Dr.Ch.Venkateswara rao, Dr.

Psims, S & NR

LOCAL ANESTHESIA Neurophysiology & Pharmacology

 For there was never yet another philosopher who could endure the toothache patiently.
- William Shakespeare

Local Anesthetics
History Definition Ideal Requirements Indications / Contraindications Classification Neurophysiology Pharmacology References

History
500s
1540 1842 1850s 1853 1884

Coca leaves first used by Peruvians for psychotropic properties Ether synthesized by Cordus Ether used as anesthetic by Dr. Crawford W. Long Cocaine isolated, hypodermic needle developed Chloroform used as anesthetic by Dr.John Snow Carl Koller introduces cocaine into medical practice

Chloroform being used as anesthesia

1850s

History
1884
1905 1921 1947 1943 1948 1959

Cocaine used Local anesthesia in dentistry by Halsted and Hall Procaine synthesized by Einhorn Cartridge syringe marketed by Cook Aspirating syringe developed Lidocaine synthesized by Lofgren Lidocaine marketed Disposable needle introduced

Definition

Local anesthetics are drugs that reversibly inhibit nerve conduction in peripheral nerve or depress excitation in nerve endings, causing loss of sensation in a circumscribed area. - MALAMED

 Ideal Requirements An idea local anesthetic should possess the following properties: Its action must be Reversible in action. It should be Stable in solution and undergo biotransformation readily within the body. It should be either Sterile or capable of being sterilized without deterioration or denaturation

 It must be Non-irritating to the tissues and produce no secondary local reaction. It should have a Low degree of systemic toxicity It should be relatively free from producing any Allergic reactions. It should have a Rapid onset and stay for sufficient duration to be advantageous. It should have sufficient penetration to be effective for topical use. It should have potency sufficient to give complete anesthesia without using harmful concentrations. Although none of the local anesthetics available for use today, can fulfill to perfection all these requirements but drugs, which have properties to fulfill majority of the requirements, are good enough to be used safely and effectively.

 Indications When it is desirable or necessary for the patient to remain in the conscious state while producing insensibility to pain in teeth and supporting structures for performing minor surgical procedures. For diagnostic and therapeutic purposes in diseases or conditions such as Trigeminal neuralgia. Long acting local anesthetics can be used for control of postoperative pain. Eg: Bupivacaine. It is required for bloodless field during surgical procedures as an adjunct when used with a vasoconstrictor

 Contraindications Absolute: There is only one absolute contraindication to the use of local anesthetic that is, the patient being allergic to the drug. In such a case using local anesthetic will produce type I allergic reactions that could even be catastrophic. Most of the patients are allergic to Esters as compared to amides.

 Relative:
In presence of some Local infections which can render the drug ineffective. The patient is uncooperative due to some mental deficiency The patient refuses regional anesthesia because of fear or apprehension. The patient is below the age of reason. In cases of major oral surgery procedures which make regional anesthesia unfeasible. Anomalies make regional analgesia difficult or impossible. Systemic conditions like renal disease or liver disease, in turn affect the metabolism and excretion of the drug.

 Advantages
The local or regional method should always be the first choice for producing anesthesia, since it offers the following advantages: The patient remains awake and cooperative & well oriented. There is very low incidence of morbidity. The patient can leave the dental office unescorted. There is little distortion of normal physiology, and the method can therefore be used to advantage poor-risk patient. The techniques are not difficult to master. No additional trained personal is necessary. The percent of failures are very less. There is no additional expense to the patient. The patient need not omit the pervious meal

 Disadvantages There are no true valid disadvantages to the use of regional anesthesia when the patient is mentally prepared for it and when there are no contraindications. In every instance when satisfactory anesthesia can be secured and the patient is cooperative, regional anesthesia is the method of choice.

