LOCAL ANAESTHETICS
These
are the drugs upon
topical
application or local injection, cause
reversible loss of sensory perception,
especially pain in a restricted area of body.
 Used for temporary and reversible
elimination of painful feelings
 These drugs are applied locally and block
nerve conduction of sensory impulses from
periphery to the CNS.
 Unlike general anaesthetics, cause loss of
feelings without inducing unconsciousness

HISTORICAL DEVOLOPMENT
 Before the use of local anesthetics, to alleviate a
patient’s pain, surgeons must perform the operation
very fast
 Modern development of the use of drugs to induce local
anesthesia probably started in the mid-19th century. The
earliest recorded use of hypothermia as a local
anesthetic is believed to be by Larrey, Nepoleon’e chief
surgeon during the retreat from Moscow. He reported
that amputations carried out at subzero temperatures
has a higher survival rate than those in warmer
conditions.
 In 1848, Arnott reported that he had used a pig’s
bladder filled with ice to alleviate pain.
Discovery of Cocaine
 In 1884, when studying the effects of cocaine on
fatigue, a colleague of Koller reported that the drug
numbed his tongue. Koller then investigated this
claim and found that cocaine hydrochloride caused
local anesthesia.
 In 1884, cocaine was widely used as a local
anesthetics.
 Cocaine is addictive, and has many other side effects.
People modified its structures and discovered
procaine in 1904.
O
O
H 2N
C 2H 5
N
C2 H5
 As the undesirable effects of cocaine (toxicity, addiction,
and others) gradually became known, new anesthetic
drugs were sought to replace it.
 November 27, 1904, German chemist Alfred Einhorn
(1856-1917) patented 18 para-aminobenzoic derivatives
that had been developed in the Meister Lucius and
Brüning plants at Höchst, in Hesse, Germany.
 Its name, novocaine, appeared for the first time in
1905 in an article published by Professor Heinrich
Braun
 Novocaine was found to be safe and quickly became
the standard local anesthetic
 In 1943-1946, Nils Löfgren and Bengt Lundquist
developed a xylidine derivative they called lidocaine
 Discovery of Lidocaine is based on the investigation
of the chemical structure of Gramine, an alkaloid
 Procaine was prepared in 1943.
 In 1957, Boaf Ekenstam et
mepivacaine and bupivacaine;
al.
synthesized
 in 1969, prilocaine was synthesized by Nils Löfgren
and Cläes Tegner ; and
 in 1972, Adams et al.developed etidocaine
 Currently, the pharmaceutical industry continues to
explore the development of safer and more effective
local anesthetics in a pursuit that has come a long
way since the earliest experiments with cocaine
MECHANISM OF ACTION
 These agents are believed to act by inhibiting sodium
channels of the nerve membrane
 They block nerve conduction by decreasing entry of
sodium ion during upstroke of action potential
 It interacts with a receptor situated in voltage
sensitive sodium channel and raise threshold of
channel opening
 So the sodium permeability fails to increase in
response to an impulse or stimulus.
 Hence they inhibits generation and conduction of
nerve impulse.
SAR
Both ester or amide based local anaesthetics
has the general formula
LIPOPHILIC CENTRE
ESTER OR AMIDE GROUP
BRIDGE
HYDROPHILIC CENTRE
 Lipophilic centre – a carboxylic or heterocylic ring
system
 Hydrophilic centre – tert or sec amine that may or
may not be cyclic. Tert amines are less irritant to
tissues so it is more useful.
 Linkage between the aromatic ring and the amino
group is either ester or amide. They may be a short
hydrocarbon chain .,oxygen,nitrogen or sulphur.
 Lipophilic centre is responsible for lipid solubility
 Hydrophylic centre for transporting drug to
membrane , to cell & to receptor .
 The best local anaesthetic action is obtained when
lipophilic and hydrophilic centre are in balance.
 pKa value – 7.5 – 9.5
 Those with pKa value below 7.5 are not sufficiently
ionised at physiologic pH ,more effective.
 Those with pKa value above 9.5 are fully ionised at
physiologic pH ,less effective.as it cannot penetrate the
cell membrane.
 The presence of piperidino or pyrrolidino group as
hydrophylic give rise to almost identical activity .
 The partition coefficient of local anaesthetics having
identical structure increases the activity to a
maximum.
 Once the peak is reached the activity starts
decreasing though the partition coefficient enhances.
 Substitution of aryl ring of local anaesthetic by alkyl,
alkoxy or alkyl amino group showed that the partition
coefficient of member of series increases with
increase in no. of
methylene groups in the
substituent.
 Maximum activity is achieved for C4 to C6 analogue
 Substitution of hydrophilic centre showed that as the
no. of C atoms increase the partition coefficient and
activity increase
 The local anaesthetic activity of benzoic acid
derivatives increase if the aryl lipophilic centre has
electron donating group and decrease with electron
withdrawing substituents .
 This is because the electron donor substituent
increases the binding to the receptor .
 Those with amide functional group bind more strongly
to receptor site .
95 % of bupivacaine bound to plasma and tissue
proteins compared with 55% of prilocaine.
 Esters local anesthetics have common basic structure,
that is, the aromatic acid and amino alkane. Procaine
Hydrochloride is the representative drug.
 Procaine was obtained by the structural modification
of natural alkaloid Cocaine.
