NSAIDs

Presented to:
Dr. Asam Raza
Presented by:
Alsha Mehwish 20012507-001
Youssra Hidayat 20012507-002
Shomal Nawab 20012507-019
Minahil Amin 20012507-029
Table of contents:

 What is inflammation……………………………………...….03
 How does inflammation occurs……………………………….07
 NSAIDS Introduction…………………………………………08
 Mechanism of action………………………………………….10
 NSAIDS Salicylates derivatives………………………………16
 SAR Aspirin………………………………………………......19
 ……………………………………..........21
 SAR of Ibuprofen……………………………………………..31
 Potency ……………………………………………………….35
 References…………………………………………………….40
What is inflammation?

 ’’Response of the body to injurious stimuli”

 So it is beneficial
Then why it is required to be suppressed ?
Because at times it can be in EXAGGERATED
form and can be
 Harmful to body
 Extremely disturbing to the patient
Inflammation:
Continue…
 Main Features

 Swelling
 Pain
 Redness
 Loss of function
NSAIDS addresses mainly FEVER, PAIN AND SWELLING.
IN ONE WAY, fever and pain are beneficial ….. HOW ?
So both phenomenon are beneficial
 Continued…
But when these reflexes are EXAGGERATED it is required to be
suppressed because
 RAISED TEMPERATURE
 May make a person incapable for doing his job.
 May inactivate several enzymes required to maintain normal
metabolism.
 In extreme cases…interfere with the state of consciousness.
 EXCESSIVE PAIN
 May interfere with the quality of life.
 May frighten the patient.
 May produce shock
 How does inflammation occur ??

Biosynthesis Of Prostaglandins
• Inflammation is caused by prostaglandins.
• Arachidonic acid is primary precursor of protanoids.
• Prostanoids are also called Ecosanoids.
• Arachidonic acid is a componant of the phospholipids of cell membrane.
• Free Arachidonic acid is released by cell damage mainly by the action of
phospholipase A2 enzyme.
• Arachidonic acid undergoes two pathways, by the enzymes cyclogenase
and lipoxygenase.
Peripheral Antinociceptive
Modulation by NSAIDs (1)

--------> PAF

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 NSAIDs Introduction
 NSAIDs are a class of drugs that relieve pain, reduce
inflammation (redness and swelling) and bring down a high
temperature (fever).

 NSAIDs are used to treat a wide range of conditions:

Headaches, painful periods, toothache, sprains and strains
infections, such as the common cold or the flu inflammation of
the joints (arthritis) and other tissues.
 NSAIDs

 NSAIDs including aspirin and acetaminophen, two of the oldest

pain medications.

 The conventional NSAIDs exert their therapeutic action by

inhibiting two iso-forms of cyclooxygenase (COX-1, the
constitutive isozyme and COX-2, the inducible isozyme), which
is the rate-limiting enzyme responsible for the biosynthesis of
the pro-inflammatory prostaglandins (PGs) such as the PGD2,
PGE2, PGF2, and PGI2.

 Thereby modulating pain transmission,attenuating

inflammation, and reducing fever.
 Mechanism of action:

 Mechanism of action was not completely known until 1971

when Vane first identified the cyclooxygenases as their
molecular targets.
 Cyclooxygenase (also known as prostaglandin endoperoxide
synthase or PGH synthase) is the rate-limiting enzyme
responsible for the biosynthesis of PGs.
 PGs are short-lived, lipidlike molecules that play a vital
role in modulating many important physiological and
pathophysiological functions including pain, inflammation, gastric
acid secretion, wound healing, and renal function.
 Continue..
 They are biosynthesized via a tissue-specific cyclooxygenase
pathway (COX-1 or COX-2) either on an as-needed basic (mostly
via the COX-1 isozyme) or via the induced and overexpressed
COX-2 isozyme because of an injury, inflammation, or infection.
 All classes of NSAIDs strongly inhibit prostaglandin synthesis in
various tissues, especially at the site of the tissue damage or
inflammation.
 This inhibition occurs at the stage of oxidative cyclization of AA,
catalyzed by the rate-limiting enzyme, cyclooxygenase (or PGH
synthase), to the hydroperoxy-endoperoxide (prostaglandin
G2,PGG2) and its subsequent reduction to key
intermediate,prostaglandin H2 (PGH2) needed for all
prostaglandin biosynthesis.
 Continue…

 Among the PGs synthesized by the action of either COX-1 or

COX-2 isozymes, PGI2 and PGE2 made at the site of injury (via
COX-2 isozyme in the inflammatory cells such as monocytes
and macrophages) and also in the brain, are known to play a
dominant role in mediating inflammation and inducing
hyperanalgesia.
 However, their synthesis in the GI tract (via COX-1 isozyme) and
in the renal tubules (via COX-1 and COX-2 isozymes), is
essential to provide cytoprotective action for restoring the
integrity of the stomach lining and maintaining renal functions
in an otherwise compromised kidney as a result of constant
insult.
 Peripheral Antinociceptive
Modulation by NSAIDs (2)

• Inhibition of Cyclo-Oxygenase

– (at least) 3 distinct categories of

inhibitors

• Reversible competitive inhibition

– Ibuprofen; piroxicam
• Reversible non-competitive inhibition
– Paracetamol
• Irreversible inactivation
– Aspirin, indomethacin
Conversion of arachidonic acid to
prostaglandins.
 Continue…

