5th unit local anaesthetics

5th UNIT
LOCAL ANAESTHETICS
Prepared by
G. Nikitha, M.Pharmacy
Assistant Professor
Department of Pharmaceutical Chemistry
Sree Dattha Institute Of Pharmacy
Hyderabad
1
Subject: Medicinal Chemistry-II
Year: B.Pharmacy 3rd Year
Semister: 1st Semister

Contents
 Introduction.
 Methods of Administration of Local Anaesthetics
 Classification .
 Drugs used in local anaesthetics.
 Mechanism of action and SAR.
 Structure and Synthesis.
 Adverse Drug Reactions and Uses.
 Reference
2

Introduction
 The term anesthesia which is derived from Greek word meaning
insensitivity or lack of feeling is defined as the absolute loss of
sensation with or without loss of consciousness to painful stimuli
such as surgical procedures, painful skin abrasions, and severe
burns etc. The agents which induce the state of anesthesia are called
anesthetics, which are of two types i.e local anesthetics and General
anesthetics.
 Local anesthetics are chemical agents which reversibly block the
conduction of impulse in all neurons when applied locally in
appropriate concentrations. They provide transient loss of sensory
perceptions (pain, touch etc.) in a restricted region of the body.
3

Ideal Properties
 Local anesthetics should be potent.
 Should be non-irritating to the tissues.
 Should be non-toxic and should not cause any permanent damage.
 Should have less systemic toxicity.
 Should be rapid and long lasting in action.
 Should act selectively and effectively when injected.
 Should not interfere with the healing process.
 Should be sterile and stable.
 Should not interfere with other drugs like miotics, antibacterial,
mydriatics etc.
 Should produce reversible action.
 Since nerve membranes are made up of lipids therefore, they should
be adequately Lipophilic to cross these membranes. They should
also be water soluble.
4

General Mechanism of Action
 Local anesthetics exert membrane stabilizing effects i.e failure in
propagation of an impulse without affecting the resting potential.
They block the entry of Na+ channels, there by inhibiting the
initiation and propagation of impulses across the nerves.
5

 Na+ channels contain an activation gate on their extracellular site
and an inactivation gate on intracellular site.
 At the resting state, activation of Na+ channels is closed.
 When depolarization occurs the activation gates opens allowing Na+
ions to flow into the nerve.
 During the repolarization the inactivation gate closes thus ceasing
the influx of Na+ ions.
 The Local anesthetics are weak bases which undergo ionization at
the physiological pH.
 The unionized form of LA is able to cross the lipophilic cell
membrane.
 Once the LA reaches the axoplasm it reionises (BH+) and binds to
the Local anesthetics reporter located within the Na+ channel in its
intracellular half.
 Binding the Local anesthetic to its receptor decreases the
permeability of Na+ ions through the voltage Na+ channels and thus
prevents the generations and conduction of nerve impulses.
6

General Properties
 Local anesthetics contain an aromatic molecule and tertiary amine
groups which are linked either by an ester or amide linkage. The
tertiary amine group is hydrophilic while aromatic part of local
anesthetic is Lipophilic in nature.
 Local anesthetics are weak bases with a pKa range of 8.0-9.0. They
are usually available in their salt forms. In in vivo conditions they
exist in their cationic forms.
1. The Local anesthetics are insoluble in water and unstable in amine
forms, but their salt forms are usually stable.
2. The Local anesthetics action is exerted better at alkaline pH. In vivo
a part of the drug is in ionized from while the rest is in unionized
form are essential for exerting local anaesthetic action. The
unionized form is essential for the penetration into the nerve which
undergoes re-ionization to cationic form. This cationic form binds to
the receptors.
7

 If the pH is acidic the local anaesthetic remains in an ionized form
which prevents its active diffusion. Hence local anaesthetics are less
effective in infected and inflamed tissues as these have acidic pH.
8

General Pharmacokinetics
Absorption
 Systemic absorption of local anaesthetics is affected by several
factors like dosage, site of injection, drug tissue binding, local blood
flow and other physic-chemical properties of the drug.
 Surface anaesthetics are well absorbed from broken kin ends, mucus
membranes and poorly absorbed from unbroken areas.
 Due to their lipophilic nature they are widely distributed.
 They easily penetrate the brain, heart, kidneys, muscle etc.
9

Metabolism:
 The amide type local anaesthetics such as lignocaine undergo
metabolism in the liver where they converted to water soluble
metabolites which finally get excreted in urine
10

General Adverse Drug Reactions
1. CNS Manifestations
2. CVS Manifestations
3. Allergic reactions/ Hypersensitivity
4. Other effects includes blockade of neuromuscular transmission with
high doses of local anaesthetics.
11

Methods of Administration of
Local Anaesthetics
1. Topical or Surface Anaesthesia
2. Infiltration Anaesthesia
3. Conduction Block Anaesthesia
a. Field Block
b. Nerve block
4. Central Nerve Block Anaesthesia
a. Epidural Block/ Peridural Block Anaesthesia
b. Spinal Block Anaesthesia
5. Intravenous Regional Anaesthesia
12

