Local anaesthetics

Definition: local anaesthetics are drugs which block both sensory and motor nerve conduction to
produce a temporary loss of sensation without loss of consciousness. They are used to abolish pain
sensation in a restricted area of the body.
Classification: local anaesthetic can be classified according to their chemical structure as follow
I. Benzoic acid derivatives:

H3 COOC

O CH CH CH 2

C O CH NCH3

CH 2 CH CH 2                    
                        Cocaine                                                                                    Hexylcaine 
                                                                                                                       

                      Meprylcaine 

II. P-aminobenzoic acid derivatives:

 

         
                             Benzocaine                                                                             Procaine 
 

 
                                                 Tetracaine        
III. Anilide derivatives:

CH3

O C2H5

NH C CH2 N

C2H5

CH3                                  
Lidocaine (lignocaine) Mepivaine
IV. Quinoline and isoquinoline derivatives

                  
                  Dibucaine                                                Dimethisoquine 
V. Piperidine derivatives

                             
                              α‐Eucaine                                                         β‐Eucaine 
 
Benzocaine 
 

 
Procaine 
 

 
 
 
 
 
 
Lignocaine 
 

 
Dibucaine 
 

 
 
Mechanism of action:
 The local anaesthetics decrease the excitability of nerve cells by decreasing the entry of Na+
ions during upstroke of action potential.
 The local anaesthetics interact with a receptor situated within the voltage sensitive Na+ channel
and raise the threshold of channel opening.
 Local anaesthetic blocks Na+ conductance by two possible modes of action, the tonic and the
phasic inhibition.
 Tonic inhibition results from the binding of LA to nonactivated closed channel while phasic
inhibition results from the binding of LA to open state or inactivate state of channels.
Structure Activity Relationship (SAR) of local anaesthetics
 The general structures of local anaesthetic may be represented by
Lipophilic portion - Intermediate chain - Hydrophilic portion

 
Lipophilic portion
 The lipophilic portion of the molecule is essential for local anaesthetic activity.
 This portion of the molecule consists either of the phenyl ring or a 2,6-dimethylphenyl group
attached to a carbonyl function through an amino group.
 In p-aminobenzoic acid derivatives, an electron donating substituent at the ortho or para
position increases the activity. e.g. amino group in tetracaine.
 Electron withdrawing substituent such as (NO2, CO, CN) reduces the local anaesthetic activity.
 Substitution of amino function present at para position by butyl group increases lipid solubility
and hence increases anaesthetic activity.
 In anilide derivatives, the 2,6-dimethyl groups are required to ensure a desirable duration of
action because these group provide steric hindrance to hydrolysis of amide bond.
Intermediate chain
 The intermediate chain always contains short alkylene chain of 1-3 carbons in length linked to
the aromatic ring via several functional groups.
 The nature of the intermediate chain determines the chemical stability and duration of action of
the drug.
 The anilides are more resistance to metabolic inactivation hence have longer duration of action.
 The placement of alkyl group in ester function e.g. in meprylcaine or amide function e.g. in
prilocaine hinders hydrolysis by metabolic enzymes thus prolongs duration of action however it
increases systemic toxicity.
Hydrophilic portion
 The amino function is considered to be the hydrophilic part of the local anaesthetic molecule.
 The hydrophilic group can be in the form of secondary or tertiary amine or part of heterocyclic
such as pyrrolidine, piperidine, morpholine.
 Tertiary amines appear to produce longer action but are more irritating.