Local Anaesthetic

Dr. Shrikant M. Ghodse

Principal K. M. Kundnani College of Pharmacy, Mumbai

14.8.2024 1
 Oxybuprocaine
Tetracaine (Benoxinate )
Cocaine
Benzocaine

Hexylcaine Phenacaine
Butamben Lidocaine

Meprylcaine
Procaine
Mepivacaine
Diperodon

Cyclomethycaine
Butacaine
Prilocaine

Cinchocaine
(Dibucaine)
Piperocaine
Propoxycaine Etidocaine 2
Synthesis of Benzocaine

3
Synthesis of Procaine

4
Synthesis of Dibucaine

5
 LOCAL ANAESTHETICS
Local anaesthetic are drugs which upon topical application or local
injection cause reversible loss of sensory perception, especially of
pain, in a restricted area of the body.

They block generation and conduction of nerve impulse at all parts of the
neurone where they come in contact, without causing any structural
damage.

6
7
• The clinically useful LAs are weak bases with amphiphilic property.

• A hydrophilic secondary or tertiary amine on one side and

• a lipophilic aromatic residue on the other are joined by an alkyl chain

through an ester or amide linkage.

8
 CLASSIFICATION
• Local Anesthetics: SAR of Local anesthetics Lidocaine/Anilide derivatives:

• Benzoic Acid derivatives: Cocaine, Hexylcaine, Lignocaine, Mepivacaine, Prilocaine,

Meprylcaine, Cyclomethycaine, Piperocaine. Etidocaine.

• Amino Benzoic acid derivatives: Benzocaine*, Miscellaneous: Phenacaine,

Butamben, Procaine*, Butacaine, Propoxycaine, Diperodon, Dibucaine

Tetracaine, Benoxinate.

9
MECHANISM OF ACTION

10
11
12
Lipophilic ring
Aromatic Linker Amine

Helps the molecule penetrate

Ester or an amide
Through biological membranes.
number of carbon atoms in the
linker is increased, the lipid
solubility, protein binding,
duration of action, and toxicity
increases.

13
 SARs of Local Anesthetics

The structure of most local anesthetic agents consists of three parts.

(a) a lipophilic ring that may be aromatic with substitution
(b) a linker of various lengths that usually contains either an ester or an amide, and
(c) An amine group that is usually a tertiary amine with a pKa between 7.5 and 9.0.

14
 SARs of Local Anesthetics

The aromatic ring adds lipophilicity to the anesthetic and helps the molecule penetrate
through biological membranes.

It is also thought to have direct contact with the local anesthetic binding site on the sodium
channel.

The aromatic ring is believed to interact with the local anesthetic binding site in a pi–pi
interaction or a pi cation interaction with the S6 domain of the sigma component of the
sodium channel.

Substituents on the aromatic ring may increase the lipophilic nature of the aromatic ring.

15
 SARs of Local Anesthetics
An SAR study of para substituted ester type local anesthetics showed that
lipophilic substituents and electron-donating substituents in the para position
increased anesthetic activity.

The lipophilic substituents are supposed to help in

▪ increase the ability of the molecule to penetrate the nerve membrane and
▪ increase their affinity at the receptor site

16
 SARs of Local Anesthetics
Electron-donating groups on the aromatic ring created a resonance effect between
the carbonyl group and the ring, resulting in the shift of electrons from the ring to the
carbonyl oxygen. As the electronic cloud around the oxygen increased, so did the
affinity of the molecule with the receptor

17
When the aromatic ring was substituted with an electron-withdrawing
group, the electron cloud around the carbonyl oxygen decreased and
the anesthetic activity decreased as well.

18
 SARs of Local Anesthetics
(b)LINKER
The linker is usually an ester or an amide group along with a hydrophobic chain of various
lengths

In general, when the number of carbon atoms in the linker is increased, the lipid solubility,
protein binding, duration of action, and toxicity increases.

Esters and amides are bioisosteric 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.

