La Advanced

LOCAL ANAESTHESIA

Presenter Dr PUNEET SINGH Moderator Prof. S RamkumarDate 18.12.09

L/O/G/O Contents

1. HISTORY2. NERVE CONDUCTION 3. THEORIES OF LA ACTION4. TOPICAL ANESTHETIC AGENTS5. INJECTABLE LA AGENTS6. VASOCONSTRICTORS7. INDICATIONS AND

CONTRAINDICATIONS OF LA8. COMPLICATIONS OF LA9. REFERENCES

HISTORY• The word ‘anesthesia’ is derived

from Greek language• The word ‘an’ means without and

‘aisthetos’ means sensation• The word was coined by Dr Oliver

Wendell Holmes in 1846.• ‘Anesthesia’ means loss of all forms

of sensation including pain , touch , temperature and pressure perception

• Analgesia means loss of sensation unaccompanied by loss of other forms sensation

• Regional analgesia refers to loss of pain sensation over a specific part of the body without loss of consciousness

• Regional anesthesia denotes loss of sensation as well as other forms of sensation

HISTORY

YEAR ESTERS AMIDES DISCOVERER1905 Procaine Alfred Einhorn1943 Lidocaine Nills Lofgren1952 Propoxycaine Clinton and

Laskowsky1953 Prilocaine Lofgren and

Tegner1956-57 Mepivacaine AF Ekenstam1957 Bupivacaine AF Ekenstam1969 Articaine H Rusching et

al1971 Etidocaine Takman

TIMEWISE DEVELOPMENT OF VARIOUS LOCAL ANESTHETICS

• Local anesthesia is defined as loss of sensation in a circumscribed area of the body caused by :

1. A depression of excitation in nerve endings

2. An inhibition of conduction process in the peripheral nerves , without the loss of consciousness

DEFINITION

NERVE CONDUCTION

Nerve structure

CLASSIFICATON OF NERVE FIBRES

Sensory Neuron• It transmits sensation of pain

• 3 major portions:

• Dendritic zone• Axon• Cell body and axoplasm

Nerve cell membrane

• Thickness : the thickness of a nerve fiber is 70 to 80 angstrom

• Structure : it consists of two layers of lipid molecules and associated proteins , lipids , carbohydrates.

• Proteins : two types a. Transport proteins b. Receptor sites

• Types of nerve fibers a. Myelinated nerve fibers b. Unmyelinated nerve

fibers

• Action potential It is the transient membrane

depolarization that result from a brief increase

in permeability of membrane to sodium ion

Nerve cell membrane

MEMBRANE POTENTIAL OF A NERVE FIBRE

• Resting state : • Phase 1

Electrical potential inside the nerve is negative

Achieved by the following mechanism :

a. Active diffusion of ions through the

membraneb. Passive diffusion of ions across the

nerve membrane because of difference in the electrical gradient

Electrophysiology of nerve conduction

Electrophysiology of nerve Conduction

• Phase 2 Depolarization

• Slow depolarization : initial phase in which EP inside the nerve becomes less negative

• Threshold potential , rapid depolarization :

the EP reaches a critical level and results in extremely rapid phase of depolarization

• Reversal of EP : this results in reversal of electrical potential , interior is positive as compared to outside

Electrophysiology of nerve Conduction

• Phase 3

Repolarization

• EP slowly becomes more negative inside the nerve cell as compared to the outside

• It reaches the resting membrane potential of minus 70 mv

Electrochemistry

• The sequence of events that occur across the nerve membrane depend on the following factors:

1. Concentration of electrolytes in axoplasm and

extracellular fluids2. Permeability of the nerve

membrane to sodium and potassium ions

ELECTROCHEMISTRY

• RESTING STATE

• The nerve membrane is slightly permeable sodium ions

• Freely permeable to potassium ions and chlorine ions

• Sodium ions migrate inside the nerve membrane because of the concentration gradient and electrostatic gradient.

ELECTROCHEMISTRY• MEMBRANE EXCITATION Depolarization :• Na ions influx rapidly into the cells resulting

in depolarization leading to decrease in negative trans membrane potential from minus 70 to minus 55 which is called the firing threshold

• Exposing the nerve to LA raises its firing threshold

• Permeability to Na ions increases dramatically• At the end of depolarization the EP is plus

40mV

ELECTROCHEMISTRY

• REPOLARIZATION :• The Action potential is terminated when

membrane repolarizes• The increased permeability to Na is

inactivated• Increased permeability to K ions is restored.• Active transport of Na ions occurs out of the

cell through Sodium Potassium pump• The energy comes from oxidative

metabolism of ATP

ELECTROCHEMISTRY

• Absolute refractory period :• The time during which there is

inability of the nerve to respond to another stimulus regardless of its strength

• Relative refractory period :• In this phase the impulse can be

generated but only by a stronger than normal stimulus

ELECTROCHEMISTRY• MEMBRANE CHANNELS :• A channel is a lipoglycoprotein firmly

situated in the membrane • It consists of an aqueous pore

spanning the membrane that is narrow enough to discriminate between Na ions and other ions

• The channel also includes a portion that changes configuration in response to changes in membrane potential , there by gating the passage of ions through the pore

ELECTROCHEMISTRY

• IMPULSE PROPAGATION• The stimulus disrupts

the resting equilibrium of the nerve membrane• The interior of the cell changes from negative to positive and exterior from positive to negative• The new electrical equilibrium results in production of local currents

ELECTROCHEMISTRY

•As a result of this current flow the interior of the adjacent area

•The interior of the adjacent area becomes less negative and exterior less positive

•Trans membrane potential decreases approaching the firing threshold for depolarization

Electrochemistry

•When trans membrane potential is reduced by 15 mV from resting potential

•Firing threshold is reached and complete repolarization occurs

•this results in setting up of local currents in adjacent area and the whole process starts new

Factors affecting nerve conduction

• Diffusion of solution :1. All local anesthetics are in formed

by a combination of weak base and strong acid

2. The purpose of the salt is to render the salt stable and soluble in water

3. RNH+ RN + H +

4. Uncharged base form and the charged ionic form both are involved in the process of nerve penetration and conduction block

Factors affecting nerve conduction

• Dissociation Constant (pKa)1. It is a measure of molecules affinity for

H+ ions2. When pH of the solution is the same value

as the pka , exactly 50% of the drug exists in the RNH+ form and half in RN form.

