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