19
 SARs of Local Anesthetics

For molecules that only differ at the linker functional groups, amides are more
stable than esters and thus have longer half-lives than esters

In general, ester groups are more susceptible to hydrolysis than amide functional
groups because of the prevalence of esterase's in the blood and the liver.

20
 SARs of Local Anesthetics
(c) Amine

Most local anesthetics contain a tertiary nitrogen with a pKa between 7.5 and 9.5.
Therefore, at physiological pH, both the cationic and neutral form of the molecule
exists.

At physiological pH, the ionized to unionized form of the anesthetic can be

calculated using the Henderson-Hasselbalch equation:

21
 Benzoic acid Derivatives

• Cocaine was the first agent used for topical anesthesia.

• It was isolated from the coca leaves

• Chemists working with the coca alkaloids noticed that the crystals
could numb their tongues.

• In 1884, a German surgeon demonstrated the successful use of

cocaine to anesthetize the cornea during eye surgery.

22
 Benzoic acid Derivatives

• Today, cocaine is used for topical anesthesia of mucous membranes

using a 4% to 10% solution.

• Cocaine has inherent vasoconstrictor properties and thus requires no

additional epinephrine.

• The toxicity of cocaine is a result of its vasoconstrictor properties and

ability to inhibit catecholamine, including norepinephrine reuptake.

• Cocaine is used primarily for nasal surgeries,

23
24
 Benzoic acid Derivatives

Hexylcaine
It is a short-acting local anesthetic.
It acts by inhibiting sodium channel conduction.
Overdose can lead to headache, tinnitus, numbness and tingling around the mouth and
tongue, convulsions, inability to breathe, and decreased heart function.

25
 Benzoic acid Derivatives
Meprylcaine (Epirocaine and Oracaine)

Meprylcaine has a relatively potent inhibitory action on the monoamine

transporter and inhibits the reuptake of dopamine, norepinephrine and serotonin

26
 Benzoic acid Derivatives
Cyclomethycaine

Cyclomethycaine is a local anesthetic.

It was first approved for use by the United States Food and Drug Administration in
1948.

27
 Benzoic acid Derivatives
Piperocaine

Piperocaine is a local anesthetic drug developed in the 1920s and used as its
hydrochloride salt for infiltration and nerve blocks.

28
 PABA Derivatives

Benzocaine is a unique local anesthetic because it does not contain a tertiary amine.

The pKa of the aromatic amine is 3.5 ensuring that benzocaine is uncharged at
physiological pH.

Because it is uncharged, it is not water soluble but is ideal for topical applications.

Benzocaine is available as a 20% solution topical spray, in a 1% gel for mucous

membrane application, and a 14% glycerin suspension for topical use in the outer ear
29
 PABA Derivatives

Butamben is a local anesthetic.

Proprietary names include Alvogil in Spain and Alvogyl
in Switzerland.
It is one of three components in the topical anesthetic
Cetacaine.
It is butyl ester of PABA

30
 PABA Derivatives

Procaine was synthesized in 1904 to address the chemical instability of

cocaine and the local irritation it produced.
pKa of procaine is 8.9; it has low lipid solubility and the ester group is
unstable in basic solutions.
Procaine is available in concentrations ranging from 0.25% to 10% with pHs
adjusted to 5.5 to 6.0 for chemical stability.
31
 PABA Derivatives

Procaine is very quickly metabolized in the plasma by cholinesterases

and in the liver via ester hydrolysis by a pseudocholinesterase,

Ester hydrolysis produces PABA, the compound responsible for the

allergic reactions common to ester anesthetics.

32
 PABA Derivatives

Butacaine is a para-aminobenzoic acid-containing local anesthetic primarily used as

a surface anesthetic for dental pain and in ophthalmology.

It has a more rapid onset of action and a more prolonged onset of action than
cocaine.

The drug was removed from the US market in 1990.

