[Molecular mechanism of action of local anesthetics].
The main target of local anaesthetics on nervous tissue is the sodium channel. Molecular biology and electrophysiology have shown different mechanisms of action on this sodium channel, which depend on the chemical structure and electrostatic charge of the local anaesthetic molecule. There are two main types of action, shown up on the isolated axon, a direct one on the sodium channel itself and an alteration in the lipids surrounding the channel. These effects have been shown on the isolated axon and explain the anaesthetic effect by an inhibition of the sodium current. Experimental studies have also shown the effects of local anaesthetics on different organelles within the cell, and so on intracellular metabolism. Mitochondrial energetic metabolism, and therefore ATP synthesis, is reduced by local anaesthetics at several levels. The respiratory enzyme chain is inhibited by small concentrations of local anaesthetic, especially NADH dehydrogenase and ubiquinone succinate dehydrogenase. Moreover, local anaesthetics increase the mitochondrial membrane permeability to protons, thus removing the moving force behind ATPase activity in ATP synthesis; this leads to a drastic fall in available energy. This effect is further increased by a direct inhibition of ATPase and ATP/ADP translocation. Other enzyme systems of other organelles are also disturbed by local anaesthetics, such as the endoplasmic reticular Ca++ ATPase, which is inhibited, so altering the calcium concentration within the cytosol. Local anaesthetics also inhibit lipolysis and glycogenesis. Receptors such as the acetylcholine receptors are blocked by local anaesthetics. The mechanism of action of these drugs on all these protein systems is two-fold: an alteration of protein structure, but also of the lipids surrounding them.(ABSTRACT TRUNCATED AT 250 WORDS)
Bendriss
P
P
Département d'Anesthésie-Réanimation, Hôpital Pellegrin, Bordeaux.
Dabadie
P
P
Mazat
J P
JP
Letellier
L
L
Erny
P
P
D000200:Action Potentials / Q000187:drug effects; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000779:Anesthetics, Local / Q000493:pharmacokinetics / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects; D006801:Humans; D007473:Ion Channels / Q000502:physiology*; D008560:Membrane Fluidity; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D011188:Potassium / Q000378:metabolism; D012964:Sodium / Q000378:metabolism
D000779:Anesthetics, Local; D007473:Ion Channels; D000255:Adenosine Triphosphate; D012964:Sodium; D011188:Potassium; D002118:Calcium
Mécanismes moléculaires de l'action des anesthésiques locaux.