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M2 Neuron Brain Behavior > 9/29 Anti-epileptics - Ryazanov > Flashcards

9/29 Anti-epileptics - Ryazanov Flashcards

1
Q

anti epileptic drugs based on type of seizure

A

black = representative

red = popular today

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2
Q

partial seizures

drugs

A

phenytoin

carbamazepine

valproate

lamotrigine

topiramate

lacosamide

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3
Q

generalized tonic-clonic

(grand mal)

drugs

A

phenytoin

carbamazepine

valproate

levetiracetam

topiramate

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4
Q

absence

(petit mal)

drugs

A

ethosuximide

valproate

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5
Q

myoclonic

drugs

A

phenobarbital

valproate

levetiracetam

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6
Q

status epilepticus

drugs

A

phenobarbital

lorazepam

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7
Q

major mechanisms of anti-seizure drugs

A
  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
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8
Q

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

A

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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9
Q

molecular targets for GABA-mediated synaptic inhibition

A

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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10
Q

example: GABA-a inhibition

A

benzodiazepines and barbiturates : GABAa receptor mediated inhibition

  • increases inflow of Cl ions into cell → hyperpolarization
  • inhibits postsyn cell
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11
Q

drug action:

Na channel inactivation

A

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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12
Q

drug action:

VG Ca channel inhibition

A

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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13
Q

drugs used for partial seizures/generalized tonic-clonic seizures

A

phenytoin

carbamazepine

valproate

barbiturates

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14
Q

phenytoin

A
  • 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

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15
Q

phenytoin toxicity

A

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
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16
Q

carbamazepine

A

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
Q

carbamazepine

PK

drug interactions

A

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
Q

carbamazepine

adverse effects

A
  • 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
Q

myoclonic seizure drugs

valproic acid

A

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
Q

valproic acid

PK

drug interactions

A

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
Q

valproate toxicity

A
  • 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
Q

absence seizure drugs

ethosuximide:

mechanism

drug interactions

toxicity

A

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
Q

status epilepticus drugs

phenobarbital

mechanism

A

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
Q

phenobarbital

PK

A

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
Q

phenobarbital

toxicity

A
  • 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
Q

anti seizure drugs:

duration of tx

A

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
Q

drugs for epilepsy in infancy

A

Primidone and phenobarbital limited due to learning issues

28
Q

issues with gabapentin

A

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
Q

felbamate issues

A

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

  • 3rd line drug for refractory cases
30
Q

lamotrigine

A

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
Q

topiramate

A

see lecture

32
Q
A

M2 Neuron Brain Behavior (53 decks)

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