LOCAL ANESTHESIA

DR.ALANGKAR SAHA1st YEAR P.G STUDENTOMFS,SSDC

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Contents….

Introduction Historical background

NEUROPHISIOLOGY--->Definition>Methods of inducing local anesthesia>Desirable properties>Structure of neuron>Configuration of biologic membrane>Myelinated and unmyelinated nerve

fiber

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>Electrophysiology of nerve conduction>Impulse propagation and spread

>Classification of local anesthetic according to biological site and mode of

>Theories of mechanism of action of local anesthesia>Dissociation of local anesthesia>Mode and site of action of local anesthesia

>Mechanism of action of local anesthesia

action

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Historical background

• 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.

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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

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DEFINITION: Local anesthesia is 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

An important feature of local anesthesia is that it produces:

LOSS OF SENSATION WITHOUT INDUCING LOSS OF CONSCIOUSNESS..

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METHODS OF INDUCING LOCAL ANESTHESIA:

Low temperatureMechanical traumaAnoxiaNeurolytic agents such as alcohol &

phenolChemical agents such as local

anesthetics

ACT N

PROPERTIES OF LOCAL 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 lowT==Time of onset of anesthesia should be

shortE== It should be effective regardless of

whether it is injected into the tissue or applied locally to mucous membranes

D==The duration of action should be long enough to permit the completion of procedure9/7/2012 INSTED

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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.

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BASIC STRUCTURE OF NEURON:

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CONFIGRATION OF BIOLOGIC MEMBRANE

Axoplasm (neural cytoplasm) is separated from extra cellular fluids by continuous nerve membrane.

Nerve membrane is 70 to 80 A0 thick.

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HETEROGENEOUS LIPOPROTEIN MEMBRANE

The membrane is flexible nonstretchable structure consisting of two layers of lipid molecules, associated proteins and carbohydrates.

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MYELINATED NERVE FIBRE

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It is enclosed in spirally wrapped layer of lipoprotein myelin sheaths.

These are specialized form of schwann cells.

Myelin sheath consists of 75% lipid,

20% protein and 5% carbohydrate.

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UNMYELINATED NERVE FIBERS

These nerve fibers are also surrounded by schwann cell sheath

Groups of unmyelinated nerve fibers share the same sheath.

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ELETROPHYSIOLOGY OF NERVE CONDUCTION

RESTING POTENTIAL: This 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.

Intracelluar And Extracelluar

Ion Concentration

ION INTRACELLUAR EXTRACELLULAR RATIO

Potassium 110 to 170 3 to 5 27:1

Sodium 5 to 10 140 1:14

Chloride 5 to 10 110 1:11

SLOW DEPOLARIRIZATION

RAPID DEPOLARIZATION:

The interior of nerve is POSITIVE in relation to exterior.

REPOLARIZATION: .

depolarization takes 0.3 msec

repolarization takes 0.7 msec

SODIUM PUMPenergy comes from the

oxidative metabolism of ATP

The entire process require 1 msec

IMPULSE PROPOGATION

IMPULSE SPREADThe 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.Conduction rate is 1.2m/sec C

DEPOLARIZED SEGMENT ADJACENT RESTING AREA

MYLINATED NERVES:

Impulse conduction in myelinated nerves occurs by means of current leaps from nodes to node this process is called as SALTATORY CONDUCTION. A

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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MODE AND SITE OF ACTION OF LOCAL ANESTHETICS

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 depolarizationProlonging the rate of repolarization

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THEORIES MECHANISM OF ACTION OF LOCAL

ANESTHETICSMany 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.

CALCIUM DISPLACEMENT THEORY:

States that local anesthetic nerve block was produced by displacement of calcium from some membrane site that controlled permeability of sodium.

SURFACE CHARGE (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.

MEMBRANE EXPANSION THEORYIt 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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MEMBRANE EXPANSION THEORYClick icon to add picture

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SPECIFIC RECEPTOR THEORY: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 eliminated and nerve conduction is interrupted.

