Local anaesthetic

Local anaesthetics (LAs) are drugs which upon topical application or local injection cause reversible loss of
sensory perception, especially of pain, in a restricted area of the body.
They block generation and conduction of nerve impulse at any part of the neurone with which they come in
contact, without causing any structural damage.

CLASSIFICATION
1. Injectable anaesthetic
a) Low potency, short duration
Procaine

Chloroprocaine

b) Intermediate potency and duration

c) High potency, long duration

Bupivacaine

Ropivacaine
Dibucaine (Cinchocaine)
2. Surface anaesthetic
a) soluble
Cocaine
Lidocaine
Tetracaine
Benoxinate

b) Insoluble
Benzocain

Butylaminobenzoate (Butamben)

Oxethazaine

Benzocaine

Benzocaine is a surface anaesthetic which prevents the transmission of impulses on nerve fibres and at nerve
Synthesis

Mechanism of Action
Benzocaine binds to sodium channel and reversibly stabilises the neuronal membrane. This reduces the
permeability of sodium channel to Na+ ions. Depolarisation of the neuronal membrane is blocked, and
hence the initiation and conduction of nerve impulses is blocked.
 Local anaesthetics are weak bases

At tissue pH (7.4)

Partly unionized Partly ionized

Penetrate the nerve membrane

Enter the axon (axonal pH is low)

Reionization of local anaesthetics

LA gains access to its receptor in the open state of the channel

LAs block the voltage-gated Na+ channel from inside; binds more tightly to inactivated state, prolongs the inactivated state

Prevent entry of Na+ ions into the neuron – decreasing the rate of depolarization

Prevent generation of action potential

No generation and conduction of impulses to CNS

Local anaesthesia

Uses
It is used for suppressing gag reflex, as a lubricant and topical anaesthetic on oesophagus,
mouth, larynx, nasal cavity, rectum, urinary tract, vagina, and respiratory tract or trachea.
Procaine

Synthesis
Route I: From: p-Aminobenzoic acid

Route II: From: 2-Chloro ethyl 4-amino benzoate

Route III: From: 2-Chloro ethanol

SAR of Local Anaesthetics

1) Lipophilic Portion
i) A local anaesthetic of this class that is clinically useful is highly lipophilic and has an
aryl radical directly attached to the carbonyl group. This plays an important role in the
binding of local anaesthetics to the channel receptor protein.
ii) Placing the aryl group with substituents that increases the electron density of
carbonyl oxygen enhances the activity of local anaesthetics.
iii) Structural modification change s the physical and chemical properties of local
anaesthetics . Placement of e lectron withdrawing substituents at ortho or para or both
the positions increase s the activity of local anaesthetics.
iv) Amino (procaine, butacaine) , alkyl amino (tetracaine) , and alkoxyl
(cyclomethycaine) groups contribute to electron density in the aromatic ring by
resonance and inductive effects. This increases the activity of local anaesthetics.
 v) Any substitution that enhances the formation of Zwitter ion will be more potent. Hence
substitution at m-position decreases the activity of local anaesthetics.
vi) The potency of tetracaine is 40 -50 times more than that of procaine. Although the
butyl group present in it increases lipid solubility, the potentiation is partially due to ele
ctron releasing property of the n -butyl group via inductive effect, which increases the
formation of Zwitter ion.
vii) Electron withdrawing group (Cl –) if present ortho to carbonyl pulls the electron density
away from carbonyl group, and makes it more susceptible to nucleophilic attack by the
esterase.
2) Intermediate Portion
i) In procaine series, the anaesthetic potency decreases in the following order: sulphur >
oxygen > carbon > nitrogen.
ii) Modifications affect the duration of action and toxicity. Amides (X = N) are more
resistant to metabolic hydrolysis than esters (X = O). Thioesters (X = S) may cause
dermatitis.
iii) Substitution of small alkyl groups (branching) around ester group
(hexylcaine/meprylcaine) or amide function delays hydrolysis and increases the
duration of action.
3) Hydrophilic Portion
i) The amino alkyl group is not necessary for local anaesthetic activity, but for forming
water-soluble salts such as HCl salts.
ii) Tertiary amines are more useful. Secondary amines have a longer duration of action,
but are more ir ritating. Primary amines are inactive and cause irritation.
iii) Placement of tertiary amino group (diethyl amino, piperidine, or pyrrolidino) forms
a product with same degree of activity.
iv) Placement of a more hydrophilic morpholino group reduces the potency.
v) The local anaesthetic drug should have increased lipid solubility and lower pKa
values to increase the onset of action and decrease toxicity.

SAR of Anilides
Given below is the general structure of anilides:

1) Aryl Group
i) The clinically useful local anaesthetic belonging to class of anilides has a phenyl group
attached via nitrogen bridge to the sp2 carbon atom.
ii) Placement of substituents on the phenyl ring with a methyl group at 2 (or) 2 and 6 -
position increases the local anaesthetic activity. The methyl substituent also provides
steric hindrance to hydrolysis of the amide bond and enhances the coefficient of
distribution.
iii) A substituent on the aryl ring that enhances the formation of Zwitter ion will be more
potent.
 1) Substituent X: This substituent may be a carbon, oxygen, or nitrogen . Lidocaine series
(X = O) has proved to be more clinically useful.
2) Amino Alkyl Group
i) The amino group can lead to salt formation and is the hydrophilic portion of the local
anaesthetic molecule.
ii) Tertiary amines (diethyl amine or piperidine) are more useful than the primary and
secondary amines, as they are more irritating to tissues.

DIBUCAINE

Cinchocaine or dibucaine is an amide local anesthetic. Among the most potent and toxic of the long-acting
local anesthetics, current use of cinchocaine is generally restricted to spinal and topical anesthesia.

USES

Cinchocaine is the active ingredient in some topical hemorrhoid creams such as Proctosedyl. It is also a component of
the veterinary drug Somulose, used for euthanasia of horses and cattle.