9/29 Anti-epileptics - Ryazanov Flashcards Preview

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Flashcards in 9/29 Anti-epileptics - Ryazanov Deck (32):
1

anti epileptic drugs based on type of seizure

black = representative

red = popular today

2

partial seizures

 

drugs

phenytoin

carbamazepine

valproate

 

lamotrigine

topiramate

lacosamide

3

generalized tonic-clonic

(grand mal)

 

drugs

phenytoin

carbamazepine

valproate

 

levetiracetam

topiramate

4

absence

(petit mal)

 

drugs

ethosuximide

valproate

5

myoclonic

 

drugs

phenobarbital

valproate

 

levetiracetam

6

status epilepticus

 

drugs

phenobarbital

 

lorazepam

7

major mechanisms of anti-seizure drugs

1. decrease Glu excitatory transmission

2. increase GABA-mediated inhibition (either pre or postsynaptic)

3. modification of ionic conductances

  • inhibition of sustained, repetitive firing of neurons via promotion of inactivated state of voltage-activated Na channels
  • inhibition of voltace-activated Ca channels

8

molecular targets for antiseizure drugs acting at excitatory (glu) synapse

1. VG Na channels

  • phenytoin
  • carbamazepine
  • lamotrigine
  • lacosamide

2. VG Ca channels

  • ethosuximide
  • lamotrigine
  • gabapentin
  • pregabalin

3. K channels : retigabine

4. SVA2 synaptic vesible proteins : levetiracetam

5. CRMP-2 (collapsin response mediator protein 2) : lacosamide

6. AMPA receptors

  • phenobarbital
  • topiramate
  • lamotrigine

7. NMDA receptors : blocked by felbamate

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molecular targets for GABA-mediated synaptic inhibition

1. GABA transporters (esp GAT1, tiagabine)

2. GABA-transaminase (GABA-T, vigabatrin)

3. GABA-a receptors (benzodiazepines)

4. GABA-b receptors

 

might also be mediated by "nonspecific" targets like VG ion channels and synaptic proteins

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example: GABA-a inhibition

benzodiazepines and barbiturates : GABAa receptor mediated inhibition

  • increases inflow of Cl ions into cell → hyperpolarization
  • inhibits postsyn cell

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drug action: 

Na channel inactivation

goal: inhibition of high-freq firing of neurons

how?

reduce ability of Na channels to recover from inactivation, i.e. prolong inactivation of Na channels

  • inactivation achieved by inactivation gate

 

ex. carbamazepine, phenytoin, topiramate, lamotrigine, valproate, zonisamide

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drug action:

VG Ca channel inhibition

goal: reduce pacemaker current underlying thalamic rehythm in spikes/waves seen in gen absence seizures

how?

inhibit T-type Ca channels

 

ex. valproate, ethosuximide

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drugs used for partial seizures/generalized tonic-clonic seizures

phenytoin

carbamazepine

valproate

barbiturates

14

phenytoin

  • alters Na, K, Ca conductance and membrane potentials
  • decreases synaptic release of glu and enhances release of GABA

 

distribution: highly bound to plasma proteins (90%)

  • incr proportion of free/active in newborns, hypoalbunimenia, uremic pts

metabolism: hepatic metabolism to active metabolites, excreted in urine

  • half life 12-36 hours
  •  low conc: first order kinetics. 5-7 days to reach steady state
  • tx range: non-linear relationship of dosage and pl concentration

drug interactions:  

  • protein-binding drugs can increase free phenytoin
  • phenytoin can induce microsomal enzymes resp for metabolism of drugs (OCPs)

 

fosphenytoin is IV precursor to phenytoin

15

phenytoin toxicity

general tox: diplopia, ataxia, gingival hyperlasia, hirsutism, neuropathy

long term use toxicity:

  • coarsening of facial features
  • mild periph neuropathy: diminished deep tendon reflexes in lower extremities
  • serum folic acid, thyroxine, vitK may decrease
  • abnormal vitD metabolism → osteomalacia

16

carbamazepine

primary drug for tx of partial, tonic-clonic seizure

 

chemically related to tricyclic antidepressants

mechanism: limits repetitive firing of APs evoked by sustained depolarization by slowing rate of recovery of VG Na channels (from inactivated state)

 

17

carbamazepine

 

PK

drug interactions

limited aqueous solubility

many anti-seizure drugs can increase conversion to active metabolites [via CYP450s]

  • induces CYP2C, CYP3A, UGT → enhances metabolism of other drugs (ex. OCPs) 

 

absorption: slow, erratic following oral admin

drug interactions: 

