NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

1112 - 222 2ND SEMESTER / ACADEMIC YEAR 2025 / MA’AM RHODA

TITLE
CONTENTS Table of Contents /Information Order

INFO INFO INFO

Mariella Gregorio 1

Mariella Gregorio 2

Mariella Gregorio 3

A MAIN TOPIC #1

TERMINOLOGY
★​ Info

A.1 SUBTOPIC #1

TERMINOLOGY
★​ Info

A.2 SUBTOPIC #2

TERMINOLOGY
★​ Info

nCO2 + nH2O + Light Energy →

(CH2O)n Carbohydrate + nO2

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NONSTEROIDAL ANTI-INFLAMMATORY DRUGS
1112 - 222 2ND SEMESTER / ACADEMIC YEAR 2025 / MA’AM RHODA

Aspirin-like/Conventional NSAIDs COX-1, Constitutive Isonzyme

CONTENTS Table of Contents /Information Order
★​ Reduces pain and inflammation but ★​ Expressed in the GIT Biosynthesis of
are non selective PGE2 and PGI2
SECTION 1: A 1
★​ Inhibits COX-1 and COX-2 ★​ Cytoprotection and platelet
Introduction to MolView
Coxibs/COX-2 Inhibitors aggregation effects
SECTION 2: B ★​ Reduces pain and inflammation and COX-2, Inducible Isoenzyme
Functional Group Identification and 2 are selective ★​ Induced and overexpressed during
Properties ★​ Inhibits COX-2 injury
★​ Synthesis of PG required by
Section 3: C 3 inflammatory cells to cause pain,
A.1 NSAIDs MOA
Preliminary Molecule Construction inflammation, and fever

SECTION 4: D 4 Cyclooxygenase
★​ Also known as prostaglandin A.2 Conventional NSAIDs and Coxibs
Identifying Different Types of Bonds Side Effects
endoperoxide synthase or PGH
SECTION 5: E 5 synthase
Molecular Geometry and 3D ★​ Rate limiting enzyme for PGs Conventional NSAIDs
Visualization ★​ These enzymes help produce certain ★​ COX-1 and COX-2 are also responsible
prostaglandins, PGD2, PGE2, PGF2a, for producing PGs that modulate
PGI2, that cause pain, inflammation, platelet activity (TXA2 and PGI2),
A OVERVIEW OF NSAIDs and fever. gastric acid secretion and
★​ NSAIDs work by blocking two COX cytoprotection (PGE2 and PGI2),
★​ NSAIDs including aspirin and isoforms - COX-1 constitutive and renal blood flow (PGE2).
acetaminophen, two of the oldest isoenzyme; COX-2 inducible ★​ Because NSAIDs block them, they can
pain medications, most widely isoenzyme cause side effects like stomach
prescribed drugs for rheumatic ★​ Blocked COX prevents oxidative ulcers, bleeding, and kidney
arthritis and other degenerative cyclization of arachidonic acid problems.
inflammatory joint diseases. (AA) into PGG2, and its subsequent ★​ Acetaminophen (Tylenol) and the
★​ Effective in relieving mild to reduction to key intermediate, newer coxib drugs are exception from
moderate pains and inflammation. prostaglandin H2 (PGH2) needed the indicated side effects
for all prostaglandin biosynthesis.

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 NONSTEROIDAL ANTI-INFLAMMATORY DRUGS
1112 - 222 2ND SEMESTER / ACADEMIC YEAR 2025 / MA’AM RHODA

