lOCAL ANAESTHETICS final.pdf Structure Activity Relationship and mode of action of local anesthetics

this pdf involve definition of local anesthetics, drugs use as local anesthetics , Structure Activity Relationship and mode of action of local anesthetics. various Route of local anesthetics like topical application, Infiltration anesthesia, nerve block anesthesia and spinal anesthesia.

1. Local Anaesthetics
DR. ANSHU R. DUDHE,
PROFESSOR, NAGPUR COLLEGE OF PHARMACY , NAGPUR

2. These are compound which prevent the generation and
the conduction of nerve impulses near to the site of
application or injection resulting in a loss of sensation
which is reversible.
Local anesthetic are most often used to produce loss of
pain without loss of consciousness. thus are also referred
to as local analgesics.

3. Distinguish Between GA and LA
Sr. No. General anaesthetics Local anaesthetics
1. Site of action CNS Peripheral nerves
2. Area of body involved Whole body Restricted area
3. Consciousness Host Unaltered
4. Care of vital function Essential Usually not needed
5. Poor health patient Risky Safer
6. Use in Nor cooperative patientPossible Not possible
7.Major surgery Preferred Cannot be used
8. Minor surgery Not Preferred Preferred

4. Routes or techniques of local anaesthesia
1.Surfaceortopicalanaesthesia:Itisproducedbyapplicationofaqueous
solutionofsaltsofseverallocalanaesthetics.Itcanalsobeproducedbyapplication
oflocalanestheticsintheformofspray,cream,ointmentorgel.
Anaesthesiaofmucousmembraneofthenose,mouth,throat,trachea,
oesophagusandgenitourinarytractisbroughtbyusinglidocaine,tetracaineand
cocaine.

5. 2. Infiltration anesthesia: Dilute solution of Local
anesthesia is infiltered under the skin in the area of
operation block sensory nerve ending. It is used minor
operations, incision, excisions, hydrocele etc.

6. Nerveblockanesthesia:Itisinducedbyinjectionintooraroundthenervetrunksor
ganglia.Bupivacaine,lignocaine,prilocaine,mepivacainaremainlyusedfornerveblock
anesthetic.Itisusedforoperationofeye,abdominalwall,fracturesetting.
spinalanesthesia:ThelocalanesthesiaisinjectedinthenerverootinCaudaequinalower
abdominalandhighlimbareanaesthesized.Spinalanesthesiaisusedoftheoperationof
lowerlimb,lowerabdominal,fracturesettingandobstetricprocedure.

7. CLASSIFICATION:
1. Esters:Cocaine, Procaine, Benzocaine, Tetracaine
2. Amides:Lidocaine (Lignocaine), Bupivacaine, Mepivacaine, Dibucaine,Ropivacaine
3.Miscellaneous:Phenocaine, Diperodon, Clove oil, Eugenol, Benzyl alcohol, Phenol
Chemical Classification:
Benzoic Acid derivatives;Cocaine, Hexylcaine, Meprylcaine, Cyclomethycaine, Piperocaine.
Amino Benzoic acid derivatives: Benzocaine, Butamben, Procaine, Butacaine, Propoxycaine, Tetracaine,
Benoxinate.
Lidocaine/Anilidederivatives: Lignocaine, Mepivacaine, Prilocaine, Etidocaine.
Miscellaneous:Phenacaine, Diperodon, Dibucaine.*

8. BENZOIC ACID DERIVATIVES
COCAINE
ThefirstlocalanesthetictobediscoveredwasCocaine,analkaloidoccurringtothe
extractof0.6to1.8%intheleavesofErythroxyloncoca(ErythroxylumCoca)andother
speciesofErythroxylum.Itpossesstronglocalanestheticactionbutalsohasvasoconstriction
andCNSactivity.Itwasfirstusedforocularanesthesia.Itisalsoassociatedwithdependence
liabilitybecauseofadverseeffect,theuseofcocaineisnowrestrictedtoitstopical
application.

