Gaba-ergic agents

Sedative-hypnotics 

• Sedative - calming, etc

• Hypnotic - sleep onset and maintenance 

• CNS depressants

  • Sedative/hypnotic class: benzodiazepines, barbiturates, Z-drugs, melatonin, orexin antagonists

  • Opioids

  • Alcohol

  • Trazodone

  • Antihistamines

  • Skeletal muscle relaxants

  • Antipsychotics

  • Mirtazapine

Drugs acting through same GABAA receptor 

Benzodiazepines (sedative-hypnotics) 

• Sedative, euphoric, and hypnotic

• Ceiling effect below lethal effects: low risk for death

• Risk for addiction: indirect DA bump

• MOAs:

  • Molecular: Allosteric potentiator at GABA_A receptors

  • Cellular: Increase GABA_A signaling in presence of GABA

  • Clinical: Increased hyperpolarization of neuron

• Drugs: -azopam or - azolam

  • Temazepam (Restoril)       

  • Lorazepam (Ativan)

  • Triazolam (Halcion)            

  • Diazepam (Valium)

  • Alprazolam (Xanax)            

  • Clonazepam (Klonopin)

  • Oxazepam  (Serax)             

  • Midazolam (Versed)

• Because of their ceiling effect, benzos cannot cause maximum GABAergic effects and are low risk for lethal oversee when taken alone 

Z-drugs or non benzodiazepine hypnotics 

• Structure unrelated to benzos but bind same site on receptor 

• Beneficial hypnotic mechanism:

  • Rapid onset of action, short half-life

  • More selective action to sleep/wake regions

    • Less sedation

    • Minor disruption of REM

• MOAs:

  • Molecular: Allosteric potentiator of GABA_A in sleep/wake regions

  • Cellular: Increase GABA_A signaling in presence of GABA

  • Clinical: Increased hyperpolarization of neuron

• Drugs:

  • Zolpidem (Ambien) 

  • Eszopiclone (Lunesta)

  • Zaleplon (Sonata)

Starts with Z = ZZZZzzzzz for sleep!

Ambient noise
Luna = moon
Sonata = relaxing music

Benzodiazepine antagonist 

• Competitive antagonist of benzos/Z-drug, not of barbiturates

• Rapid onset (1-2 minutes)

• MOAs:

  • Molecular: Competitive antagonist at benzo/Z-drug site of GABA_A 

  • Cellular: Reverses benzos/Z-drugs without blocking normal GABA activity

  • Clinical: Return to normal neuronal activity

• Drug: Flumazenil (Romazicon) 

Barbiturates

• Can directly activate GABAA receptor → lethal potential 

• Highly sedative and hypnotic

• High risk for addiction: large indirect DA bump 

• MOAs:

  • Molecular: Agonist & allosteric potentiator GABA_A 

  • Cellular: Activates GABA_A even in absence of GABA

  • Clinical: Hyperpolarization of neurons

• Drugs:

  • Phenobarbital (Luminal)

  • Secobarbital (Seconal)

  • Pentobarbital (Nembutal)

  • Thiopental sodium

  • Methohexital

Non-GABA-ergic sedative/hypnotic

• Melatonin receptor agonist

  • Contrast with Z-drugs

    • No action at GABA receptors

    • Induces normal sleep patterns 

• Ramelteon (Rozerem)

Recognize the dose-dependent effects of sedative/hypnotic CNS depressants and explain why fatal overdose does not occur with benzodiazepines alone.

CNS depression = CNS-mediated physiology decrease in activity 

• Coma, respiratory depression, C.V. failure

• Anesthesia, loss of consciousness

• Hypnosis

• Moderate sedation, cognitive impairment, rest/relax, delayed motor response time, euphoria (some addictive) 

• Mild sedation, calming, anxiolytic 

Describe the key differences between barbiturates and benzodiazepines, and between benzodiazepines and Z-drugs.

Bensoz and Z-drugs 

• Benzodiazepines

  • Acts on wide range of brain regions

  • Abnormal sleep patterns

  • General sedation/ADEs

  • Half-life longer than Z-drugs

• Z-drugs

  • Preferentially acts on sleep/wake regions

  • More normal sleep patterns (REM, etc)

  • Little general sedation/fewer ADEs

  • Very short half-life
    
    

Benzos and Barb

• Barbiturates-

  • ”stronger” - Agonist plus allosteric potentiator 

  • Directly activate GABAA receptor

  • High risk for lethal overdose

  • High risk for addiction 

• Benzodiazepines- 

  • ”weaker”- Allosteric potentiator only

    • Needs GABA release to work

  • Ceiling effect => Low risk for lethal overdose alone

  • Moderate risk for addiction 

• Barb: agonists + allosteric potentiators (can work without GABA); benzos: allosteric potentiators only (need GABA release to work)

• Barb: high risk for lethal effects; benzos: have a ceiling effect causing them to be less likely to be lethal.

Explain simply why flumazenil will not reverse barbiturate overdose.

• If the patient has a benzodiazepine in their system, the flumazenil will displace it and the benzodiazepine will have less activity. It will reverse any sedative effects.

•  If the patient has no benzodiazepines in their system then there is nothing to be displaced. You would see no effect from the Flumazenil at all.

Describe the properties of Z-drugs that make them good agents for insomnia.

• Z drugs: more specific action in sleep/wake regions produces more natural sleep patterns and less sedation. (also: have less tolerance and dependence, have rapid onset of action and short half-life) 

• Benzodiazepines

  • Acts on wide range of brain regions

  • Abnormal sleep patterns

  • General sedation/ADEs

  • Half-life longer than Z-drugs

• Z-drugs

  • Preferentially acts on sleep/wake regions

  • More normal sleep patterns (REM, etc)

  • Little general sedation/fewer ADEs

  • Very short half-life