Unit 3 - Antiepileptic Drugs Flashcards
what are the possible actions of antiepileptic drugs?
- limit excitability (nt systems)
- voltage-gated Na or Ca channels
- glutamate receptors - 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)
carbamazepine
- what is it?
- toxicity
- adverse reactions
- uses
- 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
phenytoin
- what is it?
- toxicity
- 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
oxcarbazepine
- what is it?
- toxicity
- adverse reactions
- uses
- 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
lamotrigine
- what is it?
- toxicity
- adverse reactions
- uses
- 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)
benzodiazepines
- what is it?
- toxicity
- adverse reactions
- uses
- 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
valproate
- what is it?
- toxicity
- adverse reactions
- uses
- 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?
- toxicity
- adverse reactions
- uses
- 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
ethosuximide
- what is it?
- adverse reactions
- uses
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
topiramate
- what is it?
- toxicity
- adverse reactions
- uses
- 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
Levetiracetam
- what is it?
- toxicity
- adverse reactions
- uses
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
lithium
- what is it?
- toxicity
- adverse reactions
- uses
- pharmacologic considerations
alters sodium transport and inhibits Na re-absorption in proximal tubule
- toxicity:
- -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
