Transcript INTRODUCTION to LOCAL ANESTHESIA and NEUROPHYSIOLOGY

INTRODUCTION to
LOCAL ANESTHESIA
and
NEUROPHYSIOLOGY
Definition of Local Anesthesia
a loss of sensation in a circumscribed area of
the body caused by a depression of excitation
in nerve endings
Or
an inhibition of the conduction process in
peripheral nerves; no loss of consciousness
occurs
Properties of Local Anesthetics:
1) Not irritating to the tissue
2) No permanent alteration of nerve structure
3) Systemic toxicity should be low
4) Effective whether injected or applied topically
5) Time of onset of anesthesia should be as short as possible
6) Duration of action must be long enough to complete the procedure
but not so long as to require an extended recovery
7) Should be stable in solution and easily biotransformed
8) Should not cause allergic reactions
9) Should be sterile or capable of being sterilized by use of heat
Neurophysiology
The Neuron
•The neuron is the structural unit of the nerve
•Two types of neurons
1) Sensory afferent (toward the CNS)
2) Motor efferent (away from the CNS)
Sensory Neurons: transmit pain; three parts
1) Dendritic Zone- free nerve endings;
most distal portion of the neuron
2) Axon- synapses with the CNS to transmit
input to the brain
3) Cell Body- provides metabolic support for
the entire neuron
Sensory Neurons (afferent)
Motor Neuron (efferent)
The Axon
long cylinder of neural cytoplasm (axoplasm) encased in a
thin sheath, the nerve membrane, or axolemma
axoplasm is a gelatinous substance that is separated from
extracellular fluids by a continuous nerve membrane
nerve cell membrane is ~75 Angstroms thick
all cell membranes are organized to block the diffusion of water
soluble molecules
all cell membranes are selectively permeable via specialized pores
transduce information by protein receptors responsive to chemical or
physical stimulation by neurotransmitters, hormones, light, vibrations
The Membrane
cell membrane is a bilipid layer of phospholipids
hydrophilic (polar) ends facing the outer surface and
hydrophobic (nonpolar) ends projecting to the middle of
the membrane
the nerve membrane lies at the
interface between the
extracellular fluid and the axoplasm
the nerve membrane separates highly
ionic concentrations within the axon
from those outside
The Membrane: Lipid Layer
The Membrane
the resting nerve membrane has an electrical resistance about 50 times
greater than that of the extra/intracellular fluids, thus preventing the
passage of Na, K and Cl ions down their concentration gradients
when a nerve impulse passes, electrical conductivity of the nerve
membrane increases 100-fold: increased conductivity allows the
passage of Na and K ions down their concentration gradient through
the nerve membrane
movement of these ions provides the energy for impulse conduction
along the nerve
some nerve fibers are covered in myelin, specialized Schwann cells
regular interval constrictions are called Nodes of
Ranvier which form gaps between two adjoining
Schwann cells
Electrophysiology of Nerve Conduction
•Nerve resting potential is -70 mV; this is
produced by differing concentrations of ions
on either side of the nerve membrane
•Interior of the nerve is negative compared to
the exterior before a stimulus excites the nerve
STEP 1 - Stimulus excites nerve which leads to:
1) Slow Depolarization- inside of nerve becomes
less negative
2) Threshold Potential- extremely rapid
depolarization occurs from the falling electrical
potential
3) Rapid Depolarization- interior is electrically
positive +40 mV and the outside is negative
(-70 mv)
Resting to Threshold Potential
Threshold Potential to Rapid
Depolarization
STEP 2 - after depolarization,
repolarization occurs
Repolarization- electric potential
inside the cell gradually becomes
more negative until the interior is
again restored to –70 mV
Depolarization
Repolarization
Depolarization
-excitation leads to increase in permeability of the
cell membrane to sodium ions
-transient widening of transmembrane ion channels
allow passage of the sodium ions
-rapid influx of sodium ions into the interior of the
nerve cell causes depolarization of the cell
membrane from resting to firing threshold which is
-50 to -60 mV
Firing Threshold  magnitude of the
decrease in negative trans-membrane
potential that is necessary to initiate an
action potential (impulse); getting more
positive with more influx of Na+
Firing Threshold