3. The percentage of drug existing in each from can be found out by Henderson : hasselbalch equation

Log base = ph pKa

acid

Dissociation constants (pKa) for various LA agents

Agent pKa % Base at 7.4 pH Onset of actionBenzocaine 3.5 100 -Mepivacaine 7.7 33 2 to 4Lidocaine 7.7 29 2 to 4Prilocaine 7.7 25 2 to 4Articaine 7.8 29 2 to 4Etidocaine 7.9 25 2 to 4Ropivacaine 8.1 17 2 to 4Bupivacaine 8.1 17 5 to 8Tetracaine 8.6 7 10 to 15Cocaine 8.6 7 -Chloroprocaine 8.7 6 6 to 12Propoxycaine 8.9 4 9 to 14Procaine 9.1 2 14 to 18Procainamide 9.3 1 -

Factors affecting nerve conduction

• Injection of LA close to the nerve membrane

• For maximum action the anesthetic agent ,it should be injected sufficiently close to the target nerve

Diagram showing various layers it has to diffuse:

Factors affecting nerve conduction

• pH of the tissue :

• The presence of low pH may interfere with achieving adequate anesthesia by preventing deprotonization and liberation of the free base

Factors affecting nerve conduction

• Lipid solubility and protein binding

• Higher the lipid solubility and percentage of protein binding more rapid and longer lasting are the effects

• Eg addition of butyl group to procaine results in the formation of tetracaine which has 16 times the anesthetic activity and 4 times the duration of the parent compound

Factors affecting nerve conduction

• Type of nerve:• Myelinated nerves require more time than

non myelinated nerve fibers to get anesthetized

• Myelinated nerves are protected by a insulating barrier of myelin and can be reached only at the nodes of ranvier which interrupt myelin sheath at every 2-3 mm

Factors affecting nerve conduction

• Size of the nerve :• The larger the diameter of the

nerve greater is the concentration required to prevent the impulse conduction

• LA agents produce loss of function in the following order pain , temperature , touch , propioception and skeletal muscle tone

Factors affecting nerve conduction

• Presence of Vasoconstrictor:

• Solutions with vasoconstrictors are less readily absorbed than those without a vasoconstrictor

• Vasoconstrictor delay the absorption of the agent into the cardiovascular system

Factors affecting nerve conduction

• Injection into a vascular area:

• A LA injected into a vascular area is rapidly absorbed into the cardiovascular system

• Rapid absorption reduces the effective concentration in the vicinity of the nerve fiber and results in rapid termination of analgesia

Factors affecting nerve conduction

• Presence of infection:

• Infection reduces the alkalinity of the tissues which retards the deprotonization of LA agents .

• This prevents liberation of free alkaloid base which is necessary for development of effective anesthesia

Effectiveness of local anesthetic agents

• Factors :

• The chemical nature of the drug used

• The concentration of the drug used

• The volume of the solution injected

• The rate of diffusion of both the anesthetic salt and the free base

• Addition of a vasoconstrictor

Sequence of mechanism of action

Displacement of calcium ions from sodium channel receptor

Binding of LA molecule to its receptor site

Blockade of sodium channel

Mechanism of action

Decrease in sodium permeability

Depression of rate of electric depolarization

Failure to achieve threshold potential

Mechanism of action

Lack of development of propagated action potential

Conduction blockade

Nerve signals do not reach the brain

Mechanism of actionBlocking of sodium channel by cationic LA

molecule

Theories of mechanism of action of LA

1. Acetylcholine theory2. Calcium displacement theory3. Surface charge (repulsion) theory4. Membrane Expansion Theory5. Specific Receptor Theory

Theories of LA action

• Acetylcholine theory • It is a neurotransmitter at the

nerve synapses • There is no evidence that

acetylcholine is involved in neural transmission along the body of the neuron

Theories of LA action• Calcium displacement theory :

• Local Anesthesia was produced by displacement of calcium from some membrane sites that controlled permeability to sodium

• Studies have shown that variation in concentrations of calcium did not affect local anesthetic potency

Theories of LA action• Surface charge theory or repulsion theory:

• LA agents act by binding to nerve membrane and changing the EP at the membrane surface.

• LA agents make EP at the membrane surface more positive , thus reducing the excitability of the nerve by increasing threshold potential .

• Current evidence shows resting membrane remains unaltered by local anesthetic agents

• Conventional La agents act within the channels in the nerve membrane rather than at membrane surface

Theories of LA action

• Membrane expansion theory :

• LA molecules diffuse to hydrophobic regions of excitable membrane expanding some critical regions in the nerve membrane hence increasing the permeability to sodium ions

• E.g. benzocaine which does not exist in cationic form exhibits potent topical anesthetic activity

Theories of LA action• Specific receptor theory:• Most favored theory today • Studies have shown that :• Specific receptors exist in sodium

channels on external and / or internal surface of nerve membrane

• Once LA agents get access to these receptors Na ion permeability is reduced or stopped

• Nerve conduction is interrupted

Classification of LA agents on the basis of site and mode of action

CLASS DEFINITIONS CHEMICAL SUBSTANCES

A Local anesthetic agents acting on receptor sites on the external surface of nerve membrane

Biotoxins eg teredotoxin,saxitoxin

B LA agents acting on internal surface of nerve membrane

Quaternary ammonium analogues of lidocaine and scorpion venom

C LA agents acting on receptor independent mechanisms

Benzocaine

D LA agents acting by combination of receptor dependant and receptor independent mechanism

Lidocaine, mepivacaine and Prilocaine

Various Sites of Action

Properties of an ideal LA agent

• Non irritating and produce no local reaction to the tissues to which it is applied

• Should not cause any permanent change in the nerve membrane

• Should cause minimal systemic toxicity

• It should be effective when injected into tissues and should have sufficient penetrating properties to be effective as a topical anesthetic .

