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
