Week 8: Epilepsy Flashcards
What is a seizure?
- the clinical manifestation of an abnormally excessive and hypersynchronous activity of neurones located predominantly in the cerebral cortex
- too much neuronal activity = a seizure
What are the two basic mechanisms underlying seizures?
- Too much excitation
- inward Na+ and Ca2+ currents
- increased release of neurotransmitter - glutamate, aspartate - Too little inhibition
- insufficient K+ current, inward Cl-
- decreased release of neurotransmitter - GABA
What do inhibitory interneurones do?
allow brain activity to spread in one direction, but not to spread out sideways
What might occur if localised hyperexcitability is not counterbalanced by inhibitory neurones?
- starts to spread out, involving more and more neurones
- activity spreads out sideways
- too many cells become active at once
- a visible seizure is the result
What do intracellular calcium levels tell us?
measures excitation
What is an antiepileptic drug?
- a drug which decreases the frequency and/or severity of seizures in people with epilepsy
- treats the symptom of seizures, not the underlying epileptic condition
What are the 3 potential modes of action of AEDs?
- Supress action potential
- Na+ channel blocker
- K+ channel opener - Enhance GABA transmission
- GABA uptake inhibitor - Suppression of excitatory transmission
- glutamate receptor antagonist
What would be the top 3 drugs of choice for partial simple, partial complex and generalised tonic clonic seizure?
- valproic acid
- phenytoin
- carbamazepine
What drug could you give for both absence and atypical absence seizures?
valproic acid
What drug would you give for febrile seizures?
diazepam, rectal
How do we detect absent seizures?
can only be detected by ECGs as there are no signs other than a blank expression
What is the most widely used AED in the world?
valproic acid
Who is influenced by feibrile seizures?
infants
What is GABA and how does it act?
- major inhibitory neurotransmitter
- acts via GABAa or GABAb receptors
What type of receptor is a GABAa receptor and how does this work?
ligand-gated chloride channel receptor
When the GABAa receptor is activated through the binding of GABA, the GABAa receptor forms a chloride channel so chloride ions can enter the cell
How can we enhance GABA action (and increase Cl- influx)
- barbiturates e.g phenobarbital
- benxodiazepines e.g clonazepam
- inhibit GABA transaminase
What is chlonazepam and what seizures is it effective in?
- benzodiazepine
- generalised tonic-clonic, absence and partial seizures
What is status epilepticus?
- a life threatening condition in which the brain is in a state of persistant seizure
- more than 30 minutes continous seizure activity
- two or more sequential seizures spanning this period without full recovery between seizures
- medical emergency
What drug is used to counter SE?
Diazepam - a GABAa receptor antagonist
List all the actions of benzodiazepines?
- sedative (calming)
- hypnotic (initiates or prolongs sleep)
- anxiolytic (reduces anxiety)
- anticonvulsant (reduce epileptiform activity)
- muscle relaxant
- amnesic
How do benzodiazepines work?
- increase affinity of GABA for its receptor
- increases Cl- current
- suppresses seizure focus by raising action potential threshhold
- strengthens surround inhibition - prevents spread
When are benzodiazepines toxic?
if than with other CNS depressants or with ethanol (as this can cause respiratory depression)
What are the unwanted effects of benzodiazepines?
drowsiness, confusion, amnesia, poor co-ordination
What drug should be administered in case of a BZ overdose?
a BZ-site antagonist - flumazenil
What is the main problem with BZs?
dependence –> marked withdrawel syndrome so should only be used for short term treatment
Which anti-epileptic drugs work by inhibition of Na+ chanels?
- phenytoin
- carbamazepine
Explain the 3 possible states that a voltage-dependent Na+ chanel can exist in during an action potential
- closed - before activation
- open - during depolarisation
- inactivated - shortly after the peak of depolarisation (channel doesn’t open in response to a new signal until the membrane has repolarised)
How does phenytoin work??
binds to Na+ channel in an inactivated state and slows down its recovery (takes longer to go back to the closed state where it can be activated again)
Why is phenytoin known as a ‘use-dependant block’?
- phenytoin only binds to Na+ channels that have been recently opened
- the more channels that have been opened, the more will be in the inactivated state and therefore be accessed by phenytoin
- only rapid firing neurones are blocked so does not interfere with normally firing neurones
How is phenytoin taken and what does it bind to?
taken orally - well absorbed
binds to the inside of the inner pore of the Na+ channel (NaV1.2)
what is meant by ‘free’ phenytoin?
- if taken with another drug that has the same binding site e.g valproate, this produces more ‘free’ phenytoin (because binding sites are occupied)
- the ‘free phenytoin’ is not bound to plasma protein
- this tends to increase hepatic clearance of the drug so effects can be unpredictable
Explain how phenytoin is metabolised?
- highly metabolised in the liver to an inactive metabolite
- metabolism is saturable –> liver cannot metabolise further
- small increase in dose caan lead to large increase in plasma concentration, as elimination becomes saturated
In phenytoin, what is the relationship between dose and plasma concentration?
non linear –> highly variable concentrations even with minor dosage changes
What are some minor unwanted effects of phenytoin? e.g at 100umol/L
vertigo, ataxia, headache and nystagmus (uncontrollable eye movements)
What are some severe unwanted effects of phenytoin? e.g at 150 umol/L
- confusion, intellectual deterioration
- hyperplasia of the gums, hirsutism
- hypersensitivity and rashes
- hepatatis
- foetal malformations
What is foetal hydantoin syndrome?
up to 30% of children whose mothers are taking pheytoin during pregnancy typically have:
- growth restruction
- microcephaly
- craniofacial and limb defects
- developmental delay, mental retardation
- heart defects
so it is a group of defects caused to the developing foetus by exposure to the teratogenic effects of phenytoin, or more rarely, carbamazepine
Which AEDs have mixed actions?
- valproate
- gabapentin
- levetiracetman
What is valproate used for and how is it taken?
- valproic acid
- effective against tonic-clonic and absence seizures
- can also be used in bipolar
- taken orally and well absorbed
Explain the mechanism of action of valproate?
- inhibits Na+ channels
- decrease GABA turnover
- inhibit GABA transaminase
- blocks neurotransmitter release
What is foetal valproate sydrome?
there is a 6-9% risk of congenital malformations in infants exposed to the VPA pre-natally
How beneficial is using drugs to treat epilepsy?
- 70% will be seizure free with one drug –> careful monitoring and adjustment
- 5-10% seizure free with two or more drugs
- 20% still have seizures (refractory epilepsy) –> because the seizures cannot be controlled by currently available drugs
