pharmacology of local anesthetics i

Pharmacology Of Local Anaesthesia

By: Dr. Alshaimaa Ahmed Lecturer of Oral & Maxillofacial

surgery

What is local anesthetics?

Local anesthetics are drugs that block nerve conduction when applied to a nerve fiber in appropriate concentrations.

Transient completely reversible

Characteristics of an ideal local anesthetic

Reversible anesthesia. Effective. Rapid onset and sufficient duration. Stable in solution. Stable for sterilization. Easy metabolism and excretion. Not allergic Should not have any systemic side effect. Should not be expensive.

Where do Local anesthesia work?

Nerve Membrane is the site at which local anaesthetics exert its pharmacological action

Remember >>>>> Nerve cell

Remember >>>>> Cell Membrane

Remember >>>>> Nerve Conduction

How Local anesthetics work???

Theories of action of local anaesthesia: Acetyl choline theory

Theories of action of local anaesthesia:

Calcium displacement theory


Surface Charge theory


Membrane expansion theory


Specific receptor theory

Chemical structure of local anesthetics

-------------------O

R

RAromatic portion

Ester Or

AmideAmine portion

Classification of local anaesthetics:

The classification is based on the chemical structure of the intermediate chain. Commonly used amides include: lidocaine,

Mepivacaine. Commonly used esters include: tetracaine,

procaine, cocaine. There are third group know as Quinoline.


In Laboratory >>>>> local anaesthetics is poorly soluble in water and unstable on exposure to air >>>>>in this form it is on no clinical value.

For injection >>>>> local anaesthetics are dispensed as acid salts most commonly as hydrochloride salts dissolved in sterile water or saline

Dissociation of Local Anesthetics

Dissociation of Local Anesthetics & PH

The proportion of each ionic form in the sol varies with the PH of the sol or surrounding tissue

In the presence of high conc. Of H ion (low PH), the equilibrium shifts to the left and most of anesthetic sol exists in cationic form

RNH+> RN+H+

As hydrogen ion decreases ( higher pH) the equilibrium shifts to the free base form

RNH+ < RN +H+

Action on Nerve Membrane

Outside the cellRNH RN + H+ +

H + RN RNHInside the cell

Sodium channel

Lipid bilayer

PH7.4

750 250

Action on Nerve Membrane

Outside the cellRNH RN + H+ +

H + RN RNHInside the cell

Sodium channel

Lipid bilayer

PH 6

990 10

Onset of action

It is the time required for the local anesthetics to develop adequate anesthesia.It is affected by:

The pH of the tissues and pKa of the agent.

Diffusion to the site ( anatomical barrier).

Concentration.

When will it start?? “onset”

Dissociation constant “pKa ”

It measures the affinity of a molecule for hydrogen ions

A drug with lower pKa will have a rapid onset than that of higher pKa

Diffusion

Keep in Mind:

Nerve Fiber…….single nerve cell

Endoneurium ……covers each nerve cell

Fasculi……..bundles of 500 to 1000 nerve

Perinurium……….. Cover fasculi

Perilemma….. Inner most layer of perinurium

Epineurium …… alveolar connective tissue supporting fasculi and carrying nutrient vessels

Epinural sheath ……. Outer most layer of epinerium

How deep my anaesthesia “ potency”?

The potency of a local anesthesia is its ability to provide complete analgesia under almost all circumstances.

The potency of a local anesthetic depend on:

1. Lipid solubility

2. Concentration.

How long will it stay? “ Duration”

The duration of action of local anesthetics depends primarily on the redistribution of the drug away from the site of action.

Redistribution can be altered by:

1. Protein binding.

2. Vasodilator activity

3. Individual variation in response to the drug.

Duration of action

Short acting L.A (5-40 min.): Without Vasoconstrictors:

Lidocaine 2%.

Prilocaine 4%.

Mepivacaine 3%.

Duration of action

Medium –Acting (45- 90 min.)

Lidocaine 2% with epinephrine.

Mepivacaine 2% with epinephrine

Prilocaine 4% with epinephrine.

