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MSII Pharmacology > Unit 3 - Antiepileptic Drugs > Flashcards

Unit 3 - Antiepileptic Drugs Flashcards

1
Q

what are the possible actions of antiepileptic drugs?

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

how do voltage-gated Na channel excitability limiters work?

A
  • stabilize inactive (refractory) state to inhibit recurrent depolarization
  • -takes longer for Na channels to open again, but doesn’t completely inhibit (TTX would kill)
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3
Q

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

A

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
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4
Q

how do voltage-gated Ca channel excitability limiters work?

A

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

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5
Q

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

A

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

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6
Q

how do glutamate receptor excitability limiters work?

A

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

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7
Q

what are examples of glutamate receptor excitability limiters?

A

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

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8
Q

how do GABA system enhancers work?

A

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

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9
Q

what are examples of GABA system enhancers?

A

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

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10
Q

carbamazepine

  • what is it?
  • toxicity
  • adverse reactions
  • uses
  • pharmacologic considerations
A

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)
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11
Q

what is toxicity of carbamazepine thought to be due to?

A

epoxide metabolite

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12
Q

what is the difference between toxicity and adverse reactions?

A

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

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13
Q

phenytoin

  • what is it?
  • toxicity
  • adverse reactions
  • uses (and less effective uses)
  • pharmacologic considerations
A

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
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14
Q

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

A

due to hypotension

-but IV route is useful in status elipticus

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15
Q

oxcarbazepine

  • what is it?
  • toxicity
  • adverse reactions
  • uses
  • pharmacologic considerations
A

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
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16
Q

lamotrigine

  • what is it?
  • toxicity
  • adverse reactions
  • uses
  • pharmacologic considerations
A

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)
17
Q

benzodiazepines

  • what is it?
  • toxicity
  • adverse reactions
  • uses
  • pharmacologic considerations
A

old that acts at GABA-A receptors

  • used in status epilepticus
  • dose limited by sedation
  • long-term usefulness limited by tolerance
18
Q

what are lorazepam and diazepam?

A

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)

19
Q

do you give benzodiazepines if one has one seizure?

A

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

20
Q

what is midazolam used for?

A

anesthesia or refractory status epilepticus

-IV half-life is in minutes; if orally, for 1 hour

21
Q

valproate

  • what is it?
  • toxicity
  • adverse reactions
  • uses
  • pharmacologic considerations
A

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
22
Q

what is IV valproate used for?

A

status epilepticus

23
Q

gabapentin and pregabalin

  • what is it?
  • toxicity
  • adverse reactions
  • uses
  • pharmacologic considerations
A

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
24
Q

ethosuximide

  • what is it?
  • adverse reactions
  • uses
A

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
25
Q

topiramate

  • what is it?
  • toxicity
  • adverse reactions
  • uses
  • pharmacologic considerations
A

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
26
Q

Levetiracetam

  • what is it?
  • toxicity
  • adverse reactions
  • uses
A

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
27
Q

lithium

  • what is it?
  • toxicity
  • adverse reactions
  • uses
  • pharmacologic considerations
A

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

MSII Pharmacology (43 decks)

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