Anti-Epileptics Flashcards
What are seizures?
- self sustaining and self timing episodes of synchronized neural hyperactivity that can be detected by EEG
What causes seizures or epilepsy?
- brain trauma - enough neurons die which can lead to excitotoxicity
- brain tumours
- stroke, CV events –> brain starved of O2 –> cell death –> release of glutamate
- brain infection, meningitis, fever - body makes antibody receptors against the brain
- medications
- alcohol withdrawal
- hormone fluctuations
- idiopathic epilepsy: hereditary but the cause is unknown
How does the EEG pattern differ between a normal pattern, absence seizure and tonic clonic?
normal
- no synchrony between neurons firing
- sum of neurons is low amplitude
absence seizure
- typical spike and wave pattern but there is synchrony between neurons so there is a larger sum
- all electrodes along cortex picking up seizures
tonic clonic
- a lot of neural activity and no synchrony, very high constant spiking through whole cortex
Absence seizures
- general
- briefly unconciosu, blank stare, no memory of attack
- less than 30 seconds
- 3 per second spike and wave throughpout whole brain
tonic clonic seizures
- general
- unconscious, dramatic convulsions, no memory of attack
- lasts less than 5 minutes (more then 5 is status elepticus)
- constant spiking throughout whole cortex
Simple partial seizure
- conscious (cortex still working), memory of attack, sensory/motor/emotion symptoms representative of where it is
- duration varies
- localized spiking in neocotical or limbic area of brain
Complex partial seizure
- conscious but unresponsive, automastisms, no memory of attack
- begins locoalized but spreads over time - can become tonic clonic with no intervention
- duration varies
- localized then spreading spiking in one or both temporal lobes
What are the adverse outcomes of not managing epilepsy?
- difficulty learning
- breathing in food and saliva into lungs during seizure which causes aspiration pneumonia
- injury from falls, biting and driving during seizure
- permanent brain damage
- death from seizure
- death from suicide from depression associated with epilepsy
Describe the mechanism by which seizures cause cell death through glutamate
seizures cause the release of glutamate which acts on
- NMDA receptors: opens receptor operated Ca channels
- AMPA: upon membrane depolarization, AMPA can be triggered to open voltage gated Ca channels even though they usually doesn’t let Ca through
- metabotropic receptors: GPCRs release Ca from endoplasmic reticulum
this increases Ca inside the cell which activates Ca dependent enzymes which results in
- lipid peroxidation
- proteolysis
- free radical formation
- DNA damage
- damage to mitochondria –> impairs respiration
this results in cell death
What are the classes of glutamate receptors
- AMPA
- NMDA
- metabotropic receptors
How does activation differ in epilepsy?
- in normal balance IPSPs and EPSPs are regulated
- usually want to promote inhibition or decrease inhibition
- can act on sodium potassium ion channel to promote excitation and promote hyperpolarization
What are the NT ion channel therapeutic targets?
GABA - inhibitory
Glutamate and acetylcholine - excitattory
- can regulate the synaptic enzymes
- regulated by levels of activity of neuron, production, packing, release and clearance of NTs
Voltage gated ion channels as therapeutic targets to reduce neuron excitability
- sodium ion channels: role in propagation of AP, blocking Na channels blocks electrical activation
- K ion channels: repolarization/hyperpolarization of membrane along the neuron and at terminal
- Ca channels: trigger NT release,
- Cl channels: can block them so resting potential is lower so it will not be excited as easily
4 possible MOA for different anti-seizure medication
- modulate voltage dependent sodium channels to make them less active –> less able to propagate AP which decrease excitability
- modulate GABAa or GABAergic transmission –> increase GABA which is inhibitory which makes the cell less excitable
- negative modulate voltage gated calcium channels –> role in NT release so if you negatively modulate it the cell will be less excitable, calcium channels in the thalamus are very important in absence seizures
- broad spectrum drugs with multiple targets
What drugs modulate voltage dependent sodium channels at the glutamate synapse?
Block VGNaC, presynaptic
- phenytoin (very prescribed)
- carbamazepine
- lamotrigine
- felbamate
- valproate –> acts through multiple targets and acts epigenetically to regulate gene expression
