LOCAL ANESTHETICS
Def.: These agents are used to produce anesthesia or to
abolish pain sensation in restricted areas in the
body.
Mechanism of action
Site of action: cell membrane.
It prevents the conduction by blocking the sodium ion
channels. Blocking is achieved either by
 The drug causing a physical block in the channel like a
cork in a bottle
 The drug molecule distorting the channels

Increasing the surface pressure of the cell membrane.
Ideal Local Anesthetic
It must have the following characters:
1) Nontoxic
2) Nonirritant
3) Produce vasoconstriction
4) Effective either topically or parenterally.
5) Reversible: means reversible blockade of sensory nerve
fibers with minimal effect on the motor fibers.
6)
Rapid onset with sufficient duration of action.
Adverse Reactions
As a result of overdose and its complete systemic
absorption, it can cause:
• CNS effects: Vomiting, nausea, convulsions coma
with respiratory and heart failure.
• CVS effects: Bradycardia, hypotension and shocklike state.
• Some local reactions of allergic nature e.g. edema,
pain, skin discoloration and neuritis.
Treatment (Antidote):
ultrashort-acting or short-acting barbiturate
History
Local anesthetics were derived from natural sources.
A) Cocaine
In 1532, the anesthetic properties of coca leaves became
known to Europeans from the natives of Peru, who chewed
the leaves for a general feeling of well-being and to prevent
hunger.
Later, the alkaloid cocaine was obtained from the coca leaves
which causes anesthetic effect on the tongue.


Carbomethoxy group
H3C
N
H3C
COOCH3
N
COOH
hy droly sis
O
H
Tropin
e moit
y
OH
hot dil. acid.
or alkali
O
Ecgonine
Benzoy l group
H
(Tropine carboxy lic acid)
COOH
+
+
CH3OH
2
1
COOCH3
H 3C
N
No carbomethoxy group
(no addicting liability )
7
H3C N
3
8
6
5
H
4
Cocaine



O
O
O
O
Benzoyl tropine
Ecgonine = piperidine and pyrrolidine rings.
The dotted portion of cocaine has been found to
represent the anesthesiophoric function group.
Cocaine was the first potent local anesthetic used
clinically.

Cocaine can not penetrate intact skin but is absorbed
from mucous membranes.

Cocaine blocks uptake of catecholamines (C.A.) at
adrenergic nerve endings and so it is considered potent
vasoconstrictor. This account for ulceration of nasal
septum after administration of cocaine for long periods
in higher dose.

Cocaine has many disadvantages such as addiction,
tissue irritations, poor stability in aqueous solutions and
decomposition on sterilization.
H 3C
N
No carbomethoxy group
(no addicting liability )
O
H
O
Benzoyl tropine

Later, benzoyl esters of amino alcohols were synthesized, such
as benzoyltropine.

Benzoyltropine exhibited strong local anesthetic properties
without any addicting liability. Thus, removal of the 2carbomethoxy group of cocaine also abolished the addiction.

After that, esters of p-aminobenzoic acid e.g. procaine were
discovered which not have severe local and systemic toxicity of
cocaine.
Synthetic compounds
A) Ester-type or amino-esters or cocaine-type ( procaine-type).
O
They are classified into:
H2N
I] p-Aminobenzoate derivatives
O CH2CH3
1)Benzocaine
Ethyl 4-aminobenzoate

Assay: Diazometrically.

Disadvantages: its low aqueous solubility limited its usefulness
as injectable agent.

Uses: topically for surface anesthesia of mucous membrane.

Unlike others, benzocaine not possess aliphatic amino gp
required for salt formation.

The free electrons on the aromatic amino gp are delocalized by
the ring. Thus, formation of water soluble salt is not possible.
O2N
CH3
p-nitrotoluene
Oxid.
O2N
1) esterf ication
Benzocaine
COOH
2) reduction
2) Procaine hydrochloride
O
Et
H2N
2
O
1
N
. HCl
Et
2-Diethylaminoethyl-4-aminobenzoate hydrochloride




1.
2.
Procaine is the least toxic and widely used.
Unlike benzocaine, procaine containing a basic amino
group from which water soluble salts were prepared.
In contrast to cocaine,it not causes vasoconstriction, so it
is rapidly absorbed from site of inj.
Most ester-type are used in a solution containing a
vasoconstrictor as epinephrine to serve a dual purpose:
The first one is to decrease the rate of absorption. Thus,
localize the local anesthetic at the desired site to limit
systemic toxicity.
The second one is to prolong duration of action.
1) H2N
Preparation:
Cl + HN
O
C2H5
O
C2H5
2) H2N
+
OH
N
HO
conc. H2SO4
Procaine
C2H5
Assay: Diazometrically.
CH
120 - 130 C
O
3) H N
N
+

Procaine
is used
to
form
an
insoluble salt with
CH
ONa Cl
penicillin G. The low solubility accounts for the
prolonged action of this salt.