 Inhibition of PGE2 synthesis by the conventional NSAIDs in the

parietal cells removes its ability to modulate histamine-
mediated release of gastric acid from the parietal cells.

 whereas blockade of PGI2 and PGE2 synthesis in the epithelial

cells in the stomach linings also prevents their action on the
biosynthesis and release of bicarbonate and mucous gel
desperately needed to repair damage resulting from erosion
caused by gastric acid and other aggressive factors
What is the basic difference between traditional
NSAIDs and COX-2 inhibitors?

a.  Selective COX-2 inhibitors are NSAIDs that selectively block

the COX-2 enzyme and not the COX-1 enzyme. Blocking this
enzyme prevents the production of prostaglandins by the
COX-2 enzyme that often cause the pain and swelling of
inflammation and other painful conditions. Because they
selectively block the
b. With traditional antiinflammatory drugs such as aspirin,
inflammation is reduced by blocking Cox-2, but the protective
mucus lining of the stomach is also reduced because Cox-1 is
blocked, which can cause stomach upset, ulceration, and
bleeding from the stomach and intestines..
ASPIRIN
 INTRODUCTION OF ASPIRIN

• Chemical name: acetyl salicylic acid

• Brand name: Disprin
• Uses: anti pyretic, analgesic, and anti-inflammatory
• Chemical class: salicylic acid derivative
• Therapeutic class: analgesic, antipyretic, and anti
inflammatory
Aspirin          
IUPAC nomenclature
2-Acetoxybenzoic acid
 Continue…
 Aspirin occurs as white crystals or as a white crystalline powder and must
be kept under dry conditions.
 It is not advisable to keep aspirin products in the kitchen or bathroom
cabinets, because aspirin is slowly decomposed into acetic and salicylic
acids in the presence of heat and moisture.
 Aspirin is used as an analgesic for minor aches and pains and as an
antipyretic to reduce fever. Although higher doses of aspirin can also be
used to treat inflammation, its use is often associated with many unwanted
side effects including
ulcers, stomach bleeding, and tinnitus.
 SAR Of Aspirin:

 For the optimal activity of aspirin acetyl group is necessary at

position no. 2.
 Increase in carbon chain with acetyl group will decrease the
activity.
 If carboxylic group is replaced by ester group its activity will
decrease.
 Attachment of any substituent at position no 4 the
pharmacological of aspirin will lost.
 Halogen substituent to benzene ring result in increase activity
but toxicity increases.
 Removal of OH group from salicylic results in benzoic acid, that
is less active
Synthesis:
Mechanism of action:
Mechanism of action:
 Mechanism of Action

•The acetyl group of actetylsalicyclic acid binds irreversibly with serine

residue of COX-1 (cyclooxygenase-1) enzyme which leads to its
irreversible inhibition. Due to this, the pain producing prostaglandins
production is prevented.
•The conversion of arachidonic acid to thromboxane is also prevented
which checks the platelet aggregation and thus, clotting and venous and
arterial thromboembolism is also prevented.
ARYL- AND HETEROARYLPROPANOIC ACIDS:

 Most widely used drugs worldwide because three members of this class,
ibuprofen, naproxen,and ketoprofen.
 All of the members of this class (except oxaprozin) contain a chiral carbon in the @-
position of the acetic acid side chain. Even though most are marketed as
racemates, only the (S)-enantiomer was found to have any inhibitory activity
against the COX isozymes.
 Thus, the (S)-enantiomer is believed to be solely responsible for the observed
therapeutic action as well as the drug-induced GI side effects and nephrotoxicity.
Furthermore, in most cases, the inactive (R)- enantiomer is epimerized in vivo, via
the 2-arylpropionyl coenzyme-A epimerase to its active (S)-enantiomer.
 Ibuprofen:
 Ibuprofen, 2-(4-isobutylphenyl)propionic acid (Motrin, Advil, Nuprin).
 It appears to have comparable efficacy to aspirin in the treatment of RA, but
with a lower incidence of side effects.
 It has also been approved for use in the treatment of primary dysmenorrhea,
which is thought to be caused by an excessive concentration of PGs and
endoperoxides.
 However, a recent study indicates that concurrent use of ibuprofen and
aspirin may actually interfere with the cardioprotective effects of aspirin, at
least in patients with established cardiovascular disease.169 This is because
ibuprofen can reversibly bind to the platelet COX-1 isozymes, thereby blocking
aspirin’s ability to inhibit TXA2 synthesis in platelets
Synthesis of Ibuprofen:
 SAR of Ibuprofen

Size of substituent R1
R1 = Isobutyl substituent (maximum activity). =
small substituent (-CH3 , -C2 H5 ) (reduced
activity). =longer substituents (-( CH2 )3 CH3 , -
(CH2 )5 CH3 ) (sharply reduced activity).
R2 =CH3 (maximum activity), smaller or longer
substituents (H or C2 H5 , C3 H7 ) show diminish
activity.
Mechanism of action:
Continued…
 References:

 Wilson and Gisvold’s Textbook of Organic Medicinal and

Pharmaceutical Chemistry, 12th Edition,wolters Kluwer.
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