Pharmacology of Local Anesthesia Part I

Pharmacology of Local AnesthesiaPart I

Dr. Rahaf Al-Habbab BDS. MsD.Diplomat of the American Boards of Oral and

Maxillofacial Surgery2013

Pain

Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or

described in terms of such damage.

Anaesthesia

Anaesthesia is the loss of consciousness and all form of sensation .

Local Anaesthesia is the local loss of sensation, disappearing in the following sequence ;

Pain→ Temperature→ Touch→ pressure→ Motor.

In dentistry, Only loss of pain sensation is desirable. Local Analgesia.

How Does a Nerve Impulse Occur?

Starts with a Stimulus (-90mv_-60mv) →

Depolarization of the nerve →

Na+ flows from extracellular to Intra-cellular space →

Repolarization →

K+ flows from Intra-cellular to extra-cellular space

Threshold Potential

Local Anesthesia

Normal

Between Depolarization and Repolarization, Propagation of the

Impulse occur

Local Anesthetic Agents

Are drugs that block nerve conduction when applied locally to nerve tissues in appropriate concentrations, acts on any part of the nervous system, peripheral or central and any type of

nerve fibres, sensory or motor.

Each Carpule

Local Anesthetic

Vasoconstrictor

Vehicle to make the solution isotonic

Preservative

Local Anesthesia

Chemistry:They are weak bases, insoluble in waterconverted into soluble salts by adding Hcl for clinical use.

They are composed of three parts:Aromatic (lipophilic) residue with acidic group R1.

Intermediate aliphatic chain, which is either ester or amide link R2.Terminal amino (hydrophilic) group R3 and R4.

R1CO R2 N

R3

R4

Mechanism of Action

Two Theories

Membrane expansion theory Specific receptor theory

Mechanism of ActionMembrane expansion theory

A non-specific mechanism similar to the action of general anesthetic agents.

Relies upon the lipophilic moiety of local anesthetic agent.

The molecules of the agent are incorporated into the lipid cell membrane.

The resultant swelling produces physical obstruction of the sodium channels, preventing nerve depolarization

Membrane Expansion Theory

Mechanism of Action Specific receptor theoryInject

Properties of Ideal Local Anesthetic

Possess a specific and reversible action.They stabilize all excitable membrane including motor neurons

Non-irritant with no permanent damage to tissues.No Systemic toxicity

High therapeutic ratio.

Rapid onset and long durationActive Topically or by injection

Pharmacology of Local AnesthesiaPart II

Dr. Rahaf Al-Habbab BDS. MsD.Diplomat of the American Boards of Oral and

Maxillofacial Surgery2013

Classification

Classified according to their chemical structures and the determining factor is the intermediate chain, into two groups:

Ester Amide

They differ in two important aspects:Their ability to induce hypersensitivity reaction.Their pharmacokinetics - fate and metabolism.

Ester Class

Esters: Benzocaine Procaine

Ester Class

Metabolized by Plasma Pseudocholinestrase enzyme, and partially in kidney during excretion.

Allergic reaction to esters: Does not occur to the ester agent but rather to (PABA)

Lead to the formation of Para-Aminobenzoic Acid (PABA)- Highly Allergenic

Some patients have Atypical form of pseudocholinesterase that result in the inability to metabolize esters and therefore induce toxicity.

Amide Class

Amides: Lidocaine Mepivicaine Prilocaine Bupivicaine

Amide Class

Metabolized in the liver

An exception is Prilocaine, where it is metabolized mainly in the liver with some possibility in Lung.

Excreted by Kidneys

Allergy is rare

• The kidneys are the primary execratory organ for both types of local anesthesia

• Impairment in renal function will result in incomplete removal of local anesthesia and their metabolites from the blood and possibility of toxic reaction

Physiochemical properties

These are very important for local anaesthetic activity.

Ionization: They are weak base and exist partly in an unionized

and partly in an ionized form. The proportion depend on:

The pKa or dissociation constant The pH of the surrounding medium.

Both ionizing and unionizing are important in producing local anaesthesia.

Physiochemical propertiespKa

When pKa = pH, there is equal proportion of ionized andunionized form of an agent are present in equal amounts.

The lower the pKa , the more the unionized form, the greater the lipid solubility → Higher the Onset

The higher the pKa , the more the ionized form and the slower the lipid solubility → Lower the Onset

Physiochemical propertiespKa

In general the amide type have lower pKa, and greater proportion of the drug is present in the lipid-soluble (unionized) form at the physiological pH

This produces faster onset of action. Lidnocaine 1 – 2 minutes (Amide) Procaine 2 – 5 minutes (Esters)

The lower the pKa the faster the onset

Physiochemical propertiesPartition coefficient

This measures the relative solubility of an agent in fat and water.

High numerical value means: High lipid-soluble less water-soluble.

More fat solubility, means rapid crossing of the lipid barrier of the nerve sheath.

The greater partition coefficient, The faster the onset

Physiochemical propertiesProtein binding

Local anesthetic agents bind with: α1-acid glycoprotein, which possess high affinity but

low capacity. Albumin, with low affinity but high capacity

The binding is simple, reversible and tend to increase in proportion to the side chain.

Lidnocaine is 64% bound, Bupivacaine is 96%

The duration of action is related to the degree of binding .Lidnocaine 15 – 45 minutes, Bupivacaine 6 hours

Physiochemical propertiesVasodilatation ability

Most Local anaesthetics possess a vasodilatory action on blood vessels except Cocaine.

