Epilepsy Flashcards
What can be done clinically to measure the electrical activity in the brain?
Electroencephalogram (EEG)
What leads to a seizure?
Abnormal cell firing leads to seizures associated with excess glutamate present in the synaptic cleft (extracellular concentrations are exceedingly high) - Typically stimulates GABA receptors (fine balance, inhibitory receptors to reduce tendency of stimulating AP in post-synaptic membrane). Dysfunctional GABA system, thereby excitation can’t be reduced within the glutamate CNS synapse.
What is epilepsy?
Neurological disorder characterised by sudden recurrent episodes of sensory disturbance, loss of consciousness and convulsions, associated with abnormal activity in the brain.
Burden of epilepsy
Medications influence behaviour and affect concentration. Time may be needed out of school, reducing educational exposure and quality. Experiencing seizures may influence employment opportunities, prelude driving and impact family life. Accident injury is a common consequence.
Early diagnosis and management are critical to reducing the condition’s impact. Misdiagnosis is frequent.
Outline the structure of a GABA receptor.
Pentameric organisation of the GABA receptor, and pharmacologically important binding domains. Arranged in circle to form channel pore, closed until GABA ligand is bound to recognition site.
There are 4 classical drug target sites. Identify an example for each in the diagram of an inhibitory and excitatory synapse.
1 = Receptors – Examples GABAA receptor, AMPA receptor, NMDA receptor
2 = Enzymes –Example GABA transaminase
3 = Ion channels –Examples Voltage gated sodium and calcium channel.
4 = Transport proteins - Example GABA transporter
Explain the mechanism of diazepam.
Targets GABA receptor in the postsynaptic membrane; results in increased inhibition of postsynaptic neurone. Diazepam behaves as GABA receptor agonist - contributes to increased Cl- influx into postsynaptic membrane, therefore resulting in hyper-polarisation → Making it difficult to depolarise the membrane.
Agonists activate receptors. Positive allosteric modulator (PAM) can’t activate GABA receptor itself, acts at a different sites to agonist.
GABA is required in conjugation with PAM for stimulation.
Explain the mechanism of lamotrigine.
Blocks VGSCs - prevents Na+ influx into presynaptic knob. Hence depolarisation of presynaptic membrane is reduced.
Ion-channel antagonist (VGSC antagonist)
NT release and glutamate derived excitation of postsynaptic membrane is prevented.
Explain the mechanism of pregabalin.
VGCCs blocked, reduces Ca2+ influx into presynaptic knob, results in inhibition of glutamate vesicles fusing with membrane - reduces glutamate exocytosis into the synaptic cleft. Reduction in excitatory neurotransmission.
Explain the mechanism of levetiracetam.
Binds to SV2a protein (reduces exocytosis for glutamatergic synapses) - reduces excitatory stimulation.
Explain the mechanism of tiagabine.
Inhibit GABA re-uptake protein in inhibitory neurone → enhances GABAergic transmission; results in a reduction of GABA uptake and removal from the synaptic cleft - stimulates a greater inhibitory response. Increases number of GABA molecules acting on the receptors, increasing hyperpolarisation, thus decreases stimulation of AP.
GABA re-uptake protein antagonist
Explain the mechanism of vigabatrin.
Antagonist
Inhibits GABA transaminase thus more GABA is present in synaptic knob, and packaged into vesicles and released.
What is sodium valproate and why not use it?
It is anti-epileptic drug, but it shouldn’t be used in female patients with childbearing potential.
Valproate is a non-selective drug - it acts on multiple targets i.e. VGSCs, GABA transaminase, VGCCs, NMDA receptor blockade and even enhances production of GABA. Biggest problem with non-selective drugs is the propensity for a larger number of side effects due to hitting so many targets.