9. N
O O
OO
cocaine

10. Procaine is first synthetic local anesthetic introduced in 1905. Its popularity declines after
introduction of Lidocaine in market.NH
2
COOCH
2CH
2N
C
2H
5
C
2H
5
Procaine

11. Synthesis of Procaine O
2N COOH
SO
2Cl
2
O
2N COCl
(C
2H
5)
2NHCH
2CH
2OH
N,N-diethyl amino ethanol
O
2N COOCH
2CH
2N
C
2H
5
C
2H
5
Reduction
H
2N COOCH
2CH
2N
C
2H
5
C
2H
5
Para Nitro Benzoic Acid
Procaine

12. Uses of Procaine
Procaine is a local anesthetic. Procaine causes loss of feeling (numbness)
of skin and mucous membranes.
Procaine is used as an injection during surgery and other medical and
dental procedures.
It is local anesthetic of the ester type that has a slow onset and a short duration of
action. It is mainly used for infiltration anesthesia, peripheral nerve block, and spinal
block.

13. BUTACAINE
Butacaine which is surface anesthetic with effects similar to cocaine but its action is
more rapid in onset and more prolonged.NH
2
COOCH
2CH
2CH
2N
C
4H
9
C
4H
9

14. Tetracaine
Tetracaine has a butyl group substituted on the 4-amino group. Tetracaine is used for
infiltration, surface or spinal anesthesia.Tetracaine, also known as Amethocaine, is a local
anesthetic used to numb the eyes, nose, or throat.As a result of screening of large no of
diverse compounds benzocaine and orthocaine were developed. These are used surface
anesthetics.NHC
4H
9
COOCH
2CH
2N
CH
3
CH
3
Tetracaine NH
2
COOC
2H
5
Benzocaine

15. Benzocaine :
It is an ester local anesthetic commonly used as a topical pain reliever or in cough drops.
It is the active ingredient in many over-the-counter anesthetic ointments such as products
for oral ulcers.It is also combined with antipyrineto form oticdrops to relieve ear
painand remove ear wax. It is not recommended in children.
Synthesis of Benzocaine:CH
3 CH
3
NO
2
COOH
NO
2
COOC
2H
5
NH
2
Toluene
Benzocaine1-methyl-4-nitrobenzene 4-nitrobenzoic acid
HNO
3/H
2SO
4
Oxidation
KMnO
4
C
2H
5OH/H
2SO
4

16. Uses of Benzocaine:
a. 1 % cream or lotion is available for topical application
b. It can be applied directly to wounds and ulceration surface.
c. It is indicated to treat a variety of pain related condition. Local anesthetics of oral and
pharyngeal mucous membrane and oticpain.

17. BUTAMBEN
Butambenis used as local anesthetics.
Due to its very lowwatersolubility, butamben was considered of low usability as it is only
suitable to be used as a topical anesthesia.

18. PROPOXYCAINE
Propoxycaineis a local anesthetic which acts to decrease nerve impulses and therefore
pain sensation during dental procedures.H
2N
O
O
N
OC
3H
7
C
2H
5
C
2H
5

19. BENOXINATE
Benoxinate 0.4% is a local anesthetic. It may be less irritating than tetracaine, and
the onset and duration of action are similar to tetracaine. It is used ophthalmology
and otolaryngology.H
2N
O
O
N
OC
4H
9
C
2H
5
C
2H
5

20. Amides
Ester type local anesthetics are hydrolyzed by serum
esterase and therefore have relatively short half life.
Lignocaine was introduced in 1948 and is new most widely
used local anesthetic.
Lignocaine has greater stability in solution due to presence
of methyl groups at ortho position which protect amide
group from hydrolysis. It is also used as anti-arrythmic
agent.

21. LIGNOCAINE
Lignocaine also known as Lidocaine. Lidocaine is
a medication used as a local anesthetic.
It is introduced in 1948, it is currently the
most widely used LA.
It is a versatile LA, good both for surface
application as well as injection and is
available in a variety of forms.

22. Injected around a nerve it blocks conduction
within 3 min, whereas procaine may take 15 min;
also anesthesia is more intense and longer lasting.
Vasodilatation occurs in the injected area. It is
used for surface application, infiltration, nerve
block and spinal anesthesia

23. Mepivacaine

A local anesthetic that is chemically related to
bupivacaine but pharmacologically related to lidocaine. It
is indicated for infiltration, nerve block, and
epidural/spinal anesthesia.
Mepivacaine is effective topically only in large doses and
therefore should not be used by this route. Mepivacaine is an
anesthetic (numbing medicine) that blocks the nerve
impulses that send pain signals to your brain. It is also used
as an anesthetic for dental procedures.

