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1. Suresh Bairi MS.(Pharm.), (Ph. D) Asst. Professor
UCPS, Palamuru University, MBNR
Medicinal Chemistry of Local
Anaesthetics
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2. Local anaesthetics
 Local anaesthetics are the drugs that when applied directly to
the peripheral nervous tissue blocks nerve conduction and
abolish all the sensation in that part supplied by the nerve.
 These are used in dentistry, in ophthalmology in minor surgical
operations, including endoscopy, and relieving pain in certain
medical conditions such as tumours growing on spine.
 These are also used for temporary relief of pain from insect
bites, burns, and other surface wounds
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3. Mechanism ofAction
 Conduction of nerve impulses is mediated by action
potential (AP) generation along axon.
 Cationic form of local anesthetic binds at inner
surface of Na+ channel – preventing Na+ influx (rising
phase of membrane potential) which initiates AP →
blockade ofnerve impulses (e.g., those mediating
pain).
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4. Cont..
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5. Cont..
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6. General classification of local anaesthetics
1. Natural agents : Cocain
2. Synthetic nitrogenous compounds
i)Derivatives of benzoic acid: Hexylocaine, cyclomethacain, meprylcain
ii)P-amino benzoic acid derivatives: benzocain, procain, butacain, propoxycain
iii) Derivatives of acetanilides: lignocain, mepivacain, bupivacain
iv) Derivatives of quinolines: cinchocain, dimethisoquin
3. Synthetic non-nitrogenous agents: benzyl alcohol, propane diol
4. Miscellaneous drugs: Phenacaine, Diperodon, Dibucaine, clove oil, phenol,
chlorpromazine, antihistamines.
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7. Natural agents
 Cocaine: it is an alkoloid obtained from
erythroxylon coccoa (first local anaesthetic)
 Employed topically 1-2% solution (earlier days)
for anaesthesia of ear, nose, throat, rectum and
vagina.
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8. Benzoic acid derivatives
Name R R1
Hexylocain -H
Meprylocain -H
Cyclomethycain
piperocain -H
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9. P-Aminobenzoic acid derivatives:
Name R1 R2 R3 R4 R5
Benzocain -H -H -H -
Butamben -H -H -H -
Procain -H -H -H
Butacaine -H -H -H
Propoxycai
n
-H -H -PrO
Tetracain -Bu -H -H
Bunoxynat
e
-H -BuO -H
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10. Synthesis of Benzocain
 It is used to get rid of pain caused by wounds,
ulcers and in mucus surfaces
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11. Synthesis of Procain
 It is used in infiltration anaethesia and
spinal anaesthesia (5-20%)
 It is not effective topically
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12. Anilides (amide) derivatives
Name R1 R2 Description
Lidocaine
(Lignocain)
-CH3 -CH2N(C2H5) 2 Vasodilatory action, used with
vasoconstrictors
Ointments, jelly & Topical solutions
Duration 60-75min prolonged to 2hrs
Mepivacain
(carbocaine
)
-CH3 Topically not active, longer duration of
action 120-150min
Mostly used infiltration
Prilocaine -H Used for ephineprine intolerance patients
Causes methemoglobanemia
Etidocaine -CH3 More potent than lidocaine and longer
duration of action can be used by
infiltration, epidural and regional
anaesthesia
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13. Miscellaneous LAs
 Diperodon: potent surface
anaesthetic
 Used primarily for anus
 Highly toxic upon IV administration
causes hypersensitivity reactions
• Phenacaine: mainly used
for local anaesthesia of Eye
• Dibucaine
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14. Synthesis of Dibucaine
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15. Cont..
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16. Dibucaine
 Generally used for surface anaesthesia
 When administered by IV Inhibits plasma cholinesterase
causes toxic effect.
 Neuromuscular blockers generally administered in
anaesthesia to prevent respiratory paralysis
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17. SAR of Local Anaesthetics
1. General SAR
LA s are broadly belongs to two main basic chemical structures 1. Esters (Procaine)
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18. Cont..