The amide derivative of procaine (procainamide HCl)
is a cardiac depressant.
3) Chloroprocaine hydrochloride
2-Diethylamino-4-amino-2-chloro
O
C2H5
benzoate hydrochloride
H2N
N
. HCl
Assay: Non-aqueous titration.
O
CH
o
2
5
2
5
2
2 5
Cl
4) Propoxycaine Hydrochloride

It is 2-(Diethylamino) ethyl-4-amino
-2-propoxybenzoate hydrochloride

It is not stable to autoclaving.
It has quicker onset and longer duration
of action and more potent than procaine.
It is used by injection for nerve block and
infiltration anesthesia.


O
H2N
C2H5
N
O
OC3H7
. HCl
C2H5
5) Amethocaine (tetracaine) Hydrochloride:
O
HN
N
O
C4H9
Preparation:
. HCl
CH3
2-(Dimethylamino)ethyl-4-butylaminobenzoate HCl
H2N
COOEt
CH3CH2CH2CH2Br
Na2CO3
CH3
N
HO
CH3
CH3
Trans esterfication
NaOEt
Assay: alkaloidal assay.
Compound
HN
C4H9
COOEt
• Tetracaine is one of the most easily absorbed drugs due to the
presence of nonpolar n-butyl group.
• Its solutions are more stable to hydrolysis than procaine and it
may be sterilized by boiling.
• *Mixture of sulfonamide and p-aminobenzoic acid local
anesthetics should be avoided because of their hydrolysis led
to p-aminobenzoic acid (PABA). Sulfonamides are considered
competitive inhibitors of PABA in the biosynthesis of
dihydrofolate.
CH3
O
II] Benzoate Derivatives
C N CH2 CH2 CH3 . HCl
1) Meprylcaine HCl
O
CH3
• 2-Methyl-2-(propylamino)-1propanol benzoate HCl
• It can be sterilized by autoclaving without decomposition.
• It is used in dentistry in 2% solution containing epinephrine as
an infiltration and nerve block anesthetic.
2) Cyclomethycaine sulfate (sufacaine)
Assay:
Spectrophotometrically.
O
2
O
O
1
3
CH3
N
. H2SO4
3-(2-Methylpiperidino) propyl-4-(cyclohexyloxy)
benzoate sulfate
Uses:
 topically on burns(sunburns) and mucosa of rectum in 0.25-1%.
 not used for mucous membranes of upper respiratory system or
eye.
O
CH3
3) Piperocaine HCl (Metycaine HCl)
. HCl
O
N
 It differs from cyclomethycaine
in the absence of cyclohexyloxy
group.
 Its aqueous solutions are stable to sterilization by
autoclaving. It is recommended for eye, nose and throat.
Structure activity relationship
The general structure of ester- type local anesthetics is as follows:
O
R
Ar
Et
1
O
(CH2)n
H2N
O
N
2
R
Lipophilic Intermediate Hy drophilic
portion
chain
portion
N
Et
O
reversed ester
The lipophilic portion:



It is essential for activity.This is a portion of aromatic acid
whereas benzoic and p-amino-benzoic acids are the preferred
ones.
The carbonyl group must be conjugated with an aromatic nucleus
whereas reversed esters have no local anesthetic activity.
The esters of cinnamic acid are more active than those of phenyl
acetic acid due to interruption of the extended conjugation by
methylene gp between the aromatic ring and carbonyl gp.
O
OR
OR
O
Conjugated
Cinnamic acid


OR
O
not conjugated
phenyl acetic acid
not conjugated
b-phenyl propionic acid

Introduction of electron-donating gps in the ortho or para positions of
the ring increases conjugation and binding of drug to the receptor
prolonging the action.

NH2 (procaine),an alkylamino (tetracaine) or an alkoxy gp
(propoxycaine) increase electron density to the aromatic ring by both
resonance and inductive effects,


While the opposite occur in case of electron-withdrawing
(NO2, CO and CN).

Tetracaine is 50-fold more potent than procaine. This may
be due to the n-butyl gp increase lipid solubility


propoxycaine, the presence of o-propoxy gp increase
duration of action due to protection of ester gp from
hydrolysis due to plasma esterases

This is contrary to chloroprocaine which has shorter
duration of action due to negative inductive effect of ochloro gp which pulls the electron density away from the
carbonyl function.
The intermediate chain
 It is alkyl chain of amino alcohol involved in the esters.
 The propylene gp –(CH2)3– provides the most active
compounds, next ethylene, –(CH2)2– while methylene gp, –
CH2–, makes the compounds too irritant.
The branching with small alkyl gp around the ester function
(e.g. meprylcaine) also hinders esterase catalysed hydrolysis
prolonging the duration of action.
The hydrophilic portion
 It is amine part of amino alcohols used to esterifies aromatic
acids. Its advantage is its ability to form salts with inorganic
acids producing water soluble compounds.