Classification of Local Anesthetics

Based on Site

Topical - eg: Cocaine,

Injectable - eg: Lignocaine

 Based on duration of action

Ultra short acting < 30 min 2 % Lignocaine without a vasoconstrictor Short acting 45-75 min Procaine, 2 % Lignocaine with 1:100,000 Epinephrine Medium acting 90-150 min Mepivacaine, Prilocaine, 2 % Lignocaine with 1:200,000 Epinephrine

Long acting 180 min Bupivacaine (400-450 min), Etidocaine, 5 % Lignocaine with 1:200,000 Epinephrine

 Based on its biological site & mode of action Class A :- Acting on receptor site located on external surface of nerve membrane - Tetrodotoxin Class B :- Acting on receptor site located on internal surface of nerve membrane - Quat ammonium analogues of lidocaine Class C :- Acting by a receptor-independent physicochemical mechanism - Benzocaine Class D :- Acting by combination of receptor & receptorindependent mechanisms - Lidocaine, Mepivacaine

 Based on Chemical structure Ester Group Benzoic acid esters Benzocaine, Cocaine, Butacaine, Tetracaine, Piperocaine Para amino benzoic acid esters Procaine, Chloroprocaine, Propoxycaine Amide Group Lignocaine, Bupivacaine, Mepivacaine, Prilocaine, Articaine, Dibucaine, Etidocaine, Ropivacaine Quinolone Centbucridine

 Composition of LA Solution Lignocaine HCl --(Anesthetic) 24.64 mg (2 %) Adrenaline --(Vaso constrictor) 0.0125 mg (1:80,000) Sodium metabisulphite (Reducing Agent) 0.5 mg Methyl paraben --(Preservative) 1 mg OR Cupryl hydrocuprinotoxin Thymol --(Fungicide) mg Distilled Water --(Vehicle) 100 ml

The Neuron

Resting Membrane Potential

The electrochemical state of the neuron at rest Every neuron has a separation of electrical charge across its cell membrane.
maintained because the lipid bilayer acts as a barrier to the diffusion of ions

Selective Permeability of Membranes

Some ions permitted to cross more easily than others Neuronal membranes contain ion channels
Protein tubes that span the membrane
Nongated Gated - stay open all the time - Open on the occasion of an action potential, causing a change in the permeability of the membrane (Voltage-gated & Ligand-gated)

Ion Channels

A class of integral proteins that span the cell membrane Permit Transient current flow Facilitate Depolarization, Hyperpolarization

Membrane Resting Potential

Na+ and Cl- are more concentrated outside the cell K+ and organic anions (organic acids, bicarbonates and proteins) are more concentrated inside. The overall effect of this ionic distribution is the resting potential Electrical potential difference, ranges from about -60 to -70 mV.

Resting Membrane Potential

Chloride ions,
concentrated outside the cell tend to move inward down their concentration gradient through nongated chloride channels But the relative excess of negative charge inside the membrane tend to push chloride ions back out of the cell

Two forces acting on a given ionic species Chemical forces tend to drive ions down their concentration gradients

Resting Membrane Potential

The same mechanisms operate on potassium

Resting Membrane Potential

Na is more concentrated outside than inside and therefore tends to flow into the cell down its concentration gradient
Na is driven into the cell by the electrical potential difference across the membrane.

But what about sodium? Electrostatic and Chemical forces act together on Na ions to drive them into the cell

Action Potential
(Impulse)

The change or overshoot in electrical potential of nerve or muscle fibre The basic unit of conduction in the nervous system Characteristic of axons
Because of absence of voltage-gated channels in cell body & dendrites, Action potential does not reach there.

Non-decremental conduction
all-or-none law

Action Potential Sequence

Involves the action of voltage-gated channels Exchanges of ions in and out of the cell

Action Potential
Sequence

Voltage-gated Na+ Channels open and Na+ rushes into the cell

Action Potential
Sequence

At about +40 mV, Sodium channels close, but now, voltage-gated potassium channels open, causing an outflow of potassium, down its electrochemical gradient

Action Potential
Sequence

The voltage-gated K+ channels close, but so much Potassium accumulates outside the cell that repolarization occurs
equilibrium potential of the cell is restored

Action Potential
Sequence

The Sodium Potassium Pump is left to clean up the mess

The Sodium-Potassium Pump

The energy necessary for this process is obtained from the hydrolysis of ATP (an energy carrying molecule)

Because the pump moves Na and K against their net electrochemical gradients, energy is required to drive these actively transported fluxes.

