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IC4 ASM pharmacology Flashcards

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1
Q

What are the three general types of seizures?

A
  • generalized (whole brain is affected)
  • partial (part of brain is affected)
  • status epilepticus (prolonged seizure)
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2
Q

What is the rationale behind antiepileptics?

A

seizures occur due to excessive synchronous depolarization of neurons –> therefore, antiepileptics serve to decrease membrane excitability by altering Na+ and Ca2+ conductance during action potential or to enhance inhibitory effect of GABA (inhibitory neurotransmitter)

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3
Q

What are the antiepileptics of focus for this IC?

A
  • phenytoin
  • carbamazepine
  • sodium valproate
  • benzodiazepine
  • barbiturates
  • levetiracetam
  • lamotrigine
  • topiramate
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4
Q

Of the list above, which are the first line for newly diagnosed partial and generalized tonic clonic seizures?

A

phenytoin
carbamazepine
sodium valproate

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5
Q

Describe the MOA of phenytoin

A

Blocks voltage-gated Na+ channel

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6
Q

When can phenytoin be used?

A

for all seizures except absence seizures

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7
Q

What quirks does phenytoin have?

A
  • narrow theraputic range
  • non-linear r/s between dose and plasma conc, requiring TDM (zero order kinetics)
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8
Q

Can phenytoin be used in pregnancy?

A

no; teratogenic

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9
Q

What are the common side effects of phenytoin?

A
  • CNS: dizziness, drowsiness
  • gingival hyperplasia
  • hirsutism
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10
Q

What are the rare and serious side effects of phenytoin?

A
  • hepatotoxicity (for all 1st gen ASMs)
  • hypersensitivity (SJS/TEN)
  • blood dyscrasias
  • IC6, 7: chronic S/Es - peripheral neuropathy, osteomalacia, suicidal ideation
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11
Q

Describe the MOA of carbamazepine

A

Blocks voltage-gated Na+ channel

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12
Q

When can carbamazepine be used?

A

for all seizures except absence seizures (same as phenytoin)

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13
Q

What are the common side effects of carbamazepine?

A
  • CNS (dizziness, drowsiness, ataxia)
  • GI (N/V, constipation)
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14
Q

What are the rare and serious side effects of carbamazepine?

A
  • hepatotoxicity (1st gen ASM)
  • blood dyscrasia (eg. anemia)
  • hypersensitivity (SJS, TEN)
    (same as phenytoin)
  • IC6, 7: hyponatremia, peripheral neuropathy, osteomalacia
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15
Q

Can carbamazepine be used in pregnancy?

A

no; teratogenic (major congenital malformation)
switch to levetiracetam/lamotrigine

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16
Q

Can carbamazepine be used in renal impairment?

A

yes; renal elimination is not the major route of elimination
! BUT - may cause renal toxicity (eg. interstitial nephritis, hyponatremia) - use w caution

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17
Q

Can carbamazepine be used in hepatic impairment?

A

yes - use w caution as major route of elimination; may cause hepatotoxicity

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18
Q

Can carbamazepine be used in elderly?

A

yes - use w caution if >65

(causes/exacerbates SIADH or hyponatremia + increased risk of psychiatric effects)

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19
Q

What quirks does carbamazepine have?

A
  1. undergoes autoinduction (induces CYP3A4) –> shortens half life with repeated doses, requiring dose increments over time
  2. PGx: risk of SJS/TEN for patients with HLA-B.1502 and HLA-A.3101
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20
Q

When is carbamazepine contraindicated?

A
  • concomitant use of MAOis
  • bone marrow depression
  • HLA-B.1502 or HLA-A.3101 positive
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21
Q

What is an important DDI to look out for carbamazepine?

A

clarithromycin (macrolide abx)

carbamazepine - 3A4 inducer + substrate –> ↓ conc of clarithromycin

clarithromycin - 3A4 inhibitor + substrate –> ↑ conc of carbamazepine

management: avoid clarithromycin and use other abx

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22
Q

Describe the MOA of sodium valproate

A
  1. Blocks voltage-gated Na+ and Ca2+ channels
  2. Inhibits GABA transaminase (enzyme that breaks down GABA inhibitory neurotransmitter)
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23
Q

When can sodium valproate be used?

A

all seizures, including absence seizures

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24
Q

What are the common side effects of valproate?

A
  • CNS: dizziness, drowsiness
  • GI: N/V, stomach upset, stomach cramp, diarrhoea
  • increase in appetite, weight gain (unique to valproate)
  • temporary hair loss
  • trembling of fingers & hands
  • irregular and/or painful menstruation
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25
Q

What are the serious side effects of valproate?

A
  • hypersensitivity, SJS/TEN
  • hepatotoxicity (1st gen ASM)
  • pancreatitis (unique to valproate)
  • blood dyscrasias (thrombocytopenia)
  • severe weakness/dizziness
  • suicidal ideation
  • blurred vision or double vision/unsteady movement
26
Q

What ‘PK quirk’ does sodium valproate have?

A

high plasma protein binding; even displaces other antiepileptics

saturable protein binding at therapeutic range; higher conc = higher free unbound conc = more likely to experience S/Es or toxicity

27
Q

Can valproate be used in pregnancy?

A

no unless alternatives failed/unacceptable

28
Q

Can valproate be used in breastfeeding?

A

yes; compatible
but weight risk vs benefits

29
Q

Can valproate be used in renal impairment?

A

yes - 1st gen ASMs mainly hepatically cleared

30
Q

Can valproate be used in hepatic impairment?

