Local Anesthetics • History: • Lidocaine Mechanism of Action • Characteristics for an Ideal Local anesthetic

1. • Local anesthetics
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Local Anesthetics
 Local anesthetics are drugs that when given topically or parenterally to a
localized area, produce a state of local anesthesia by reversibly blocking the
nerve conduction that transmit the feeling of pain from this area to the
brain.
 As their action is reversible, so after their use, it is followed by complete
recovery in nerve functions with no risk of structural damage to nerve fiberes
of the cells.
 History:
 Cocaine: First natural local anesthetic which was isolated from Coca
leaves but it has disadvantages of euphoria and addiction.
 Procaine: First synthetic local anesthetic (LA) but it has slow onset,
short duration of action and causes allergy.
 Lidocaine: First modern LA. It is the most widely used LA today but it
causes vasodilatation at the site of application
Mechanism of Action:
They prevent the conduction and formation of action potential by either
fully or partially blocking the sodium Na+
ion channels ⇒ no significant

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change in the membrane potential ⇒ conduction of action potential along the
neuron would be prevented.
N.B.: Action potential = the ability of nerve cells to be excited
 Characteristics for an Ideal Local anesthetic :
1. It should produce reversible block of sensory nerve fibres with
minimal effect on the motor fibres.
2. It should have rapid onset with sufficient duration of action without
systemic toxicities.
3. It should be non-irritating to tissues.
4. It should be effective upon injection or local action.

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4. • Local anesthetics
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 Structure-Activity Relationships (SAR): According to Lofgren’s
classification, the LA has 3-parts:
A) Liphophilic Portion (Aryl Group):
The lipophilic portion of the molecule is essential for L.A. activity
because it is responsible for penetration into the cell membrane.
1- Electron-donating group on ortho or para positions increases
anesthetic activity. e.g.:
 p-Amino group (NH2) in procaine and butacaine.

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 p-Butylamino group in tetracaine.
 p-Propanoxy group in proparacaine.
2- Electron-withdrawing group (-NO2, -CO, -CN) decreases anesthetic
activity.
B) Intermediate Chain:
The intermediate chain is responsible for the onset of action.
↑ pKa ⇒  LA activity (pKa must be 7.5-9).
1- Short carbon chain(- 3C) in length: ↑ length ⇒↑ pKa ⇒ LA activity.
2- Presence of small alkyl groups around the ester increases duration of
action (as in etidocaine).
3- Generally, L.A. with ↑ lipid solubility and  pKa values ⇒↑ onset and 
toxicity.
C) Hydrophilic Portion:
The hydrophilic portion is responsible for water solubility and binding to
the receptor.
1- The tertiary alkylamine function is need for binding to Receptor.
 It forms water-soluble salts

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2- The hydrophilic group can be in the form of a secondary amine or part of
a heterocycle but secondary amines are more irritating to the tissues and
primary amines decreases anesthetic activity.
Binding of Ester-Type LA to Receptor Sites (Prototype)
Classification of LAs:
1. Amino Amides (Lidocaine Derivatives).
2. Amino Esters.
3. Miscellaneous.
Amides Esters Miscellaneous.
Bupivacaine Benzocaine
Dimethisoquin
Etidocaine Chloroprocaine
Phencaine
Levobupivacaine Cocaine
Lidocaine Procaine
Mepivacaine Tetracaine
Prilocaine
Ropivacaine

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Cocaine
 The parent (natural) drug.
 It is the alkaloid isolated from coca leaves.
Procaine (Novocain)
2-(N,N-Diethylamino)ethyl-4-aminobenzoate
 It is the first synthetic LA (prototype).
 It has  tissue penetration ⇒  LA activity.
Ethyl p-aminobenzoate

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 It has  LA activity.
Lidocaine (Xylocaine, Lignocaine)
2-(Diethylamino)-N-(2,6-dimethylphenyl)acetamide
 It is very lipid soluble ⇒↑ onset and ↑ duration of action than procaine
and tetracaine.
 It makes vasodilatation ⇒ needs to be administered with a
vasoconstrictor such as adrenaline (epinephrine).

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Synthesis of Lidocaine
NH2
CH3
CH3
Cl Cl
O
N
H
CH3
CH3
Cl
O
HN
N
H
CH3
CH3
N
O
Lidocaine