COMPOSITION

PROPERTIES
&
MECHANISM OF LOCAL ANESTHETICS

DR.SIDDHARTH DHANARAJ
ORAL & MAXILLOFACIAL SURGEON

DEFINITION
Local anesthesia has been
defined as a loss of sensation in
a circumscribed area of the body
caused by a depression of
excitation in nerve endings in
peripheral nerves.
An important feature of local anesthesia is
that it produces : loss of sensation without
producing loss of consciousness

Definition :
Drugs that cause reversible loss of sensory
perception specially of pain in a restricted
area of the body, when applied topically or
local injection.
LA if applied to a mixed nervesensory and
motor impulses are interruptedresulting in
muscular paralysis and loss of autonomic
control.

Action of local
anesthetic
The concept
They prevent both
the generation and
the conduction of a
nerve impulse.
It sets up a chemical
roadblock between
the source of impulse
(e.g. the scalpel
incision in soft
tissues) and the

Historicalbackground
COCAINE -first local anesthetic agent-isolated
by Nieman -1860 -from the leaves of the coca
tree.
Its anesthetic action was demonstrated by
Karl Koller in 1884.
First effective and widely used synthetic local
anesthetic -PROCAINE -produced by Einhorn in
1905 from benzoic acid and diethyl amino
ethanol.
8

It anesthetic properties were identified by Biberfield

and the agent was introduced into clinical practice by
Braun.
LIDOCAINE- Lofgren in 1948.
The discovery of its anesthetic properties was followed
in 1949 by its clinical use by T. Gordh

PROPERTIESOFLOCAL
ANESTHESIA
I==It should not be irritating to tissue to which it
is applied
N==It should not cause any permanent alteration
of nerve structure
S==Its systemic toxicity should be low
T==Time of onset of anesthesia should be short
E== It should be effective regardless of whether
it is injected into the tissue or applied locally to
mucous membranes
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D==The duration of action
should be long

It should have the potency sufficient to give complete

anesthesia with out the use of harmful concentration
solutions

It should be free from producing allergic reactions

It should be free in solution and relatively undergo
biotransformation in the body

It should be either sterile or be capable of being

sterilized by heat with out deterioration.
11

ELETROPHYSIOLOGYOF
NERVECONDUCTION

There is an electrical charge across the membrane.

This is the membrane potential.
The resting potential (when the cell is not firing) is a
negative electrical potential of -70mv that exists
across the nerve membrane, produced by different
concentrations of either side of the membrane.
The interior of nerve is NEGATIVE in relation to exterior.
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ActionPotentials
At rest: Na+& K+ channels closed. -70mV
Fibre stimulated: Na+channel opens, Na+ enters
cell. Potential rising
Cell depolarised, Na+ channel closes. +20mV
K+ channel opens, K+ exits cell, potential falling
Fibre repolarised, Na+& K+ channels closed. Na/K
pump restores balance. -70mV
Result is a voltage gradient along axon, causing a
current. This causes configurational change in Nachannels in the next segmentconduction
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SLOWDEPOLARIRIZATION

RAPIDDEPOLARIZATION:

TheinteriorofnerveisPOSITIVEinrelationtoexterior.
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REPOLARIZATION:
.

SODIUM PUMP
energy comes from the
oxidative metabolism of ATP
Depolarization takes 0.3 msec
Repolarization takes 0.7 msec
The

entire process require 1 msec

15

MYLINATEDNERVES:
Impulse conduction in myelinated nerves occurs
by means of current leaps from nodes to node
this process is called as SALTATORY
CONDUCTION.
It is more rapid in thicker nerves because of
increase in thickness of myelin sheath and
increase in distance between adjacent NODES
OF RANVIER.
If conduction of impulse is blocked at one node
the local current will skip over that node and
prove adequate to raise that membrane
potential at next node to its firing potential and
produce depolarization.
Conduction rate of myelinated fibers is 120m/sec.
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What about Myelinated Nerve Fibers ?

Conduction rate comparison

C fiber is 1.2 m/sec

A- and A-deltaup to 120

m/sec

IMPULSEPROPOGATION
IMPULSE SPREAD
The propagated impulse travels along the nerve
membrane towards CNS. The spread of impulse
differs in myelinated and unmyelinated nerve fibers.

UNMYELINATED NERVES: The high resistance cell

membrane and extra cellular media produce a rapid
decrease in density of current with in a short
distance of depolarized segment.
The spread of the impulse is characterized as a slow
forward-creeping process.

THEORIESMECHANISMOF
ACTIONOFLOCALANESTHETICS
Many theories have been promulgated
over the years to explain the mechanism
of action of local anesthetics.
ACETYLECHOLINE THEORY: Stated that
acetylcholine was involved in nerve
conduction in addition to its role as a
neurotransmitter at nerve synapses.
There is no evidence that acetylcholine is
involved in neural transmission.
20

CALCIUMDISPLACEMENTTHEORY:

States that local anesthetic nerve block was produced

by displacement of calcium from some membrane site
that controlled permeability of sodium.

