MECHANISM OF ACTION OF LOCAL ANAESTHETICS AND LOCAL ANAESTHETIC DRUGS Contents 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. History. Definition.

Properties Of An Ideal Anaesthetic Agent. Nerve Conduction. Impulse Propagation / Impulse Spread. Mode And Site Of Action Of Local Anaesthetics. Theories Explaining Mechanism Of Action Of Local Anesthesias. How Local Anaesthesia Works? Local Anaesthetic Molecule. Mechanism Of Action Of Local Anaesthesia.

11. Biological Basis For Failure Of Local Anaeshtetics. 12. Induction Of Local Anaesthesia. 13. Factors Affecting Development Of Adequate Anaesthesia. 14. Factors Affecting Effectiveness Of Local Anaesihesia. 15. Factors Affecting Duration Of Anaesthesia. 16. 18. Classification Of Local Anaesthetic Agents. Conclusion 17. Local Anaesthetic Agents.

history:
Discovery of cocaine in 1884 by Carl Kaller marks the birth of LA as it was introduced into clinical practice. In 1901 -E. Mayer suggested use of small quantity of adrenaline to solution of cocaine to promote vasoconstriction, protruding the duration and intensify the depth of anaesthesia. Cocaine and adrenaline - derived from natural sources because variation in quality and efficacy. This lead to production of LA'S in lab. Thus, procaine synthesized in 1904 by Einhom 1948 marks .the launch of amide linked LA'S with lignocaine by Lofgren.

Definition: Local or regional anaesthesia, as a therapeutic modality, may be defined as a transient, regional loss of sensation to a painful or potentially painful stimulus, resulting from a reversible interruption of peripheral conduction along a specific neural pathway to its central integration and perception in the brain.

Properties of an ideal anaesthetic agent:

1. Reversible action. 2. Non-irritating to tissues and no secondary local reaction. 3. Low degree of systemic toxicity. 4. Rapid onset and sufficient duration of action. 5. Patient enough to give complete anaesthesia without use of harmful concentrations. 6. Sufficient penetrating properties to be effective as topical anaesthetic. 7. Non-allergic. 8. Stable in solution and readily undergo biotransformation in the body.

9. Sterile/ capable of being sterilized by heat without deterioration.

Common properties of injectable local anesthetics:

1. 2. 3. 4. 5. 6. 7. 8. All are synthetic. All contain amino groups. All form salts with strong acids. Salts are water soluble. Concentration of unionized free base increase in alkaline medium. Unionized free base is soluble in lipids. Salts are acid in reaction and relatively stable. Metabolism hydrolysis by plasma cholinesterase i. \Biotransformation in liver 9. Compatible with epinephrine or allied drugs.

10. Incompatible with metal salts of Hg, Ag, etc. 11. Reversible action. 12. All effect nerve conduction in a similar manner. 13. High plasma concentration. 14. Toxic systemic effect. Little / no irritating tissue effect in b. anaesthetic concentration.

Physiology of Nerve Conduction

\ "Electrophysiological theory of nerve conduction" proposed by Hodgkin and Huxley (1952) According to this concept - 'Nerve cell lies in a milieu of body water and the' major extracellular cation in this milieu is -sodium and major intracellular cation is potassium.

At rest:

Potassium ions -> Intracellular : Extracellular 30 : I Therefore potential across nerve cell membrane is -50 to -70 millivolts. This is called resting membrane potential

Excitation of Nerve: 1. Impulses initiated by Chemical, Thermal, Mechanical or

Electrical stimuli. 2. A stimulus excites the nerve leading to - slow depolarization - electric potential becomes slightly less negative. This leads to an increase in the permeability of cell membrane to Na+ ions 3. Falling electrical potential reaches a critical level called "THRESHOLD/ FIRING POTENTIAL". It is the decrease in the negative trans membrane potential required to initiate 'an electron potential. 4. This causes Rapid Depolarization i.e. reversal of electrical potential, with the interior of the nerve membrane becoming the charged and outside -ve charged.
5. After reaching a peak of+35 Repolarization occurs.
- ~7;r17 >'.~7777 '' rir7171111 ~'< a r: ~3fjr;

6. After the return of RMP to its original level (-70mN) and slight excess of Na+ exists within the nerve cell and excess of K+ extracellularly. Active transport of na' ions out of the cell and K+ ions into the cell occurs via the Na+ - K+ pump. Energy required for the active transport is provided by ATP.

Impulse Propagation:
Once depolarization of a segment of nerve occurs, it produces local currents that begin flowing between the depolarized area and adjacent resting area.

