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54
All these vasa nervorum absorb local anesthetic molecules, removing them from the nerve trunk. Lymphatic
vessels also participate in this process, albeit minimally
(<1%) (Asher1892; Schou1961).
Basic Membrane Proteins
Three membrane proteins are essential to conducting electrochemical impulses, the sodium–potassium pump, and
the sodium and potassium channels. All three are integral
membrane proteins (spanning the entire cell membrane)
which, as their names infer, transport sodium (Na
+
potassium (K
) ions.
Sodium–Potassium Pump
The sodium–potassium pump (Na+/K+ pump) was discovered in 1957 by Skou, although there were precedents.
Initially called the sodium pump (Skou 1957), it is an
enzyme (sodium–potassium ATPase, Na
+/K+
essential to all animal cell membranes (ScheinerBobis2002). This bulbous integral protein transports Na
+
ions and has three subunits (Scheiner- Bobis2002):
and K
● The alfa (α) subunit, with a molecular mass of
100–113
and α
the Na
● The beta (β) subunit, with a molecular mass of 60 kDa
and three isoforms (β
● The gamma (γ) subunit, with a molecular mass of
7–11
kiloDaltons (kDa) and four isoforms (α
), is where adenosine triphosphate (ATP) bonds to
4
+
and K+ ions.
, β2, and β3), apparently stabilizes α.
1
+/K+
kDa, is believed to modulate Na
pump activity,
although its exact function is not known.
+/K+
Na
ATPase pumps three Na+ ions out and two K+
ions into the cell per ATP molecule hydrolyzed
(Guyton1987; Butterworth and Strichartz1990; ScheinerBobis2002). As the enzyme pumps both ions against their
respective electrochemical gradients, the process is active,
i.e. it consumes energy. Interestingly, the Na
can increase its activity as circumstances require (Guyton
and Hall2007).
+/K+
The function of the Na
pump is essential to the
osmotic regulation of cell volume (Scheiner- Bobis2002), for
the cell contains sizeable quantities of negatively charged
organic proteins and other molecules too large to flow out of
the cell. They consequently attract positively charged ions
+
such as Na
every two K
, although as three Na+ ions are pumped out per
+
ions pumped in, inducing a net ionic loss,
there is less water in the cell (Guyton and Hall2007).
+/K+
Another essential Na
pump function is its role in
nerve impulse conduction, which is of particular interest
in the present context, as discussed later.
+
) and
ATPase)
, α2, α3,
1
+/K+
pump
Sodium Channels
Sodium channels (Na+ channels) are glycoproteins
(Catterall 1984, 1988) with three subunits, α, β
(Table4.2). Their glycosylated groups are located on the
outer surface of the cell membrane (Butterworth and
Strichartz 1990). The structure–function relationship is
still poorly understood (Ulbricht2005). As these proteins
are 11.8
nm in diameter (Catterall 1984), they span and
project beyond the cell membrane, which is just 7–10
thick (Catterall1984; Butterworth and Strichartz1990).
The α subunit has four domains (D1–D4) with six
membrane-
spanning helicoid α segments (S1–S6)
(Ulbricht 2005). These segments are connected by intraand extracellular loops (Catterall 2000; Ulbricht 2005)
(Figure 4.5). The local anesthetic receptor is located in
domain D4, segment 6, concurring with amino acids phenylalanine and tyrosine, the sites of which vary with
sodium channel isoform or subtype. Segment S4 is positively charged and the pore lies between S5 and S6
+
(Ulbricht 2005). The Na
(Scheiner-
+
when hydrated (Lipscombe2005), flow through the pore,
Bobis 2002; Lockless et al. 2007), or 0.19 nm
ions, with a 0.095- nm radius
which on the outer end has a diameter of 0.3–0.5 nm
(Catterall1984,1988; Fozzard etal.2005).
