47 - Anticonvulsant drugs

Question 1

anticonvulsant drugs

mechansim of action: stabiliize and reduce neuronal ___ ( ___ E/I balance)
1) decrease ___ influx, prolong inactivation of ___ channels
2) reduction of ___ influx (critical for absense seizures)
3) enhance ___ mediated neuronal inhibition
4) antagonism of excitatory transmitters (i.e., ___ )
5) other targets (i.e., levetiracetam)

Answer 1

• excitability
• reduce
• Na, Na
• Ca
• GABA
• glutamate

Question 2

drugs that decrease Na influx and prolong inactivation of Na channels (6)

Answer 2

• carbamazepine
• oxcarbazepine
• phenytoin
• lacosamide
• lamotrigine
• valproate

Question 3

drugs that reduce calcium influx (absence seizures) (3)

Answer 3

• ethosuximide
• lamotrigine
• valproate

Question 4

drugs that enhance GABA mediated neuronal inhibition (6)

Answer 4

activates GABAA receptor
- barbiturates
- benzodiazepines

increases GABA levels
- valproate
- gabapentin

inhibits GABA tranaminase
- vigabatrin

inhibits GAT-1
- tiagabine

Question 5

antagonism of excitatory transmitters (glutamate) (2)

Answer 5

• felbamate - antagonist of NMDA receptors
• topiramate - antagonist of kainate/AMPA receptors

Question 6

why are few drugs targeting K channels to treat seizures

Answer 6

think about side effects in other organs! will really mess other things up

Question 7

molecular targets at the excitatory (glutamatergic) synapse

presynaptics targets
- ___ and ___ channels

post-synaptic targets
- ___ and ___ receptors

Answer 7

• Na, Ca
• NMDA, AMPA

Question 8

molecular targets at the inhibitory (GABAergic) synapse

presynaptic targets
- GABA transporter ( ___ )
- GABA ___ (GABA-T)

post synaptic targets
- GABA ___ and GABA ___ (?)

Answer 8

• GAT-1
• transaminase
• A, B

Question 9

treatment: focal seizures and genrealized tonic-clonic seizures

a number of antiseizuure drugs have a common ___ ring structure

Answer 9

heterocyclic

Question 10

treatment: focal seizures and genrealized tonic-clonic seizures

hydantoins: ___ (Dilantin)
- oldest non-sedative antiseizure drugs
- MOA: binds and stabilizes the ___ state of Na channels (not isoform ___ , thus can target Na channels in the brain as well as other parts of the body)

other drugs in this class with a similar mechanism of action
- ___ (Cerebyx) - injectable phosphate prodrug
- ethotoin (fewer SE, but less effective than phenytoin)
- mephenytoin (more toxic than phenytoin)

Answer 10

phenytoin
- non-sedatice
- inactivated
- selective
- fosphenytoin

Question 11

T or F: phenytoin and other anticonvulsants (carbamazepine, valproate) act by binding and stabilizing the activated state of Na channels

Answer 11

FALSE
inactivated

Question 12

Hydantoins: phenytoin PK, interactions, toxicity

phenytoin ___ kinetics are dose-dependent. leads to non-linear PK
- small increases in drug dose can lead to dramatic increases in blood concentration

drug interactions
- can be displaced from plasma proteins by other drugs like ___, leading to an increase in its plasma concentration
- induced liver CYPs, increasing rate of metabolism of other drugs like ___

SE
- arrhythmia
- visual: ___ (involuntary eye movements), ___ (blurred vision)
- ataxia
- GI symptoms
- sedation
- gingival hyperplasia
- hirsutism
- hypersensitivity reactions (skin rash)

Answer 12

elimination
- valproate
- carbamazepine
- nystagmus, diplopia

Question 13

iminostilbenes: carbamazepine (Tegretol) and oxcarbazepine (Trileptal)

carbamazepine
- structure: ___ compound (used to treat bipolar depression)

MOA: binds and stabilizes the ___ state of Na channels

drug interactions
- ___ liver CYPs, increasing the rate of metabolism of itself and other drugs (phenytoin, ethosuximide, valproate, clonazepam)

toxicity:
- blurred vision
- ataxia
- GI disturbances
- sedation at high doses
- serious skin rash (Stevens-Johnson Syndrome/toxic epidermal necrolysis)
- DRESS hypersensitivity

