Nursing Pharmacology Chapter 12:  Anxiolytics and Sedative-Hypnotics

• Stages of central nervous system depression:  Non-benzodiazepine (e.g. barbiturates) sedative-hypnotic drugs produce a dose-dependent sequence of CNS depression  

  • With increasing dosage: 

    1. Calming or drowsiness {sedation}

    2. Sleep {pharmacological hypnosis}

    3. Unconsciousness

    4. Coma

    5. Surgical anesthesia

    6. Fatal respiratory/cardiovascular depression

• Classification of central nervous system depressants

  • Benzodiazepines (e.g.,diazepam (Valium), midazolam (Versed), clonazepam (Klonopin)

  • Barbiturates (amobarbital, pentobarbital (Nembutal), thiopental (Pentothal))

  • Miscellaneous agents (e.g. paraldehyde (Paral), meprobamate (Miltown), ethchlorvynol (Placidyl))

• Possible biochemical mechanism of action of anxiolytics, sedatives and hypnotics especially barbiturates and benzodiazepines.

  • Benzodiazepines

    • Benzodiazepines act on GABA_A receptors

      •  

        GABA_A Receptor Schematic

        GABAA receptor:  "Left:  GABAA monomeric subunit imbedded in a lipid bilayer (yellow lines connected to blue spheres).  Right:  Five subunits symmetrically arranged around the central chloride anion conduction pore."4,5,6

         

    •  GABA receptor: a pentameric protein, consists of several subunits designated α (mainly responsible for the pharmacology of the receptor), β and  γ which is required for high affinity benzodiazepine binding. 

      • Electrophysiological Effects: Benzodiazepines enhance GABA-activated hyperpolarizing chloride currents.

  • Ethanol

    • Several sites and mechanisms may be responsible for ethanol-mediated CNS depression:

    • Direct membrane effects:

      •  Dissolves into lipid membranes affecting the function of membrane proteins, such as receptors and ion channels.

      •  Decreases GABA-receptor mediated synaptic inhibition

      •  Inhibits the NMDA glutamate receptor (inhibits an excitatory effect)

      •  Potentiates the action of serotonin (5-HT) at excitatory 5-HT₃ receptors.

      •  Since these receptors are often localized on inhibitory interneurons, ethanol-enhanced activation results in increased inhibition.

  • Barbiturates

    • Barbiturates activate inhibitory GABA_A while inhibiting excitatory AMPA receptors. 

      • AMPA receptors are the subtype of glutamate receptors sensitive to kainate or quisqualate.

    • Barbiturates interact differently than benzodiazepines at GABA receptors. For example, the gamma subunit is not required for barbiturate activity.

    • The combination of these receptor effects may result in the profound central nervous system depression that occurs with higher barbiturate doses.

• 1. Hobbs, W.R, Rall, T.W., and Verdoorn, T.A., Hypnotics and Sedatives: Ethanol In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp. 361-383.

• 2. Madsen U Brauner-Osborne H Greenwood JR Johansen TN Krogsgaard-Larsen P, Liljefors T Nielsen M Frolund B GABA and Glutamate receptor ligands and their therapeutic potential in CNS Disorders. In Gad SC Drug Discovery Handbook, N.J.:  Wiley-Interscience/J. Wiley, 797-907, 2005.

• 3. Benzodiazepines: http://en.wikipedia.org/wiki/Benzodiazepine .

• 4. Clayton T, Chen JL, Ernst M, Richter L, Cromer BA, Morton CJ, Ng H, Kaczorowski CC, Helmstetter FJ, Furtmüller R, Ecker G, Parker MW, Sieghart W, Cook JM (2007). "An updated unified pharmacophore model of the benzodiazepine binding site on gamma-aminobutyric acid(a) receptors: correlation with comparative models". Curr. Med. Chem. 14 (26): 2755–75.

• 5.  Campagna-Slater V, Weaver DF (January 2007). "Molecular modelling of the GABAA ion channel protein".nbsp;J. Mol. Graph. Model. 25 (5): 721–30.

• 6.  Samcar F. Ericksen SS Kucken AM Teissere JA Czajkowski C Structural determinants for high-affinity zolpedem binding to GABA-A receptors. Mol. Pharmacol. 71(2):  38-46.

• 7.  Streejithk2000, Chemgirl131 http://en.wikipedia.org/wiki/File:GABAA-receptor-protein-example.png .

• 8.  Shao & Boghog2 Schematic structure of the GABAA receptor. http://en.wikipedia.org/wiki/File:GABAA_receptor_schematic.png .