It is observed that benzocaine which lacks the basic
aliphatic amine, has potent local anesthetic activity. Thus,
3ry amine is needed for formation of water soluble salts,
suitable for pharmaceutical preparations.
The anesthetic activity increases with the size of the alkyl
gps (R1, R2), the maximum being at C3-C4. R1 and R2 may
be identical, unsaturated groups or hydrogen and alkyl
group.
3ry amines  useful local anesthetics.
2ry amines  long acting but irritant.
1ry amines  not active.
B) Isogramine
 In 1930, the discovery of the local anesthetic activity of
isogramine (isomer of alkaloid gramine,3-derivative) led to the
synthesis of lidocaine (anilide or reversed amide).
 Lidocaine(xylocaine) is the first non-irritating, amide-type local
anesthetic agent with lesser allergic reactions than esters.
 Its aqueous solution is stable because of the stablility of amide
functionality.
 Structurally, lidocaine can be viewed as an open-chain analog
of isogramine and thus is a bioisosteric analog of isogramine.
CH3
O
N
H
N(CH3)2
N
CH3 H
Isogramine
Lidocaine
2-(Dimethylaminomethyl)indole
N(C2H5)2
B)amino-amides or isogramine-type (lidocaine-type).
1) Lidocaine HCl or lignocaine HCl (Xylocaine)
O
HN
H 3C
Et
N
O
Et
O
HN
CH3
H 3C
CH3
. HCl
2-(Diethylamino)-N-(2,6-dimethyl
phenyl)acetamide
HN
N
CH3
. HCl
Mepivacaine HCl
H 3C
N
CH3
C 4H 9
. HCl
Bupivacaine
N-(2,6-Dimethylphenyl)-1-methyl or butyl -2piperidinecarboxamide HCl
Assay: non aqueous titration.
Use:
 The salt is used for infiltration, peripheral nerve block and
epidural anesthesia.
 Lidocaine is effective as antiarrhythmics.
2) Mepivacaine HCl (Carbocaine)

Its duration of action is longer than lidocaine.
3) Bupivacaine HCl (Marcaine)

Its duration of action is 2-3 times longer than lidocaine or mepivacaine.
H
4) Dibucaine HCl (Cinchocaine HCl) Nupercaine
O
N
Et
N
Assay: non aqueous titration.
Et
 It is the most potent, toxic and
. HCl
CH
longest acting one
N
O
 Used topically and in
2-Butoxy-4-[2-(diethylamino)
spinal anesthesia.
ethyl]cinchonamide
Structure Activity Relationship: (amino amide series)
 The general structure of local anesthetic can be represented as
follow:
4
Lipophilic portion
Intermediate chain
9
Hy rophilic portion
Lipophilic portion:
 The lipophilic portion is essential for activity and consists of
phenyl group attached to CO function (sp2 carbon) through NH
gp.
 Thus, the COOH gp of the amino-ester series is replaced by its
isosteric NHCO moiety in amino-amide series.
 Substitution of the phenyl with a methyl gp in the 2- or 2- and 6position enhances activity.
The amide bond is more stable to hydrolysis than the ester. In
addition, o,o`-methyl substituents provide steric hindrance to
the hydrolysis of the amide bond.
The intermediate chain

In lidocaine series, lengthening of the alkylene chain from one
to two or three increases pKa from 7.7 to 9.0 or 9.5,
respectively reducing local anesthetic potency.

Here, branching around the amide function (etidocaine), also
hinders amidase catalyzed hydrolysis prolonging the duration
of action.
Advantages of lidocaine derivatives over procaine ones
1.
More stable to hydrolysis.
2.
Can be sterilized by autoclaving.
3.
More potent.
4.
Lower side effects: less local irritation than procaine type.
5.
Used as alternatives for patients sensitive to procaine type
local anesthetic.

6.
7.
Effective without vasoconstrictors. It used for patient sensitive
to epinephrin.
Lidocaine derivatives undergo enzymatic degradation not in
plasma but primarily in the liver through degradation of amide
bond.
N.B.:

Patient possessing a genetic deficiency in the enzyme
pseudocholinesterases is unable to hydrolyze ester-type local
anesthetic agents and show reduced tolerance to these drugs.
Thus, amide-type agents are preferable.

On the other hand, patients with liver diseases may show
reduced tolerance to amide-type agents due to they are mainly
metabolized in liver. Thus, ester-type drugs are preferable.

Most of clinically used local anesthetics have pKa 89.5.

Drugs with higher pKa values are almost completely ionized
at physiological pH and therefore are hindered in reaching the
receptor sites.

For this same reason, local anesthetics can be ineffective in
inflammation areas because in these areas, pH being lower,
facilitates ionization of their molecules and consequently
hinders their penetration into nerve fibers.

On the other side, compounds with lower pKa values are not
sufficiently ionized and although they reach the target are less
potent.