LOCAL ANESTHETICS

Def.: These agents are used to produce anesthesia or to abolish pain sensation in restricted areas in the body.Mechanism of action Site of action: cell membrane. It prevents the conduction by blocking the sodium ion

channels. Blocking is achieved either by The drug causing a physical block in the channel like a

cork in a bottle The drug molecule distorting the channels Increasing the surface pressure of the cell membrane.

Ideal Local Anesthetic

It must have the following characters:

1) Nontoxic

2) Nonirritant

3) Produce vasoconstriction

4) Effective either topically or parenterally.

5) Reversible: means reversible blockade of sensory nerve fibers with minimal effect on the motor fibers.

6) Rapid onset with sufficient duration of action.

Adverse ReactionsAs a result of overdose and its complete systemic absorption, it can cause:• CNS effects: Vomiting, nausea, convulsions coma with respiratory and heart failure.• CVS effects: Bradycardia, hypotension and shock- like state.• Some local reactions of allergic nature e.g. edema, pain, skin discoloration and neuritis.

Treatment (Antidote): ultrashort-acting or short-acting barbiturate

History Local anesthetics were derived from natural

sources.A) Cocaine

In 1532, the anesthetic properties of coca leaves became known to Europeans from the natives of Peru, who chewed the leaves for a general feeling of well-being and to prevent hunger.

Later, the alkaloid cocaine was obtained from the coca leaves which causes anesthetic effect on the tongue.N COOCH3

H3C

O

OH

Benzoyl group

Carbomethoxy group

hydrolysis

hot dil. acid.or alkali

N COOHH3C

OH

H

COOH

CH3OH+ +

Ecgonine

(Tropine carboxylic acid)

Ecgonine = piperidine and pyrrolidine rings. The dotted portion of cocaine has been

found to represent the anesthesiophoric function group.

Cocaine was the first potent local anesthetic used clinically.

NH3C

COOCH3

O

O

1 2

3

45

6

7

8

NH3C

O

OH

No carbomethoxy group

(no addicting liability)

Benzoyl tropineCocaine

Cocaine can not penetrate intact skin but is absorbed

from mucous membranes.

Cocaine blocks uptake of catecholamines (C.A.) at adrenergic nerve endings and so it is considered potent vasoconstrictor. This account for ulceration of nasal septum after administration of cocaine for long periods in higher dose.

Cocaine has many disadvantages such as addiction, tissue irritations, poor stability in aqueous solutions and decomposition on sterilization.

Later, benzoyl esters of amino alcohols were synthesized, such as benzoyltropine.

Benzoyltropine exhibited strong local anesthetic properties without any addicting liability. Thus, removal of the 2-carbomethoxy group of cocaine also abolished the addiction.

After that, esters of p-aminobenzoic acid e.g. procaine were discovered which not have severe local and systemic toxicity of cocaine.

Benzoyl tropine

NH3C

O

OH

No carbomethoxy group

(no addicting liability)

Synthetic compoundsA) Ester-type or amino-esters or cocaine-type ( procaine-type).

They are classified into:I] p-Aminobenzoate derivatives1)1) Benzocaine Assay: Diazometrically. Disadvantages: its low aqueous solubility limited its usefulness as injectable agent. Uses: topically for surface anesthesia of mucous membrane. Unlike others, benzocaine not possess aliphatic amino gp required for salt

formation. The free electrons on the aromatic amino gp are delocalized by the ring. Thus,

formation of water soluble salt is not possible.

O CH2CH3

O

H2N

O2N CH3

Oxid.O2N COOH

1) esterfication

2) reductionBenzocaine

Ethyl 4-aminobenzoate

p-nitrotoluene

2) Procaine 2) Procaine hydrochloridehydrochloride

Procaine is the least toxic and widely used. Unlike benzocaine, procaine containing a basic amino

group from which water soluble salts were prepared. In contrast to cocaine,it not causes vasoconstriction, so it

is rapidly absorbed from site of inj. Most ester-type are used in a solution containing a

vasoconstrictor as epinephrine to serve a dual purpose:

1. The first one is to decrease the rate of absorption. Thus, localize the local anesthetic at the desired site to limit systemic toxicity.

2. The second one is to prolong duration of action.

O

N

Et

Et

H2N . HCl

1

2

O

2-Diethylaminoethyl-4-aminobenzoate hydrochloride

Preparation:

Assay: Diazometrically. Procaine is used to form an insoluble salt

with penicillin G. The low solubility accounts for the prolonged action of this salt.

The amide derivative of procaine (procainamide HCl) is a cardiac depressant.

3) Chloroprocaine hydrochloride3) Chloroprocaine hydrochloride 2-Diethylamino-4-amino-2-chloro benzoate hydrochlorideAssay: Non-aqueous titration.