21

SURFACECHARGE(REPULSION)THEORY:
Proposed that local anesthetic acted by binding to nerve
membrane and changing the electrical potential at the
membrane surface. Cationic drug molecule were aligned at
the membrane water interface, and since some of the local
anesthetic molecule carried a net positive charge, they
made the electrical potential at the membrane surface
more positive, thus decreasing the excitability of
nerve by increasing the threshold potential. Current
evidence indicate that resting potential of nerve
membrane is unaltered by local
anesthetic.
22

MEMBRANEEXPANSIONTHEORY

It states that local anesthetic molecule diffuse to

hydrophobic regions of excitable membranes,

producing a general disturbance of bulk membrane
structure, expanding membrane, and thus preventing
an increase in permeability to sodium ions. Lipid
soluble LA can easily penetrate the lipid portion of cell
membrane changing the configuration of lipoprotein
matrix of nerve membrane. This results in decreased
diameter of sodium channel, which leads to inhibition
of sodium conduction and neural excitation.
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MEMBRANEEXPANSIONTHEORY

24

SPECIFICRECEPTORTHEORY:

The most favored today, proposed that local

anesthetics act by binding to specific receptors on

sodium channel the action of the drug is direct, not
mediated by some change in general properties of
cell membrane. Biochemical and electrophysiological
studies have indicated that specific receptor sites for
local anesthetic agents exists in sodium channel
either on its external surface or on internal
axoplasmic surface. Once the LA has gained access to
receptors, permeability to sodium ion is decreased or
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eliminated and nerve conduction
is interrupted.

CLASSIFICATIONOFLOCALANESTHETIC
SUBSTANCESACCORDINGTOBIOLOGICALSITE
ANDMODEOFACTION
CLASS A: Agents acting at receptor site on external
surface of nerve membrane
Chemical substance: Biotoxins (e.g., tetrodotoxin and
saxitoxin)

CLASS B: Agents acting on receptor sites on internal

surface of nerve membrane
Chemical substance: Quaternary ammonium analogues
of lidocaine, scorpion venom
26

CLASS C: Agents acting by receptor independent of

physiochemical mechanism
Chemical substance: Benzocaine

CLASS D: Agents acting by combination of receptors

and receptor independent mechanisms
Chemical substance: most clinically useful anesthetic
agents (e.g., lidocaine, mepivacaine, prilocaine)

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BASED ON THE SOURCE

NATUAL

SYNTHETIC
OTHERS
BASED ON MODE OF APPLICATION
INJECTABLE
TOPICAL
BASED ON DURATION OF ACTION
ULTRA SHORT
SHORT
INTERMEDIATE
LONG

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Local anesthetics
Esters
Esters of
benzoic
acid

Butacaine
Cocaine
Benzocaine
Hedylcaine
Piperocain
e
Tetracaine.

Esters of
paraaminobenzoic
acid

Chloroprocain
e
Procaine
propoxycaine

Amides
Articaine
Bupivacain
e
Dibucaine
Etidocaine
Lidocaine
Mepivacain
e
prilocaine

Quinoline

centbucridine

If the local anesthetic has two is

in its name; its an amide
Lidocaine
Prilocaine
Bupivacaine
Articaine
Mepivacaine

Differences
ESTERS
Short duration of action
Less intense analgesia
Higher risk of hypersensitivity
ESTER linked LA s are rarely
used.
Hydrolyzed by Plasma
Cholinesterase in blood.
Rarely used for Infiltration
anesthesia
But useful for topical ana on
mucous membranes.

AM IDE S
Produce more intense and
longer lasting ana.
Bind to alpha1 acid
glycoprotein in plasma
Not hydrolyzed by Plasma
Cholinesterase, but in liver

Rarely cause hypersensitivity

reactions- no cross reactivity
with ESTER L A s.

Drug should reach Nerve through tissue

Hydrophilic
Drug should enter Neuron ( Nerve )
Lipophilic

DISSOCIATIONOFLOCALANESTHETICS
Local anesthetics are available as salts (usually
hydrochlorides) for clinical use.
The salts, both water soluble and stable, is
dissolved in either sterile water or saline.
In this solution it exists simultaneously as
unchanged molecule (RN), also called base and
positively charged molecules (RNH+) called cations.

RNH+ ==== RN+ H+

33

 The relative concentration of each ionic form in the

solution varies in the pH of the solution or surrounding
tissue.
In the presence of high concentration of hydrogen ion
(low pH) the equilibrium shifts to left and most of the
anesthetic solution exists in cationic form.

RNH+ > RN+ + H+

As hydrogen ion concentration decreases (higher pH)
the equilibrium shifts towards the free base form.

