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 mol/ml/hr), is the least toxic, where a tetracaine,

hydrolyzed 16 times more slowly than chloroprocaine (0.3 mol/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 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.

Facilities:

1Toxicity

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 Extracellular Ratio

(MEQ/L) (MEQ/L)

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

Depression of the rate of electrical depolarization

Log Base Acid

= pH – pKa

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

Natural

Mephetermine

Metaraminol

Phenyl ephrine

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 :

Non catecolamines

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.

Alpha ()

Beta ()

Activation of receptors causes vasoconstriction.

1 excitatory – post synaptic

2 inhibitary – post synaptic.

Activation of receptors produces smooth muscle relaxation (vasodilation

and brondiodilation) and cardiac stimulation (increased heart rate and

strength of contractions).

1 Found in heart and small intestines and are responsible for cardiac

stimulation and lipolysis

2 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 -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

Health & Medicine

local toxicity

local anesthetic drug

local anesthetic i

local anesthetic solution

synthetic local anesthetic

introduction local anesthesia

definition local anesthesia

malamed local anesthetic