Subunits β
and β2 are long, glycosylated extracellular
1
domains with folds reminiscent of those in immunoglobulins or myelin (Catterall 2000; Ulbricht 2005), a single
transmembrane segment, and a small intracellular domain
(Catterall2000).
+
To date nine Na
channel subtypes or isoforms have
been identified, which differ in structure, expression pattern, biophysical properties, and location (Lai et al. 2004;
Ulbricht2005). Local anesthetics, which are scantly specific in this regard, block all nine (Lai etal.2004; Fozzard
et al. 2005). The subtypes of greatest relevance here are
sited on the sensory neurons that propagate nociceptor
(pain) signals, such as Na
1.8, Nav 1.9 (Lai etal.2004; Wells
v
etal.2007), and in the dental pulp, especially Na
etal.2008). Molecules may be developed in the future to
Table4.2 Atomic mass andpercentage ofcarbohydrates
insodium channel subunits.
Subunit Atomic mass (kDa) Carbohydrates (%)
α 260 15–30
β
1
β
2
Reference Catterall (2000)
36 25
33 25
Catterall (1988)
Lai etal. (2004)
, and β2
1
nm
1.7 (Luo
v
t.me/Dr_Mouayyad_AlbtousH
Amino terminus
DOMAIN 1 DOMAIN 2 DOMAIN 3 DOMAIN 4
Carboxy terminus
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OUT
123456 123456 123456 123456
IN
N
PORE
Figure4.5 Structure of sodium channel alpha (α) protein. N is the amino terminus and C is the carboxy terminus.
C
55
act specifically on certain types of sodium channels,
thereby reducing risks such as cardiotoxicity.
As inflammatory mediators such as prostaglandins sensitize sodium channels, inducing depolarization with less
intense stimuli (hyperalgesia), local anesthetics block
sodium channels less effectively under those circumstances
(Lai etal.2004).
Sodium channels play a pivotal role in nerve impulse
formation and propagation. They are normally closed, but
when stimulated they open (Figure4.6) to allow the
+
inward flow of extracellular Na
+
gradient, for Na
(150
mEq/l) than intracellular (15 mEq/l) fluids (Elmslie
concentration is greater in extracellular
further to a concentration
passive
2001; Lipscombe2005) (Figure4.7).
Potassium Channels
Potassium channels (K+ channels), studied by the
MacKinnon group, are protein structures with two functional subunits (Doyle etal.1998; Lee etal.2005).
1) The 1.2- nm long, 0.35- nm diameter pore (at its narrow-
est) (MacKinnon2003) is the site of the selectivity filter
+
that governs which K
ions flow out of the open channel (Lee etal.2005). The filter is sited at a quarter of the
length from the extracellular edge, opening on to the
central cavity prior to the end of the pore. Upstream of
the filter the cavity widens to 1 nm (MacKinnon2003).
The determining factor for ion selection would appear
to be size (Lockless et al. 2007) and potassium, at
0.133
nm (Doyle et al. 1998; MacKinnon 2003;
Lockless et al. 2007) and 0.266 nm when hydrated
+
(Lipscombe2005), is larger than the 0.095- nm Na
.
2) The voltage sensor around the pore is a structure that
when stimulated by alterations in membrane voltage
opens the pore by changing the configuration of the top
of the central cavity.
(a)
3
1
2
3
5
4
6
4
2
1
(b)
3
1
2
4
5
3
6
4
2
1
Figure4.6 Sodium channel pore: (a) closed; (b) open.
The two subunits have different structures and properties and as they bond only loosely, they must be anchored
in the membrane to perform their functions (Lee
etal.2005).
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Na
K
+
–+
+
–+
+
–+
+
–+
Cell membrane
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56
Extracellular Intracellular
+
............................. 150 mEq/l................. 15 mEq/l
+
............................... 5 mEq/l..................... 150 mEq/l
Figure4.7 Intra- and extracellular Na+ and K+ concentrations
(rounded values).