Classification
1. Natural Agents: Cocaine
2. Synthetic nitrogenous agents:
a. Derivatives of Para-amino benzoic acid
Freely soluble- Procaine, Amethocaine
Poorly soluble- Benzocaine, Orthocaine
b. Derivatives of benzoic acid: Hexylcaine, Meprylcaine,
Piperocaine, Cyclomethycaine,
c. Derivatives of Acetanilide: Prilocaine, Lignocaine, Mepiracaine
d. Derivatives of Quinoline: Cichocaine, dimethisoquin
3. Synthetic nitrogenous agents: Benzyl alcohol, propanediol
4. Miscellaneous Drugs with Local Action: Clove oil, Phenol,
Chloropremazine
13

 Classification Based on Mode of Administration
1. Injectable anaesthetics
a. Low potency and short duration: Procaine, Chloroprocaine
b. Intermediate potency and duration: Prilocaine, Lidocaine
c. High potency and long duration: Bupivacaine, Tetracaine,
Ropivacaine, Dibucaine
2. Surface anaesthetics
a. Soluble: Cocaine, Lidocaine, Tetracaine
b. Insoluble: Benzocaine, Oxethazaine, Butameben
14

 Classification Based on Chemical nature
1. Benzoic acid derivatives:
15
Name R1 R2
Hexylcaine -H
Meprylcaine -H

Piperocaine -H
Cyclomethycaine
16
Cocaine:

2. Para-amino benzoic acid derivatives:
17
Name R1 R2 R3 R4 R5
Benzocaine H H H -CH2-CH3 ---------
Butamben H H H -(CH2)3-
CH3
----------
Procaine H H H -CH2-CH2

Tetracaine n-Butyl H H -CH2-CH2
Butacaine H H H -CH2-CH2-
CH2
Benoxinate H n-Butyl H -CH2-CH2
propoxycaine H H n-
propoxy
-CH2-CH2
18

3. Anilide derivatives:
19
Name R1 R2
Lidocaine CH3
Mepiracaine CH3

Prilocaine H
Etidocaine CH3
20

4. Miscellaneous Drugs
21
Phenacaine
Diperodon
Dibucane

SAR of Benzoic Acid Derivatives:
Most of these local anaesthetics are tertiary amines available as Hcl
salts with pKa in the range of 7.5 to 9.0. Any structural modification
of the local anaesthetics that cause change in pKa will have
pronounced effect to reach hypothetical receptor or the binding site.
1. Lipophilic
 The clinical useful local anaesthetics of this class possess aryl
radical that is attached directly to the carbonyl group and are highly
Lipophilic. They appear to play an important role in the binding of
the local anaesthetics to the channel receptor protein
23

 Placement of aryl group with substituent that increases the electron
density of the carbonyl oxygen enhances the activity.
 Structural modification leads to change in physical and chemical
properties. Electron withdrawing substituent in ortho, para or at
both the position leads to an increase of its local anaesthetics
property.
 Amino (procaine, butacaine) alkyl amino (tetracaine) alkoxyl
(cyclomethycaine) group can contribute to electron density in the
aromatic ring by both resonance and inductive effects. Hence the
increase in local anaesthetic property.
 Any substitution that enhances zwitter ion formation will be more
potent. Hence meta-position substitution decreases activity.
24

25
Zwitter ion
• Tetracaine is more potent than procaine (40-50 times). Although the butyl
group present in it increases lipid solubility, the potentiation is partly due to
electron releasing property of the n-butyl group via inductive effect which
intends to increase the formation of zwitter ion.
• Presence of electron withdrawing group such as Cl- ortho to carbonyl pulls
electron density away from carbonyl group thus making it more susceptible
for nucleophilic attack by the esterase.

2. Intermediate:
 In procaine series anaesthetic potency decreases in the following
order sulphur, oxygen, carbon and nitrogen.
 Modifications also affect the duration of action and toxicity. In
general amides (X-N) are more resistant to metabolic hydrolysis
than esters (X-O). Thoiesters (X-S) may cause dermatitis.
 Placement of small alkyl groups (branching) around ester group
(hexylcaine/ meprylcaine) or the amide function also hinder
hydrolysis, and hence, increase in duration of action.
26

3. Hydrophilic Portion
 The amino alkyl group is not necessary for local anaesthetic activity
but it is used to form water soluble salts such as Hcl salts.
 Tertiary amines are more useful agents. The secondary amines
appear to have longer duration of action, but they are more
irritating. Primary amines are not active or cause irritation.
 The tertiary amines groups may be diethyl amino, piperidine, or
pyrolidino leading to a product that exhibits same degree of activity,
essentially.
 The more hydrophilic morpholino group usually leads to diminished
potency.
 In general, the local anaesthetic drug should have increased lipid
solubility and lower pKa values that leads to rapid onset and lower
toxicity.
27

 Cocaine
It is a natural alkaloid obtained from coca tree Erythroxylon coca.
Chemically, Cocaine is methylbenzoyl ester of ecgonine. It was the
first local anaesthic to be discovered. It is too toxic to be used
parenterally, but is still being employed topically to produce
anaesthesia.
Structure:
 IUPAC: methyl-3-benzoyloxy-8-methyl-8-azabicyclo octane-2-
carboxylate
Properties:
Colorless to white crystals or white powder, Slightly soluble in
water, soluble in volatile oils, ethyl
ether, benzene, chloroform, toluene; very soluble in ethanol;
insoluble in glycerol, petroleum ether
28
Molecular Formula:
C17H21NO4

