L20 - epilepsy Flashcards
(71 cards)
1
Q
what is a seizure
A
Clinical manifestations of abnormally excessive and hypersynchronous activity of neurones located predominantly in the cerebral cortex
2
Q
ionic cause of excitation
A
inwards Na+ and Ca2+ currents
3
Q
neurotransmitters for excitation
A
glutamate, aspartate
4
Q
ionic cause of inhibition
A
insufficient inward current of Cl- or outward current of K+
5
Q
neurotransmitter for inhibition
A
insufficient release of GABA
6
Q
what synapses onto the excitatory neurone
A
inhibitory neurone
7
Q
what % of neurones are interneurones
A
10-20%
8
Q
role of inhibitory neurones
A
to keep neurone activity tightly focussed as it flows through the brain - prevents it spreading sideways
9
Q
mechanism of a seizure
A
localised hyper excitability spreads into surrounding neuronal networks and involves more and more neurones (activity spreads sideways), resulting in a seizure
10
Q
how to measure excitation
A
intracellular calcium levels
11
Q
anticonvulsant
A
a drug decreasing the frequency/severity of seizures in people with epilepsy
12
Q
measurement of calcium levels to measure excitation:
A
- 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
13
Q
what do anti epileptic drugs do
A
treat symptoms of seizures, not the underlying epileptic condition
14
Q
modes of action of anticonvulsants
A
- suppress action potential
- enhance GABA transmission
- suppress excitatory transmission
15
Q
how do AED suppress action potentials
A
- sodium channel blocker or modulator
- potation channel opener
16
Q
how do AED enhance GABA transmission
A
- GABA uptake inhibitory
- GABA mimetrics
17
Q
what are GABA mimetrics
A
drugs which have the same effects as GABA
18
Q
how do AED suppress excitatory transmission
A
glutamate receptor antagonist
19
Q
most widely used AED
A
valproic acid
20
Q
febrile seizures
A
seizures in infants
21
Q
main inhibitory neurotransmitter in CNS
A
GABA
22
Q
what % of synapses is GABA found at
A
30%
23
Q
GABA receptors
A
GABAa and GABAb
24
Q
GABAa receptor
A
ligand-gated chloride channel receptor
25
GABAb receptor
G protein-couples receptor
26
which GABA receptor is most relevant in seizures and epilepsy
GABAa
27
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
28
GABA enhancement
benzodiazepines or barbiturates (have binding sites for GABA) --> resulting in an influx of chloride ions
29
which drugs can be used to inhibit GABA uptake back into the presynaptic neurone
vigabatrin
| tiagabine
30
methods of enhancing GABA action
- enhancing action of GABAa receptors
- inhibiting GABA transaminase
- inhibiting GABA uptake by pre-synpatic neurone
31
barbiturate drug which enhances action of GABAa receptors
phenobarbital
32
barbiturate
CNS depression drug
33
benzodiazepines drug which enhances action of GABAa receptors
clonazepam
34
benzodiazepines
sedatives
35
examples of benzodiazepines
clonazepam
clorazepate
diazepam (valium) and lorazepam
36
clonazepam
Effective in generalized tonic-clonic, absence and partial seizures
37
Clorazepate
Effective against partial seizures
| - Used in conjunction with other drugs
38
Diazepam (Valium) and lorazepam
Effective against status epilepticus when given i.v.
39
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)
40
actions of benzodiazepines
- sedatives
- hypnotic
- anxiolytic
- anticonvulsant
- muscle relaxant
- amnesic
41
mechanisms of action of benzodiazepines
increase affinity of GABA for its receptor
- increase Cl current
- strengthens surrounding inhibition (preventing spreading)
- raising action potential threshold
42
unwanted effect of benzodiazepines
sedation - respiratory depression
tolerence
dependence
43
what to give in case of overdose of benzodiazepines
flumazenil
BC-site antagonist
prevents BC binding to GABAa receptor
44
most frequent drugs which inhibit Na channels
phenytoin
carbamazepine and oxcarbamazepine
lamotrigine
45
voltage gated sodium channels at resting potential
closed
46
voltage gated sodium channels when inactivated
Brief period after activation, channel does not open in response to a new signal
47
voltage gated sodium channels when sodium enters the cell
open
48
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
49
what happens when Na+ channels are inhibited
AP cannot arise in next neurone and signal is inhibited
50
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
51
when does phenytoin bind
when sodium channels have recently opened (inactivated channels)
52
what type of block is phenytoin
use dependent block
53
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
54
tonic blockage
When there are long intervals between impulses, the level of inhibition of each impulse is the same
55
phasic blockage
When intervals between impulses is short, the level of inhibition increase with each impulse
56
pharmacokinetics of phenytoin
taken orally
| well absorbed
57
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
58
metabolism of phenytoin in the liver
95% metabolised to an inactive meyabolite
59
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
60
unwanted effects of phenytoin - mild
vertigo
ataxia
headache
61
unwanted effects of phenytoin - severe
```
confusion
hyperplasia in gums
megaloblastic anaemia
hypersensitivity and rashes
foetal malformations (cleft palate)
hepatitis
```
62
foetal hydantoin syndrome clinical features
intrauterine growth restriction with microcephaly, resulting in dysmorphic features in face and lumps and growth and mental retardation
63
foetal hydantoin syndrome
A group of defects caused to the developing foetus by exposure to the teratogenic effects of phenytoin or, more rarely, carbamazepine
64
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
65
how is valproate taken and absorbed
orally - well absorbed in GI tract
66
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
67
mechanisms of valproate
- inhibits Na channels (weaker than phenytoin)
- decreased GABA turnover
- blocks neurotransmitter released by blocking T-type Ca2+ channels
68
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)
69
why may valproate cause genetic disabilities
it is an inhibitor of histone deacetylase (HDAC)
70
normal deacetylation of chromatin
- chromatin becomes closed so transcription factors can't bind
- genes cannot be transcriped
71
consequences of valproate inhibiting HDAC
hyperacetylation of chromatin
| - increased transcription of gene
