Anticonvulsants Flashcards
MOA of anticonvulsants
-stabilize and reduce neuronal excitability (reduce E/I balance)
Mechs/targets of anticonvulsant drugs
- dec Na influx (promote Na channel inactivation)
- dec Ca influx (crucial for absense seizures)
- Enhance GABA-mediated neuronal inhibition
- Antagonism of excitatory transmiters (like glutamate)
- some others
Drugs that dec Na influx
-ox + carbamazepine
-phenytoin
-lacosamide
-lamotrigine
-valproate
drugs that dec Ca influx
-ethosuximide
-lamotrigine
-valproate
-crucial for absence seizures
drugs that enhance GABA
-barbituates (activate GABA)
-benzos (“)
-valproate (inc GABA levels)
-gapapentin (inc GABA release)
vigabatrin (inhibits GABA transaminase)
-tiagabine (inhibits GAT-1)
Drugs that antagonize excitatory transmitters (like glutamate)
-felbamate (NMDA antagonist)
-topiramate (kainate/AMPA antagonist)
Molecular targets at excitatory (glutamatergic) synapse
-pre synaptic:
-Na (phenytoin, carbamazepine, lacosamide, lamotrigine, valproate)
-Ca channels (ethosuximide (absence), lamotrigine, levetiracetam, valproate)
-post-synaptic:
-NMDA (felbamate)
-AMPA receptors (topiramate)
Molecular targets at the inhibitory (GABAergic) synapse
-pre-synaptic:
-GABA transporter (GAT-1): tiagabine
-GABA transaminase (GABA-T): vigabatrin
-post: GABA A+B receptors (phenobarbital, benzos)
-also gabapentin and pregabalin inc GABA release
Common anticonvulsant structure
-heterocyclic ring (5C)
-X group at top of penagon
-if N: hydantoin (phenytoin)
-if C-N: barbituates (phenobarbital)
-if C: succinimides (ethosuximide)
Hydantoins
-phenytoin
-fosphenytoin (prodrug)
-ethotoin (less se, less effective)
-mephenytoin (more toxic)
Hydantoin (phenytoin) MOA
-binds and stabilizes inactivates state of Na channels
-not isoform selective = can target channels in brain and periphery
Phenytoin PK
-elimination dose-dependent
-non-linear PK
-as blood concentration inc, liver enzymes become saturated
-small inc in drug dose can lead to dramatic inc in blood concentration
Phenytoin drug interactions
-displaced from plasma proteins by other drugs (valproate) = inc in blood concentration
-induces P450 in liver = inc metabolism of other drugs (carbamazepine)
Phenytoin side effects
-arrhytmia
-visual
-ataxia
-GI
-sedation (high doses)
-gingival hyperplasia, hirsutism (hair)
-hypersensitivity skin rash
Iminostilbenes drugs
-carbamazepine
-oxcarbamazepine (less toxicity
Carbamazepine structure
-tricyclic (tx bipolar)
-similar 3D structure to phenytoin
Carbamazepine MOA
-binds and stabilizes inactivated state of Na channels
carbamazepine drug interactions
-induces P450
=inc metabolism of itself and others (phenytoin, ethosuximide, valproate, clonazepam)
Carbamazepine toxicity
-blurred vision
-ataxia
-sedation (high doses)
-SJS
-DRESS
Lacosamide MOA
-enhance inactivation of Na channels
Lacosamide toxicity
-deramtological reactions
-cardiac risk (PR prolongation)
-visual disturbances
Barbituate drugs
-phenobarbital
-primidone (moa more similar to phenytoin)
Phenobarbital
-barbituate
-drug of choice in infants up to 2 months
-3D structure similar to phenytoin
drug of choice in infants up to 2 months
-phenobaribtal
phenobarbital MOA
-bind allosteric site on GABAA
-inc DURATION of Cl- channel opening events
=enhance GABA inhibitory signaling
Phenobarbital drug interactions and toxicites
-induces P450
-sedation
-dependence (abuse)
Primidone
-barbituate w MOA similar to phenytoin than phenobarbital
Benzodiazepine drugs
-diazepam
-clonazepam
Diazepam clinical
-useful for tonic-clonic status epilepticus
-often admin as rectal gel for acute tx
Diazepam MOA
