Thursday, January 17, 2008

Chap 22: Sedative/Hypnotics

- sedative = anxiolytics = reduce anxiety + exert calming efx - CNS depressive efx minimal
- hypnotics = CNS depression = produce drowsiness + induce sleep state
- many sedatives - increase dose = hypnotics- drug A = alcohol, barbiturates --> can cause anaesthesia + death
- drug B = BZD, newer hypnotics --> needs higher dose to cause anaesthesia

Chemical classifications of sedative/hypnotics
  • most BZD contain carboxamide group
- barbiturates
  • glutethimide + meprobamate - different structures than barbiturates but similar efx
  • ethanol, chloral hydrate
- zolpidem (imidazopyridine), zaleplon (pyrazolopyrimidine), eszopiclone (cyclopyrrolone), ramelteon (melatonin receptor agonist), buspirone (slow-onset anxiolytic agent)
  • all structurally unrelated to BZD but similar MOA
- antipsychotics, antidepressants, antihistamine

Absorption + distribution
- depends on fat solubility
- all cross placental barrier + CNS system, detectable in breast milk --> CNS depressant efx

Metabolism (Biotransformation)
  • liver clears all BZD
  • phase I (oxidization) and II (conjugation)
  • individual drugs has different biotransformation --> some after phase I are metabolically active hence longer T1/2
- barbiturates
  • hepatic oxidation to form alcohols, acids + ketones
  • usually slow in metabolism hence barbiturates have long T1/2 eg phenobarbital 4-5 days
  • beware of multiple dosing
- newer hypnotics
  • zolpidem reaches peak in 1.6 hrs --> elimination T1/2 1.5-3.5 hrs
- by kidney

Molecular pharmacology of GABA*vA receptor
- binds to molecular components of GABA*vA receptors
- GABA*vA receptors - neuron membranes in CNS
A model of the GABAA receptor-chloride ion channel macromolecular complex (others could be proposed). A heterooligomeric glycoprotein, the complex consists of five or more membrane-spanning subunits. Multiple forms of a, b, and g subunits are arranged in different pentameric combinations so that GABAA receptors exhibit molecular heterogeneity. GABA appears to interact with a or b subunits triggering chloride channel opening with resulting membrane hyperpolarization. Binding of benzodiazepines to g subunits or to an area of the a unit influenced by the g unit facilitates the process of channel opening but does not directly initiate chloride current.

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