O
N
O
O
O
H
O
Cocaine
O
H2N
Procaine
N
 From Cocaine to Procaine
 Benzoate moiety is very important
 Methoxycarbonyl is not needed for maintaining
of activity
 Tropane bicycles moiety is not necessary
 Methyl amino benzoate have local anesthetic
effect
 The aminoalkyl side chain is very important
Benzoate moiety is very important
O
N
N
O
OH
O
O
H
O
Cocaine
OH
H
Ecgonine
+ HO
+ CH3OH
O
 Methoxycarbonyl is not needed for maintaining activity
N
O
O
O
O
H
H
O
O
Tropacocaine
Lidocaine Hydrochloride
 Amide bond is stable than ester bond
 Two vicinal methyl groups introduce steric
hindrance
Not easier to be hydrolyzed either in acidic or basic
atmosphere
The hydrolysis rate by enzyme inside body is
relatively slow
CLASSIFICATION



Natural agents: Cocaine
Synthetic nitrogenous compounds:
1. Benzoic acid derivatives : Piperocaine, Hexylcaine
2. Aminobenzoic acid derivatives : Benzocaine ,
Procaine , Procainamide, Amethocaine, Orthocaine
3. Acetanilide derivatives : Lidocaine, Prilocaine ,
Mepivacaine , Bupivacaine
4. Quinoline derivatives: Dimethisoquine, Cinchocaine
Miscellaneous : Dibucaine, Benzyl alcohol, Eugenol
BENZOIC ACID DERIVATIVES
Piperocaine (mety caine)
O
O
(CH2)N3
H3C
3-(2-Methy l piperidino )propy l benzoate
BENZOIC ACID DERIVATIVES
Piperocaine (mety caine)
O
O
(CH2)3
N
H3C
3-(2-Methy l piperidino )propy l benzoate
BENZOIC ACID DERIVATIVES
Piperocaine (mety caine)
O
O
(CH2)3
N
H3C
3-(2-Methy l piperidino )propy l benzoate
SY NTHESIS
CO.Cl
+
COO.(CH2)3.Cl
HO.(CH
2)3. Cl
-HCl
benzoy l chloride
3- chloro 1- propanol
-HCl
N
H
COO.(CH2)3. N
H3C
piperocaine
USE: f or ey e, throat and caudal analgesia
CH3
Hexylcaine hydrochloride (cycaine hydrochloride)
COO.CH.CH2.NH
CH3
HCl
1-(Cy clohexy lamino)-2-propany l benzoate hy drochloride
USE:as surf ace anaesthesia
AMINOBENZOIC ACID DERIVATIVES
BENZOCAINE
H2N
H5C2OOC
Ethy l p-aminobenzoate
SY NTHESIS
CH3
NO2
4-Nitrotoluene
H5C2OOC
COOH
+
KMnO4
C2H5OH , H
[O]
esterif ication
NO2
4-Nitrobenzoic acid
H5C2OOC
Sn/ HCl
[H]
O2N
4-Nitroethy l benzoate
USE: to get rid of pain caused due to wounds , ulcers and mucous surf ace
H2N
benzocaine
Procaine (novocaine)
H2N
C2H5
C2H5 N
(CH2)2 OOC
2-(Diethy lamino) ethy l-p-amino benzoate
SY NTHESIS
NH2
H2N
+
HO.(CH2)2.N(C2H5)2
COO(CH2)2N(C2H5)2
HOOC
4-Aminobenzoic acid
2-ethy l diamino ethanol
use : less toxic and most commonly used local anaesthetic
procaine
Procainamide
C2H5
N (CH2)2 HNOC
C2H5
H2N
N[2-(Diethy l amino) ethy l] p-amino benzamide
SY NTHESIS
H2 N OC
CO NH(CH2)2 N(C2H5)2
+
H2N
p-aminobenzamide
USE: as a local anaesthetic
Cl (CH2)2 N(C2H5)2
NH2
procainamide
LIDOCAINE DERIVATIVES ( ANILIDES)
Lidocaine
CH3
NH CO -CH2 -N (C2H5)2
CH3
N,N-(Diethy l amino aceto )-2,6-xy lidine
SY NTHESIS
CH3
H3C
NH2
condensation
+
Cl.CO.CH2Cl
CH3
2,6 -xy lidine
-HCl
NH CO.CH2.Cl
+
CH3
H N (C2H5)2
-HCl Condensation
Chloroacety l chloride
CH3
NH
CO .CH2 .N (C2H5)2
CH3
Lidocaine
USE: It is a potent local anaesthetic and is twice as activ e as procaine
It has v asodilating acion , but is used with v asoconstrictor adrenaline to prolong its activ ity .
Prilocaine
H3C
NH
CO
CH-NH-(CH2)2CH3
CH3
2-(Propy l amino ) o-propiono toluidine
USE: it has lesser v asodilatory action than adrenaline
hence used without adrenaline. Not ef f ectiv e topically
MISCELLANEOUS DRUGS
Dimethysoquin( quinisocaine)
CH2.CH2.CH2.CH3
N
O (CH2)2 N (CH3)2
3-n-buty l-1-[2-(dimethy l amino )ethoxy ] -isoquinoline
USE: It is a surf ace anaesthetic and used in ointments or lotions f or the relief of
irritation, itching , pain or burning.
Dibucaine(cinchocaine)
CONH.(CH2)2 N.(C2H5)2
N
O(CH2)3.CH3
3-Butoxy -N-[-(diethy lamino)ethy l]-4-quinoline carboxamide
USE: as inf iltration , surf ace and spinal anaesthesia
SY NTHESIS
O
O
Acety lation
O
COCOOH
O
(CH3CO)2O
NaOH
N
N
H
NHCOCH3
COCH3
isatin
COCl
Cy clisation
HOOC
COOH
PCl5
N
Cl
OH
N
condensation
-HCl
CO.NH.(CH2)2.N(C2H5)2
CO.NH.(CH2)2.N(C2H5)2
sodiumbutoxide
N
-NaCl
Cl
N
dibucaine
O(CH2)3.CH3
N
H
O