Epilepsy 2: Anticonvulsants Flashcards
1
Q
what are the NICE guidelines for focal seizures ?
A
- first line: carbamasepine, lamotrigine
- second line: oxcarbazepine, valproate, levitiracetam
- adjunct: combination + gabapentin, topiramate
2
Q
what are first line treatments for focal seizures ?
A
carbamasepine, lamotrigine
3
Q
what are second line treatments for focal seizures ?
A
oxcarbazepine, valproate, levitiracetam
4
Q
what are adjuct treatments for focal seizures ?
A
combination + gabapentin, topiramate
5
Q
what are the NICE guidelines for tonic-clonic seizures ?
A
- first line: valproate (not WCBA), lamotrigine
- second line: oxcarbazepine, carbamazepine
- adjunct: combinations + levetiracetam, clobazam, topiramate
6
Q
what are first line treatments for tonic-clonic seizures ?
A
valproate (not WCBA), lamotrigine
7
Q
what are second line treatments for tonic-clonic seizures ?
A
oxcarbazepine, carbamazepine
8
Q
what are adjunct treatments for tonic-clonic seizures ?
A
combinations + levetiracetam, clobazam, topiramate
9
Q
what are the NICE guidelines for absence seizures ?
A
- first line: valporate (not WCBA), ethosuximide
- second line: lamotrignine
- adjunct: combinations + specialist advice
10
Q
what are first line treatments for absence seizures ?
A
valporate (not WCBA), ethosuximide
11
Q
what are second line treatments for absence seizures ?
A
lamotrignine
12
Q
what are adjunct treatments for absence seizures ?
A
combination + specialist advice
13
Q
what does WCBA men ?
A
women of child bearing age
14
Q
what are the 3 main methods of anti-convulsants ?
A
- Ca2+ channel inhibition (receptor potentiation)
- GABAergic potentiation (uptake inhibition)
- Na+ channel inhibitio (metabolism inhibition0
15
Q
What is the risk associated with valproate?
A
Valproate appears to have a risk of being a teratogen if given to men who may become fathers.
Teratogens are substances that can cause developmental malformations in a fetus.
16
Q
What does the BNF state about valproate use in men and women under 55?
A
Valproate cannot be used in women or men under 55 without two specialists agreeing that it is needed.
This reflects a precautionary approach to prescribing valproate.
17
Q
According to the old guidance, who can use valproate?
A
Valproate can be used in males and women who cannot have children.
This indicates a shift in guidelines regarding the safety of valproate.
18
Q
What is the current first line treatment for focal seizures?
A
Levetiracetam is now recommended as a first line treatment for focal seizures.
This change reflects an updated clinical guideline.
19
Q
What is the current status of carbamazepine in the treatment of focal seizures?
A
Carbamazepine has been relegated to second line treatment for focal seizures.
This indicates a shift in the preferred treatment options.
20
Q
What is the current status of valproate for absence seizures?
A
Valproate has been relegated to a second line treatment for absence seizures.
This change suggests a reconsideration of its safety and efficacy.
21
Q
what are the mechanisms of phenytoin as an antiepileptic medication ?
A
to stabalise voltagge-gated sodium channels in inactivated state
22
Q
what is phenytoin used for ?
A
tonic-clonic and partial seizures
can worsen absence and myoclonic seizures
23
Q
phenytoin chemical composition (draw)
A
24
Q
due to the side effects, phenytoin is no longer a first-line treatment. What are the side effects it can produce ?
A
- teratogenic (produces birth defects)
- risk of lupus
- cerebellar atrophy
- acne, hirsuitism (extra hair growth)
- gingival overgrowth (gums start to grow)
25
what are the problems of the pharmacokinetics of phenytoin ?
plasma levels react in different ways, have to be monitored
26
what kind of antiepileptic is carbamezapine ?
- blocks voltage-gated sodium channels
- secondary action on GABA-A receptors
27
what is the chemical structure of carbamazepine ?
