Chapter 13: Antiseizure Drugs Flashcards
seizures are caused by ___ in the brain, so the treatment for them is to ___
irregular electrical activity, reduce electrical activity
___ is the primary excitatory NT in the CNS
glutamate
___ is the primary inhibitory NT in the CNS
GABA
if we consider neuronal circuits to exist in a balance of excitation and inhibition, a disturbance in this balance can lead to excessive activity which can lead to ___
seizures
the irregular AP of seizures disrupts CNS signalling and can lead to ___, ___, ___ or ___
unconsciousness, convulsions, confusion or altered awareness
blocking Na and Ca ion channels on the PRESYNAPTIC neuron has what effect on activity?
prevents glutamate release and lowers activity
blocking Na and Ca channels on the POSTSYNAPTIC neuron has what effect on activut?
reduces excitability of the postsynaptic neuron and lowers activity
what is the effect of increasing K channel efflux on activity?
more K out gives hyper polarization which reduces excitability
what is the effect of targeting synaptic fusion proteins (SV2A) on activity?
reduces fusion of NT vesicles with presynaptic membrane, inhibiting release and lowering activity
besides lowering excitability signals, we can also enhance ____ signals to reduces seizures
inhibitory
we can increase the inhibitory output of postsynaptic neuron by doing what 3 things concerning GABA?
- activate GABA A receptor
- preventing GABA reuptake
- preventing GABA metabolism
what needs to be inhibited to reduce GABA re-uptake at from the synapse?
GAT-1 transporter
what needs to be inhibited to reduce GABA metabolsim>
GABA transaminase
___ and ___ are examples of voltage gated Na channel blockers
carbamazepine, phenytoin
Na channels blockers bind to the ___ configuration and prevent the channel from ___
inactive; retiring to its resting state
what types of neurons are most susceptible to Na channel blockers?
those which are more active and spend more time at depolarized membrane potentials (those that cause seizures)
blocking Na channels uses 2 types of blocks, what are they and how do they work?
- use-dependent block: most active get blocked
2. voltage-dependent block: most depolarized get blocked
what is important about Na channel blockers having more selectivity for overactive neurons?
preserves normal neuronal function of other neurons and maintains na channel functions in other parts of the body, such as the heart
carbamazepine and phenytoin are ___ inducers
CYP
phenytoin is highly ____
protein bound
most drugs follow first order kinetics, where a ____ of drug is removed per unit time
constant fraction
in zero order kinetics, a constant ___ of drug is removed per unit time
quantity
when phenytoin levels in the blood rise too high, the ____ is reached and the kinetics switch from 1st to ___ order
max capacity of liver to metabolize the drug; 0
what is a consequence of phenytoin stitching over to 0th order at high doses?
even small increases in dose may cause large changes in serum drug concentrations and can lead to ADR very quickly
the most common ADR observed with Na channel blockers result from reduced ____
neuronal transmission
with high doses or Na channel blockers, ___ can occur due to reduced neuronal transmission in the CNS
sedation
what are some ADR of Na channel blockers?
- visual disturbances (eye movement and double vision)
- dizziness
- ataxia
- sedation
- rare hypersensitivity reactions
there is a relatively rare but important hypersensitivity reaction to phenytoin and other structurally similar drugs (carbemazepine), what is it called and what does it look like?
DRESS; drug rash with eosinophilla and systemic symptoms
aside from DRESS; what are some other hypersensitivity reactions that can be seen w/ Na channel blockers?
rash, fever, agranulocytosis
gabapentin was originally developed as a _____mimetic, however, it does not bind to the receptor or any other inhibitory receptor in the CNS at any relevant dose; however it is able to reduce ___
GABA; seizures
gabapentin works by modulating the presence of ___ channels on membrane surface
Ca
when gabapentin binds to the ___subunit of the Ca channel, what happens to the channel;?
alpha 2 delta; remains internalized, not trafficking back to the membrane like it normally would
how does gabapentin preventing Ca channel trafficking to the membrane affect seizures?
less Ca channels means less Ca into neuron, leading to less NT release and reduced excitability
gabapentin relies on a ___ for GI absorption
transporter
how can the amount of gabapentin become saturated?
if the transporter becomes saturated
gabapentin can be used to treat seizures, but is not the most effective; it is used mostly in the management of ___ where Ca channels appear upregulated
neuropathic pain
ADR of gabapentin include :
drowsiness, dizziness, ataxia, tremor, headache
retigabine is a ____ of K channels
positive allosteric modulator
what is the effect of retigabine on seizures?
increase the efflux of K, causing hyper polarization, reducing excitability
what are the ADR of retigabine?
drowsiness, dizziness, blurred vision, confusion
what is the MOA of Levetiracetam for management of seizures?
bind to SVA 2 to prevent fusion of NT (glutamate) vesicles to presynaptic membrane, preventing their release and reducing activity
does levetiracetam have hepatic metabolism? what is the effect of this?
no; results in few drug-drug interactions
the majority of Levetiracetam is excreted in what form by what route?
unchanged; urine
what are the ADR of Levetiracetam?
sedation, ataxia, dizziness
barbiturates are more commonly used as ___ rather than sedatives
anti-seizure
it is though that barbiturates may have additional mechanisms to managing seizures (besides Cl reducing activity), what are they?
may involve ca channels and/or AMPA receptors to further educe activity
what is the MOA of Tiagabine?
inhibits the GAT-1 transporter, allowing GABA to remain in the synapse longer and prolongs the inhibitory effects of the GABA receptor
Give 2 reasons drug-drug interactions may be high in Tiagabine
- highly protein bound
2. metabolized by CYP3A4, which metabolized most drug
what are some ADR of Tiagabine?
dizziness, ataxia, drowsiness, tremor, confusion
what is the MOA of Vigabatrin?
GABA transaminase inhibitor (blocks GABA metabolism)
what allows Vigabatrin to have a long duration of action?
it binds reversibly to GABA-T
Vigabatrin is structurally similar to ___
GABA
what is a unique ADR of Viagabatrin? How serious is it?
may cause retinal dysfunction due to loss of GABA-T in retina. The vision loss is not substantial, but is irreversible
t/f the effectiveness of anti-seizure drugs often outweighs the not knowing the MOA
t
Valproate/ valproic acid is used in the treatment of ___ and __
seizures and mood disorders
valproate has many drug interactions, including with __-and __
phenytoin and phenobarbital
what are 2 common ADR of valproate?
significant weight gain and GI upset
Topiramate likely acts on ___, ___ and ___ to reduce activity
Na channels, GABA receptors and glutamate receptors
what are some ADRs of Topiramate?
impaired cognitive function, dizziness, weight loss
