Local anesthesia final

INTRODUCTION
Local anesthesia is a widely used and accepted method of pain
control during operative dental procedure. The development and acceptance
of dental treatment can be credited to local anesthesia which offers freedom
from pain. It also helps dentist to achieve the primary goal of their
profession i.e. painless treatment & more comfort to the patient. Local
anesthetics have also got acceptance during operative procedures under
general anesthesia.
HISTORICAL BACKGROUND
• In 1951, Pravez described the hypodermic syringe.
• In 1853, Alexander Wood, a Scottish physician, invented hollow
metal needle. Until this date it was difficult to give medication into
tissue or i.v.
• Cocaine is the first local anesthetic agent and is a naturally occurring
alkaloid.
• It was isolated by Nieman from the leaves of the coca tree.
• Its anesthetic action was demonstrated by Karl Koller. In 1884, he
applied the cocaine to the conjuctiva of the human eye and produced
local anesthesia
• The first effective and widely used synthetic local anesthetic was
procaine
• It was produced by Einhorn in 1905 from benzoic acid and diethyl
amino ethanol.
• It anesthetic properties were identified by Biberfield and the agent
was introduced into clinical practice by Braun.

• LIDOCAINE was synthesized by LofGren in 1948. The discovery of
its anesthetic properties was followed in 1949 by its clinical use by T.
Gordh.
• Thereafter, series of potent anesthetic soon followed with a wide
spectrum of clinical properties.
DEFINITION
Local anesthesia has been defined as a loss of sensation in a
circumscribed area of the body caused by depression of excitation in nerve
endings or an inhibition of the conduction process in peripheral nerves.
by STANLEY F. MALAMED
Local anesthetic agent is any chemical capable of blocking nerve
conduction when applied locally to nerve tissue in concentrations that will
not permanently damage such tissue.
Various methods of inducing local anesthesia are :
i) Mechanical trauma
ii) Low temperature
iii) Anoxia
iv) Chemical irritants
v) Neurolytic agents such as a alcohol and phenols
vi) Chemical agents such as local anesthetics.

IDEAL PROPERTIES OF LOCAL ANESTHESIA
The following are the properties deemed most desirable for local
anesthetic
i) It should be non irritating to the tissues to which it is applied.
Most of the local anesthetics are relatively non irritating. Dyclonine, a
potent topical anesthetic, is not administered by injection because of its
tissue irritating properties. On the other hand, Lidocaine and tetracaine are
both effective anesthetics when administered by injection or topical
application.
ii) It should not cause any permanent alteration of nerve structure.
The local anesthetic solution should bring about transitory ionic
exchange or alteration in the nerve membrane & should not cause any
damage to nerve fibers.
iii) The systemic toxicity should be low
Toxicity is defined as the adverse reaction of an organism to a given
dose of an agent. The end point in determining laboratory toxicity is a
fatality.
The minimal amount of drug needed to kill 50% of the test animals is
the MLD 50. Toxicity may be either general or local. The general toxicity or
systemic toxicity refers to the effect of a drug on the entire organism, while
the local toxicity refers to the effect on cellular structure and is often termed
as ‘cytotoxicity’.
iv) It must be effective regardless of whether it is injected into the tissue
or applied locally to mucous membranes.
i.e. they should be potent enough to produce their action without
locally irritating the tissues and increasing the risk of systemic toxicity.

v) The time of onset of anesthesia should be as short as possible.
vi) The duration of action must be long enough the permit completion of the
procedure yet not so long as to require an extended recovery.
vii) It should have a potency sufficient to give complete anesthesia without
the use of harmful concentrated solutions.
Potency of a local anesthetic drug is defined as the minimal strength and
dose of the drug that produces neural blockade and provides the conditions
desired that permit surgery.
viii) It should be relatively free from producing allergic reactions
ix) It should be stable in solution and readily undergo bio-transformation in
the body.
x) It should either by sterile or be capable of being sterilized by heat without
deterioration.
PHARMACOLOGY OF LOCAL ANESTHETICS
Local anesthetics, when used for the management of pain, differ from
most other drugs commonly used in are very important manner. Virtually,
all other drugs, regardless of the route through which they are administered,
must ultimately enter into the circulatory system in sufficiently high
concentrations before they can begin to exert a clinical action. Local
anesthetics however, when used for pain control, cease to provide a clinical
effect when they are absorbed from the site of administration into the
circulation.

Classification of local anesthetics :
I. Based on the chemical structure
ESTERS :
i) Esters of benzoic acid :
- Butacaine
- Cocaine
- Ethyl amino benzoate (benzocaine )
- Hexylaine
- Piperocaine
- Tetracaine.
ii) Esters of Para amino benzoic acid :
- Chloroprocaine
- Procaine
- Propoxycaine
AMIDES :
- Articaine
- Bupivacaine
- Dibucaine
- Etidocaine
- Lidocaine
- Mepivacaine
- Prilocaine
QUINOLINE :
- Centbucridine

II. Based on biological site and mode of action :
i) Class A  agents acting at receptor site on external surface of
nerve membrane e.g. – tetradotoxin, saxitoxin.
ii) Class B  agents acting at receptor sites on internal surface of
nerve membrane e.g.: quaternary ammonium analogue of lidocaine.
- Scorpion venom
iii) Class C  agent acting by a receptor independent physio-
chemical mechanism e.g.: Benzocaine
iv) Class D  agents acting by combination of receptor and receptor
independent mechanism.
E.g.: - Lidocaine
- Mepivacaine
- Procaine
III. Based on the source :
i) Natural – cocaine
ii) Synthetic – lidocaine
iii) Others – ethyl alcohol
IV. Based on mode of application :
i) Topical
ii) Injectable
V. Based on duration of action :
i) Ultra short acting (<30 min)
- Procaine without vasoconstrictor
- 2% chlorprocaine without vasoconstrictor
- 2% lidocaine without vasoconstrictor

- 4% prilocaine without vasoconstrictor for infiltration.
ii) Short acting (45-75 min) :
- 2% lidocaine with 1:100,000 epinephrine
- 2% mepivacaine with 1:20,000 levernordefrin
- 4% prilocaine when used for nerve block
- 2% procaine 0.4% propoxycaine with a vasoconstrictor.
iii) Medium acting (90-150 min) :
- 4% prilocaine with 1:200,000 epinephrine
- 2% lidocaine, 2% mepivacaine with a vasoconstrictor may
produce Pulpal anesthesia of this duration
iv) Long acting (180 min or longer) :
- 0.5% bupivacaine with 1:200,000 epinephrine
- 0.5% or 1.5%. etidocaine with 1:200,000 epinephrine.
v) Based on onset of action :
- Short
- Intermediate
- Long
PHARMACOKINETICS OF LOCAL ANESTHETICS :
Uptake :
All local anesthetic posses a degree of vasoactivity, most producing
dilation of the vascular bed into which they are deposited, although the
degree of vasodilation may vary.
Esters local anesthetics are potent was dilating drugs. PROCAINE is
probably the most potent vasodilator and is after used clinically for
vasodilatation when peripheral blood flow has been compromised due to
accidental intra arterial injection of thiopental. (thiopental may produce

arteriospasm with an attendant decrease in tissue perfusion, which could
lead, if prolonged, to tissue death, gangrene etc.
Cocaine is the only local anesthetic that consistently produces
vasoconstriction. The initial action of cocaine is vasoconstriction, which is
followed by an intense and prolonged vasoconstriction. It is produced by an
inhibition of the rupture of catecholamines (example norepinephrine) into
tissue binding sites. This results in an excess of free norepinephrine which
leads to a prolonged) and intense state of vasoconstriction.
A significant clinical effect of vasoconstriction is an increase in the
rate of absorption of the local anesthetic into the blood, thus decreasing the
duration of pain control while increasing the anesthetic blood lend and the
potential for overdose.
Oral route :
With the exception of cocaine, local anesthetic drugs are absorbed
poorly, if at all, from the GIT following oral administration. Additionally,
most local anesthetics (especially lidocaine) undergo a significant hepatic
first pass effect following oral administration. Following absorption of
lidocaine from the GIT into the eneterohepatic circulation, a fraction of drug
is carried to the liver, where approximately 72% of the dose is
biotranformed into inactive metabolites. This has seriously hampered the
use of lidocaine as an oral anti-dysrthythmic drug.
In November 1984, Astra pehamae verticals introduced an analogue
of Licocaine, TOCHAINIDE hydrochloride, which is effective orally.
Topical route :
Local anesthetic are absorbed at differing rates after application to
mucous membranes: in the tracheal mucosa, uptake is almost as rapid and
IV administration, in pharyngeal mucosa, uptake is slower, and in