28
what can carbamezapine be used for ?
- first line treatment of focal seizures
- second line for tonic-clonic
29
what other things can carbomazepine be used for ?
- mood stabilizer
- (scizophrenia)
- neuropathic pain
30
what are some drugs related to carbamazepine ?
- oxycarbazepine
- esilcarbazpeine
## Footnote
fewer side effects
31
what are issues with the pharmacokinetics of carbamazepine ?
- auto-induces CYP3A4 that metabolises it (enzyme)
- takes a while to reach steady plateau
- intercation with grapefruit juice
- many interactions (because of CYP3A4)
## Footnote
CYP means other drugs metabolised more quickly and can also create competition
32
what are some side effects of carbamazepine ?
- teratogenic
- risk of lupus
- worsens JME and absence seizures
- cognitive problems and mood changes
## Footnote
potential to cause psychosis
33
what are the mechanisms of lamotrigine ?
sodium channel blocker
## Footnote
some secondary mechanisms
34
what is lamotrigine used for ?
- first line treatment for tonic-clonic seizures
- second line for absence
35
what are the beenfits of lamotrigine over vaporate ?
lamotrigine is safe for women of child bearing age
36
what seizures can lamotrigine make worse ?
myoclonic seizures at high doses (careful with JME)
37
what is another use of lamotrigine ?
mood stabiliser used to treat bipolar disorder or added to antipsychotic drugs to treat schizophrenia
38
what are some side effects of lamotrigine ?
- sedation, sleep disturbance, rash
- binds to eye pigment (consequences unkown)
39
what is the essential problem in epilepsy ?
- too much excitation
- too little inhibition
40
what kind of transmission in GABAergic ?
inhibitory
## Footnote
by boosting this we can have antiepileptic actions
41
what are the three main targets of GABAergic transmission for antepileptic drugs ?
- GAT1 transporter (PRE)
- GABA-A receptor (POST)
- GABAT (PRE)(astrocyte)
42
how do benzodiazepines work ?
- potentiate the actions of GABA-A receptors (via allosteric site)
43
what are the 3 main benzidiazepines ?
- clobazam (adjunct medication)(anxiety)
- clonazepam (refractory epilepsy)
- diazepam (status epilepticus)
## Footnote
refreactory epilepsy = not treatable with other drugs
44
what are the side effects of benzodiazepines ?
- sedation
- tolerance
- dependence
- seizures on withdrawl
45
what is a related class of drugs similar to benzodiazepines ?
barbiturates
## Footnote
similar action but worse side effects as directly activate GABA-A/ only perscribed by specialists in difficult cases
46
what is the mechanism of Tiagabine as an anti-epileptic drug?
- inhibitor of GAT1 (GABA transporter)
- increases synaptic con. of GABA
47
what is the trade name of Tiagabine ?
gabatril
48
what is Tiagabine used as ?
an add on/ adjunct medication in partial (focal) seizures
49
what are other uses of Tiagabine ?
- used in panic attacks
- neruopathic pain
50
what are some side effects of Tiagabine ?
- sedation, dizziness
- paraesthesias (tingling sensation)
- provokes seizures in non-epileptic patients
51
52
what happens in an overdose of tiagabine ?
- ver sedating
- seizures
- amnesia
- confusion
53
what is the mechanism of vigabatrin ?
- irreversible GABA-T inhibitor (GABA transaminase)
- increases amount of GABA in presynaptic nerve terminal
54
what does GABA-t do ?
metabolises GABA to SSA (Succinic semialdehyde)
55
what is the trade name for vigabatrin?
sabril
56
what is vigabatrin used for ?
- adjunct medication
also
- panic atacks
- addicitions
57
why is vigabatrin being irreversible important ?
- it has a short plasma half life
- so once daily is ok and actions persist even when cleared from plasma
58
what are some side effects of vigabatrin as an anti-epileptic drug?