A

no;
not recommended in mild-moderate, contraindicated in severe
(hepatotoxicity is a S/E)

(vs carbamazepine - while 1st gen = mainly hepatic, it can be used w caution in hepatic impairment)

31
Q

What side effects of antiepileptics are dose related?

A
  • CNS: drowsiness, confusion, slurred speech, nystagmus (eye movement), ataxia (lack of coordination)
  • nausea
  • unusual behaviour
  • mental changes
  • coma
32
Q

What side effects of antiepileptics are non dose related?

A
  • hirsutism
  • acne
  • gingival hyperplasia (gum overgrowth)
  • folate deficiency
  • osteomalacia (bones become soft)
  • hypersensitivity (SJS)
33
Q

Describe the MOA of benzodiazepines

A

binds to regulatory site on ligand-gated Cl- channel –> potentiates GABA-induced Cl- influx –> hyperpolarization –> membrane potential further away from threshold potential –> inhibition of generation of AP

TLDR: enhances effects of inhibitory GABA neurotransmitter

34
Q

What are some common benzodiazepines?

A

‘-lam’ –> midazolam, triazolam, alprazolam
‘-pam’ –> clonazepam, lorazepam, diazepam

35
Q

What are the benzodiazepines that can be used for status epilepticus?

A
  • midazolam
  • lorazepam
  • diazepam
36
Q

What are the side effects of benzodiazepines?

A

all due to CNS depression;
* drowsiness
* confusion
* amnesia
* impaired muscle coordination (don’t drive or operate heavy machinery)

37
Q

What happens during acute toxicity/overdose of benzodiazepines?

A

severe respiratory depression

38
Q

What substance increases the risk of respiratory depression when used with benzodiazepines?

A

alcohol

39
Q

What is the treatment for benzodiazepine overdose?

A

flumazenil (benzodiazepine antagonist)

40
Q

Why are benzodiazepines not commonly used anymore?

A

risk of tolerance and dependence

41
Q

Describe the MOA of barbiturates

A

same as benzos, but binds at a diff site;

binds to regulatory site on ligand-gated Cl- channel –> potentiates GABA(A)-induced Cl- influx –> hyperpolarization –> membrane potential further away from threshold potential –> inhibition of generation of AP

42
Q

State an example of a barbiturate

A

phenobarbital

43
Q

When is phenobarbital used?

A

in pediatric/neonatal patients (IV loading dose –> IV/PO maintenance dose)

44
Q

Why is barbiturates no longer commonly used?

A

dose-dependent depression on CNS

45
Q

Can flumazenil be used for the treatment for barbiturate overdose?

A

nO~

46
Q

Describe the MOA of levetiracetam

A

unclear;
thought to be due to binding to SV2a protein found on surface of synaptic vesicles, preventing release of neurotransmitter

47
Q

When can levetiracetam be used?

A
  • monotherapy: partial onset seizures in newly diagnosed epilepsy
  • adjunctive therapy: partial seizures, generalized seizure (myoclonic, tonic-clonic)
48
Q

Describe the PK profile of levetiracetam

A

linear with low inter and intra-subject variability (opp of phenytoin)

49
Q

What are the common side effects of levetiracetam?

A
  • headache
  • vertigo
  • cough
  • depression
  • insomnia
50
Q

What are the rare and severe side effects of levetiracetam?

A
  • agranulocytosis
  • suicidal thoughts
  • delirium, dyskinesia

IC6, 7: behavioural disturbances

51
Q

Describe the MOA of lamotrigine

A

blocks voltage-gated Na+ channel

52
Q

When can lamotrigine be used?

A
  • monotherapy: typical absence seizures
  • adjunctive/monotherapy: partial seizures, generalized (incl tonic-clonic)
  • initial/adjunctive: Lennox-Gastaut syndrome (severe childhood epilepsy)
53
Q

Quick recap: what are the medications that can be used for absence seizures?

A
  • sodium valproate
  • lamotrigine
54
Q

What drugs decrease the half-life of lamotrigine when coadministered tgt?

A
  • carbamazepine
  • phenytoin

both are known potent inducers (though based on google search lamotrigine is not predominantly cleared by P450 system, just use this fact to memo bah)

55
Q

What drugs increase the half-life of lamotrigine when coadministered tgt?

A

sodium valproate

56
Q

What are the common side effects of lamotrigine?

A
  • headache
  • aggression
  • tiredness
57
Q

What are the rare and severe side effects of lamotrigine?

A
  • hypersensitivity (SJS/TEN)
  • hepatic failure
  • agranulocytosis (same as levetiracetam)
  • hallucination
  • movement disorder (worsens PD)
58
Q

Describe the MOA of topiramate

A

unclear;
thought to be same as benzos & barbiturates (activate GABA-A to potentialte GABA-induced chloride influx)

59
Q

When can topiramate be used?

A
  • monotherapy: partial seizures, generalized (tonic-clonic)
  • adjunctive: Lennox-Gastaut syndrome (severe childhood epilepsy)
  • prophylaxis of migraine headaches in adults (not for acute treatment)
60
Q

What are the common side effects of topiramate?

A
  • depression
  • fatigue
  • nausea
  • weight loss
61
Q

What are the rare and severe side effects of topiramate?

A
  • neutropenia (VS agranulocytosis for levetiracetam & lamotrigine)
  • mania
  • tremor
  • transient blindness
  • hypersensitivity (SJS/TEN; same as lamotrigine)
  • hepatic failure (same as lamotrigine)
  • IC6, 7: speech fluency
62
Q

When do we test for antiepileptic drug levels?

A
  • assess compliance
  • assess toxicity
  • titrate phenytoin dose (most impt)

IC7: indications for TDM - determine individual therapeutic range, assess lack of efficacy + toxicity + loss of efficacy

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