Oxcarbazepine
- reduced toxicity compared to carbamazepine

Answer 13

• tricyclic
• inactive
• induces

Question 14

Lacosamide (Vimpat)

MOA: enhances ___ of voltage gated Na channels

toxicity:
- dermatological reactions
- cardiac risks ( ___ interval prolongation)
- visual disturbances

Answer 14

inactivation
PR

Question 15

molecular targets at the excitatory (glutamatergic) synapse

presynaptic targets
- ___ channels (phenytoin, carbamazepine, lacosamide)
- ___ channels

post-synaptic targets
- ___ and ___ receptors

Answer 15

• Na
• Ca
• NMDA, AMPA

Question 16

barbiturates and benzodiazepines bind an ___ regulatory site on the GABA A receptor

Answer 16

allosteric

Question 17

Barbiturates

___ (Luminal)
- drug of choice in infants up to ___ months of age

MOA: binds to an ___ regulatory site on the GABA A receptor, increases duration of ___ channel opening events (and thus enhances GABA inhibitory signaling)

• drug interactions: induces liver CYP enzymes
• toxicity: sedation, physical dependence (potential of abuse)

___ ( Mysoline)
MOA: may be more similar to that of ___ than phenobarbital

Answer 17

phenobarbital
- 2
- allosteric

primidone
phenytoin

Question 18

Benzodiazepines

___ (Valium)
- especially useful for ___ often administered as a ___ gel for acute control of seizure activity

MOA: binds to an ___ regulatory site on the GABA A receptor, increases ___ of Cl channel opening events (enhancing GABA inhibitory signaling)

toxicity:
- sedation
- physical dependence (tolerance) not useful for ___ treatment

Clonazepam
- useful for acute treatment of epiliepsy and ___ seizures
- simialar properties as for diazepam

Answer 18

Diazepam
- tonic-clonic status epilepticus
- rectal
- allosteric, frequency
- chronic
- absence

Question 19

molecular targets at the inhibitory GABAergic synapse

presynaptic targets
- GABA trasporter ( ___ )
- GABA ___ (GABA-T)

post-synaptic targets
- GABA A receptors ( ___ and ___ )

Answer 19

GAT-1
transaminase
phenobarbital, benzodiazepines

Question 20

gabapentin (Neurontin): used as an ___ anti-seizure therapy (also used for neuropathic pain and migraine)
- ___ analog

MOA: increases ___ release, decreases presynaptic ___ influx, thereby reducing glutamate release

toxicity
- sedation
- ataxia
- behavioral changes

pregabalin (Lyrica)
- similar

Answer 20

adjunct
- GABA
- GABA, Ca

Question 21

___ (Sabrile)
- used as an ___ therapy for refractory patients
- analog of ___

MOA: ___ inhibitor of GABA ___ (GABA-T), the enyme responsible for degrading GABA

toxicity
- sedation
- weight gain
- agitation
- psychosis
- depression
- visual field defects

___ (Gabatril): also used as ___ therapy
MOA: inhibits GABA ___ (GAT-1)
toxicity
- nervousness
- depression
- tremor
- sedation
- ataxia

Answer 21

vigabatrin
- adjunct
- GABA
- irreversible, transaminase

tiagabine, adjunct
- transporter

Question 22

molecular targets at the inhibitory (GABAergic) synapse

presynaptic targets
- GABA transporter (GAT-1) - ___
- GABA transamainase - ___

post-synaptic targets - GABA A receptors - ___ and ___

and gabapentin and pregabalin

Answer 22

• tiagabine
• vigabatrin
• phenobarbital, benxodiazepines

Question 23

targets at the excitatory, glutamatergic synapse: NMDA and AMPA

NMDA receptor: glutamate binding triggers an influx of __ and ___ and an efflux of ___

AMPA receptor: glutamate binding triggers an influx of ___ and efflux of ___. This is also true of a 3rd ionotropic glutamate receptor, ___ receptor

Answer 23

• Na, Ca, K
• Na, K, kainate

Question 24

___ (Felbatol)
- used 3rd line for refractory cases (especially ___ seizures)

MOA: ___ recceptor antagonist

toxicity
- severe ____ (why its 3rd line)