-binds to allosteric regulatory site on GABAA
=inc FREQUENCY of Cl channel opening
=enhanced GABA inhibitory signaling
Diazepam toxicity
-sedation
-dependence
-not useful for chronic tx
Clonazepam clinical
-acute tx of epilepsy and ABSENCE seizures
-similar properties as diazepam
GABA analogs
-Gabapentin
-Pregabalin
Gabapentin/Pregabalin clinical
-adj anti-sz (also neuropathic pain and migraine)
-analog of GABA
Gabapentin/pregabalin MOA
-inc GABA release
-dec presynaptic Ca influx
=reduce glutamate release
Gabapentin/pregabalin toxicity
-sedation
-ataxia
-behavioral changes
Vigabatrin
-adj tx for refractory pt
-analog of GABA
Vigabatrin MOA
-IRREVERSIBLE inhibitor of GABA transaminase (GABA-T) (enzyme that degrades GABA)
Vigabatrin toxicity
-sedation
-wt gain, agitation, psyhosis
-depression
-visual defects
Tiagabine MOA and toxicity
-inhibits GABA transporter (GAT-1)
-nervousness, depression, tremor
-sedation
-ataxia
NMDA receptor
-glutamate binding triggers influx of Na and Ca and effluc of K
AMPA (and kainate) receptor
-glutamate binding triggers influx of Na and efflux of K
Felbamate MOA and toxicity
-3rd line for refractory (esp focal sz)
-NMDA receptor antagonist
-severe hepatitis
Topiramate MOA and toxicity
-mono or adj tx
-AMPA and kainate receptor antagonist
-confusion, cognitive probs
-sedation
-vision loss
Drugs to treat absence sz
-succinimides (ethosuximide)
Ethosuximide MOA and toxicity
-tx absence sz
-block T-type Ca channels in thalamic neurons
-GI distress
-sedation
-psychiatric disturbances
Which of the following statements is TRUE?
(A) Tiagabine inhibits GABA transaminase.
(B) Gabapentin increases Cl- influx in postsynaptic neurons.
(C) Topiramate is an NMDA receptor antagonist.
(D) Phenytoin is stabilized by the co-administration of
carbamazepine.
-Gabapentin inc Cl- influx in postsynaptic neurons
Drugs to treat focal, generalized tonic-clonic, and absence sz
-clonazepam
-lamotrigine
-valproate
-levetiracetam
Lamotrigine use
-primary or adj for focal and primary generalized sz
-including absence
-also used for bipolar
lamotrigine structure
-phenyltriazine
-N aromatic ring + aromatic ring w Cl
Lamotrigine MOA
-inhibits Na and voltage-gated Ca channels
-disrupts synaptic glutamate release
Lamotrigine toxicity
-sedation
-ataxia
-serious skin rash (SJS)
Valproate use and structure
-focal, generalized, absence, bipolar, migraine
-fatty acid (ionized at pH7)
valproate MOA
-inhibits Na and Ca channels
-inc GABA levels (stimulate glutamic acid decarboxylase or GABA-T
valproate drug interactions
-displaces phenytoin from plasma proteins
-inhibits phenytoin, carbamazepine, phenobarbital, lamotrigine
Valproate toxicity
-GI distress
-hyperammonemia
-hepatotoxicity (can be fatal, monitor)
-sedation, wt gain, tremor
Levetiracetam use
-focal, generalized, myoclonic, status epilepticus
Levetiracetam MOA
-binds synaptic vesicular protein SV2A
=interfere w synaptic vesicle release and NT
-interfere w Ca influx and interneuronal Ca signaling
-candidate for refractory status epilepticus bc of weirdo mech
Brivaracetam
-analog of levetiracetam that acts via similar mech
-higher affinity for SV2A
genes
Tx for partial and generalized tonic-clonic sz
-pretty much everything
-not topiramate, clonazepam, suximides
Myoclonic sz tx
-topiramate
Absence sz tx
-ethosuximide
-methosuximide
-triethadione
tx for partial and generalized and myoclonic sz
felbamate
tx for partial and generalized and absence sz
-gabapentin
tx for myoclonic and absence sz
-clonazepam
tx for partial and generalized AND myoclonic AND absence
-lamotrigine
-levetiracetam
-valproate
-zonisamide