Exterior Axoplasm Exterior
+– ++–– +– +––+ +–
–+–+–+–+–+–+–
+– ++–– +– +––+ +–
–+–+–+–+–+–+–
+– ++–– +– +––+ +–
–+–+–+–+–+–+–
+– ++–– +– +––+ +–
–+–+–+–+–+–+–
Potassium channels play a secondary role in nerve
impulse formation and propagation. They are normally
closed and open later and longer than sodium channels to
help recover the resting potential by allowing K
flow passively (without consuming energy) from the axoplasm, where they are highly concentrated (150 mEq/l), to
the cell exterior, where concentration is lower (5
(Elmslie2001; Lipscombe2005) (Figure4.7).
Peripheral Nerve Neurophysiology
The basic texts on peripheral nerve neurophysiology were
published in 1952 by Hodgkin and Huxley, who worked
with giant (0.4–0.8 mm in diameter), unmyelinated Atlantic
squid (Loligo pealeii and Loligo forbesii) axons. These were
large enough for the thinnest (0.15 mm) and most precise
electrodes available at the time to penetrate the axon
through the membrane (Hodgkin and Huxley1952a,b) and
measure the action potential and intraion exchange (Hodgkin and Huxley 1952b; Hodgkin
et al. 1952c). In the following description of peripheral
nerve physiology, some of the data initially reported by
Hodgkin and Huxley (Hodgkin and Huxley 1952b) are
adapted to results in mammals, and corrected and rounded.
Fundamentals
A number of preliminaries are in order for a clearer understanding of the process described below.
● Intra- and extracellular fluids are electrolytic solutions
carrying positively charged ions (cations) such as sodium
+
), potassium (K+), or calcium (Ca+) or negatively
(Na
charged (anions) such as organic phosphates, sulfates, or
protein ions. Most anions are bound to molecules too
large to exit the cell.
● To pump three Na
cell against the concentration gradient, the cell membrane’s Na
+/K+
and extracellular
+
ions out of and two K+ ions into the
ATPase consumes energy.
Figure4.8 Electrochemical imbalance adjacent to intercellular
side of cell membrane.
+
ions to
● When at rest, the cell membrane Na
but when stimulated it opens to allow the passive
mEq/l)
(without energy) inflow of extracellular Na
with the concentration gradient.
● When at rest, the cell membrane K
but when stimulated it opens to allow the passive (without energy) outflow of intracellular K
ing with the concentration gradient.
● Despite the presence of large numbers of positively or nega-
tively charged ions along the membrane, imbalance is in fact
minimal. Only a small proportion of axoplasmic ions (from
1 per 3million to 1 per 100million) (Guyton and Hall2007)
moves to create a negative potential of around −70 mV adjacent to the intracellular side of the membrane (Figure4.8).
As such electrochemical imbalance occurs only around the
membrane, the potential of −70
absent in the rest of the axoplasm and extracellular fluids.
Membrane Potentials: Membrane at Rest (Polarized)
The axon membrane exhibits a negative electrical imbalance
of −70 mV along its entire surface due to the prevalence
of negative charges, but only on the inner side. This interior/
exterior charge differential is called the membrane potential
or resting potential and the membrane is said to be polarized.
Such polarization is maintained by the Na
which, as noted, extrudes three Na
ions imported into the axoplasm, creating a standing
charge imbalance (Butterworth and Strichartz 1990;
Scheiner- Bobis2002).
Action Potentials: Excited Membrane
The membrane is excited by electrical, chemical,
mechanical (pressure, squeezing, etc.) or thermal (heat,
cold) stimulants. By exciting the membrane these
t.me/Dr_Mouayyad_AlbtousH
+
channel is closed,
+
in keeping
+
channel is closed,
+
, likewise in keep-
mV is present there and
+/K+
+
ions for every two K+
pump
57
MEMBRANE POTENTIAL
Membrane
ACTION POTENTIAL
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mV+40
0
DEPOLARIZATION
THRESHOLD
–55
–70
Out
In
Figure4.9 Action potential showing the variations in mV and ion (Na+ and K+). Movements and changes in membrane charge with
+/K+
Na
pump operating and Na+ and K+ channels open. Schematic drawn.
