lecture 47 Flashcards
yang - pharmacology of anticonvulsant drugs
what is the main MOA of anticonvulsant drugs?
stabilize and reduce neuronal excitability (reduce E/I balance)
what are the subsequent different types of MOA of anticonvulsant drugs?
decrease Na influx, prolong inactivation of Na+ channels
reduction of calcium influx (absence seizures)
enhance GABA-mediated neuronal inhibition
antagonism of excitatory transmitters (like glutamate)
other targets (levetiracetam)
what are excitatory presynaptic targets?
Na and Ca channels
what are excitatory postsynaptic targets?
NMDA and AMPA receptors
what are inhibitory presynaptic targets?
GABA transporter 1 (GAT-1)
GABA transaminase (GABA-T)
what are inhibitory postsynpatic targets?
GABAa receptors
GABAb receptors ?
what is the MOA of phenytoin (dilantin)?
binds and stabilizes the inactivated state of Na channels (not isoform selective thus can target sodium channels in the brain as well as other parts of the body)
what are other drugs with similar MOA to phenytoin?
fosphenytoin (cerebyx) – injectable phosphate prodrug
what is the PK of phenytoin?
elimination kinetics are dose-dependent leads to non-linear PK
what are drug-drug interactions with phenytoin?
displaced from plasma proteins by other drugs (like valproate) leading to an increase
induces liver P450 enzymes, leading to increasing rate of metabolism of other drugs (like cabamazepine)
what are the SE of phenytoin?
arrhythmia
visual (involuntary eye movements and blurred vision)
ataxia
GI symptoms
gingival hyperplasia, hirsutism
hypersensitivity reactions (skin rash)
what is the main structural component of carbamazepine?
tricycline compound
what is MOA of carbamazepine?
binds and stabilizes the inactivated state of Na+ channels
what are drug-drug interactions of carbamazepine?
induces liver cytochrome P450 enzymes
what is the toxicity associated with carbamazepine?
blurred vision, ataxia, GI disturbances
sedation at high doses, serious skin rash (SJS/TEN)
DRESS syndrome, hypersensitivity rxn
what is the MOA of lacosamide?
enhances inactivation of voltage-gated Na+ channels
what is toxicity associated with lacosamide?
dermatological reactions
cardiac risk (PR interval prolongation)
visual disturbances
what drugs specifically target pre-synaptic Na+ channels?
phenytoin, carbamazepine, lacosamide
what drugs are barbiturates?
phenobarbital (luminal) and primidone (mysoline)
what barbiturate should be used in infants?
phenobarbital up to 2 mo
what is the MOA of phenobarbital?
binds to an allosteric regulatory site on the GABAa receptor increases duration of Cl- channel-opening events (thus enhances GABA inhibitory signaling)
what are the drug-drug interactions of phenobarbital?
induces P450 enzymes
what are toxicity associated with phenobarbital?
sedation
physical dependence (potential of abuse)
what is the MOA of primidone?
more similar to phenytoin than phenobarbital despite being a barbiturates
what drugs are benzodiazepines?
diazepam (valium) and clonazepam (klonopin)
when should diazepam vs clonazepam be used?
diazepam –> tonic-clonic status epilepticus; acute control as a rectal gel
clonazepam –> acute treatment of epilepsy and absence seizures
what is the MOA of diazepam?
binds to an allosteric regulatory site on the GABAa receptor increases frequency of Cl- channel-opening events thus enhancing GABA inhibitory signaling
what is the toxicity associated with diazepam?
sedation
physical dependence (tolerance) –> not useful for chronic treatment then
what inhibitory drugs specifically target post-synaptic GABAa receptors?
phenobarbital
benzodiazepines
what is the MOA of gabapentin?
increases GABA release
decrease presynaptic Ca2+ influx, thereby reducing glutamate release
what is the toxicity of gabapentin?
sedation
ataxia
behavioral changes
what is the moa of vigabatrin (sabrile)?
irreversible inhibitor of GABA transaminase (GABA-T), the enzyme responsible for degrading GABA
what is the toxicity of vigabatrin?
sedation
depression
visual field defects
what is the moa of tiagabine (gabatril)?
inhibits GABA transporter (GAT-1)
what is the toxicity associated with tiagabine (gabatril)?
sedation
ataxia
what inhibitory drugs target pre-synaptic targets?
tiagabine - GAT 1
vigabatrin - GABA T
what does the NMDA receptor do?
glutamate binding triggers an influx of Na/Ca and an efflux of K
what does the AMPA receptor do?
glutamate binding triggers an influx of Na and efflux of K
what is the moa of felbamate (felbatol)?
NMDA receptor antagonist
what is toxicity associated with felbamate?
severe hepatitis (which is why its a third line drug in refractory cases like focal seizures)
what is the moa of topiramate (topamax)?
AMPA and kainate receptor antagonist
what is the toxicities associated with topiramate (topamax)?
confusion
cognitive dysfunction
sedation
vision loss
what drugs target post-synaptic excitatory receptors?
NMDA - felbamate
AMPA - topiramate
what is the MOA of ethosuximide (zarontin)?
blocks T-type Ca2+ channels (low threshold current) in thalamic neurons
what do T-type Ca2+ channels do?
thought to be involved in generating the rhythmic discharge of an absence attack
what are toxicities associated with ethosuximide (zarontin)?
GI distress
sedation
what is the MOA of lamotrigine (lamictal)?
inhibits Na+ and voltage-gated Ca2+ channels
what is the toxicity of lamotrigine (lamictal)?
sedation
ataxia
serious skin rash (SJS/TEN)
what is the MOA of valproate (depaken)?
inhibits Na and Ca channels
what are the drug-drug interactions of valproate?
displaces phenytoin from plasma proteins
inhibits the metabolism of phenytoin, carbamazepine, phenobarbital, and lamotrigine
what are the toxicities of valproate?
GI distress
hyperammonemia
hepatotoxicity (can be fatal so careful monitoring is necessary)
what is the moa of levetiracetam (keppra)?
binds the synaptic vesicular protein SV2A and thus interferes with synaptic vesicle release and neurotransmission
also appears to interfere with calcium entry through Ca2+ channels and with intraneuronal calcium signaling
what is unique about levetiracetam?
could be a candidate for the treatment of status epilepticus cases that are refractory to other therapies
what drug targets excitatory pre-synaptic Ca channels?
ethosuximide
lamotrigine
levetiracetam
valproate
