local anesthetics · 2020. 7. 9. · local anesthetics desirable characteristics rapid onset of...

Local Anesthetics

1Dr. Amged SirElkhatim

Common Exposure to Local anaesthetics:

Definition:

• Local anaesthetics are drugs which upon

topical application or local injection cause

reversible loss of sensory perception,

espicially of pain in a localized area of the

body.

• Loss of sensory as well as motor

impulses.

• No structural damage to the neurons.

Local Anesthetics

DESIRABLE CHARACTERISTICS

Rapid onset of action

Brief, reversible block of nerve conduction

Low degree of systemic toxicity

Soluble in water and stable in solution

Effective on all parts of the nervous

system, all types of nerve fibers and

muscle fibers

What are the drugs?

(Classification)1. Injectable anaesthetic:

Low potency, short duration – Procaine and Chlorprocaine

Intermediate potency – Lidocaine (Lignocaine) and Prilocaine

High potency and long duration – Tetracaine, Bupivacaine,

Ropivacaine, Etidocaine, Mepivacaine and Dibucaine (Cinchocaine)

2. Surface anaesthetic:

Soluble – Cocaine, Lidocaine, Tetracaine and Benoxinate

Insoluble – Benzocaine, Butylaminobenzoate and Oxethazine

3. Miscellaneous drugs:

Clove oil, phenol, chlorpromazine and diphenhydramine etc.

Another Classification ?

• Local anesthetics are classified by their

chemistry into two classes.

What are they?

Answer

–Esters

–Amides

Short acting

Metabolized in the plasma and tissue

fluids

Excreted in urine

Chemistry of LA

Esters–Short acting

–Metabolized in the

plasma and tissue

fluids

–Excreted in urine

Amides–Longer acting

–Metabolized by

liver enzymes

–Excreted in urine

C

Chemistry of LA – (LAs are Weak Bases)

C O

O

R N

R

R

NH

O

R N

R

R

Aromatic portion Amine portion

Intermediate chain

ESTER

AMIDE

LIPOPHILIC HYDROPHILIC

The Discovery & Development of Local Anesthetics

• As early as 1532, saliva from chewing the coca

leaves often was used to relieve painful

wounds (lead compound).

• First isolated in 1860 (structure ??).

• First used as a local anesthetic in 1884.Dr. Amged SirElkhatim 9

• Psychic Dependence was and still the major

drawback of cocaine!!

• Other drawbacks:

- Allergic reactions.

- Tissue irritations.

- Poor stability in aqueous solution.

Dr. Amged SirElkhatim 10

• Structure of cocaine was not known until 1924.

• The structures of the hydrolysis products were

elucidated.

Dr. Amged SirElkhatim 11

• A variety of benzoyl esters of amino alcohols,

including benzoylatropine, exhibited strong

local anesthetic properties without any

addicting liability.

Dr. Amged SirElkhatim 12

• Further modifications resulted in the

discovery and synthesis of procaine in 1905.

• Lack of severe local and systemic toxicities of

cocaine (prototype).

• Short duration of action (combination with

epinephrine).

Dr. Amged SirElkhatim 13

• Further modifications for the purpose of

enhancing the intrinsic potency and the

duration of action of procaine resulted in

tetracaine, the most potent, long-acting ester-

type local anesthetic agent, which is used in

spinal anesthesia.

Dr. Amged SirElkhatim 14

• Good anesthetizing properties and low toxicity.

• Poor water solubility (no hydrophilic portion).

• No parenteral solutions.

Dr. Amged SirElkhatim 15

• Isogramin, a natural alkaloid, serendipitously

was found to have local anesthetic properties.

• This observation led to the discovery and

synthesis of lidocaine (Xylocaine).

• Lidocaine is a bio-isoteric analogue of

isogramine

Dr. Amged SirElkhatim 16

• Isogramin, a natural alkaloid, serendipitously

was found to have local anesthetic properties.

• This observation led to the discovery and

synthesis of lidocaine (Xylocaine).

• Lidocaine is a bio-isoteric analogue of

isogramine

Dr. Amged SirElkhatim 17

Dr. Amged SirElkhatim 18

Dr. Amged SirElkhatim 19

Dr. Amged SirElkhatim 20

Mechanism of Action of Local Anesthetics

• Local anesthetic agents block nerve

conductance and produce anesthesia as a result

of their selective actions on membrane-bound

sodium channels.

• Generally local anesthetics block the action

potential by first penetrating the nerve

membranes in their un-ionized forms and then

binding to a site within the channels in their

ionized forms.

Dr. Amged SirElkhatim 21

Effect of pH Changes on the local anesthetic Activity

• Most of clinically useful local anesthetics are

tertiary amines with a pKa of 7.0 to 9.0.

• Thus, under physiological conditions, both

protonated forms [BH+] and the un-ionized,

molecular forms [B] are available for binding

to the channel proteins.

Dr. Amged SirElkhatim 22

• 90% of the blocking actions of lidocaine may

be attributed to [BH+], whereas 10% may

result from [B] and, perhaps, at a hydrophobic

binding site other than the primary binding

site.

• Benzocaine has been suggested to bind to this

hydrophobic binding site.

Dr. Amged SirElkhatim 23

Structure Activity Relationship (SAR)

• Lipid solubility, pKa, and metabolic

inactivation.

Dr. Amged SirElkhatim 24

Modification of the Lipophilic Portion

• Determines physical and chemical properties!

Dr. Amged SirElkhatim 25

• Ortho or para (or both) electron-donating

substituent increases local anesthetic potency.Dr. Amged SirElkhatim 26

• Zwitterionic form has a greater affinity for the

receptor.

• Electron-donating substituents enhance the

formation of the zwitterionic.Dr. Amged SirElkhatim 27

• Greatly reduced anesthetic potency.

• Prohibits the formation of the zwitterionic form.

Dr. Amged SirElkhatim 28

• Resonance delocalization of the electrons of

the meta substituent is not possible.

• Only affect the lipophilicity.

Dr. Amged SirElkhatim 29

• Tetracaine is 50-fold more potent than

procaine due to:

- Increasing lipid solubility.

- Electron-releasing property.Dr. Amged SirElkhatim 30

Dr. Amged SirElkhatim 31

• Both propoxycaine and lidocaine have a

relatively longer duration of action.

• Chloroprocaine has a shorter duration of

action.

Dr. Amged SirElkhatim 32

Modification of the Intermediate Chain

• It influences the duration of action and relative

toxicity.Dr. Amged SirElkhatim 33

Modification of the Intermediate Chain

• It Hinders esterase- or amidase-catalyzed

hydrolysis, prolonging the duration of action.Dr. Amged SirElkhatim 34

Modification of the Hydrophilic Portion

Dr. Amged SirElkhatim 35

• Formation of water-soluble salt.

• Onium ions produced by protonation of the

amine group also are required for binding to

the receptors.Dr. Amged SirElkhatim 36

Stereochemistry

• So far, no stereochemical requirments for the

local anesthetic activity.

Dr. Amged SirElkhatim 37

• Only two optically active local anesthetics

currently being marketed.

• Lower cardiac toxicity.

Dr. Amged SirElkhatim 38

• Responsible for cardiac toxicity.

Dr. Amged SirElkhatim 39

• Good anesthetic activity.

• No CNS side effects.

• Clinically used as antiarrhythmic agent.

Dr. Amged SirElkhatim 40

Synthesis of Procaine

Dr. Amged SirElkhatim 41

Synthesis of Lidocaine

Dr. Amged SirElkhatim 42