JSS Academy of Higher Education & Research

(Deemed to be University)
Accredited ‘A+’ Grade by NAAC
Sri Shivarathreeshwara Nagara, Mysuru – 570 015
Karnataka, INDIA

B.Pharm Digital Education Program

 FACULTY OF PHARMACY
B.Pharm

BP601T. MEDICINAL CHEMISTRY – II

UNIT-5
Local Anesthetics

SUB TOPIC(1/10):
Definition

Classification & MOA

SAR

Synthesis
Definition:
Local anaesthetics are drugs which upon topical application or local injection cause
reversible loss of sensory perception, especially of pain in a localized area of the
body.
Block generation and conduction of nerve impulses at a localized site of contact
without structural damage to neurons.
Clinically used:
to block pain sensation from or sympathetic vasoconstrictor impulses to specific areas
of the body
Loss of sensory as well as motor impulses
Local Vs General Anaesthesia

General anaesthetics Local anaesthetics

Site of action CNS Peripheral nerves
Area Whole body Restricted areas
Consciousness Lost Unaltered
Preferential use Major surgery Minor surgery
Use in non Possible Not possible
cooperative patients
Poor health patients Risk Safer
Classification
Esters
Benzocaine
Procaine/ Proparacaine
Amide
Bupivacaine
Levobupivacaine
Lidocaine/Lignocaine
Mepivacaine
 Structureof Local Anaesthetics
Lipophilicgroup Hydrophilicgroup
Amide
or
Ester link
Chemical classification
1. Benzoic acid derivatives

Cocaine Hexylcaine Meprylcaine

Cyclomethycaine Piperocaine
2. Amino Benzoic acid derivatives:

Benzocaine* Butamben Procaine*

Butacaine Propoxycaine Tetracaine

 Benoxinate

3. Lidocaine/Anilide derivatives:

Lignocaine Mepivacaine Prilocaine

Etidocaine

12
4. Miscellaneous:

Phenacaine Diperodon

Dibucaine*/ Cinchocaine
Based on their safety
Class A: Tetradotoxin, Saxitoxin
Class B: Lidocaine, quaternary ammonium analogous
Class C: Benzocaine, Procaine, Mepivacane, Bupivacaine
Class D: Prilocaine
The FDA has a drug classification system based on the risks to pregnant women and
their fetuses. Of the five categories (A, B, C, D, and X) lidocaine is considered in
Category B, the safest of the local anesthetics. Mepivicaine and bupivacaine are
Category C and may be used with caution.
Based on mode of application
Based on mode
of application

Topical Injectable

-Lidocaine
-Mepivacaine
Soluble Insoluble -Tetracaine
-Bupivacaine
-Dibucaine
-Cocaine -Benzocaine
-Lidocaine -Butylaminobenzoate
-Tetracaine
-Benoxinate
Based on duration of action

Based on duration
of action

Ultra Short Long

Medium
short
-Chlorprocaine-Lidocaine -Mepivacaine-Bupivacaine
-Procaine -Prilocaine -Articaine -Etidocaine
Based on potency

Based on potency

Low Intermediate High

-Chlorprocaine -Lidocaine -Bupivacaine

-Procaine -Mepivacaine -Etidocaine
-Tetracaine
Mechanism of Action

Location

Local anaesthetic receptors are located in the Na + channel of axonal membrane

Structure

The receptor consists of two gates

i.Activation gate or ‘m’ gate

ii.Inactivation gate or ‘h’ gate

The action of ‘h’ gate is mainly responsible for the blocking of Na + channel
 readily penetrates through axonal
Equalibrium membrane
+
BH B
Ionised form Base form
Un treated nerve

Treated nerve fibre

Increase in con. dereases the
action potential and their by
decreases the depolarisation
SAR of Local Anaesthetics
 Structure Activity Relationship (SAR)

Lipophilic Ester or Hydrophilic

center amide group Bridge
center

Short C-chain
Carboxylic or heterocyclic Secondary or
O, N or S
(Important for diffusion tertiary amine,
across membrane) cyclic or
non-cyclic
Structure-activity relationships (SAR) of benzoic acid derivatives
The benzoic acid derivatives are represented as follows:

Aryl group
•Lipophilic portion of the molecule is essential for local anaesthetic activity, most of clinically
useful local anaesthetics consists of aromatic group attached directly to the carbonyl group.
•Attachment of aromatic group or 2,6- dimethyl phenyl group directly to the carbonyl function
through –NH- group (amide series), both groups are lipophilic, play important role in binding to
local anaesthetic channel protein.
• Structural modification of this portion of molecule has a profound effect on its physical and
chemical properties, which in tern alters local anaesthetic activity.
• Substitution of electron donating group at para or ortho (or both) position increases local
anaesthetic activity
eg. Aromatic amine (procaine, chlorprocaine, propoxycaine), alkamino (tetracaine), analkoxy
(proparacaine, propoxycaine) group contributes electron density to the aromatic ring by both
resonance and inductive effect, their by enhances local anaesthetic activity (over non
substituted meprylcaine) O
R O

N(C2H5)2
CH3
H O
N
O C3H7
H2N

CH3 Procaine: R= H (pKa= 8.8)