POLARIZATION
RESTING
+
3Na
++
70mV
Pump
Na
+/K+
2K
+++
–––
+
Stimulus
REFRACTORY PERIOD
ABSOLUTE
–––
+++
+
Na
stimulants disrupt the resting balance, changing the
voltage from −70 to +40
mV adjacent to the inner surface of the membrane due to the predominance of positive ions, after which the resting status is restored. This
REPOLARIZATION
RELATIVE
+
K
HYPERPOLARIZATION
+++++
–––––
Milliseconds
repolarization phase, the voltage- gated sodium channel is
inactivated. During this absolute refractory period the
membrane fails to react to any further stimulus, no matter
how intense.
process, known as the action potential, lasts for only a
few, normally 2–4, milliseconds (ms), but may vary with
circumstances and type of nerve fiber. Its three phases
are described below (Figure4.9).
Phase 1: Depolarization
Any of the stimuli mentioned opens the sodium channels
(closed in the resting position), with the passive inward
+
flow of Na
(low concentration and prevalence of negative charges
ions induced by the electrochemical gradient
inside). The voltage inside the axon therefore starts to
change to less negative values.
This process is initially fairly slow, but when the differential reaches around −15 mV (de Jong1977; Malamed2004;
Guyton and Hall2007), varying from −70 to −55 mV, the
excitation threshold is crossed. Irrespective of the stimulus
and its intensity, in keeping with the all or nothing law, full
+
depolarization is triggered and the Na
channels are
opened wide with a massive inward flow of Na
electric charge is neutralized (0 mV) or a maximum of
+
until the
Phase 2: Repolarization
Two events taking place during repolarization govern the
membrane recovery of its resting potential after maximum
depolarization (+40
● The Na
+
channels close to stop the inward flow of Na+.
mV).
For a short time, these channels are inactive (not only
closed) and cannot open.
+
● The K
channels open more slowly and for a longer time,
+
allowing K
where the K
ions to flow from the axoplasm outward,
+
concentration is lower, helping to offset
and reduce depolarization.
+/K+
Na
ity (pumping Na
ATPase pumps throughout, intensifying its activ-
+
in and K+ out) to restore the resting sta-
tus (−70 mV) (Guyton and Hall2007).
The relative refractory period, which appears during the
repolarization period, lasts through hyperpolarization, and
only very intense stimuli can re- trigger depolarization and
+
re- open the closed Na
channels after inactivation.
+40 mV is reached alongside the inner surface of the
membrane.
From the excitation threshold (−55 mV) to maximum
depolarization (+40 mV), and even briefly during the
Phase 3: Hyperpolarization
This phase is known as hyperpolarization because after
reaching its resting level (−70 mV), the membrane becomes
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58
slightly more negative for a few milliseconds (because the
+
channels remain open longer than the Na+ channels),
K
after which the Na
+/K+
pump restores resting status.
Curiously, hyperpolarization is also called “more positive
after action potential” instead of the more logical “more
negative after action potential”. Tradition has maintained
that apparent misnomer, which stems from the practice of
the earliest researchers to measure voltage outside the cell
(−70
mV is the inside value). Sodium channel inactivation
during the refractory period ensures that nerve impulses
can be propagated in one direction only (Wildsmith1986).
Propagation ofthe Action Potential
In the presence of an action potential the adjacent parts of
the axon membrane are excited/stimulated and the electrochemical impulses spread swiftly along the nerve fiber in
the form of a depolarization–repolarization–hyperpolarization wave.
Once initiated, the impulse travels constantly along the
nerve fiber irrespective of the power or the nature of the
stimulus that prompted it, for the propagation energy is
released by the axon itself along its entire length. A very
intense stimulus is expressed by a higher frequency of
action potential and the enlistment of more axons to carry
the impulse.