Refractory Period
Two types Absolute
When Na+ channels close, at peak of AP, they do not reopen for a time

Relative
Membrane hyperpolarized Some Na+ channels still refractory

Propagation of the Action Potential

Action Potential spreads down the axon in a chain reaction Unidirectional
it does not spread into the cell body and dendrite due to absence of voltage-gated channels there Refraction prevents spread back of impulse across axon

Propagation of the Action Potential

Speed of propagation is also assisted by the myelin sheath Nodes of Ranvier - Regular gaps in the myelin sheath at 1mm intervals
Increase conduction speed up to 15 times Saltatory Propagation

What is Pain?
The International Association for the Study of Pain Pain is "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage" (Merskey, 1986).

Monheim: An unpleasant emotional experience usually initiated by noxious stimulus and transmitted over a specialized neural network to the CNS where it is interpreted as such.

TRIGEMINAL SYSTEM
Sensory input

Gasserian ganglion

Trigeminal spinal nucleus (Medullary dorsal horn)

Second-order neurons
( T CELL )

Thalamus

Pain Theories
Specificity theory Descartes (1644), Von Frey (1829)
A straight channel from skin (pain receptors) to brain (pain centre)

Pattern theory Goldscheider (1894)

Stimulus intensity & central summation are critical determinants of pain

Gate control theory Melzack & Wall (1965)

Ronald Melzack

Patrick Wall

Brain receives messages about injury by way of gate control system which is influenced by Injury signals Other afferent impulses Descending Control

Theories of Action of L.A

Acetylcholine theory
Ach involved in nerve conduction Disapproved

Calcium displacement theory

Ca2+ displaced from membrane site alters Na2+ permeability Disapproved

Surface charge (repulsion) theory

Cationic drug molecules bind to nerve membrane making it more +ve, thus increasing the threshold potential causing decreased excitability Disapproved

Theories of Action of L.A

Membrane expansion theory
Drug molecule penetrates the lipid portion of membrane & brings about a change in the configuration of lipoprotien matrix, leading to inhibition of Na2+ conductance hence inhibiting neural excitation.

Theories of Action of L.A

Specific receptor theory
Drug molecules bind to specific receptors present on the external or internal axoplasmic surface of sodium channels & by acting directly on them, decrease or eliminate permeability to Na2+ leading to interruption of nerve conduction.

Classification of Local Anesthetics

Based on Site Topical - eg: Cocaine, Injectable - eg: Lignocaine

Classification of Local Anesthetics

Based on duration of action
Ultra short acting Short acting Medium acting Long acting < 30 min 45-75 min 90-150 min 180 min
2 % Lignocaine without a vasoconstrictor

Procaine, 2 % Lignocaine with 1:1,00,000 Epinephrine

Mepivacaine, Prilocaine, 2 % Lignocaine with 1:2,00,000 Epinephrine

Bupivacaine (400-450 min), Etidocaine, 5 % Lignocaine with 1:2,00,000 Epinephrine

Classification of Local Anesthetics

Based on its biological site & mode of action
Class A :- Acting on receptor site located on external surface of nerve membrane - Tetrodotoxin
Class B :- Acting on receptor site located on internal surface of nerve membrane - Quat ammonium analogues of lidocaine Class C :- Acting by a receptor-independent physicochemical mechanism - Benzocaine Class D :- Acting by combination of receptor & receptorindependent mechanisms - Lidocaine, Mepivacaine

