lecture 47

Question 1

what is the main MOA of anticonvulsant drugs?

Answer 1

stabilize and reduce neuronal excitability (reduce E/I balance)

Question 2

what are the subsequent different types of MOA of anticonvulsant drugs?

Answer 2

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)

Question 3

what are excitatory presynaptic targets?

Answer 3

Na and Ca channels

Question 4

what are excitatory postsynaptic targets?

Answer 4

NMDA and AMPA receptors

Question 5

what are inhibitory presynaptic targets?

Answer 5

GABA transporter 1 (GAT-1)
GABA transaminase (GABA-T)

Question 6

what are inhibitory postsynpatic targets?

Answer 6

GABAa receptors
GABAb receptors ?

Question 7

what is the MOA of phenytoin (dilantin)?

Answer 7

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)

Question 8

what are other drugs with similar MOA to phenytoin?

Answer 8

fosphenytoin (cerebyx) – injectable phosphate prodrug

Question 9

what is the PK of phenytoin?

Answer 9

elimination kinetics are dose-dependent leads to non-linear PK

Question 10

what are drug-drug interactions with phenytoin?

Answer 10

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)

Question 11

what are the SE of phenytoin?

Answer 11

arrhythmia
visual (involuntary eye movements and blurred vision)
ataxia
GI symptoms
gingival hyperplasia, hirsutism
hypersensitivity reactions (skin rash)

Question 12

what is the main structural component of carbamazepine?

Answer 12

tricycline compound

Question 13

what is MOA of carbamazepine?

Answer 13

binds and stabilizes the inactivated state of Na+ channels

Question 14

what are drug-drug interactions of carbamazepine?

Answer 14

induces liver cytochrome P450 enzymes

Question 15

what is the toxicity associated with carbamazepine?

Answer 15

blurred vision, ataxia, GI disturbances
sedation at high doses, serious skin rash (SJS/TEN)
DRESS syndrome, hypersensitivity rxn

Question 16

what is the MOA of lacosamide?

Answer 16

enhances inactivation of voltage-gated Na+ channels

Question 17

what is toxicity associated with lacosamide?

Answer 17

dermatological reactions
cardiac risk (PR interval prolongation)
visual disturbances

Question 18

what drugs specifically target pre-synaptic Na+ channels?

Answer 18

phenytoin, carbamazepine, lacosamide

Question 19

what drugs are barbiturates?

Answer 19

phenobarbital (luminal) and primidone (mysoline)

Question 20

what barbiturate should be used in infants?

Answer 20

phenobarbital up to 2 mo

Question 21

what is the MOA of phenobarbital?

Answer 21

binds to an allosteric regulatory site on the GABAa receptor increases duration of Cl- channel-opening events (thus enhances GABA inhibitory signaling)

Question 22

what are the drug-drug interactions of phenobarbital?

Answer 22

induces P450 enzymes

Question 23

what are toxicity associated with phenobarbital?

Answer 23

sedation
physical dependence (potential of abuse)

Question 24

what is the MOA of primidone?

Answer 24

more similar to phenytoin than phenobarbital despite being a barbiturates

Question 25

what drugs are benzodiazepines?

Answer 25

diazepam (valium) and clonazepam (klonopin)

Question 26

when should diazepam vs clonazepam be used?

Answer 26

diazepam --> tonic-clonic status epilepticus; acute control as a rectal gel clonazepam --> acute treatment of epilepsy and absence seizures

Question 27

what is the MOA of diazepam?

Answer 27

binds to an allosteric regulatory site on the GABAa receptor increases frequency of Cl- channel-opening events thus enhancing GABA inhibitory signaling

Question 28

what is the toxicity associated with diazepam?

Answer 28

sedation physical dependence (tolerance) --> not useful for chronic treatment then

Question 29

what inhibitory drugs specifically target post-synaptic GABAa receptors?

Answer 29

phenobarbital benzodiazepines

Question 30

what is the MOA of gabapentin?

Answer 30

increases GABA release decrease presynaptic Ca2+ influx, thereby reducing glutamate release

Question 31

what is the toxicity of gabapentin?

Answer 31

sedation ataxia behavioral changes

Question 32

what is the moa of vigabatrin (sabrile)?

Answer 32

irreversible inhibitor of GABA transaminase (GABA-T), the enzyme responsible for degrading GABA

Question 33

what is the toxicity of vigabatrin?

Answer 33

sedation depression visual field defects

Question 34

what is the moa of tiagabine (gabatril)?

Answer 34

inhibits GABA transporter (GAT-1)

Question 35

what is the toxicity associated with tiagabine (gabatril)?

Answer 35

sedation ataxia

Question 36

what inhibitory drugs target pre-synaptic targets?

Answer 36

tiagabine - GAT 1 vigabatrin - GABA T

Question 37

what does the NMDA receptor do?

Answer 37

glutamate binding triggers an influx of Na/Ca and an efflux of K

Question 38

what does the AMPA receptor do?

Answer 38

glutamate binding triggers an influx of Na and efflux of K

Question 39

what is the moa of felbamate (felbatol)?

Answer 39

NMDA receptor antagonist

Question 40

what is toxicity associated with felbamate?

Answer 40

severe hepatitis (which is why its a third line drug in refractory cases like focal seizures)

Question 41

what is the moa of topiramate (topamax)?

Answer 41

AMPA and kainate receptor antagonist

Question 42

what is the toxicities associated with topiramate (topamax)?

Answer 42

confusion cognitive dysfunction sedation vision loss

Question 43

what drugs target post-synaptic excitatory receptors?

Answer 43

NMDA - felbamate AMPA - topiramate

Question 44

what is the MOA of ethosuximide (zarontin)?

Answer 44

blocks T-type Ca2+ channels (low threshold current) in thalamic neurons

Question 45

what do T-type Ca2+ channels do?

Answer 45

thought to be involved in generating the rhythmic discharge of an absence attack

Question 46

what are toxicities associated with ethosuximide (zarontin)?

Answer 46

GI distress sedation

Question 47

what is the MOA of lamotrigine (lamictal)?

Answer 47

inhibits Na+ and voltage-gated Ca2+ channels

Question 48

what is the toxicity of lamotrigine (lamictal)?

Answer 48

sedation ataxia serious skin rash (SJS/TEN)

Question 49

what is the MOA of valproate (depaken)?

Answer 49

inhibits Na and Ca channels

Question 50

what are the drug-drug interactions of valproate?

Answer 50

displaces phenytoin from plasma proteins inhibits the metabolism of phenytoin, carbamazepine, phenobarbital, and lamotrigine

Question 51

what are the toxicities of valproate?

Answer 51

GI distress hyperammonemia hepatotoxicity (can be fatal so careful monitoring is necessary)

Question 52

what is the moa of levetiracetam (keppra)?

Answer 52

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

Question 53

what is unique about levetiracetam?

Answer 53

could be a candidate for the treatment of status epilepticus cases that are refractory to other therapies

Question 54

what drug targets excitatory pre-synaptic Ca channels?

Answer 54

ethosuximide lamotrigine levetiracetam valproate