Local Anaesthetics

Local Anaesthetics
Bachelor of Pharmacy 3rd Year
Medicinal Chemistry
Medicine

1. Local Anaesthetics
Department of Pharmaceutical Sciences
Rashtrasant Tukadoji Maharaj Nagpur University
Nagpur-444 033
Presented by
Vedant Pravin Pawar
B.Pharm III
rd Year
Medicinal Chemistry II

2. Table of Content
•Introduction
•Chemistry of Local Anaesthetics
•Methods of Administration
•Classification
•Mechanism of Action
•Metabolism Of Local Anaesthetics
•Structure Activity Relationship
•Drug Profile
•References

3. •Local anaesthetics are drugs that when applied directly to the peripheral nervous tissues blocks nerve
conduction and abolishes all the sensations in that part supplied by the nerve.
•The term ‘Anaesthetics’ is derived from the Greek word ‘Anaisthetos’ meaning “without sensation”.
•They are generally applied to the somatic nerves and capable of cutting on axons, cell body, dendrites and
synapses.
•These are used in dentistry, in ophthalmology, in minor surgical operations, including endoscopy and for
relieving pain in certain medical conditions such as tumours growing in the spine, temporary relief from pain
of insect bites, burns, and other surface wounds.
Introduction

4. Chemistry Of Local Anaesthetics
The clinically useful LAs are weak base with amphiphilic property. A hydrophilic secondary or
tertiary amine on one side and a lipophilic aromatic residue on the other are joined by an alkyl
chain through an ester or amide linkage.
Ester-Linked LA
•Cocaine
•Procaine
•Chloroprocaine
•Tetracaine
•Benzacaine
•Lidocaine
•Bupivacaine
•Dibucaine
•Prilocaine
•Ropivacaine
Amide LAs compared To Ester LAs
•Produce more intense and longer
lasting anaesthesia.
•Bind to a1 acid glycoprotein in plasma.
•Not hydrolysed by plasma esterases.
•Rarely cause hypersensitivity reactions
no cross sensitivity with ester LAs.
Because of their short duration, less
intense analgesia and higher risk of
hypersensitivity, the ester-linked LAs
are rarely used for infiltration or nerve
block, but are still used topically.
Amide-Linked LA

5. Methods of administration
•Surface or Topical Anaesthesia :- Applied to the mucous membrane. Eg. Conjuctiva, Larynx, Throat,
Damaged skin surface, etc.
•Infiltration Anaesthesia :- The drug is injected subcutaneously to paralyse the sensory nerve endings
around the area to be rendered insensitive. Eg. an area to be incised or for tooth extraction.
•Nerve Block Anaesthesia :- The local anaesthesia is injected as close as possible to the nerve trunk
supplying the specific area to be anaesthetised. This blocks conduction in both sensory and motor fibres.
Eg. minor operations on the limb are possible.
•Epidural Anaesthesia :- This is a special type of nerve block anaesthesia in which the drug is injected
into the epidural space. It is technically a more difficult procedure. The roots of the spinal nerves are
anaesthetized

6. •Spinal Anaesthesia :- The drug administered into subarachnoid space, i.e., into thr cerebrospinal fluid ,
to paralyse the roots of the spinal nerves. This method is used to induce anaesthesia for abdominal or
pelvic surgical operations.
•Caudal Anaesthesia :- This is smaller to epidural anaesthesia where the injection is made through
sacral hiatus into the vertebral canal which contains the cauda equina. Eg. It is used for the operations
on the pelvic viscera.
Saddle block is a variation of spinal anaesthesia where the injection is made into the lower part
of the subarachnoid space. The drug normally settles in the lower part of the dural space. It is used in
obstetrics and for surgery in the perineal region

7. Based on the Chemical Structure, Local Anaesthetics are classified as follows:
Local Anaesthetics
Benzoic
Acid Derivative

Acid Derivative
Lidocaine
Anilide Derivative
Miscellaneous
Drugs
•Cocaine
•Hexylcaine
•Meprylcaine
•Cyclomethycaine
•Piperocaine
•Benzocaine
•Butamben
•Procaine
•Butacaine
•Propoxycaine
•Tetracaine
•Benoxinate
Amino Benzoic
•Lignocaine
•Mepivacaine
•Prilocaine
•Etidocaine
•Bupivacine
•Phenacaine
•Diperodon
•Dibucaine
•Dimethizoquine
•Pramoxine
•Dyclonine
Classification

