LA mechanism
Voltage gated sodium channel (VGSC)
Neurons
differ in size and type
different in susceptibility to LA
selectivity of a nerve block is determined by:
Ionization state to the receptor target of local anesthetics
nerve impulse firing rate
highly folded alpha subunit
Primary mechanism of LA neuronal block
specific inhibition of VGSC
located along long nerve axon
Quiescent nerve cell membrane is impervious to sodium
excitation of neuron temporarily increases sodium conductance
excitation by chemical messengers at the synapse results in progressive unidirectional depolarization
related to sodium influx (conductance)
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repolarization before threshold potential can be reached
nerve conductance fails tonic block
stabilized by one of two beta subunits
2 beta subunits, on either side of the alpha polypeptide subunit, stabilize alpha pore forming subunit
comprised of 4 homologous domains
each composed of 6 structurally similar transmembrane helices
S1 - S6
S5
S4
sensitive to changes in voltage
mediates the opening of the pore
form the central aqueous pore when folded
extracellular loops linking S5 and S6 sit onto of the pore
S6
forms the ion selective gate
normally only allows sodium to travel into central pore
LA target the central pore region formed by S6 and S5
region between 3rd and 4th alpha domains
can change shape in response to to voltage gated opening of the pore
conformational change - "H" loop folds upward and blocks further ion passage through the aqueous channel even thought the pore channel itself is still open
H-gate mechanism is the basis for unidirectional nerve conduction
LA specifically bind to the are formed by S6 helices of domains 1, 3, and 4
Potassium channels
thought that LA may also inhibit potassium channels in the nerve axon
structurally similar to the voltage gated sodium channel, and to some extend calcium channels
may contribute to pain inhibition by LA, but sodium channel is considered the primary LA targets
3 possible conformations
Activated
Inactivated
Resting
prior to activation
aqueous channel closed
H-gate open
on sensing change in voltage - aqueous gate opens
at the same time primes the H-gate by altering conformation
aqueous channel open, H-gate open but primed to close
After a short period of ion flow into the cell, H-gate fully closes
blocks further ion movement
aqueous channel open, H-gate closed
Hilary Parsons D20300
Reason why axonal impulse conduction is unidirectional
Nerve impulses
unidirectional
sodium channel conformation
Structural properties of the ion channel that allow 3 conformational changes
charged (ionized) molecules are aqueous soluble
need to become unionized (lose their charge) to efficiently pass through the lipid membrane
LA cannot enter the narrow extracellular entrance to the aqueous pore channel - must enter through the axonal cell membrane into the cytoplasm
majority of LA dose must enter pores from the cytoplasm
LA primarily enters the aqueous pore channel from the cytoplasmic side- must be ionized to do so
Hydrophobic pathway (very small percent use this)
very low percentage of the more lipid soluble drugs may reside long enough in the membrane to diffuse through the walls of the ion channel and enter the pore without having to pass into the cytoplasm
Ionized/non-ionized step acts as a rate limiting step for LA
LA are weak bases
normal tissue ~pH 7 they are mostly ionized
inflamed tissue < pH 7
low pH conditions may cause a very high percentage of weak base drugs to be ionized and unable to dissolve into the cell membrane and enter the nerve
VGSC must be open
pH -pKa = - #
the aqueous channel (M-gate) and the H-gate must be open
Use -dependent blockade
nerve signal frequency
the higher the frequency of nerve pulses, the more effective the block
frequency-dependent conduction block = transitional block = Wedensky block = use-dependent block
an [LA] that reduces signal by 40% at 1Hz may be expected to reduce a signal by 80% at 40Hz (Hz=hertz = frequency, number of events/sec)
infrequent nerve pulses = less LA binding = most LA diffuses away
there must be some initial depolarizing signal occurring along the axon ignorer for the channels to open and to the LA to enter and bind
the more frequently the signal occurs, the more frequently the channels open, the more drug can enter and block the channel
once bound inside the VGSC it is thought the LA molecule stabilizes the channel in the inactive state - preventing the normally rapid recovery to the resting state and readiness for reactivation
Some anesthetics are more sensitive to use dependent (phasic) block than others
inactivated channels are like a valve for the depolarizing wave
allowing it to travel forward but preventing immediate re-activation or re-opening of the ion channels in the section of the axon where the wave has just passed
eventually channel returns to the resting state , sensitive to voltage changes and is ready to open again
Myelinated
Nodes of Ranvier = unmyelinated regions of the nerve axon
number of nodes directly proportional to neural fiber diameter
Normally: anesthetic must block at least 3 nodes
axonal size
rate of drug penetration
In the same given area a large neuron will have fewer nodes of Ranvier covered with drug than a smaller neuron = less likely sufficient amount of sodium channels will be blocked to effectively achieve inhibition of nerve impulses
location within the nerve bundle
Nerve location
LA must diffuse through local tissue into the nerve bundle
there will always be a concentration gradient of the LA