esophageal and bladder mucosa, uptake is even slower than occurs through
the pharynx.
Whenever there is no layer of intact skin present; local anesthetics
exert their action following the topical application. Sunburn remedies
usually contain lidocaine, benzocaine etc in ointment formulation. Applied
to intact skin do not provide an anesthetic action, EMLA has been
developed to provide surface anesthesia for intact skin.
Injection :
The rate of uptake of local anesthesia after injection (s.c., I m., i.v.) is
related to both the vascularity of the injection site and the vasoactivity of the
drug.
i.v. Administration of local anesthetics provides the most rapid
elevation of blood levels and is used in the primary treatment of ventricular
dysrhythmias such as premature ventricular contractions.
Metabolism :
A significant different between the two major classes of local
anesthetics, the esters and the amides, is the means by which they undergo
metabolic breakdown.
Metabolism of local anesthetics is important, because the overall
toxicity of a drug depends on a balances between its rate of absorption into
the blood stream at the site of injection and its rate of removal from the
blood through the processes of tissue uptake and metabolism.
Esters :
Ester local anesthetics are hydrolyzed in the plasma by enzyme
pseudocholine-esterase. The rate of hydrolysis has an impact on the
potential toxicity of a local anesthetic. Chloroprocaine, the most rapidly

hydrolyzed (4.7 µmol/ml/hr), is the least toxic, where a tetracaine,
hydrolyzed 16 times more slowly than chloroprocaine (0.3 µmol/ml/hr) has
the greatest potential toxicity.
Procaine undergo hydrolysis to para-amino benzoic acid (PABA) and
diethyl amino alcohol. Allergic reactions that occur in response to ester
drugs are usually not related to the parent compound i.e. procaine, but rather
to PABA.
Approximately 1 out of every 2800 persons has an atypical form of
pseudocholine esterase, which causes an inability to hydrolyze ester local
anesthetics and other chemically related drug (e.g. succinylcholine). Its
presence leads to a prolongation of higher blood levels of the local
anesthetic and an increased potential for toxicity.
Succinylcholine is a short-acting muscle relaxant employed
frequently during the induction phase of general anesthetics. It produces
respiratory arrest (apnea) for a period of approximately 2-3 min. Then
plasma pseudocholinesterase hydrolyzes succinylcholine, blood level falls,
and spontaneous respiration resumes. Persons with atypical pseudocholine
esterase are unable to hydrolyze succinylcholine at a normal rate; therefore
the duration of apnea is prolonged.
Amides:
The metabolism of the amide local anesthetic is more complete them
that of esters. The primary site of biotransformation of amide drugs is the
liver. Prilocaine undergoes primary metabolism in the liver, with some also
possibly occurring in the lungs. Prilocaine undergoes most rapid
biotransformation than the other amides.
Patients with lower than usual hepatic blood flow (hypotension,
congestive heart failure) or poor liver function (cirrhosis) are unable to

biotransform amide local anesthetics at a normal rate. This leads to
increased anesthetic blood levels and potentially increased toxicity.
Prilocaine, the parent compound, cannot produce
methemoglobinemia, but orthotoluidine, a primary metabolite of prilocaine,
does induce the formation of methemoglobin, which is responsible for
methemoglobinemia.
Lidocaine does not produce sedation, however, its two metabolites –
monoethyl glycinexylidide and glycinexylidide – are currently thought to be
responsible for this clinical action.
Excretion :
The kidney are the primary excretory organ for both the local
anesthetic and its metabolites. A percentage of a given dose of local
anesthetic drug will be excreted in the urine unchanged.
Esters appear in only very small concentrations as the parent
compound in the urine. This is because they are hydrolyzed almost
completely in the plasma. Amides are usually present in the urine as the
parent compound in a greater percentage than are esters, primarily because
of their more complex process of biotransformation.
Patients with significant renal impairment may be unusable to
eliminates the parent local anesthetic compound or its metabolites from the
blood, resulting in slightly elevated blood levels and an increased potential
for toxicity.

INDIVIDUAL LOCAL ANESTHETIC AGENTS
Although many drug are classified as local anesthetics and find use
within the health professions, only a handful are currently used in dentistry.
1. Lidocaine:
Concentration - 2%
Potency - 2X Procaine
Toxicity - 2X Procaine
Metabolized - Liver
Excreted - Kidney
% Vasoconstrictor Duration
2 without pulp - 5-10 mins
tissue - 1-2 hrs
2 1:50,000 epi pulp - 60 mins
tissue - 3-5 hrs
2 1:100,000 epi pulp - 60 mins
tissue - 3-5 hrs
Time to onset 2-3 mins
Half life 90 mins
Maximum recommended dose
(Malamed) 4.4 mg/kg (2 mg/lb)
(manufac.)
w/o epi 4.4 mg/kg (2 mg/lb)

with epi 6.6 mg/kg (3 mg/lb)
Maximum safe dose - 2% with 1:100,000epi
Malamed - 300 mg or 8 carpules
manufac. - 500 mg or 13.5 carpules
2. Mepivacaine
Concentration - 2% or 3%
Toxicity - 1.5-2X Procaine
Metabolized - Liver
Excreted - Kidney
% Vasoconstrictor Duration *
3 without pulp - 20-40 mins
tissue - 2-3 hrs
2 1:20,000 pulp - 60-90 mins
Levonordefrin tissue - 3-5 hrs
2 1:100,000 epi pulp - 45-60 mins
1:200,000 epi tissue - 2-5 hrs
* weak vasodilator
Time to onset 1.5-2 mins
Half life 1.9 hrs
(Malamed) 4.4 mg/kg (2 mg/lb)

(manufac.) 6.6 mg/kg (3 mg/lb)
Maximum safe dose - 3% w/o vasoconstrictor
Malamed - 300 mg or 5.5 carpules
manufac. - 400 mg or 8 carpules
Maximum safe dose - 2% with constrictor
Malamed - 300 mg or 8 carpules
manufac. - 400 mg or 11 carpules
3. Prilocaine
Concentration - 4%
Toxicity - 1X Procaine
Metabolized - Liver and Lungs
orthotoluidine produced
Excreted - Kidney
4 without pulp - 10 mins infiltra.
60 mins block
tissue - 1.5-4 hrs
4 1:200,000 epi pulp - 60-90 mins
tissue - 3-8 hrs

Half life 1.6 hrs
all forms 6 mg/kg (2.7 mg/lb)
Max safe dose
all forms 400 mg or 5.5 carpules
4. Bupivacaine
Concentration - 0.5%
Potency - 8X Procaine (4X Lidocaine)
Toxicity - 8X Procaine (4X Lidocaine)
Metabolized - Liver
Excreted - Kidney
0.5 1:200,000 epi pulp - 90-180 mins
tissue - 4-9 hrs,
up to 12 hrs reported
Half life 2.7 hrs
Maximum recommended dose 1.3 mg/kg (0.6 mg/lb)
Maximum safe dose 90 mg or 10 carpules

5. Etidocaine
Concentration - 1.5%
Potency - 8X Procaine (4X Lidocaine)
Toxicity - 4-8X Procaine (2-4X Lidocaine)
Metabolized - Liver
Excreted - Kidney
1.5 1:200,000 epi pulp - 90-180 mins
tissue - 4-9 hrs
Time to onset 1.5-3 mins
Half life 2.6 hrs
Maximum recommended dose 8 mg/kg (3.6 mg/lb)
Maximum safe dose 400 mg or 15 carpules
6. Procaine
Concentration - 2-4%
Potency - 1
Toxicity - 1
Metabolized - hydrolyzed in plasma by pseudocholinesterase to PABA
Excreted - Kidney
No longer available in dental carpules
Half life 0.1 hr
Duration pulp - 30-60 mins

(with v/c) tissue - 2-3 hrs
Maximum recommended dose 6.6 mg/kg (3 mg/lb)
Maximum safe dose 400 mg
Strong vasodilation - very short duration of pulpal anesthesia
High incidence of allergic reactions
Drug of choice for Tx of inadvertant intra-arterial injection (relieves pain
and spasm)
RATING OF DRUGS
In the search for more potent and less toxic agents, simultaneously
there has developed a number of methods for testing these drugs to evaluate
their usefulness and safety in clinical practice. Two drugs are used as a
standard for comparison.
- Procaine
- Cocaine
• Hirshfelder and Bieter originally received many techniques for
comparing activity and toxicity. Most method used laboratory animals
for initial testing and screening. These include the skin of a frog, cornea
of a rabbit, and muscle-nerve preparations.
• The intra-dermal wheal technique in humans provides information both
on potency and on cytotoxicity .
• A sensitive technique to determine both functional change and organic
cellular change was the tissue culture technique developed by Corssen
and Allen. Excised strips of human tracheal and bronchial mucosa were
cultivated in a balanced physiologic solution. The explants showed

continued ciliary activity and rotary motion, and increased or decreased
rotary motion is evidence of drug influence.
A comparative study showed that procaine and lidocaine affected the
tissue at concentration of 0.1% and failed to produce permanent injury even
at concentrations upto 20%. Tetracaine and dibucaine should a considerably
higher toxicity. Cocaine occupied an intermediate position.
SAFETY OF LOCAL ANESTHESIA
The safety of a local anesthetic drug is dependent on the relation to
potency to toxicity.
Safety α potency
If potency is high, toxicity is low and the margin of safety will be
large.
• The ratio of potency to toxicity is called the anesthetic index
SURGICAL CONSIDERATIONS
Pre-block evaluation:
All patients who are candidates for regional anesthesia should be
completely evaluated.
A complete history and physical examination should be done. It is
very important to know the types of medication the patient may be taking
for various medical conditions. It is equally important to determine if the
patient is on any type of anticoagulant.
1
Toxicity
α