8. Mechanism of action
•Local Anaesthetics block both the generation and the conduction of the nerve impulse. The
blockade probably results from the biochemical changes caused by the drug. Immediately
after the nerve impulse had passed, the pores again become smaller.
•Sodium ions are pumped out of the fibre, at the same time potassium ions are transported
into the fibre.
•Local anaesthetics decrease the permeability of cell membrane to sodium and thus preventing
sodium depolarization.
•The onset of action is related primarily to the pKa of the Local Anaesthetic. Those with lower
pKa(lidocaine, mepivaciane) are fast acting while those with higher pKa(procaine, tetracaine)
are slow acting.

9. Metabolism Of Local Anaesthetics
•LA with Ester Group
•LA with Amide Group
•Metabolized in Plasma by Plasma Pseudo-Cholinesterase enzyme.
•Metabolized in Liver by Esterase enzyme to give p-amino benzoic acid and
corresponding alcohols.
•Toxicity occurs in patients with plasma pseudo-cholinesterase enzyme deficiency
(1 out of 2500).
•Metabolized in Liver by the Microsomal enzymes.
•Toxicity occurs in patients with impaired liver function (Liver Dysfunction).

10. Structure activity Relationship
SAR Of Benzoic Acid Derivatives
Most of these local anaesthetics are tertiary amines available as HCl salts with pKa in the range of
7.5-9.0. Any structural modification of the local anaesthetic that causes change in pKa will have
pronounced effect to reach hypothetical receptor or the binding sites.

11. I. Lipophilic Group
•The clinically useful Local Anaesthetics of this class possess an aryl radical that is attached
directly to the carbonyl groups and are highly lipophilic. They appear to play an important role in
the binding of Local Anaesthetics to the Na Channel receptor protein.
•Placement of aryl group with substituents that increases the electron density of the carbonyl
oxygen enhances the activity.
•Electron withdrawing substituents in ortho and para or at both the positions leads to an increase
of its local anaesthetic property.
•Amino (procaine, butacaine), alkyl amino (tetracaine), alkyl (cyclomethycaine) group can contribute
in local anaesthetic property
•Any substitution that will trigger Zwitter ion formation will be more potent. Hence , m-position
substation decreases the activity.

12. II. Intermediate Group
•In procaine series, anaesthetics potency decreases in the following order.
Sulpher > Oxygen > Carbon > Nitrogen
•Modifications also affect the 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.
•Placement of small alkyl groups (branching) around ester group (hexylcaine/meprylcaine) or
the amide function also hinder hydrolysis, and hence, increase in duration of action.

13. III. Hydrophilic Portion
•The amino alkyl group is not necessary for local anaesthetic activity, but it is used to form
water soluble salts such as HCl salts.
•Tertiary amines are more useful agents. The secondary amines appear to have a longer
duration of action, but they are more irritating. Primary amines are not active.
•The tertiary amino group maybe diethyl amino, piperidine, or pyrolidino, leading to a product
that exhibits same degree of activity essentially.
•The more hydrophilic morpholino group usually leads to diminished potency.
•In general, the local anaesthetic drugs should have increased lipid solubility and lower pKa
values that leads to rapid onset and lower toxicity.

14. SAR Of Analides
I. Aryl Group
•The clinically useful local anaesthetics of this type possess a phenyl group attached to the
sp
2 carbon atom through a nitrogen bridge.
•Placement of substituents on the phenyl ring with a methyl group in the 2 / 2 & 6-position
enhances the activity. In addition, methyl substituent provides steric hindrance to hydrolysis
of the amide bond and enhances the coefficient of distribution.
•Any substitutions on aryl ring that enhances zwitterion formation will be more potent.

15. II. Substitution X
•X may be carbon, oxygen, or nitrogen among them lidocaine series (X=O) has provided more
useful products
III. Amino Alkyl Group
•The amino function has the capacity for salt formation and is considered as the hydrophilic
portion of the molecule.
•Tertiary amines (diethyl amine, piperidine) are more useful because the primary and
secondary amines are more irritating to tissues.