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SPECIFIC RECEPTOR THEORYClick icon to add picture

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CLASSIFICATION OF LOCAL ANESTHETIC SUBSTANCES

ACCORDING TO BIOLOGICAL SITE AND MODE OF ACTION

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

CLASS C: Agents acting by receptor indipendent 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• MEDIEM• LONG9/7/2012 SSDC,OMFS

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BASED ON ONSET OF ACTION• SHORT• INTERMEDIATE• LONG

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DISSOCIATION OF LOCAL ANESTHETICS

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+

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+ < 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

MECHANISM OF ACTION OF LOCAL 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

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…

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Local anesthetic agent

Classification Contents Uptake Distribution Metabolism Excretion Clinical action of specific agents Anesthetics for topical application Clinical manifestation of local

anesthetic overdose

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COMERCIALLY PREPARED LOCAL ANESTHESIA CONSISTS OF:

Local anesthetic agent (xylocaine, lignocaine 2%)

Vasoconstrictor (adrenaline 1: 80,000)

Reducing agent (sodium metabisulphite)

Preservative (methylparaben,capryl hydrocuprienotoxin)

Fungicide (thymol)vehicle (distillde

water,NACL)

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REDUCING AGENT

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 INCRESES 9/7/2012

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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.

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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.

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VEHICLE

The anesthetic agent and the additives referred to above are dissolved in distilled water & sodium chloride.

This isotonic solution minimizes discomfort during injection.

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. The chemical characteristics are so balanced that they have both lipophilic and hydrophilic properties. If hydrophilic group predominates, the

ability to diffuse into lipid rich nerves is diminished. If the molecule is too lipophilic it is of little clinical value as an injectable anesthetic, since it is insoluble in water and unable to diffuse through interstitial tissue.

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LOCAL ANESTHETIC AGENT

The local anesthetics used in dentistry are divided into two groups:

ESTER GROUP

AMIDE GROUP

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ESTER GROUP:It is composed of the followingAn aromatic lipophilic groupAn intermediate chain containing an ester linkageA hydrophilic secondary or tertiary amino group

AMIDE GROUP:It is composed of the followingAn aromatic, lipophilic groupAn intermediate chain containing amide linkageA hydrophilic secondary or tertiary amino group

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CLASSIFICATION OF LOCAL ANESTHETICS

ESTERS

Esters of benzoic acidButacaine

Cocaine

Benzocaine

Hexylcaine

Piperocaine

Tetracaine

Esters of Para-amino benzoic acid

Chloroprocain

Procaine

Propoxycaine

bd(t)ch p

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AMIDES

Articaine

Bupivacaine

Dibucaine

Etidocaine

Lidocaine

Mepivacaine

Prilocaine

Ropivacaine

QUINOLINE

Centbucridine

ABCDE LMPR

PHARMACOKINETICS OF LOCAL ANESTHETICS

UPTAKE: 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 blood level and potential for

over dose.

ORAL ROUTE:

Except cocaine, local anesthetics are poorly absorbed from GIT

Most local anesthetics undergo hepatic first-pass effect following oral administration.

72% of dose is biotransformed into inactive metabolites

TOCAINIDE HYDROCHLORIDE an analogue of lidocaine is effective orally

TOPICAL ROUTE:

Local anesthetics are absorbed at different

rates after application to mucous

membranes, in the tracheal mucosa

uptake is as rapid as with intravenous

administration.

In pharyngeal mucosa uptake is slow

In bladder mucosa uptake is even slower

Eutectic mixture of local anesthesia (EMLA)

has been developed to provide surface

anesthesia for intact skin.

INJECTION:

The rate of uptake of local anesthetics after injection is related to both the vascularity of the injection site and the vasoactivity of the drug.

IV administration of local anesthetics provide the most rapid elevation of blood levels and is used for primary treatment of ventricular dysrhythmias.

RATES AT WHICH LOCAL ANESTHETICS ARE ABSORBED AND REACH THEIR PEEK BLOOD LEVEL

ROUTE TIME TO PEAK LEVEL (MIN)

INTRAVENOUS 1TOPICAL 5

INTRAMUSCULAR 5-10

SUBCUTANEOUS 30 - 90

DISTRIBUTION

Once absorbed in the blood stream local

anesthetics are distributed through out

the body to all tissues.

Highly perfused organs such as brain,

head, liver, kidney, lungs have higher

blood levels of anesthetic than do less

higher perfused organs.

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.

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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 then Chloroprocaine has the greatest potential toxicity.

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AMIDE LOCAL ANESTHETICS:

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.

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EXCREATIONKidneys 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 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.

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CLINICAL ACTION OF SPECIFIC AGENT

PROCAINE:

Classification: ester

Chemical formula: 2diethyleaminoethyl 4aminobenzoate hydrochloride.

Metabolism: hydrolyzed rapidly in plasma by plasma pseudocholinesterase

Excretion: more then 2% unchanged in urine(90% as PABA, 8% as diethyleaminoethanol).