Facilities:
A nerve block should be considered to be a surgical procedure. The
environment used while performing the technique must be given serious
consideration. The obtain maximum success, the operating room should
have following features:
- Prefer ventilation
- Adequate lighting
- Temperature control
- Provisions for asepsis
Equipment necessary for treatment of complications and drug
reactions must be provided. This includes an oxygen supply and means for
administration by positive pressure.
Asepsis :
Aseptic precautions are similar to those that attend any surgical
procedure. The field should be prepared should be given special
consideration, since the patient is not anesthetized, any irritating chemicals
should be Betadine have been successful. For outpatients, plain 70% ethyl
or isopropyl alcohol is most suitable sinus it is an effective antiseptic, leaves
no skin coloration, and doss not stain clothes. Sterile drapes are placed
judiciously with respect to the site of the block.
Skin preparation :
The classic technique of preparing the skin consists of a soap-water
scrub and/or 70% ethylorisopropyl alcohol for 5 minutes. Skin contains an
average of 200-600 bacteria per square inch of surface area, and this
technique will reduce the bacterial count to less than 100 bacteria/square
inch, when followed by the application of 70% ethylorisopropyl alcohol, the

number of bacteria will be reduced further to 20-40 bacteria /inch. However,
the efficacy of antiseptics over the use of soap-water, alcohol sequences is
not well established.
Iodine preparations are recommended and have been singularly
effective. The disinfectant property is directly related to the amount of free
iodine. Tincture of iodine (1%) provides over 300ppm of free iodine;
povidone- iodine (betadine) contains about 20-25ppm.
For maximum protection and the use of a single application of an
antiseptic, chlorhexidine 0.5% in 70% ethylorisopropyl alcohol or 1%
tincture of iodine is most effective, and from the antimicrobial point is
presented as the gold standard.
ANATOMIC CONSIDERATIONS
To understand the mode of action of local anesthetic drugs, the
fundamental of nerves should be understood; thus a review of the relevant
characteristics and properties of nerve anatomy and physiology is described
here.
Structure of nerve fibers:
The neuron
The neuron or nerve cell is the structural unit of the nervous system.
There are two basic types of neuron :
• The sensory (afferent) neuron
• The motor (efferent) neuron
Sensory neurons that are capable of transmitting the sensation of pain
consists of three major portions. The dendritic zone, which is compared of
an arborization of the nerve endings, is the most distal segments of the
sensory neuron. These free nerve endings respond to stimulation produced

in the tissues in which they lie, provoking an impulse that is transmitted
centrally along the axon. The axon is thin cable-like structure that may be
quite long. At its mesial (or central) end there is an arborization similar to
that seen in dendritic zone. However, in this cover the arborizations from
synapses with various nuclei in the CNS, to distribute incoming (sensory)
impulses to their appropriate sites within the CNS for interpretation. The
cell body, or soma, is the third fait of the neuron. In the sensory neuron, the

cell body is located at a distance from the axon, or the main pathway of
impulse transmission in this nerve. The cell body of the sensory nerve is
therefore not included in the process of impulse transmission, its primary
function being to provide the vital metabolic support for the entire neuron.
Nerve cells that conduct impulses from the CNS peripherally are
termed motor neurons and are structurally different from the sensory
nervous, in that their cell body is interposed between the axon and the
dendrites. In motor neurons the cell body not only is an integral component
of the impulse transmission system but also provides metabolic support for
the cell.
Microscopy
Resolution of the membrane structure and its histochemistry reveal a
bimolecular lipid layer around on each side by a protein sheet. The
lipid molecules are arranged with the hydrophobic arms extending
toward each other and the hydrophobic poles oriented toward either the
extracellular fluid or the axoplasm.
Between the lipid molecules are water filled channels. Permeability of
the membrane is mediated by these ion channels, such channels are formed
in the lipid membrane layers by various short-chain peptides in a helical
manner of approximately four turns in length the outer lipoprotein
molecules are tightly packed and impede the movements of sodium ions,
amino acids and proteins, but potassium and chloride ion pass relatively
freely. Hence the membrane is designated as semi permeable.

Schwann cells and myelin:
All nerve fibers are incompletely surrounded by nucleated cells called
Schwann cells. As the more complex nervous systems have evolved and the
need arouse to rapidly convey sensory and motor impulses, insulation of
nerve fibers become necessary. This is structurally accomplished for certain
nerve fibers by the sheath cells manufacturing myelin, a fatty substance with
insulating properties. This myelin is deposited around the membrane of the

nerve fiber in cylindrical of the nerve fiber in cylindrical layers or
concentric lamellae. Such insulation reduces current loses and enhances the
efficiency of impulse transmission.
Myelinated nerve fibers :
Most mammalian nerve fibers, except the smallest, are myelinated. At
regular intervals, the myelin coaling is thin or absent these points or gaps
occur approximately every 0.5 –3 mm and are known as the nodes of
Ranvier. At these points, the nerve fiber itself comes into contact with
extracellular fluid. Impulses are there fore promulgated jump-wise
(Saltatory) fashion.
It is to be recognized that myelin limit access of local anesthetics to
the nerve fiber membrane to produce conduction block in myelinated fibers
thus requires a higher concentration of local anesthetic. Furthermore, a
sufficient amount of the anesthetic must be available and applied for a
minimum distance along the length of any nerve fiber (usually at a
minimum span of two –three adjacent nodes) or a minimum distance of 8-10
mm of the nerve must be exposed.
Anatomy of a mixed nerve :

Most peripheral nerves are mixed, consisting of various afferent and efferent
fibers tightly packed together. Individual fibers or axis cylinders are each
cased by a thin membrane, or endoneurium; a variable number of 100-1000
of such are bound together in bundles or fasciculi by the perineurium. The
perineurium of a fasciculus is compared of 5-15 layer of fibroelastic tissue,
depending on the diameter of a bundle. It is noted that the perineurium is
thicker at distal sites (i.e. at the wrist) than at the axillae. Furthermore, the

inner most layer of the perineurium, the perilemma, is lined with a smooth
mesothelial membrane. This appears to be the main diffusional barrier.
Embryologically, the perilemma is a continuation of the pia -
arachnoid membrane covering the brain and spinal cord. It is the peripheral
equivalent of the control blood brain barrier. A collection of 5-20 or more of
these bundles are surrounded by the epineurium and lie in a matrix of the
epineural space consisting of loose areolar tissue, nutrient blood vessels,
lymphatics and fat.
In such construction, one can identify those fasciculi that are centrally
located called the core bundles & those which are close to the surface or
nerve sheath called the mantle bundle of axons.
PHYSIOLOGIC CONSIDERATIONS
Many fundamental discoveries have led to more complete
understanding of the action of local anesthetic agents. Such findings have
been anatomic, physiologic and biochemical.
The function of a nerve is to carry messages from one part of the
body to another. These messages, in the form of electrical action potentials
are called impulses. The nerve impulse is a transient wave of electrical
excitation that travels from point to point down to length of a nerve fiber.
Action potentials are transient membrane depolarizations that result
from a brief increase in the permeability of the membrane to sodium, and
usually also from a delayed increase in the permeability to potassium,
impulses are initiated by chemical, thermal, mechanical, or electrical
stimuli.
Note : Once an impulse is initiated by a stimulus in any particular nerve
fiber, the amplitude and shape of that impulse remain constant, regardless of
changes in the quality of the stimulus or its strength.