Action potentials are propagated differently in unmyelinated and myelinated nerve fibers.
● In the former the depolarization–repolarization–hyper-
polarization wave (electrochemical impulse) travels continuously at a lower speed because more energy is needed
to surmount the resistance encountered.
● In the latter the depolarization–repolarization–hyperpo-
larization wave (the action potential) jumps from one
node of Ranvier to the next (saltatory conduction), where
the axon membrane is in contact with extracellular fluids,
establishing ion exchange. For that reason, many fewer
+
net Na
and K+ ions move along the myelinated than the
unmyelinated fibers, raising the propagation speed and
lowering the energy required. Nonetheless, ion activity
+
and the number of Na
channels are much greater in the
nodes of Ranvier than on the surface of unmyelinated
+
nerves (110Na
channels per μm2 in unmyelinated fibers
versus 2000–12 000in nodes of Ranvier) (Catterall1984).
That prevents stimuli from triggering the action potential
and consequently inhibits the propagation of the nerve
impulse (Hille1966; de Jong1977; Strichartz1981).
+
Although the K
channels are also blocked by local anesthetics, the effect is less intense, particularly as regards
inhibition of nerve impulse conduction (Ritchie1975).
Mechanism
Local anesthetic action appears to be governed by the
mechanism described below (Ritchie1975; Strichartz1981;
Wildsmith1986; Butterworth and Strichartz1990). When
the local anesthetic reaches the extracellular surface of the
+
axon, its ionized (cationic, BH
) and neutral base (salt, B)
states are in equilibrium. Their respective proportions
depend on the local anesthetic’s pKa value.
The liposoluble neutral base (B) can penetrate the phospholipid bilayer in the axon membrane, particularly the
apolar zone in the hydrophobic, liposoluble center
+
(Ritchie 1975). With that inflow a new BH
− B equilibrium is reached. The local anesthetic receptor in the Na
channel to which the anesthetic bonds can be reached in
one of two ways (Strichartz 1981; Wildsmith 1986;
Butterworth and Strichartz1990; Fozzard etal.2005).
1) The quickest is via B, once in the cell membrane
(hydrophobic or external path).
+
2) The most powerful way to block the Na
+
from the axoplasm via BH
+
pore in the Na
channel (hydrophilic or internal path).
, which flows into the open
channel is
The local anesthetic penetrates the axon membrane
differently depending on whether it is myelinated or
unmyelinated.
● In unmyelinated fibers the local anesthetic bathes the entire
surface of the nerve fiber along the axon, although its distri-
bution is not wholly uniform (Franz and Perry1974).
● In myelinated fibers the local anesthetic only penetrates
and acts on the axon membrane at the nodes of Ranvier,
where there is no myelin and the axon is in contact with
extracellular fluids.
Differential Nerve Block
Local anesthetics have been shown to anesthetize different
nerve fibers with unequal efficacy. The factors conditioning efficacy are listed below:
+
Mechanisms ofLocal Anesthesia
Widely accepted evidence now available shows that local
anesthetics act by temporarily blocking Na
inducing the membrane to remain at its resting potential.
1) The first is nerve fiber thickness. Logically, fibers with a
smaller diameter are more readily anesthetized (Gasser
and Erlanger1929; Franz and Perry1974) because the
+
channels,
smaller the diameter, the fewer the Na
need to be blocked (de Jong1977).
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+
channels that
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2) The second is the presence or otherwise of myelin.
Unmyelinated fibers are anesthetized more readily than
myelinated fibers, particularly where the myelin layer is
thick (Franz and Perry1974).
3) The third is the frequency of the stimuli transmitted by
the nerve fibers and therefore the type of stimulus.
Fibers carrying stimuli such as pain have a high action
potential frequency per second and consequently are
anesthetized more easily (frequency- or use- dependent
or phase block). Fibers carrying motor stimuli, with a
lower action potential frequency, are less readily anesthetized (Franz and Perry1974).
