L20 - epilepsy Flashcards
what is a seizure
Clinical manifestations of abnormally excessive and hypersynchronous activity of neurones located predominantly in the cerebral cortex
ionic cause of excitation
inwards Na+ and Ca2+ currents
neurotransmitters for excitation
glutamate, aspartate
ionic cause of inhibition
insufficient inward current of Cl- or outward current of K+
neurotransmitter for inhibition
insufficient release of GABA
what synapses onto the excitatory neurone
inhibitory neurone
what % of neurones are interneurones
10-20%
role of inhibitory neurones
to keep neurone activity tightly focussed as it flows through the brain - prevents it spreading sideways
mechanism of a seizure
localised hyper excitability spreads into surrounding neuronal networks and involves more and more neurones (activity spreads sideways), resulting in a seizure
how to measure excitation
intracellular calcium levels
anticonvulsant
a drug decreasing the frequency/severity of seizures in people with epilepsy
measurement of calcium levels to measure excitation:
- brain slides bathed in Mg2+
- free artificial CSF leads to recurrent spontaneous seizures
- after removing Mg2+, there is a transition period where the tissue behaves as if it were expecting surges of activity, which are then overcome by inhibitory neurones
- normal background behaviour in the network is followed by a sudden collapse of inhibition
- strong excitatory signals dominate cellular responses and these produce step-like waves of local excitation at the network level
- this is observed in Ca imaging
what do anti epileptic drugs do
treat symptoms of seizures, not the underlying epileptic condition
modes of action of anticonvulsants
- suppress action potential
- enhance GABA transmission
- suppress excitatory transmission
how do AED suppress action potentials
- sodium channel blocker or modulator
- potation channel opener
how do AED enhance GABA transmission
- GABA uptake inhibitory
- GABA mimetrics
what are GABA mimetrics
drugs which have the same effects as GABA
how do AED suppress excitatory transmission
glutamate receptor antagonist
most widely used AED
valproic acid
febrile seizures
seizures in infants
main inhibitory neurotransmitter in CNS
GABA
what % of synapses is GABA found at
30%
GABA receptors
GABAa and GABAb
GABAa receptor
ligand-gated chloride channel receptor
GABAb receptor
G protein-couples receptor
which GABA receptor is most relevant in seizures and epilepsy
GABAa
GABAa receptor binding site and action
when GABAa receptor is activated through binding, it forms a chloride channel, allowing chloride ions to enter the cell
GABA enhancement
benzodiazepines or barbiturates (have binding sites for GABA) –> resulting in an influx of chloride ions
which drugs can be used to inhibit GABA uptake back into the presynaptic neurone
vigabatrin
tiagabine
methods of enhancing GABA action
- enhancing action of GABAa receptors
- inhibiting GABA transaminase
- inhibiting GABA uptake by pre-synpatic neurone
barbiturate drug which enhances action of GABAa receptors
phenobarbital
barbiturate
CNS depression drug
benzodiazepines drug which enhances action of GABAa receptors
clonazepam
benzodiazepines
sedatives
examples of benzodiazepines
clonazepam
clorazepate
diazepam (valium) and lorazepam
clonazepam
Effective in generalized tonic-clonic, absence and partial seizures
Clorazepate
Effective against partial seizures
- Used in conjunction with other drugs
Diazepam (Valium) and lorazepam
Effective against status epilepticus when given i.v.
status epilepticus
a life-threatening condition in which the brain is in a state of persistent seizure
(more than 30min continuous seizure or two or more sequential seizures without full recovery between)
actions of benzodiazepines
- sedatives
- hypnotic
- anxiolytic
- anticonvulsant
- muscle relaxant
- amnesic
mechanisms of action of benzodiazepines
increase affinity of GABA for its receptor
- increase Cl current
- strengthens surrounding inhibition (preventing spreading)
- raising action potential threshold
unwanted effect of benzodiazepines
sedation - respiratory depression
tolerence
dependence
what to give in case of overdose of benzodiazepines
flumazenil
BC-site antagonist
prevents BC binding to GABAa receptor
most frequent drugs which inhibit Na channels
phenytoin
carbamazepine and oxcarbamazepine
lamotrigine
voltage gated sodium channels at resting potential
closed
voltage gated sodium channels when inactivated
Brief period after activation, channel does not open in response to a new signal
voltage gated sodium channels when sodium enters the cell
open
why action potentials jump down axons
- myelination prevents AP from leaking out of axon
- charge spreads alone axon until it reaches the Node of Ranvier, where there is no myelination
- this is packed with Na+ channels
- here, AP jump down the axon
what happens when Na+ channels are inhibited
AP cannot arise in next neurone and signal is inhibited
action of phenytoin
binds to the inactivated state of the Na+ channel and slows down its recovery - meaning membrane takes longer to repolarise when inactivated
when does phenytoin bind
when sodium channels have recently opened (inactivated channels)
what type of block is phenytoin
use dependent block
use dependent block
the more channels which have been opened, the more in the inactivated state hence the more available to be targeted to phenytoin
tonic blockage
When there are long intervals between impulses, the level of inhibition of each impulse is the same
phasic blockage
When intervals between impulses is short, the level of inhibition increase with each impulse
pharmacokinetics of phenytoin
taken orally
well absorbed
consequence of free phenytoin (if other drugs have bound these so cannot be taken up)
increases hepatic clearance of the drug so effects can be unpredictable
metabolism of phenytoin in the liver
95% metabolised to an inactive meyabolite
phenytoin half life and metabolism
half life increases as dose increases
- as we increase dose, rate of metabolism cannot keep up
- small increase in dose can lead to a large increase in plasma concentration
unwanted effects of phenytoin - mild
vertigo
ataxia
headache
unwanted effects of phenytoin - severe
confusion hyperplasia in gums megaloblastic anaemia hypersensitivity and rashes foetal malformations (cleft palate) hepatitis
foetal hydantoin syndrome clinical features
intrauterine growth restriction with microcephaly, resulting in dysmorphic features in face and lumps and growth and mental retardation
foetal hydantoin syndrome
A group of defects caused to the developing foetus by exposure to the teratogenic effects of phenytoin or, more rarely, carbamazepine
valproate
- Not related chemically to the other classes of anti-epileptics
- Unusual in that it is effective against both tonic-clonic and absence seizures
- Can also be useful in bipolar depressive illness as a mood stabiliser
how is valproate taken and absorbed
orally - well absorbed in GI tract
foetal valproate syndrome
There is a 6-9% risk of congenital malformations in infants exposed to VPA prenatally, compared to 2-3% in the general population
mechanisms of valproate
- inhibits Na channels (weaker than phenytoin)
- decreased GABA turnover
- blocks neurotransmitter released by blocking T-type Ca2+ channels
how does valproate decrease GABA turnover
Inhibition of succinic semialdehyde dehydrogenase, thereby indirectly inhibiting GABA transaminase
- May lead to increased synaptic GABA levels (in the synaptic cleft)
why may valproate cause genetic disabilities
it is an inhibitor of histone deacetylase (HDAC)
normal deacetylation of chromatin
- chromatin becomes closed so transcription factors can’t bind
- genes cannot be transcriped
consequences of valproate inhibiting HDAC
hyperacetylation of chromatin
- increased transcription of gene
