Med Chem - Epilepsy

Question 1

how can epilepsy be acquired

Answer 1

insult to the brain - like trauma, infection, stroke tumor

or a genetic mutation in ion channel or neurotransmitter genes/proteins that control brain excitability

Question 2

in epilepsy, there is:

____ activity of voltage gated ion channels (___, ___, and ____)

_____ GABA neurotransmission

_____ excitatory neurotransmission

alteration of ______ ion concentrations (__ and ___)

Answer 2

increased activity of voltage gated ion channels (sodium, calcium, and potassium)

decreased GABA neurotransmission

increased excitatory neurotransmission (glutamate)

alteration of EXTRACELLULAR ion concentrations (calcium and potassium)

Question 3

true or false

for epilepsy, we want drugs to decrease GABA activity

Answer 3

FALSE - increase GABA activity

Question 4

*** what enzyme synthesizes GABA?? what is the precursor?

Answer 4

glutamic acid decarboxylase

precursor is L-glutamate

Question 5

**what is the first enzyme that metabolizes GABA

Answer 5

GABA transaminase
also uses PLP as a cofactor!!

Question 6

what happens after GABA transaminase metabolizes GABA with PLP as a cofactor

Answer 6

becomes an aldehyde, then an acid

then goes through krebs cycle to become alpha-ketoglutarate and is recycled back to become L-glutamate and start the process again

Question 7

true or false

T-type calcium channels are high threshold

Answer 7

FALSE - low threshold

require only weak depolarization for activation

Question 8

MOA ezogabine

Answer 8

facilitate potassium efflux, thus helping to hyperpolarize the membrane

Question 9

name an antiepileptic that works by inhibiting the release of glutamate

Answer 9

lamotrigine

Question 10

name 3 antiepileptics that block the T type calcium channel

Answer 10

ethosuximide
valproate
zonisamide

Question 11

name 2 antiepileptics that block the L type calcium channels

Answer 11

gabapentin
pregabalin

Question 12

levitiracetam MOA

Answer 12

binds synaptic vesicle2A

prevents glutamate release

Question 13

what do all of the 1st gen antiepileptics structurally have in common (except for potassium bromide)

Answer 13

ureide moeity

Question 14

true or false

barbiturates are lipophilic strong acids

Answer 14

false - lipophilic weak acids

Question 15

are barbiturates well distributed in the CNS

Answer 15

yes

Question 16

what is primidone

Answer 16

a barbiturate

Question 17

MOA phenobarbital

Answer 17

inhibits sodium channels and enhances GABA transmission

Question 18

explain how the pH of the urine affects the excretion of barbiturates

Answer 18

increased basicity of the urine (alkalinization) increases the rate of phenobarbital excretion

this is bc the N’s will be positively charged and ionized!

Question 19

DDI concern barbiturates

Answer 19

protein bound

inducer of CYP3A4

inducer of UDP-glucuronyltransferase

Question 20

primidone concern

Answer 20

it’s metabolized to phenobarbital and PEMA, a toxic metabolite

while these are active, PEMA’s toxicity is a concern

Question 21

true or false

primidone has the same MOA as phenobarbital

Answer 21

true

Question 22

MOA phenytoin

Answer 22

prolongs the open/inactivated state of sodium channels

stabilizes the inactivation gate!!!

blocks repetitive firing

Question 23

what was the first anticonvulsant that could be separated from sedative-hypnotic activity

Answer 23

phenytoin

Question 24

true or false

phenytoin is a WEAKER ACID than barbiturates

Answer 24

true

Question 25

true or false phenytoin affects resting neurons

Answer 25

false - does not

Question 26

explain the absorption of phenytoin

Answer 26

limited and erratic absorption bc it absorbs CO2 in solution, decreasing the pH and making more acidic. the drug precipitates

Question 27

hydantoin prodrug

Answer 27

fosphenytoin

Question 28

why was fosphenytoin designed

Answer 28

overcome the solubility issues with sodium phenytoin

Question 29

name 4 classes of anticonvulsants with a ureide moiety

Answer 29

barbiturates hydantoins oxazolidinediones succinimides

Question 30

name an oxazolidindione derivative and a succinimide derivative

Answer 30

oxa - trimethadione succinimide - ethosuximide

Question 31

why were succinimides discovered

Answer 31

better toxicity profile and are safer than oxazolidinediones

Question 32

MOA of oxazolidinediones and succinimides

Answer 32

blocks low threshold T type calcium channels decreased hyper-excitability of thalamic neurons

Question 33

is valproic acid teratogenic

Answer 33

yes

Question 34

which benzodiazepine is particularly useful for treating status epilepticues

Answer 34

midazolam

Question 35

benzodiazepines are ___ fused to ____

Answer 35

benzene fused to an azepine

Question 36

MOA benzodiazepines

Answer 36

enhance the inhibitory effect of GABA also diminish voltage gates sodium, potassium, and calcium channels

Question 37

name an iminostilbene

Answer 37

carbamazepine

Question 38

name Y-position modified GABA analog

Answer 38

vigabatrin

Question 39

how are gabapentin and pregabalin transported across membrane

Answer 39

NOT through passive diffusion - zwitterionic and polar transported through active transport by L-amino acid transporters bc resemble isoleucine and leucine

Question 40

which has higher bioavailability and why - pregabalin or gabapentin

Answer 40

pregabalin bc pregabalin is a substrate for MULTIPLE l amino acid transporters and not just LAT-1

Question 41

MOA vigabatrin and tiagabine

Answer 41

vigabatrin - irreversible (suicide) inhibitor of GABA transaminase tiagabine - selective inhibitor of GABA-1 transporter. thus, increased GABA and thus the inhibitor action of GABA is prolonged

Question 42

BBW vigabatrin

Answer 42

irreversible bilateral visual field constriction

Question 43

what does GABA transaminase do

Answer 43

metabolizes GABA so inhibiting the enzyme (like vigabatrin) increases GABA

Question 44

"potent inhibitor of GABA reuptake into neurons and glial cells"

Answer 44

tiagabine selectively inhibits GABA-1 transporter

Question 45

true or false felbamate is a GABA analog

Answer 45

FALSE - not a GABA analog dicarbamate analog

Question 46

MOA felbamate

Answer 46

multi MOA NMDA receptor antagonist, potentiates GABA currents, inhibits sodium channels, etc

Question 47

true or false atropaldehyde is the major metabolite of felbamate

Answer 47

false - major is COOH minor is atropaldehyde - but gives toxicities like aplastic anemia, hepatotoxicity

Question 48

topiramate is ___ at its core

Answer 48

D-fructose

Question 49

topiramate was originally designed as what kind of drug

Answer 49

antidiabetic

Question 50

topiramate is relatively _____ compared to other anti epileptics

Answer 50

hydrophilic

Question 51

topiramate is too hydrophilic to be passively absorbed. how does it get into the brain?

Answer 51

by D-glc transporter due to structural similarity

Question 52

true or false topiramate has multi MOA

Answer 52

true antagonizes AMPA receptors, increased GABA transmission, blocks sodium and calcium channels

Question 53

name 2 cyclic GABA analogs

Answer 53

leviteracetam brivaracetam

Question 54

the "racetam" class is characterized by what structural feature

Answer 54

N-substituted pyrrolidinone core

Question 55

1 MOA of brivaracetam that keppra does not have

Answer 55

inhibits voltage gated sodium channels

Question 56

"functionalized amino acid" ____ derivative

Answer 56

lacosamide serine derivative