Local anaesthetics Dr. S. Parthasarathy - PowerPoint Presentation

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Local anaesthetics

Dr. S. Parthasarathy

MD., DA., DNB, MD (

Acu

),

Dip.

Diab

. DCA, Dip. Software statistics

PhD (

physio

)

Mahatma Gandhi medical college and research institute ,

puducherry

– India

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What is it ??

A drug reversibly blocks the nerve conduction beyond the point of application, if applied in appropriate concentrations .

Other drugs !!

Quinidine

,

phenergan

, TCADs --- no

Slide3

History

Koller

is credited with introducing local anesthetics into medical practice when he used cocaine to numb the cornea before operating on the eye.

Isolation of

cocaine by

Neimann

, in

1860

Procaine was

first synthesized

in 1904,

In

lidocaine

1943 -- but the hierarchy is

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History

ESTERS

AMIDES

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The basic chemical structure- 3 parts:

1.

Lipophilic

group-

an aromatic group, usually an unsaturated benzene ring.

2

. Intermediate bond-

a hydrocarbon connecting chain, either an ester (-CO-) or amide (-HNC-) linkage. The intermediate bond determines the classification of local anesthetic.

3.

Hydrophilic group-

a tertiary amine and proton acceptor.

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COO - ester

CONH – amide

OR

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Amides Esters

Bup

i

vacaine

Benzocaine

Et

idocaine

Chloroprocaine Levobupi

vacaine Cocaine L

idocaine Procaine Mep

ivacaine Tetracaine

Pr

i

locaine

Rop

i

vacaine

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Isomerism

Many medications contain

chiral

molecules which exist as

stereoisomers

.

Chiral

molecules are asymmetrical and the direction of the configuration helps to categorize the isomer

. R and SPolarized light to right – D

Polarized light to left - L

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Bupi and ropi

Bupivacaine

is a long acting amide local anesthetic that can be associated with significant toxicity issues.

S-

bupivacaine

is almost as potent as the

racemic

preparation but is less toxic. It takes larger doses of S-

bupivacaine

to cause cardiac arrest and seizure activity than

racemic

preparations. Ropivacaine is a second local anesthetic that is a pure S-

ropivacaine

.

Slide12

Structure Activity Relationships (Onset, Potency, Duration)

p L P = O P D

p

=

pKa

=

o

nset

L

= lipophilicity =

potency

P = protein binding = duration

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Frequency dependent block

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Local anesthetics are prepared as a water soluble hydrochloride salt and generally have a pH of 5-6.

If the preparation contains epinephrine, the solution must be acidic to create a stable environment. pH of 3-4.

. To enhance clinical onset, carbonated solutions of epinephrine containing local anesthetics have been used instead of HCL solutions.

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pKa

Because local anesthetics are weak bases, increasing the pH (“

alkalinization

”) of solution increases the ratio of base to

cation

.

Henderson-

Hasselbalch

equation can be used to

quantitate the ratio:pKa

(local anesthetic) – pH(solution) = Log ([cation

]/[base])NH3

+ HCl = NH4+ +

cl

-

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pK

a

(local anesthetic) – pH(solution) =

Log ([

cation

]/[base])

If pH is less , the cationic form is more

If the pH is more the unionized form is more

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Local

anaesthetic

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Exceptions to pKa

Two notable exceptions are

chloroprocaine

and

benzocaine

.

Chloroprocaine

has a high

pKa and rapid onset.

Benzocaine does not exist in an ionized form and exerts its effects by alternate mechanisms.

Slide23

Lipophilic

Slide24

Nerve cell membrane

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Pharmacodynamics

Analgesic effect has been reported following intravenous

lidocaine

administration in many acute and chronic conditions.

Other than Na channels

inhibition of G-protein coupled receptor signaling

Inhibit NGF

Slide26

Differential blockade

Bupivacaine

and

etidocaine

are both potent, long acting local anesthetics.

Bupivacaine

exhibits a more potent sensory than motor block.

Etidocaine

exhibits an equally effective sensory and motor block.

Ropivacaine, on the other hand, exhibits a potent sensory block similar to

bupivacaine but motor blockade appears less intense.