These local currents flow from +ve to -ve extending for several mms along the nerve membrane. Backward movement is prevented by the unexcitable, refractory segment. Therefore wave depolarization can spread in only one direction.

Impulse Spread:
In non-myelinated axons the impulse moves forward by sequential depolarization of short adjoining membrane segments. In myelinated nerves impulse conduction occurs by means of current leaps from node to node by the process of 'Saltatory conduction" which is much faster and more energy efficient than that which is employed in unmyelinated fibres.

Conduction rate:
Unmyelinated -fibres -1.2m/secs. . Myelinated A-alpha / A-delta fibres - 14.8 to 120m/seconds. Mode of Action of Local Anesthetics: Local anaesthetics alter the process of impulse generation and transmission in one or more of the following ways: 1. Altering the basic RMP of nerve membrane. 2. Altering the threshold, potential. 3. .Decrease the rate of depolarization. 4. Prolong the rate of repolarization.

Site of action of LA:

Is the outer bimolecular lipoprotein layer of the nerve membrane.

Theories explaining mechanism of action of LA: 1. Acetylcholine theory. 2. Calcium displacement theory. 3. Surface charge theory. 4. Membrane expansion theory. 5. Specific receptor theory.

1) Acetylcholine theory:
'Acetylcholine was involved in nerve conduction in addition to its role as a neurotransmitter at the nerve synapses'. But, there is no such evidence.

2) Calcium displacement theory; 'LA nerve block was produced by displacement of Ca2' from some membrane site that controlled the permeability to Na According to evidence, varying the concentration of Ca2' ions bathing a nerve, does not effect LA potency.

3) Surface charge theory: This theory proposed thata. Local anaesthetics acted by binding to nerve membrane and changing the electrical potential at membrane surface. b. Cationic (RNH+) drug molecules were aligned at membranewater interface and they made the electrical potential at the membrane surface more positive, thus decreasing excitability of nerve by increasing threshold potential.

Demerits ofthe theory: 1. RMP of nerve membrane is unaltered by local anesthetics. 2. Conventional local anesthetics act within the membrane channels rather than at the membrane surface. 3. This theory cannot explain the activity of uncharged anaesthetic molecules in blocking nerve impulses (eg lignocaine). 4) Membrane Expansion Theory: Local Anaesthetics (highly lipid soluble) Penetrate lipid portion of cell membrane Change in configuration of nerve membrane Decrease in diameter of Na channels Inhibition of Na conductance/neural excitation

merits 1. Explains local anaesthetic activity of unionized drugs (ex:benzocaine) 2. Nerve membranes do expand and become more 'fluid' when Demerit: No evidence that nerve conduction is entirely blocked by membrane expansion per se.

5) Specific Receptor Theory:

1. Local anaesthetics act by binding to specific receptors on the sodium channel-either on its external surface or on the internal axoplasmic surface. 2. Once the local anaesthetic has gained access to the receptors, permeability to sodium ions is decreased or eliminated and

nerve conduction is interrupted.

External Receptor site:

2 naturally occurring biotoxins - Tetrodotoxin and Saxitoxin are known to block Na+ influx by acting on external receptor.

Internal Receptor site:

Sites within cell membrane release Ca2' ions because sudden increase in permeability to Na+

Local anaesthetics:
Compete with ca for same receptor Thus, Ca2' is displaced by LA Thus, preventing initiation of depolarization.
r ppp ~ ~ ~~CI ~I'ICF

Local Anaesthetic Molecule

All local anaesthetics are amphipathic i.e. they posses both Lipophilic and Hydrophilic character.

Basic molecular structure of local anaesthetic agents: The PKG dissociation constant is a measure of a molecules affinity for hydrogen ions (H+). The relative proportions between uncharged base and the charged cations depends on the pH of the solution and the PKG of the specific compound. When the PKG and pH of solution are same half of the drug exists in the free base form and half exists as the cation. The relationship may be expressed as pH = PKG-log (RNH+-RN). Since the PKG is constant for any specific compound the relative proportion of the free base and the charged cationic form in the LA solution depends on the pH of solution.

Hypothesized Mechanism of action of local anaesthetics:

1. LA agents are available as acid salts of weak gases. 2. The LA weak base (BNHOH) must be combined with a strong acid (HCI) in order to make acid salt (BNHCL) that is soluble in solution. 3. For this solution to act as an LA it must dissociate into a free base (BH).
4. Basic environment found in normal tissues is necessary for this (normal tissue pH = 7.4).