A review of the classification of nerve fibers in Table4.1
shows the following (Wildsmith1986):
● Smaller, unmyelinated or scantly myelinated fibers car-
rying high-
frequency stimuli are readily anesthetized:
– Small, free nerve endings usually carrying pain.
– Polymodal C fibers carrying second, burning, diffuse,
persistent pain.
– Sympathetic postganglionic fibers of the autonomic
nervous system, such as polymodal C fibers.
– Sympathetic preganglionic fibers of the autonomic
nervous system, such as B fibers.
● Anesthetization is also attained fairly readily in some-
what thicker, scantly myelinated fibers, including:
– Polymodal C and Aδ fibers carrying temperature sen-
sitivity (heat, cold).
– Polymodal C and Aδ fibers carrying sensitivity to
pressure.
– Aδ fibers carrying first, sharp, fast, localized pain.
● The fibers most difficult to block, typically A alfa (Aα), A
beta (Aβ), and A gamma (Aγ), are thick and heavily myelinated, with a longer internodal distance (between
nodes of Ranvier) and carrying lower frequency (motor
and proprioceptive) impulses.
Despite the morphological differences in polymodal C
and Aδ fibers, local anesthetics can effectively anesthetize
both (de Jong1977).
Tonic andPhase Block
Both the ionized and neutral forms of local anesthetics can
+
produce “tonic” and “phase” block in Na
channels,
although the characteristics differ (Strichartz 1981;
Wildsmith1986; Butterworth and Strichartz1990; Fozzard
etal.2005).
● When the membrane is kept at resting potential with the
+
channels closed, local anesthetics are said to effect
Na
tonic block, primarily via the neutral base lodged within
the membrane.
● When the membrane is excited, with action potentials
present and the Na
is said to induce phase (or frequency-
+
channels open, the local anesthetic
or use- dependent)
block. Such blocks, which are more powerful, are primarily produced by the ionized (cationic) form that bonds to
the receptor at the inner side of the pore from the axoplasm (Fozzard etal.2005).
Critical Length
This section addresses the question of the length of nerve
fiber that should be coated by local anesthetics to block
nerve impulse conduction. It is pertinent because depolarization activates the membrane several millimeters beyond
the initiation site (de Jong1977). Experimental research
has established that distance for myelinated and unmyelinated fibers, as follows:
● In unmyelinated fibers the local anesthetic should coat
and block around 3–4
● In myelinated fibers at least three successive nodes of
mm (de Jong1977).
Ranvier should be blocked (Blair and Erlanger 1939;
Tasaki1953) (Figure4.10).
One of the thickest nerve trunks requiring dental block is
the myelinated inferior alveolar nerve, in which the nodes
of Ranvier are spaced at 0.5–1.8
mm (Rood1978a,1978b).
Blocking three nodes consequently calls for coating
around 6 mm of nerve trunk with the anesthetic
Figure4.10 Comparison of anesthetic coverage
of nodes of Ranvier in thin and thick axons.
Thin axon
Thick axon
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(Rood 1978a, 1978b). In practice, however, since the
anesthetic does not diffuse regularly, to guarantee a
minimum block the distance to be coated should be somewhat longer than the experimental value (de Jong1977).
Transient Receptor Potential Channel
The function of TRPV1, the transient receptor potential
cation channel, subfamily V, member 1, was discovered in
the twenty-
first century. The first breakthrough came
with the identification of capsaicin receptors and their
role in pain mechanisms (Caterina etal.1997). Capsaicin
is the active ingredient in hot peppers such as chili, cayenne, and wasabi. This family of receptors is presently
referred to as vanilloid receptors (transient receptor
potential vanilloide [TRPV]), six of which have been discovered. The first is the formerly labeled capsaicin receptor, now known as TRPV1.
Found on the membranes of pain neurons (nociceptors),
+
TRPV1 is an integral protein similar to K
channels. This
receptor is a nonselective cation channel, allowing the
++
inflow of Ca
times more permeable to Ca
, Na+ and so on, although it is five to nine
++
ions (Butterworth and
Oxford2009).
