ASMs MOA

Question 1

Background on excitatory synapses:

What postsynaptic receptors does Glutamate bind to?

Answer 1

1. AMPA receptors

• Upon glutamate binding to AMPA receptors, receptor opens to permit Sodium entry into the cell

2. 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

Question 2

Background on inhibitory synapses:

What postsynaptic receptor does GABA bind to?

Answer 2

GABA-A receptors

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

Question 3

Background on inhibitory synapses:

How is GABA removed from the synaptic cleft?

Answer 3

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

Question 4

[ASMs that act on glutamate system]

ASMs that block sodium channels:

Answer 4

• Phenytoin
• Carbamazepine
• Sodium valproate
• Lamotrigine
• Topiramate

Question 5

[ASMs that act on glutamate system]

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

Answer 5

• Lamotrigine
• Topiramate

• Levetiracetam
• Phenobarbital
• Phenytoin

Question 6

[ASMs that act on glutamate system]

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

Answer 6

• Sodium valproate

Question 7

[ASMs that act on glutamate system]

ASMs that bind to glutamate AMPA receptors

Answer 7

• Phenobarbital
• Topiramate
• Levetiracetam

Question 8

[ASMs that act on glutamate system]

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

Answer 8

• Levetiracetam

Question 9

[ASMs that act on glutamate system]

ASMs that block glutamate NMDA receptors

Answer 9

• Sodium Valproate
• Topiramate

Question 10

[ASMs that act on GABA system]

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

Answer 10

• Benzodiazepine
• Barbiturates

• Topiramate

Question 11

[ASMs that act on GABA system]

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

Answer 11

• Sodium Valproate

Question 12

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

Answer 12

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

Question 13

Phenytoin MOA

Answer 13

• Block voltage-dependent Na+ channels, thereby blocking depolarization and generation of action potential

• Inhibit high-voltage activated calcium channels

Question 14

Carbamazepine MOA

Answer 14

• Blockade of voltage-dependent Na+ channels

Question 15

Valproate MOA

Answer 15

• 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

Question 16

[Benzodiazepines]

Benzodiazepines MOA

**BZDs also used as hypnotic, anxiolytic

Answer 16

• 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

Question 17

[Phenobarbital]

Phenobarbital MOA

Answer 17

• Potentiates GABA-A mediated Cl- currents, at a site distinct from BZDs
• Binds to AMPA receptors

• Inhibit high-voltage activated calcium channels

Question 18

Levetiracetam MOA

Answer 18

• 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

Question 19

Lamotrigine MOA

Answer 19

• 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

Question 20

Topiramate MOA

Answer 20

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

Question 21

[Benzodiazepines PK]

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

Answer 21

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

Question 22

[Benzodiazepines]

Benzodiazepines are NOT first line for new onset epilepsy because:

Answer 22

• Abuse potential
• Addictive
• Toxicity

*May be considered for refractory cases, or as adjunctives

Question 23

[Benzodiazepines]

BZDs are the initial therapy of choice for _________

Answer 23

Status epilepticus

Question 24

[Benzodiazepines]

What is used to treat Benzodiazepine toxicity/overdose?

Answer 24

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

Question 25

[Benzodiazepines] Benzodiazepine ADRs include:

Answer 25

- Sedation, somnolence - Drowsiness, confusion, amnesia - Impaired muscle coordination, impairs manual skills

Question 26

[Benzodiazepines] Benzodiazepine tolerance and dependency - what are the withdrawal effects?

Answer 26

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

Question 27

[Phenobarbital] Phenobarbital tolerance and dependence How does this affect its use?

Answer 27

- 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)

Question 28

[Phenobarbital] Is Flumazenil effective for treating barbiturate overdose?

Answer 28

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

Question 29

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

Answer 29

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)

Question 30

Dose-dependent depression of CNS - Benzodiazepine VS Barbiturate

Answer 30

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**

Question 31

Topiramate uses

Answer 31

- Adjunctive therapy for Lennox-Gastaut syndrome - **Prophylaxis of migraine** headaches

Question 32

PK of Topiramate:

Answer 32

- 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)