ICL 5.2: Anti-Seizure Neuropharmacology Flashcards
what is epilepsy?
epilepsy is a disease of the brain defined by any of the following conditions:
- at least two unprovoked seizures occurring more than 24 hours apart
- one unprovoked seizure and a probability of further seizures similar to the general recurrence risk after two unprovoked seizures (approximately 60% or more)
- epilepsy syndrome
what are the characteristics of an ideal drug?
- improved efficacy –> no seizures
- few side effects –> no new problems in patient’s daily life
- easy dosing scheduling –> no chance for dosing mistakes
- minimal drug interactions –> no need to adjust other medicines
- expense not prohibitive –> cost will not prevent taking the AED
- maximizing quality of life
you have to consider all of these when deciding what drug to put your patient on
what happens during an excitatory post-synaptic potential?
the presynaptic neuron is depolarized and there’s a Ca+2 influx which leads to the release of the glutamate NT
glutamate binds to NMDA and AMPA receptors which leads to a Ca+2 and Na+ influx into the postsynaptic neuron which activates it
what happens during an inhibitory post-synaptic potential?
the presynaptic neuron is depolarized and Ca+2 enters which leads to the release of GABA
GABA binds to the GABA(A) or GABA(B) receptors on the postsynaptic neuron which causes an influx of Cl- and efflux of K+ which hyperpolarizes the neuron
this is basically the mechanism by how anti-seizure medications work!
how do most epilepsy medications work?
they work at the presynaptic terminals at the Na+ channel and they block the influx of Na+
ex. phenytoin, carbamazepine, valproic acid, felbamate, rufinamine, lemotrigine, lacosamide, topiramate, zonisamide, oxcarbazepine
which drugs works on the AMPA receptors on the post-synaptic neuron?
topiramate and perampanel
AMPA receptors bind glutamate and allow for the efflux of K+ and influx of Na+ aka depolarization of the cell so topiramate blocks the AMPA receptor
which epilepsy drug works on the SV2A protein in the pre-synaptic neuron?
levetiracetam
SV2A protein is involved in the regulation of neurotransmitter release from the presynaptic neuron so levetiracetam inhibits it and therefore prevents the release of excitatory NTs
what is the MOA of gabapentin and pregabalin?
GABA analogs but they don’t work on GABA receptors, they work on the alpha2delta receptors of the presynaptic neuron and inhibit the Ca+2 channel
what is the MOA of vigabatrin?
it inhibits GABA-T which usually metabolizes GABA in the presynaptic neuron
without GABA-T, there is plenty of GABA around to perform its inhibitory function and prevent seizures
which epilepsy medications are GABA receptor agonists?
- benzodiazepines
- felbamate
- topiramate
- zonisamide
- barbiturates
what things do you consider when choosing which epilepsy drugs to use?
- seizure type and syndrome
- etiology and EEG (supportive)
- patient characteristics like if they also have migraines or bipolar disorder etc.
- conventional vs. new agents (new is usually more expensive)
- expertise and drug monitoring
- cost
epilepsy drugs target which structures/molecules?
- channels (Na+, K+, Cl-, Ca+) –> blocking Na+ and Ca+2 channels
- glutamate receptors (antagonists)
- SVA2 protein (blockers)
- GABA (receptor agonist)
- cannabinoids
- cytokines?
- genes?
how many drugs is preferentially when treating epilepsy?
- use a single agent at maximally tolerated doses before introducing second agent which initially should also be used as monotherapy –> appropriate first line agent will control seizures in 50-60 % of patients
- avoid sudden discontinuation of drugs as it may lead to worsening of seizures, unless life threatening side effects
sometimes you can combine agents with different mechanisms of agents for synergy –> this is more controversial because it can have more side effects
what are the conventional medications used for primary generalized epilepsy?
- valproate
works for absence and for all other primary generalized epilepsy
- ethosuximide (for absence epilepsy only!)
what are the new medications used for primary generalized epilepsy?