• It should have a short time of onset

Properties of an ideal LA agent

• It should have enough potency to give complete anesthesia without the use of harmful concentrated solutions

• Should be stable in solution

• Should readily undergo biotransformation in the body

• Should be sterile or be capable of being sterilized by heat without deterioration

Classification of LA

1. Naturally occurring e.g. cocaine2. Synthetic compounds

Nitrogenous compounds 1. Derivatives of PABAo Freely soluble eg procaineo Poorly soluble eg benzocaine

2. Derivatives of acetanilide eg lignocaine

3. Derivatives of quinolones eg cinchocaine

Classification of LA

2.Derivatives of acridine eg bucricaine

Non nitrogenous compounds eg benzyl

alcohol, propanediol

3. Miscellaneous drugs Clove oil, phenol ,

chlorpromazine certain antihistaminics

eg diphenhydramine

Classification of LA• On the basis of chemical structure

1. ESTERS esters of benzoic acid eg cocaine , benzocaine , butacaine

Esters of para – aminobenzoic acid eg procaine , chloroprocaine , propoxycaine

1. AMIDES Articaine, bupivacaine ,

lidocaine , mepivacaine , prilocaine

Classification of LA

• On the basis of duration of action

Short acting : articaine, lidocaine , mepivacaine , prilocaine

Long acting : bupicaine , etidocaine , bucricaine

Properties common to LA• All are synthetic compound• All the agents contain amino group• All the agents form salts with strong acids• These salts are soluble in water and acid

in reaction• An alkali increases concentration of

unionized free base• The unionized free base is soluble in lipids• The chemical characteristics are so

balanced that LA have both lipophilic and hydrophilic properties

PROPERTIES OF LA

• The salts are acid in reaction and relatively stable

• The agents either get hydrolyzed by plasma cholinesterase or undergo biotransformation in liver

• The actions of LA is reversible • These drugs are compatible with

epinephrine and allied drugs • The agents are capable of producing toxic

systemic effects when a sufficiently high plasma concentration is reached

PROPERTIES OF LA• Potency: depends upon the chemical

structure of the LA• Duration of the anesthesia depends

upon molecular configuration of the LA and presence of vasoconstrictor

• Toxicity: the first symptom of toxicity of all synthetic local anesthetic agents usually manifested by signs and symptoms of CNS stimulation.

• All local anesthetic agents cause inhibition of contractility of myocardium

Individual local anesthetics

• Cocaine :• Alkaloid obtained from leaves of

cocoa tree (erythroxylon cocoa)• It is methylbenzoyl ester of ecgonine

which is chemically related to atropine

• It is drug of dependence and major abuse

• The concentration used to produce local anesthesia is poisonous to many structures like lucocytes and tissue cells

Individual local anesthetics• Procaine :• It is a aminoethyl ester of para-

aminobenzoic acid • First synthesized by Einhorn in

1905

Procaine • It is non irritant and much less

toxic than cocaine• Does not produce dependence• It can reduce the effectiveness of

sulphonamides because of excessive amounts of PABA which is a metabolite of procaine can reverse the action of sulphonamides

Pharmacology• Procaine has been the standard of

comparison for potency and toxicity with other local anesthetics for the past 50 years

• It has been assigned a potency and toxicity of 1

• The vasodilatation caused by procaine is more profound than all other LA agents

• The effect is very brief if used without a vasoconstrictor

Pharmacology• Procaine is readily absorbed when

injected into the tissues • Its ability to diffuse into intestinal

tissues is poor • Hydrolysis:• Procaine is hydrolyzed to PABA and

diethyl aminoethanol in the plasma• Its reaction is catalyzed by the

enzyme plasma cholinesterase present in plasma and the liver

Pharmacology• Availability in dentistry :• Procaine is used in dentistry as 4 %

solution and in combination as 2 % solution

• It is marketed as 2 % solution in a combination of 0.4 % propoxycaine and 1 : 30,000 levarterenol or 1 : 20,000 levonordefrin

• Onset and duration of action:• The onset of action takes 3-5 minutes and

the duration of pulpal anesthesia is 30 min

Pharmacology• Maximum recommended dose :• It is 15-20 mg/kg body weight not to exceed

1000mg• Toxic reaction :• CNS : it is capable of producing both stimulation

and depression• CVS : • in small amounts it has no effect on CV system

except dilation of microcirculation in the area of injection

• In high doses procaine produces sudden and profound CV collapse with marked and generalized vasodilatation accompanied by severe bradycardia or asystole

Pharmacology• Respiratory system:

• Mild doses have minimal direct effects

• Higher doses cause relaxation of bronchioles

• Higher doses cause severe respiratory depression as a result of depression on central nervous system

Topical anesthetic agents• BENZOCAINE (ethyl p-amino

benzoate)• It is a ester of aminobenzoic

acid(ABA)• It does not contain basic nitrogen

group• It is poorly soluble in water• It is an irritant and can cause toxic

symptoms if absorbed into cardiovascular system

• Eg gingicaine, hurricaine, handicaine stix

Topical anesthetic agents

• Dentipatch• Lidocaine transoral delivery

system• Low solubility in water and slow

absorption prolongs the duration of action and decreases its toxicity

• Cinchocaine : potent but a toxic topical LA agent

• It is not indicated for infiltration or block anesthesia

Topical anesthetic agents

• Water soluble topical anesthetic agent

• Lidocaine hydrochloride:• It is available in 2% , 5 % , 10%

and 15 %• Has better tissue penetration• Maximum recommended dose is

200 mg • Used to prevent gag reflex during

dental treatment

Injectable local anesthetics• LIGNOCAINE

(Lidocaine,xylocaine,octocaine,dentocaine)

• Chemistry:

Lidocaine • It is an amide and an acetanilide

derivative

• It is first non ester type of local anesthetic agent used in dentistry

• White crystalline powder with melting point of 69 C and used as a hydrochloride salt

Chemistry • It is stable , soluble in water as

hydrochloride salt , can be stored for a long time at room temperature

• It withstands boiling and autoclaving

• It is compatible with all types of vasoconstrictors

• pH of the plain solution is 5 to 5.5 while that of solution containing a vasoconstrictor is 3 to 3.5

Pharmacology • Diffusion : it rapidly diffuses

through interstitial tissues into lipid rich nerves giving a rapid onset of anesthesia

• Dissociation constant (pKa) :7.85 it favors deprotonisation and produces adequate unionized form of free base for diffusion into the membrane