RNH+ <34 RN + H+

The relative proportion of ionic form also depends on pKa or

DISSOCIATION CONSTANT, of the specific local anesthetic.
The pKa is a measure of molecules affinity for H + ions.
When the pH of the solution has the same value as pKa of the local
anesthetic, exactly half the drug will exists in the RNH + form and
exactly half in RN form.
The percentage of drug existing in either form can be determined by
Henderson Hasselbalch equation
Log

base/acid = pH - pKa

35

 Henderson hasselbach equation Determines

how much of a local anesthetic will be in a nonionized vs ionized form . Based on tissue pH and
anesthetic Pka .
Injectable local anesthetics are weak bases
(pka=7.5-9.5) When a local anesthetic is
injected into tissue it is neutralized and part of
the ionized form is converted to non-ionized The
non-ionized base is what diffuses into the nerve.

36

 Hence if the tissue is infected, the pH is lower

(more acidic) and according to the HH equation;
there will be less of the non-ionized form of the
drug to cross into the nerve (rendering the LA
less effective)
Once some of the drug does cross; the pH in the
nerve will be normal and therefore the LA reequilibrates to both the ionized and nonionized
forms; but there are fewer cations which may
cause incomplete anesthesia.

37

MODEANDSITEOFACTIONOF
LOCALANESTHETICS
Local anesthetic agent interferes with excitation
process in a nerve membrane in one of the
following ways:

Altering the basic resting potential of nerve

membrane

Altering the threshold potential

Decreasing the rate of depolarization
Prolonging the rate of repolarization
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MECHANISMOFACTIONOFLOCAL
ANESTHETICS
The following sequence is proposed mechanism of
action of LA:

Displacement of calcium ions from the sodium

channel receptor site

Binding of local anesthetic molecule to this

receptor site

Blockade of sodium channel

39

Decrease in sodium conductance

Depression of rate of electrical depolarization
Failure to achieve the threshold potential level
Lack of development of propagated action
potential

Conduction blockade
40

Na + Na +
Na + Na +

THE
CARTRIDGE

Components of the
Cartridge

The 1.8 ml dental cartridge consists of four parts:

1) Cylindrical glass tube
2) Stopper (Plunger, Bung)
3) Aluminum Cap
4) Diaphragm
Carpule = registered trade name for the dental
cartridge introduced by Cooke-Waite laboratories
in 1920

Bubble In The Cartridge: 1-2 mm bubble can be

found in the cartridge which is nitrogen gas that
is inserted into the cartridge when it is sealed to
keep oxygen out; avoids oxygen oxidizing the
vasopressor

Extruded Stopper: liquid was frozen at some

point leading to extrusion sterile environment of
the solution can no longer be guaranteed; it
only takes one day for alcohol to diffuse through
the diaphragm; alcohol is neurolytic and can

Syringe
Components
1.) Needle adapter
2.) Piston with
harpoon
3.) Syringe barrel
4.) Finger grip
5.) Thumb ring
49

 American Dental Association (ADA) criteria for

acceptance of LA syringes:
1-Durable and re-sterilzable or packaged in a sterile
container (if disposable).
2-Accept a wide variety of cartridges and needles of
different manufactures (universal use)
3-Inexpensive, light weight, and simple to use with one
hand.
4-Provide effective aspiration and the blood be easily
observed in the cartridge. The incidence of positive
aspiration may be as high as 10%-15% in some injection
techniques.

50

Needle
The Needle Gauge: the larger the gauge the
smaller the internal diameter of the needle
Usual dental needle gauges are 25,27, & 30
Length:
1-Long(approximately 40 mm "32-40 mm"), for
NB.
2-Short(20-25 mm).
3-Extra-short(approximately 15 mm), for PDL.

51

Componentsofneedle

52

COMERCIALLYPREPAREDLOCALANESTHESIA
CONSISTSOF:

Local anesthetic agent (xylocaine,

lignocaine 2%)
Vasoconstrictor (adrenaline 1: 80,000)
Reducing agent (sodium metabisulphite)
Preservative (methylparaben,capryl
hydrocuprienotoxin)
Fungicide (thymol)

53

REDUCINGAGENT
Vasoconstrictors are unstable in solution and
may oxidize especially on prolong exposure to
sunlight this results in turning of the solution
brown and this discoloration is an indication
that such a solution must be discarded.
To overcome this problem a small quantity of
sodium metabisulphite is added - competes
for the available oxygen.
SHELF LIFE INCREASES
54

PRESERVATIVE
Modern local anesthetic solution are very
stable and often have a shelf of two years
or more. Their sterility is maintained by the
inclusion of small amount of a preservative
such as capryl hydrocuprienotoxin.
Some preservative such as methylparaben
have been shown to allergic reaction in
sensitized subjects.