The impulse remains constant without loosing strength as it passes
along the nerve because the energy used for its propagation is derived from
energy that is released by the nerve fiber along its length and not solely
from the initial stimulus.
De Jong described impulse conduction as being like the active
progress of a spark along a fuse of gunpowder. Once lit, the fuse burns
steadily along its lengths, one burning segment providing the energy
required to ignite its neighbour such is the situation with impulse
propagation along a nerve.
ELECTROPHYSIOLOGY OF NERVE CONDUCTION :
The following is a description of electrical events that occur within a
nerve during the conducting of an impulse:
Step 1 :
A nerve processes a resting potential. This is a negative electrical
potential of 10mV, that exists across the nerve membrane, produced by
differing concentrations of ion on either side of the membrane. The interior
of the nerve is negative in relation to the exterior.
Step 2 :
A stimulus excites the nerve, leading to following sequence of events.
a) An initial phase of slow depolarization the electrical potential within
the nerve becomes slightly less negative.
b) When the falling electrical potential reaches a critical level, an
externally rapid phase of depolarization results, this is termed as
threshold potential or firing threshold.
The firing threshold is actually the magnitude of the decrease in
negative transmembrane potential that is required to initiate an action
potential (impulse).

c) This phase of rapid depolarization results in a reversal of the
electrical potential across the nerve membrane. The interior of the
nerve is now electrically positive in relation to the exterior. An
electrical potential of +40mV exists on the interior of the nerve cell.
Step 3 :
Following these steps of depolarization, repolarization occurs. The
electrical potential gradually becomes more negative inside the nerve
cell relative to the outside until the original resting potential of 10mV
is again achieved.
The entire process requires 1msec; depolarization takes 0.3msec and
depolarization takes 0.7msec.
ELECTROCHEMISTRY OF NERVE CONDUCTION :
The preceding sequence of events depends on two important factors.
i) The concentration of electrolytes in the axoplasm (interior of the
nerve cell) and extracellular fluids.
ii) The permeability of the nerve membrane to sodium and potassium
ions.
INTRACELLULAR AND EXTRACELLULAR IONIC
CONCENTRATIONS
Ion Intracellular
(MEQ/L)
Extracellular
(MEQ/L)
Ratio
Potassium (K+
) 110-170 3-5 27:1
Sodium (Na+
) 5-10 140 1:14
Chloride (Cl-
) 5-10 110 1:11
These significant differences in ion concentration exists because the
nerve membrane exhibit selective permeability.

RESTING STATE :
In the resting state the nerve membrane is :
• Slightly permeable to sodium ions
• Freely permeably to potassium ion
• Freely permeably to chloride ions.
Potassium remains within the axoplasm, despite its ability to diffuse
freely through the nerve membrane and its concentration gradient (passive
diffusion usually occurs from a region of greater concentration to one of
lesser concentration), because the negative charge of the nerve membrane
restrains the positively changed ions by electrostatic attraction.
Chloride remains outside the nerve membrane instead of moving
along its concentration gradient into the nerve all because the apposing,
nearly equal, electrostatic influence forces out ward migration. The net
result is no diffusion of chloride through the membrane.
Sodium can migrates is usually because both the concentration
(grater outside) and the electrostatic gradient (positive ion attracted by
negative intracellular potential) favor such migration only the fait that the
resting nerve membrane is relatively impermeably to sodium prevents a
massive influx of this ion.

MEMBRANE EXCITATION :
Depolarization : Excitation of nerve segment to an increase in
permeability of the cell membrane to sodium ions. This is accomplished by
a transient widening of transmembrane ion channels sufficient to permit the
unhindered passage of hydrated sodium ions. The rapid influx of sodium
ions to the interior of the nerve cell causes a depolarization of the nerve
membrane from its resting level to its firing threshold of approximately 50-
70mV.
(Exposure of the nerve to a local anesthetic basis its firing threshold).
When firing threshold is reached, permeability of the membrane to sodium
increases dramatically, and sodium ion rapidly enters the axoplasm. At the
end of depolarization (the plate of action potential), the electrical potential
of the nerve is actually reversed; an electrical potential of +40mV exists.
The entire depolarization requires 0.3msec.

Depolarization : The action potential is terminated when the nerve
repolarises. This is caused by extinction or inactivation of increased
permeability to sodium. In many cells permeability to potassium also
increases, resulting in the efflux of K+
, leading to a more rapid membrane
repolarization and return to its resting potential.
The movement of sodium ions into the cell during depolarization and
subsequent movement of potassium ions out of the cell during repolarization
are passive  not requiring the expenditure of energy, river the ions moves
along their concentration gradient.
Active transfer of sodium ion out of the cell occur via the “sodium
pump”. An expenditure of energy is needed to move sodium ions out of the
nerve cell against their concentration gradient, this energy comes from the
oxidative metabolism of ATP.
The entire process of repolarization requires 0.7msec
Immediately after a stimulus has initiated an action potential, a nerve
is unable, (for a time) to respond to another stimulus, regardless of its
strength. This is termed the absolute refractory period. This is followed by a
relative refractory period, during which a new impulse can be initiated bout
only by a stronger their normal stimulus. The relative refractory period
continuous to decrease until the normal level of excitability returns, at
which point the nerve is said to be repolarised.
The nature of nerve conduction is summarized as a depolarization –
repolarization process.
Membrane channels :
Discrete aqueous pores through the excitable nerve membrane, called
sodium (or ion) channels, are molecular structures that mediate its sodium
permeability. The channel is a lipoglycoprotein firmly situated in the
membrane. It consists of an aqueous pore spanning the membrane that is

narrow enough at least at one point to discriminate between sodium and
other ions. (Na+
posses through 12 times more easily than K+
) the channel
also includes a portion that changes configuration in response to change in
membrane potential, thereby gating the passage of the ions through the pore.
Sodium channels have an internal diameter of approximately 0.3 x 0.5 nm.
A sodium ion is “thinner” than either a potassium or chloride ion and
should therefore diffuse feely down its concentration gradient thought
membrane channels into the nerve cells. This does not occur, however,
because all these ions attract water molecules and thus become hydrated.
Hydrated sodium ions have a radius of 3.4 A0
, which is greater than 2.2A0
radius of potassium and chloride ions. Sodium ions are therefore too charge
to pass through the narrow channels when a nerve is at rest.
Recent evidence indicates that channel specificity exists, in that the
sodium channels differ from potassium channels.
The gates on the sodium channels are located near the external
surface of the nerve membrane, whereas those an the potassium channel are
located near the internal surface of the nerve membrane.
IMPULSE PROPAGATION :
Following the initiation of an action potential by a stimulus, the
impulse must move along the surface of the axon. Energy for impulse
propagation is derived from the nerve membrane is the following manner:
The stimulus disrupts the resting equilibrium of the nerve membrane,
the trans membrane potential is recurred momentarily – the interior of the
cell changing from negative to positive and the exterior changing from
positive to negative. This now electrical equilibrium in this segment of
nerve produces local currents that begin flouring between the depolarized
segment and the adjusting resting area. These local currents flow from
positive to negative, extending for several mm along the nerve membrane.

As a result of this current flow, the interior of the adjacent area
becomes less negative and its exterior less positive. Trans membrane
potential decreases, approaching firing threshold for depolarization. When
the trans membrane potential is decreased by 1.5mV from resting potential,
firing threshold is reached and complete depolarization occurs. The newly
depolarized segment sets up local current in adjacent resting membrane, and
the entire process starts anew.
Conditions in the segment that has first depolarized return to normal
following the absolute and relation refractory periods. Because of this the
wave of depolarization can spread in only one direction. Backward
(retrograde) movement is presented by the unexcitable refractory segment.
IMPULSE SPREAD :

The propagated impulse travels along the nerve membrane toward the
CNS. The spread the impulse differs depending on whether or not a nerve is
myelinated.
Unmyelinated nerves :
An unmyelinated nerve fiber is basically a long cylinder with a high-
electrical resistance cell membrane surrounding a low resistance conducting
core of axoplasm, all of which is bathed in low resistance extracellular
fluid.
The high resistance cell membrane and low resistance intracellular
and extracellular media produce a rapid decrease in the density of current
within a short distance of the depolarized segment. In areas immediately
adjacent to this depolarized segment, local current flow may be adequate to
initiate depolarization in the resting membrane. Further among it will prove
to be inadequate to achieve firing threshold.
The spread of an impulse is can unmyelinated nerve filers is therefore
characterized as a relatively slow forward – creeping process.
Myelinated nerves :
Impulse conduction in myelinated nerve occurs by means of current
leap from node to node – a process termed as salutatory conduction. (salt are
is the latin verb “to leap”. This from of impulse conduction process to be
much faster and more energy efficient than that which is employed in
unmyelinated nerves.
MODE AND SITE OF ACTION OF LOCAL ANESTHETIC :

It is possible for the local anesthetic agents to interfere with the
excitation process in a nerve membrane in one or more of the following
ways:
i) Altering the basic resting potential for the nerve
ii) Altering the threshold potential
iii) Decreasing the rate of depolarization
iv) Prolonging the rate of repolarization
It has been established that the primary effects of local anesthetic
occur during the depolarization phase of the action potential. These effects
include a decrease in the rate of depolarization, particularly in the phase of
slow depolarization. Because of this, cellular depolarization is not sufficient
to reduce the membrane potential to firing level, and a propagated action
potential does not develop.
Site :
The nerve membrane is the site at which local anesthetic agent exert
their pharmacologic actions.
Mechanism of action :
The local anesthetic is a weak base which must be combined with a
strong acid in order to makes the acid salt that is soluble for use in solution.
RNHOH + HCl  RNHCL + H2O
Weak strong acid water
Base acid salt
To act as local anesthetic, it must dissociate into a free base, for
which a basic environment found in normal tissue is necessary.