Biotransformation

• It undergoes transformation in the liver

• Metabolism : it is metabolized by liver microsomal fixed function oxidases

• It is not affected by plasma cholinesterase's

• Agents of choice in patients with insufficient amounts of the enzyme

• Excretion : lidocaine and its breakdown products are excreted in urine by kidney to some extent (10%) and other mechanisms (90%)

Biotransformation • Potency : twice as potent as procaine • Toxicity : twice as that of procaine • Action on blood vessels : action is

less than that of procaine but more than of mepivacaine and prilocaine

• Time of onset of action : rapid (2-3 min)

• Duration of action : it depends upon • Type of injection: nerve block > infiltration• Amount of vasoconstrictor used

Biotransformation

• Effective dental concentration : 2%• Anesthetic half life : 1.6 hours• Maximum recommended dose(MRD)

• LA agents with a vasoconstrictor– 7.0 mg / kg body wt but not to exceed

500mg• LA agents without a vasoconstrictor

– 4.4 mg / kg body wt but not to exceed 300mg

• Council on dental therapeutics of ADA recommend MRD of lidocaine with or without a vasoconstrictor= 4.4mg/kg BW

Availability

• Dental cartridges : 2% lidocaine with epinephrine 1 : 80,000 in India

• Vials : 2% lidocaine without epinephrine

• 2% lidocaine with epinephrine 1:80,000,1:100,000,1:200,000

Toxicity • CNS : first produce stimulation

followed by depression

• Manifestation of stimulation vary from mild restlessness to severe convulsions

• Depression is manifested as drowsiness to loss of consciousness

Toxicity • CVS :

1. Moderately large doses : it produces overall inhibition of contractility of heart muscle

2. Large doses : it is given IV 50-100 mg to correct ventricular arrhythmias that occur during surgical procedures

Toxicity • Vasculature : vasodilatation is

produced by a direct relaxing effect on smooth muscle of vessel wall

• In toxic doses it causes hypotension and vasculatory collapse

• Respiratory : small doses cause mild bronchodialatation

• Large doses cause respiratory arrest(apnea)

Mepivacaine • Used in 3% concentration• MRD is 4.4mg/body wt not

exceeding 300mg

Bupivacaine • It is an amide• Butyl group replaces ethyl group

at the hydrophilic end

Bupivacaine • It is a long acting LA (6-8hr)

• MRD :

• Used in 0.25% and 0.5% concentration

• Mrd is 1.3 mg /kg body wt not to exceed 90mg

Comparison of various LA agents

Properties Mepivacaine Bupivacaine Prilocaine

Trade Names Scandonest,Polocaine,Carbocaine

Marcaine,Sensorcaine

Citanest,Citanest Forte

Chemical Str Amide,with N-Methyl group at hydrophilic end

Amide,with butyl group replacing ethyl group at hydrophilic end

Amide , derivative of toluidine

Onset 1 . ½ - 2 min 6-10 min 2-3 min

Duration of action

2-3 hr 6-8 hr 2-3 hr

Potency Similar to lignocaine

4 Times as lignocaine

Lesser than lignocaine

Metabolism Hepatic oxidases Hepatic amidases

Hepatic amidases

Comparison of various LA agents

Properties Mepivacaine Bupivacaine Prilocaine

Toxicity Similar to lignocaine

Similar to lignocaine

Lesser than lignocaine

Excretion Kidney Kidney Kidney

Ph –plain solution --sol with VC

4.53.0-3.5

4.5-6.03.0-4.5

4.53.0-4.0

Effective dental concentration

2% with VC and 3% without VC

0.25 and 0.5 % 3% and 4%

Half life 1.9 hrs 2.7 hrs 1.6 hrs

MRC 6.6 mg /kg bw not to exceed 400mg

1.3 mg / kg bw not to exceed 90mg

6mg / kg bw not to exceed 400mg

Prilocaine • Use in concentration of 4%• MRD is 6.0mg/kg body wt maximum

of 400mg

• Comparative properties of LA agents

LA AgentWith VC

Regional InfiltrationOnset of anesthesia

RegionalOnset of anesthesia

Duration of anesthesia infiltration

Lignocaine 5 min 3 min 3 hrs 2 hrs

Prilocaine 3 min 4 min 3 hrs 2 hrs

Bupivacaine 5 min 2-5 min 5-6 hrs 5 hrs

Procaine 7 min 4 min 2.5 hrs 2 hrs

Etidocaine • It is classified as an amide• It is considered long acting LA

agent• Prepared by Takman in 1971• The chemical structure is identical

to lidocaine except for a propyl substitution and ethyl addition

Etidocaine • Effective dental concentration :

1.5 %• Onset of action 3min

Etidocaine • Both etidocaine and bupivacaine

provide adequate surgical anesthesia hence they are also used for post operative pain management

• Also used in the management of chronic pain either as symptomatic , diagnostic or definitive therapy

Centbucridine • It is an acridine derivative and

also a quinolone derivative

• It is used in concentration of 0.5 %

• Potency is 5-8 times that of lidocaine with equally rapid onset of action and equivalent duration of action

Centbucridine • It has longer duration of action

than lignocaine • It has some amount of inherent

vasopressor activity , therefore it does not require addition of a vasopressor for infiltration anesthesia

• It has less CNS and CNS toxicity than lignocaine

• It can be given to patients with h/o allergy to lignocaine because of different chemical structure

Centbucridine • Availability : solution of mg/ml in

form of 30 ml vials

• Adverse effects : does not effect CNS or CVS unless given in very large doses

• Indications / uses : subarachnoid and extra dural anesthesia ,IV regional anesthesia ,intraocular surgery, dental extraction

Ropivacaine • Structurally similar to

mepivacaine and bupivacaine• It is a long acting LA agent

belonging to amide group• Indications:

• Epidural obstetric anesthesia ,surgical anesthesia , management of post surgical pain

• It is advisable in patients in whom the use of vasoconstrictors is contraindicated

Ropivacaine • Advantages :• Vasoconstrictive effect at small

dosages• A significantly smaller depression of

cardiac conductivity than bupivacaine• Duration of action:• Similar to bupivaciane and etidocaine• Pulpal anesthesia achieved IA nerve

block lasted for 2-6 hrs• Mandibular soft tissues anesthesia

lasted for 5-9 hrs

Ropivacaine • Adverse drug reaction :• Elimination half life is 25 min

• Ropivacaine has considerable margin of safety between convulsive and lethal doses than doses of bupivacaine and also lesser dysrhythmogenic potential than bupivacaine

