Local anesthetics

Local anesthetics have various clinical uses to treat acute or

chronic pain or to prevent the sensation of pain during
procedures
 Mechanism of action
Act by blocking the nerve conductance in both sensory
and motor neurons leading to loss of pain sensation as
well as impairment of motor function

Blocking occurs by binding selective sites on the sodium

channels in the excitable membrane which reduces the
passage of Na+ through pores and interfer with action
potential

They have no effect on the pain receptors or the synthesis

of pain mediators
 Mechanism of action.
Generally, local anesthetics interfere with Na+ ion channel passage across
the nerve cell membrane. The greatest effect is on small, unmyelinated
nerves. Myelinated nerves are also susceptible due to access at the nodes
of Ranvier.

3
Mechanism II
The unionized form of local anesthetics diffuses through the nerve cell
membrane to a specific hydrophobic binding site on the Na+ ion channel. The
ability to exist in an ionized form improves water solubility and there may be
polar interactions between the drug and the binding site.
All the injectable anesthetics exist as a equilibrium mixture of ionized and
unionized forms.
CH3 O
N
OCH3

H+
H
CH 3 O
N+
OCH3

O
4
 The first to be discovered

The lead drug was cocaine (natural product) but it has many
side effects like addiction, allergy, irritation and poor water
solubility
 Other compounds

The second drug synthesized was benzoyltropine which

exhibited strong local anesthetic properties without the
addicting liability of cocaine

can be structurally classified as either the procaine type or the

lidocaine type
 Structure activity relationship (SAR)

Structural modifications that alter

the lipid solubility, pKa, and
metabolic inactivation have a
pronounced effect on the local
anesthetic properties

For the study of SAR the

compounds were divided into
three portions:
Lipophilic portion
Intermediate chain
Hydrophilic portion
Lipophilic portion
In the amino ester series, an electron-donating substituent in the ortho or
para (or both) positions increases local anesthetic potency.

Such groups as an amino (procaine, chloroprocaine. and propoxycaine), an

alkylamino (tetracaine), or an alkoxv (proparacaine and propoxycaine)
group can contribute electron density to the aromatic ring by both
resonance and inductive effects, thereby enhancing local anesthetic
potency over nonsubstituted analogue (meprylcaine).

This was benificial for Benzocaine which lacks the hydrophilic amine portion is still
active as local anesthetic

Addition of electron withdrawing group (-NO2, -CN, -X, CO2Et) reduce the local
anesthetic activity and reduce the duration of action
 In lidocaine-type local anesthetic, the substitution on the aromatic ring must
be ortho to protect it from amide hydrolysis and ensure desirable duration of
action

Addition of another substituent to the aromatic ring increases the activity

(alkyl group of 3-4 C increases the activity and then drop off)

Insertion of methyl between the benzene ring and the carbonyl reduces the
potency of the local anesthetic. Addition of substituent to the meta position
of the ring will only increase (alkoxy) or decrease (-NH2) the lipophilicity of
the compound.
Intermediate chain

The nature of intermediate chain indicates the stability of the drug, duration
of action and relative toxicity.

Amino amides are more resistant to hydrolysis than amino esters

The placement of small alkyl group around the ester or the amide increase
resistace to enzymes and prolong the duration of action which may also
increase the systemic toxicity unless it is more selective (levobupivacaine)

In lidocaine series, lengthening the alkylene chain from 1-3 C increased the
pKa of the tertiary N group from 7.7-9.5 which reduces the potency of the
drug

Esters and amides are bioisosteres having similar sizes, shapes, and
electronic structures. The similarity in their structures means that esters and
amides have similar binding properties and usually differ only in their stability
in vivo and in vitro.
 Hydrophilic portion

The most clinically useful local anesthetics are those which have secondary,
tertiary or part of nitrogen heterocycle

Primary amines are irritating while quaternary has poor penetration of

tissues
The ionized form of the tertiary amine is required for binding the receptor
Local anesthetics with higher lipid solubility and lower pKa values appears
to exhibit more rapid onset and lower toxicity