  • phenobarbital, phenytoin, valproate can increase metabolism of carbamazepine via induction of CYP3A4
  • may enhance biotransformation of phenytoin
  • may lower conc of other anti-seizure drugs (ex. valproate)

18

carbamazepine

 

adverse effects

  • drowsiness, blurred vision, diplopia, headache, dizziness, ataxia, nausea/vomiting
  • mild leukopenia, hyponatremia common
  • high dose? thrombocytopenia
  • high dose/rapid escalation → rash

 

  • Asian pts: carbamazepine-induced Stevens-Johnson syndrome

19

myoclonic seizure drugs

 

valproic acid

mechanism:

  • inhibits sustained repetitive firing via prolonged recovery of VG Na channels (in inactivated state), possibly small reductions in T-type Ca currents
  • increases amount of GABA recovered from brain
  • in vitro: can stimulate activity of GABA synthetic enzyme, inhibit GABA degradation enzymes

20

valproic acid 

 

PK 

drug interactions

absorbed rapidly/completely after oral admin

peak conc: 1-4 hours

usually about 90% bound to pl protein initially (fraction drops as concentration is incr)

maybe carrier-mediated transport in/out of CSF

 

metabolism: UGT, beta-ox

  • half life approx 15 hr

 

drug interactions:

  • inhibits metabolism of phenytoin and phenobarbital, lamotrigine, lorazepam
  • can displace phenytoin and other drugs from albumin

21

valproate toxicity

  • transient GI sx: anorexia, nausea, vomiting
  • CNS sx: sedation, ataxia, tremor
  • chronic use: rash, alopecia, stim of appetite → weight gain
  • dose-related tremor, hair thinning/loss, platelet drop, thrombocytopeia
  • hepatic fx: elevation of hepatic transaminases in plasma
  • acute pancreatitis, hyperammonemia
  • teratogenic effects like neural tube defects

22

absence seizure drugs

 

ethosuximide:

mechanism

drug interactions

toxicity

reduces low threshold T-type Ca current

  • T-type Ca channels implicated in pacemaker current in thalamic neurons that generate the rhythmic cortical discharge of absence seizure

drug interactions

  • valproic acid can decrease ethosuximide clearance and cause higher steady-state conc

toxicity

  • common: gastric distress (pain, nausea, vomiting)
  • transient lethargy or fatigue
  • urticaria/skin rxns (Stevens-Johnson syndrome, systemic lupus erythematosus, eosinophilia, etc)

23

status epilepticus drugs

 

phenobarbital

 

mechanism

low tox, low cost

mechanism: unknown

  • enhancement of inhibitory processes
    • suppression of high-freq firing neurons through action on Na conductance and Ca currents (L-, N-type)
    • enhances GABA receptor mediated current (prolongs Cl current)
  • depression of excitatory responses (glu release)

 

24

phenobarbital

 

PK

absorption:

  • oral abs is slow but complete
  • 40-60% bound to plasma proteins; similarly bound in tissues, incl brain
  • up to 25% eliminated by pH-dep renal excretion unchanged

metabolism: 

  • CYP enzymes: mainly CYP2C9 (also CYP2C19 and CYP2E1)

drug interactions:

  • induces UGT enzymes, CYP2C, CYP3A

25

phenobarbital

 

toxicity

  • sedation, but tolerance can be developed
  • nystagmus and ataxia (excessive dosage)
  • irritability and hyperactivity in children
  • agitation and confusion in elderly
  • scarlatiniform or morbilliform rash (and maybe other manifestations of drug allergy) in 1-2% of patients
  • megaloblastic anemia during chronic phenobarbital tx of epilepsy (responds to folate, osteomalacia, high dose vitD)

26

anti seizure drugs:

duration of tx

usually cont'd for at least 2 years

after 2 years, consider tapering/discontinuing tx if pt is seizure free

 

high risk after discont:

  • EEG abnormalities
  • structural lesions
  • abnormal neuro exam
  • hx of freq seizures or medically refractory seizures prior to control

27

drugs for epilepsy in infancy

Primidone and phenobarbital limited due to learning issues

 

28

issues with gabapentin

v high dose needed to achieve improvement in seizure control

  • used mainly down the road as adjunctive tx

 

adverse effects: somnolence, dizziness, ataxia, headache, tremor

29

felbamate issues

causes aplastic anemia, severe hepatitis (acute hepatic failure) at high rates

  • 3rd line drug for refractory cases

30

lamotrigine

can cause toxic epiderman necrolysis and Stevens Johnson syndrome

ped pts at high risk of rash, maybe potentially life threatening dermatitis (1-2% pts)

 

adverse effects: dizziness, headache, diplopia, nausea, somnolence, skin rash

31

topiramate

see lecture

32

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