MEDICINAL CHEMISTRY

PHSC 2201L
BS PHARMACY 2 – 2ND SEMESTER

ANESTHETICS
ANESTHESIA
 Local Anesthetics
 General Anesthetics

LOCAL ANESTHETICS
 Local anesthetics are the drugs, which produce
insensitivity in a limited area by blocking the generation
and conduction of nerve impulses.
o interrupt pain impulses in a specific region of
the body without loss of patient
consciousness.
o decrease the permeability of cell membrane
to sodium thus prevents depolarization.
o Epidural, regional, nerve blockers, spinal, and
topical
o Cocaine, novacaine, benzocaine.

EFFECT OF PH IN LOCAL ANESTHETICS

 Anesthetics in solution exist both in an uncharged or
base form and a charged or ion form.
 The proportion of each form of anesthetic is dependent
upon the acidity of the environment (pH) and the
tendency for the base form to transform into its ion
form.
 A measure of the strength of this tendency is called the
dissociation constant (pKa). BENZOCAINE
 Local anesthetics have pKa between 7.7 and 9.3,  Benzocaine is a unique local anesthetic since it does
which permits them to exist in both ionized and non- not contain a tertiary amine.
ionized forms at physiologic pH 7.4  Used for endoscopy, bronchoscopy, and topical/local
 For optimal activity, the unionized form is necessary for anesthesia.
diffusion through and across the neuronal membrane  pKa of the aromatic amine is 3.5 ensuring that it is
 Within the nerve only the ionized form of the molecule uncharged at physiological pH
produces anesthesia by conduction blockade.  Onset of action is within 30 seconds with a duration of
10-15 minutes
MECHANISM OF ACTION
 Decrease the excitability of sensory nerve cells without
affecting the resting potential.
 Reversibly bind to the voltage gated Na+ channel
blocking Na+ transport and therefore nerve conduction