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most common clinical use of local anesthetics

Regional anesthesia and analgesia.

Topical

Infiltration

Blocks

Neuraxial

etc

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Other actions

Blunt responses to tracheal instrumentation

attenuating increases in intraocular pressure, intracranial pressure, and intra-abdominal pressure during airway instrumentation.

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Other actions The primary site of action is the myocardium, where decreases in electrical excitability, conduction rate, and force of contraction occur.

Depressed NMJ

The local anesthetics depress contractions in the intact bowel and in strips of isolated intestine.

also relax vascular and bronchial smooth muscle,

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Additives

Carbonation

of local anesthetics results

in a more rapid onset and a more profound degree of conduction blockade, ph higher , More

nonionized

form, speeder onset ,

CO2 released

diffues

inside – acidic- more ionized better action

Less tachyphylaxix Sodabicarb

1 ml / 20 ml of lignocaine

0.1 ml /20 ml of bupivacaine

Slide32

Additives Vasoconstrictors – epinephrine – 1 in 2

lakh

– 5

mic

/ ml.

Mixtures of local

anaesthetics

–

EMLA Ligno

+ bupi = OK but ?? A solution containing 50% of the toxic dose of local anesthetic A, and 50% of the toxic dose of local anesthetic B, will have the same implications as 100% of the toxic dose of either local anesthetic alone

.

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Additives

Glucose

The specific gravity of hyperbaric (or ‘heavy’)

bupivacaine

is

1.026

at 20 ◦C.

The specific gravity of cerebrospinal fluid is

1.005

at 37 ◦C,Warming of the local anesthetic solutions can also bring about a modified onset time

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Additives

Hyaluronidase

, supplied as a white fluffy powder, is used to facilitate the spread through connective tissues following subcutaneous or intramuscular injection.

Slide35

Additives Drug Receptor Uses

Opioids

/ mu and kappa Central ,

periph

Clonidine

2-adrenoceptor Central

periphe

Ketamine

NMDA Central

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Duration of Action

. Local anesthetics are classified as follows:

Short acting: procaine and

chloroprocaine

Moderate acting:

lidocaine

,

mepivacaine

, prilocaine Long acting:

tetracaine, bupivacaine

, etidocaine,

ropivacaine, levobupivacaine

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Pharmacokinetics

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Metabolism

The metabolism : ester vs. amide.

Ester local anesthetics undergo extensive hydrolysis in the plasma by

pseudocholinesterase

enzymes (plasma cholinesterase or

butyrylcholinesterase

). - - rapid, resulting in water soluble metabolites which are excreted in the urine.

The ester that is an exception is cocaine. In addition to ester hydrolysis cocaine is partially metabolized in the liver (N-

methylation

).

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Metabolism Procaine and

benzocaine

are metabolized to p-

aminobenzoic

acid (PABA), which has been associated with allergic reactions

When ester local anesthetics are placed in the CSF, metabolism does not occur until there has been vascular absorption of the local anesthetic. CSF does not contain esterase enzymes

.

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Metabolism Amide local anesthetics are metabolized primarily by

microsomal

P-450 enzymes in the liver

(N-

dealkylation

and hydroxylation)

and, to a lesser extent, in other tissues.

Most studied

lignocaine

Monoethyl

glycine xylidide

--- xylidine

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Some drug interactions

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Side effects

The hydrolysis of all ester-linked local anesthetics leads to the formation of

para-aminobenzoic

acid (PABA) or a substituted PABA.

True allergic reactions are associated with amino ester-linked local anesthetics, not amino amide-linked one

Tissue Toxicity

Myotoxicity

and neurotoxicity

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Cardiovascular Toxicity

bupivacaine

exhibits a much stronger binding affinity to resting and inactivated sodium channels than

lidocaine

Bupivacaine

dissociates from sodium channels during cardiac diastole much more slowly than

lidocaine

Hence

bupi

cardiotoxicity is more dangerous

Slide46

Methemoglobinemia

The metabolism of

prilocaine

in the liver results in the formation of

O-

toluidine

, which is responsible

for the oxidation of hemoglobin

to methemoglobin

. The methemoglobinemia associated with

prilocaine is spontaneously reversible or may be treated by IV

methylene blue.

