MEDICINAL CHEMISTRYIII
Lecture 2
Saturday 12/ 5/ 1432H
Prof. Dr. Wafaa Zaghary
Analgesic
Classifications of analgesic:
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The traditional manner of classifying pain relieving drugs
has been on the basis of strong and addictive (or narcotic)
compounds and the mild analgesics (or non-narcotic).
Mild analgesics
a. Analgesic –antipyretic
b. Anti-inflammatory analgesic analgesics

Strong analgesics
a. Narcotic Analgesic
b. Agonist/antagonist analgesic
Antipyretics

Are those drugs which have an effect on body
temperature and are usually restricted to
cases where the temperature rises and may
be dangerous in itself as those diseases
which are not responding to chemotherapy
e.g. viral diseases. This is mediated through
the
thermoregulatory
centre
in
the
hypothalamus.
Analgesic

Drugs that relieve mild to
moderate pain such as headache,
myalgia…etc.
when an anti-inflammatory effect
is not needed.
Anti-inflammatory


1.
2.
3.
Anti-inflammatory drugs are those drugs used in
connective tissue diseases. Inflammation is a normal
protective response to tissue injury caused by noxious
chemicals, physical trauma or a microbiological agent.
It is divided into 3 stages:
The initial response to tissue injury:
It is mediated by the release of autocoids like:
histamine, serotonin, leukotriene, prostaglainds …etc.
Immune response; immunologically competent cells
are activated in response to antigens released during
the inflammatory response.
In these cases the reaction is changed to chronic
inflammation reaching to the underlying tissues as in
rheumatic arthritis (pain and deleterious effect upon
cartilage and bone).

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This damage causes leukocytes to release liposomal
enzymes (hydrolytic enzymes proteases…..).
Anti-inflammatory drugs may act by interfering with one
or more of these processes:-antibody production or antigen-antibody complex.
-interference with the formation and release of chemical
mediator of inflammation.
-stabilization of liposomal membranes.
Characters of NSAIDs


Carboxylate or enolic H (acidic H)
compounds anion attached to a cationic site
in the receptor.
Lipophilic group, non coplanar with the with
ring bearing the carboxylic acid function.
Kiefer et al. Nature 405, 97-101 (2000)
Mild analgesics
Analgesic-Antipyretic
Drugs in this category have the ability to
alleviate mild and on occasion severe pain.
These agents are also effective in reducing
fever to normal level.
Examples :Acetanilide, acetophenetidine (phenacetin) and
acetaminophen (paracetamol).


Both acetanilide and phenacetin are
metabolized to the active acetaminophen.
Non –Steroidal Anti-inflammatory
Drugs (NSAIDs)


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These agents have analgesic and anti-inflammatory
effects and owe their therapeutic and side effects to
inhibition of cyclooxygenase enzymes.
There are two forms, of cyclooxygenase.
A constitutive form……..(cyclooxygenase-1)
An inducible form……..(cyclooxygenase-2)


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Thus, a new hypothesis has been suggested
to explain the effects of NSAIDs;
Inhibition ofcyclooxygenase-2 accounts the
therapeutic benefits.
Inhibition ofcyclooxygenase-1 accounts the
side effects.


Aspirin is considered the prototype of mild
analgesic and anti-inflammatory agent.
NSAIDs are still evaluate by comparison
to it. Physician still considered the first
agent of choice for the treatment of
rheumatic conditions.
NSAIDs may be classified on basis of their
basic chemical structure as:
I.
II.
III.
IV.
V.
VI.
VII.
VIII.
Salicylates
Para-aminophenol derivatives
Anthranilates
Aryl acetic acids
Aryl propionic acid
Pyrazolinone derivatives
Acidic Enolic Compounds
Cox-2 inhibitors
I- Salicylates
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
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Aspirin
Acetyl salicylic acid, aspirin, 2-acetoxy
benzoic acid
Acetyl salicylic acid is the prototype of
NSAIDs.
Synthesis
Inhibition of COX by Aspirin


Attempts to modify aspirin chemically to either
circumvent its potential gastro-intestinal intolerance:
-its poor aqueous solubility, its poor stability towards
hydrolysis, makes liquid dosage forms impossible.
The modification involved
derivatization of the carboxy function (such as ester
removal in vivo),
variation of he acyl group (to increase stability) into the
benzene ring,
forms a simple alkyl or alkoxy group to fluorinated
phenyl such as Diflunisal
Diflunisal

Uses
Anti-inflammatory, analgesic and antipyretic
The main side effects are gastrointestinal
disturbances, headache and rash.
Metabolism of aspirin


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Most of salicylates are rapidly absorbed after oral
administration. Because they are weak acids, they
are absorbed from stomach.
All esters and salts of salicylic acid are initially
hydrolyzed to give the free salicylic acid.
Major metabolite of salicylic acid is its conjugation
with ether, glucouronic acid and glycine.
Minor metabolites result from microsomal aromatic
hydroxylation
Structure Activity Relationships

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The active moiety …….. salicylate anion
Benzoic acid itself has weak activity.
OH group at m-, or p- to the OH group abolish
activity
4-aminosalicylic acid is inactive…….because
Substitution of halogen on the aromatic ring ……….
Substitution of aromatic ring at position 5 increase
anti-inflammatory activity e.g. Diflunisal.