CHANGES IN ELECTRICAL POTENTIAL OBSERVED SYNTHESIS OF BENZOCAINE

DURING A NERVE IMPULSE STEP 1

STEP 2

1|DEAN G.
MEDICINAL CHEMISTRY
PHSC 2201L
BS PHARMACY 2 – 2ND SEMESTER
PREPARATION OF BENZOCAINE
Step 1: Preparation of p-aminobenzoic acid
1. Place 15g (0.09 mol) of p-nitrobenzoic acid in a 1-liter
round bottom flask fitted with a reflux condenser.
2. Introduce 35g (0.295 mol) of powdered tin and 75 ml of
concentrated HCl.
3. Heat the mixture gently until the reaction commences
and remove the flame.
4. Shake the flask frequently and take care that the
insoluble acid adhering to the sides of the flask is
transferred to the reaction mixture: occasional gentle
warming may be necessary.
5. After about 20 minutes, most of the tin will have reacted
and a clear solution remains.
6. Allow to cool somewhat and decant the liquid into a 1-
liter beaker; wash the residual tin by decantation with
15 ml of water and add the washings to the contents of
the beaker.
7. Add concentrated ammonia solution until the solution
is just alkaline to litmus and digest the suspension of
precipitated hydrated tin oxide on a steam bath for 20
minutes.
8. Add 10g of filter aid (Celite), stir well at the pump and
wash with hot water.
9. Transfer the filter cake to a beaker, heat on a water
bath with 200ml of water to ensure extraction of the
product and refilter.
10. Concentrate the combined filtrate and washings until
the volume has been reduced to 175-200mL: filter off
any solid which separates.
11. Acidify the liquid to litmus with glacial acetic acid and
evaporate the water bath until crystals commence to
separate; cool in ice, filter the crystals at the pump and
dry in the steam oven
Step 2: Preparation of ethyl p-aminobenzoate
(esterification of p-aminobenzoic acid)
1. Place 80ml of absolute ethanol in a 250 mL two-necked
flask equipped with a double surface reflux condenser
and a gas inlet tube.
2. Pass dry hydrogen chloride through the alcohol until
saturated; increase in weight about 20g; remove the
gas inlet tube, introduce 12g of p-aminobenzoic acid
and heat the mixture under reflux for 2 hours.
3. Upon cooling, the reaction mixture sets to a solid mass
of the hydrochloride of ethyl p-aminobenzoate. It is
better, however, to pour the hot solution into 300mL of
water (no hydrochloride separates) and add solid
sodium carbonate carefully to the clear solution until it
is neutral to litmus.
4. Filter off the precipitated ester at the pump and dry in
the air.
GENERAL ANESTHESIA
General anesthetics are the drugs, which produce controlled,
reversible depression of the functional activities of the central
nervous system producing loss of sensation and consciousness.
1. Inhaled General Anesthetics
2. Injectable General Anesthetics
INHALED GENERAL ANESTHETICS
 The Ion-Channel and Protein Receptor Hypothesis –
Anesthetics interact with transmembrane ligand-gated
ion channels such as the inhibitory GABA
(chlorideselective ion channels) receptors and
excitatory nicotinic acetylcholine receptors (Na+ ion
channels), which are respectively potentiated and
inhibited by general anesthetics by either allosterically
modulating the opening of ion channels (e.g., Cl−, K+)
or modulate activity by directly interacting with the ion
channel (e.g., Na+).
 Ex. Nitrous Oxide, Halothane, Enflurane, Desflurane,
Isoflurane
INJECTABLE GENERAL ANESTHETICS
Propofol, R-Etomidate, and Thiopental
o Act by enhancing GABAergic neurotransmission by
interacting at the GABA receptors
Ketamine
o Acts as an antagonist within the cationic channel of the
NMDA receptor complex (N-methyl-D-aspartate).  It
prevents the flow of cations through the channel
causing deactivation of neurons.
WORKSHEET
1. Reflux condensers are used to cool the vapors that
heated fluids emit and change their physical state back
to liquid by means of a straight, spiraled or coiled
circulation cooling method. By reducing the loss of
solvent, a mixture can be heated for extended periods.
2. The purpose of adding sulfuric acid is to catalyze the
esterification reaction between p-aminobenzoic acid
and ethanol, facilitating the formation of benzocaine.
3. The principles involved in the preparation of
benzocaine include esterification, acid-base
reactions, and precipitation. Esterification converts
p-aminobenzoic acid and ethanol into benzocaine,
2|DEAN G.
MEDICINAL CHEMISTRY
PHSC 2201L
BS PHARMACY 2 – 2ND SEMESTER

acid-base reactions neutralize the reaction mixture,

and precipitation forms benzocaine as a solid.
4. Fischer esterification is a chemical reaction between
a carboxylic acid and an alcohol, catalyzed by an acid,
to form an ester and water. In the preparation of
benzocaine, p-aminobenzoic acid reacts with ethanol
in the presence of sulfuric acid catalyst to form
benzocaine and water.

5. It is necessary to use absolute ethanol in the

preparation of benzocaine to ensure the purity of the
final product. Absolute ethanol is free from water,
which could interfere with the esterification reaction
and purity of benzocaine. Water can hydrolyze the
ester linkage, reducing the yield and purity of
benzocaine.

6. Benzocaine is commonly used in the medical field as

a local anesthetic. It is often found in various over-the-
counter products such as topical creams, sprays, and
lozenges, where it provides temporary relief from pain
and discomfort caused by minor skin irritations, insect
bites, sunburn, and sore throat. Benzocaine works by
blocking nerve signals in the body, numbing the area
where it is applied, and thereby reducing sensations of
pain and itching. Additionally, it is used during medical
procedures such as endoscopy and catheter insertion
to numb mucous membranes and minimize discomfort
for the patient.

7. Sodium carbonate serves two main roles in the

esterification of p-aminobenzoic acid:

1. *Neutralization*: After the esterification reaction is

complete, the reaction mixture typically contains
excess sulfuric acid, which is acidic. Sodium carbonate
is added to neutralize the acidic components in the
mixture, ensuring that the reaction reaches completion
and the desired product, benzocaine, forms efficiently.

2. *Removal of Acidic Impurities*: During the

neutralization process, sodium carbonate reacts with
any remaining sulfuric acid to form sodium sulfate and
carbon dioxide. This reaction helps to remove acidic
impurities from the reaction mixture, promoting the
formation of a purer product. Additionally, it prevents
the acidic impurities from interfering with subsequent
steps in the synthesis process.

3|DEAN G.