- lamotrigine
- topiramate
- levetiracetam
- zonisamide
- perampanel
which drugs do you use for partial/focal epilepsy?
you can basically use anything so just pay attention to the specific patient
for example, if someone is on an oral contraceptive, levetiracetam doesn’t interfere with efficacy while carbamazepine does
Carbamazepine Phenytoin Valproate Oxcarbazepine Lamotrigine Topiramate Levetiracetam Zonisamide Gabapentin Pregabalin Lacosamide Esclicarbazepine Brivaracetam Perampanel Cenobamate
how is anti-seizure medication research done?
patients are identified with refractory seizures then patients are either placed on placebo or different dosages of the medication and seizure frequency is counted over 12 weeks and then they’re tapered off the meds
you’re looking for a % seizure reduction from baseline and more than 50% response rate
what are the side effects of anti-epileptic medications?
- rash (especially with sodium channel drugs like phenytoin, carbamazepine, lemotrigine, oxcarbazepine are notorious)
- bone marrow suppression –> leukopenia, aplastic anemia, thrombocytopenia (carbamazepine, phenytoin and phenobarbital)
- liver failure
what are the side effects of phenytoin?
- rash
2 gingival hyperplasia
- ataxia
what are the side effects of carbamazepine?
- ataxia
- rash
- neutropenia (BM suppression)
- liver toxicity
- Steven Johnson syndrome
what are the side effects of valproate?
- weight gain
- teratogenic (birth defects)
- hepatotoxic
- pancreatitis
what are the side effects of perampanel?
- agression
2. mood changes
what are the side effects of gabapentin/pregabalin?
- dizziness
2. weight gain
what are the side effects of zonisamide?
renal stones
what are the side effects of lamotrigine?
rash
what are the side effects of levetiracetam?
- behavioral abnormalities
2. sedation
what are the side effects of topiramate?
- weight loss
- renal stones
- teratogenicity
what are the side effects of lacosamide?
dizziness
when epilepsy patients try multiple drugs, which drug is the most effective?
the first drug!!
we have no idea why this happens but when you switch to a 2nd new drug the efficacy drops and if you switch to a 3rd new drug it drops even more!
so with drug A, 50-60% of people will be seizure free
with drug B another 10-15% of people will be seizure free
then 5-10% of people need drugs B+C to be seizure free
if needed you can do surgery and if that doesn’t work you try investigational trials
what causes resistance or lack of response to anti-seizure mediation?
the BBB and metabolism via the kidney and GI system are a big problem with anti-epileptic drugs
one mechanism is similar to cancer called drug resistance genes which prevent the medications from getting inside the cells and lead to a lack of response
how long does it take for epilepsy medication to start working?
about 5 half lives (day 5 or 6)
so when you start a medication don’t expect effects on day 1 or 2
are immediate release or extended release medications better for seizure treatment?
extended release
that’s because with immediate release there’s peaks and troughs which cause side effects at the peaks and seizures when down in the trough
on the other hand, extended release is more constant so you don’t experience that and get optimal seizure control without side effects
extended releasesmeds also have higher compliance rates!
what is the problem with dosing phenytoin?
some people are rapid metabolizers and require a high dose of medications while others are slow metabolizers and even at slow doses will have toxicity
phenytoin is one of the drugs that follows zero order kinetics requiring careful monitoring of both dose and levels –> it’s a curve and not a line so you hit a point where the serum levels are just crazy high and can be toxic
which epilepsy drug is a CYP2C9 inhibitor?
valproic acid
which epilepsy drug is a CYP3A4 inducer?
- carbamazepine
- phenytoin
- phenobarbital
- oxcarbazapine
what are the implications of some epilepsy drugs being metabolic enzyme inhibitors vs. inducers?
so carbamzepine is a metabolic enzyme inducer while valproic acid is a metabolic enzyme inhibitor
so if you’re on both, CBZ will lower the effect of VPA while VPA will increase CBZ levels and you’ll get a mismatch of cytosines from this combination
also if people drink grapefruit juice, this inhibits metabolism so you have to be careful with people drinking that when on epileptic drugs
which epilepsy drugs interact with oral contraceptives?