24. Prilocaine
Prilocaineis an amino amide type local
anesthetic. Prilocaine is also used in dentistry.
 It is also often combined with Lidocaine as a
topical preparation for dermal anesthesia.

25. Etidocaine
It is an injectable local anesthetic during surgery,
labor, and delivery. Etidocaine has a long duration
of activityCH
3
H
N
O
C
2H
5
N
C
3H
7
CH
3
C
2H
5

26. Miscellaneous
Phenacaine
 Phenacaine, also known asholocaine,is alocal
anesthetic. It is approved for ophthalmic useC
2H
5O
CH
3
H
N N
OC
2H
5

27. Diperodon
a local anesthetic used as the hydrochloride salt;
applied to the skin for abrasions, irritations, and pruritus
and intrarectally for relief of pain from hemorrhoids.HN O
O
CH
N
O
HN
O

28. DIBUCAINE
Dibucaine is also known as Cinchocaine. It is the most
potent, most toxic and longest acting LA. It is used as a
surface anesthetics on less delicate mucous
membranes (anal canal). Use for spinal anesthesia of
long duration has declined after the availability of
bupivacaine.

29. Synthesis of Dibucaine

30. STRUCTURE ACTIVITY RELATIONSHIP (SAR) OF
LOCAL ANESTHETICS
The X maybe Carbon, Oxygen, Nitrogen, Sulfur
1. Local anesthetics have a hydrophobic (Lipophilic group) at one end
and a hydrophilic group at other end. Hydrophobic group is provided by
an aromatic moiety where as hydrophilic part is a tertiary amine or some
time secondary amine.
:Ar C
O
X
Hydrophobic group
Amino alkyl group
Hydrophilic group

31. 2. The hydrophobic group provides lipid
solubility to the drug molecules and hydrophilic
group provides water solubility to the local
anesthetics. The hydrophilic part is responsible
to be involved in the binding of drug to the
receptor. Hydrophobicity increases both potency
and duration of action of local anesthetics.

32. Aromatic Ring Attached to either ester group or Amide
group.NH
2
COOCH
2CH
2N
C
2H
5
C
2H
5
Procaine
(Ester Derivative)
H
3C CH
3
NHCOCH
2N
C
2H
5
C
2H
5
Lidocaine
(Amide derivative)

33. 4. The presence of non polar molecule in the ring like n-
butyl group on the aromatic Nitrogen atom of ester like
compound increase lipid solubility.
eg. TetracaineNHC
4H
9
COOCH
2CH
2N
CH
3
CH
3
Tetracaine

34. 5. The electron donating substituent in the ortho or
para position increases local anesthetics activity
such as amino group (Procaine), alkyl group
(Lidocaine) alkyl amino group (Tetracaine).

35. 6. Electron with drawing group such as (-NO
2)
reduces the local anesthetic activity.
7. Amino alkyl group is considered to be the
hydrophilic part of local anesthetic. Tertiary amine
appears to produce longer action but they are more
irritating. Primary amines are not very active.

37. 8. Amino alkyl group may be a part of hetero
cyclic ring e.g MepivacaineCH
3
CH
3
NH C
O
N
CH
3
Mepivacaine
9. The pKa Value of Clinically useful Local
anesthetic generally lies between 7.5 to 9.5.

38. MODE OF ACTION :
Local anesthetics block nerve conduction by
decreasing the entry of Na
+
ions during the upstroke
of action potential. As the concentration of the Local
anesthetics is increased the rate of action potential
and maximum depolarization decreases causing
slowing of conduction.

40. The Na
+
channel has an activation gate near
extracellular mouth and inactivation on gate (I) at
intracellular mouth. In resting state activation gate
is closed. In activated stage threshold
depolarization opens the activation gate allowing
the Na
+
ion to flow in within a few sec. the
inactivation gate closes and ion flow ceases.

41. Mode of Action
local anesthetics interact with a receptor situated
within the voltage sensitive Na
+
channel and raise
threshold of channel opening at physiological pH.
 The local anesthetic molecule is partly ionized the
equilibrium between the unionized base form (B) and
the ionized cations form (BH
+
) depend on the pKa of
the local anesthetics.


42. The cationic form (BH
+
) of local anesthetics
binds to the receptor. The receptor has higher
affinity or is more accessible to the local
anesthetics in the activated state compared to
resting state. Binding of local anesthetics to its
receptor stabilizes the channel in the inactive
state and thus reduces the probability of channel
opening