Module 7:
Local Anesthetic Mechanism
By Lauren McCormick
primary mechnism
specific inhibition of voltage gated sodium channels (VGSC) along nerve axon
inhibition by binding of drugs to specific site within ion channel
nerve cell membrane impermeable to sodium
excitation of neuron increases sodium conductance
unidirectional depolarization
drugs that reduce rate of polarization will slow signal conduction
VGSCs
highly folded alpha subunit
1-2 beta subunits
4 homologous domains
each comprised of 6 similar trans-membrane helices (S1-S6)
linked by cytoplasmic/extracellular loops
S4 transmembrane helix in each of the 4 domains
sensitive to voltage changes
mediates opening of pore
S5, S6 form central aqueous pore channel when folded
extracellular loops linking S5 & S6 sit above the pore and form the ion selectivity gate (allows sodium to travel into central pore channel)
S3, S4 change shape in response to voltage gated opening of the pore when properly folded
cytoplasmic loops w/ "h" folds upwards & blocks ion passage through the aqueous pore channel
"h" gated mechanism
local anesthetics target S5 & S6 helices; bind to area formed by S6 helices of the 1,3, and 4 domain
on either side of alpha subunit; stabilize alpha pore forming subunit
Tetrodotoxin
sodium channel specific toxin
binds external loop region irreversibly
prevent ion flux into cell in response to voltage signals
bound channels must be replaced by new channels before nerve can function again
potassium channel inhibition
K+ channel has 4 identical subunits
similar to VGSCs
blockade may contribute to pain inhibition by local anesthetics
sodium channel is primary target
Sodium Channel Mechanism
resting state
aqueous channel closed, h-gate open
change in voltage sensed
aqueous pore channel opens, primes h-gate by altering conformation (in preparation to close)
h-gate fully closes
ion movement blocked
ion flows into cell
aqueous channel open, h-gate closed
channel fairly rapidly recovers to resting state
Unidirectionality
3 conformation states of ion channel causes unidirectional axonal impulse conduction
inactivated channels act like a valvae for depolarizing wave
prevents immediate re-activation
until channel returns to resting state & is sensitive to voltage once more
Local Anesthetics
recall:
charged molecules are aqueous soluble, must lose charge to pass through lipid membrane
the more lipid soluble anesthetics may stick around long enough in membrane to diffuse through walls of ion channel & enter pore w/o passing from cytoplasm
"hydrophobic pathway"
majority of drug will diffuse through membrane into cytoplasm
"hydrophilic pathway"
ionized/non-ionized step = rate limiting step for local anesthetics
LAs are weak bases
ionized at pH7
lose effectiveness in inflamed (low pH) tissues
high % of drug is ionized & unable to dissolve into cell membrane to enter nerve
LA preferentially binds open or inactivated channel
more charged LAs may access binding site from cytoplasm via open channels
Differential Nerve Block
majority of anesthetic dose must enter pores from cytoplasm
pores must be actively open w/ h-gate open
use (state) dependent block
higher frequency of nerve pulse
more effective block
other names:
- frequency-dependent conduction
- phasic block
- transitional block
- Wedensky inhibition
concentration reduces signal by 40% at 1Hz --> expected to reduce signal by 80% at 40Hz
infrequent nerve pulses
less LA binding
most LA diffuses away
Basal or Tonic block
increasing nerve pulse frequency increases phasic block
in presence of LA, an increased nerve pulse frequency from 1,2,3 to 25hz, overall sodium current is reduced
some LAs are more sensitive to dependent (phasic) block
neurons differ size & type
therefore differ susceptibility to local anesthetics
nodes of ranvier
unmyelinated regions of nerve axon
number of nodes directly proportional to neural fiber diameter
anesthetic must completely block at least 3 nodes
if anesthetic coverage is insufficient, AP may still be reduced of blocked if 70% of Na+ channels blocked per node
Target Nerves
LAs block narrow rapid firing nerves first
A-delta/B, then C
Adelta and Agamma blocked similarly
Agamma blockade leading to rapid flaccid paralysis
Blockade is dynamic
varying myelination
differential spread of receptor expression
varying site of drug administration
Future
"rediscover" old drugs
variations on existing molecules
anesthetic recovery
therapeutic
overdose prevention
drug delivery system improvements
chiral compounds
ropivacaine
levobupivicaine (s-enantiomers)
improvement of LD50
Tonicaine
lidocaine derivative 9x more potent (still experimental)
Lipid emulsions
emergency tx for local anesthetic toxicity
act as a "sink" for lipophilic drugs; equilibrium rxn drives drug off target and into emulsion
Phentolamine mesylate (Oraverse)
reverses vasoconstrictor effects, rapid reversal of anesthetic diffusion
liposomes
nano-sized vesicles, surface activated
microspheres (biodegradable polymer) and cyclodextrins (cyclic oligosaccharide)
slow release of drug as polymer degrades