O

ClH2N

O+ HN

C2H5

C2H5

OH

H2N

O+ N

C2H5

C2H5HO

ONa

H2N

O

+ N

C2H5

C2H5Cl

conc. H2SO4

/ under pressure

120 - 130oC

Procaine

1)

2)

3)

O

N

C2H5

C2H5

H2N . HCl

O

Cl

4) Propoxycaine Hydrochloride It is 2-(Diethylamino) ethyl-4-

amino -2-propoxybenzoate

hydrochloride

It is not stable to autoclaving. It has quicker onset and longer

duration of action and more potent than procaine.

It is used by injection for nerve block and infiltration anesthesia.

O

N

C2H5

C2H5

H2N . HCl

O

OC3H7

55 ) )Amethocaine (tetracaine) Amethocaine (tetracaine) HydrochlorideHydrochloride::

O

N

CH3

CH3

HN . HCl

O

C4H9

2-(Dimethylamino)ethyl-4-butylaminobenzoate HCl

H2N COOEtCH3CH2CH2CH2Br

Na2CO3

HN COOEt

C4H9

NCH3

CH3HO

Trans esterficationNaOEt

Compound

Preparation:

Assay: alkaloidal assay.

• Tetracaine is one of the most easily absorbed drugs due to the presence of nonpolar n-butyl group.

• Its solutions are more stable to hydrolysis than procaine and it may be sterilized by boiling.

• *Mixture of sulfonamide and p-aminobenzoic acid local anesthetics should be avoided because of their hydrolysis led to p-aminobenzoic acid (PABA). Sulfonamides are considered competitive inhibitors of PABA in the biosynthesis of dihydrofolate.

II] Benzoate Derivatives

1) Meprylcaine HCl• 2-Methyl-2-)propylamino)-1-

propanol benzoate HCl

• It can be sterilized by autoclaving without decomposition.

• It is used in dentistry in 2% solution containing epinephrine as an infiltration and nerve block anesthetic.

O

C

O

N CH2 CH2 CH3 . HCl

CH3

CH3

2) Cyclomethycaine sulfate (sufacaine)Assay:

Spectrophotometrically.

Uses: topically on burns(sunburns) and mucosa of rectum in 0.25-1%. not used for mucous membranes of upper respiratory system or

eye.

3) Piperocaine HCl )Metycaine HCl) It differs from cyclomethycaine

in the absence of cyclohexyloxy

group. Its aqueous solutions are stable to sterilization by

autoclaving. It is recommended for eye, nose and throat.

O

O

O

N

CH3

. H2SO4

1

2 3

3)-2-Methylpiperidino )propyl-4-)cyclohexyloxy) benzoate sulfate

O

O

N

CH3

. HCl

Structure activity relationshipThe general structure of ester- type local anesthetics is as

follows:

The lipophilic portion: It is essential for activity.This is a portion of aromatic

acid whereas benzoic and p-amino-benzoic acids are the preferred ones.

The carbonyl group must be conjugated with an aromatic nucleus whereas reversed esters have no local anesthetic activity.

The esters of cinnamic acid are more active than those of phenyl acetic acid due to interruption of the extended conjugation by methylene gp between the aromatic ring and carbonyl gp.

Ar O

O

(CH2)n N

R1

R2

Lipophilic

portion

Intermediate

chain

Hydrophilic

portion

O N

Et

Et

H2N

O

reversed ester

Introduction of electron-donating gps in the ortho or para positions of the ring increases conjugation and binding of drug to the receptor prolonging the action.

NH2 (procaine),an alkylamino (tetracaine) or an alkoxy gp (propoxycaine) increase electron density to the aromatic ring by both resonance and inductive effects,

While the opposite occur in case of electron-withdrawing

(NO2, CO and CN).

OR

O

OR

O

OR

O

Conjugated not conjugated not conjugated Cinnamic acid phenyl acetic acid b-phenyl propionic acid

Tetracaine is 50-fold more potent than procaine. This may be due to the n-butyl gp increase lipid solubility

propoxycaine, the presence of o-propoxy gp increase

duration of action due to protection of ester gp from hydrolysis due to plasma esterases

This is contrary to chloroprocaine which has shorter duration of action due to negative inductive effect of o-chloro gp which pulls the electron density away from the carbonyl function.

The intermediate chain It is alkyl chain of amino alcohol involved in the esters. The propylene gp –(CH2)3– provides the most active

compounds, next ethylene, –(CH2)2– while methylene gp, –CH2–, makes the compounds too irritant.

The branching with small alkyl gp around the ester function (e.g. meprylcaine) also hinders esterase catalysed hydrolysis prolonging the duration of action.