Duration of action

Long –Acting (> 90 min.)

Bupivacaine 0.5% with epinephrine.

Etidocaine 1.5% with epinephrine.

Recovery from local anaesthesia By Diffusion>>>> in slower rate than onset

Readministration of Local anesthetics

Recurrence of immediate profound anesthesia

Difficulty reachieving profound anesthesia

(Tachyphylaxis …….increased tolerance to the drug that administrated readetly)

Tachyphylaxis caused by: edema localized hemorrhage – clot formation – decreased ph of the tissue)

the local anaesthetic >>>> absorbed from the site of administration into circulation.

The presence of a local anaesthetic drug in the circulatory system means that drug will be transported to every part of the body.

What does body do to the drug ?What the drug do to the body?

Pharmacokinetics

UptakeLocal Action:

All local anesthetics posses a degree of vasoactivity, mostly vasodilatation except Cocaine which causes vasoconstriction.

Oral Route: All local anesthetics are poorly absorbed from the GIT

except cocaine Most LA undergo hepatic first-pass after

administration where 72% of the drug is transformed into inactive metabolites

Topical Route

Application to mucous membranes the tracheal mucosa Intact skin

Injection

The rate of uptake of local anesthetic after parental administration (subcutaneous, intramuscular or iv) is related to vascularity of the site and vasoactivity of the drug

Distribution

Local anesthetic absorbed and distributed to all tissues in the body.

Intravascular injection results in a sequential distribution first to the lung then rapidly distributed to other organs with large blood supplies, especially the brain, heart, liver, kidneys, spleen and then to muscle and fat.

Biotransformation

Esters

Metabolized In plasma by the enzyme pseudocholine esterase

Amides

Metabolism In the liver by microsomal enzymes

Excretion

Kidneys are excretory organs for ester & amide anesthetics and their metabolites

Patients with renal dysfunction may be unable to eliminate local anesthetics

Pharmacodynamics of Local anesthetics

LA are chemicals that reversibly block action potentials in all excitable membranes

Most of the systemic actions are related to their blood or plasma level, the higher the level the greater will be the clinical action

Central nervous system

All local anesthetics cross the blood-brain barrier At low therapeutic ,non toxic doses no CNS effects

of any clinical significance is manifested At higher toxic overdose levels the primary

clinical manifestations is generalized tonic-clonic convulsions

Between these two extremes there are preconvulsive signs and symptoms

Preconvulsive stageSigns(objectively observable)

• Slurred speech

• Shivering

• Muscle twitches

• Visual disturbance

• Drowsiness

• Disorientation

Symptoms (Subjectively felt)

• Numbness of tongue and circumoral region

• Warm flushed feeling of skin

Convulsive stage

Further elevation of LA blood levels leads to signs and symptoms of Tonic conic convulsive episode

further increase will lead to depression

preconvulsive & convulsive stages

Dose releated

Mechanism

Inhibitory impulses

Faclitatory impulses

Central nervous system

Analgesia Mode elevations

Cardiovascular system

Action on myocardium : local anesthetics produce a myocardial

depression that is related to drug blood level

Decrease cardiac excitability Decrease conduction rate Decrease force of contraction Used for treatment of cardiac dysrhythmias

Cardiovascular systemDirect action on peripheral vasculature: All Local anaesthetics cause vasodilatation

except cocaine which is a vasoconstrictor all except cocaine cause hypotension

Respiratory System

Has dual effect on respirations At non overdose level they have a direct

relaxant action on bronchial smooth muscle As a result of CNS depression respiratory

arrest may occur

Vasodilatation effect of local anesthesia

Increase rate of absorbtion Higher plasma levels of local anaesthesia Decrease in both depth and duration of local

anesthesia Increased bleeding at the site of treatment

Vasoconstrictors

vasoconstrictors constrict blood vessels

It counteract vasodilating effect of the local anesthetics.

Vasoconstrictors

Advantages:

Increase the concentration of drug at the site:

Prolong anesthetic duration.