Pharmacokinetics:
Topical and nasal route of administration, cocaine is metabolized to
benzoylecgonine and ecgonine methyl ester, which are both
excreted in the urine. In the presence of alcohol, a further active
metabolite, cocaethylene is formed, and is more toxic then cocaine
itself.
Adverse Drug Reactions:
 CVS manifestations include vasoconstriction, rise in blood pressure,
Tachycardia and myocardial infarction.
 Allergic reactions, mydriasis, hyperglycaemia and hyperthermia are
other adverse effects with cocaine.
 At large doses, it causes sexual dysfunction and sexual disinterest
etc.
 Anorexia (loss of appetite), emaciation, tremors, emotional
disturbances etc, are seen.
 Drug independence is one of the serious toxic side effects of
cocaine and withdrawal symptoms include CNS depression.
29

Therapeutic Uses:
Cocaine is no longer used for producing through parental route. It is
employed as a topical anaesthetic. 1-2 % solution of cocaine is
required for including anaesthesia of ear, nose, throat, rectum and
vigina.
Dose:
Formulated as 1-2 % solution, for anaesthesia of the ear, nose, throat,
rectum and vagina, applied topically.
30

 Hexylcaine
Hexylcaine hydrochloride is also known as cyclaine and osmocaine.
It is a short acting local anesthetic that acts through inhibition of
sodium channels. Patients experience an overdose may present with
headache, tinnitus, numbness and tingling around the mouth and
tongue, convulsions, inability to breathe, and decreased heart
function. Hexylcaine has been discontinued in the US market.
Structure:
IUPAC: 1-(cyclohexylamino)propan-2-yl benzoate
Properties:
It is a white powder, soluble in water and chloroform
31
Molecular Formula: C16H23NO2

Pharmacokinetics:
Topical and nasal route of administration, metabolized in liver
(Hydrolyzed by plasma esterases to benzoic acid and other
derivatives)
 Headache, Tinnitus
 Numbness around the mouth and tongue
 Tingling around the mouth and tongue
 Inability to breathe
 Decreased heart function
 Difficulty breathing
 Swelling of Lips, tongue, chest pain
 Dizziness, drowsiness
 Anxiety, convulsions
 Nausea, vomiting
32

Therapeutic Uses:
 Hexylcaine is a benzoic acid ester, is a local anaesthetic that has
been used for surface anaesthesia of mucous membranes. Local
anesthetics produce a transient block of nerve conduction by
interfering with sodium channels.
Dose:
 For infiltration anaesthesia 1%, for nerve block anaesthesia, 1% and
2% solution, and for topical application to skin and mucus
membrane 1% to 5%.
33

 Meprylcaine
Structure:
IUPAC: [2-methyl-2-(propylamino)propyl] benzoate
Properties:
Oil, practically insoluble in water. Soluble in alcohol, ether,
acetone, oils.
34

Pharmacokinetics:
I.v, subcutaneous route of administration, metabolized in liver,
eliminated through kidneys.
 Difficulty breathing
 Allergic reactions
 Chest pain, Irregular heart rate
 Drowsiness
 Anxiety, convulsion
 Nausea, vomiting
Therapeutic Uses:
 Used as local anaesthetics
35

 Cyclomethycaine
Structure:
IUPAC: 3-(2-methylpiperidin-1-yl)propyl 4-cyclohexyloxybenzoate
Properties:
It is a white crystalline powder, soluble in water and chloroform.
36

Pharmacokinetics:
Oral route of administration, metabolized in liver, eliminated through
kidneys.
 Difficulty in breathing
 Pain in chest, Vasoconstriction, Tachycardia
 Anxiety, Cardio toxicity by blocking Na+ channels.
Therapeutic Uses:
Used to relieve pain from damaged skin mucous membrane of
rectum, vigina, urinary bladder .
Dose:
The usual dose for topical purpose is 0.25% to 1% in suitable form.
37

 Piperocaine
Structure:
IUPAC: 3-(2-methylpiperidin-1-yl)propyl benzoate
Properties:
White odorless crystals or a white crystalline powder, stable in air,
freely soluble in water, alcohol and chloroform.
38

Pharmacokinetics:
Ophthalmic, Topical route of administration, metabolized in Plasma.
 Blurred vision
 Redness of the clear part of the eye
 Sensitivity to light
 Severe stinging in the eye
 Tearing
 Throbbing eye pain
 Tearing of eyes
 Bloody eye
 Burning, stinging, itching, redness, or irritation of the eye
 Change in vision
39

Therapeutic Uses:
 Piperocaine (Metycaine) is a local anesthetic drug. It is an ester and
primarily is a sodium channel blocker.
 Piperocaine can partially inhibit dopamine. It is known as a alpha-1-
proteinase inhibitor. Used in the form of its hydrochloride as a local
or spinal anesthetic and in dental anesthesia.
40

Amino benzoic acid derivatives
41

 Benzocaine
It is a synthetic nitrogenous derivative of PABA which is poorly
water soluble. It generally exhibits poor penetration through skin. It
is available as ointments, gels, liquids and as sprays.
Structure:
IUPAC: ethyl4-aminobenzoate
42

Properties:
White crystalline powder, or colorless crystals, sparingly soluble in
water; it is more soluble in dilute acids and very soluble in ethanol,
chloroform, and ethyl ether.
Mechanism of Action:
Benzocaine binds to sodium channels and reversibly stabilizes the
neuronal membrane which decreases its permeability to sodium
ions. Depolarization of the neuronal membrane is inhibited thereby
blocking the initiation and conduction of nerve impulses.
43