33
 PABA Derivatives
Propoxycaine

Propoxycaine hydrochloride inhibits voltage-gated sodium

channels, and thereby inhibits the ionic flux required for the
initiation and conduction of impulses.

Propoxycaine hydrochloride application can lead to a loss of

sensation.

Its is PAS derivatives

34
 PABA Derivatives

Tetracaine was developed to address the low potency and short duration of action of procaine.

Adding the butyl side chain on the para nitrogen increases the lipid solubility of the drug and
enhances the topical potency of tetracaine.

Tetracaine 4% gel is superior than eutectic mixture with lidocaine (EMLA) (an emulsion of lidocaine
and prilocaine) in preventing pain associated with needle procedures in children

35
 PABA Derivatives

Oxybuprocaine

Oxybuprocaine is structurally related to procaine

Oxybuprocaine (also known as Benoxinate) is a local anesthetic, which is used especially in ophthalmology and
otolaryngology.

Oxybuprocaine binds to sodium channels and reversibly stabilizes the neuronal membrane which decreases its
permeability to sodium ions.

36
 Anilide Derivatives
Lidocaine was the first amino amide synthesized in 1948 and has
become the most widely used local anesthetic.

The tertiary amine has a pKa of 7.8 and it is formulated as the

hydrochloride salt with a pH between 5.0 and 5.5.

Lidocaine can also be used for infiltration, peripheral nerve and plexus blockade, and
epidural anesthesia
Absorption of lidocaine will be decreased with the addition of epinephrine to the local
anesthetic.
Toxicity increases in patients with liver disease and those with acidosis, which
decreases plasma protein binding of lidocaine.
CNS toxicity is low with seizure activity reported with high 37
Metabolism of Lidocaine

38
 Anilide Derivatives

Mepivacaine

• It is an amino-amide type local anesthetic agent widely used to provide regional analgesic and
anesthesia.
• Mepivacaine hydrochloride is available in 1% to 3% solutions and is indicated for infiltration
anesthesia, dental procedures, peripheral nerve block, or epidural block.
• Mepivacaine is rapidly metabolized in the liver with 50% of the administered dose excreted into the
bile as metabolites
• The primary metabolic products are the N-demethylated metabolite and the 3 and 4 phenolic
• metabolites excreted as their glucuronide conjugates
39
 Anilide Derivatives

Prilocaine

It is local anesthetic of the amino amide type first prepared by Claes Tegner and
Nils Lofgren.

Ortho-toluidine, a metabolite of prilocaine, may cause methemoglobinemia, which

may be treated with methylene blue.

Prilocaine may also be contraindicated in people with sickle cell anemia

40
Anilide Derivatives

41
 Anilide Derivatives
Etidocaine differs from lidocaine by the addition of an alkyl

chain and the extension of one ethyl group on the tertiary

amine to a butyl group.

The additional lipophilicity gives etidocaine a quicker onset, longer half-life,

and an increased potency compared with lidocaine.

Etidocaine is the most potent amino amide local anesthetic and is used for
epidural anesthesia, topical anesthesia, and for peripheral nerve or plexus
block.

42
 Miscellaneous

Phenacaine

Phenacaine, also known as holocaine is a local anesthetic.

It is approved for ophthalmic use.

43
 Miscellaneous

Diperodon

Diperodon is a local anaesthetic, by the action of hydrolases in blood serum is decomposed.

44
 Miscellaneous
Dibucaine (Cinchocaine) is a topical amide anesthetic available in over-the-
counter creams and ointments used to treat minor conditions such as
sunburns and hemorrhoids.

Dibucaine is highly toxic when taken orally, inducing seizures, coma, and
death in several children who accidentally ingested it.

Metabolites of dibucaine identified in the urine of rats, rabbits, and humans included hydroxylated
metabolites of the quinoline ring, monohydroxylated and dihydroxylated metabolites of the O-alkyl side
chain (2’- and 3’-position), and the N-de-ethylated dibucaine metabolite

45