- visual disturbances
- depression, psychosis, sedation
- teratogenic actions
59
what is sodium valproate ?
an anti-epileptic drug whose main mechanisms of action are GABAergic
60
what are the three different forms of valproate ?
- sodium valproate
- valproic acid
- mixture = vaproate semisodium
## Footnote
no difference of action for each formulation/ sold under same name in different countries
61
what can sodium valproate be used for ?
first line treatment for a range of epilepsies
62
what are the specific mechanisms of sodium valproate ?
- GABAt inhibitor (increases GABA synthesis ?)
- enhances post-synaptic GABA function ?
- inhibits sodium channels ?
- inhibits calcium channels ?
63
what are the two main brand names for sodium vaproate and what are they used for ?
- epilim: epilepsy
- depakote: bipolar, migranes (add on for schizophrenia)
64
what are some valproate side effects ?
- sudden onset of liver toxicity
- powerful teratogenic (not WCBA)
- associated with congitive problems/ brain structure changes with long term use (debatable/reversible?)
65
how is valproate a teratogenic drug and what can this cause ?
- folic acid antagonist
- anencephally, spina bifida risk increases x20
- autistic spectrum disorder
- cleft palate
- limb defects
66
what is foetal valproate syndrome and what is it characterised by?
- as a result of the teratogenic effects of valproate
- high forehead
- flat nasal bridge
- broad base of nose
- shallow philtrum (cleft lip)
- long upper lip
67
what are the mechanisms of gapapentinoids ?
- structures similar to GABA
- bind to alpha2delta subunit of calcium channel
- goal: reduce number of calcium channels on cell surface
68
what are the natural ligands of the alpha2delta calcium channels and when these bind what happens compared to gabapentinoids?
- leucine and isoleucine
- gets transporter to cell surface
BUT
- if gabapentinoids binds channel is retained within cell and broken down
69
what are the two main gabapentinoids ?
- Gabapetin / 'neurontin
- pregabalin / 'lyrica'
70
what is the secondary effect of pregabalin ?
increases GAD (glutamate decarboxylase) levels which leads to increase in GABA
## Footnote
GAD involved in synthesis of GABA
71
what are gabapentin and pregabalin (gabapentinoids) used for ?
adjunct medication for focal seizures; pregabalin also as monotherapy and anxiety
## Footnote
and neuropathic pain
72
what are some side effects of gabapentin/pregabalin ?
- sedation/dizziness
- suicidal thought
- abuse potential
- seizures upon withdrawl (new or precipitation of old)
73
when can gabapentnoids be fatal ?
when combined with methadone
74
how do calcium channel blockers work for anti-epileptic drugs ?
inhibit calcium channels ON the cell surface
## Footnote
different to gabapentinoids
75
what are the mechanisms of ethosuximide ?
- blocks T type calcium channels
76
what is ethosuximide used for ?
- first line treatment for absence seizures
but can worsen other types of epilepsy
77
what are the benefits of ethosuximide vs valporate ?
- lacks liver toxicity seen with valproate
- risk of birth defects is slightly less
78
what are some dife effects of ethosuximide ?
sedation, nausea, mood changes
79
what can levetiracetam (keppra) be used for ?
focal, myoclonic and tonic-clonic seizures
80
what is the mechanism of levetiracetam ?
- inhibits presynaptic calcium channels
- binds to SV2A (involvedin release of neurotransmitter)
- OVERALL: reduces neurotransmitter release
81
what are some side effects of levetiracetam ?
- psychiatric: depression, agitation, aggression, suicide-ideation, psychosis
- Stevens-Johnson syndrome
82
what is steven-johnson syndrome ?
- immune skin disorder
- skin blisters and peels + lesions on mouth or body openings
- happens with medication or virus
## Footnote
very rare/ not unique to levetiracetam
83
what is the more serious form of steven-johnson syndrome ?
toxic epidermal necrolysis
- top layer of skin slides off
84
what are examples of some drugs that can trigger SJ syndrome ?
