflammation
BBB breakdown
What molecular changes can occur in Epileptogenesis
Neuronal channels: NA, K, Ca, Cl, HCO3
Receptors: GABA, AMPA, NMDA, Ach
Neurotransmitter transporters
Neuro
What are the functional changes which occur in Epileptogenesis
gap junctions
Glia (which act to buffer extracellular environment)
What do AEDs do to sodium channels
Prolongs inactivated state of channel
- Block increases with repetitive activation
- Reduces burst firing
Why is Persistent Sodium current important in epilepsy
What drugs target the Persistent Sodium current
Persistent sodium current means Na+ is let into neurons persistently which means neurone is slightly more depolarised and more likely to fire off an action potential
Some AEDs selectively bind to Na persistent channels—-> Lacosamide
How do some sodium channels cause epilepsy
Caused by mutations in sodium channels (outcome of mutation depends on Gain or Loss of channel function and neuron implicated- inhibitory vs excitatory)
What can some brain lesions do to Na p channels
Cause change in sodium channel function (acquired channelopathy)
What can Loss of function mutations in Sodium channels in interneurons might have epilepsy worsened by
Lamotrigine
How do some AEDs promote inhibition
What drugs do this
Enhance Cl- current at GABA receptors
BEnzidiazepines
Barbiturates
Topiramate
Mode of action of Vigabatrin
Reduce GABA degradation or uptake (it is a GABA transaminase inhibitor)
Higher GABA levels prevents fading of inhibition
Mode of action of Tiagabine
IS it commonly used
reduce GABA degradation or reuptake by acting as a GABA reuptake inhibitor
Higher GABA levels prevent fading of inhibition
Not commonly used because it is not universally effective
What is the mode of action of perampanel
AMPA receptor inhibitor
Mode of action of Levetiracetam and Brivaracetam
SV2a inhibitor
Mode of action of Zonisamide, Topiramate
Na channel, Carbonic anhydrase inhibition
What are seizures caused by
Abnormal burst firing and synchronisation in normal/modified neural circuits