16. Benzoic Acid Derivative
General Structure Of Benzoic Acid Derivative
Ex. :-
•Cocaine
•Hexylcaine
•Meprylcaine
•Isobucaine
•Piperocaine
•Cyclomethycaine

17. Cocaine
•Cocaine is the first local anaesthetics discovered. It is an alkaloid obtained from the leaves of
Erythroxylon cocca. It is a white crystalline powder, very soluble in water, freely soluble in
alcohol, and slightly soluble in methylene chloride.
•It is still employed topically as a 1% or 2% solution for the anaesthesia for the ear, nose,
throat, rectum and vagina because of its intense vasoconstrictive action though it is considered
too toxic for any anaesthesia procedure requiring injection.
Methyl (1R,2R,3S,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate

18. Hexylcaine
•Hexylcaine is a white powder, soluble in water, and chloroform. It is regarded as an all-purpose
soluble local anaesthetic agent. The onset and duration of action is almost similar to that of
lignocaine. It is mainly used as surface anaesthetic.
•It is still employed as a infiltration anaesthesia, 1%; for nerve block anaesthesia, 1% and 2%
solution; and for topical application to skin and mucous membrane, 1% to 5%.
1-(cyclohexylamino)propan-2-yl benzoate; hydrochloride

19. Meprylcaine
•It is also known as Epirocaine and Oracaine
•It is a local anaesthetic with stimulant properties that is structurally related to dimethocaine.I
•It is used in dentistry in 2% solution containing epinephrine as as infiltration and nerve block
anaesthetic.
[2-methyl-2-(propylamino)propyl]benzoate; hydrochloride

20. cyclomethycaine
•It is a white crystalline powder, soluble in water and chloroform. Used to relieve pain from
damaged skin, mucous membrane of rectum, vagina, and urinary bladder.
•It is applied topically with a usual dose of 0.25% to 1%.
3-(2-methyl piperidine)propyl-p-(cycloheyloxy)benzoate sulphate

21. piperocaine
•It is a small, white, crystalline powder, soluble in water and chloroform.
•It is used as surface anaesthesia for eyes, throat and caudal analgesia.
3-(2-methyl piperidin-1-yl)propyl benzoate; hydrochloride

22. P-amino Benzoic Acid Derivative
General Structure Of p-Amino Benzoic Acid Derivative
Ex. :-
•Benzocaine
•Butamben
•Procaine
•Benoxinate
•Butacaine
•Propoxycaine
•Tetracaine
•Chloroprocaine

23. benzocaine
•It is a white crystalline powder or colourless crystals, freely soluble in alcohol, slightly soluble
in water.
•It is used to get rid of the pain caused by wounds, ulcers and in mucous surface.
•It is a topical anaesthesia where only 1% to 20% should be used in ointment, cream and aerosol
for skin.
•It is nonirritant and nontoxic.
•It is also knowns as Americane.
Ethyl 4-aminobenzoate

24. Synthesis Of Benzocaine

25. Structure Activity Relationship Of Benzocaine :-
•Conjugation of aryl moiety to carbonyl group directly enhances the local anaesthetic activity.
•It possess both low potency and low systemic toxicity.
•Ester present in procaine makes it less resistant to hydrolysis than amides.
•Amino ethyl group is used to form water soluble salt such as HCl Salts.
•Secondary amines appear to have a longer duration of action but they are more irritating.

26. Butamben
•It is a local anaesthetic of relatively low solubility and used in similar manner to benzocaine.
•It is more efficacious than its corresponding ethyl ester when applied to intact mucous
membranes.
•It is a topical anaesthesia where only 1% to 2% should be administered in conjugation with other
local anaesthetics in ointments, creams, suppositories and aerosols.
•It is also knowns as Butesin.

Butyl p-aminobenzoate
Butyl p-aminobenzoate

27. Procaine
•It is a white crystalline powder or colourless crystals, soluble in water and alcohol.
•It has the advantage of lacking of local irritation, minimal systemic toxicity, longer duration of
action and low cost.
•It can be effectively used for causing anaesthesia by infiltration, nerve block, epidural block or
spinal anaesthesia.
•It is also knowns as Navocaine.

