Local Anesthetics Sar

SAR OF

LOCAL ANESTHETICS

Somnath Mondal

ChemistryAll local anesthetics are weak bases, classified as tertiary amines.

IIIIIII

O

NH C CH2 N

CH2

CH2

CH3

CH3

CH3

CH3

I

I

I

I

I

I

I

I

I

IIIIII

I. AROMATIC RING

II. ESTER OR

AMIDE LINKAGE

III. HYDROCARBONCHAIN

IV. TERTIARY AMINE GROUP

Component structure of local anesthetics that form four distinct chemical subunits.

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O

C CH2 N

CH2

CH2

CH3

CH3

CH3

CH3

CH2H2N

Amino-esters

O

NH C CH2 N

CH2

CH2

CH3

CH3

CH3

CH3

Amino-amides

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O

HN C CH2 N

CH2

CH2

CH3

CH3

CH3

CH3

Procaine oORr Novocaine

Aromatic Amides

O CH2 N

CH2

CH2

CH3

CH3

O

C CH2H2N Lidocaine or lognocaine

Aromatic acid esters

C

O

O

N CH3

COO CH3

Cocaine

Natural Ester

I. AROMATIC RING

Lipophilic Portion

II. INTERMEDIATE CHAIN

Ester or amide linkage along with hydrocarbon chain

III. TERTIARY AMINE GROUP

Hydrophilic PortionSomnath Mondal

CH2 N

R2

R3I. AROMATIC RING

II. ESTER OR

AMIDE LINKAGE



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I.AROMATIC RING Lipophilic Portion

R1

YZ N

R3

R2

n

亲脂部分

NH S

O> > >

When par a or or t ho posi t i on have el et r on donat i ng gr uop, act i vi t y i ncr eased

The lipophilic center is usually either a carbocyclic or heterocyclic ring system

Most of the cases it is Carbocyclic and in few cases it is heterocyclic ring and their reactivity shown below

CarbocyclicAromatic ring

SN O

i) The aryl radical (Aromatic ring )attached directly to the carbonyl group enhances local anaesthetic activity. It is lipophilic centre of compound.

a) Ring Nature:

II. ESTER OR

AMIDE LINKAGE CH2 N

R2

R3III. HYDROCARBON

CHAIN


I. AROMATIC RING

R1

R’1

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ii) The compounds containing aryl-vinyl group (Ar-CH = CH -) does not having local anaesthetic activity, because of the mesomeric effect of aryl radical does not extend to carbonyl group.

iii) Alicyclic and aryl aliphatic carboxylic acid esters are also active local anesthetics

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b) Aromatic ring Substituents:

Local anaesthetic activity improves if the aryl lipophilic center (Specially ortho or Para) has electron donor substitution but decreases with electron acceptor substituents.This is may be due to i) Electron releasing group alkoxy, amino and alkyl amino …by releasing

electron ….. increases electron density of carbonyl oxygen….impart more stability to this group ..hence enhances the activity.

ii) Some believe that the electron releasing group (e.g. alkyl substitution -CH3) in aryl group at ortho or Para position enhances the activity by providing steric hindrance to the hydrolysis of amide linkage and contributes lipid solubility.

iii) The number of methylene groups is substituted to aryl moiety; the maximum activity is achieved for the C4 to C6 homologues.

II. ESTER OR

AMIDE LINKAGE CH2 N

R2

R3III. HYDROCARBON

CHAIN

IV. TERTIARY AMINE GROUPR1

R’1

I. AROMATIC RING

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II. INTERMEDIATE CHAINEster or amide linkage along with hydrocarbon chain

i) Ester or amide linkage

II. ESTER OR

AMIDE LINKAGE CH2 N

R2

R3



R’1

O COOH2N CH2 CH2 N

C2H5

C2H5Procaine

C O C

O

Eg. Cocaine, Procaine, TetracaineEster

CN C

O

Amide, Lidocaine,Mepivicaine,Bupivacaine

O NH

CH3

CH3

CH2C

O

N

C2H5

C2H5LidocaineSomnath Mondal

Ester or amide linkage between the aromatic moiety and hydrocarbon chain and its modification with functional group like

C S

O

C O

O

C S

O

C N

H

O

C CH2

O

C N

H

O

C C

H2

O

affect both Pharmacodyanamics & Pharmacokinetics property of the Localanesthetics.

PharmacodyanamicsThe order of conduction anaesthetic potency i.e activity

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Pharmacokinetics properties like stability, Metabolism (metabolic product) which in turn alter the toxicity profile of the particular group of compound.

The order of Stability

C O

O

C S

O

C N

H

O

C CH2

O

Ester linkage Local anesthetics are hydrolyzed in plasma by pseudocholinesterase. One of the by-products of metabolism is paraaminobenzoicacid, the common cause of allergic reactions seen with these agents.

Where, as amide linkage Local anesthetics, are having very low

incidence of allergic reaction as amide’s biotransformation depends on

Hepatic metabolic enzymes due to which amide’s derivatives are having

Longer duration of action than esters.

True allergic reactions are rare (especially with lidocaine).

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ii) Hydrocarbon chain

II. ESTER OR

AMIDE LINKAGE CH2 N

R2

R3



R’1

2-3 carbon short chain is optimum for local anesthetics activity, chain length more than 3 carbon atom decreases the activity.

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III.HYDROPHILIC PORTION

.

The amino alkyl group is the hydrophilic part of molecule. In general amino alkyl group is not necessary for activity, but it is used to from water soluble salts. . Example : Benzocaine

Hence, depending, upon the nature of the nitrogen of the amino group, both activity of local anaesthetic and irritation property alters.Hence, Most of the available compounds are having tertiary nitrogen atom.

For optimum activity, the Nitrogen must be Tertiary (3o) or Secondary (2o). But when the nitrogen atom is Primary (1o) both the activity and irritant properties changes i.e activity decreases and irritant property increases.

II. ESTER OR

AMIDE LINKAGE CH2 N

R2

R3



R’1

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IIIIIII

CH2 N

R2

R3I. AROMATIC RING

II. ESTER OR

AMIDE LINKAGE



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IIIIIII

O

NH C CH2 N

CH2

CH2

CH3

CH3

CH3

CH3

I. AROMATIC RING

II ESTER OR

AMIDE LINKAGE

III. HYDROCARB

ONCHAIN IV. TERTIARY AMINE

GROUP

Somnath Mondal

Local Anesthetics Sar

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