14. Epilepsy Drugs

Question 1

Seizures are due to a neuronal imbalance due to membrane depolarization leading to enhanced excitatory receptor function (too much glutamate) and reduced what function?

Answer 1

Reduced gaba function (too little gaba)

Question 2

There are 4 classes of drugs that treat seizures aka Anti-Epileptic Drugs = AEDs and those include novel mechanism drugs, blocking low threshold T type Ca2 channels, enhancing inhibitory (GABA) transmission and drugs that suppress?

Answer 2

excitatory (glutamate) transmission

*since there is too much glutamate and not enough Gaba

Question 3

To suppress excitatory glutamate transmission, one group of drugs does this by suppressing voltage gated Nav channels. NaV channels have a resting state in which activation gate is closed and inactivation gate is open, and open state where activation gate is open (during depolarization), and a fast inactivated state where?

Answer 3

inactivation gate is closed once depolarization occurs**

Question 4

NaV channels also have a inactived closed state in which both activation and inactivation gates are closed, this occurs after fast inactivation state, and then the channel resets and goes back to resting state. When can the NaV channel blockers access the pore for the activation gate to block?

Answer 4

When activation gate is in Open state or in fast inactivated state, NOT resting state because activation gate (and its pore where NAv blockers bind is CLOSED

Question 5

Pharmacological activity of AED NaV blockers is state and use-dependent, state being the channell needs to be opened for it to bind, and use dependent, meaning?

Answer 5

the more seizures = more Nav frequency* opening and closing= more efficacy of the drug binding

Question 6

The following drugs prolong fast inactivation state of NaV ion channels: Carbamazepine (Oxcarbazepine/Eslicarbazepine), Lamotrigine, Phenytoin, Topiramate, valproic acid and lacosamide (zonisamide/rufinamide), which of these drugs is also show to enhance slow inactivation of NaV channels?

Answer 6

Lacosamide - Blocks both activation and inactivation gates to not allow release of glutamate (presynaptic terminal)

Question 7

Another way to suppress excitatory glutamate transmission is via supressing ligand gated AMPA and NMDA channels on post synaptic terminals. Perampanel and what drug are AMPA (ligand gated ion channels Na/Ca)- receptor antagonists, which inhibit binding of glutatmate to post synaptic terminals?

Answer 7

Perampanel and Topiramate*

Question 8

What is the only drug that is used as an atagonist at NMDA receptors, which bind and block glutamate from entering the post synpatic neuron?

Answer 8

Felbamate

Question 9

Another way to help with seizures is be enhancing GABA transmission via blocking GABA reuptake or blocking its metabolism. GABAa binds it receptor on post synaptic neuron, which allows Cl to go through, causing hyperpolarization, blunting AP propagation. What drug blocks presynaptic GAT-1 reuptake, not allowing GABA to be taken back up = increasing amount of gaba at post synapatic neuron?

Answer 9

Tiagabine

Question 10

What drug only blocks metabolism of GABA by blocking GABA-T, which increases the amount of gaba?

Answer 10

Vigabatrin

Question 11

What drug has many actions, regarding presynaptic gaba-ergic transmission, it enhances glutamic acid decarboxylase (which increases gaba production), as well as inhibits its metabolism via blocking GABA-T and SSD?

Answer 11

Valproic Acid (note- is also Na Channel blocker)

Question 12

Another way to enhance inhibitory GABA transmission is by potentiating GABAa receptor Cl currents post-synaptically, this is done by barbiturates, benzodiazapines and what drug, which is one of the two AEDs with 3 functions?

Answer 12

Topiramate (GABA-A agonist, inc frequency of GABAa receptor activation AND fast inactivation of NaV channels AND AMPA receptor antagonist)***

Question 13

Benzodiazepines bind to a distinct site on the post-syn gaba receptor, and it potentiates gaba binding, allowing Cl channels to open with greater FREQUENCY, the three drugs commonly used include clonazepam, diazepam and?

Answer 13

Lorazepam

gaba-dependent

Question 14

Barbiturates bind to a distinct site and increases the DURATION of Cl channel opening (doesnt need gaba to function like BZDs do). Lethality is more common in barbs than BZDs for this reason, commonly used barbs include primidone, and what, which is also converted in the body from primidone?

Answer 14

Phenobarbital

gaba-independent*

Question 15

Another way to treat seizures is to BLOCK low threshold T-type Ca2+ channels, which mediate spike and wave activity in the thalamus- HALLMARK of absence (petit mal) seizures, so AEDs that inhibit Ttype Ca channels are useful for controlling absence seizures… What is the drug that has one function, and it is antagonism of T Type Ca channels that target cortex-thalamus oscillation- used ONLY in absence seizures?

Answer 15

Ethosuximide

Question 16

Along with ethosuximide, what other two meds which have multiple MOAs and also are antagonists of Ttype Ca channels on the presynaptic glutamate neuron?