Chlorprocaine: R= Cl(9.1)
Propoxycaine: R= OC2H7 (9.1)
Increase in the Zwitterionic form increases the local anaesthetic activity
Increase in the Zwitterionic form shows greater affinity towards local anaesthetic receptor
This is true in case of benzocaine for affinity towards binding site (lack of basic amino group)
O O
+
N(C2H5)2 N(C2H5)2
O O
H
.. ..
H2N H2N

- -
O O H

N(C2H5)2 N(C2H5)2
O O +

+ +
H2N H2N
• Substitution of electron withdrawing group such as –NO 2 group reduces activity
• Addition of any aromatic substitution enhances the formation of resonance through electron
donation or inductive effect thus increases local anaesthetic activity.
• Insertion of methylene group between the aromatic moiety and the carbonyl function
reduces the formation of Zwitterion and their by decreases local anaesthetic activity
eg. O

O N(C2H5)2

H2N
• Addition of NH2 or alkoxy to meta position of the aromatic ring do not causes resonance
and delocalization of electrons. The addition of this only increases the lipophilicity of the
molecule. eg. Benoxinate Proparacaine
O O

C4H9O N(C2H5)2 H2N N(C2H5)2

O O

H2N (9.0) C3H7O (9.1)

• Tetracaine is 50 folds more potent than procaine because of its increase lipophilicity of
n-butyl group. The potentiation of action is due to its electron releasing property of n-butyl
group via inductive effect which indirectly enhances electron density of p-amino group
O
which in tern increases Zwitterionic & receptor affinity
N(C2H5)2
O

C4H9HN

03/16/25 29
• Important aspect obsorved in aromatic substitution by SAR studies is Amino amides
(lidocaine), the o, oɪ dimethyl group required to provide suitable protection of amide
hydrolysis & there by increases duration of action. Similarly propoxycaine (o- propoxy group)
• Substitution of halogen leads shorter action eg. Chlorprocaine (because chloro group pulls
the electrons from carbonyl function, thus makes it more susceptible to nucleophilic attack
by plasma cholinesterase.
 O
Aminoalkyl
Bridge X Aryl X

•The bridge X may be carbon, oxygen, nitrogen, or sulphur.

•In an isosteric procaine series, anaesthetic potency decreased in the following order: sulphur,
oxygen, carbon, nitrogen.
•These modifications also affect duration of action and toxicity. In general, amides (X=N) are
more resistant to metabolic hydrolysis than esters (X=O). Thioesters (X=S) may cause
dermatitis.
•In procaine-like analogues, branching (especially at the alpha carbon) will increase duration
of action. This effect is not seen in the lidocaine series.
•Increasing the chain length will increase potency but will also increase toxicity.
• The intermediate chain usually contains short chain alkyl group usually one to three carbon
linked to aromatic ring and several functional groups
• The nature of intermediate chain determines the chemical stability which influences duration
of action, relative toxicity
eg. Amino amides are more resistant to metabolic hydrolysis than amino esters and thus
have longer duration of action.
• The placement of small alkyl group (ie. branching), especially around the ester function (eg.
meprylcaine) or the amide function (eg. Bupivacaine, etidocaine, proilocaine or ropivacaine)
resist the hydrolysis by esterases or amidases and shows longer duration of action
• In lidocaine series, lengthening of the alkyl chain from 1 to 2 or 3 increases pKa of the
terminal 3o nitrogen from 7.7 to 9.0 or 9.5 respectively. Increase in chain length
decreases local anaesthetic potency as a result of reduction of Onium ions under
physiologic conditions (onium ions are required for binding to receptor)

Etidocaine Lidocaine Prilocaine

Aminoalkyl group
•The aminoalkyl group is not necessary for local anaesthetic activity, but it is used to form
water-soluble salts (HCl salts).
30 -NH- result in more useful agents
20 -NH- appear to be of longer activity, but they are more irritating
10 -NH- are not very active and cause irritation
•The tertiary amino group may be diethylamino, piperidine, or pyrrolidino, leading to the
products that exhibit essentially the same degree of activity.
•The more hydrophilic morpholino group usually leads to diminished potency.
•Some analogues have no amino group at all, such as benzocaine. They are active but have
poor water solubility
 CH3 O
H
N O N
N

O R
CH3 C4H9O
Mepivacaine R= CH3 (7.6)
Pramoxine
Bupivacaine R= n-C4H9(8.1)

O
O

C2H5
N

H2N
C4H9O
Benzocaine
Dyclonine
Synthesis
Benzocaine

Procaine
Cocaine
Course Specific Objectives
 To create experts in the field of Medicinal Chemistry,
physiology of drugs, structure, mechanism and synthesis
 To create an entry platform in the field of Medicinal
Chemistry/ Pharmaceutical Chemistry for fresh graduates.
 To help students build their career in drug chemistry,
design and synthesis.
References

 Wilson and Giswold’s Organic medicinal and Pharmaceutical Chemistry

 Foye’s Principles of Medicinal Chemistry.
 Goodman and Gilman’s, The Pharmacological Basis of Therapeutics
K.D.Tripathi. Essentials of Medical Pharmacology, , JAYPEE Brothers
Medical Publishers (P) Ltd, New Delhi.
Contemporary Drug Synthesis Douglas S. Johnson, Drago R.
Sliskovic, Bruce D. Roth, Jie Jack Li, 2004.