Pharmacokinetics:
 Dental, Topical, oral route of administration, metabolized into at
least three compounds by acetylation and hydrolysis.
 Benzocaine and its acetylated metabolite are rapidly eliminated
across the gills while the more polar de-ethylated and de-ethylated-
acetylated metabolites are excreted at slower rates primarily in the
urine.
45

 stinging,
 burning, or itching,
 skin tenderness or redness, or
 Dry white flakes.
 headache, weakness,
 dizziness,
 breathing problems,
 fast heart rate, and
 gray or bluish colored skin (rare but serious side effects of
benzocaine);
 severe burning, stinging, or sensitivity where the medicine is
applied;
 swelling, warmth, or redness; or
 Oozing, blistering, or any signs of infection.
46

Therapeutic Uses:
 Benzocaine topical is used to reduce pain or discomfort caused by
minor skin irritations, sore throat, sunburn, teething pain, vaginal or
rectal irritation, ingrown toenails, hemorrhoids, and many other
sources of minor pain on a surface of the body.
 Benzocaine is also used to numb the skin or surfaces inside the
mouth, nose, throat, vagina, or rectum to lessen the pain of inserting
a medical instrument such as a tube or speculum.
 It can be used for performing minor surgeries in the eye.
Dose:
Formulated as 5%, 6% creams 15-20% gels and 5-20% ointment
applied topically.
47

 Butamben
Structure:
IUPAC: butyl 4-aminobenzoate
Properties:
A white, odorless, crystalline, tasteless powder. that is mildly soluble
in water (1 part in 7000) and soluble in alcohol, ether, chloroform,
fixed oils, and dilute acids. It slowly hydrolyses when boiled with
water.
48

Pharmacokinetics:
 Dental, Topical route of administration.
 The metabolic pathway of butamben follows the same pattern of
other local anesthetics and it is driven mainly by the hydrolysis via
cholinesterase for the formation of inert metabolites.
 The metabolites found in plasma after cholinesterase processing are
disposed of in the urine.
 A Skin Rash, Itching, Allergic reaction
 A Stinging Sensation On The Skin, A Type Of Allergic Reaction
Called Angioedema
 Erythema Or Skin Redness, Hives, Irritation of mouth
 Skin Inflammation Due To A Topically Applied Medication
 Drowsiness, headache, Tremors
 Irregular heart rate, low blood pressure
49

Therapeutic Uses:
 Used as local anaesthetics.
 Butamben was indicated for the treatment of chronic pain due to its
long-duration effect. It is also indicated as a surface anesthetic for
skin a mucous membrane and for the relief of pain and pruritus
associated with anorectal disorders.
Dose:
 Topical gel: 14%/2%/2%
 Topical liquid: 14%/2%/2%
 Ointment: 14%/2%/2%
 Topical aerosol: 14%/2%/2%
 Topical Anesthetic:
 Minor dermal procedure
 Normal intact skin for local analgesia: Apply 2.5 g of cream over
20-25 cm of skin surface or 1 anesthetic disc (1 g over 10 cm) for at
least 1 hour
 Major dermal procedure
 Apply 2 g of the cream per 10 cm of skin surface and allow to
remain in contact with skin for at least 2 hours
50

 Procaine
It was the first synthetic local anaesthetic to be introduced. It is a
nitrogenous derivative of PABA which is freely water soluble. It is
not used as surface anaesthethic as it is ineffective when applied
topically. It has a slower on set of action than lidocaine and
prilocaine and its duration of action is also short.
Structure:
IUPAC: 2-(diethylamino)ethyl 4-aminobenzoate
51
Molecular Formula :C13H20N2O2

Properties:
A white, odorless, crystalline powder, Soluble in water, alcohol, ethyl
ether, and benzene, ether, slightly soluble in chloroform, insoluble
in ethanol.
Procaine acts mainly by inhibiting sodium influx through voltage
gated sodium channels in the neuronal cell membrane of peripheral
nerves. When the influx of sodium is interrupted, an action potential
cannot arise and signal conduction is thus inhibited. The receptor
site is thought to be located at the cytoplasmic (inner) portion of the
sodium channel. Procaine has also been shown to bind or
antagonize the function of N-methyl-D-aspartate (NMDA) receptors
as well as nicotinic acetylcholine receptors and the serotonin
receptor-ion channel complex.
52

Synthesis:
 Method-1: Preparation from 4-amino benzoic acid
53

 Method-2: Preparation from 2-chloroethyl P-amino benzoate
54

 Method-3: Preparation from 4--nitro benzoic acid
55

Pharmacokinetics:
 Procaine being a vasodilator requires the addition of vasodilators
like epinephrine retard its synthetic absorption. Procaine is poorly
absorbed from mucus membrane. It is rapidly hydrolyzed from liver
and plasma estarases to its metabolites, PABA and diethylamino
ethanol where in the PABA inhibits the action of sulphonamides.
 The cerebrospinal fluid contains little or no esterases, hence when
procaine is given through this route it remains active until it gets
absorbed into the systemic circulation.
56