• It has less cardio toxicity than bupivaciane

Ropivacaine • Its duration of action is 20%

shorter than bupivacaine

• Availability :

• Ampoules and vials have 2,5,7.5, and 10 mg / ml (0.2 – 1%) solutions

Articaine • It was prepared by h Rusching in

1969

• 4% articaine HCl with 1:100000 epinephrine bitartarate in 1.7 ml glass cartridges is available

• It is an amide• Only amide type of LA agent

containing a thiophene ring • It also has a ester group

Articaine • Biotransformation :

• In plasma by plasma cholinesterase's

• In the liver by hepatic microsomal enzymes

• Once in blood it is absorbed from injection site and hydrolyzed to articainic acid

• Has extremely short half life of 27 min

Articaine • Time of onset , duration , depth of

anesthesia is similar to lidocaine 2% with 1 : 100,000 epinephrine

• 4% articaine solution with epinephrine has onset of 1.5 min to 3.0 min for maxillary infiltrations and lasts for2-3 hrs

• It lasts for 3-4 hrs in mandibular nerve blocks

Articaine• Effective dental concentrations :• 4% with 1: 100,000 or 200,000

epinephrine• Indications• Extended minor oral surgical

procedures• Long appointments in cosmetic

surgery• Full mouth rehabilitation• Periodontal surgery • Multiple implant placements

Articaine • Reports of toxic reactions to

articaine are extremely rare

• Raid inactivation of articaine by plasma esterases may explain the apparent lack of overdose reactions following its administration

• Articaine and prilocaine have been associated with incidence of mandibular and lingual paresthesia

Selection of local anesthetic• Factors on which selection

depends upon:

1. Duration of action2. Need for control of post operative

pain3. Physical and mental status of the

patient4. Concomitant medications

Selection of local anesthetic• On the basis of duration of action

LA are grouped into 1. Ultra short acting agents :

duration of action < 30 minutes2. Short acting agents : duration of

action is 4 to 75 minutes3. Medium acting agents : duration

of action is 90 to 150 minutes4. Long acting agents : duration of

action is 180 minutes or longer

Selection of local anesthetic

• Short acting LA :

1. Procaine without a vasoconstrictor

2. 2-chloroprocaine without a vasoconstrictor

3. 2% lidocaine without a vasoconstrictor

4. 4% prilocaine without a vasoconstrictor for infiltration

Selection of local anesthetic

• Short acting agents :

1. 2% lidocaine with 1:100,000 adenaline

2. 2% mepivacaine with 1: 200,000 levonordefrine

3. 4% prilocaine , 0.4 % propoxycaine with a vasoconstrictor

4. 2% prilocaine when used for nerve block

Selection of local anesthetic

• Medium acting agents :1. 4% prilocaine with 1:200,000

epinephrine2. 2% lidocaine and 2%

mepivacaine with a vasoconstrictor

• Long acting agents 1. 0.5% bupivacaine with

1:200,000 epinephrine2. 0.5% or 1.5 % etidocaine with

1:200,000epinephrine

Selection of local anesthetic

• Need for control of post operative pain

• LA agents serve as additional medications that eliminate need for post operative analgesics

• Bupivacaine and etidocaine have shown to produce longer duration of analgesia even after other sensations have returned

Selection of local anesthetic

• Physical , mental and mental status of the patient

• Coexisting medical conditions should be considered like hypertension and diabetes

• A history of allergy to a specific local anesthetic agent should be taken

• In malignant hyperpyrexia the use of amide LA agents is contraindicated

Selection of local anesthetic

• Children and mentally challenged adults are fascinated by tingling sensation hence they end up traumatizing their lip , tongue or cheeks

• Hence administration of long term LA agents is contraindicated in such patients

Selection of local anesthetic

• Concomitant medications:

• Vasoconstrictors are contraindicated in patients who are talking

1. MAO inhibitors 2. Tricyclic (TCA) antidepressants

Vasoconstrictors

• Vasoconstrictors are adjuncts added to LA agents added to LA solutions to :

1. To oppose vasodilatation caused by these agents

2. To achieve hemostasis

Vasoconstrictors • Actions :

1. It decreases blood flow to the site of injection

2. It decreases the rate of absorption of LA agents into the CVS

3. It lowers the plasma level of LA agent hence decreasing the systemic toxicity of the agent on the body

Vasoconstrictors

4. Higher volumes of LA agents remain in and around the nerve for longer periods thereby increasing the duration of action of most local anesthetic agents

5. It decrease bleeding from the site of injection because of decreased perfusion

It is useful when bleeding is expected during surgical procedures

Vasoconstrictors • VCs can be classified on the basis of

their mode of action :1. Direct acting agents : they stimulate

or exert their action directly on the adrenergic nerve terminals eg epinephrine , Norepinephrine , dopamine , levonordefrine , isoproterenol

2. Indirect acting agents : act by releasing norepinephrine from the adrenergic nerve terminals eg tyramine , amphetamine , methamphitamine , hydroxyamphetamine

Vasoconstrictors

3. Mixed acting drugs : these drugs have both direct and indirect actions eg metaraminol, ephedrine

Vasoconstrictors • Adrenergic receptors : 2 types: 1. Alpha receptors : activation results

in vasoconstriction2. Beta receptors : subclassified into

alpha , beta and gamma1. B1 receptors are found in heart

and small intestine .responsible for cardiac stimulation , renin release

2. B2 receptors found in bronchi , vascular beds and uterus

3. 3. B3 receptors are found in brown and white adipose tissue and are responsible for lipolysis

Vasoconstrictors

Dilution of vasoconstrictors:

• 1:1000 means 1gm or 1000mg of solute contained in 1000 ml of solution

• Hence , 1:1000 dilution contains 1000 mg in 1000ml or 1.0 mg/ml of solution

Epinephrine • Chemical properties :

1. They are stable and highly soluble in water

2. Slightly acidic and relatively stable if protected from air

3. Deterioration is through oxidation . It is hastened by presence of metal ions.

4. The shelf life of LA solution containing vasoconstrictor is slightly shorter than that of a solution without a vasoconstrictor

Epinephrine• Source : it is secreted mainly by

adrenal medulla. It is synthetically manufactured and obtained from adrenal medulla of animals

