GABA Drugs

Question 1

Benzos v. Barbiturates

Answer 1

• Barbiturates
  
  • Bind to distinct site on GABA A receptor to directly activate receptor (even in absence of GABA)
  • Opens the Cl- channel for longer so more Cl- in cell
  • Use- epilepsy, anesthesia (sedative and hypnotic)
  • Can be fatal esp if w/ alcohol or other CNS dep
• Benzodiazepines
  
  • Inc GABA affinity (so need GABA present to work)
  • Use- anti-anxiety, amnesia, muscle relaxant, treat seizures, sedation, hypnosis
  • Not lethal on own

Question 2

Flumazenil

Answer 2

• specific competitive antagonist that binds to same site as benzos to reverse their effect if needed
  
  • Used if someone ODs on benzos
  • Short half-life (30-60 min) so must monitor)

Question 3

Neurosteroids

Answer 3

• Steroids made locally in CNS
• Bind to sites w/in transmembrane domains of alpha and beta subunits of GABA A receptors
• Uses- pos GABA modulation (anti-anxiety, anti-convulsant, sedative, anesthetic) v. GABA A antagonists
• Alphaxalone - synthetic neurosteroid used as anesthetic

Question 4

Alcohol

Answer 4

GABA A receptors - potentiate

Question 5

Diazepam

Answer 5

Benzo

Valium

Anti-anxiety by potentiating/ inc affinity for GABA receptors

Question 6

Phenobarbital

Answer 6

AKA luminal

Barbiturate

Question 7

Propofol

Answer 7

• IV anesthetic
• mainly work on beta subunits
• Potentiate GABA receptors at clinical levels BUT can directly activate GABA receptors at higher levels

Question 8

3 Mechanisms of Anti-epileptics

Answer 8

• Mediate synaptic transmission - benzos (klonopin/valium) AND barbiturates (LUMINAL)
• GABA agonist - gabapentin (Neurontin)
• Block GABA reuptake - Tiagabine (Gabitril)

Question 9

Sleep Aids

Answer 9

• “Z drugs”
• Bind to same site on alpha subunit of GABA receptors as benzos but structurally different
  
  • Selective sedation, less rebound, less toelrance
• Potentiate receptor function
• Examples- zolpidem (ambien), zaleplon (sonata), eszopiclone (lunesta)
  
  • Ambien has 30 min onset and 2-3 hr half-life; highest affinity for alpha 1 receptor
• Side effects- sleep eating and sleep driving

Question 10

3 Types of GABA Recptors

Answer 10

• A- fast; ligand-gated Cl- channels
• B- slower; GPCRs (use G alpha i to inhibit cAMP)
• C- also ligand-gated Cl- channels BUT pharmacologically different and localized to retina

Question 11

GABA A Receptors (Structure and Mechanism)

Answer 11

• 5 subunits - usually 2 alpha, 2 beta and 1 gamma (or delta)
• Form central pore that is permeable to Cl- ions
• Binding of GABA –> Cl- flows into cell –> hyperpolarization –> dec likelihood of AP (neuronal inhibition)
• **Multiple isoforms exist -relevant because some isoforms may be concentrated in specific parts of brain which leads to diversity of effects