Answer 16

Valproic Acid and Zonisamide (which prolong fast inactivation of NaV channels)
VA also is a GABA-T inhibitor

Question 17

Levetiracetam and what other medication are novel medications, that inhibit SV2A which allows closure of vesicles in the presyn glutamate neuron, without SV2A- vesicles are not made and glutamate is not released into the synaptic cleft?

Answer 17

Brivaracetam

*SV2A = synaptic vesicle 2A

Question 18

Pregabalin and what other medication are novel meds, that block a2d subunit of P/Q-type Ca2+ channels on the presynaptic glutamate neuron, decreasing glutamate release, both of these drugs commonly used in chronic pain conditions such as fibromyalgia, diabetic neuropathy, etc?

Answer 18

Gabapentin

Question 19

What novel AED OPENS K+ channels on pre and post synaptic terminals of glutamate neurons, inhibiting glutamate release and post synaptic uptake?

Answer 19

Ezogabine

Question 20

What drug is a presynap glutamate NaV channel blocker, a post synaptic glutamate AMPA receptor blocker, and a post-synaptic GABA promoting agent via inc flux of Cl?

Answer 20

Topiramate

Question 21

What drug is a presynap glutamate NaV channel blocker, a presynaptic GABAT/SSD blocker, and a Ca2+ T-type channel blocker for absence seizures?

Answer 21

Valproic Acid

Question 22

What drug is a cannabidiol that is commonly used in combo with other AEDs, with an MOA that is unknown, but it does not bind to CBD receptors, used in pediatric seizure syndromes including dravet and lennox-gastaut syndrome?

Answer 22

Epidiolex

Question 23

There are two broad warning/risks for ALL of the AEDs, this includes abrupt withdrawal of antiepileptic medication may precipitate status epilepticus, and there is an increase in?

Answer 23

Suicidal behavior and ideation

Question 24

What medication has zero order kinetics (saturable), is a well known inducer of CYP450*, and causes gingival hyperplasia and hypocalcemia along with vitamin D deficiencies and osteoporosis?

Answer 24

Phenytoin

Question 25

Osteopenia/porosis are associated with chronic admin of carbamazepine, phenytoin, phenobarbital and valproic acid, all of which induce CYP450 dependent vitamin D catabolism, reducing amount of Vit D….

Answer 25

MEOW

Question 26

What medication is a well known inducer of CYP450, and commonly induces auto-induction (self metabolism), and is associated with leukopenia, neutropenia, and thrombocytopenia?

Answer 26

Carbamazepine

Question 27

What is an analog of carbamazepine with fewer CNS/ hematological SEs due to formation of an alternative active metabolite, and is a less potent CYP450 inducer, aka S-licarbazine?

Answer 27

Oxcarbazepine

Question 28

What medication needs to be monitored due to a high fatality risk, is a inducer of CYP450 and commonly causes CNS depression?

Answer 28

Phenobarbital

Question 29

What medication causes PERMANENT vision loss, and is only prescribeable via REMS program (risk evaluation and mitigation strategy?

Answer 29

Vigabatrin

Question 30

The MC drug drug interactions associated with CYP450 induction is via carbamazepine, phenytoin and?

Answer 30

phenopharb

Question 31

The 3 CYP450 inducers mentioned can INCREASE clearance of OCPs (estrogen), leading to pregnancy, increase clearance of warfarin causing less coagulation, and increased clearance of HIV causing an elevated risk for?

Answer 31

HIV replication

Question 32

Lamotrigine and what mediaction inhibits conjugation of drugs by UGT (glucuronosyltransferase) causing accumation of parent drugs (esp each other when used together)?

Answer 32

Valproic Acid

Question 33

Phenytoin, Carbamazepine, and Phenobarbitol induce* conjugation of drugs by UGT causing a reduction of parent drug, meaning there is an increase in ?

Answer 33

the durgs metabolite (note- this is why these three drugs are no longer used)

Question 34

Newer AEDs such as levetiracetam, topiramate, oxcarbazepine, gabapentin, pregabalin, and vigabatrin minimize drug interactions and do not get cleared by the liver, instead they are cleared via?

Answer 34

The kidney- so renal insufficiency requires dose adjustment*

Question 35

Status epilepticus ias a medical emergency, and is a seizure that persists for a sufficienct length of time or is repeated frequently enough that recovery between attacks does not occur- see with abrupt withdrawal of AEDs, BZDs, opioids, alcohol, brain mass/trauma, infection and fever. First line therapy is via IV and is what?

Answer 35

Lorazepam or Diazepam

Question 36

If there is no IV, give midazolam IM, in the second IV- give fosphenytoin, phenytoin, levetiracetam, or what?

Answer 36

Valproic Acid

Question 37

If lorazepam/diazepam/midazolam/fosphenytoin/phenytoin/levitiracetam does not work and status epilepticus continues, continue onto second thereapy, which is repeat *fosphenytoin or try first line drug not already given, intubate/ventilate, BP/cardiac monitoring, and prepare for continuous infusion with midazolam or?

Answer 37

Propofol