5. In submucosa - After injection of local anaesthetic solution

B~y CC ~~ Q~H cl U"

6. Outside nerve sheath8~~ ~ Ilr 8~ ~-- cC

7. Unionized, lipophilic free base (BN) diffuses readily through lipid composed nerve sheath. 8. In interstitial fluid space between nerve sheath and nerve cell membrane. 9. Thus, an ionized, hydrophilic form of LA molecule (BNH+) is formed. 10.BNH~ passes through the pore in the nerve cell membrane displacing the Ca ions from Na channel receptor site.

Displacement of Ca2+ ions from Na+ channel receptor. I LA molecule binds to receptor site. Therefore Na+ channel blocked. Decrease in Na+ conductance Depression of rate of electrical depolarization. Failure to achieve threshold potential. Lack of development of propagated action potential CONDUCTION BLOCKADE

BIOLOGICAL BASIS FOR FAILURE OF LA Area of infection Low tissue pH (acidic) Increased H+ concentration since environment is acidic bcoz of Infection
B~tu s. ...._, Q~~'' f U"

-Slow rate of dissociation Abundant H+

SHH~ ~* ~Zrr t Hf

- Reaction shifts towards left by law of mass action Decrease in formation of BN Therefore minimum diffusion across nerve sheath. Therefore little / no BNH+ formed to act on nerve cell membrane Therefore no conduction blockade.

Induction of LA: 1. Following the administration of LA into soft tissue near a nerve, molecules of the LA travel the distance from one side to another according to concentration gradient. 2. During the phase LA molecule diffuses from its extraneural site of deposition towards the nerve. 3. Mantle bundles that is the fasiculli located near the surface of the nerve are the first ones to the reached by LA and exposed to a higher concentration of it. 4. Core bundles - that is the fasiculli located closer to center of nerve are contacted by LA after much delay, hence are exposed to a much lower concentration of LA solution due to greater distance the solution must travel. Also as the LA solution diffuses into the nerve it is increasingly diluted by tissue fluids, absorbed by capillaries arid lymphatics or undergoes enzymatic hydrolysis. Thus the core fibers are exposed to a decreased concentration of LA. This explains the clinical situation of inadequate pulpal anaesthesia developing in the presence of subjective symptoms of adequate soft tissue anaesthesia.

FACTORS AFFECTING DEVELOPMENT OF ADEQUATE ANAESTHESIA

1. Type of nerve: Myelinated nerves require greater concentration of LA solution and more time to be blocked than non-myelinated fibres. 2.. Size of nerve: Larger the diameter of nerve fibre greater the anaesthetic concentration required to prevent impulse conduction.
3. Length of nerve:

A minimum of 8-10mm of nerve must be covered by anaesthetic solution to ensure thorough blockade. 4. Functional fibre type: Local anaesthetics produce a loss of function of nerve fibres in the following order: a. Pain. b. Temperature. c. Touch. d. Proprioception. e. Skeletal muscle tone.

FACTORS AFFECTING EFFECTIVENESS OF LA

1. Condition of tissues: Too high / low pH of tissues I Failure of anaesthesia 2. Concentration of local anaesthetic agent in tissues Excessive dilution of LA with blood/tissue fluids Faulty / no anaesthesia

q3. Absorption of LA Too rapid absorption into systemic circulation Decrease in depth and duration of anaesthesia. 4. Chemical nature of individual drug. 5. Concentration of drug used. 6 .Volume of solution injected. 7. Rate of diffusion of both the anaesthetic salt and free base. 8. Addition of vasoconstrictors. - which influences the time during which the free base remains in contact with the nerve.

FACTORS AFFECTING DURATION of ANAESTHESIA

1. Individual variation in response to drug administration. 2. Accuracy in administration of drug. 3. Status of tissue at site of drug administration. 4. Anatomical variation. 5. Type of injection administered (infiltration / nerve block).

Classification of Local Anaesthetic agents: L According to Chemical Structure: A. Natural : Ex, cocame. B. Synthetic Nitrogenous compounds: 1. Deprivatives of paraamino benzoic acids: a. Freely soluble ex: Procaine, amethocaine. b. Poorly soluble ex:-Benzocaine, orthocame.

2.Deprivative of acetanilide:Ex.Lignocaine. 3. Quinoline deprivatives. Ex: Cinchocaine. C. Synthetic non-nitrogenous compounds ex: Benzyl alcohol, Propanediol

D. Miscellaneous drugs with local action: Ex: Clove oil, phenol, chlorpromazine, certain antihistamine ex: diphenhydramine.
Ill, Classification according to intermediate group

A. Esters ex: Procaine. B. Amides ex: Lignocaine IV. Classification of local anesthetic substances according to biological site and mode of action: Classification Class A Site of action Receptor site on external surface of newer membrane Examples
Biotoxins

Class B

Receptor sites on internal surface of nerve membrane

Quaternary NH4 analogous of lignocaine

Class C

Receptor independent Physico -chemical mechanism

benzocaine

Class D

Combination of receptor and receptor independent mechanisms

RP~n7'n~inP.