Produces more profound anesthesia.

Decrease the blood level of the drug, thus reduce the risk of toxicity.

Decrease bleeding at site.

Vasoconstrictors

Systemic effects of vasoconstrictors:

Vasoconstrictors are sympathomimetic i.e. they mimic the action of norepinephrine on sympathetic effector organs where they bind to specific receptors called adrenergic receptors.

These receptors are divided into alpha (α) and beta (β ) receptors.

Vasoconstrictors

Alpha (α) receptors

Alpha 1 (α1)

Alpha 2 (α2)

Smooth muscles of the BVs

vasoconstriction

Inhibitory receptors

Vasoconstrictors

Beta (β ) receptors

Beta 1 (β 1)

Beta 2 (β 2)

In the heart increase rate and

force of contraction

In bronchi bronchodilationIn coronaries vasodilation.

Vasoconstrictors

Nor-epinephrine excites mainly alpha receptors and to slight extent beta receptors.

Epinephrine excites both receptors with slight predominant effect on beta ones.

Vasoconstrictors

Mode of action:

In the small amounts commonly used in dentistry,

vasoconstrictors stimulate alpha receptors located

in the walls of the arterioles in the area of injection

causing vasoconstriction which in turn slowing the

removal of the anesthetic

Vasoconstrictors

Disadvantages:

Local anesthetic molecules are relatively stable

and degrade very slowly. As a result, the shelf

life of local anesthetic depends mostly on the

stability of the vasoconstrictor.

For this reason, sodium metabisulphite is used a

s a preservative or stabilizer for the

vasoconstrictor molecule.

Systemic effect

Vasoconstrictors

Dilution of vasoconstrictors:

The dilution of vasoconstrictors is commonly

referred to as a ratio (e.g. 1:1000) this ratio

can be interpreted and converted as the

following:

1:1000 means that there is one gram

(1000mg) of the drug in 1000 ml (1 litre) of

solution, or 1.0 mg/ml of solution.

What is meaning of 1:100.000 epinephrines ?

1: 1000 = 1 mg / ml

1: 50.000 = 0.02 mg / ml

1: 100.000 = 0.01 mg / ml

1: 20.000 = 0.05 mg / ml

Content of carpule contain 1: 100.000 epinephrine.

0.01 mg x 1.8 ml

----------------------- = 0.018 mg / carpule.

11:100.000 = 0.01

mg / ml 1 ml

? 1.8 ml

Vasoconstrictors

Epinephrine:

Nature:

Known as adrenaline.

Most commonly used due to its strong action.

Stability:

Unstable, undergo oxidation by heat.

Sodium bisulphite preservative used to delay oxidation

Epinephrine (adrenaline):

Systemic effect:

Increase blood pressure.

Increase heart rate.

Increase cardiac output.

Increase myocardial oxygen consumption.

Vasculature

Hemostasis: vasoconstriction followed by vasodilatation

Termination : reuptake – inactivated in blood by COMT & MAO.

Available concentration: 1:50.000- 1: 100.000 (in Canada) and 1:80.000- 1:300.000 in other countries

Maximum permeable dose:

For healthy patient 0.2mg in appointment:

10 ml of 1:50,000 dilution (5 crtridges).

20 ml of 1:100,000 dilution (11 cartridges).

40 ml of 1:200,000 dilution (22 cartridges).

For cardiac patient 0.04 mg/appointment:

2ml of 1:50,000 dilution (1 cartridge).

4ml of 1:100,000 dilution (2 cartridges).

8ml of 1:200,000 dilution (4 cartridges).

Vasoconstrictors Norepinephrine (levarterenol):

Nature:

Known as noradrenaline .

Stability:

Undergo deterioration on exposure to light.

Systemic effect:

Increase blood pressure.

Decrease heart rate.

Decrease cardiac output.

It is 1/8 as effective in raising the blood sugar as epinephrine.

The norepinephrine act almost on receptors . It is one fourth as potent as epinephrine.