RNHCI  RNH+
+ CI-
This positively charged (RNH+
) molecules is called certain and is
hydrophilic. It further dissociated outside the nerve sheath resulting in an
unionized lipophillic molecule called the base
RNH+
RN + H+
The relative proportion of each ionic form in the solution caries with
the pH of the surrounding tissues. In a acidic environment (low pH) the
equilibrium shifts to the left and most of the anesthetic solution exists in
cationic form
RNH+
> RN + H+
As hydrogen ion concentration decreases (higher pH), the equilibrium
shift toward the free base form:
RNH+
< RN + H+

The relative proportion of the ionic forms also depends on the pKa or
dissociation constant of the specific local anesthetic. The pKa is a measure
of a molecules affinity for hydrogen ions (H+
). When the pH of a solution
has the same value as the pKa of the local anesthetic drug, exactly half the
drug will exist in the RNH+
form and half in RN form.
The percentage of drug existing in either form can be determined for
the Henderson – Hasselbalch equation :
This non ionize lipophillic local anesthetic molecules (RN) diffuses
readily through the lipid composed nerve sheath. After his molecules
passage into the interstitial fluid between the nerve sheath and the nerve cell
membrane. Here it undergoes another reaction will the for hydrogen found
here. This free hydrogen ion is liberated from the buffer system reaction
according in the area. The reaction results in the formation of an ionized
hydrophilic form of local anesthetic molecule.
RN + H+
RNH+
This molecule in nerve call membrane displaces calcium ions for the
sodium channel receptor site.
↓
Binding of the local anesthetic molecules to this receptor site
↓
Blockade of sodium channel
↓
Decrease in sodium conduction
↓
Log Base
Acid
= pH – pKa

Depression of the rate of electrical depolarization
↓
Failure to achieve the threshold potential level
↓
Lack of development of propagated action potentials
↓
Conduction blockade
THEORIES OF MECHANISM OF ACTION OF L.A.
Many theories have been proposed over the years to explain the
mechanism of action of local anesthetics.
i) Acetyl chorine theory :
According to this theory, liberation of acetyl chorine at synaptic
function alters the permeability of plasma membrane, and permits
depolarization which is responsible for continuous pulse-transmission. The
local anesthetic agents prevents the depolarization and pulse transmission by
their effect on acetyl chorine.

This theory is not accepted because acetyl chorine is the neurotransmitter at
the synaptic function, there is no evidence that acetyl chorine is involved in
neural transmission along the body of the neuron.
ii) Calcium displacement theory :
This theory was once quite popular and maintained that local
anesthetic nerve block was produced by the displacement of calcium from
some membrane sites that controlled permeability to sodium.
Evidence that varying the concentration of calcium ions bathing a
nerve does not effect local anesthetic potency has diminished the credibility
of this theory.
iii) Surface charge (repulsion) theory :
This theory proposed that local anesthetic acted by binding to nerve
membrane and changing the electrical potential at the membrane surface.
Cationic (RNH+
) drug molecules were aligned at the membrane water

interfere, and since some of the local anesthetic molecules carried a not
positive charge, they made the electrical potential at the membrane surface
more positive, thus decreasing the excitability of the nerve by increasing the
threshold potentials.
Current evidence indicates that the resting potential of the nerve
membrane is unaltered by local anesthetics (they do not become
hyperpolarized) and that conventional local anesthetics act within the
membrane channels rather than at the membrane surface. Also the surface
charge theory cannot explain the activity of uncharged anesthetic molecules
in blocking in blocking nerve impulses (e.g. benzocaine).
iv) Membrane expansion theory :
This theory states that local anesthetic molecules diffuse to
hydrophobic regions of excitable membrane, producing a general
disturbance of the bulk membrane structure, expanding some critical regions
in the membrane, and thus preventing an increase in the permeability to
sodium ions. Local anesthetics that are highly lipid soluble can easily
penetrate the lipid portion of the cell membrane, producing a charge in
configuration of the lipoprotein matrix of the nerve membrane. This results
in decreased diameter of sodium channels, which leads to an inhibition of
both sodium conductance and neural excitation.

This theory serve an a possible explanation for the local anesthetic activity
of a drug such as benzocaine, which does not exist in cationic form yet still
exhibits potent topical anesthetic activity. It has been demonstrated that
nerve membrane do, infect, expand and become more ‘fluid’ when exposed
to local anesthetics. However, there is no direct evidence that nerve
conduction is entirely blocked by membrane expansion per se.
v) Specific receptor theory :
It is the most forward theory today and proposes that local anesthetics
act by binding to specific receptors on the sodium channel. The action of the
drug is direct and not medicated by some charge in the general properties of

the cell membrane. Both biochemical and electrophysiological studies have
indicated that a specific receptor site for local anesthetic agents exist in the
sodium channel either on its external surface or on the internal axoplasmic
surface. Once the local anesthetic has gained access to the receptors,
permeability to sodium ions is decreased or eliminated and nerve
conduction is interrupted.
KINETICS OF LOCAL ANESTHETICS
When a local anesthetics drug is injected and deposited about the
nerve bundle, drug movement into the nerve bundle and into individual
nerve cells follows a regular series of steps to achieve a state of nerve block.
Fours aspect are to be considered with respect to onset and
maintenance of the state of block. The require of movement is as follows:
ii) Diffusion to the nerve and into the nerve bundles. This depends on
the aqueous solubility.

iii) Process of penetration into the nerve cell. This depends on non
ionized (base) form.
iv) Retribution of the agent in a nerve fiber cell. This depends on
aqueous solubility
v) The fixation to the nerve cell components. This depends on the
affinity of cation form to channel receptors.
As the anesthetic state is being established, the process of removal of the
drug from the site of injection into the vascular space begin. The
processes become more prominent with their and four aspects of
recovery from block and disposition of drug may be considered:
i) Absorption : Extracellular drug enters the vascular spaces and
continuous during anesthetic block.
ii) Release process : The nerve fiber releases the fixed drug as the
gradient of concentration reverses with time.
iii) Redistribution to other organs and tissues occurs after absorption
iv) Destruction and elimination.
DIFFUSION OF LOCAL ANESTHETICS :
Following the administration of a local anesthetic into the soft tissues
near a nerve, (local anesthetic solution should be deposited as near to the
nerve as possible without penetrating or spearing the nerve sheath. An
injection into the perineural space will compress the nerve bundles and also
cause ischemia) the molecules of the local anesthetic transverse the distance
from one site to another according to their concentration gradient.

During the induction phase of anesthesia, the local anesthetic moves from
its extraneural site of deposition toward the nerve (as well is in all the other
direction). This process is termed as diffusion. It is the unhindered migration
of molecules or ions through a fluid medium under the influence of the
concentration gradient penetration of an anatomical barrier to diffusion
occurs when a drug passes through a tissue that tends to restrict the
molecular movement. The perineurium is the greatest barrier to penetration
of local anesthetics.
Diffusion an penetration are relatively slow process and speed of
overt of anesthetic action is essentially proportional to the log of
concentration of the drug i.e. the rate of diffusion is governed by the
concentration gradient ( the greater the initial concentration of the local
anesthetic, the faster will be the diffusion.
Mantle bundles one the first ones reached by local anesthetic and are
exposed to a higher concentration of it. They are usually blocked completely
shortly after the injection of a local anesthetic. Core bundles are contacted
by the drug only after much delay and by a lower anesthetic concentration

