Lecture 6 Flashcards
What is the cause of epilepsy?
An imbalance of excitatory and inhibitory neurotransmitters- high frequency discharge by a group of neurons which causes abnormal firing of neurons which causes seizures
excitatory= Glutamate and asparate
inhibitory= GABA and glycine
How many people does epilepsy effect?
1 in 2000 people
How is epilepsy classified?
Is partial or generalised across the 2 hemispheres- classified by seizure properties and not cause. Can have limited activity in a focus
Describe types of seizure activities and their symptoms
1) In motor cortex, effecting muscle contraction- some if contained to one area
2) hypothalamus= autonomic discharge
3) reticular formation= loss of consciousness- dictates if complex or simple
What are the genetic causes of epilepsy?
11 GEFS and 2 other mutations found in SCN1A receptor (voltage gated sodium channel) which causes up stroke of APs. Also found in nicotinic Rs and K+ channels
What are the types of seizures?
1) Tonic phase= rapid firing, seizure and loss of consciousness- associated with Ca2+
2) Generalised seizure (grand mal)= leads to neurotoxicity and neurodegeneration
3) petit mal= typical oscillatory pattern but different behaviour between the 2 hemispheres. Seen in children- only lasts a second, very quick. Diagnosed by specific oscillatory pattern mediated by Ca2+ channels
4) Partial= controlled to one area of the brain, limited spread and not all electrodes show abnormal activity.
How is epilepsy treated?
Need to increase activity of inhibitory neurons e.g. GABA
1) Bind directly to the receptor- Benzos e.g. clobazam and clonazepam, Barbiturates e.g. primidone (complex pharmacokinetics)
2) Uptake inhibitors e.g. triagabine
3) Metabolic inhibitors e.g. vigabatrin (can cause depression) and valproate (problems binding to proteins)
How do GABA metabolic inhibitor drugs work?
GABA is a product of the Kreb’s cycle- from alpha oxaloacetate to glutamine to glutamate to GABA- catalysed by GAD whose transcription is stimulated by valproate. GABA is broken down by GABA transaminase which is inhibited by vigabatrin (suicide inhibitor)
How does sodium valproate work as an anti-epileptic?
works to inhibit histone deacetylases which supress gene transcription- it helps to activate GAD transcription
How can excitatory neurons be targeted to treat epilepsy?
Can target glutamate R- work at level of receptor but can be difficult. Work at level of glutamate release. Use Na+ channel blockers which bind to inactivated channels to prolong the duration of inactivation and limit the spread of the seizure.
What are the types of Na+ channel blockers used to treat epilepsy?
1) Phenytoin= used for most seizure types but bad for grand mal. Complex pharmacokinetics therefore correct dosing is needed. Can cause ataxia
2) carbamazepine= most widely used due to reduced side effect profile. Shouldn’t be used in combo with other drugs
3) Lamotrigine= used in combo with other drugs, preferred. Could cause ataxia, less toxic than other drugs
How are absent seizures treated?
With Ca2+ channel blockers:
1) ethosuximide
2) GABA pentin= more broad drug that binds to the alpha 2 delta subunit to prevent trafficking to the membrane
What is the function of levetiracetam?
Is a SV2 inhibitor which effects either how much glutamate stored in vesicles or vesicle fusion. Used to treat epilepsy (anti-convulsant).