Classification of Local Anesthetics

Based on Chemical structure
Ester Group
Benzoic acid esters
Benzocaine, Cocaine, Butacaine, Tetracaine, Piperocaine

Para amino benzoic acid esters

Procaine, Chloroprocaine, Propoxycaine

Amide Group
Lignocaine, Bupivacaine, Mepivacaine, Prilocaine, Articaine, Dibucaine, Etidocaine, Ropivacaine

Quinolone
Centbucridine

Composition of LA Solution
Lignocaine Hcl --(Anesthetic) Adrenaline --(Vaso constrictor) Sodium metabisulphite (Reducing Agent) Methyl paraben --(Preservative)
OR

24.64 mg (2 %) 0.0125 mg (1:80,000) 0.5 mg 1 mg 1 mg

Cupryl hydrocuprinotoxin Thymol --(Fungicide) Distilled Water --(Vehicle)

OR

100 ml

Ringers Lactate

Lignocaine
Chemistry
- Diethyl 2 , 6 - dimethyl acetanilid
- White Crystalline powder with M.P = 69 o C - Easy diffusion rapid onset ( 2-3 min ) - pH = 6.5 - Anesthetic half life = 1.6 hrs End products - 4 hydroxy 2 , 6 dimethyl aniline

Maximum Dose of Lignocaine

Without Vasoconstrictor :
4.4 mg / kg of body wt = 300 mg in a 70 kg individual = 12.5 ml of solution

With Vasoconstrictor :
7.2 mg / kg of body wt = 500 mg in a 70 kg individual = 20 ml of solution

(Acid-base considerations)
Most local anesthetics are weak bases, pKa 7.5-9.0. Local anesthetics have two forms, ionized and nonionized. The nonionized form can cross the nerve membranes and block the sodium channels.

So, the more nonionized form present, the faster the onset of action.
Decrease in pH shifts equilibrium toward the ionized form, delaying the onset of action. Usually prepared as a salt (e.g., with HCl) to increase stability, water solubility. When injected, 5%-40% is converted to the nonionized free base.

Alveolar mucosa

O H 2N COCH 2CH 2

C 2H 5 N H

H 2N

O COCH 2CH 2 N

C 2H 5

+ H
C 2H 5

C 2H 5

Cationic acid

Nonionized base

[1.0]

Log Base = pH p Ka Acid (Henderson-Hasselbalch equation)

Lipoid barriers

(nerve sheath)

Extra cellular fluid For procaine (p K a = 8.9) at tissue pH (7.4) Nerve membrane Base = 0.03 Acid Axoplasm

Base

Acid

[1.0]

* Base Acid

[3.1] [2.5]

Structure of Local Anesthetics

Aromatic end Intermediate Chain Amine end

D: Procaine F: Lidocaine

E: Tetracaine G: Mepivacaine

Physical Properties (structure)

Ester: R 1COOR 2N R3 R1 Lipophilic aromatic residue. R2 Aliphatic intermediate connector. R3 , R 4 Alkyl groups, occasionally H.

R4
Amide: R NHCOR N
1
2

R3

R4
C 2H 5 (Procaine) C 2H 5

Example:
H2 N COO(CH 2) 2N

Exception:

Benzocaine, which lacks a substituted amino group

COMMONLY USED LOCAL ANESTHETICS

Amino Esters ester linkage between the aromatic end and the intermediate chain Amino Amides amide link

Procaine
Concentration - 2-4% Potency - 1 Toxicity - 1 Metabolized - hydrolyzed in plasma by pseudocholinesterase to PABA Excreted - Kidney
Time to onset 6-10 mins Half life < 1 hr Duration pulp - 30-60 mins (with v/c) tissue - 2-3 hrs Max rec dose Max safe dose 6.6 mg/kg 400 mg

No longer available in dental carpules

Lidocaine
% 2 2 Vasoconstrictor without 1:50,000 epi 1:100,000 epi Duration pulp - 5-10 mins tissue - 1-2 hrs pulp - 60 mins tissue - 3-5 hrs pulp - 60 mins tissue - 3-5 hrs