 diarrhea that is watery or bloody;
 peeling skin , severe pain, or changes in skin color where the
medicine was injected;
 dizziness, joint or muscle pain;
 fast or pounding heartbeats;
 numbness, tingling, pain, swelling, or redness in your arms or legs;
 confusion, agitation, depression, unusual thoughts or behavior;
 chest pain, problems with vision or speech;
 feeling like you might pass out;
 fever, chills, dizziness, muscle pain, rapid breathing or heart rate;
 uncontrolled muscle movements, problems with balance or walking;
 pale skin, easy bruising or bleeding, unusual weakness;
 sore throat, flu symptoms;
 urinating less than usual or not at all;
57

 rash or itching with swollen glands, joint pain, or general ill feeling;
or
 Slow heart rate, weak pulse, fainting, slow breathing.
 pain where the injection was given;
 vaginal itching or discharge;
 white patches in your mouth or throat;
 nausea, vomiting;
 blurred vision, ringing in your ears;
 headache, dizziness; or
 mild skin rash,
 Difficulty breathing; swelling of your face, lips, tongue, or throat.
58

Therapeutic Uses:
 Used for infiltration, peripheral nerve block and in spinal
anaethesia.
 It can also be used for central nerve block anaethesia.
 Its amide derivative used as an antiarryhthmic drug.
 Procaine penicillin has antibacterial activity.
Dose:
 Formulated as 1-2% solution and 10% injection, given parenterally.
 Usual infiltration 50ml of 0.5% solution
 Usual peripheral nerve block 25ml of 1% or 2% solution
 Usual epidural 25ml of 1.5% solution
59

 Butacaine
Structure:
IUPAC: 3-(dibutylamino)propyl 4-aminobenzoate
Properties:
It is a white crystalline ester, Soluble in Water.
60
Molecular Formula: C18H30N2O2

Pharmacokinetics:
Topical, parental route of administration, metabolized in liver,
eliminated through kidneys.
 Sleepiness, muscle twitching,
 ringing in the ears, changes in vision,
 low blood pressure, and an irregular heart rate
 Concerns exist that injecting it into a joint can cause problems with
the cartilage.
 Concentrated bupivacaine is not recommended for epidural
freezing, Lower blood plasma concentrations.
 circumoral numbness,
 facial tingling, vertigo, tinnitus,
 restlessness, anxiety, dizziness, seizure, coma
 hypotension, arrhythmia, bradycardia, heart block, cardiac arrest.
61

Therapeutic Uses:
 Used by dentists to minimize pain during tooth extract.
 Used to relieve pain in lower back, surgeries and in spinal
anaesthesia, central nerve block anaesthesia.
Dose:
 Several instillatiocs of 2% solution about 3 minutes apart allows
most surgical procedure.
62

 Tetracaine
Structure:
IUPAC: 2-(dimethylamino)ethyl 4-(butylamino)benzoate
Properties:
It is a white crystalline powder, slightly hygroscopic in nature,
soluble in alcohol, freely soluble in water.
63

Pharmacokinetics:
Ophthalmic, Topical, Subarachnoid, Intraspinal, Oral route of
administration. Being an ester type local anaesthetic, tetracaine gets
hydrolyzed by plasma and liver esterases to PABA which is highly
allergic. The metabolism is usually slow which makes it highly
toxic.
 Blurred vision, redness of the clear part of the eye, severe stinging
in the eye, tearing
 sensitivity to light, throbbing eye pain, Bloody eye
 burning, stinging, itching, redness, or irritation of the eye
 change in vision
 nausea, vomiting, Irregular heart rate
 Drowsiness, Dizziness , Swelling, irritation of skin
 Breathing problems, Sleep disorders, Loss of hearing
64

Therapeutic Uses:
 Tetracaine is prominently used for the induction of spinal
anaesthesia. It is topically applied on the nose, eye, throat and
respiratory passages.
Dose:
 Usually Subarachnoid 0.5 to 2ml as 0.5%, topically 0.1ml of 0.5%
solution to conjunctiva.
65

 Benoxinate
Structure:
IUPAC: 2-(diethylamino)ethyl 4-amino-3-butoxybenzoate
Properties and Pharmacokinetics:
White crystalline powder soluble in water. Ophthalmic route of
administration,
66

 temporary stinging and burning in the treated eye,
 eye irritation,
 conjunctival redness,
 contact dermatitis on fingertips, and
 Allergic reaction (rare).
 blurred vision, and
 punctate keratitis
Therapeutic Uses:
 Used as local anaesthetics, in eye surgery.
Dose:
 Removal of foreign bodies and sutures, and for tonometry: 1 to 2
drops (in single instillations) in each eye before operating.
67

 Propoxycaine
Structure:
IUPAC: 2-(diethylamino)ethyl 4-amino-2-propoxybenzoate
68

Pharmacokinetics:
Topical route of administration. Metabolism: This drug his
hydrolyzed in both the plasma and the liver by plasma esterases,
excreted through kidneys.
 Blurred vision
 Sensitivity to the light
 Tearing
 Vision Problems
 Allergic reaction
Therapeutic Uses:
 Used for infiltration and nerve block anaesthesia.
Dose:
 Usually 2 to 5ml of 5% solution
69

SAR of Anilide derivatives:
General structure of anilide is represented as follows:
1. Aryl group
 The clinically useful local anaesthetics of this type possess a phenyl
group attached to the sp2 carbon atom through a nitrogen bridge.
 Placement of substituent on the phenyl ring with a methyl group in
the 2 or 2 and 6-position enhances the activity. In addition the
methyl substituent provides steric hindrance to hydrolysis the amide
bound and enhances the coefficient of distribution.
 Any substitution on the aryl ring that enhances zwitter ion
formation will be more potent.
71

72
2. Substituent of X
•X may be carbon or nitrogen among them lidocaine series (X-O) has
provided more useful products.
3. Amino alkyl group
•The amino function has the capacity for the salt formation and is consider
as the hydrophilic portion of the molecule.
•Tertiary amines (diethyl amine, piperidine) are more useful because the
primary and secondary amines are more irritating to tissues.

