5/18/2022

Local Anesthetics
Definition :
These are drugs that when given either topically or
parentrally to a localized area, produce a state of local
anesthesia (loss of sensation without loss of
consciousness) by reversible blocking of the nerve
conductance that transmit the feeling of pain from this
area to the brain.

Mechanism of Action
The membrane of the nerve cell has sodium ion channels
which allow the influx of Na+ ions leading to excitation and
conductance .

The local anesthetic binds at selective sites of the

sodium channel so interfere with the movement of
Na+ ions across the nerve membrane preventing
the ability of the nerve cells to be excited ( block
nerve conductance and pain sensation).

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Most of the clinically useful local anesthetics are

tertiary amine and can be protonated under the
physiological condition and exist in equilibrium with
its conjugated acid .

The non-ionised base (B) can diffuse through the neuronal

membrane, then it partially ionises again to BH+. The ionised
form BH+ enters the sodium channel (from the interior of the
nerve fibre) and combines with a specific receptor within the
channel that results in channel blockade.

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Ideal PKa for the local anesthetic is between 7.5-

9.5.
Drug with PKa< 7.5 it will present mainly in the unionized
from at the physiological PH not effective as local
anesthetic although it can penetrate the membrane.

Drug with PKa> 9.5 it will present mainly in the

ionised form at the physiological PH less effective as
local anesthetic as it has difficulty in penetrating the
membrane.

Classification of local anesthetics

1-Ester Derivatives

a) Benzoic acid derivatives

b) p-aminobenzoic acid derivatives

2- Amino Amide derivatives (Anilides)

3- Miscellaneous

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Structure Activity Relationship of local

anesthetics ( ester derivatives)

Formation of the zwitterion improve the binding of the

L.A. with the receptor

1- Any substitution on the aromatic ring that

can enhance the formation of this zwitterion
through resonance or inductive effects will
improve the potency of the L.A and its
affinity. eg.
(NH2, RNH, R2N or RO) N.B. in para position not in meta

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2- Substitution with electron withdrawing gps as

NO2, CO or CN reduce the potency.

a) Benzoic Acid Derivatives

1- Cocaine
Applied topically to mucous membrane e.g eyes, throat,
nose . Side effects……

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2- Hexylcaine HCl (cyclaine)

Uses:
1-Topical anesthesia for mucous membranes.
2- Spinal and nerve block anesthesia

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3- Meprylcaine HCl (oracaine)

Has longer duration than hexylcaine why? Due to

more branching around the ester group
>>>>>>>>>steric effect that decreases the attack
by esterase enzyme.

❑ Used in dentistry and nerve block anesthesia.

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b) p-aminobenzoic acid derivatives

1- Benzocaine (americaine)

Metabolism:

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2- Procaine hydrochloride (novocaine)

Metabolism:

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Why do p. aminobenzoic acid derivatives

have allergic reaction?
Because they are metabolized giving Para
aminobenzoic acid which responsible for such
reactions.
They have drug - drug interaction with
sulphonamides WHY?
Because sulphonamides compete with PABA for
bacterial dihydropetroate enzyme and increase
the amount of PABA decrease such
competition…..
N.B. anticholinesterase

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3-Chloroprocaine HCl (Nesacaine)

It has rapid onset, higher potency due to increased lipophilicity by

Cl atom however, it has shorter duration due to the presence of
Cl ortho to the carbonyl of the ester function which increases its
rate of hydrolysis by esterase more than procaine and
benzocaine

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4-Tetracaine HCl (pontocaine)

Uses:
It is applied topically (due to increased lipid solubility) as
solution to the eye to anesthetizes cornea and as a
cream in dermatological disorders.

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Tetracaine is 50 fold more potent and longer

duration than procaine ?

due to the butyl amino gp. At para position which increase

the lipid solubility and increase the formation of zwitter ion
and hence increases binding with the receptor and potency.

It has higher positive inductive effect than amino group and

so decreases the positive charge on the carbonyl gp.
decreasing its attack
by esterase enzyme.

N.B. Cl has ipophilicity with electron withdrawing effect while butyl amino has lipophilicity
with electron donating effect

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B- Amino Amide derivatives :Anilide

derivatives

Advantages of anilide drs. Over benzoic ester drs.:

1- Less metabolized and have longer duration of
action :
a- due to replacement of the easily metabolized
(COO) group of ester by isosteric less reactive –
NHCO (amide) group

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b- The presence of two ortho methyl groups attached to the

phenyl ring protect the amide from the attack by the
metabolizing enzyme by both electronic and steric effects.

2- More potent and effective with or without vasoconstrictor.

3- less allergic reactions and not contraindicated with

sulphonamide antibacterial agents why? But more likely to
produce CNS side effects

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1-Lidocaine (xylocaine. Lignocaine)

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1-Lidocaine (xylocaine. Lignocaine)

Lidocaine has CNS side effect as it penetrates BBB

then N-dealkyated to the CNS toxic monoethyl
metabolite

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2- Tolycaine

No C.N.S. side effect of lidocaine why?

Tolycaine has an o-carbomethoxy gp. which is
rapidly hydrolyzed in the blood to the polar
carboxylate group and, thus, is unable to cross
the blood–brain barrier.

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4- Bupivacaine HCl (marcaine)

The racemic mixture has cardiotoxicity due to the R

isomer so it is not surprising to see the approval of
levobupivacaine, the S-enantiomer of (±)-bupivacaine
with less cardiotoxicity.
Uses
1- It has long duration
2- Used mainly for infiltration and regional nerve block
anesthesia.

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