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3153 Seizure & Epilepsy > ASMs MOA > Flashcards

ASMs MOA Flashcards

1
Q

Background on excitatory synapses:

What postsynaptic receptors does Glutamate bind to?

A
  1. AMPA receptors
  • Upon glutamate binding to AMPA receptors, receptor opens to permit Sodium entry into the cell
  1. NMDA receptors (main)
  • Upon glutamate binding to NMDA receptors, receptor opens to permit Calcium entry; additionally, calcium may enter via low-voltage activated calcium channels / t-type calcium channels
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2
Q

Background on inhibitory synapses:

What postsynaptic receptor does GABA bind to?

A

GABA-A receptors

  • Upon binding to GABA-A receptors, receptors open to allow entry of Cl- ions
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3
Q

Background on inhibitory synapses:

How is GABA removed from the synaptic cleft?

A

GABA-transporter-1 (GAT-1) reuptake of GABA into presynaptic membrane; then degradation by gamma-aminobutyric acid aminotransferase (GABA-T)

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4
Q

[ASMs that act on glutamate system]

ASMs that block sodium channels:

A
  • Phenytoin
  • Carbamazepine
  • Sodium valproate
  • Lamotrigine
  • Topiramate
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5
Q

[ASMs that act on glutamate system]

ASMs that inhibit presynaptic high-voltage activated calcium channels to slow down hyperactive neurons

A
  • Lamotrigine
  • Topiramate
  • Levetiracetam
  • Phenobarbital
  • Phenytoin
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6
Q

[ASMs that act on glutamate system]

ASMs that inhibit low-voltage activated t-type calcium channels:

A
  • Sodium valproate
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7
Q

[ASMs that act on glutamate system]

ASMs that bind to glutamate AMPA receptors

A
  • Phenobarbital
  • Topiramate
  • Levetiracetam
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8
Q

[ASMs that act on glutamate system]

ASMs that bind to SV2A protein (synaptic vesicle protein 2A) to inhibit synaptic release of glutamate

A
  • Levetiracetam
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9
Q

[ASMs that act on glutamate system]

ASMs that block glutamate NMDA receptors

A
  • Sodium Valproate
  • Topiramate
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10
Q

[ASMs that act on GABA system]

ASMs that bind to GABA-A receptor thus prolonging opening of Cl- channel and permitting Cl- influx:

A
  • Benzodiazepine
  • Barbiturates
  • Topiramate
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11
Q

[ASMs that act on GABA system]

Increase GABA turnover by inhibiting GABA transminase (enzyme that breaks down GABA)

A
  • Sodium Valproate
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12
Q

How might GAT-1 (GABA reuptake transporter) and GABA-T (GABA-transaminase) be used to stop seizures?

A
  • Inhibitor of GAT-1: Tiagabine
  • Inhibitor of GABA transaminase: Vigabatrin, sodium valproate
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13
Q

Phenytoin MOA

A
  • Block voltage-dependent Na+ channels, thereby blocking depolarization and generation of action potential
  • Inhibit high-voltage activated calcium channels
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14
Q

Carbamazepine MOA

A
  • Blockade of voltage-dependent Na+ channels
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15
Q

Valproate MOA

A
  • Blockade of voltage-dependent Sodium channels
  • Blockade of low voltage-activated t-type Calcium channels
  • Blocks NMDA receptors
  • Also inhibits GABA transaminase (enzyme that breaks down GABA), leading to increased GABA
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16
Q

[Benzodiazepines]

Benzodiazepines MOA

**BZDs also used as hypnotic, anxiolytic

A
  • Potentiates action of inhibitory GABA neurotransmitters, thereby potentiating influx of Cl- ions, leading to hyperpolarization

It binds to an allosteric site of the channel, enhancing binding of GABA to GABA-A receptor, resulting in greater entry of Cl- ions which hyperpolarizes the cell and reduces neural excitability

17
Q

[Phenobarbital]

Phenobarbital MOA

A
  • Potentiates GABA-A mediated Cl- currents, at a site distinct from BZDs
  • Binds to AMPA receptors
  • Inhibit high-voltage activated calcium channels
18
Q

Levetiracetam MOA

A
  • Binds to SV2A protein (synaptic vesicle protein 2A) found in the walls of vesicles that contain glutamate (thereby impairing the synaptic release of glutamate, decreasing neuronal excitability)
  • Inhibit high-voltage activated calcium channels
  • Binds to AMPA receptors
19
Q