 Lidocaine:
The agents of this class are more stable to hydrolysis. They are
more potent have lower frequency of side effects and induce less
irritation than benzoic acid derivatives.
Structure:
IUPAC: 2-(diethylamino)-N-(2,6-dimethylphenyl)acetamide
Properties:
White crystalline powder, Characteristic odor, very soluble in water,
benzene, ethyl ether, ethanol, and chloroform, freely soluble in
alcohol, ether.
73
Molecular Formula: C14H22N2O

Pharmacokinetics:
 Infiltration, Ophthalmic, Topical, Subcutaneous, Epidural, Intra-
articular, Perineural, Intravenous, Cutaneous, oral route of
administration. Rapidly absorbed from GIT, and respiratory tract. It
is also absorbed from mucosa and skin.
 It is metabolized in liver where it gets dealkylated by CYP450 to its
metabolites, monethyl glycine, xylidide. The metabolites excreted in
urine.
 Low blood pressure (hypotension), Cardiac arrest,
Abnormal heartbeat
 Swelling (edema), Redness at injection site, Small red or purple
spots on skin, Skin irritation, Severe allergic reactions (anaphylaxis)
 Constipation
 Headache, Nausea, Vomiting
 Confusion, Dizziness, Drowsiness, Numbness and tingling, Tremor,
Seizures
 Irritation symptoms (topical products); i.e., redness, swelling
 Methemoglobinemia, Malignant hyperthermia
74

Therapeutic Uses:
 Topically on mucus membrane
 Used for Infiltration, nerve block and epidural anaesthesia.
 Used as spinal anaesthesia, 5% hyperbaric solution of lidocaine is
used
 Used as transdermal path for post herpetic
 Used as surface anaesthesia
 Used for producing dental anaesthesia
 It is combine with opioid analgeics for epidural administration
 Uses as an antiarrhthymic agent for managing ventricular
arrhythmais
 It is the drug of choice in individuals sensitive to procaine and
ephinephrine.
Dose:
 Infiltration or epidural up to 600 ml (or 100 ml with epinephrine) as
0.5% solution, 2% topical solution, 2% jelly, 2% ointment.
75

 Mepivacaine:
Structure:
IUPAC: N-(2,6-dimethylphenyl)-1-methylpiperidine-2-carboxamide
Properties:
White crystalline powder, Characteristic odor, freely soluble in
water, alcohol, very slightly soluble in methylene chloride.
76

Pharmacokinetics:
 Epidural, Infiltration, Intracaudal, Subcutaneous route of
administration.
 Rapidly metabolized, with only a small percentage of the anesthetic
(5 percent to 10 percent) being excreted unchanged in the urine. The
liver is the principal site of metabolism, with over 50% of the
administered dose being excreted into the bile as metabolites.
 It is rapidly metabolized, with only a small percentage of the
anesthetic (5 percent to 10 percent) being excreted unchanged in the
urine. The liver is the principal site of metabolism, with over 50%
of the administered dose being excreted into the bile as metabolites.
77

 numbness and tingling of the lips, tongue, and oral tissues;
 nervousness, Lightheadedness, unconsciousness, and
 dizziness, confusion, depression, drowsiness, tremors, convulsions,
 blurred vision, slurred speech
 possible respiratory arrest,
 sweating, and, Metallic taste, Ringing in ears, Head ache
Therapeutic Uses:
It will block the nerve impulses that send pain signals to brain,
spinal block.
Dose:
Infiltration and nerve block 20ml of 1% or 2% solution in sterile
saline caudal, peridural 15 to 3o ml of 1% solution in modified
ringer’s solution.
78

 Prilocaine:
Structure:
IUPAC: N-(2-methylphenyl)-2-(propylamino)propanamide
Properties:
White crystalline powder or colorless crystals, freely soluble in
water, alcohol, very slightly soluble in acetone.
79

Pharmacokinetics:
Infiltration, Dental, Submucosal, Subcutaneous, Parentral,
Intra-articular; Intramuscular; Topical route of administration,
it is metabolized in both the liver and the kidney and excreted
via the kidney.
 slow or shallow breathing,
 pale or bluish skin around the mouth or lips,
 dizziness, fainting, fast/slow/irregular heartbeat,
 mental/mood changes (e.g., confusion, nervousness),
 seizures, or Severe drowsiness.
 Redness, swelling, tingling/burning, or lightening of
the skin may occur.
80

Therapeutic Uses:
 Widely used as dental procedures
 Used for Infiltration, Epidural, nerve block anaestheia.
 For anaesthetizing intact skin, eutectic mixture of lignocaine and
prilocaine is used
 Used in patients with hypertension, diabetes, thyrotoxicosis,
because this drug is not combined with epinephrine.
Dose:
 Usually therapeutic nerve block 3 to 5 ml of 1% or 2% solution,
infiltration 20 to 30 ml of 1% or 2% solution, peridural, caudal,
regional 15 to 20 m of a 3% solution, infiltration and nerve block,
0.5 to 5 ml of a 4% solution, formulated as 5% cream applied by
topical route.
81

