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Sedative Hypnotics

 

  • Sedative- Relieves anxiety and produce Calmness
    Hypnotic- Produce Drowsiness and encourage the onset and maintenance of a state of Sleep.
  • Benzodiazepines (BZDs) are most commonly used sedative and hypnotics

Clinical Use:

  1. For relief of anxiety
  2. As a component of balanced anesthesia (intravenous administration)
  3. For insomnia
  4. As diagnostic aids or for treatment in psychiatry
  5. For treatment of epilepsy and seizure states
  6. For control of ethanol or other sedative-hypnotic withdrawal states
  7. For muscle relaxation in specific neuromuscular disorders
  8. For sedation and amnesia before and during medical and surgical procedures

 

Classification

  1. Barbiturates

Long acting (t1/2= 100hrs)

Short acting (t1/2= 30-50hrs)

Ultra short acting (t1/2= 5-10hrs)

Phenobarbitone

Pentobarbitone

Butobarbitone

Amobarbital

Secobarbital

Mephobarbitone

Thiopentone

Methohexitone

 

  1. Benzodiazepines

HYPNOTIC

ANTICONVULSANT

ANTIANXIETY

Diazepam

Flurazepam

Nitrazepam

Alprazolam

Temazepam

Triazolam

Diazepam

Clonazepam

Lorazepam

Clobazam

Nitrazepam

Chlorazepate

Diazepam

Chlordiazepoxide

Oxazepam

Lorazepam

Alprazolam

 

 

  1. Ultrashort
    1. Midazolam
  2. Short
    1. Triazolam
  3. Intermediate
    i. Alprazolam           
    ii. Nitrazepam          
    iii. CLonazepam       
    iv. Clobazem                   
    v. Clorazepate
  4. Long
    i. Diazepam             
    ii. Chlodiazepoxide   
    iii. Flunitrazepam     
    iv. Flurazepam
  5. Longest
    i. Chlordizepoxode   
    ii. Diazepam
  1. Atypical NON-BZDs
    i. Zolpidem                     
    ii. Zopiclone
    iii. Zaleplon                           
    iv. Eszopiclone   
    v. Indiplon
  1. 5-HT1A partial agonist
    1. Buspirone  
  2. Melatonin Agonist
    1. Ramelteon
    2. Agomelatine 
  3. Miscellaneous
    1. Chloral Hydrate
    2. Glutethimide
    3. Ethanol 

Gaba Receptor

  • The GABAA receptor has a pentameric structure assembled from five subunits (each with four membrane-spanning domains) selected from multiple polypeptide classes .αβ γ δ ε π ρ ε τ χ).
  • A major isoform of the GABAA receptor that is found in many regions of the brain consists of two α1 two β2, and one γ2 subunits.
  • This receptor, which functions as a Chloride Ion Channel, is activated by the inhibitory neurotransmitter GABA.
  • Sedative-hypnotics have a low affinity for GABAB receptors, which are activated by the spasmolytic drug (baclofen)

GABA

Endogenous agonist at GABAA receptor which promotes Cl- influx

MUSCIMOL

Agonist at GABAA site

BICUCULLINE

Competitive antagonist at GABAA receptor

PICROTOXIN

Blocks Cl- chanael noncompetitively; acts on picrotoxin sensitive site

BARBITURATE

Agonist at an allosteric site (? picrotoxin site); prolong GABA action; open Cl- channel

ALCOHOL AND INHALATIONAL ANAESTHETICS

Open Cl- channel directly; allosteric facilitation of GABA

BENZODIAZEPINES

Agonist at an allosteric BZD site + facilitate GABA action

β CARBOLINES

Inverse agonist at BZD site + impede GABA action .

FLUMAZENIL

Competitive antagonist at BZD site

 

MAO of sedative and hypnotics:

  Barbiturates

Increase the duration of the GABA-gated chloride channel openings.

At high concentrations, the barbiturates may also be GABA-mimetic, directly activating chloride channels. These effects involve a binding site or sites distinct from the benzodiazepine binding sites.

Depress the actions of the excitatory neurotransmitter glutamic acid via binding to the AMPA receptor.

At very high concentrations, barbiturates depress voltage sensitive Na+ and K+ channels as well.

Benzodiazepenes

Increase in the frequency of channel-opening events.

Atypical/Non BZD

In contrast to benzodiazepines, zolpidem, zaleplon, and eszopiclone bind more selectively because these drugs interact only with GABAA receptor isoforms that contain 1 subunits.

 

*In overdose; BZDs suppress only hypoxic drive of respiration; while barbiturates both hypoxic & neurogenic drive.

 

 

 





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