Lignocaine: Classification: Amide Chemical formula - 2-diethylamino 2,' 6-acetoxylidide hydrochloride.

i r N

Prepared by -Nils Lofgren, 1943. Introduced in -1948 Metabolism: In the liver, by microsomal fixed function oxidases, to monoethyiglycerineand xylidide. Xylidide - local anesthetic and potentially toxic. Excretion: Via kidneys <l 0% unchanged > 80% various metabolites

Vasodilating properties: Considerably less than procaine, more than prilocaine / mepivacaine. pKa-7.9 pH of plain solution-6.5 pH of vasoconstrictor-containing solution - 5.0-5.5 Onset of action - Rapid (2-3 mins) Effective dental concentration - 2%

Anaesthetic half-life - 1.6 hrs. Topical anaesthetic action - Yes. Maximum recommended dose: Manufacturer's recommended dose for adults: a. With epinephrine - 7.0mg/kg body wt not to exceed 500mg. b. Without vasoconstrictor 4.4mg/kg body wt not to exceed 300mg. For children with epinephrine - 3.2mg/eb. Dosage regimen suggested by Council on Dental Therapeutics of ADA and VSP convention. 4.4 mg/kg - with / without vasoconstrictor. Comments: 1. Lignocaine has replaced procaine as a gold standard. against which all new LA'S are compared. 2. Non-allergic. 3. Available in 3 formulations: 2% lignocaine without vasoconstrictor i.e. 20mg lignocaine in lOOO mI of water. ii. iii. 2% + 1: 50,000 epinephrine. 2% +1:100,000 epinephrine

2% lignocaine without vasoconstrictor

- Vasodilating effect.

- Limits pulpal anaestehsia to only 5 to 10 minutes - Higher blood levels of drug - Increase in risk of adverse reaction - Increase in bleeding in region of drug deposition 2% with epinephrine 1:50,000:

- Causes decrease in blood flow to area of infection. - Decrease in blood level of anesthetic.
- Decrease in bleeding in area of injection due to a-stimulatory actions of epinephrine.

- Increase in duration of action - 60 mins of pulpal anaesthesia and 3 to 5 hrs of soft tissue anaesthesia. - Recommended for hemostasis. Bupivacaine: Classification - Amide Chemical formula - 1-butyl- 26 pipecoloxylidide Potency : 4 (compared with lidocaine) Toxicity: Less than 4 times of lidocaine and mepivacaine Metabolized: Liver by amidases Excretion : via the kidney 16% uncharged Vasodilating properties: Relatively significant more than lidocaine. Pka-8.1 pH of plain solution - 4.5-6.0 pH of vasoconstrictor containing solution 3 - 4.5

Onset of action - similar to lidocaine (6-10 mins). Effective dental consideration - 0.5%. Anaesthetic half life : 2.7 hrs. Dose: 0.6mg/lb or 1.3mg/kg of body weight. Maximum dose not to exceed 40mg. It is available as 0.5% solution with 1:20,0000 epinephrine. Indications for its utilization: 1. Lengthy dental procedure for which pulpal deep anesthesia in

excess of 90 .minutes is required e.g. full mouth reconstruction; excessive perio procedures. 2. Management of postoperative pain.

Duration of pulpal analgesia: 90-180 minutes soft tissue 4-8 hours upto 12 hours. Bipivacaine is not recommended in younger patients or in whom the risk of postoperative soft tissue injury produced by self mutilation is increased, such as a physically and mentally disabled person. Rarely indicated in children.

Conclusion
1. In summary, when the pre-unionized anaesthetic base is in contact with the nerve membrane in sufficient concentration, a conduction block with result. 2. As a general rule, larger the nerve, the greater the concentration and the longer the time of exposure necessary for development of analgesia. Small sensory fibres are affected more rapidly and by lower concentrations than large motor fibres. 3. The choice of a local anaesthetic solution should be based upon knowledge of: - Chemistry, pharmacology and toxicology of solutions. - Patient's general physical and emotional condition. -Duration needed. - Concomitant medications that may be in effect. of procedure and postoperative pain control if

4. Local anaesthetic solutions are eventually absorbed into the general circulation and can have toxic manifestations. They should be chosen with consideration and basic rules of good technique should be followed during their use.