Theories of general anaesthetics

MODE OF ACTION OF GENERAL ANAESTHETICS

 Mode of action of general anaesthetics

  • There have been many attempts to explain the mechanism of general anaesthetics at a molecular level. but none is satisfactory,because
    • The rate at which anaesthesia can be induced and wakefulness resumed focuses attention on short term biochemical events
    • Wide variation in the structure of anaesthetic drugs
    • Ability of anaesthetics to cause superimposed selective and specific anaesthetic side effects such as reductions in myocardial contractility.
  • An important neurophysiological action common to most general anaesthetics is to depress both spontaneous and evoked neuronal activity in many regions of the brain. A number of theories have been put forth to explain the anaesthetic action. But, a unitary theory of narcosis is not available. The general characteristics exhibited by anaesthetics are that they act at hydrophobic sites on excitable membranes and the ultimate site of the effect is protein.
    • Meyer and Overtone theory: According to this theory, to be an anaesthetic it must be soluble in oil. The higher the solubility in oil, the greater was its anaesthetic potency. Ether and chloroform fit conveniently into the above hypothesis, but at present there are many objections to this theory.
    • Colloidal theory: This theory states that, colloids of nerve protoplasm form a loose compound with the anaesthetic.
    • Surface tension theory: According to this theory, a reduction in the surface tension of neuronal membrane is brought about by the anaesthetics.
    • Permeability theory: General anaesthetics are said to impair the permeability of neuronal membranes as a result of which depolarization and subsequent activation fail to occur.
    • Pauling and Miller theory: Pauling and Miller theory states that microcrystals (clatharates) are formed by the anaesthetic vapour. These in turn reduce the conductance.
    • Reduced energy formation theory: This theory states that general anaesthetics depress the formation of high energy bonds.
    • Cell membrane expansion theory: This theory states that inhalation anaesthetics are hydrophobic and therefore distribute to sites in which they are removed from aqueous environment and because of the close correlation between potency and lipophilicity, it is theorized that these anaesthetics act on the cell membrane lipid layer. It is thought that their presence distorts the membrane structure, which in turn causes occlusion of the pores through which ions pass (example – sodium channel). This theory also explains the pressure reversal of anaesthesia.
  • Although there is no pharmacologic antagonist to inhalation anaesthetics, very high ambient pressure causes reversal of the anaesthetic state. Because pressure acts by reducing the volume, the reversal of anaesthetic with pressure suggests that an increase in lipid volume is somehow involved in the process.
  • Current idea – they exert actions through different molecular mechanisms
  • Inhalational anaesthetics, barbiturates, benzodiazepines – potentiation of GABAA receptor
  • Ketamine (dissociative) – inhibition of NMDA type of glutamate receptor
  • Some fluorinated GAs – inhibit cation movement by closing nicotinic ACh receptor
  • In total –receptor operated ion channels are the major site of action – thereby depressing synaptic transmission.
Last modified: Tuesday, 15 May 2012, 11:34 AM