47 - Anticonvulsant drugs Flashcards
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)
- excitability
- reduce
- Na, Na
- Ca
- GABA
- glutamate
drugs that decrease Na influx and prolong inactivation of Na channels (6)
- carbamazepine
- oxcarbazepine
- phenytoin
- lacosamide
- lamotrigine
- valproate
drugs that reduce calcium influx (absence seizures) (3)
- ethosuximide
- lamotrigine
- valproate
drugs that enhance GABA mediated neuronal inhibition (6)
activates GABAA receptor
- barbiturates
- benzodiazepines
increases GABA levels
- valproate
- gabapentin
inhibits GABA tranaminase
- vigabatrin
inhibits GAT-1
- tiagabine
antagonism of excitatory transmitters (glutamate) (2)
- felbamate - antagonist of NMDA receptors
- topiramate - antagonist of kainate/AMPA receptors
why are few drugs targeting K channels to treat seizures
think about side effects in other organs! will really mess other things up
molecular targets at the excitatory (glutamatergic) synapse
presynaptics targets
- ___ and ___ channels
post-synaptic targets
- ___ and ___ receptors
- Na, Ca
- NMDA, AMPA
molecular targets at the inhibitory (GABAergic) synapse
presynaptic targets
- GABA transporter ( ___ )
- GABA ___ (GABA-T)
post synaptic targets
- GABA ___ and GABA ___ (?)
- GAT-1
- transaminase
- A, B
treatment: focal seizures and genrealized tonic-clonic seizures
a number of antiseizuure drugs have a common ___ ring structure
heterocyclic
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)
phenytoin
- non-sedatice
- inactivated
- selective
- fosphenytoin
T or F: phenytoin and other anticonvulsants (carbamazepine, valproate) act by binding and stabilizing the activated state of Na channels
FALSE
inactivated
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)
elimination
- valproate
- carbamazepine
- nystagmus, diplopia
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
- tricyclic
- inactive
- induces
Lacosamide (Vimpat)
MOA: enhances ___ of voltage gated Na channels
toxicity:
- dermatological reactions
- cardiac risks ( ___ interval prolongation)
- visual disturbances
inactivation
PR
molecular targets at the excitatory (glutamatergic) synapse
presynaptic targets
- ___ channels (phenytoin, carbamazepine, lacosamide)
- ___ channels
post-synaptic targets
- ___ and ___ receptors
- Na
- Ca
- NMDA, AMPA
barbiturates and benzodiazepines bind an ___ regulatory site on the GABA A receptor
allosteric
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
phenobarbital
- 2
- allosteric
primidone
phenytoin
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
Diazepam
- tonic-clonic status epilepticus
- rectal
- allosteric, frequency
- chronic
- absence
molecular targets at the inhibitory GABAergic synapse
presynaptic targets
- GABA trasporter ( ___ )
- GABA ___ (GABA-T)
post-synaptic targets
- GABA A receptors ( ___ and ___ )
GAT-1
transaminase
phenobarbital, benzodiazepines
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
adjunct
- GABA
- GABA, Ca
___ (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
vigabatrin
- adjunct
- GABA
- irreversible, transaminase
tiagabine, adjunct
- transporter
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
- tiagabine
- vigabatrin
- phenobarbital, benxodiazepines
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
- Na, Ca, K
- Na, K, kainate
___ (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
felbamate
- focal
- hepatitis
topiramate
- monosaccharide
- AMPA, kainare
molecular targets at the excitatry (glutamatergic) synapse
presynaptic targets
- Na channels - ___ , ___ , and ___
- Ca channels
post-synaptic targets
- NMDA receptors - ___
- AMPA receptors - ___
- phenytoin, carbamazepine, lacosamide
- felbamate
- topiramate
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
- absence
- T, Ca, thalamic
- rhythmic, thalamocortical
molecular targets at the excitatory (glutamatergic) synapse
presynaptic targets
- Na channels - ___ , ___ , and ___
- Ca channels - ___
post synaptic
- NDMA receptors - ___
- AMPA receptors - ___
- phenytoin, carbamazepine, lacosamide
- ethosuximide
- felbamate
- topiramate
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
B) Gabapentin inreases Cl influx in post synaptic neurons
___ (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)
Lamotrigine
- focal, generalized, absence
- Na, Ca
- Stevens-Johnson
___ (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
valproate
- focal, generalized, absence
- fatty
- Na, Ca
- GABA
- phenytoin
___ (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
levetiracetam
- focal, generalized, myoclonic
- synaptic vesicular
- status epilepticus
- higher
molecular targets at the excitatory (glutamatergic) synapse
presynaptic targets
- Na channels (5)
- Ca channels (4)
post synaptic targets
- NMDA receptors - ___
- AMPA receptors - ___
- phenytoin, carbamazepine, lacosamide, lamotrigine, valproate
- ethosuximide, lamotrigine, levetiracetam, valproate
- felbamate
- topiramate
T or F: genetic and phenotypic heterogeneity suggest therapeutic implications in SN2A related disorders
True
what is this? PGx or something?