It influence the duration of action of the agent.Prilocaine is 50% bound to proteins but has a longer

duration than Lidnocaine (64%) since it possess no strong vasodilatory effect.

Affect the duration of action of the agent

Summary

Rapid Onset: Low pKa value– more unionized – Amides Higher Partition coefficient – more lipid soluble High PH

Long duration of action: High protein binding. Low vasodilatation property.

Pharmacology of Local AnesthesiaPart III

Dr. Rahaf Al-Habbab BDS. MsD.Diplomat of the American Boards of Oral and

Maxillofacial Surgery2013

Physiochemical properties

Maximum Dose (mg/kg)

Duration of Action

Onset pKa Agent

4.5 Short Fast 7.8 2% Lidocaine

7 Moderate Fast 7.8 2% Lidocaine + Epi

6.6 Short-Moderate

Fast 7.7 3% Mepivicaine

6.6 Moderate Fast 7.7 2% Mepivicaine + Levo

1.3 Long Moderate 8.1 0.5% Bupivicaine +EpiAdult-7Child-5

Moderate Fast 7.8 4% Articaine + Epi

8 Short Fast 7.8 4% Prilocaine

8 Moderate Fast 7.8 4% Prilocaine + Epi

8 Long Fast 7.9 1.5% Etidocaine + Epi

Local Anesthesia

Local Anesthetic Concentration0.5%=5mg/ml1.0%=10mg/ml2.0%=20mg/ml3.0%=30mg/kl4.0%=40mg/ml

Note: Each Carpule contains 1.8 cc

Vasoconstrictor Concentration

1:20 000=0.05 mg/ml (50mcg/ml)

1:50 000=0.02mg/ml (20mcg/ml)

1:100 000=0.01mg/ml (10mcg/ml)

1:200 000=0.005mg/ml (5mcg/ml)

Therefore 1 carpule of 2% drug with 1:100 000 Vasoconstrictor contains36mg of Drug0.018mg or 18mcg of vasoconstrictor

How to calculate the maximum dose of L.A?

Multiply patients weight (kg) by the maximum dose of the L.A Divide the result by the L.A value (1.8x20=36 in 2% lidocaine)

Example:Calculate the maximum dose of 2% Lidocaine with 1:100 000 epi,in a 150 lbs patient: • 150 ÷ 2.2 = 68kg• 68 x 7 = 477mg• 477 ÷ 36 = 13.25 Cartridge

Vasoconstrictors

Originally added to reduce systemic uptake in an attempt to limit toxicity

Prolong the duration Produces profound anaesthesia. Reduce operative bleeding.

Two types:

Sympathomimetic naturally occurring. Synthetic polypeptides, Felypressin

Epinephrine (Adrenaline)

Hormone and Neurotransmitter released from the Adrenal Gland, act on Adrenergic receptors.

Has both Alpha and Beta activity, affecting α1, α2, β1, β2 and β3

Uses in dentistry:• Local anaesthetic solution.• Gingival retraction cords.• In the ER as life-saving drug in anaphylaxis.

Mechanism of action:• Interact with adrenergic receptors in the vessels and muscles:

α1 & α2 producing vasoconstriction in skin & MM β2 stimulation causing vasodilatation in skeletal muscles.

Vasoconstrictors Systemic effect

Being a naturally occurring hormone, it exert a number ofphysiological responses on the different systems;

The heart :Has direct and indirect action.

Direct action on β1 receptors increases the rate and force of contraction raising cardiac output.

Indirect action, increase pulse and cardiac output, lead to rise in systolic blood pressure, (not with dental dose)

Vasoconstrictors Systemic effect

Blood vessels:Contain α1, α2 and β2 adrenoreceptors in the vessels of theskin, mucous membrane and skeletal muscles. α1 receptors causes vasoconstriction since theyare susceptible to endogenous nor-epinephrineand exogenous epinephrine. Reduce operativebleeding

Vasoconstrictors Systemic effect

Haemostasis: The vasoconstriction effect. Adrenaline promote platelets aggregation in the

early stages.

Lungs: Stimulation of β2 receptors in the lung lead to

bronchial muscle relaxation, life-saving in bronchial (spasm)

constriction during anaphylactic reaction.

Systemic EffectSummery

Vasoconstriction (α1) Increase Heart Rate (β1) Increase Cardiac Output (β1) Decrease Blood Pressure (α2) (β2 effect in skeletal muscles) Bronchodilatation (β2 effect on smooth muscles)

Local Anesthesia ToxicityCauses

Accidental IV administration

Overdose

Local Anesthetic Toxicity Risk Factors

Geriatric (Pediatric): Slower metabolism Multiple medications can cause adverse drug reaction

Cimitidine medication: Histamine H2-Receptor Antagonist, inhibits P-450 (Hepatic oxidative enzyme)

needed for metabolism, causes accumulation of local anesthetic

Propranolol or β-blockers: Decrease hepatic blood flow decreasing L.A clearance

Administration of Opioids with L.A:Increases sensitivity

Local Anesthesia ToxicitySigns and Symptoms

CNS Effects:• L.A readily crosses the BBB• Usually first S/S or overdose are CNS related• Spectrum of activity with increasing dose.

CVS Effect:• More resistant than CNS so appears later• At toxic doses LA causes depression of myocardium and

decreased SVR

Thank You