___ (Topamax)
- used as a monotherapy or adjunct therapy
- structure: substituted ___ (unique structure compared to other anticonvulsants)

MOA: ___ and ___ receptor antagonist

toxicity
- nervousness
- confusion
- cognitive dysfunction
- sedation
- vision loss

Answer 24

felbamate
- focal
- hepatitis

topiramate
- monosaccharide
- AMPA, kainare

Question 25

# molecular targets at the excitatry (glutamatergic) synapse presynaptic targets - Na channels - ___ , ___ , and ___ - Ca channels post-synaptic targets - NMDA receptors - ___ - AMPA receptors - ___

Answer 25

- phenytoin, carbamazepine, lacosamide - felbamate - topiramate

Question 26

# Succinimides ethosuximide (Zarontin) - pure ___ seizure drug - MOA: blocks ___ type ___ channels (low threshold current) in ___ neurons - these channels are thought to be involved in generating the ___ discharge of an absence attack (remember: generalization involves ___ signaling) toxicity - **GI distress** - **Sedation** - psychiatric disturbances

Answer 26

- absence - T, Ca, thalamic - rhythmic, thalamocortical

Question 27

# molecular targets at the excitatory (glutamatergic) synapse presynaptic targets - Na channels - ___ , ___ , and ___ - Ca channels - ___ post synaptic - NDMA receptors - ___ - AMPA receptors - ___

Answer 27

- phenytoin, carbamazepine, lacosamide - ethosuximide - felbamate - topiramate

Question 28

which of the following statements is TRUE? A) tiagabine inhibits GABA transaminase B) Gabapentin inreases Cl influx in post synaptic neurons C) Topiramate is an NMDA receptor antagonist D) Phenytoin is stabilized by the co-administratin of carbamazepine

Answer 28

B) Gabapentin inreases Cl influx in post synaptic neurons

Question 29

___ (Lamictal) - uses: primary or adjunct therapy for ___ and primary ___ seizures, including ___ ; also used in bipolar disorder - structure: phenyltriazine MOA - **inhbits ___ and voltage gated ___ channels** toxicity - sedation - ataxia - **serious skin rash ( ___ - ___ syndrome/toxic epidermal necrolysis)

Answer 29

Lamotrigine - focal, generalized, absence - Na, Ca - Stevens-Johnson

Question 30

___ (Depaken) - uses: ___ and ___ seizures, including ___; bipolar disorder, migraine headache - structure: ___ acid (ionized at physiological pH) MOA: - inhibits ___ and ___ channels - increases ___ levels by stimualting glutamic acid decarboxylase or inhibiting GAT-1 or GABA-T drug interactions - displaces ___ from plasma proteins - inhibits the metabolism of phenytoin, carbamazepine, phenobarbital, lamotrigine toxicity - **GI distress** - **hyperammonemia** - **hepatotoxicity (careful monitoring)** - sedation - weight gain - tremor (at high dose) | dirty

Answer 30

valproate - focal, generalized, absence - fatty - Na, Ca - GABA - phenytoin

Question 31

___ (Keppra) - uses: ___ , ___ , and ___ seizures, and status epilepticus MOA - binds the ___ protein, SV2A, and thus interferes with release and neurotransmission - due to unique MOA, it is candidate for treatment of ___ cases that are refractory to other therapies brivaracetam (Briviact): analog of levetiracetam that acts via a simialr mechanism, but with ___ affinity for SV2A

Answer 31

levetiracetam - focal, generalized, myoclonic - synaptic vesicular - status epilepticus - higher

Question 32

# molecular targets at the excitatory (glutamatergic) synapse presynaptic targets - Na channels (5) - Ca channels (4) post synaptic targets - NMDA receptors - ___ - AMPA receptors - ___

Answer 32

- phenytoin, carbamazepine, lacosamide, lamotrigine, valproate - ethosuximide, lamotrigine, levetiracetam, valproate - felbamate - topiramate

Question 33

T or F: genetic and phenotypic heterogeneity suggest therapeutic implications in SN2A related disorders

Answer 33

True | what is this? PGx or something?