LOCAL ANESTHETICS

LOCAL ANESTHETICS

Local anesthetics are mainly used to produce loss of sense of pain in particular area of the body. They act by blocking both sensory and motor nerve conduction to produce a temporary loss of sensation with out a loss of consciousness.

Local anesthetics are drugs with reversibly prevent the generation and propagation of active potentials in all excitable membranes including nerve fibres by stabilizing the membrane.
They are administered locally in correct concentration; block the nerves that carry the pain sensation and automatic impulses in local areas of the body.

Local anesthetics are used in dentistry, ophthalmology and minor surgical operations including endoscopy. They are also used topically for temporary relief of pain insect bites, burns wounds.

On the basis of method of administration and sites of action of the anesthetics agent, they are in different types.

Surface or Topical Anaesthesia : - The local anaesthic is applied directly to the mucosal surface damaged skin surface, wounds or burns to relief pain or itching. It must be able to penetrate tissues readily. Example – Lignocaine.

Infiltration Anaesthesia:- The drug is injected subcutaneously to paralyse the sensory nerve endings around the area with is to be anaesthetized.

Example – An area to be incised or for tooth extraction –(Prilocaine).

Nerve block Anaesthesia:- The local anesthetic is injected as close as possible to the nerve trunk supplying the specific area to be anaesthetized. This block conduction is both sensory and motor fibres.

Spinal Anaesthesia:- The drug is injected subarachnoid space and is to cerebrospinal fluid to paralyse the roots of spinal nerves. It is used to induce anesthesia for abdominal or pelvic surgical operations.

Epidural Anaesthesia:- The drug is injected in to epidural space and the root of spinal nerves are anaesthetized. It is mainly used for painless childbirth.

Caudal Anaesthesia:- It is similar to epidural anesthesia where the injection is made through sacral hiatus in to the vertebral canal which contains cauda equina. It is used for operation on the pelvic viscera.

Classification

1. Naturally occurring local anaesthetic:- Ex- Cocaine (ester).


2. Esters: -
   a) P-aminobenzoic acid derivative (PABA)- Benzocaine, Procaine, Tetracaine, Butacaine, orthocaine, Benoxinate.
   b) Esters of benzoic acid- Meprylcaine, Cyclomethycaine,(propoxycaine), Hexylcaine, Piperocaine.


3. Amides or Anilides :- Lignocaine, Prilocaine, Mepivacaine, Bipivacaine, Pyrrocaine, Etidocaine, Diperodone.


4. Piperidine or Tropane derivatives :-Alpha- Eucaine, Benzamine, Euphthalmin.


5. Quinoline derivatives :- Dibucaine (Chincocaine)


6. Isoquinoline derivative:- Dimethisoquine.


7. Miscelleneous :- Phenacaine (Amidine), Pramoxine, Euginol, benzyl alcohol, Phenol, Dyclomine, Saligenin.

Esters of P-Amino Benzoic acid

Benzocaine
Butacaine
Benoxinate
Propoxycaine

Esters of Benzoic acid Derivative

Meprylcaine

Amide and Anilides


Etidocaine

Quinoline Derivatives

Miscelleneous

SAR for local anaesthetic containing ester linkage

General Structure :

Aryl – CO – X - Amino alkyl Chain

1. The aryl radical attached directly to the carbonyl group enhances local anaesthetic activity. It is lipophilic centre of compound.
2. Alicyclic and aryl aliphatic carboxylic acid esters are also active local anaesthetics.


3. The compounds containing aryl-vinyl group (Ar-CH = CH -) does not having local anaesthetic activity, because of the mesomeric effect of aryl radical does not extend to carbonyl group.
4. The aryl substituents such as alkoxy, amino and alkyl amino groups at ortho or para position increases electron density of carbonyl oxygen enhances the activity.


5. The number of methylene groups is substituted to aryl moiety; the maximum activity is achieved for the C4 to C6 homologues.


6. The bridge X may be carbon, oxygen, nitrogen or sulphur. The nature of X affects duration of action and relative toxicity. The conduction anaesthetic potency decreases in the order of S, O, C and N.


7. The amino alkyl group is the hydrophilic part of molecule. The local anaesthetic activity decreases and irritation property increases in the following order. 10 <>


8. In general amino alkyl group is not necessary for activity, but it is used to from water soluble salts. Example : Benzocaine.


9. Local anaesthetic activity improves if the aryl lipophilic center has electron donor substitution but decreases with electron acceptor substituents

SAR for local anaesthetic containing an amide linkage

1. The alkyl substitution (-CH3) in aryl group at ortho or Para position enhances the activity by providing steric hindrance to the hydrolysis of amide linkage and contributes lipid solubility.


2. In general X may be carbon (Isogramine), oxygen (lidocaine) (or) nitrogen (Phenacaine) for good activity.


3. The relative activity of amino alkyl group is similar to the ester linkage containing compounds.

Mechanism of action

1. It sufficient number of sodium channels are blocked, there would be no significant charges in membrane potential and so the conduction of an action potential along the neuron would be prevented.
2. Blocking of conduction would automatically prevent the release of neuro transmitter at the presynaptic site.
3. Increasing the concentration of calcium ions of the extra cellular fluid may enhance or reduce the activity by affecting the opening of sodium channels.
4. Local anesthetic containing both lipophilic and hydrophilic groups may penetrate the excitable cells and decrease the excitability which associated with membrane of sodium ions across the membrane. Therefore local anesthetic interfere with sodium movements and interferes with excitability of cells.
5. The local anesthetic activity is dependant on its entering the channel from inside the neuron.