The hydrophilic portion It is amine part of amino alcohols used to esterifies aromatic

acids. Its advantage is its ability to form salts with inorganic acids producing water soluble compounds.

It is observed that benzocaine which lacks the basic aliphatic amine, has potent local anesthetic activity. Thus, 3ry amine is needed for formation of water soluble salts, suitable for pharmaceutical preparations.

The anesthetic activity increases with the size of the alkyl gps (R1, R2), the maximum being at C3-C4. R1 and R2 may be identical, unsaturated groups or hydrogen and alkyl group.

3ry amines useful local anesthetics. 2ry amines long acting but irritant. 1ry amines not active.

B) Isogramine In 1930, the discovery of the local anesthetic activity of

isogramine (isomer of alkaloid gramine,3-derivative) led to the synthesis of lidocaine (anilide or reversed amide).

Lidocaine(xylocaine) is the first non-irritating, amide-type local anesthetic agent with lesser allergic reactions than esters.

Its aqueous solution is stable because of the stablility of amide functionality.

Structurally, lidocaine can be viewed as an open-chain analog of isogramine and thus is a bioisosteric analog of isogramine.

N

H

N(CH3)2N

N(C2H5)2

O

HCH3

CH3

Isogramine Lidocaine 2)-Dimethylaminomethyl(indole

B)amino-amides or isogramine-type (lidocaine-type). 1) Lidocaine HCl or lignocaine HCl )Xylocaine)

Assay: non aqueous titration.Use: The salt is used for infiltration, peripheral nerve block and

epidural anesthesia. Lidocaine is effective as antiarrhythmics.2) Mepivacaine HCl )Carbocaine) Its duration of action is longer than lidocaine.

3) Bupivacaine HCl )Marcaine) Its duration of action is 2-3 times longer than lidocaine or mepivacaine.

HNN

Et

EtO

CH3H3C

. HCl

2-(Diethylamino)-N-(2,6-dimethylphenyl)acetamide

HN

O

CH3H3C

N

C4H9 . HCl

HN

O

CH3H3C

N

CH3 . HCl

N-(2,6-Dimethylphenyl)-1-methyl or butyl -2-piperidinecarboxamide HCl

Mepivacaine HCl Bupivacaine

4) Dibucaine HCl (Cinchocaine HCl) NupercaineAssay: non aqueous titration. It is the most potent, toxic and longest acting one Used topically and in spinal anesthesia.Structure Activity Relationship: )amino amide series) The general structure of local anesthetic can be represented as follow:

Lipophilic portion: The lipophilic portion is essential for activity and consists of phenyl

group attached to CO function (sp2 carbon) through NH gp. Thus, the COOH gp of the amino-ester series is replaced by its

isosteric NHCO moiety in amino-amide series. Substitution of the phenyl with a methyl gp in the 2- or 2- and 6-position

enhances activity.

N

NN

EtO

H

Et

OC4H9

. HCl

2-Butoxy-4-[2-(diethylamino)ethyl]cinchonamide

Lipophilic portion Intermediate chain Hyrophilic portion

The amide bond is more stable to hydrolysis than the ester. In addition, o,o`-methyl substituents provide steric hindrance to the hydrolysis of the amide bond.

The intermediate chain In lidocaine series, lengthening of the alkylene chain from one

to two or three increases pKa from 7.7 to 9.0 or 9.5, respectively reducing local anesthetic potency.

Here, branching around the amide function (etidocaine), also hinders amidase catalyzed hydrolysis prolonging the duration of action.

Advantages of lidocaine derivatives over procaine ones1. More stable to hydrolysis.2. Can be sterilized by autoclaving.3. More potent.4. Lower side effects: less local irritation than procaine type.5. Used as alternatives for patients sensitive to procaine type

local anesthetic.

6. Effective without vasoconstrictors. It used for patient sensitive to epinephrin.

7. Lidocaine derivatives undergo enzymatic degradation not in plasma but primarily in the liver through degradation of amide bond.

N.B.: Patient possessing a genetic deficiency in the enzyme

pseudocholinesterases is unable to hydrolyze ester-type local anesthetic agents and show reduced tolerance to these drugs. Thus, amide-type agents are preferable.

On the other hand, patients with liver diseases may show reduced tolerance to amide-type agents due to they are mainly metabolized in liver. Thus, ester-type drugs are preferable.

Most of clinically used local anesthetics have pKa 8-9.5.

Drugs with higher pKa values are almost completely ionized at physiological pH and therefore are hindered in reaching the receptor sites.

For this same reason, local anesthetics can be ineffective in inflammation areas because in these areas, pH being lower, facilitates ionization of their molecules and consequently hinders their penetration into nerve fibers.

On the other side, compounds with lower pKa values are not sufficiently ionized and although they reach the target are less potent.