 Etidocaine
Structure:
IUPAC: N-(2,6-dimethylphenyl)-2-[ethyl(propyl)amino]butanamide
Properties:
White crystalline powder, soluble in water, freely soluble in alcohol,
very slightly soluble in acetone.
82

Pharmacokinetics:
 Parental route of administration, undergoes hepatic metabolism,
eliminated through urine. It has rapid onset of action, is more potent
and has a longer duration of action than lidocaine.
 headedness, , nervousness, , apprehension, euphoria,
 confusion, dizziness, drowsiness,
 tinnitus, blurred or double vision,
 vomiting,
 sensations of heat, cold or numbness,
 twitching,
 Tremors, convulsions, unconsciousness, respiratory depression and
arrest.
 bradycardia, and cardiovascular collapse, which may lead to cardiac
arrest.
 Allergic reactions are characterized
by cutaneous lesions, urticaria, edema or anaphylactoid reactions.
83

Therapeutic Uses:
 Used for Infiltration and nerve block anaestheia.
 In peridural analgesia, it is used to relax abdominal muscles and to
block motor nerves.
Dose:
 Solution for injection 1% without epinephrine.
 Formulated as 0.5% scream applied topically.
84

 Phenacaine
Structure:
IUPAC: N,N'-bis(4-ethoxyphenyl)ethanimidamide
Properties:
It exists as small white odorless and crystalline powder, soluble in
water.
86

 . Blurred vision
 Sensitivity to the light
 Tearing
 Vision Problems
 Allergic reaction
Therapeutic Uses:
 Used as local anaesthesia for eye surgery.
Dose:
 To the conjunctiva as 1% to 2% ointment or as a 1% solution
87

 Diperodon
Structure:
IUPAC: 2-[(phenylcarbamoyl)oxy]-3-(piperidin-1-yl)propyl N-phenyl
carbamate
Properties:
It exists as fine, white crystalline, odorless power with a
characteristically bitter taste followed by a sense of numbness,
soluble in water,
88

Itching , redness, burning of skin
Therapeutic Uses:
Potent surface anaesthetic, used primarily for anus.
Dose:
Topically 0.5 to 1% solution, to the mucous membrane
89

 Dibucane
Structure:
IUPAC: 2-butoxy-N-[2-(diethylamino)ethyl]quinoline-4-carboxamide
Properties:
It exists as white powder, slight characteristic odor, Soluble in
alcohol and acetone, ether, chloroform; insoluble in water, alkaline
aqueous solutions.
90

Local anesthetics block both the initiation and conduction of nerve
impulses by decreasing the neuronal membrane's permeability to
sodium ions through sodium channel inhibition. This reversibly
stabilizes the membrane and inhibits depolarization, resulting in the
failure of a propagated action potential and subsequent conduction
blockade.
Pharmacokinetics:
Topical, I.v route, rectal of administration, metabolized in liver
eliminated through kidneys
92

 A Skin Rash, A Stinging Sensation On The Skin
 A Type Of Allergic Reaction Called Angioedema
 Erythema Or Skin Redness, Hives
 Itching, redness, Skin Inflammation Due To A Topically Applied
Medication
 Drowsiness, headache, Tremors
 Low blood pressure, Decrease lung function
Therapeutic Uses:
 It is used as surface anaesthetic in anal canal, rectum.
 Used topically for relieving pain and itching due to sunburn, insect
bites or minor skin irritations
 Ointment or suppositories are used for relieving itching and pain
associated with haemorrhoids (piles).
Dose:
 Topically to the skin as 0.5% ointment or lotion 2 to 4 time/day
93

Most of the widely used local anaesthics are divided into two main
classes:
 Ester type local anaesthetics which are developed from cocaine and
are considered as derivative of benzoic acid.
 Amide type local anaesthetics developed from isogramine and are
considered as derivatives of aniline. Both these classes in general
contain the basic structural formula.
 Lipophilic or Hydrophilic center-----Ester/amidegroup----X-----
hydrophilic center
 X- Bridge or linkage between hydrophilic and hydrophobic groups.
95

1. Lipophilic/ Hydrophobic centre:
Presence of Lipophilic portion is necessary for a local anaesthetic in
order to exhibit lipid solubility. These portion aids in the penetration
of drug into the lipid bilayer of cell membrane. The Lipophilic part
is either an aromatic group or an aryl group directly attached to a
carbonyl group (amine ester) via -NH group. Any alternation on this
portion affects the physical and chemical properties of a drug which
in turn has impact on its local anaesthetic activity. As Lipophilicity
increases there is an increase in potency of the compound.
a. For Esters
All the ester type local anaesthetics possess the basic formula
96