 Amide 2. Amide ( Lidocaine)
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19. Cont..
 LA’s activity and duration of action is very much
dependent upon the stability of those structures
 The main factor the stability of these two derivatives is the
hydrolysis of esters and amides
 Xylidine ion is a poor leaving group than the diethyl
amino ethyloxide group, which is responsible for slower
hydrolysis of the lidocaine amide bond, resulting more
stable and longer duration of action
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20. Cont..
 By the introduction of electron withdrawing group (O-
Chloro) in procaine (chloroprocaine) makes the ester
linkage more susceptible to hydrolysis therefore
chlorprocaine having shorter duration of action.
 Introduction of electron-releasing group O-Propoxy group
(propoxycain) makes the ester hydrolysis difficult as
compared to procaine hence proxycain having longer
duration of action
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21. 2. SAR of Ester Derivatives
i) Aryl group (substitution on aryl group) :
 Chloroprocaine: Chloro substitution in the 2- position. the
electron withdrawing chlorine destabilises the ester link to
hydrolysis
 Chlorine is hydrolysed by plasma more than four times faster
than procaine and having rapid onset of action21

22. Cont..
 The presence of non-polar n-butyl group on the aromatic ring
probably accounts for the grater lipid solubility of tetracaine,
which is one of most easily absorbed drugs
 Presence of 3-BuO group appears to stabilize the molecular
hydrolysis as in bunoxinate
 The aryl group is attached directly to the carbonyl group
conjugation of the aromatic moiety with carbonyl group
enhances the LAs activity
 Substitution of the aryl moiety with substituents that increase
the electron density of the carbonyl oxygen enhances the
activity22

23. Cont..
 The favourable substituents include alkoxy, amino and
alkyl amino in para and ortho positions and these alter the
lipophilic activity
ii) Bridge X : X may be carbon, oxygen, nitrogen or sulphur
 In an isosteric procaine series anaesthetic potency
decreases in the order, these modifications affects duration
of action and toxicity
 Amides X=N most resistant to metabolic hydrolysis than
(X=O); thio esters (X=S) may cause demerits
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24. Cont..
iii) Aminoalkyl group:
 This is considered to be hydrophilic part of local
anaesthetic molecule
 Territory amines appear to produce longer duration of
action but they are more irritating
 Primary amines are not very active and causes irritating.
 Alkyl groups including the intermediate chain linked to X,
primarily influence the relative lipid solubility
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25. 3.SAR of Amide derivatives
Aryl group at 2 or 6 with methyl group enhances the
activity
And the methyl substituents provides more steric
hindrance to the hydrolysis of amide bonds
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26. Cont..
X may be carbon(Isogramine), oxygen (Lidocaine) or
nitrogen (phenacain) Lidociane (X=O) has provided
useful product
Aminoalkyl group: it is hydrophilic portion of the
molecule and undergoes salt formation
Tertiary amines are more useful clinically and 1o, 2o
are more irritating.
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27. 4. Coefficient Distribution:
 Nerve membrane consists primary lipids, increasing the lipid
solubility a series of compounds facilitated penetration of nerve
membrane.
 The potency of local anaesthetic is directly proportional to
distribution coefficients in vitro.
 Substitution of aryl group by alkyl, alkoxy, alkylamino groups
leads to homologous series in which partition coefficient with
increasing CH3 groups at C4, C5 or C6
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28. Cont..
 Branching of N-alkyl groups in often accompanied by an
intensification of activity
 Territory amino group may be diethyl amino, piperidino or
pyrrolidino with the same degree of activity.
 Clinically useful agents exhibits Pka values in the range of
8.0 – 9.5 because of the compounds with higher Pka
values ionised 100% at Physiological PH and so have
difficulty in reaching the bio-phase.
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