-decrease in negative transmembrane potential of
+15 mV; from –70 mV to –55 mV is necessary to
reach the firing threshold; voltage differences of
less than +15 mV will not induce firing
-exposure to a nerve with local anesthetic raises its
firing threshold
-elevating the firing threshold means that more
sodium must pass through the membrane to
decrease the negative transmembrane potential
to a level where depolarization occurs
-when the firing threshold is reached,
sodium rapidly enters the axoplasm due to
increased membrane permeability
-depolarization lasts ~ .3 msec
Repolarization
The action potential is terminated when
the membrane repolarizes; this is caused
by the inactivation of increased
permeability to sodium
The movement of Na+ and K+ during
depolarization is passive
Repolarization
After the membrane potential returns to –70 mV
there is still a slight amount of excess sodium
within the nerve cell and a slight excess of
potassium extracellularly
Sodium is moved out of the cell using ATP and
the sodium pump
Repolarization requires ~ .7 msec
Absolute Refractory Period  the nerve
is unable to respond to another stimulus
regardless of its strength
Relative Refractory Period  a new
impulse can be initiated at this time but
only by a stronger than normal stimulus;
follows the absolute refractory period
Membrane Channels
Sodium channels line the excitable nerve membrane which
are lipoglycoproteins situated firmly in the membranes
Sodium passes through the channels 12 times easier than
potassium
Sodium ions are “thinner” than potassium or chloride ions
and should therefore move easily down concentration
gradients through membrane channels into the nerve cell,
however:
However, sodium ions are hydrated at rest and increase in
size to 3.4 Angstroms; they are too large to pass through the
sodium channels when the nerve is at rest
Membrane Channels
Membrane Channels
Potassium and chloride can pass through these gated
channels
During depolarization the gated transmembrane sodium
channels change their configuration to allow the sodium
ions to enter the cell
Impulse Propagation
Activation of an action potential by a stimulus
Disruption of the resting nerve membrane potential
Interior of the cell goes from negative (–70 mV) to positive (+40 mV)
Exterior of the cell changes from positive to negative
Local currents begin flowing between the depolarized segment and the
adjacent resting area
Local currents flow from positive to negative extending for several
mm along the nerve membrane
As a result, the interior of adjacent areas become less negative and the
exterior becomes less positive
Impulse Propagation
Impulse Propagation
Transmembrane potential decreases approaching firing threshold for
depolarization
When transmembrane potential decreases by 15mV from resting
potential, firing threshold is reached and rapid depolarization occurs
The newly depolarized segment sets up local currents and it all starts
over again
Newly depolarized segments return to resting state after absolute and
relative refractory periods
Waves of depolarization can move in only one direction due to the
absolute and relative refractory periods, thus retrograde (backward)
movement is prevented
Impulse Spread
1) Unmyelinated Nerves
-high electrical resistance cell membrane
-slow forward “creeping” spread of impulses
-conduction of unmyelinated C fibers is1.2 m/sec
2) Myelinated Nerves
-insulating myelin separates the extra/intracellular charges
-the farther apart the charges the smaller the current necessary
to charge the membrane
-current leaps from node to node  saltatory conduction
Myelinated Nerves
if conduction of an impulse is blocked at one node, the local
current skips that node and continues to the next node
A minimum of 8 to 10 mm of nerve must
be covered by anesthetic solution to
ensure adequate block of impulse spread
Mode and Site of Action of Local Anesthetics
Local anesthetics interfere with the excitation process in the
nerve membrane in one or more of the following ways:
1) Altering the basic resting potential of the nerve membrane
2) Altering the threshold potential (firing level)
3) Decreasing the rate of depolarization*
4) Prolonging the rate of repolarization
Because of local anesthetics, cellular
depolarization is not sufficient to
reduce the membrane potential of a
nerve fiber to its firing threshold and a
propagated action potential
does not develop
Where Do Local Anesthetics Work?