2-(Diethylamino)ethyl-p-aminobenzoate
2-(Diethylamino)ethyl-p-aminobenzoate

28. Synthesis Of Procaine from 2-Chloro ethanol

29. Synthesis Of Procaine From p-Amino Benzoic Acid
Synthesis Of Procaine From 2-Chloro ethyl 4-amino benzoate

30. Structure Activity Relationship Of Procaine :-
•Presence of aryl radical appears to play an important role in the binding of local
anaesthetics to the channel receptors. Amino group attached to the aryl ring contributes to
electron density in the aromatic ring by both resonance and inductive effect. Hence increases
the local anaesthetic activity.
•Ester present in procaine makes it less resistant to hydrolysis than amides.
•Amino ethyl group is used to form water soluble salt such as HCl Salts.
•Tertiary amine present makes it more useful agent.
•In contrast to cocaine, it does not causes vasoconstriction, so it is rapidly absorbed from the
site of injection.

31. butacaine
•It is a white crystalline powder of amino benzoic acid ester, it is insoluble in water and soluble in
alcohol.
•It is useful in lumbar epidural blockade and is suitable for continuous epidural analgesia in
labour.
•It has a slow onset of action, taking up to 30 min.
•It is also knowns as Butyn Sulphate.

3-(di-butyl amino)-1-propane-p-amino benzoate
3-(di-butyl amino)-1-propane-p-amino benzoate

32. Propoxycaine
•It is a structural isomer of proparacaine, and is less toxic with slightly lower potency than that
of proparacaine.
•Its local anaesthetic potency is reported to be 7 or 8 times more than that of procaine.
•It is mainly used for infiltration and nerve block anaesthesia.
•It is also knowns as Blockhain.

2-(diethyl amino)ethyl-4-amino-2-propoxy benzoate
2-(diethyl amino)ethyl-4-amino-2-propoxy benzoate

33. Tetracaine
•It is a white crystalline powder, slightly hygroscopic in nature, soluble in alcohol and freely
soluble in water.
•It is 10 times more toxic and potent than procaine. Its duration of action is twice than that of
procaine.
•It is an all purpose local anaesthetic drug used frequently in surface, infiltration block, caudal
and spinal anaesthesia.
•It is also knowns as Anethaine.

2-(Dimethyl amino) ethyl-p-(butyl amino) benzoate
2-(Dimethyl amino) ethyl-p-(butyl amino) benzoate

34. Binoxinate
•It is used in ophthalmology and otalaryngology.
•It is use to temporarily numb the front surface of the eye, while measuring the eye pressure or
removing a foreign body.
•It may be less irritating than Tetracaine, and the onset and duration of action are similar to
Tetracaine.
•It is also knowns as Oxybuprocaine.

4-(diethyl amino)ethyl-4-amino-3-butyloxy-benzoate
4-(diethyl amino)ethyl-4-amino-3-butyloxy-benzoate

35. Lidocaine / Analide Derivative
General Structure Of Lidocaine / Analide Derivative
Ex. :-
•Lidocaine
•Mepivacaine
•Prilocaine
•Etidocaine
•Bupivacaine

36. Lignocaine
•It is a white crystalline powder, very solublebin water and freely soluble in alcohol.
•It has a local vasodilation action, but usually used with vasoconstrictor adrenaline to prolong the
local anaesthetic activity.
•It is also used as a Class-I Anti-arrhythmic agent.
•It is also knowns as Lidocaine.

3-(di-butyl amino)-1-propane-p-amino benzoate
3-(di-butyl amino)-1-propane-p-amino benzoate

37. mepivacaine
•It is a white crystalline powder freely soluble in water and in alcohol, very slightly soluble in
methylene chloride.
•It is a local anaesthetic used for infiltration, peridural, nerve block and caudal anaesthesia.
•It has a significantly longer duration of action than that of Lidocaine.
•It is also knowns as Polocaine.

N-(2,6-dimethyl)-1-methyl-2-piperidin carboxamide
N-(2,6-dimethyl)-1-methyl-2-piperidin carboxamide

38. prilocaine
•It is a white crystalline or colourless crystals, very slightly soluble in acetone, freely soluble in
water and alcohol.
•It is a local anaesthetic of amide type used for surface infiltration and nerve block anaesthesia.
•It has a duration of action in between short acting Lidocaine and longer acting Mepivacaine.
•It is also knowns as Citanest hydrochloride.

2-(Propylamino)-o-propiono toludine
2-(Propylamino)-o-propiono toludine

39. Etidocaine
•It is a white crystalline or colourless crystals, soluble in water, freely soluble in alcohol.
•It is used clinically in epidural, infiltrative and regional anaesthesia.
•It has greater potency and longer duration of action than that of Lidocaine .
•It is also knowns as Duranset.