Benzocaine has no N and still potent as local anesthetic but with poor water
solubility
 SAR of Local Anesthetics

Lipophilic portion Intermediate chain Hydrophilic portion

> > >

N S O n= 2 or 3
H

Y R3
Z n N

R1 R2
secondary amine, tertiary
electrondonating group amine, piperidine,
substituted in ortho and pyrrolidine, morpholine
para position will pKa value: 7.5-9.0
increase the activity;
electronwithdrawing
group substituted will
lower the activity
 SAR of Local Anesthetics (cont)

Lipophilic portion Intermediate chain Hydrophilic portion

Y R3
Z N
n
R2
R1
n= 2 or 3

O O O O
Y=-CH2-, -O-, lower the activity Stability: C O < C S < C NH < C CH2-
Y=-CH=CH- (conjugated function
group), keep the activity O O O O
Potency: C S > C O > C CH2-> C NH
Vasoconstrictors Used in Combination with Local Anesthetics

Many anesthetic preparations are commercially available combined with the

vasoconstrictor epinephrine.
Some anesthetics are also combined with other agents such as
norepinephrine, phenylephrine, oxymetolazone, or clonidine to achieve a
desired formulation.
The epinephrine in the anesthetic solution has multiple purposes. As
a vasoconstrictor,The injected epinephrine will constrict capillaries at
the injection site and thus limit blood flow to the area.
The local anesthetic will thus stay in the immediate area of injection
longer and not be carried away to the general circulation.
Reduce the systemic toxicity from the anesthetic and increase the
duration of anesthetic activity at the site of injection. The lack of
blood flow in the immediate area will also decrease the presence of
metabolizing enzymes and this also increase the duration of action
of the anesthetic locally
 It is not recommended that anesthetics with a vasoconstrictor be used in
tissue served by end-arterial blood supply (fingers, toes, earlobes, etc.). This
is to prevent ischemic injury or necrosis of the tissue.
Epinephrine has also been shown to counteract the myocardial depressant
effects of bupivacaine when added to a bupivacaine epidural solution.
 Allergic Reactions to Local Anesthetics

metabolite of the anesthetic or a preservative in the anesthetic.

Allergies to the ester anesthetics are more common than allergies to the
amide anesthetics.
the ester anesthetics may be metabolized to PABA, which is believed to be
responsible for the allergic reactions
Although the amide type local anesthetics are not metabolized to PABA they
may contain a paraben preservative that can be metabolized to PABA like
compounds.
Parabens are methyl, ethyl, propyl, and butyl aliphatic esters of PABA.
In addition to parabens, anesthetics may be preserved with metabisulfites
that are also known to cause allergic reactions in sensitive patients, especially
patients with asthma
PABA also blocks the mechanism of action of the sulfonamide antibiotics
Methemoglobinemia
Cyanosis as a result of the formation of methemoglobinemia may occur
after the administration of the local anesthetics,Lidocaine, prilocaine, and
benzocaine.
When normal hemoglobin is oxidized by a drug or drug metabolite, it forms
methemoglobin. Methemoglobin contains the oxidized form of iron, ferric
iron (Fe3) rather than the reduced ferrous iron (Fe2) that hemoglobin
contains.
The oxidized iron cannot bind to oxygen, and methemoglobinemia results
when the methemoglobin concentration in the blood reaches 10 to
20 g/L (6%12% of the normal hemoglobin concentration).
Cyanosis results and does not respond to treatment with 100% oxygen.
Patients with increased risk factors : children younger than 2 years, anemic
patients, those with a genetic deficiency of glucose-6-phosphate
dehydrogenase or nicotinamide adenine dinucleotide methemoglobin
reductase or those exposed to excessive doses of the causative local
anesthetic symptoms of methemoglobinemia occur.
treatment is an intravenous infusion of a 1% methylene blue solution, 1
mg/kg body weight, over 5 minutes