That will lead to severe vasoconstriction in the peripheral circulation (ischemia in the palate )

Available consentration 1:300.000

Norepinephrine:


For healthy patient 0.34 mg/appointment.

For cardiac patient 0.14 mg/appointment.

Vasoconstrictors

Levonordefrin:

Nature:

It is synthetic vasoconstrictor. It has direct action on the receptors(75%) & it is 15% as potent as epinephrine

Stability:

Unstable, undergo oxidation and deterioration.

Sodium bisulphite used to delay oxidation.

Systemic effect:

Less effective in contrating blood vessels and in raising blood pressure than epinephrine.

It is 1/10 as active as epinephrine in increasing blood sugar.

Levonordefrin:

Concentrations in L.A:

1:20,000.


Maximum dose is 1 mg/appointment (11 cartridges).

Vasoconstrictors

Phenylephrin:

Nature:

Synthetic. It has direct action on the receptors(95%) & it is 5% as potent as epinephrine

Stability:

Most stable vasoconstrictor used in dentistry.

Concentrations in L.A:

Used in dental practice with 4% procaine in 1:2500 dilution.

Phenylephrin:


For healthy patient 4 mg/appointment.

Far cardiac patient 1.6 mg/appointment.

Vasoconstrictors

Felypressin:

Nature:

Synthetic analogue of the antidiuretic hormone vasopressin. Act directly on the smooth muscles in the wall of the blood vesseles

It is non sympathomimetic amine, so it has no effect on adrenergic nerve transmission safe for hyperthyroid patients.

Systemic effect:

It has oxytoxic action so it is contraindicated in pregnant women.

Concentration in L.A:

Used in dental practice with 3% prilocaine in a 0.03 IU/ml dilution.


For cardiac patients is 0.27 IU

What we will find in the market????

Ester Types Local Anesthesia

Procaine (Novocain) Propoxycaine Tetracaine (topical anaesthesia)

Procaine ( Novocain)

Nature → ester types L.A.

Metabolism → in plasma by pseudocholinestrases enzymes.

Excretion → Via kidney.

Onset: 6-10 min

Dental concentration → 2% or 4% conc.

2% solution gives from 12-15 minutes of anesthesia

The addition of 1:100.000 adrenaline prolong the duration to 30-45 minutes

The addition of 1:50.000 adrenaline prolong the duration to 60-90 minutes.

Propoxycaine HCL

Nature → ester types L.A.

Metabolism → in plasma by pseudocholinestrases enzymes.


Onset: rapid 2-3 min

Dental concentration → 0.4% conc.

It is combined with procaine to provide more rapid onset and a more profound anaesthesia

Amides Local Anesthesia

Lidocaine. Mepivacaine. Articaine HCl. Bupivacaine HCL Prilocaine HCL

Lidocaine(Lingospan, octocaine, Xylocaine)

Amide.

Metabolism: liver.

Excretions: kidneys.

Duration of action: without V.C. 5 mins.

Pregnancy classification: B

Onset of action :2-3 min.

Effective dental concentration: 2%

Maximum dose → 300 mg without V.C & 500 mg with V.C

Mepivacaine HCl( carbocaine, Isocaine, polocaine,

scandanest) Amide.

Metabolism: liver.

Excreation: kidneys.

Vasodilating properties: produce slight V.D.

Duration of action: without V.C. 20-40 min.

Onset of action: rapid 1.5-2 min.

Effective dental concentration: 3% without V.C.; 2% with a V.C.

Pregnancy classification: C

Concentrations of V.C.: 2% with levonordefrin (1:20,000), 2% with epinephrine (1:100,000).

Articaine HCl( Articadent, orbbloc, septocaine)

Amide.

Metabolism: it is the only amide-type local anesthetic that contains an ester group, so biotransformation occurs in both the plasma and liver.

Excretion: kidneys.

Onset of action: 1-3 min.

Effective dental concentration: 4% with 1:100,000 or 1:200,000 epinephrine.

Clinically it is claimed that maxillary buccal infiltration, on occasion, provides palatal soft- tissue anesthesia.