because of the greater distance that the solution must transverse and the
greater number of barrier it must cross.
As the local anesthetic diffuses into the nerve, it becomes
increasingly diluted by tissue fluids and is absorbed by capillaries and
lymphatics; ester anesthetics undergo almost immediate enzymatic
hydrolysis. Thus the core fibers are exposed to a decreased concentration of
local anesthetic, a fat that may explain the clinical situation of inadequate
Pulpal anesthesia developing in the presence of subjective symptoms of
adequate oft tissue anesthesia.
Fibers near the surface of the nerve (mantle fibers) tend to innervate
more proximal regions (e.g. molar area with an inferior alveolar nerve
block), whereas fibers in the care bundles innervate the more distal points of
nerve distribution (e.g. incisors).
Lipid solubility of a local anesthetic appears to be related to its
intrinsic potency. Local anesthetics with greater lipid solubility produce
more effective conduction blockade at lower concentrations than do the less
lipid soluble solutions.
The degree of protein binding of the anesthetic molecule is
responsible for the duration of local anesthetic activity. Vasoactivity affect
both the anesthetic potency and the duration of anesthesia provided by a
drug.
Absorption :
After injection of a local anesthetic agent and exposure of a grain
nerve to its effect, the agent is diluted in the extracellular fluid and taken up
by capillaries. Ultimately, all of the agents enters the blood steam.
The blood supply to a tissue is a crucial factor in determining rate of
absorption. Direct i.v. injection provides the most rapid absorption rate and
produces high plasma levels. Topical application to many mucous

membranes results in the next highest plasma levels. indeed, application to
the pharynx and tracheo-bronchial tree may produce blood levels
comparable to slow i.v. injection.
I.m. infection of local anesthetics provide the next highest levels. The
lowest levels occurs after subcutaneous and intracutaneous infections.
vasoconstrictor agents further limit the absorption of agents from there sites.
No absorption occurs through unbroken skin, but if the skin is
abraded, significant plasma levels are attained. In burn site, the absorption
depends on the degree of the burn.
Disposition :
Little or no destruction of local anesthetics occurs in situ at the tissue
sites of injection. This can be explained by an example. Chlorprocaine
provides a local block for more than 1hours, while the agent undergo
complete hydrolysis in plasma within 5 minutes.
Redistribution :
A redistribution to other organs and tissues remote from the site of
injection ensues. Concentration in these is dependent on regional blood
flow. Those organs that are usual rich with a high blood flow, such as the
ling, liver and kidney, concentrate more amount of drug. The greatest
percentage of an injected dose distributes to skeletal muscle due to its large
mass.
Destruction :
Detoxification is primarily dependent on liver enzymes. Breededown
of esters occurs in the plasma. The primary site of amide metabolism is the
liner.

REINJECTION OF LOCAL ANESTHETIC
Not infrequently a dental procedure will outlast the duration of
clinically effective pain control and a repent infection of local anesthetic
will be required.
Recurrence of immediate propound anesthesia :
At the this of reinjection, the concentration of local anesthetic in the
mantle fibers is below that in the more centrally located core fibers. The
partially recovered mantle fibers still contain some local anesthetic,
although not enough to provide complete anesthesia.
After deposition of a new high concentration of anesthetic the nerve,
the mantle fibers are once again exposed to a concentration gradient directed
inward toward the nerve. This combination of residual local anesthetic and
the newly deposition supply results in a rapid onset of profound anesthesia
with a small volume of local anesthetic drug bring administered.
Difficultly in re-achieving profound anesthesia :
In this situation, effective control of pain does not occur even after
reinjection of local anesthetic agent. This is explained by following
phenomenon.
Tachyphylaxis : Is defined as an increasing tolerance to a drug that is
administered repeatedly.
Although difficult to explain, tachyphylaxis is probably brought about
through some or all of the following factors: edema, localized hemorrhage,
clot formation, transudation, hypernatremia, and decreased pH of tissues.
the first form factors isolate the nerve from contact with the local anesthetic

solution. Hypernatremia, raises the sodium ion gradient, thus counteracting
the decrease in sodium ion conduction brought about by the local anesthetic.
The last factor, a decrease in pH of the tissues, is brought about by the first
infection of the acidic local anesthetic, the ambient pH in the area of
injection may be somewhat lower, so that fever local anesthetic molecules
are transformed into the free base (RN) on reinjection.
POTENTIATION OF ACTION OF LOCAL ANESTHESIA
It is a common practice to old various agents to anesthetic solutions in
order to increase the intensity or duration of action.
VASOCONSTRICTORS :
The value of vasoconstrictors in prolonging local anesthetic action has
been well established. As a result of local vasoconstriction the absorption of
the local anesthetic is delayed, and the effect of the anesthetic is allowed to
continue at the local site.
Role of vasoconstrictor in local anesthetic solution is as follows 
- By constricting blood vessels, vasoconstrictors decrease blood flow
(perfusion) to the site of injection.
- Absorption of the local anesthetic into the cardiovascular system is
slowed, resulting in lower anesthetic blood levels
- Lower local anesthetic blood levels decrease the risk of local
anesthetic toxicity.
- Higher volumes of the local anesthetic agent remain in and around
the nerve for longer periods, thereby increasing the duration of action
of most local anesthetics

- Vasoconstrictors decrease bleeding at the site of their administration
and are useful, when increased bleeding is anticipated.
The actions of the vasoconstrictors so resemble the response of
adrenergic nerves to stimulation that they are classified as sympathomimetic
a adrenergic drugs. There drug have many clinical actions brides
vasoconstriction.
Sympathomimetic drug many also be classified according to their
chemical structure.
I. According toChemical structure :
Catecholamines :
• Epinephrine
• Norephinephrine
• Dopamine
• Levonordefrin
• Isoproterenol
Non catecholamines
• Amphetamine
• Methamphetamine
• Hydroxy-amphetamine
• Ephedrine
• Mephetermine
• Metaraminol
• Phenyl ephrine
Natural

II. According to Modes of action :
i) Direct – acting drugs :
They exert their action directly on adrenergic receptors.
• Epinephrine
• Nor epinephrine
• Levonordefrin
• Isoproterenol
• Dopamine
• Methoxamine
• Pheylephrine
ii) Indirect – acting drugs :
They act by releasing norepinephrine from adrenergic nerve terminals.
• Tyramine
• Amphetamine
• Methamphatamine
• Hydroxynphetamine
iii) Mixed – Acting Drugs :
with both direct and indirect actions.
• Metaraminal
• Ephedrine.
ADRENERGIC RECEPTORS :
The concept of adrenergic receptors was proposed by ahlquist in 1948
and is well accepted today. Adrenergic receptors are found in most tissues
of the body. Ahlquist recognized two types of adrenergic receptors.
Non catecolamines

• Alpha (α)
• Beta (β)
Activation of α receptors causes vasoconstriction.
α1  excitatory – post synaptic
α2  inhibitary – post synaptic.
Activation of β receptors produces smooth muscle relaxation (vasodilation
and brondiodilation) and cardiac stimulation (increased heart rate and
strength of contractions).
β1 Found in heart and small intestines and are responsible for cardiac
stimulation and lipolysis
β2  found in bronchi, vascular beds, and uterus and produces
brondiodilation and vasodilation.
Dilutions of vasoconstrictors:
The dilution of vasoconstrictors in commonly referred to as a ratio.
Dilution Mg/ml Therapeutic use
1:1,000 1.0 Emergency medicine
(IM/Sc anaphylaxis)
1:2,500 0.4 Phenylephrine
1:10,000 0.1 Emergency medicine
(IV cardiac arrest)
1:20,000 0.05 Levonordefrin
1:30,000 0.033 Norepinephrine
1:50,000 0.02 Local anesthesia
Based on the inhibitory or excitatory actions of
catecolamines on smooth muscle.

1. Epinephrine
• Most potent and widely used vasoconstrictor in dentistry
• Source: 80% of medullary secretion, also available as a synthetic
• Mode of action is both a and b , with b being predominate
Systemic Effects of Epinephrine
• Myocardium -Increase heart rate and cardiac output
• Pacemaker -Increase risk of dysrhythmia
• Coronary Artery-Dilation of coronary artery
• Blood Pressure -Increased systolic pressure, effect on diastolic pressure
is dose related
• Cardiovascular -Decrease cardiac efficiency
• Vasculature -Vasoconstriction in skin, mucous membrane & kidneys
-Vasodilation in skeletal muscle in small doses,
vasoconstriction in large doses
• Respiratory - Bronchodilator
• CNS - Not a potent CNS stimulant
• Metabolism - Increase oxygen consumption
Termination of Epinephrine
• Reuptake
• COMT and MAO
• Excreted unchanged in urine (1%)
Clinical Manifestations of Epinephrine Overdose
• CNS stimulation - fear, anxiety, tremor, pallor, dizziness

• Cardiac dysrhythmia
• Ventricular fibrillation
• Drastic increase in BP - can cause cerebral hemorrhage
• Angina in patients with coronary insufficiency
Maximum Dose for Dental Appointment
• Normal healthy patient
0.2 mg. per appointment
• Significant cardiovascular impairment
0.04 mg per appointment
Clinical Applications for Epinephrine
• Acute allergic reaction
• Bronchospasm
• Cardiac arrest
• Hemostasis
• Produce mydriasis
• Vasoconstrictor
• Norepinephrine
Source: 20% of adrenal medulla secretion, also available in synthetic form
Mode of action - almost exclusively a , b effect in heart