• Mode of action :• It acts directly on both alpha and

beta receptors ; beta effects predominates

Epinephrine• Maximum recommended dose of

epinephrine:

• According to American heart association for normal healthy adult individual mrd is 0.2 mg / appointment

• For medically compromised patient it is 0.04 mg / appointment

Epinephrine • Systemic actions:• Myocardium :• Stimulation of beta receptors

results in :– Positive ionotropic effect– Positive chronotopic effect– Cardiac output and heart rate are

increased• Pacemaker cells : it stimulates

beta 1 receptors and increases the irritability of pacemaker cells leading to greater incidence of dysarrythmias

Epinephrine • Coronary arteries :• It produces a dilatation of coronary

arteries resulting in increased coronary blood flow

• Blood pressure:• Systolic Bp is increased• Diastolic:

– It is decreased in small doses – It is increase in large doses

Epinephrine • Cardiovascular system :

– Increased stroke volume– Increased heart rate – Increased cardiac output – Increased strength of contraction– Increased systolic and diastolic

pressures– Increased myocardial oxygen

consumption

Epinephrine • Blood vessels :

• Primary action is on micro cirulation– Constriction of blood vessels

supplying skin , mucous membrane and kidneys

• Rebound phenomenon :– Injection of adrenaline directly into

tissues at surgical sites leads to a high concentration at the tissue

– The stimulation of alpha receptors leads to vasoconstriction

Epinephrine – Biotransformation leads to low

tissue levels of epinephrine– This stimulates alpha receptors and

beta 2 action predominates – The action on blood vessel changes

and vasodilatation occurs– Some bleeding occurs some time

after surgical procedure

Epinephrine • Respiratory system:

• Alpha effect on smooth muscle of bronchioles hence is a potent bronchodilator

• Central nervous system:

• At therapeutic doses is does not stimulate the CNS

• Only stimulates when excessive dosage is given

Epinephrine • Metabolism: • Actions of epinephrine is

terminated by the following methods :

– Primarily by the reuptake by the adrenergic nerves

– Inactivated by the enzyme catechol – O – aminotransferase (COMT) and monoamine oxidase (MAO) , both present in the liver

– Very small amounts are excreted unchanged in the urine

Epinephrine • Overdose :• Factors producing toxic

manifestation:– Large volumes– High concentration of

vasoconstrictors– In advertant vascular injection

• Systemic side effects:– Small doses :– CN effects like Fear, tremor , anxiety ,

tension , restlessness , headache , weakness , pallor , dizziness , respiratory difficulty and palpitation

Epinephrine • Large doses :

– Cardiac dysrhythmias , dramatic increase in both systolic and diastolic BP, ventricular fibrillation is possible but rare ,anginal episodes may be seen in patients with coronary insufficiency

• Clinical applications in dentistry:– For achieving hemostasis– To decrease absorption into cvs

system– To prolong duration of action

Epinephrine • Availability

• In India it is available as :– 1:80,000– 1:100,000– 1:200,000

Epinephrine • A. normal healthy adult patients 0.2mg per appointment

– 10 ml of a 1:50,000 dilution (5 cartridges)

– 16ml of a 1 : 80,000 dilution (8 cartridges)

– 20ml of a 1: 100,000 dilution (10 cartridges)

– 40ml of a 1:200,000 dilution (20 cartridges)

Epinephrine• B. patients with clinically

significant cardiovascular disease

0.04 mg per appointment – 2ml of a 1:50,000 dilution (1

cartridge)– 3.2ml of a 1:80,000 dilution (1.6

cartridge)– 4ml of a 1:100,000 dilution (2

cartridge)– 8ml of a 1:200,000 dilution (4

cartridge)

Norepinephrine • Comparison of epinephrine and

norepinephrineProperties Epinephrine Norepinephrine

Receptor activity Powerful stimulant of alpha and beta receptors

Stimulates both alpha and beta but alpha effect dominates

Blood pressure Lesser effect Greater increase in BP than epinephrine

Central nervous system

Greater stimulation at higher doses

Does not stimulate cns at therapeutic doses

Cardiovascular system Greater effect on stimulation of cardiovascular system

Lesser extent

Bronchi Dilatation Little or no effect

Heart rate Increase in Hr is of greater degree

Increase in HR is of lesser degree

Norepinephrine • It is not commonly used in

dentistry• Felypressin :

• It is available as a vasoconstrictor in combination with prilocaine

• Proprietary name : Octapressin• Chemical structure : it is a non –

sympathomimetic amine a synthetic analog of vasopressin

Norepinephrine • Mode of action : it acts by directly

stimulating vascular smooth muscles

• It has little effect on heart or on adrenergic nerve transmission

• Its action are more pronounced on venous rather than arteriolar microcirculation

Norepinephrine • Systemic actions :

– Myocardium : no direct effects– Coronary arteries : may impair

coronary blood flow– Vasculature : constriction of facial

vessels causing facial pallor– Uterus : antidiuretic and oxytoxic

actions , contraindicated in pregnant patients

– Maximum dose : pts with CVS impairment

• MRD is 0.27 IU

Norepinephrine – Side effects and overdose : wide

margin of safety

– Clinical applications : used as a vasoconstrictor with local anesthesia

– Availability : it is used in dentistry in a dilution of 0.03IU/ml with prilocaine 3%

– Disadvantages : it is primarily a vasoconstrictor of venous vessels . Not as effective in providing hemostasis

Norepinephrine • Indications :

– It may be safely used in patients with medical problems eg mild to moderate cardiovascular disease including hypertension and Hyperthyroidism

– It can be used in patients on antidepressant drugs such as tri or tetra cyclic antidepressants or mao inhibitors

Norepinephrine • Contraindications :

– It is not recommended where hemostasis is required

– Pregnancy : contraindicated because of oxytoxic action

Selection of a vasoconstrictor• Selection depends upon :

1. Length of surgical or dental procedure

2. Requirement for post operative pain control

3. Requirement for hemostasis during the surgical procedure

4. Medical or physical status of the patient and concurrent medications

Selection of a vasoconstrictor

• Various dilutions available in India and MRDDilutions Normal adult

healthy individuals (.2mg)

Medically compromised individuals (0.04mg)