Vasodilating properties: produces the greatest vasodilation of all currently used local anesthetics.

pKa : 9.1

pH of plain solution: 5 to 6.5

pH of vasoconstrictor-containing solution: 3.5 to 5.5

Onset of action: 6 to 10 min

Effective dental concentration: 2% to 4%

Anesthetic half-life: 0.1 hour

Topical anesthetic action: not in clinically acceptable concentration

LIDOCAINE

Classification: Amide

Chemical formula: 2diethyleamino2,6acetoxyldidehydrochloride

Metabolism: in the liver by the microsomol fixed function oxidases, to monoethylglyceine and xylidide.

Excretion: via kidneys; less than 10% unchanged, more than 80% various metabolites

Vasodilating properties: considerably less than those of procaine; however, more than those of Prilocaine or mepivacane

pKa : 7.9pH of plain solution: 6.5pH with vasoconstrictor: 5.0 to 5.5Onset of action : 2 to 3 min Effective dental concentration : 2%Anesthetic half life: 1.6 hoursTopical anesthetic action: yes, acceptable

concentration 5%Maximum recommended dose: with

adrenaline 7.0 mg/kg body weight not to exceed 500 mg. with out adrenaline 4.4mg/kg not to exceed 300mg

Lidocaine is available in three formulations:- 2% with out vasoconstrictor, 2% with epinephrine 1:50,000 and 2% with epinephrine 1: 100,000

Plain lidocaine with out a vasoconstrictor has a Vasodilating effect that limit pulpal anesthesia to only 5 to 10 min

2% lidocaine with epinephrine 1:50,000 causes a decrease in blood flow to the injection, appx 60 min of pulpal anesthesia and 3 to 5 hrs of soft tissue anesthesia is achieved.

The epinephrine dilution is 0.02 mg/ml of solution or 0.036mg per cartridge.

MEPIVACAINE

Classification: AMIDE

Chemical formula: 1methyle

2’,6’pipecoloxylidide hydrochloride

Metabolism: in the liver by microsomol

fixed function oxidases.

Excretion: via kidneys appox 1% to 16%

of anesthetic dose is excreted unchanged

Vasodilating properties: produces slight

vasodilation

pKa : 7.6

pH of plain solution: 4.5

pH with vasoconstrictor: 3.0 to 3.5

Onset of action : 1.5to 2 min

Effective dental concentration : 2%with vasoconstrictor, 3% with

Out vasoconstrictor

Anesthetic half life: 1.9 hours

Topical anesthetic action: not in clinically acceptable concentration

Maximum recommended dose: with adrenaline 6.6mg/kg body weight not to exceed 400 mg.

BUPIVACAINE:

Classification: AMIDE

Chemical formula: 1butyl

2’,6’pipecoloxydide hydrochloride

Metabolism: in the liver by amidases

Excretion: via kidneys 16% of anesthetic

dose is excreted unchanged

Vasodilating properties: greater then

lidocaine, Prilocaine and mepivacane, less then procaine

pKa : 8.1

pH of plain solution: 4.5 to 6

pH with vasoconstrictor: 3.0 to 4.5

Onset of action : 6 to 10 min

Effective dental concentration : 0.5%

Anesthetic half life: 2.7 hours

Topical anesthetic action: not in clinically acceptable concentration

Maximum recommended dose: with adrenaline 1.3mg/kg body weight not to exceed 90 mg.

ANESTHETIC FOR TOPICAL APPLICATION

BENZOCAINE:

Poor soluble in water

Not suitable for injection

Localized allergic reaction may occur following prolonged and repeated use

Reported to inhibit the antibacterial action of sulfonamides

LIDOCAINE:

Is available in two forms for topical application lidocaine base and lidocaine hydrochloride.

LIDOCAINE BASE: Which is poorly soluble in water used in 5% concentration indicated in ulcerated abraded or lacerated tissue.

LIDOCAINE HYDROCHLORIDE: which is available as a water soluble preparation used in 2% concentration

Penetrates tissue more efficiently then base form

Greater risk of toxicity then base form.

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Eutectic mixture of local anesthesia (EMLA)

surface anesthesia for intact skin.

CLINICAL MANIFESTATION OF LOCAL ANESTHETIC OVERDOSE

SIGNS:LOW TO MODERATE OVERDOSE LEVELS: Confusion Talkativeness Apprehension Excitedness Slurred speech Generalized stutter Muscular twitching, tremor of face and

extremities Elevated BP, heart rate and respiratory

rate

MODERATE TO HIGH BLOOD LEVELS: Generalized tonic clonic seizure, followed

by Generalized CNS depression Depressed BP, heart rate and respiratory

rate

SYMPTOMS: Headache Light headedness Auditory distrurbances Dizziness Blurred vision Numbness of tongue and perioral tissues Loss of consciousness

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