Unit 3 - Antiepileptic Drugs Flashcards Preview

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Flashcards in Unit 3 - Antiepileptic Drugs Deck (27):

what are the possible actions of antiepileptic drugs?

1. limit excitability (nt systems)
-voltage-gated Na or Ca channels
-glutamate receptors
2. enhance inhibition
-GABA system


how do voltage-gated Na channel excitability limiters work?

-stabilize inactive (refractory) state to inhibit recurrent depolarization
--takes longer for Na channels to open again, but doesn't completely inhibit (TTX would kill)


what are examples of voltage-gated Na channel excitability limiters?

primary activity: phenytoin, carbamazepine, oxcarbamazepine, lamotrigine
secondary activity: valproate, felbamate, topiramate

all have similar efficacy, metabolism, and toxicities
-hepatic enzyme inducers (may also auto-induce to increase own metabolism)
-potentially teratogenic and may decrease birth control efficacy


how do voltage-gated Ca channel excitability limiters work?

as they are presynaptic membrane channels, blocking Ca influx leads to less excitatory neurotransmiter release
-useful for treating neuropathic pain


what are examples of voltage-gated Ca channel excitability limiters?

primary: ethoxuximide (T-type in thalamus for childhood absence seizures), gabapentin and pregabalin (high voltage type)
secondary: topiramate, felbamate, phenobarbitol, lamotrigine, levitiracetam


how do glutamate receptor excitability limiters work?

as they are in post-synaptic membranes with ligand-gated cation channels, they work similarly to voltage-gated Ca and Na channels


what are examples of glutamate receptor excitability limiters?

felbamate - NMDA receptor blocker
topiramate - partially active as AMPA and kainate receptor blocker
selective and specific AMPA and kainate receptor blockers are in development


how do GABA system enhancers work?

inhibitory GABA-A receptors are on post-synaptic membranes of inhibitory synapses (ligand-gated Cl- channels)
-increase threshold to depolarization


what are examples of GABA system enhancers?

primary: phenobarbitol, benzodiazepenes (bind to receptor)
secondary: valproate, topiramate, gabapentin, leviteracetam (GABA transaminase-binder), felbamate, tigabine (GABA reuptake inhibitor)


-what is it?
-adverse reactions
-pharmacologic considerations

Na channel blocker
-toxicity: sedation, ataxia, diplopia (dizzy, drunk, double vision)
-ASE: rash 15%, rarely Stevens-Johnson
--mild hepatic enzyme elevation common
--mild myelosuppression (decreased WBC)
-uses: more effective for complex partial epilepsy (focal seizures) than primary generalized
--useful in bipolar affective disorder and treating neuropathic pain
--preferred to phenobarbitol, phentoin, and valproate (less effective, but better ASE)
-consider: highly protein bound, hepatic metabolism (autoinduction and heteroinduction effects other hepatically metabolized meds)
--can cause contraceptive failure
--short half-life (6-10 hr; may use extended release preparations)


what is toxicity of carbamazepine thought to be due to?

epoxide metabolite


what is the difference between toxicity and adverse reactions?

toxicity: predictable mech of action causes these things
ASE: not predictable from mech of action


-what is it?
-adverse reactions
-uses (and less effective uses)
-pharmacologic considerations

Na channel blocker
-toxicity: dizziness, nystagmus, ataxia, incoordination (dizzy, drunk, double visino)
-ASE: long-term (takes a while to get them, so best for short-term use)
--mild hepatotoxicity and myelosuppression
--gingival hyperplasia (may lose teeth), rash, hirsutism, lupus-like reaction
--longer term: cerebellar degeneration, peripheral neuropathy, osteoporosis
-uses: effective against tonic-clonic seizures of primary generalized epilepsy or partial onset and secondarily generalized seizures
--effective for acute seizures even if not related to epilepsy
--less effective for absence, myoclonic, or atonic seizures
-considerations: highly protein bound hepatic metabolizer (enzyme inducer that can effect other hepatically metabolized meds)
--can be associated with contraceptive failure
--variable but longer half-life (24-36 hr), usually once daily dosing


why is the IV infusion of phenytoin limited? but what is it useful for?

due to hypotension
-but IV route is useful in status elipticus


-what is it?
-adverse reactions
-pharmacologic considerations

Na channel blocker
-same efficacy and indications as carbamazepine (prodrug designed to bypass carbamazepine epoxide)
-less protein bound, less autoinduction, fewer interactions, less toxic
-useful in treating neurogenic pain