Specific Receptor Theory  local anesthetics act by binding to specific receptors on the
sodium channel
the action of the drug is direct and is not mediated by some change
in the general properties of the cell membrane
a specific receptor site for local anesthetics exists in the sodium channel which eliminates
permeability to sodium ions
Therefore: no impulse conduction
Tertiary amine local anesthetics inhibit
influx of sodium during nerve conduction
Mechanism of Action of Local Anesthetics
1) Displacement of calcium ions from the sodium channel receptor site
2) Binding of the local anesthetic molecule to this receptor site
3) Blockade of the sodium channel
4) Decrease in sodium conductance
5) Depression of the rate of electrical depolarization
6) Failure to achieve the threshold potential level (firing level)
7) Lack of development of propagated action potentials
8) Conduction blockade
1) The nerve remains in a polarized state, therefore
there is no depolarization because the ionic
movements responsible for the action potential fail
to develop
2) The membrane’s electrical potential remains
unchanged, therefore local currents do not
develop and the self-perpetuating mechanism of
impulse propagation is stalled
3) Nerve block produced by local anesthetic is
called a nondepolarizing nerve block
Local Anesthetic Molecules
Majority of local anesthetics are tertiary amines
(except Prilocaine)
All local anesthetics are amphipathic
(lipophilic/hydrophilic)
Three main parts of the local anesthetic molecule:
1) Lipophilic Part (aromatic ring)
2) Intermediate Chain (amide or ester)
3) Hydrophilic Part (ethyl alcohol/acetic)
The lipophilic part of the local anesthetic is the largest portion
of the molecule
Hydrophilic part of the local anesthetic is an amino derivative
of ethyl alcohol or acetic acid
Local anesthetics without a hydrophilic portion are not
suitable for injection but are good topical anesthetics, i.e.,
Benzocaine
What Form Do Local Anesthetics
Exist in the Cartridge?
Labs prepare local anesthetics as basic: poorly soluble
in water and unstable on exposure to air; they have
little to no clinical value in this state
Since they are weakly basic, they combine readily
with acids to form local anesthetic salts which makes
them soluble in water and stable
Local anesthetics used for injection
are dispensed as salts, most
commonly the hydrochloride salt,
dissolved in either sterile water
or saline; so in the cartridge they
are salts
pH Variations
Acidification of tissues decreases local anesthetic
effectiveness
Inadequate anesthesia results when local anesthetics are
injected into inflamed/infected tissues
pH of normal tissues ~ 7.4
pH of inflamed tissues ~ 5.5
Local anesthetics containing epinephrine or other
vasopressors are acidified by the manufacturer to inhibit the
oxidation of the vasopressor
Clinically, the lower the pH the more
burning on injection slower onset of
anesthesia
pH of the interior of the nerve remains
unchanged and stable despite wide
variations in extracellular fluid pH;
so it is with the pH of the extracellular
fluid that determines the success or
failure of local anesthetics
Why not increase the pH of the
local anesthetic in the cartridge?
ANSWER: Because the local
anesthetic base is unstable, it would
precipitate out of alkalinized solutions
The extracellular fluid pH is most
important when it comes to the free
base getting into the nerve sheath; if
the extracellular pH is acidic, as with
an infection, the local anesthetic can
not enter the nerve in order to do its
job; the free base state will never
appear or so few molecules will cross
the nerve membrane and inadequate
anesthesia will occur
Effect of decreased pH on actions of
local anesthetic
Less free base (RN) molecules available to diffuse across nerve sheath
Block anesthesia can be successful
even in the presence of infection;
do not inject directly into the
infection because it can be spread
throughout the connective tissue
Dissociation of Local Anesthetics
The local anesthetic salt is dissolved in sterile water
or saline
-It exists simultaneously as:
1) uncharged molecules (free base) (RN) (Class C)
2) positively charged molecules (cation) (RNH+)
(Class D)
Dissociation of Local Anesthetics
pKa is a measure of a molecule’s
affinity for hydrogen ions (H+);
when the pH of a solution has the
same value as the pKa, 50% of the
drug exists as the free base (RNH+)