2-(Ethyl propyl amino)-2’,6’-butyroxylide
2-(Ethyl propyl amino)-2’,6’-butyroxylide

40. Miscellaneous drugs
Miscellaneous Drugs :-
Ex. :-•Phenacaine
•Diperdon HCl
•Dimethizoquine
•Dibucaine
•Pramoxine HCl
•Dyclonine HCl
Their are few medical compounds which have proved to be potent local anaesthetics
and could not be accommodated conveniently into any of the previous categories
discussed, are grouped together under this category.

41. phenacaine
•It is a small white odourless crystalline powder.
•It is structurally related to anilides in that the aromatic ring is attached to a sp
2 carbon through
a nitrogen bridge.
•It is chiefly employed as 1% solution for effecting local anaesthesia for the eye.
•It is also knowns as Holacaine Hydrochloride.

N,N’-bis(4-Ethoxyphenyl) acetadamide
N,N’-bis(4-Ethoxyphenyl ethanindamide)

42. Diperodon
•It is a white crystal soluble in water.
•It is a potent surface anaesthetic, used primarily for anus.
•It is very toxic in nature.
•It is also knowns as Diothane.

3-(1-Poperidinyl)-bis(phenylcarbamate)-1,2-propandiol
3-(1-Poperidinyl)-bis(phenylcarbamate)-1,2-propandiol

43. Dibucaine
•It is a white powder with slightly characteristic odour, somewhat hygroscopic, and darkens on
exposure to light.
•It is soluble in chloroform, alcohol, water and ether.
•Its anaesthetic activity is similar to those of procaine or cocaine when injected.
•It is also knowns as Nupercaine.

2-Butoxy-N-(2-(diethyl amino)ethyl)-4-quinoline carboxamide
2-Butoxy-N-(2-(diethyl amino)ethyl)-4-quinoline carboxamide

44. Synthesis Of Dibucaine

45. Structure Activity Relationship Of Dibucaine :-
•The lipophilic group is the bicyclic quinoline, which is attached to the sp
2 Carbon atom
through NH group.
•Amide bond present is more stable to hydrolysis than the ester.
•Lengthening the alkyl chain present on the amino group increase the pKa from 7.7 to 8.5
and simultaneously decreases the local anaesthetic potency.
•Branching around amide group also hinders amides catalyzed hydrolysis prolonging the
duration of action.
•That’s why it is the most potent long-acting local anaesthetics used as infiltration, surface
and spinal anaesthesia.

46. Pramoxine
•It is a white crystal and a white crystalline powder with numbing taste, may have slight aromatic
odour.
•It is soluble in chloroform, freely soluble in alcohol and water, very slightly soluble in ether.
•It is a less toxic surface anaesthesia.
•It is also knowns as Tranaolene.

4-(3-(4-Butoxy pheenoxy)propyl)morpholine. HCl
4-(3-(4-Butoxy pheenoxy)propyl)morpholine. HCl

47. Dyclonine
•It is a white crystal and a white crystalline powder may have slight odour.
•It is soluble in chloroform, alcohol and water, insoluble in ether and hexane.
•It is used to relieve minor sore throat and mouth discomfort.
•It is also knowns as Dyclone.

1-(4-Butoxy phenyl)-3-(1-piperidinyl)-1-propanone. HCl
1-(4-Butoxy phenyl)-3-(1-piperidinyl)-1-propanone. HCl

48. Dimethisoquine
•It is a white crystal and a white crystalline powder may have slight odour.
• It is a surface anaesthesia used as an ointment or lotion for relief from irritation, itching, pain
or burning.
•It is used topically to the skin asa 0.5% ointment or lotion 2 to 4 times a day.
•It is also knowns as Quinosocaine.

3-Butyl-1-(dimethylamino)ethoxy isoquinoline
3-Butyl-1-(dimethylamino)ethoxy isoquinoline

49. References
•Textbook Of Medicinal Chemistry Vol.1 By V. Algarsamy
•Essential Medical Pharmacology 8
th Edition By KD Tripathi
•Medicinal Chemistry 4
th Edition By Ashutosh Kar
•Wilson and Giswold’s Organic Medicinal and Pharmaceutical Chemistry

50. Thank You !