Slide47

Toxicity IV > tracheal >

intercostal

> caudal >

paracervical

> epidural > brachial > sciatic > subcutaneous

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Treatment of Systemic Toxicity from Local Anesthetics

Prevention

aspiration for blood,

use of a small test dose of local anesthetic

slow injection

fractionation of the rest of the dose of local anesthetic

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Treatment of systemic toxicity is primarily supportiveInjection of local anesthetic should be stopped.

Oxygenation and ventilation should be maintained

If needed

intubate

and ventilate

Midaz

,

thio

if seizures , ephedrine IVF

IV lipid for bupi

Can we give propofol??

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Neural Toxicity of Local Anesthetics

local anesthetic–induced injury to Schwann cells, inhibition of fast axonal transport, disruption of the blood-nerve barrier, decreased neural blood flow disruption of cell membrane integrity

radiculopathy

to be approximately 0.03% and of paraplegia to be approximately 0.0008%.

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Myotoxicity

Toxicity to skeletal muscle is an uncommon side effect of local anesthetic injection.

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Individual local

anaesthetics

--Some pearls

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Cocaine

Sympathetic stimulation

Vasoconstriction

Temperature rise

Local 10% solution and paste

Brompton

mixture with heroin for terminally ill

Slide54

Procaine Very short acting– no toxicity

weak drug

Vasodilator

Suxa

PABA – allergic reaction

No longer in use

Slide55

Cinchocaine (dibucaine)

Dibucaine

number

Scoline

apnea

Slide56

Lidocaine

is also used in ointment, jelly, viscous, and aerosol preparations for a variety of topical anesthetic procedures.

IVRA

Anti

arrythmic

Pain relief - IV

inherent potency, rapid onset, moderate

duration of action, and topical anesthetic activity

Slide57

Mepivacaine

similar to that of

lidocaine

It is ineffective as a topical anesthetic agent.

The metabolism of

mepivacaine

is greatly prolonged in the fetus and newborn; not employed for obstetric anesthesia

Slide58

Drug doses and toxic doses

Procaine

7 mg/kg; not to exceed 350-600 mg

Chloroprocaine

Without epinephrine: 11 mg/kg; not to exceed 800 mg total dose

With epinephrine: 14 mg/kg; not to exceed 1000 mg

Slide59

PrilocaineBody weight <70 kg: 8 mg/kg; not to exceed 500 mg

Body weight >70 kg: 600 mg

Ropivacaine

5 mg/kg; not to exceed 200 mg for minor nerve block

Slide60

Lidocaine

Without epinephrine: 4.5 mg/kg; not to exceed 300 mg

Lidocaine

with epinephrine With epinephrine: 7 mg/kg

Bupivacaine

Without epinephrine: 2.5 mg/kg; not to exceed 175 mg total dose

Bupivacaine

with epinephrine

With epinephrine: Not to exceed 225 mg total dose

Slide61

What does a local do ??

Local anesthetic is deposited near a nerve.

A portion of the local anesthetic is removed due to tissue binding and circulation.

If the local anesthetic is an ester, a portion of the deposited local anesthetic will be removed by local hydrolysis, in addition to tissue binding and circulation.

The remaining local anesthetic penetrates the nerve sheath.

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What does a local do ?? 5. Local anesthetic penetrates the axon membranes and

axoplasm

.

This step is dependent on

pKa

and

lipophilicity

.

6. Local anesthetic binds to Na+ channels preventing their opening by inhibiting conformational changes

7.Local anesthetics may also bind to the channel pore and block the passage of Na+.

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What does a local do ??

8.During onset, impulse blockade is incomplete. Partially blocked fibers are inhibited by repetitive stimulation. The reverse is true during recovery.

9. The primary route for local anesthetics is the hydrophobic route, within the axon membrane.

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What does a local do ?? 10

. Clinical onset of blockade is due to the slow diffusion of local anesthetic molecules into the nerve, NOT by binding to ion channels and inhibition of impulse propagation, which occurs at a faster rate. Recovery occurs in reverse.

LA s have no role in RMP.

Slide65

Individual detailing of local

anaesthetics

are not done in the hope

That the individual postgraduates will read

Slide66

Thank you all