ASMs MOA Flashcards
Background on excitatory synapses:
What postsynaptic receptors does Glutamate bind to?
- AMPA receptors
- Upon glutamate binding to AMPA receptors, receptor opens to permit Sodium entry into the cell
- 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
Background on inhibitory synapses:
What postsynaptic receptor does GABA bind to?
GABA-A receptors
- Upon binding to GABA-A receptors, receptors open to allow entry of Cl- ions
Background on inhibitory synapses:
How is GABA removed from the synaptic cleft?
GABA-transporter-1 (GAT-1) reuptake of GABA into presynaptic membrane; then degradation by gamma-aminobutyric acid aminotransferase (GABA-T)
[ASMs that act on glutamate system]
ASMs that block sodium channels:
- Phenytoin
- Carbamazepine
- Sodium valproate
- Lamotrigine
- Topiramate
[ASMs that act on glutamate system]
ASMs that inhibit presynaptic high-voltage activated calcium channels to slow down hyperactive neurons
- Lamotrigine
- Topiramate
- Levetiracetam
- Phenobarbital
- Phenytoin
[ASMs that act on glutamate system]
ASMs that inhibit low-voltage activated t-type calcium channels:
- Sodium valproate
[ASMs that act on glutamate system]
ASMs that bind to glutamate AMPA receptors
- Phenobarbital
- Topiramate
- Levetiracetam
[ASMs that act on glutamate system]
ASMs that bind to SV2A protein (synaptic vesicle protein 2A) to inhibit synaptic release of glutamate
- Levetiracetam
[ASMs that act on glutamate system]
ASMs that block glutamate NMDA receptors
- Sodium Valproate
- Topiramate
[ASMs that act on GABA system]
ASMs that bind to GABA-A receptor thus prolonging opening of Cl- channel and permitting Cl- influx:
- Benzodiazepine
- Barbiturates
- Topiramate
[ASMs that act on GABA system]
Increase GABA turnover by inhibiting GABA transminase (enzyme that breaks down GABA)
- Sodium Valproate
How might GAT-1 (GABA reuptake transporter) and GABA-T (GABA-transaminase) be used to stop seizures?
- Inhibitor of GAT-1: Tiagabine
- Inhibitor of GABA transaminase: Vigabatrin, sodium valproate
Phenytoin MOA
- Block voltage-dependent Na+ channels, thereby blocking depolarization and generation of action potential
- Inhibit high-voltage activated calcium channels
Carbamazepine MOA
- Blockade of voltage-dependent Na+ channels
Valproate MOA
- 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
[Benzodiazepines]
Benzodiazepines MOA
**BZDs also used as hypnotic, anxiolytic
- 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
[Phenobarbital]
Phenobarbital MOA
- Potentiates GABA-A mediated Cl- currents, at a site distinct from BZDs
- Binds to AMPA receptors
- Inhibit high-voltage activated calcium channels
Levetiracetam MOA
- 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
Lamotrigine MOA
- 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
Topiramate MOA
- Blocks Sodium channels
- Blocks Calcium channels
- Binds to glutamate AMPA receptors
- Binds to glutamate NMDA receptors
- Bind to GABA-A receptor
[Benzodiazepines PK]
List examples of short-acting, intermediate-acting, and long-acting BZDs. How long are their durations of action?
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
[Benzodiazepines]
Benzodiazepines are NOT first line for new onset epilepsy because:
- Abuse potential
- Addictive
- Toxicity
*May be considered for refractory cases, or as adjunctives
[Benzodiazepines]
BZDs are the initial therapy of choice for _________
Status epilepticus
[Benzodiazepines]
What is used to treat Benzodiazepine toxicity/overdose?
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
[Benzodiazepines]
Benzodiazepine ADRs include:
- Sedation, somnolence
- Drowsiness, confusion, amnesia
- Impaired muscle coordination, impairs manual skills
[Benzodiazepines]
Benzodiazepine tolerance and dependency
- what are the withdrawal effects?
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
[Phenobarbital]
Phenobarbital tolerance and dependence
How does this affect its use?
- 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)
[Phenobarbital]
Is Flumazenil effective for treating barbiturate overdose?
No, because phenobarbital binds to a separate site on GABA-A receptor (from BZD, and Flumazenil)
[Barbiturates PK]
List examples of ultra-short-acting, short-acting, and long-acting barbiturates. How long are their durations of action?
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)
Dose-dependent depression of CNS
- Benzodiazepine VS Barbiturate
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
Topiramate uses
- Adjunctive therapy for Lennox-Gastaut syndrome
- Prophylaxis of migraine headaches
PK of Topiramate:
- 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)