2. Norepinephrine
• 1/4 potency of epinephrine
Systemic Effects of Norepinephrine
• Myocardium - increase force of contraction
• Pacemaker - increase stimulation causing dysrhythmia
• Heart rate - decrease heart rate
• Coronary artery - increase coronary flow
• Blood Pressure - increase both systolic and diastolic
• Cardiovascular - increase stroke volume, decrease cardiac output
• CNS - no effect at therapeutic doses
• Metabolism - increase basal metabolic rate, increase blood sugar
Elimination of Norepinephrine
• Reuptake
• COMT and MAO
• Excreted unchanged in urine
Overdose of Norepinephrine
• Same as epinephrine
• Can cause sloughing of tissue due to a effect
Availability in Dentistry

• With mixture of procaine and propoxycaine, in a concentration of
1:30,000
MaximumDosefor Dental Appointment
• Healthy patient
• Medically compromised
3. Levonordefrin
Proprietary name - Neo-Cobefrin
Source: synthetic
Mode of action - mostly a , 25% b
Systemic action - same as epinephrine, but to a smaller degree
Termination - COMT and MAO
Availability - 1:20,000 concentration with Mepivacaine or mixture of
Propoxycaine/Procaine
Maximum dose for all patients
1 mg. per appointment

4. Phenylephrine Hydrochloride
Proprietary name - Neo-Synephrine
Source : synthetic
Mode of action - 95% a
Systemic Action of Phenylephrine Hydrochloride
• Myocardium - little effect
• Pacemaker - little effect
• Coronary artery - increase blood flow
• Blood Pressure - increase systolic and diastolic
• Heart rate - bradycardia
• Respiratory - bronchodilator, but not effective for bronchospasm
• CNS - minimum effect
• Metabolism - some increase in metabolic rate
Termination - hydroxylation to epinephrine
Clinical application - vasoconstrictor, nasal decongestant
Availability - 1:2500 with 4% procaine
Maximum Dose for Phenylephrine Hydrochloride
• Normal healthy patient
4 mg. per appointment

• Medically compromised
Factors in selection of Vasoconstrictor
• Length of the dental procedure
• The need for hemostasis during and following procedure
• The medical status of the patient
Vasoconstrictor Factors to Consider
• High BP, Cardiovascular disease
• Hyperthyroidism
• MAO Inhibitors (anti-depressant)
• Tricyclic antidepressants
• Patient using cocaine-never use epinephrine !!
RECENT ADVANCES AND FUTURE TRENDS IN PAIN
CONTROL
Through local anesthesia remains the backbone of pain control in
dentistry, research has continued, in both medicine and dentistry, to seek
new and bester means of managing pain associated with many surgical
treatments.
i) Centbucridine :
It is a quinalone derivative with five to eight times the potency of
lidocaine and with an equally rapid onset and an equivalent duration of
action. Significantly is does not effect central nervous system or

cardiovascular system adversely except when administered in very large
doses.
It has been used in subarachnoid and epidural anesthesia and in
intravenous regional anesthesia.
Vacharejani et al compared the efficacy of 0.5% Centbucridine
concentration with that of 2% lidocaine for dental extraction in 120 patients.
They reported that a degree of analysis attained with Centbucridine that
compared well to that obtained with lidocaine. Centbucridine was well to
related, with no significant parameters and no serious side effects. when
administered to overdose, Centbucridine function as a true stimulant of the
CNS unlike lidocaine.
ii) Ropivacaine :
It is a long- acting amide anesthetic, similar to bupivacaine and
etidocaine in duration of activity. It is structurally similar to mepivacaine
and bupivacaine, but is unique in that it is prepare as a isomer rather than as
a racemic mixture.
Data indicate that it has a greater margin of safety between
convulsive and lethal doses than does bupivacaine. The elimination ½ life of
ropivacaine is 25.9 minutes which is considerably shorter than that of other
amides. Ropivacaine has demonstrated decreased cardio-toxicity relation to
bupivacaine, but its clinical duration of action is approximately 20% shorter.
The primary use of ropivacaine in anesthesiology has been for
regional nerve block (especially epidural). Its potential for use in dentistry
as another long-acting local anesthetic appears great, but awaits clinical
evaluation.
iii) EMLA :

Intact skin is an imperious barrier to the penetration of drugs,
including topical anesthetics. Yet once skin is damaged, as occurs in
sunburn or injury, anesthetic drugs such as solarcaine could be applied
topically for the relief of pain. For years a drug or a technique was sought
that would permit needles to be inserted painlessly through intact skin. The
development of oil-in-water emulsion containing high concentrations of
lidocaine and prilocaine in base form resulted in EMLA (eutectic mixture of
local anesthetics), which has been shown to provide anesthesia of intact skin
profound enough to permit venipunture to be performed painlessly.
EMLA consists of a 5% cream containing 25mg/g lidocaine and
25mg/g prilocaine. It is applied to the skin for at least 1 hour before the
anticipated procedure. The cream is covered with an occlusive dressing.
Research has demonstrated the effectiveness of EMLA in many aspects of
pediatrics, including venepuncture, vaccination, suture removal, lumbar
puncture, minor otological surgery. It is also effective in minor
gynecological and ecological procedures, and dermatological surgery
including split-thickness, post herpetic neuralgia, debridement of infected
ulcers, and inhibition of itching and burning in adults.

The potential for toxic local anesthetic blood levels developing with EMLA
is minimal. Peak plasma anesthetic concentrations occurring 180 minutes
after application have been quite low. The use of EMLA in infants under the
age of 6 months is contraindicated because of the possibility of a metabolite
of prilocaine inducing methemoglobinemia. Adverse responses noted
included transient and mild skin bleeding and Erythema.
Several studies have reported on the intra-oral use of EMLA cream.
EMLA decreased patient reports of pain to needle insertion and anesthetic
administration significantly in both the greater palatine and nasopalatine
injection compared to placebo application. However, the use of EMLA in an
attempt to obtain Pulpal anesthesia has provided conflicting reports.

iv) pH alterations :
The administration of local anesthetics into skin and to a lesser
degree, oral mucous membranes is frequently uncomfortable. Though many
factors are involved in this including the speed of injection, volume of
solution, density of the tissues, and a lot of psychology, the acidic pH of the
anesthetic solution play a significant role in provoking discomfort during
local anesthetics injections. The pH of a “plain” local anesthetic solution is
approximately 5.5, whereas that of a vaso-presser-containing solution is
about 4.5. The addition of substance to the anesthetic that alkalinize the
solution should make the drugs administration more comfortable. in
addition, the anesthetic drug, at a higher pH, should have a more rapid onset
of action and greater potency.
Two strategies have been used to achieve this effect : the addition of
sodium bicarbonate to the anesthetic solution, and the addition of carbon
dioxide. Carbonation of local anesthetics is not really new, their use being
described as early as 1965.
The addition of sodium bicarbonate to a local anesthetic solution
immediately prior to injection alkalinizes the solution, increasing the
number of uncharged base molecules (RN). This uncharged ionic form is
lipid soluble and able to diffuse through the nerve membrane, a formulation
of lidocaine with epinephrine plus sodium bicarbonate (pH 7.2) provide a
more rapid onset of anesthetic block (onset = 2 min) than commercially
prepared pH 4.55) lidocaine plus epinephrine (onset = 5 min). However if
the pH of the solution is too high, local anesthetic will precipitate out as the
drug base, thereby decreasing their shelf life.
Alkalinization of epinephrine pre anesthetic solution proffers no
benefit. Recommendation for preparation of the local anesthetic with
bicarbonate after divided between part 4.2% bicarbonate with 10 parts local
anesthetic, and 1 part 8.4% bicarbonate in 5 parts local anesthetic.