Recent research appears to show that when this channel
is stimulated its filter opens, allowing the inflow of the cati-
+
onic form (BH
caine, which block the Na
) of local anesthetic molecules such as lido-
+
channels from the axoplasm
(Butterworth and Oxford2009). As the selective filter in
this channel is 0.6–1.0 nm and lidocaine molecules are estimated to measure 3
× 0.68 × 0.47 nm (Glówka etal.1996),
the entry pore may expand dynamically to allow anesthetic
inflow (Butterworth and Oxford2009). The actual significance of this mechanism has yet to be determined.
Nerve Block Kinetics
Local anesthetics differ from most drugs used in medicine in
that they are deposited near the target structures. When a
local anesthetic solution is injected periorally, the subcutaneous deposit diffuses from the injection site to the surrounding tissues. If, for instance, 1 ml of a 2% local anesthetic
is injected, the space occupied is a sphere with a radius of
0.62 cm. As the solution diffuses concentrically (ideally), the
anesthetic molecules spread and the sphere grows. The concomitant dilution lowers the initial concentration: when the
radius of the sphere is 2.62 cm the volume is 76 ml and the
concentration 0.026% (Schilli1977) (Table4.3).
As local anesthetic solutions diffuse along the least resistant
pathways, they do not spread uniformly, as mentioned earlier,
for the soft and hard tissues in the mouth constitute more or
less compact barriers. They can be penetrated by the local
Table4.3 Sphere- like diffusion of1 ml of2% anesthetic.
Sphere radius (cm) Anesthetic (%) Volume (ml)
0.62 2 1
1.12 0.34 6
2.62 0.062 76
Data from Schilli (1977).
ource:
S
anesthetic but at the expense of lowering its concentration
even further. In addition, some of the molecules are captured
nervous (such as adipose) tissues and others are absorbed
nonand removed from the area by blood and (to a lesser extent)
lymph vessels. Some of the anesthetic molecules nonetheless
reach the nearby nerve trunks and nerve endings.
Induction Stage
Once in the nerve trunk, the anesthetic molecules spread
in two stages (de Jong1977). They reach and hence anesthetize the fascicles nearest the surface of the nerve trunk
first. Given the greater distance, wider diffusion and larger
number of barriers to be permeated to reach the fascicles in
the center of the nerve trunk, anesthetization there takes
longer. As a result anesthesia is somatotopic, for the fascicles on the surface of the nerve trunk normally innervate
the closest, and the fibers in the center the more distant
tissues and organs. In inferior alveolar nerve block, for
instance, the first lower molar is anesthetized before the
mandibular incisors, which are located farther from the
mandibular block site (Table4.4).
Other factors impacting the time to onset or the time it
takes to numb tissues include the concentration of the anes-
thetic (the higher the concentration, the earlier is onset)
and nerve trunk thickness (the thinner, the earlier). The
anesthetic concentration in- and outside the nerve trunk
ultimately reaches equilibrium.
Recovery Stage
Recovery from nerve trunk block follows the same pathway
as the induction stage, but in reverse order. The extraneural
store of local anesthetic continues to decline due to dispersion, capture by connective and adipose tissue, and vessel
absorption, lowering the concentration to below the value
inside the nerve trunk. The anesthetic seeps out of the fascicles nearest the outer surface of the nerve trunk first,
inducing early recovery in these fibers. As the concentration of the anesthetic is higher in the central fascicles,
anesthesia lasts longer in the more distant tissues.
Recovery is slower than induction, for once the anesthetic
binds to the nerve fibers its release takes time. The pattern
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Table4.4 Mean onset (in minutes) ofpulpal anesthesia after mandibular block with2% lidocaine, 1:100 000 epinephrine.