Lamotrigine MOA

A
  • Blocks voltage-gated sodium channels, therefore inhibits release of glutamate (excitatory neurotransmitter), impeded sustained repetitive neuronal depolarization
  • Inhibits high-voltage activated calcium channels to slow down hyperactive neurons
20
Q

Topiramate MOA

A
  • Blocks Sodium channels
  • Blocks Calcium channels
  • Binds to glutamate AMPA receptors
  • Binds to glutamate NMDA receptors
  • Bind to GABA-A receptor
21
Q

[Benzodiazepines PK]

List examples of short-acting, intermediate-acting, and long-acting BZDs. How long are their durations of action?

A

Short-acting: 3-8h

  • Midazolam, Triazolam
  • Not commonly used as Epilepsy is chronic, not acute; moreover, short-acting BZDs require repeated dosing

Intermediate-acting: 10-20h

  • Clonazepam, Lorazepam

Long-acting: 1-3 days

  • Diazepam, Clobazam
  • Faster onset, longer half-life
22
Q

[Benzodiazepines]

Benzodiazepines are NOT first line for new onset epilepsy because:

A
  • Abuse potential
  • Addictive
  • Toxicity

*May be considered for refractory cases, or as adjunctives

23
Q

[Benzodiazepines]

BZDs are the initial therapy of choice for _________

A

Status epilepticus

24
Q

[Benzodiazepines]

What is used to treat Benzodiazepine toxicity/overdose?

A

Flumazenil

  • Selective GABAA receptor antagonist, binds to the BZD binding site

BZD toxicity: BZDs can cause severe respiratory depression and excessive sedation, esp if used concurrently with alcohol, opioid, CNS depressants

25
Q

[Benzodiazepines]

Benzodiazepine ADRs include:

A
  • Sedation, somnolence
  • Drowsiness, confusion, amnesia
  • Impaired muscle coordination, impairs manual skills
26
Q

[Benzodiazepines]

Benzodiazepine tolerance and dependency
- what are the withdrawal effects?

A

Tolerance:

  • Depends on frequency of use, tolerance develops faster for epilepsy than for use to induce sleep

Dependence:

  • Dependence can develop
  • Abuse potential
  • Withdrawal effects include disturbed sleep, rebound anxiety, tremor, convulsions => important to withdraw gradually
27
Q

[Phenobarbital]

Phenobarbital tolerance and dependence

How does this affect its use?

A
  • Phenobarbital has higher tendency than BZDs
  • Severe withdrawal symptoms

=> Therefore, phenobarbital use as a sedative-hypnotic largely replaced by BZDs

=> Use as AED (antiepileptic) mainly for pediatric and neonatal patients (IV loading dose, followed by IV or oral maintenance dose)

28
Q

[Phenobarbital]

Is Flumazenil effective for treating barbiturate overdose?

A

No, because phenobarbital binds to a separate site on GABA-A receptor (from BZD, and Flumazenil)

29
Q

[Barbiturates PK]

List examples of ultra-short-acting, short-acting, and long-acting barbiturates. How long are their durations of action?

A

Ultra-short acting: 20min

  • IV induction of anesthesia (e.g., thiopental)

Short-acting: 3-8h

  • Sedative, hypnotic (e.g., pentobarbital, amobarbital)

Long-acting 1-2 days

  • Anticonvulsant (e.g., Phenobarbital)
30
Q

Dose-dependent depression of CNS

  • Benzodiazepine VS Barbiturate
A

As dose of BZD/Barbiturate increases, CNS effect increases

(Sedation, disinhibition, anxiolylitic => hypnosis => anesthesia => medullary depression => coma)

Babiturates have a more linear relationship between dose and CNS effects, while BZD’s CNS effects taper off

  • BZD less likely to cause more CNS depression
  • Barbiturate more likely to cause more CNS depression, and even coma; hence its use as an ASM is limited
31
Q

Topiramate uses

A
  • Adjunctive therapy for Lennox-Gastaut syndrome
  • Prophylaxis of migraine headaches
32
Q

PK of Topiramate:

A
  • Long plasma half life (20-30h)
  • Predominantly renally cleared (30-55%)
  • 15% protein binding
  • NOT a potent inducer of drug-metabolizing enzymes (moderate inducer of CYP3A4 at doses >200mg/day, moderate inhibitor of CYP2C19)

3153 Seizure & Epilepsy (13 decks)

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