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.

Sunday, January 6, 2008

Chap 42: Bone Mineral Homeostasis

- Ca + PO4 - 2 most important minerals for cell function
- Bone is major storage

  • 98% of total 1-2kg of Ca
  • 85% of 1kg of PO4
- 2 hormones important - PTH and Vit D
Non hormonal agents affecting bone mineral homeostasis
- analog of pyrophosphate
- inhibit formation and dissolution of hydroxyapatite crystals in/out skeletal system
- predilection for bone - effects come from osteoclasts
- <10%> take with empty stomach --> 50% accumulates in bone, 50% renally excreted unchanged
- SE:

  • gastric irritation/esophageal irritation --> glass of H2O, sitting upright 30 mins
  • osteonecrosis of the jaw
  • renal damage
- clinical uses

  • alendronate - seemed to increases bone mineral density over 2 yrs hence used in osteoporosis/# NOF
  • zolendronate - hyperCa 2ary to malignancy
  • pamidronate - same as above but cheaper, less potent