Tooth Chaney etal. (1991) Hinkley etal. (1991) McLean etal. (1993) Kanaa etal. (2006) Goldberg etal. (2008)
First molar 8.2 8.8 10.8 5.4 8.0
First premolar 10.2 10.6 11.8 8.9 7.0
Lateral incisor 13.0 14.3 17.2 13.3 12.0
See Table16.2, Chapter16.
involved is approximately exponential, with initial speedy
recovery gradually slowing through the end of the process.
Recovery time is impacted by a number of factors.
1) A higher anesthetic concentration entails longer duration.
2) The thinner the nerve trunk, the longer the duration of
the effect.
3) Nerve function also affects duration, for anesthesia lasts
longer in pain than in motor fibers. That effect is associated with the thinner diameter, lack of myelin and the
type of block (phase or use-
dependent) involved.
Re- Injection
If more anesthesia is injected before the peripheral fascicles recover their resting potential, re-
block is nearly
immediate, with no somatotopic phasing between near
and far tissues (de Jong 1977). Moreover, the effect is
attained with smaller amounts of anesthetic than initially,
since the fibers are already coated with anesthetic.
Tachyphylaxis
Tachyphylaxis, in this context the loss of anesthetic efficacy in successive injections immediately after the anesthetic effect reverts, is a manner of tolerance (de Jong1977;
Choi etal.1997; Vadhanan etal.2015). Surprisingly, however, its presence cannot be proven in laboratory studies.
Tachyphylaxis (Greek: tachys = fast and phylaxis =
protection) to local anesthetics has been known since
the 1960s (Kongsgaard and Wemer2016). However, in a
systematic review in 2016 it was noted that the number
of documented cases was very low and mainly in epidural, intrathecal anesthesia, or in regional blocks with
continuous anesthesia, but there were no registered
cases of regional blocks in dentistry (Kongsgaard and
Wemer2016).
Although not fully understood, the possible causes of
this condition are as follows (Vadhanan etal.2015):
1) The nerves may be altered by edema or microhemor-
rhaging due to the toxicity of local anesthetics (de
Jong1977; Vadhanan etal.2015).
2) Successive injections may cause acidosis. Local
anesthetic solutions with sympathomimetic vasoconstrictors, such as epinephrine, have an acidic pH. After
injection this pH is neutralized by tissue fluids.
Nonetheless, successive injections in the same site may
saturate the buffer capacity of the fluids, in which case
+
acidity persists. At acid pH the cationic form (BH
) prevails over the neutral form (B) of the anesthetic, retarding and reducing penetration across cell membranes
(Cohen etal.1968; de Jong1977; Vadhanan etal.2015).
3) Successive injections may induce hypernatremia. Local
anesthetic solutions contain sodium chloride (NaCl) to
balance tissue osmolarity and prevent tissular irritation.
+
Repeated injections in the same site may raise Na
concentration and lower the effect of the anesthetic on
sodium channels (de Jong1977; Vadhanan etal.2015),
although this has not been proven.
4) Pharmacokinetics may reduce the intranervous concen-
tration of the local anesthetic significantly (Vadhanan
etal.2015), an effect observed in experiments with rats
in vivo (Choi et al. 1997). The mechanism possibly
involved is vasodilation as the initial anesthetic action
recedes, hastening the removal of further doses of the
solution.
Re-
injection of the local anesthetic 15 minutes after the
effect of the local anesthetic reverts should be avoided, for
otherwise 25–35% more solution is required to attain the
same efficacy (de Jong1977).
Resistance toLocal Anesthetics
Some cases of resistance to the action of local anesthetics
have been described in medical (Miller etal.1981; Kavlock
and Ting 2004) and dental (Beckett and Gilmour 1990)
practice. The symptoms are short duration or insufficient
effect attributable not to conventional causes of failure
(Chapter19) but to genetic alterations that induce structural variations in some sodium channel isoforms (Panigel
and Cook2011; Clendenen etal.2016). Although the frequency of such anomalies is presently unknown, it is
assumed to be low.
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