1:80,000 16 3.2

1:100,000 20 4

1:200,000 40 8

Contraindications to Vasoconstrictors

1. Patients with significant cardiovascular disease eg ischemic heart disease , hypertension , cerebral strokes

2. Patients with certain uncontrolled non cardio vascular disease eg Thyrotoxicosis or hyperthyroid states and diabetes mellitus

3. Patients receiving non specific beta blockers , monoamine oxidase inhibitors, tricyclic antidepressants and phenothiazines

LA cartridges and vials

• Local anesthetic vials contains :

1. Local anesthetic drug2. Vasopressor/vasoconstrictor

drug3. Sodium chloride or ringers

solution4. Distilled water5. General preservatives

Constituent of LA vials

Constituents Amount

Lignocaine hydrochloride(2%)

21.3 mg

Adrenaline bitartarate (1:200,00)

0.005 mg

Sodium meta bisulphite 0.5 mg

Methlyparaben 1.0mg

Sodium chloride 6.0 mg

Water for injection To make 1 ml

Local Anesthetics vials• Clinical relevance :

• There is increased burning sensation experienced on injection of an older cartilage with a vasopressor than with a fresher one

• Once the cartridge is opened it should be used with in reasonable time

• LA without vasoconstrictors have a shelf life of 48 months and with vasoconstrictors 18 to 12 months

Preservatives • General preservatives :

• Methyl paraben : it is a bacteriostatic and fungi static agent

• Thymol : it is antiseptic , fungi static , and antihelminthic

• Chlorbutol

L/O/G/O

INDICATIONS & CONTRAINDICATIONS OF

LA

INDICATIONS• Extraction and minor surgical procedures.• Diagnostic purposes.• To reduce hemorrhage : During surgery LA is administered at

the site. Lignocaine prevent cardiac arrhythmia

• In Conjunction with sedation technique : Nervous patients in which N2O with high

concentration of O2 is inhaled, followed by an injection of LA.

• Can be given as an analgesic : Postoperatively long acting

LA (Bupivacaine)

• If patient is unfit for GA.

INDICATIONS

CONTRAINDICATIONS

Based on :

1. Local Conditions 2. Systemic conditions3. Due to constituents of LA4. Interactions between drugs

LOCAL CONDITIONS

1. Sepsis

2. Periostitic tooth

3. Local vascular abnormality

SEPSIS• Normal PH 7.4

• Sepsis PH 5 – 6

• If Ph is less acidic media penetration of lipophilic molecule will be less Lesser cationic molecules present intracellularly less binding with Na channel poor conduction blockade.

• Needle penetration into an infected sites spread of infection osteomyelitis or facial cellulitis.

PERIOSTITIC TOOTH• Impossible to achieve anesthesia of

sufficient depth.

• Theories :1. Pain produces many stimuli in the nerve,

unable to block the conduction of all impulses

2. PH of inflamed products in the region more acidic than usual

3. Hudson mentioned the theory stating spread of inflammation along the myelin sheath which restricts the absorption of LA

4. Increased vascularity of tissues surrounding the periostitic tooth hence LA is removed by blood stream before it works

PERIOSTITIC TOOTH

LOCAL VASCULAR ABNORMALITY

• In Haemangioma Trauma by needle produce hemorrhage

MEDICAL CONDITIONS1. Toxemia

2. Hemophilia & Other Hemorrhagic diathesis

3. Leukemia

4. Anticoagulant therapy

5. Steroid therapy

6. Liver dysfunction

7. Renal diseases

Medical conditions• In debilitating conditions like

uncontrolled DM, Nephritis, Septicemia and Toxemia retarded healing

• Use of LA cause additional wound due to needle track Ulceration Secondary inf.

Medical conditions• Conditions like Hemophilia, Christmas disease,

purpura , von willebrand’s disease , severe liver dysfunction Bleeding tendencies

• Supra periosteal infiltration superficial hematoma

• Inferior alveolar block deep bleeding in pterygomandibular region track down to neck fatal respiratory obstruction

• Regional nerve block to be avoided

• In Leukemia excessive hemorrhage may occur, severe anemia

• Decreased resistance infection & cellulitis difficult to control

Medical conditions

ANTICOAGULANT THERAPY• Heparin, Warfarin, Phenindione used in

treatment of coronary artery occlusion & thrombotic condition

• Risk of hemorrhage if drug dose is high• Level of anticoagulants are estimated

by PT• It is recommended that anticoagulants

are stopped before extraction or if PT levels are satisfactory

• Hematologist opinion sought upon treatment involving administration of LA

STEROID THERAPY• Patients receiving steroids for

conditions like Rh Arthritis, allergic disorders, skin complaints Atrophy of adrenal cortex

• Reason : Regeneration of adrenal tissue is slow process still effect of atrophy even steroid therapy terminated before 2 yrs

• Patients protective mechanism against stress is lost faints, nausea, vomiting , hypotension may be FATAL

• Hydrocortisone injection is required

• LA administration may evoke stress hence pt will require an additional steroid dosage

STEROID THERAPY

LIVER DYSFUNCTION• Impairment of liver function may result

from infective hepatitis, malaria, cirrhosis or secondary carcinomatous disease

• Complications such as bleeding disease, infection of the needle wound healing process is poor

• Administration of drugs which are de toxified in the liver

• Care to be taken from needle stick injury

RENAL DISEASE• Leads to impaired excretion of drug including

LA

• Uremia - type of autointoxication due to retention of waste products fall in blood Ca & acidosis

• LA to be AVOIDED , consider emergency treatment

• Procaine is an ideal LA ( it is broken down in plasma)

Constituents of LA• Associated with LA

• Epilepsy : LA – cerebral stimulant induce epileptic attack

• Should not be treated with LA unless well stabilized and talking anticonvulsive drugs

Associated with Vasoconstrictor

1. CVS disease2. Hypertension3. Rheumatic fever4. Radiation therapy5. Hyperthyroidism6. Diabetes Mellitus

CVS DISEASE• Adrenaline may precipitate

Angina(rare)

• Even in dilute solutions adrenaline may induce cardiac arrhythmia, VF, death rarely

• Good LA reduces endogenous catecholamine release

• Ex : 2 % lignocaine with 1:80,000 adrenaline

• Intravascular administration of adrenaline act on receptors of aortic arch & carotid sinus leads to sudden rise in BP