and 50% exists as the cation (RN)
Low pH (acidic) shifts toward the
cationic form; more RNH+
High pH (basic)  shifts toward the
free base form; more RN
The relative proportions of ionic forms
(RNH+, RN) depends on three variables:
1) pH of the local anesthetic solution
2) pH of the surrounding tissues
(infection or not)
3) pKa or dissociation constant of the
specific local anesthetic
higher pKa
increased H+
increased Onset Time
Bupivacaine with pKa ~8.1 will take longer to work
because there are fewer free base molecules
available to penetrate the nerve membrane
it can take up to 8 minutes at pH of 7.4 (tissue pH)
(especially with infection present)
Four Factors Are Involved In The Action of a
Local Anesthetic:
1) Diffusion of the drug through the nerve sheath
2) Binding of the drug at the receptor site in the membrane
channel
3) Free bases (RN) cross the nerve membrane
4) Cation (RNH+) blocks the receptor
The uncharged, lipid-soluble free base (RN)
form of the local anesthetic is responsible
for diffusion through the nerve membrane
Local Anesthetics with lower pKa have large
number of free base molecules (RN) that are
able to diffuse through the nerve sheath
But the anesthetic action of this drug is
inadequate because at intracellular pH of 7.4 a
very small number of base molecules dissociate
back to the cationic form (RNH+) necessary for
binding at the receptor site
(e.g., Benzocaine = pKa 3.5)
The rate of onset is related to the pKa
of the local anesthetic
Bupivacaine at pKa 8.1 has a slower
onset than Lidocaine pKa 7.7
Antioxidants and pH
Antioxidants are added to local anesthetics to delay the
oxidation of the vasopressor; oxidation will turn the solution a
reddish-brown
Sodium bisulfite is a common antioxidant placed in local
anesthetic solution
Lidocaine 2% with a pH of 6.8 is acidified to a pH of 4.2 with
the addition of the antioxidant sodium bisulfite
The shelf life of local anesthetics decrease as the pH of the
solutions decreases
The large buffering capacity of the tissue
(pH 7.4) is able to maintain a normal tissue
pH, however, it takes a longer time to do so
after an injection of a pH 4.2 solution than
with a pH 6.8 solution
the end result is a slower clinical onset of
action while the tissue pH equilibrates the
pH of the solution with the pH of the
tissues
Barriers to Diffusion of the Solution
Induction of Local Anesthesia
Mantle Bundles (OUTSIDE)
-fasciculi that are located near the surface of the nerve
-first ones reached; exposed to higher concentration of
the solution
-blocked completely shortly after injection
-innervates more proximal regions of the nerve
(molars from IANB)
Core Bundles (INSIDE)
-fasciculi found closer to the center of the nerve
-must delay before onset of anesthesia;
lower concentration of solution
-explains why patient may have inadequate
pulpal anesthesia in the midst of profound
soft tissue anesthesia
-innervates more distal regions of the nerve
(incisors from IANB)
Induction Time
Factors Under Clinician’s Control:
1) Concentration of the drug
2) pH of the local anesthetic solution
Factors not Under Clinician’s Control:
1) Diffusion constant of the anesthetic drug
2) Anatomical diffusion barriers of the nerve
What is the order of recovery from Local
Anesthetic?
Follows same diffusion patterns as induction only in the
reverse order
Mantle fibers lose anesthesia before the core fibers
Third molars would regain sensation before incisors if an
inferior alveolar nerve block were administered
Recovery is a slower process than induction because the local
anesthetic molecule is bound to the drug receptor site in the
sodium channel and is released more slowly than it is absorbed
What if I need to re-inject a patient?
At the time of re-injection, the concentration of local
anesthetic in the mantle fibers is less than the
centrally located core fibers
The partially recovered mantle fibers still contain
some level of local anesthetic, although not enough
to provide complete anesthesia
Upon re-injection, the mantle fibers are again
subjected to a high concentration of local anesthetic
solution inward toward the nerve
-The combination of residual local anesthetic and the
newly deposited supply results in rapid onset of
profound anesthesia with a smaller volume of the
drug being administered
-Tachyphylaxis is an increased tolerance to a drug
that is administered repeatedly; this could result in
less anesthesia after re-injection