Epilepsy 2 Flashcards
what is an epileptic drug ?
a drug which decreases the frequency and/or severity of the seizures
- the drugs are able to treat the symptoms of seizures but not the underlying epileptic condition
what does the treatment of epilepsy require ?
it requires the form of epilepsy to be determined
what is the aim of anti epileptic treatment ?
to maximise the quality of life by minimizing seizures and adverse drug effects
what is the effectiveness of antiepileptic drugs on seizures ?
up to 80% of patients can expect partial or complete control of seizures
when are antiepileptic drugs implicated ?
when a patient has 2 or more seizures in a short interval- 6m to a year
- the initial therapy is to only use one drug (monotherapy)
what are the treatment goals in epilepsy ?
no seizures no side effects monotherapy once daily dosing no blood tests - these are rarely all achieved
what are the advantages of monotherapy ?
fewer side effects
decreased drug-drug interactions
better compliance
lower costs
what is the percentage increase in taking a second drug?
it only causes a significant improvement in 10% of patients
what are the statistics for epileptic patients taking therapy ?
70% seizure free with one drug - still requires careful monitoring and adjustments
5-10% seizure free with 2 or more drugs
20% still have seizures (refractory epilepsy)
what are the common causes of failure of antiepileptics?
1) improper diagnosis of the type of seizures
2) incorrect choice of drug
3) inadequate or excessive dosage
4) poor compliance
what are the general features needed for appropriate clinical advice for treatment?
- essential to have an accurate and comprehensive diagnosis
- the underlying causes must be treated- hypoglycaemia, infection, tumour
- adequate description of symptoms needs to be provided
- EEG
what are the principals of pharmacological treatment 1 ?
- use the appropriate drug for the type of seizure
- use one drug and increase the dose till therapeutic result is gained or until toxicity appears
- the treatment needs to be monitored by blood tests
- if another drug is also required then it should be implemented however if the effect is beneficial, then the removal of the first drug should be considered
what are the principals of pharmacological treatment 2?
if monotherapy fails then 2 drugs can be used - the drugs used should be reviewed
add a 3rd drug if necessary
it may be necessary to accept that significant reduction in seizure frequency is the best that can be achieved
what factors contribute to compliance ?
- actually taking the drug is required for it to be effective
non-compliance is an important issue in poor control
patients have to be fully involved in their treatment
patients views have to be respected
why dont patients comply ?
- poor communication
- poor memory- seizures partly in temporal lobe can impact on cognition
- poor understanding of instructions
- misinformation
- side effects
- poor dose regimes
- difficult to swallow or nasty tasting medication
what are the drugs of choice for partial simple and partial complex seizures ?
carbamezepine
phenytoin
valproic acid - this is the most widely used epileptic drug in the world
what are alternative drugs used to treat partial simple or partial complex seizures ?
lamotrigine gabapentin levetiracetam topiramate tiagabine oxcarbazepine phenobarbital
what are the drugs of choice for generalised tonic clonic seizures ?
carbamazepine
phenytoin
valproic acid
what are alternative drug treatments for generalised tonic clonic seizures ?
lamotrigine
topirmate
phenobarbital
what are the drugs of choice for absence seizures ?
ethosuximide
valproic acid
what are alternative drugs for the treatment of absence seizures ?
lamotrigine
clonazepam
what is the drug of choice for the treatment of atypical absence atonic, myclonic seizures ?
valproic acid
what is an alternative drug for the treatment of atypical absence atonic, myclonic seizures ?
clonazepam
what is the drug of choice for febrile seizures ?
diazepam- take rectally
what are the alternative treatments for febrile seizures ?
diazepam taken intravenously
valproic acid
what are the 3 modes of actions of epileptic drugs ?
1) suppress action potentials
2) enhance GABA transmission
3) suppression of excitatory transmission
how are action potentials suppressed?
sodium channel blocker or modulator
potassium channel opener
how is GABA transmission enhanced?
GABA uptake inhibitor
GABA mimetics
how is excitatory transmission suppressed?
glutamate receptor antagonist
what are the mechanisms of action for anticonvulsant activity ?
enhancement of GABAergic transmission
inhibition of sodium channels
mixed actions- combination of above and also inhibiting neurotrnsmitter release
what drugs can be used to enhance GABA transmission ?
PHENOBARBITAL- enhance action of GABAa receptors with barbituates - this has issues with dependency
CLONAZEPAM- enhance action of GABAa receptors with benzodiazepams
VIGABATRIN- inhibits GABA transaminase
TIGABINE- inhibit GABA uptake
what is the mode of action of phenobarbital ?
binds to allosteric barbiturate binding site- low to moderate doses
it potentiates the actions of endogenous GABA - increasing chlorine influx
what is phenobarbital effective/ineffective against ?
effective- partial and tonic clonic seizures
ineffective- absence seizures
what is the main unwanted effect of phenobarbital?
sedation
overdose causes coma due to direct activation of GABAa receptors
what is clonazepam effective against?
generalised tonic clonic, absence and partial seizures
what is clorazepate effects against ?
partial seizures - often used in conjunction with other drugs
what is diazepam and lorazepam effective against ?
statsus epilepticus when give by iv
describe the structure of GABAa receptors ?
multiple subunits- 19 subunit genes
pentameric- combination of alpha, beta, and gamma subunits eg 2 alpha, 2 beta and one gamma
the combinations of different subunits varies throughout different brain regions
different receptor subtypes have different functions
benzodiazepams binds between alpha and gamma subunits
what are the actions caused by benzodiazepams ?
sedative - calming hyponotic anxiolytic anticonvulsant muscle relaxant amnesic - anterograde after admin
what is the mechanism of benzodiazepines ?
