Mechanism of action of local anaesthetics

Action of local anaesthetics (LAs)
LAs block action potential generation by blocking sodium channels.
LAs are amphiphilic molecules, with a hydrophobic aromatic group and a basic amine group.
LAs probably act in their cationic form but must reach their site of action by penetrating the nerve sheath and axonal membrane as unionised species; they, therefore, have to be weak bases.
Many LAs show use-dependence (depth of block increases with action potential frequency). This arises:
because anaesthetic molecules gain access to the channel more readily when the channel is open
because anaesthetic molecules have higher affinity for inactivated than for resting channels.
Use-dependence is mainly of importance in relation to antidysrhythmic and antiepileptic effects of sodium channel blockers.
LAs block conduction in the following order: small myelinated axons, non-myelinated axons, large myelinated axons. Nociceptive and sympathetic transmission is thus blocked first.