Mechanism of Local Anesthetics
primary mechanism: inhibition of voltage gated sodium channels located along long nerve axon
nerve is usually impervious to sodium
chemical excitation allows sodium to flow in
unidirectional depolarization
drugs can reduce the rate and degree of depolarization
voltage gated sodium channel
highly folded alpha subunit stabilized by one or two beta subunits
alpha subunit has 4 domains, each with 6 structurally similar transmembrane helices
S4 transmembrane helix is sensitive to voltage changes and mediates opening of the pore
S5 and S6 helices form the central aqueous pore when folded
region can change shape in response to voltage gated opening of the pore and the cytoplasmic loop folds upward and blocks further ion passage
local anesthesia binds area formed by S6 helices of domains 1, 3, 4
local anesthetics may also inhibit potassium channels
potassium channels = 4 identical subunits
structurally similar to voltage gated sodium channels
3 possible configurations
prior to activation = resting state; aqueous channel closed, h-gate opened
voltage change --> aqueous pore channel opens and primes h-gate; aqueous channel open, h-gate open but primed to close
after short period of ion flow into the cell, h-gate fully closes and blocks further ion movement; aqueous channel open, h-gate closed
inactivated channels prevents immediate re-activation or re-opening of the ion channels
local anesthesia preferentially binds to open or inactivated channels
charged LAs tend to access binding site from cytoplasm via open channels
only a low percentage of the drug
lipophilic or uncharged LA may assess via membrane
ionization/de-ionization is rate limiting step
use (or state) dependent block
refers to activation state of ion channel
more frequently the signal occurs, more frequently the channels open and more drug can enter and block the channel
once LA bound to pore channel, the molecule stabilizes the channel in inactive state, preventing normal rapid recovery
conventional LAs exhibit 10-fold range in frequency dependence
differential nerve block
neurons differ in size and type
number of nodes of ranvier directly proportional to neural fiber diameter
anesthetic must completely block at least 3 nodes
even if coverage is insufficient, action potential may still be reduced if around 70% of Na+ channels are blocked per node
LAs block narrow rapid firing nerves first (Adelta/B>C)
blockade is dynamic since myelination, differential spread of receptor expression and site of drug administration varies
LA must diffuse through local tissue and into nerve bundle so concentration gradient of drug; mantle axons exposed to higher concentrations of drug than core fibers
future dvpt's
chiral compounds such as s-enantiomers have lower off-target receptor binding and lower systemic toxicity
oraverse: phentolamine mesylate: non-selective adrenergic antagonist; reverses vasoconstrictor effects; increased rate of anesthetic diffusion from site
lipid emulsions
routinely used as emergency tx for LA toxicity; acts as lipid sink for lipophilic drugs
liposomes: nano-sized lipid vesicles allowing encapsulation of drugs; surface may be activated; lipid suspensions of the drug that provide moderately slow release of drug
microspheres and cyclodextrins: biodegradable solid materials that can gradually release drug as they degrade