Carbon dioxide enhances diffusion of local anesthetic through nerve
membranes, providing a more rapid onset of nerve block. As Co2 diffuses
through the nerve membrane, intracellular pH is decreased, raising the
intracellular concentration of charged cations (RNH+
), the form of
anesthetic that attaches to receptor site in sodium channels. Since the
cationic form of the drug does not readily diffuse out of the nerve, the
anesthetic becomes concentrated within the nerve trunk (termed “ion
trapping”, providing a longer duration of anesthesia.
The problem clinically has been that of the carbonated anesthetic
agent is not injected almost immediately after opening of the vial, the Co2
will diffuse out of solution, significantly diminishing the solution’s
effectiveness. The anesthetic drug must be administrated within a short time
after preparing the syringe.
v) Hyaluronidase :
hyaluronidase is an enzyme that breaks down intracellular cement. It
has been advocated as an additive to local anesthetics because if permits
injected solutions to spread and penetrate tissues.
The primary use of hyaluronidase has been in plastic surgery,
dermatology and ophthalmologic procedure, primarily in retero bulbar nerve
blocks, where it has been demonstrated to seep both the onset of anesthesia
and the area of anesthesia significantly when compared with non-
hyaluronidase containing anesthetic solutions. The duration of anesthesia is
slightly decreased when hyaluronidase is added, but the benefits associated
with its addition more than out weigh this minor inconvenience.
Hyaluronidase is available as hydase in a lyophilized powder, as well
as in a stabilized solution. It is added to the anesthetic cartridge just before

administration by removing approximately one third of the anesthetic
solution and refilling the cartridge with hyaluronidase.
Allergic reactions have been reported following hyaluronidase
administration.
vi) Ultra –long acting local anesthetics :
Tetradotoxin and saxitoxin are classified as biotoxins. Tetradotoxin is
found in puffer fish and saxitoxin is found in certain species of
dinoflagehlates. They specifically block the sodium channel on the outer
membranes surface and thus produce conduction blockade. Though these
agents are about 250,000 times as potent as procaine in providing
conduction blockade of isolated nerve preparations, they both are highly
toxic and will not pass readily through the epineurium surrounding
peripheral nerves; they therefore provide little or no conduction blockade of
the sciatic nerve. However, when administered via sub-arachnoid block in
sheep, they induced spinal anesthesia of almost 24 hours duration.
Unfortunately , there biotoxins are difficult to synthesize and are not very
stable in aqueous solutions, thereby significantly limiting their usefulness.
vii) Felypressin :
It is an analogue of vasopressin (the antidiuretic hormone), has been
available in dental local anesthetic cartridges in many European countries,
most often in combination with prilocaine. It is a direct stimulator of
vascular smooth muscle (primarily venous), having little direct effect on the
heart or on adrenergic nerve transmissions. It may be used safely in patients
in whom a medical problem (e.g., hypertension).
Hypothyroidism / contraindicates the administration of epinephrine.
Because it acts primarily on the venous circulation, felypressin is not as

effective as conventional vasoconstrictors in providing hemostasis during
surgical procedures. It is marketed under the trade name octapressin and is
used in concentration of 0.03 10/ml.
viii) Electronic dental anesthesia :
The use of electricity as a therapeutic modality in medicine and
dentistry is not new. The first recorded report of electrotherapy dates from
46 A.D., when Scribonius Largus, used the torpedo fish to relieve the pain
of gout.
The use of transcutaneous electrical nerve stimulation (TENS) and
more recently, its dental progeny, electronic dental anesthesia (EDA), has
developed since. The mid 1960’s into techniques that appear to have utility
in the battle against pain.
Mechanism of action :
At the low frequency setting of 2 Hz, which is most often used in the
management of chronic pain, TENS produces measurable changes in the
blood level of L-tryptophan, serotonin and β-endorphins. L-tryptophan, a
precursor of serotonin, is present in the blood in decreasing amounts as the
duration of TENS increased. By contract, serotonin levels in the blood
increase with times serotonin possesses analgesia actions, elevating the pain
reaction threshold. At the same time, levels of beta –endorphins and
enkephains in the cerebral circulation also increase, Beta-endorphin and
enkephalins are potent analgesics produced by the body in response to
certain types of stimulation. Because blood levels of serotonin end beta –
endorphins remain elevated for several horns following the terminated of

TENS therapy, patients benefit from this residual analgesic action in the
immediate post-treatment period.
In mechanism by which EDA operates to prevent acute pain during
surgery / dentistry is somewhat different. It is feet that the Melzack and wall
gate control theory of pain provides an adequate explanation for the
precaution of acute pain provided by EDA. Used at high frequency (120 Hz
or greater), EDA causes the patient to experience a sensation most often
described as “vibrating”, “throbbing”, “pulsing” or “twitching”. This
involves the stimulation of larger diameter (A fibers), which transmit the
sensations of touch, presence and temperature now, pain impulse which is
transmitted to the CNS along the smaller A-delta and C fibers, will come
upon a “closed” gate and be unable to reach the brain, where it is translated
into physical pain. Thus, larger-fiber is said to inhibit central transmission
of the overall effects of small-fiber input, when the pain impulse fails to
reach the brain, the sensation of pain does not occur.
Blood levels of serotonin and endorphins are likewise elevated during
high-frequency stimulation and probably play a secondary role in providing
acute pain control during most dental treatment.
Today TENS is an accepted treatment modality in the management of
an overgrowing variety of chronic pain disorders:
- Causalgia
- Phantom limb pain
- Post herpetic neuralgia
- Intractable cancer pain
- Lower back pain
- Spinal cord injury
- Ileus
- Peripheral nerve injury
- Bursitis

- Parturition
- Polycythemia vera
- Cervical back pain
- Post operative pain
- Diabetic ulceration.
The application of a low frequency electrical current to an area that
has recently been injured can be of benefit to the patient in two ways 
i) It acts to increase tissue perfusion produced capillary and
arteriolar dilation while stimulating the contraction of skeletal muscles.
The net effect of there two process is to provide a pumping action in the
area of application of the current.
Therapeutically, a 1-hour treatment at a low frequency (2.5 H2) helps
to decreased edema and the increased perfusion and skeletal muscle
stimulation act to “dense” the area of tissue injury breakdown products. This
spreads up the recovery process.
ii) A second benefit in the secondary from injury is the analgesic
action it possesses.
EDA Indications :
i) TMJ/MPD (chronic pain)
ii) Administration of local anesthesia
iii) Nonsurgical periodontal procedure
iv) Restorative dentistry
v) Fixed prosthodontic procedures
EDA Contraindications :
• Cardiac pacemakers
Acute pain

• Neurological disorders
- Status post – cerebrovascular accident
- History of transient ischemic attacks
- History of epilepsy
• Pregnancy
• Immaturity (in ability to understand) the concept of patient control of
pain)
- Very fond pediatric patient
- Older patients with senile dementia
- Language communication difficulties.
EDA advantages :
• No need for needle
• No need for injection of drug
• Patient is in control of the anesthesia
• No residual anesthetic effect at the end of procedure
• Residual analgesic effect remain for several hours
EDA disadvantages :
• Cost of the unit
• Training
• Learning curve  initial success may be low but will increase with
experience.
• Intra oral electrodes – weak link in the entire system.

CONTENTS
1) Introduction
2) Historical background
3) Definition
4) Ideal properties of L.A.
5) Pharmacology of LA.
- Classification
- Pharmacokinetics – uptake, distribution, metabolism excretion
- Individual drugs
6) Rating of drugs
- Safety

7) Anatomic consideration
- Structure of nerve fibers
- Schwann cells and myelin sheath
- Myelinated nerve fibers
- Anatomy of mixed nerve.
8) Physiologic considerations
- Electrophysiology of nerve conductive
- Electrochemistry of nerve conductive
- Impulse propagation
- Impulse spread
9) Mode and site of action of local anesthetic
- Mechanism of action
- Effect of pH
- Theories of L.A.
10) Kinetics of L.A.
- Diffusion, absorption, redistribution, elimination
- Reinjection
11) Potentiation of action of local anesthetics- vasoconstrictors
12) Surgical consideration
- Pre block evaluation
- Asepsis
- Skin preparation
13) Recent advances and future trends in pain control
14) References

REFERENCES
1. Principles of anesthesiology, 3rd edition, vol- 2, Vincent J. Collins
2. Local anesthesia- mechanism of action and clinical use- Benjamin G
Cohino
3. Handbook of local anesthesia, 5th edition, Stanley F. Malamed
4. Monehim”s local anesthesia and pain control, Benett
5. Current trends in pain research and therapy, Vol 4, chronic pain
reactions, mechanism and modes of therapy
6. Local anesthesia- M. L. Kuzin

7. DCNA- Local anesthetics reviewed,46 (4), 2002
DEPARTMENT OF ORAL, MAXILLOFACIAL AND
RECONSTRUCTIVE SURGERY
BAPUJI DENTAL COLLEGE AND HOSPITAL,
DAVANGERE

SEMINAR
ON
CPR
MODERATOR CHANDRA

DEPARTMENT OF ORAL MAXILLOFACIAL AND
RECONSTRUCTIVE SURGERY
BAPUJI DENTAL COLLEGE AND HOSPITAL,
DAVANGERE
LOCAL ANESTHESIA: DEFINITION,
NEUROPHYSIOLOGY, MODE OF ACTION

MODERATOR PRESENTER
DR. DAYANAND M.C. DR. LOKESHCHANDRA

Local anesthesia final

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Viewers also liked

Viewers also liked (20)

Similar to Local anesthesia final

Similar to Local anesthesia final (20)

More from Indian dental academy

More from Indian dental academy (20)

Recently uploaded

Recently uploaded (20)

Local anesthesia final