Local anaesthetic agents are the drugs which are applied to achieve a selective analgesia or anaesthesia of relatively restricted areas of the body.

1. Local anesthetics

2.  Local anaesthetic agents are the drugs which are applied to achieve
a selective analgesia or anaesthesia of relatively restricted areas of
the body.
 To be useful clinically, the action should always be reversible.
 These drug are mainly used for the temporary relief of localized
pain and itching due to minor burns, insect bites, allergic response,
in dentistry and minor surgical procedures.
 A local anaesthetic in contact with a nerve trunk can prevent the
initiation and the transmission in both sensory and motor nerves.
 Sites of action of local anaesthetic –
 1- topical anaesthesia
 2- infiltration anaesthesia
 3- nerve block
 4- spinal anaesthesia
 5- peridural block

3.  1- topical anaesthesia-
 It is used to relieve pain or itching at mucous surfaces, damaged skin surface,
wounds or burns.
 Local anaesthetic agents is ineffective if it is applied directly to the unbroken skin
 2- infiltration anaesthesia
 In minor operations, a Local anaesthetic is injected at one or more sites in and
around the area which is to be anaesthetized.
 The finer nerve ending in such area are affected by this method.
 3) Nerve block-
 A relatively higher concentration of local anaesthetic is injected as close as possible
to the main nerve trunk supplied, the area in which anaesthesia is required during
surgery.

4.  4- spinal anaesthesia
 In this case Local anaesthetic is injected into the subarachnoid space to block the
roots of those nerve supplied to the site of operation
 5) Peridural block-
 Local anaesthetic is injected into the peridural space and comes into contact with
the dura and the region outside the dura matter and thus covers and anaesthetizes
the root of the spinal nerves.

5. Mode of action
 1) Sodium Channel:
 The nerve membrane is composed of liquid as well as protein equal to the quantity of liquids.
 The Na + channel is segmented protein, of which four segments span the axon membrane, there
are two gates.
 The M-gate in the middle and the H- gate at the inner opening.
 Both gates must be open to allow passage of the ion.
 2) the association of local anesthetic molecule within the membrane may affect
selective permeability characteristic of the nerve membrane by increasing the
degree of disorder of the lipids that constitute the nerve membrane.
 3) interaction with calcium-
 Calcium exit in the membrane in bound state.
 It is the release of this bound calcium which initiate the action potential and ion permeability
changes.
 local anesthetic agents displace the bound calcium from these sites and form more stable bonds
with calcium thereby inhibiting ionic fluxes.
 4) some local anesthetic agents increase the threshold potential
 5) Refractive period:
 Immediately after an impulse prorogation, the axon remains completely unexcitable. Some
drugs extend or prolong this refractory period.
 6) Conduction velocity:
 This is the velocity at which an impulse is conducted along the nerve.

6. Classification
 A) Ester:
 1) Aminoalkyl ester of P- aminobenzoic acid.
 2) alkyl ester of P- aminobenzoic acid.
 3) ester of P- aminobenzoic acid.
 B) Amides:
 1) Aminoacylamide
 2) Aminoalkylamides.
 C) Urethanes.
 D) Aminoketones
 E) Aminoethers
 F) Miscellaneous agents.

11. SAR
 In almost all the cases, the linkage between the aromatic group and
the alkyl chain is either of the ester or amide type
 Nature of this bond is a determined of the certain pharmacological
properties of these agents.
 The potency of local anesthetic compound should be directly
proportional to partition coefficient.
 I ) SAR for LA agents an ester linkage-
 1) Aryl group
 2) Bride ‘X’
 3)Aminoalkyl group

12.  1) Aryl group-
 An aryl radical attached directly to the carbonyl group, result into enhance local
anesthetic ( LA) activity
 Similarly alicyclic and aryl aliphatic carboxylic acid ester are also active LA
 In aryl vinyl radical ( Ar- CH=CH-), the mesomeric effect of the aryl radical does
not extend to the carbonyl group and hence such compound are not effective
clinically.
 The aryl substitution which increase the electron density of the carbony oxygen
enhance activity. E.g. alkoxy, amino and alkyl amino group at ortho and para
position
 2) Bride ‘X’
 Here X may be carbon, nitrogen, oxygen, or sulphur.
 The nature of X affect duration of action and relative toxicity.
 3) Aminoalkyl group
 The amino group is considered as the hydrophilic part of the molecule
 The activity decrease and irritation property increases in the order 1<2<3 amine
 The alkyl position only influences the lipid solubility
 In general the amino alkyl group is not necessary for LA activity but it is used to
form water soluble salts.

13.  II ) SAR for LA agents an amide linkage-
 1) Aryl group
 2)Substituent X
 3) Amino alkyl group
 1) Aryl group
 The alkyl substitution ( particularly CH3) at ortho or para position enhance the
activity
 2)Substituent X
 In general X may be carbon , Oxygen or nitrogen
 3) amino alkyl group-
 The nature and its relative contribution to activity is same as in the compound
contaning ester linkage.