increase affinity of GABA for its receptor
- increases chloride influx
- suppresses seizures by raising action potential threshold
- strengthens surround inhibition which prevents spread
what are the side effects of benzodiazepines ?
sedation= main one
also has problems with tolerance and dependence therefore long term use is avoided
can cause respiratory depression if taken intravenously
confusion, amnesia and poor coordination
when can benzodiazepines potenitally be lethal ?
if they are taken with other CNS depression
if they are taken with ethanol it could cause respiratory depression
what drug is used in a benzodiazepine overdose ?
flumazenil- antagonist
what effects become tolerant during benzodiazepine admin?
anticonvulsant activity and sedative/hyponotic effects
what are the marked withdrawal symptoms of BZs?
symptoms include anxiety, tremor and dizziness
they are difficult to wean patients off if they have been used for a long time - therefore they are used only for short term treatment
describe vigabatrin
its an analogue of GABA
GABA is metabolised by GABA transaminase
forms covalent bonding with GABA transaminase and inhibits the enzyme
short half life yet has long lasting effects
what is vigabatrin useful to treat ?
generalised tonic clonic
partial seizures
what are the main unwanted effects of vigabatrin ?
depression and psychotic disturbances
describe tagabine
newer analogue of GABA
crosses BBB
blocks the uptake of GABA into presynaptic neurones
what is tiagabine used to treat ?
generalised tonic clonic
partial seizures
what are the main unwanted effects of tiagabine ?
tiredness
dizziness
GIT upsets
which antiepileptic drugs causes sodium channel inhibition ?
phenytoin
carbamazepine and oxcarbamazepine
lamotrigine
describe phenytoin
non sedative analogue of phenobarbital
has narrow therapeutic range and non-linear pharmacokinetics
what is phenytoin useful to treat ?
effective for partial and secondary generalised seizures and status epilepticus
little effect on absence seizure
what is phenytoins mechanism of action ?
it binds to the inactivated state of sodium channels and slows down its recovery back to closed state
what does it mean by phenytoins inhibition is use dependent ?
phenytoin only binds to sodium channels that have been opened so therefore known as use dependent block
- only blocks rapidly firing neurons, doesnt interfere with normally firing neurons
what are the pharmacokinetics of phenytoin ?
taken orally- well absorbed
very highly protein bound - plasma proteins, especially albumin (80-90%)- same binding site as many other drugs - therefore if taken together it produces more free phenytoin
incrase hepatic clearance of the drug so effects can be unpredictable
what part of phenytoin interacts with sodium channels ?
free phenytoin is the active moiety that interacts with sodium channels
what is the metabolism of phenytoin like ?
it is highly metabolised by the liver 95% to an inactive metabolite
metabolism is saturable
half life increases with concentration to about 20 hours
the steady state plasma concentration is not proportionate to the dose- a small increase in dose can cause large increase in plasma concentration because elimination becomes saturated
due to phenytoins kinetics what does this mean for dosing ?
minor dosage changes can have highly variable changes in concentration
what are the mild unwanted effects of phenytoin ?
at 100 micromol/litre
- vertigo
- ataxia
- headache
- nystagmus
what are the severe side effects of phenytoin ?
at 150 micromole/litre confusion intellectual deterioation hyperplasia of the gums, hirsutism megaloblastic anaemia hypersensitivity and rashes foetal malformation- cleft palate hepatitis
what is carbamazepine used to treat ?
effective against complex partial seizures
also useful against various forms of neuropathic pain
what does carbamazepine do ?
binds to the same site on sodium channels as phenytoin
- taken orally and its effects are inhibited by a number of drugs
what are the unwanted effects of carbamazepine ?
induces cytochrome p450 enzymes - increases metabolism of other drugs therefore best not to mix with other antiepileptics
it is the metabolite carbamazepine expoxide thought to cause unwanted effects
- mild to moderate= dizziness, drowsiness, ataxia, water retention and GIT effects
- severe= mental and motor disturbances
what are the different metabolic properties of oxcarbamazepine compared to carbamazepine ?
less induction of liver enzymes
MHD is a metabolite which is thought to cause much of the antiepileptic effects
fewer side effects due to lack of production of carbamazepine epoxide
what is gabapentin and what is its mechanism of action ?
analogue of GABA - was intended as a GABA antagonist but doesnt act on GABA receptor
- inhibits L-type calcium channels
- decreases GABA turnover
what is valporate, what is it used to treat?
its effective against both tonic clonic and absence which is unusual
can also be useful in bipolar disorder
taken orally
what is the mechanism of action of valporate ?
inhibits sodium channels but less than phenytoin
decreases GABA turnover - inhibits succinic semialdehyde dehydrogenase and thereby directly inhibits GABA transaminase and this may lead to increase synaptic GABA levels
blcoks NT release by blocking T-type calcium channels
what is the mechanism of action of levetiracetam ?
inhibit NT release
- binds to synpatic vesicle protein (SVA2) involved in vescicle NT exocytosis
- binding affinity is directly proportional to seizure protection
inhibits calcium mediated synaptic vesicle release
may also inhibit calcium channel function directly
what is levetiracetam effective in ?
partial seizures and possibly other seizure types
usually used in conjunction with other drugs
what are the unwanted effects of levetiracetam ?
well tolerated overall
somnolence, dizziness, asthenia and irritability are the most common but they are generally transient
what is the association with antiepileptics and pregnancy ?
seizures are very harmful for pregnant women
- monotherapy is usually better
- folic acid is recommended for every pregnant woman with epilepsy
- phenytoin, valproic acid are absolutely contraindicated
- oxcarbamazepine is better than carbamazepine
what is foetal valproate syndrome ?
6-9% risk of congenital malformation in infants exposed to valproic acid prenatally compared to normally only 2-3%
valproic acid has teratogenic effects - the mechanism of action of these effects are unknown