- phenytoin
- phenobarbital
- carbamazepine
- topiramate
- oxcarbazepine
which epilepsy drugs interact with anticoagulants?
- phenytoin
- phenobarbital
- carbamazepine
- warfarin
which anti-epileptic drugs are available via IV?
Phenytoin
Phenobarbital
Valproate
Levetiracetam
Lacosamide
Brivaracetam
Ketamine
what happens to women during pregnancy on AEDs?
during pregnancy, antiseizure medication levels drop and as a result you can have breakthrough seizures
this is related to volume expansion and greater fluid presence in the woman
what are the common malformations caused in pregnant women taking AEDs?
- neural tube defects*** –> valproate
- urogenital defects –> phenytoin, phenobarbital, barbiturates
- cardiac malformation –> phenytoin, carbamazepine, barbiturates
- cleft lip/palate –> phenytoin, lamotrigine
- facial dysmorphology –> phenytoin, valproate
- spina bifida
AEDs can effect development over a long period of time even after the birth of the child and can cause cognitive function – fortunately we have new drugs that don’t have as much cognitive disability side effects
these drugs have a higher effect early on in development though days 0-70
why do AEDs cause defects in utero?
- ischemia
- formation of free radicals
- apoptosis of neurons
- decreased folate metabolism
- suppression of fetal neurons
all of these can cause cognitive defects!!
we can try to decrease this by giving the mom folate vitamins!
what is the risk of a fetal malformity in a mom on AEDs?
only 3-7% (:
but it gets higher if you put the mom on 3 or 4 drugs at the same time
which drug was shown to effect the cognitive function of a kid who’s mom was on AEDs while pregnant?
valproate
but if you supplement with folic acid the IQ of the kid was higher! this also helps with neural tube defects, bonus!
which AEDs can be safely given to pregnant women?
- lamotrigine
- levetiracetam
- gabapentin
- lacosamide
which AEDs shouldn’t be given to pregnant women in fear of a fetal malformity or cognitive effects?
- topiramate
- valproate
- zonisamide
which AEDs should be used for elderly patients?
retention was better for lamotrigine > gabapentin > carbmezapine
they basically all had the same rate of seizure free time so lamotrigine is best since it has the highest compliance!
what non-pharmacological treatments can be used for epilepsy treatment?
- keto diet –> produces acidosis which is the opposite of the alkalosis environment that seizures happen in!
- respective surgery to the temporal lobe or to the lesion causing seizures (70% success rate!)
- brain stimulation
- vagus nerve stimulation
why does vagus nerve stimulation help epilepsy?
stimulate the left vagus which deactivates the thalmocortical tract which are often involved in breakthrough seizures
what is responsive neurostimulation?
a device implanted into the brain which picks up the seizure and then zaps it and reduces the refractory period and it controls the seizure that way
very effective
a 41 year old woman develops a rash after starting treatment for epilepsy. which of the following ASDs is most likely to be associated with the risk of a rash?
A. gabapentin
B. carbamazepine
- topiramate
- valproate
- pregabalin
B. carbamazepine
a 30 year old woman is currently 8 weeks pregnant. which of the following ASDs is most likely to be associate with neural tube defect?
A. lacosamide
B. gabapentin
C. valproate
D. lamotrigine
E. zonisamide
C. valproate
it’s also been seen with lamotrigine too though but it’s most severe with valproate
which of the following ASDs follows zero order pharmacokinetics?
A. carbamzepine
B. pregabalin
C. zonisamide
D. phenytoin
E. valproate
D. phenytoin
a 45 year old man develops continuous seizure activity. what duration is consistent with the standard definition of status epilepticus?
5 minutes
most seizures are 1 minute or less