55

FUNGICIDE
In the past some solutions tended to
become cloudy due to the proliferation of
minute fungi.

In several modern solutions a small quantity

of thymol is added to serve as fungicide and
prevent this occurrence.

56

VEHICLE
The anesthetic agent and the additives
referred to above are dissolved in distilled
water & sodium chloride.
This isotonic solution minimizes discomfort
during injection.

57

Cartridge Contents

Local anesthetic drug is the main player !!

Calculation of mg of drug in the cartridge

Example:

2% lidocaine in a cartridge

(1.7ml)
2% = 20mg/ml
and we have 1.7ml so
20 mg/ml
X 1.7 ml= 34 mg
this means we have 34mg of lidocaine in a cartridge

How about 3% Mepivacaine in a cartridge

3% = 30mg/ml
and we have 1.7ml so

ans: 51mg

Dilution of
Vasoconstrictors

Dilution is commonly referred to as ratio

Example, 1 to 1000 [1:1000]

Concentration of 1:1000 means

1gram (1000mg) of solute (drug) in 1000ml solution

So 1000mg / 1000ml = 1.0mg/ml of solution

Questions:
1:100,000 dilution.... whats the concentration in (mg/ml)
Again, 1 here mean 1000mg

1000mg / 100,000 = 0.01 mg/ml or 10 mcgm/ml

1:200,000 dilution.... whats the answer in mg/ml
- Answer is 5 mcgm/ml or 0.005mg/ml

you got it, Right?

Since you did it so good.. If you have 1.7ml solution of the

1:100,000
dilution of epi.. How much epi is there?

PHARMACOKINETICSOFLOCAL
UPTAKE:

ANESTHETICS

When injected into soft tissue most local anesthetics

produce dilation of vascular bed.
Cocaine is the only local anesthetic that produces
vasoconstriction, initially it produces vasodilation
which is followed by prolonged vasoconstriction.
Vasodilation is due to increase in the rate of
absorption of the local anesthetic into the blood, thus
decreasing the duration of pain control while
increasing the anesthetic 60blood level and potential for

The blood level is influenced by the following

factors:
Rate of absorption into the blood stream.
Rate of distribution of the agent from the
vascular compartment to the tissues.
Elimination of drug through metabolic and/or
excretory pathways.
All local anesthetic agents readily cross the
blood-brain barrier, they also readily cross the
placenta.

61

METABOLISM(BIOTRANSFORMATION)
ESTER LOCAL ANESTHETICS:
Ester local anesthetics are hydrolyzed in the plasma by the enzyme pseudocholinesterase.
Chloroprocaine the most rapidly hydrolyzed, is the least toxic.
Tertracaine hydrolyzed 16 times more slowly than Chloroprocaine ,hence it has the greatest potential
toxicity
.

62

AMIDELOCALANESTHETICS

The metabolism of amide local anesthetics is more

complicated then esters. The primary site of
biotransformation of amide drugs is liver.
Entire metabolic process occurs in the liver for
lidocaine, articaine, etidocaine, and bupivacaine.
Prilocaine undergoes more rapid biotransformation
then the other amides.

63

EXCRETION

Kidneys are the primary excretory organs for both the local
anesthetic and its metabolites
A percentage of given dose of local anesthetic drug is
excreted unchanged in the urine.
Esters appear in only very small concentration as the parent
compound in urine.
Procaine appears in the urine as PABA (90%) and 2%
unchanged.
10% of cocaine dose is found in the urine unchanged.
Amides are present in the urine as a parent compound in a
greater percentage then are esters.
64

Mepivacaine

Potency: similar to lidocaine

Metabolism: Liver
Onset of action: Rapid (1.5 to 2
mins)
Anesthetic t : 1.9 hours
Maximum Recommended Dose
(MRD):
4.4mg/kg
Absolute maximum 300mg
5.5 cartridges will be maximum # used

on a patient.

Mepivacaine

Mild vasodilating properties

Longer duration vs other agent w/o vasoconstrictor

3% Mepivacaine plain provides

20-40 mins pulpal anesthesia

2-3 hours soft tissue anesthesia

Indication:
When vasoconstrictor is NOT indicated
Most often used in pediatric / geriatric patient

Types
3% without vasoconstrictor (MCG: Carbocaine)
2% with vasoconstrictor ( Levonodefrin )

Types of
Vasoconstrictors

Natural catecholamines
Epinephrine
Norepinephrine

Dopamine

Synthetic catecholamines
Isoproterenol
Levonordefrin

Non-catecholamines
Amphetamine,

Ephedrine,Methamphetamine

REFERENCES
HANDBOOK OF LOCAL ANESTHESIABY STANLEY F.MALAMED. 6TH EDTN.
LOCAL ANESTHESIA IN DENTISTRY
J.A.BAART & H.S.BRAND.