-what is it?
-adverse reactions
-pharmacologic considerations

Na channel blocker
-toxicity: dizziness, sedation, ataxia, diplopia (dizzy, drunk, double vision)
-ASE: rash 3%, rarely Stevens-Johnson (but dose related, so slow initial titration is important)
-uses: effective for primary generalized epilepsy, partial complex and secondary generalization epilepsy, absence
--indication for use in children
--less effective for and may exacerbate myoclonic seizures
--useful in bipolar effective disorder and treating neuropathic pain
-considerations: hepatic metabolism and enzyme-inducer, but less protein bound (must be glucoronidated to be excreted)
--can cause contraceptive failure moreso than others
--competes for excretion and has synergistic action with Valproic acid (Depakote)


-what is it?
-adverse reactions
-pharmacologic considerations

old that acts at GABA-A receptors
-used in status epilepticus
-dose limited by sedation
-long-term usefulness limited by tolerance


what are lorazepam and diazepam?

short-acting benzodiazepines
-both need high levels for effect, and half-life is irrelevant (only last 5-15 minutes for diazepam, slightly more for lorazepam, merely to buy time for more treatment)


do you give benzodiazepines if one has one seizure?

no need, b/c these stop on their own and don't require treatment


what is midazolam used for?

anesthesia or refractory status epilepticus
-IV half-life is in minutes; if orally, for 1 hour


-what is it?
-adverse reactions
-pharmacologic considerations

unknown mechanism, but somehow involved with Na channels and GABA system
-toxicity: sedation, tremor
-ASE: nausea, weight gain, hair loss, hyperammonemia, teratogenic 4-8% (but doesn't affect birth control)
-uses: broad spectrum of activity
--effective VS absence, myoclonic, tonic-clonic seizures of primary generalized epilepsy, as well as partial onset and secondarily generalized seizures
--used in treatment of (non-depressed) bipolar affective disorder and migraine prophylaxis
-considerations: highly PRO bound, rapid hepatic metabolism (rapidly absorbed) thus short half-life
--can use extended release preparations


what is IV valproate used for?

status epilepticus


gabapentin and pregabalin
-what is it?
-adverse reactions
-pharmacologic considerations

very nontoxic GABA analogs that inhibit Ca currents
-used as adjunctive treatment for partial complex epilepsy
-more commonly used for neuropathic pain

for gabapentin only: pharmacologic consideration
-absorption limited at AA transporter in intestine (safe if overdose)
-limited protein binding
-no evidence of metabolism in humans (elimination unchanged in urine)
-no interaction with other medications, or serious organ toxicity
--however, toxicity is related to sedation


-what is it?
-adverse reactions

T-type that blocks Ca currents in thalamo-cortical circuits
-effective against absence seizures only
-readily absorbed with minimal first-pass metabolism, not protein bound
-half-life 40-60 hours (allows 1 dose a day)
-ASE: nausea (transient), sedation, irritability


-what is it?
-adverse reactions
-pharmacologic considerations

AMPA and Kaniate Ca channel blocker (as well as activity at Na channels and GABA)
-uses: effective against partial onset and secondarily generalized seizures + primary generalized epilepsy
--effective for migraine prophylaxis (as hyperexcitable)
--has some carbonic anhydrase activity
-toxicity: sedation, cognitive "word finding" difficulties
-ASE: mild metabolic acidosis (from carbonic anhydrase) --> respiratory compensation --> mild alkalosis --> calcium ionization --> tingling (can be mitigated w/ vit C, organic acid to acidify drug)
--modest weight loss (CA makes soda taste bad)
--kidney stones and rare acute glaucoma


-what is it?
-adverse reactions

widely used Ca channel blocker
-toxicity: sedation (but usually well tolerated)
-ASE: irritability (1/4 to 1/3 people), aphasia, thrombocytopenia
-uses: effective VS partial onset and secondarily generalized seizures
--some evidence of activity VS primary generalized epilepsy
--binds to synaptic vesicle protein 2 resulting in less nt release


-what is it?
-adverse reactions
-pharmacologic considerations

alters sodium transport and inhibits Na re-absorption in proximal tubule
--low level sedation, dizziness, thirst, increased urination, fine tremor
--high level: giddiness, ataxia, blurred vision, large amount of dilute urine
--caution: Brugada syndrome (hereditary arrythmia) is contra-indicated; ask for family history of sudden death <45 yo
-uses: treatment of bipolar affective disorder (mood stabilization) or cluster headaches (off-label use)
-considerations: contraindicated if arrhythmia or dehydration
--drug interactions with diuretics, ARB, NSAID