• Dental extraction should be carried with aspirating syringes

STEROID THERAPY

HYPERTENSION

• Common in elderly ladies

• Felypressin is preferred

RHEUMATIC FEVER

• No contraindications to use LA with adrenaline unless CVS problems are present

• Intravascular injections must be avoided

RADIATION THERAPY• Special care to be taken on pts

undergone radiation therapy by deep X rays, radium needle or radon seeds

• Effect of radiation decreased blood supply due to fibrosis of bone marrow Impairment of healing

• Healing depends on blood supply thereby to avoid LA with vasoconstrictor

HYPERTHYROIDISM• Patients may be extremely nervous &

emotional – unable to cooperate under LA

• Sympathomimetics Vasoconstrictors should not be administered - may precipitate TOXIC CRISIS

• Even small dose of Adrenaline may cause tachycardia, faintness, chest pain

• Felypressin is a drug of choice• Active Thyrotoxicosis - Premedication

should be given for LA

DIABETES MELLITUS• Common metabolic disease in which

blood sugar level is raised

• No contraindications to use LA with or without vasoconstrictor

• Although adrenaline & Nor adrenaline raise the blood sugar level to lesser extent stimulating break down of liver glycogen into glucose

INTERACTION BETWEEN DRUGS

1. TCA

2. TETRACYCLIC ANTIDEPRESSANTS

3. MAOIs

4. SULPHONAMIDES

5. GENERAL ANESTHESIA

6. COCAINE & SYMPATHOMIMETIC DRUGS

TRICYCLIC ANTIDEPRESSANTS

• LA with Adrenaline , Nor adrenaline Interact with TCA Increasing BP & heart rate

• LA with Felypressin is preferable

• Plain Prilocaine or mepivacaine can be used

• Ex : Amitriptyline, Nor triptyline, Imipramine

TETRACYCLIC ANTIDEPRESSANTS

• Same as TCA but safer than TCA

• Reason : do not interfere with uptake by which catecholamine neurotransmitters are removed

• Ex: Maprotiline HCl, Mianserin HCl

MAOI s• Prescribed for major depression,

Obsessive compulsive disorders

• It was assumed that MAOI interact with vasoconstrictor to produce hypertensive crisis

• Recent evidence shows no such occurrence except with Phenylephrine

• Ex : Iproniazid, Phenelzine ,Tranylcypromine

SULPHONAMIDES

• Ester LA : Procaine, Tetracaine may inhibit the bacteriostatic action of Sulphonamide.

GENERAL ANAESTHETICS

• Increased possibility of cardiac dysarrhythmias when patients receiving halogenated GA, are administered epinephrine

• Felypressin may be used

COCAINE & SYMPATHOMIMETICS

• Cocaine – CNS, CVS Stimulant, Stimulates nor epinephrine release & inhibits its reuptake in adrenergic nerve

terminals catecholamine hypersensitivity

• Produce Tachycardia & Hypertension Increase cardiac output & myocardial O2

requirements Myocardial Ischemia, lethal dysrhythmia, anginal pain, myocardial infarction or cardiac arrest

• If possible LA with vasopressor should not be administered to pts who have used cocaine on the day of their dental appointment

COCAINE & SYMPATHOMIMETICS

Complications of local anesthesia

• It can be divided into two :

1. Local complications2. Systemic complications

Local complications• Complications arising from drugs or

chemicals used for local anesthesia:1. Soft tissue injury : in the form of self

inflicted trauma to the lips, tongue or cheeks

2. Sloughing of tissues : it could be in the form of

1. Epithelial desquamation

2. Sterile abscess

3. Tissue necrosis or sloughing

Local complications• Complications arising from

injection technique :1. Breakage of anesthetic cartilage2. Breakage of the needle3. Needle stick injuries4. Hematoma 5. Failure to obtain local anesthesia6. Accidental IV admission

Local complications• Complications arising from both :1. Pain on injection2. Burning sensation on injection3. Infection 4. Trismus5. Edema6. Mucosal blanching7. Persistent anesthesia/paraesthesia8. Persistent or prolonged pain

Local complications8. Post injection Herpetic lesions or

Post anesthetic Intra oral lesions9. Facial nerve paralysis and visual

disturbances10.Diplopia or double vision (infra

orbital block)11.Transient Squints or double vision

(posterior superior alveolar blocks)

Systemic complications• Vasodepressor syncope

• Adverse drug reactions (allergic reactions , anaphylaxis , toxic reactions , idiosyncratic reactions )

Systemic complications

• Vasovagal attack :

• It is defined as a sudden loss of consciousness secondary to cerebral ischemia

• The cerebral ischemia is secondary to vasodilatation or an increase in peripheral vascular bed with accompanying drop in blood pressure

Systemic complications• Adverse drug reactions :• Allergic reactions : a antibody antigen

reaction is responsible for an allergic reaction

• Type I : anaphylactic , IgE antibodies• Type II : cytotoxic , IgG,IgM

antibodies• Type III : immune complex disease ,

mediated by soluble immune complexes

• Type IV : delayed or mediated • Type V : idiopathic • These are mediated by skin rash ,

urticaria ,pruritis , edema , erythema , wheezing

Systemic complications

• Anaphylactic reactions :• It is life threatening or most

devastating allergic reaction of a drug

• Toxic reactions :• They are those clinical signs and

symptoms that manifest as a result of administration of an excess amount of the drug which produces elevated levels in the body

Systemic complications

• Idiosyncratic reactions :• The condition is difficult to

define , it is any reaction that cannot be classified as allergic or toxic reaction is often labeled as idiosyncratic reaction

• Hence the signs and symptoms are strange or bizarre

• There could be a presence of emotional factor

Systemic complications

• TACHYPHYLAXIS

• It is defined as increasing tolerance to a drug that is administered repeatedly.

• It is brought about by some factors like edema, localized hemorrhage , clot formation , transudation , hypernatremia , and deceased pH of the tissue

References

1. Handbook of local anesthesia – Melamed2. Local analgesia in dentistry – Robert and

Sourey3. Contemporary oral and maxillofacial

surgery – Peterson , Ellis , Hupp4. Handbook of Local anesthesia –

Monheims5. Manual of local anesthesia in dentistry –

AP Chitre

Thank you