1. Pharmaceutical Chemistry II Lecture 4
Joseph O. Oweta | PHC 3201

2. Local Anaesthetics
Local anaesthetics are the drugs, which produce insensitivity in a limited area by blocking the generation and conduction of nerve impulses.
They interrupt pain impulses in a specific region of the body without loss of patient consciousness.
They are applied locally or injected to produce loss of sensation in the required area.
Local anaesthetics decrease the permeability of cell membrane to sodium thus prevents depolarisation.
Normally, the process is completely reversible and the agent does not produce any residual effect on the nerve fibre.

3. Mechanism of Action
Cork Like action (Physical Block Vs )

4. Chemistry of LA’s

5. Chemistry of LA’s
All local anaesthetics drugs except cocaine are synthetic.
Traditionally there have been two main groups available for use, the Esters and the Amides.
Both types of anaesthetics have three main structural parts as follows:

6. Chemistry of LA’s Aromatic ring—the lipophilic portion.
Intermediate Chain—provides the link/spatial separation between the aromatic ring(lipophilic) and the amino group (hydrophilic). Local anaesthetics are classified on the basis of the intermediate chain.
Secondary or tertiary amino terminus (amino group)—the hydrophilic portion. Generally local anaesthetics are secondary or tertiary amines. The nitrogen is linked through an intermediary chain to a lipophilic portion (most often aromatic ring system).

7. Chemistry of LA’s
The amine functional group of local anaesthetics exists either as the neutral amine or positively charged ammonium cation, depending up on their dissociation constant (pKa value) and the actual pH value.
The protonated local anaesthetic possesses both a polar hydrophilic moiety (protonated nitrogen) and a non-polar lipophilic moiety (ring system).
The pKa of typical local anaesthetics lies between 7.7—9.3.
Chemically used local anaesthetics are either esters or amides. The structural element is unimportant for efficacy. Even drugs containing a methylene bridge such as chlorpromazine or imipramine would exert a local anaesthetics effect

8. EFFECT OF pH ON ACTION OF LA’s
Anaesthetics in solution exist both in an uncharged or base form and a charged or ion form.
Dependant on pH (Environment) and pKa of the LA
Normally, pKa lies between 7.7—9.3.
Therefore existence in both states at about 7.4
NB:
Only the unionised form can penetrate the membrane
Within the nerve, only the ionised form can cause anaesthesia by conduction blockade

9. EFFECT OF pH ON ACTION OF LA’s
As a rule, anaesthetics with dissociation constants closest to the pH of normal tissues are most effective at producing profound anaesthesia.

10. EFFECT OF pH ON ACTION OF LA’s
In the presence of tissue injury, inflammation, or infection, the local environment becomes acidic and pH may fall to 5.5 to 5.6 (purulent environment).
This lower pH has a pronounced effect on dissociation, lowering extraneural concentrations of base and, making adequate levels of intraneural anesthetic difficult to attain.
The best anesthetic to use in this situation is mepivacaine.

11. Ester Anaesthetics
Ester anesthetics are metabolized in the plasma by the enzyme pseudocholinesterase.
Procaine undergoes hydrolysis to para-aminobenzoic acid (PABA), which is excreted unchanged in the urine, and diethylamino alcohol, which undergoes further transformation prior to excretion.
Allergic reactions that occur in response to ester anesthetics are usually not in response to the parent compound but rather to the para aminobenzoic acid (PABA), which is a major metabolic product of all ester-type local anesthetics.
Approximately 1 in 3000 persons has an a typical form of pseudocholinesterase, resulting in the inability to hydrolyze the ester-type local anesthetics. This in turn may cause a prolongation of high blood levels of the agent and increased toxicity.

12. SARs: Ester LAs (1)
General structure: Aryl – CO – X - Amino alkyl Chain
The aryl radical attached directly to the carbonyl group enhances local anaesthetic activity. It is the lipophilic centre of compound.
Alicyclic and aryl aliphatic carboxylic acid esters are also active local anaesthetics.
The compounds containing aryl-vinyl group (Ar-CH = CH -) do not have local anaesthetic activity, because the mesomeric effect of aryl radical does not extend to carbonyl group.
The aryl substituents such as alkoxy, amino and alkyl-amino groups at ortho or para positions increase electron density of carbonyl oxygen, thus enhancing the activity.
For the number of methylene groups substituted to aryl moiety; the maximum activity is achieved for the C4 to C6 homologues.
Alicyclic = Aliphatic and Cyclic e.g Cycloproprane
Aryl = Benzyl
Mesomeric = Resonance

13. General structure: Aryl – CO – X - Amino alkyl Chain
SARs: Ester LAs (2)
General structure: Aryl – CO – X - Amino alkyl Chain
The bridge X may be carbon, oxygen, nitrogen or sulphur. The nature of X affects duration of action and relative toxicity. The conduction anaesthetic potency decreases in the order of S, O, C and N.
The amino alkyl group is the hydrophilic part of molecule. The local anaesthetic activity decreases and irritation property increases as hydrophilicity of the compound increases, due to decreased solubility.
In general amino alkyl group is not necessary for activity, but it is used to form water soluble salts. E.g. Benzocaine does not have it.
Local anaesthetic activity improves if the aryl lipophilic center has electron donor substituents but decreases with electron acceptor substituents.

14. SARs: Amide LAs
The alkyl substitution (-CH3) in the aryl group at ortho or para position enhances the activity by providing steric hindrance to the hydrolysis of amide linkage and contributes to lipid solubility.
In general X may be carbon (Isogramine), oxygen (lidocaine) or nitrogen (Phenacaine) for good activity.
The relative activity of the aminoalkyl group is similar to the ester linkage containing compounds.

15. Classification
1. Natural agents : Cocaine 2. Synthetic nitrogenous drugs : A. Derivatives of para amino benzoicacid : Procaine, Amethocaine, Benzocaine, Orthocaine. B. Derivatives of acetanilide : Lidocaine C. Derivatives of quinoline : Cinchocaine 3. Synthetic non-nitrogenous drugs : Benzyl alcohol, propanediol 4. Miscellaneous : Phenol, antihistamines.

16. Natural agents : Cocaine
Source:
Cocaine is an alkaloid obtained from the leaves of Erythroxylon cocca and other species of Erythroxylon indigenous to Peru and Bolivia.
Chem:
Cocaine is an ester of benzoic acid and a nitrogen containing base.
It has the fundamental structure required for local anesthetic activity.

17. Benzocaine Name, Synthesis and structure
Ethyl-4-amino benzoate

18. 2-Diethylaminoethyl-p-aminobenzoic acid
Procaine
2-Diethylaminoethyl-p-aminobenzoic acid
Synthesis by Hoffman’s elimination reaction

19. Assignment Read and Make notes about the structures and syntheses of:
Lignocaine
Amethocaine(Syn)
Cinchocaine
Cyclomethicaine (Syn)
Bupivacaine