Coxibs Three (3) precursors of PGs prostaglandins that cause pain and
★​ Designed to mainly inhibit COX-2, ★​ 8,11,14-eicosatrienoic acid | 1(=) swelling.
reducing pain and inflammation ★​ 5,8,11,14-eicosatetraenoic acid | 2(=)
without significantly affecting COX-1 ★​ 5,8,11,14,17-eicosapentaenoic acid |
3(=)
*See tabulation - NSAIDS EFFECTS: DESIRED Arachidonic Acid
AND UNDESIRED ★​ 5,8,11,14-eicosatetraenoic acid | 2(=)
★​ Derived from linoleic acid or is
ingested from diet.
★​ Esterified into phospholipids
★​ Synthesis can be inhibited using
A.3 Vane et al. Hypothesis of
Corticosteroids by inhibiting the
Conventional Effects of NSAIDs COX Pathway
activity of phospholipase A2.
Conversion of Arachidonic Acid to PGs
Constitutive COX-1 Isoenzyme Inhibition
★​ Causes undesirable side effects. B.1 Prostaglandin Tissue-Specific Steps Description
Inducible COX-2 Isoenzyme Inhibition COX Pathways
★​ Responsible for therapeutic action. 1 When the body needs
★​ This hypothesis stimulated extensive Via COX-1 prostaglandins (for pain,
development of selective Coxib drugs. ★​ on an “as needed basis” inflammation, etc.), an enzyme
★​ It is active all the time and produces called phospholipase A2 releases
Most COX-2 inhibitors, except celecoxib prostaglandins (hormone-like arachidonic acid from cell
(Celebrex), first FDA approved COX-2 drug substances) as needed for normal membranes
inhibitor, were withdrawn due to the risk of body functions like protecting the
heart attacks and strokes, especially in heart stomach lining and helping blood clot. 2 COX-1 and COX-2 enzymes then
patients. Via COX-2 convert arachidonic acid into PGG2
★​ on an induced or overexpressed (to then to PGH2, a key building block
produce many copies) pathway for different prostaglandins
B Prostaglandin Synthesis
★​ It is usually inactive but gets
activated (induced) when there is 3 PGH2 is further changed into
★​ Short lived, lipid-like molecules
inflammation, injury, or infection, specific prostaglandins (PGE2,
★​ Modulates pain, inflammation, gastric
leading to the production of PGD2, PGF2α, PGI2), and
acid secretion, wound healing, anp
thromboxane A2 (TXXA), which
renal function

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NONSTEROIDAL ANTI-INFLAMMATORY DRUGS
1112 - 222 2ND SEMESTER / ACADEMIC YEAR 2025 / MA’AM RHODA

control things like pain, swelling, /hCOX-2 inhibition of COX-1

stomach protection, and blood flow by COX-2 inhibitors
Ile 523 Val 523 Valine is smaller, is thought to occur
/Val 509 making COX-2's because non existent
C Structure–Activity Relationships active site bigger, side pockets in
of NSAIDs so COX-2 inhibitors COX-1 isoenzyme
(like celecoxib) can
fit. His 513 Arg 499 Adds a positive
C.1 Structure and Binding of charge in COX-2,
Cyclooxygenases Ile 434 Ile 434 Creates a which helps COX-2
/Val 420 hydrophilic side inhibitors bind.
His 513 pocket in COX-2,
★​ COX-1 and COX-2, though very Arg 531 allowing selective Arg 120 Arg 120 COX-2 inhibitors
similar, X-ray crystal structure /Arg 499 inhibitors or large /Arg 104 don’t have a
analysis show key differences that (basic) substituents to bind carboxyl group
affect how drugs bind to them. such as celecoxib. (-COOH), the group
★​ These differences are important for from NSAIDs that
the selectivity of NSAIDs and COX-2 Larger COX-2 interacts with Arg
inhibitors like celecoxib. inhibitors (with a 120/Arg 104
methylsulfonylphenyl
group) take time to Only positively
fully block the charged residue in
enzyme. This the active site; binds
happens because to carboxylate anion
part of the molecule of AA and NSAIDs.
(the sulfonamide
group) needs time to Tyr 385 Tyr 385 Found on opposite of
adjust and fit into a /Tyr 371 active site
Key Amino Acids Structure Defining of hydrophobic side
COX pocket inside COX-2​ Catalytic site where
oxygen binds to or is
COX-1 COX-2 Effect on Function Simple competitive activated to start

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NONSTEROIDAL ANTI-INFLAMMATORY DRUGS
1112 - 222 2ND SEMESTER / ACADEMIC YEAR 2025 / MA’AM RHODA

prostaglandin
formation.

Ser 530 Ser 530 Not involved in

/Ser 516 binding AA substrate

Aspirin binds here,

responsible for
irreversible
inactivation
(madikit) of COX.

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