Concentration - 2% Potency - 2X Procaine Toxicity - 2X Procaine Metabolized - Liver Excreted - Kidney

Time to onset 2-3 mins Half life 90 mins Max rec dose w/o epi 4.4 mg/kg with epi 6.6 mg/kg Maximum safe dose w/o epi 300 mg with epi 500 mg

Mepivacaine
% Vasoconstrictor 3 without Duration * pulp - 20-40 mins tissue - 2-3 hrs pulp - 60-90 mins tissue - 3-5 hrs pulp - 45-60 mins tissue - 2-5 hrs * weak vasodilator

Concentration - 2% or 3% Potency - 2X Procaine Toxicity -2X Procaine Metabolized - Liver Excreted - Kidney

2 1:20,000 Levonordefrin 2 1:100,000 epi 1:200,000 epi

Time to onset 1.5 - 2 mins Half life 1.9 hrs Max rec dose w/o epi 4.4 mg/kg with epi 6.6 mg/kg Maximum safe dose w/o epi 300 mg with epi 500 mg

Prilocaine
% Vasoconstrictor Duration 4 without pulp - 10 mins tissue - 1.5-4 hrs 4 1:200,000 epi pulp - 60-90 mins tissue - 3-8 hrs

Concentration - 4% Potency - 2X Procaine Toxicity - 1X Procaine Metabolized - Liver and Lungs orthotoluidine produced Excreted - Kidney

Time to onset Half life Max rec dose all forms Max safe dose all forms

2-4 mins 1.6 hrs 6 mg/kg 400 mg

Bupivacaine
Concentration - 0.5% Potency - 8X Procaine (4X Lidocaine) Toxicity - 8X Procaine (4X Lidocaine) Metabolized - Liver Excreted - Kidney

Time to onset Half life

6-10 mins 2.7 hrs

Max rec dose 1.3 mg/kg Max safe dose 90 mg

% Vasoconstrictor Duration 0.5 1:200,000 epi pulp - 90-180 mins tissue - 4-9 hrs, up to 12 hrs reported

Properties of local anaesthetics

drug
cocaine

onset
medium

duration
medium

tissue penetration
good

plasma half-life
~1h

main unwanted effects

cardiovascular and CNS effects due to block of amine uptake CNS: restlessness, shivering, anxiety, occasionally convulsions followed by respiratory depression CVS: bradycardia and decreased cardiac output, vasodilatation, which can cause cardiovascular collapse less tendency to cause CNS effects

notes
Rarely used, only as spray for upper respiratory tract no longer used

procaine

medium

short

poor

<1h

lingocaine (lidocaine)

rapid

medium

good

~2h

widely used for local anaesthesia .also used i.v. For treating ventricular arrhythmias mepivacaine is similar used mainly for spinal and corneal anaesthesia widely used because of long duration of action. Ropivacaine is similar, with less cardiotoxicity widely used, not for obstetric analgesia because of risk of neonatal methaemoglobinaemia

amethocaine bupivacaine

very slow slow

long long

moderate moderate

~1h ~2h

as lingocaine

as lingocaine, but greater cardiotoxicity no vasodilator activity, can cause methaemoglobinaemia

prilocaine

medium

medium

moderate

~2h

Mechanism of Action
Axonal membrane
Local anesthetics interfere with propagation of the action potential by blocking the increase in sodium permeability during depolarization.

Mechanism of Action
Mixed nerve
Local anesthetics provide pain relief by blocking nociceptive fibers. Other fibers are affected as well. Sensitivity to local anesthetics depends on: fiber diameter, fiber type, and degree of myelination. Sensory modalities are affected in the following order: pain, cold, warmth, touch, and pressure.