It is also claimed that articaine can provide pulpal and lingual anesthesia when administered by infiltration in the adult mandible

Prilocaine (Citanest)

Nature → Amides Local Anesthesia.

Metabolism → In liver, kidney & lung so it undergo biotransformation more rapidly than other amide.

Excretion → Via kidney faster than other amide. (most safe)

Dental concentration → 4% with or without V.C.

V.C used with it is 1:200.000 Epinephrines.

Onset of action → Its onset of action is slightly slower than Lidocaine

Maximum dose → 6 mg/ kg body weight or 400 mg

Bupivacaine (Marcaine)

Nature → Amides Local Anesthesia + long acting L.A.

Metabolism → In liver.


Dental concentration → 0.25% – 0.5% conc. With 1:200.000 Epinephrine .

Onset of action → Rapid onset of action equal to lidocaine.

Maximum dose → 2 mg/ kg body weight for adult- 90 mg as maximum dose .

What is meaning of 2% xylocaine ?

2% xylocaine = 20 mg / ml.

Content of 2% xylocaine in one carpule = 20 mg x 1.8 ml = 36 mg/carpule.

20 mg / ml

1 ml

? 1.8 ml

Maximum doses of Local Anesthesia

The doses of local anesthetic drugs are presented in terms of milligrams of drug per unit of body weight.

The administration of a maximum dose based on body weight produces a local anesthesia blood level just below the threshold for an overdose (toxic) reaction.


Local anesthetic

mg/Kg MRD (mg)

Articaine

With V.C.7.0 500

LidocaineNo V.C.

With V.C.4.44.4

300300

MepivacaineNo V.C.

With V.C.

4.44.4

300300


Local Anesthetic

Percent concentration mg/ml X 1.8 ml = mg/

cartridge

Articaine 4 40 72

Lidocaine 2 20 36

Mepivicaine23

2030

3654

Calculation of the max dose Patient : 22 years old, Healthy , 50 kg Local Anaesthesia >>>> Lidocaine 2% epinephrine

1:100.000 Lidocaine 2% = 36mg/ cartilage Patient max dose= 50* 7 mg/kg = 350 mg (MRD) Number of cartilage = 350/ 36 = 9 cartilage

What if the patient is cardiac ?

What if the dentist use another local anaesthetic drug ?

Total dose of Both local anaesthetics should not exceed the lower of the two calculated dose.

What is maximum dose of V.C. in normal and cardiac patients?

Type of V.C. Maximum dose in

normal patient

Maximum dose in cardiac

patient

Epinephrine1:100.000 0.2 mg 0.04 mg

Norepinephrine

1 :30.0000.34 mg 0.14 mg

Levonordefrine

1:20.0001 mg 0.2 mg

Phenylephrin

1:25004 mg 1.6 mg

Felypressin

0.03 IU0.27 IU,

Factor in selection of a local anesthesia for a patient

Length of time pain control is necessary Potential need for posttreatment pain control Possibility of self mutilation in the post operative

period Requirment for hemostasis Presence of any contraindication to local anaesthetic

solution selected for administration

Topical anesthesia

Topical Anesthesia

Produce painless needle injection.

Used for some procedures as removal of very loose primary teeth or suture removal or before gingival curettage.

Reduce patient apprehension.

Topical Anesthesia

Characteristics:

Can not penetrate intact skin.

Its concentration is higher than injectable one to

facilitate its diffusion through mucous membrane.

Higher concentration increase its risk of toxicity

because the topical anesthesia has no V.C.

Topical Anesthesia

Characteristics:

The anesthesia is effective only on 2.3 mm depth of

the tissues on which it is applied.

Available in the form of spray or gel, the gel form is

more preferred because it can be dispensed in a

premeasured doses.

Topical Anesthesia

Types of local anesthesia:

Benzocaine.

Lidocaine HCl.

Lidocaine base.

Tetracaine HCL.

Cocaine HCl.

EMLA (Eutectic Mixture of Local Anesthesia).

pharmacology of local anesthetics i

Documents