Medical Pharmacology: Sedative Hypnotics Drugs

Medical Pharmacology Chapter 12: Anxiolytics and Sedative-Hypnotics

Table of Contents
Stages of CNS depression Classification of central nervous system depressants Possible biochemical mechanism of action of anxiolytics, sedatives and hypnotics Effects on cardiovascular, respiratory and central nervous systems. Comparative Advantages and disadvantages of sedative-hypnotic classes Anxiolytics Hypnotics Specific Drug Classes Specific Drugs and Classes Barbituates Benzodiazepines Others	Preoperative Medications: The Role of Sedative Hypnotics and Other Drugs and Issues Benzodiazepines Opioids Antihistamines (including both sedative uses and effects on gastric acid secretion) Antacids Patients who should receive prophylaxis against aspiration Proton Pump Inhibitors Antiemetic Drugs Anticholinergic Agents Centrally-acting α₂ agonists Steroids Antibiotics Insulin Preoperative medication differences between adults and children

Preoperative medication for ambulatory surgery

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

**Benzodiazepine binding site on the GABA_A receptor: pharmacophore model^2,3**

"A pharmacophore model of the benzodiazepine binding site on the GABA_A receptor.¹ White sticks represent the carbon atoms of the benzodiazepine diazepam, while the green represents carbon atoms on the nonbenzodiazepine CGS-9896. Red and blue sticks are oxygen and nitrogen atoms that are present in both structures. The red spheres labeled H1 and H1/A3 are, repsectively, hydrogen bond donating and accepting stites in the receptor, while L1, L2, and L3 denote lipophilic binding sites."³

Benzodiazepines act on GABA_A receptors

**GABA_A Structure**

GABA_A receptor: "View of the receptor from the extracellular face of the membrane. The subunits are labeled according to the GABA_A nomenclature and the approximate locations of the GABA and benzodiazepine (BZ) binding sites are noted (between the α- and β-subunits and between the α- and γ-subunits respectively)." (image on the left) The nicotinic acetylcholine receptor is structurally very similiar to the GABA_A receptor.^4,5,6 Schematic of a GABA_A receptor protein.⁷

**GABA_A Receptor Schematic**

GABA_A receptor: "Left: GABA_A monomeric subunit imbedded in a lipid bilayer (yellow lines connected to blue spheres). The four transmembrane α-helices are depicted as cylinders. The disulfide bond in the N-terminal extracellular domain which is characteristic of the family of cys-loop receptors (which includes the GABA_A receptor) is depicted as a yellow line. Right: Five subunits symmetrically arranged around the central chloride anion conduction pore. The extracellular loops are not depicted for the sake of clarity."^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". J. Mol. Graph. Model. 25 (5): 721–30.

6. Sancar F, Ericksen SS, Kucken AM, Teissére JA, Czajkowski C (January 2007). "Structural Determinants for High-Affinity Zolpidem Binding to GABA-A receptors". Mol. Pharmacol. 71 (1): 38–46.

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

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

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