Developing local anesthetic block

40 A B 0 C D

Membrane potential (mV)

40

80 0 1 2 3

Time (msec)

Critical length theory

Pharmacokinetics
Absorption
Local anesthetics are absorbed when ingested. Some local anesthetics may be absorbed in toxic amounts after topical use. Absorption after an injection depends on drug solubility in lipid and in water, tissue vascularity and local anesthetic and vasoconstrictor effects on local circulation.

Pharmacokinetics
Metabolism and excretion
Esters are hydrolyzed by plasma and liver esterases. Longer-acting esters are often metabolized more slowly. Sulfonamide therapy may be neutralized by PABA liberation. Patients with altered pseudo-cholinesterase activity may be highly sensitive to these drugs.

 Amides are metabolized in the liver. Patients with severe hepatic damage or advanced congestive heart failure may be unusually sensitive to these drugs. Some amides are partially excreted unchanged in the urine.

Local anesthetic metabolism

Ester

Hydrolysis

Hydrolysis CH 3 O N

Amide
Hydroxylation and conjugation R1

R3

NHC CH

R2

R4

N-de-alkylation (and cyclization)

Need.
All clinically effective injectable L.A have some degree of vasodialating activity
absorption of L.A into CVS removal from injection site Rapid diffusion of L.A from inj site duration of action & depth of anesthesia. Higher plasma level of L.A risk of toxicity bleeding at inj site.

Addition of vasoconstrictor to L.A..

Constriction of blood vessels tissue perfusion Slow absorption into CVS low anesthetic blood level risk of toxicity. Higher volume of L.A around nerve duration of action bleeding at inj site

Classification
Pyrocatechin derivatives
- Epinephrine & Norepinephrine

Catecholamines
Epinephrine, Dopamine, Isoproterenol

Benzol derivatives
- Levonordefrin

Noncatecholamines
Amphetamine, Ephedrine, Methoxamine

Phenol derivatives
- Phenylephrine

Epinephrine
( Adrenaline ) A sympathomimetic amine produced by adrenal medulla. Acts directly on both and adrenergic receptors ( effect predominate ) Biotransformation : - Re uptake by adrenergic nerves - inactivated in blood by catechol-O-methyltranferase (COMT) & monoamine oxidase (MAO) - 1 % excreted unchanged in urine Clinical application :
- Acute allergic reactions - Bronchospasm - Cardiac arrest - For hemostasis - With L.A

Local anesthetics - vasoconstrictors

Ratios
Epinephrine is added to local anesthetics in extremely dilute concentrations, best expressed as a ratio of grams of drug : total cc of solution. Expressed numerically - a 1:1000 preparation of epinephrine would be
1 gram epi 1000 cc solution

1000 mg epi
= 1000 cc solution =

1 mg epi 1 cc

Local anesthetics - vasoconstrictors

Therefore, a 1 : 200,000 solution of epinephrine would be
1 gram epi 1000 mg epi

200,000 cc solution

=
or

200,000 cc solution

5 mcg epi
1 cc solution

Conclusion
Not only understanding the neurological
mechanism of orofacial pain is vital but also it

equally important to consider psychosocial

dimension of pain as well as the judicious use of drugs available & THEN proceed to manage and/or control the diverse manifestation of the pain ACCORDINGLY.

 Some pains are physical, some pains are mental, But the pain which is both physical and mental is. Dental. Ogden Nash

References
Rowbotham, Nimmo & Smith. Anesthesia, vol 2, second edition, 1990. Monheims Local Anesthesia and Pain Control in Dental Practice, eighth edition, 1997. Malamed SF. Handbook of local anesthesia. 5th ed. St. Louis: Mosby;2004. Delcomyn, Fred. Foundations of Neurobiology. W.H. Freeman and company, 1998. Yagiela JA. Local anesthetics. In: Yagiela JA, Neidle EA, Dowd FJ,editors. Pharmacology and therapeutics for dentistry. 4th ed. St. Louis:Mosby; 1998. Jeffrey. P. Okeson, Bells Orofacial pain, 5th edition, 1998.