 The aryl may be directly attached to the carbonyl moiety or through
a vinyl group. Direct attachment of the carbonyl moiety is known to
increase the local anaesthetic activity.
 The aryl groups can be either aryl or aryl alicyclic compounds.
Presence of aryl vinyl radicals (Aryl-CH CH-) or an alkylene
(methylene group) between the aryl radical and carbonyl moiety
result in compounds that are clinical ineffective.
 Presence of electron withdrawing groups like NO2 decreases the
local anaesthetic activity.
 Presence of electron donating like alkoxy, amino, alkylamino
groups as substituent at ortho and para position on the aryl group,
increases the activity of local anaesthetic due to resonance and
inductive effect.
 Examples: Propaxicaine (contains alkoxy substituents), Procaine
(contain amino- substituents), Tetracaine (contains alkylamino
substituent).
97

b. For Amides:
The amide type local anaesthetics possess the general formula,
 Aryl moiety must be a 2,6-dimethyl phenyl group attached through
a NH group to the sp2 carbon atom of .
 Methyl group substitution at 2,6 position (ortho or para positions)
present on aryl moiety increases the local anaesthetic activity.
Substitution by methyl group not only increases the lipid solubility
but also provides resistance to hydrolysis (by providing stearic
hindrance).
98

2. Bridge(X)
The hydrophilic portion is bridged to an ester group via short
hydrocarbon chain or with the help of oxygen, sulphur, atoms. The
ester or amide groups link the Lipophilic portion and the
hydrophobic portion of local anaesthetics.
a. For Esters
 The bridge (X) might be carbon, oxygen, nitrogen or sulphur
moiety. The duration of action and the toxicity exerted by a local
anaesthetic depends upon moiety present as –X-.
 Thio esters i.e X-S produce skin irritations like dermatitis hence
they are rarely used as local anaesthetics.
b. For Amides
 X might be carbon (isogramine), nitrogen (Phenacaine) or oxygen
(lidocaine). The preferred atom is oxygen because when X-O
clinically useful products have been produced.
 Generally compounds containing X-N (i.e amides) are more stable
to hydrolysis and hence are preferred over compounds containing
X-O.
99

3. Hydrophobic Center
The Hydrophobic portion plays a role in aiding the movement of
the drug to the cell and thus facilitates the binding of the drug to the
receptors. The hydrophilic centre can be tertiary amines are more
preferred as they are less irritating to the tissues. Substitution of the
hydrophilic will be more number of carbon atoms increases the
partition coefficient and thus increases the activity of local
anaesthetic.
a. For esters
 This group does not have any role in exerting anaesthesia but is
useful to prepare water soluble compounds. Generally, tertiary
amines are preferred because of their rapid solubility. Secondary
amines exhibits long duration of action but are highly irritating.
Primary amines are not used because of lack of activity and also
because they cause irritation.
 Molecules like benoxinate are resistant to hydrolysis because of the
presence of 3-butoxy group.
 Tetracaine is readily absorbed because of the presence of n-butyl
group (non polar group) on the aryl nitrogen which tends to increase
the lipid solubility of tetracaine.
100

b. For Amides
 This group necessary for forming water soluble compounds.
Generally tertiary amines are preferred as they are more useful
clinically than the secondary and primary amines which are more
irritating.
 The nerve membranes are generally lipodial in nature. As increase
in the Lipophilic character enhances the penetration of local
anaesthetic into the membrane, but decreases the solubility of the
drug in the extracellular and intracellular fluids. An increase in the
hydrophilic portion of local anaesthetic decreases the drug
penetration into the membrane. Hence the local anaesthetic should
possess an equal balance for both Lipophilic and hydrophilic
centers.
 Substitution of aryl ring by alkyl, alkoxy or alkyl amino groups
tends to give homologues series that shows an increases in partition
coefficient upon increase in the number of methylene substituent
attached to the aryl moiety. Maximum activity is exerted by the
compounds belonging to C4 to C6 homologues series.
101

 Binding of local anaesthetics to plasma and tissue proteins is due to
the presence of van der waals force, dipole-dipole attractions and
electrostatic attractions. Moreover compounds exhibiting high
potency and long duration of action tend to binds strongly to the
plasma and tissue proteins.
102

 Presence of electron donating substituent on the aryl Lipophilic
center increases the activity of benzoic acid derivatives, whereas
presence of electron withdrawing substituent tends to decrease the
activity of local anaesthetics. This is because electron withdrawing
groups decreases the strength of carbonyl dipole by accepting
electron from carbinol group and thus decreases dipole-dipole
attraction with the receptors.
 Different enantiomers of local anaesthetics exhibit difference in
terms of their selectivity and toxicity.
 Examples: Ropivacaine and (-) laevo bupivacaine are less toxic than
bupivacaine. S(-)bupivacaine is less toxic than R(+)bupivacaine.
 The activity and duratiod of action of local anaesthetics depends
upon their stability. Hydrolysis reaction explains about the stability
of both ester and amide type local anaesthetics.
103

Reference books
 Text book of Medicinal chemistry volume-1-3rd edition by
V.Alagarasamy.
 Text book of Medicinal chemistry volume-2-3rd edition by
V.Alagarasamy.
 Medicinal chemistry by Rama Rao Nadendla.
 Principals of Medicinal chemistry volume-1 by Dr. S.S. Kadam, Dr.
K.R. Mahadik, Dr.K.G. Bothara.
 Faye’s Principles of Medicinal Chemistry- 7th edition by Thoms
L.Lemke, Victoria F.Roche, S. Willam Zito.
 Medicinal Chemistry- 4th edition by Ashutosh Kar
 Medicinal and Pharmaceutical Chemistry by Harkishan Singh, V.K
Kapoor.
 Wilson and Gisvolid’s Textbook of Organic Medicinal and
Pharmaceutical chemistry-12th edition by John M. Beale, John. H.
Block.
104

5th unit local anaesthetics

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