- lamotrigine
- phenytoin
- valproate
- oxycarbazepine
- ethosuximide
- carbamazepine
85
what are the mechanisms of action for Topiramate ?
- potentiation of GABA-A receptors
- block of AMPA and kainate receptors
- block of sodium channels
- block of calcium channels
- inhibition of carbonic anhydrase
86
what can topiramate be used for ?
- adjunct treatment for tonic-clonic seizures
- migranes
- bipolar
- alcoholism
## Footnote
or potentially used alone
87
what are the side effects of topiramate ?
- sedation
- cognitive problems
- psychiatric side effects
- teratogenic
88
What percentage of people can control their epilepsy using antiepileptic drugs?
Around 70%
89
What is one alternative treatment for epilepsy for those who do not respond to antiepileptic drugs?
Ketogenic diet
90
How does the ketogenic diet compare to the Atkins diet?
It is like an extreme version - very high fat, very low carbohydrate and controlled protein
91
What percentage of calories does the classic ketogenic diet involve coming from fat?
Around 90%
92
Who is the ketogenic diet most often used for?
Children
93
What is the potential outcome for children placed on the ketogenic diet?
About 50% will see a significant decrease in the number of seizures
94
What is a possible extreme result of the ketogenic diet for some children?
Some even become seizure free
95
What is a challenge mentioned regarding the ketogenic diet for children?
It would be very difficult to stick to that sort of food long-term
96
what approach is often used after AEDs are proven ineffective ?
- removal of damaged tissue in specific areas of the brain that generate seizures
- produces adverse side effects but benefits often outweigh this
97
what is a Rasmussen's encephalitis and what is a surgical technique used to help treat this ?
- inflammatory condition that results in frequent seizures and can leave patients with epilepsy even once inflammation has resolved
- does not respond well to AED
- hemispherectomy used to control seizures
## Footnote
often done in right hand side of the brain
98
what is a surgery technique that can be used to treat intractable epilepsy ?
corpus callosotomy if not resonding to AEDs
## Footnote
(severes tract of corpus callosum)
99
what is the corpus callosum ?
white matter tract that connects the hemispheres of the brain
100
what is a corpus callosotomy used to treat and what are some adverse effects ?
- intractable epilepsy
- cognitive impairments
- difficulty with language
- alien hand syndrome
## Footnote
alien hand syndrome - hand has mind of its own
101
what can seizure dogs be used for ?
- absence seizures; while px is unaware of environment
- can altert others of situation; comfort/saftey
- larger dogs can place owners in recovery position or break owners fall
- can provie warning of seizure/ can sense this up to an hour before
102
what is optogenetics ?
uses light gated channels or pumps to modify the behaviour of neurons
103
optogenetics in treating epilepsy in animal models
- mouse injected with Kainic acid and has seizure activity
- transgenic mouse expresses channel rhodopsin in GABAergic neurons
- when neurons are stimulated by blue light using fibre-optic probe implanted in hippocampus seizure acitivity is abolished
104
what are DREADDs?
- designer receptors exclusively activated by designer drugs
105
what is the system through which DREADDs work ?
- engineered form of a receptor is introduced into target cells
- mutated receptor no longer responds to normal endogenous ligands, only to synthetic drug
106
when have DREADDs been shown to be used in epilepsy ?
- animal model of focal epilepsy
- engineered muscarinic acetylcholine receptor
- only responds to clozapine-N-oxide not ACh
107
what drug auto-induces CYP3A4 ?
carbamazepine
108
Which category of controlled drugs is gabapentin in, under the Misuse of Drugs Act?
category C
109
Which of the following drugs is likely to worsen absence seizures?
carbamazepine
110
what are first line treatmenets for absence seizures ?
ethosuximide,
valproate
## Footnote
lamotrigine as alternative
111
what kind of drug is clobazam and what are its mechanisms ?
benzodiazepine
- allosteric modulator at GABA-A receptors
112
wha tkind of drrug is carbamzepine ?
sodium channel blocker
