8 Nsaids 08 08 2023

VIT
 1. The inflammatory response is a normal (desirable)

defense mechanism.
 2. The side effects are undesirable.
 3. Normal inflammatory response has an on/off switch.
 4. In chronic inflammation something has gone wrong
with the OFF switch
 5. Therefore we need drugs to control the inflammatory
reaction.
Complement system
histamine
serotonin
bradykinin - major contributors to symptoms of inflammation
leukotrienes - increase vascular permeability
- increase mobilization of endogenous mediators of inflammation
prostaglandins PGE2 ‑ promote edema and leukocyte infiltration
PGI2 ‑ increase vascular permeability, enhance pain producing
properties of bradykinin
Sensitized lymphocytes release soluble factors ( which recruit &
mobilize macrophages to the inflammed tissue.)
Additional activated macrophages produce enhanced levels of

enzymes and mediators
Thereby involving macrophages in the defense against

microorganisms and foreign antigens
BUT remember that the inflammatory cells have the potential to

destroy surrounding tissue.
 Redness - due to local vessel dilatation
 Heat - due to local vessel dilatation
 Swelling – due to influx of plasma proteins and
phagocytic cells into the tissue spaces
 Pain – due to local release of enzymes and
increased tissue pressure
 The key enzyme in the cyclooxygenase pathway
is the enzyme cyclooxygenase (COX).
 There are two forms of cyclooxygenase, COX1

(the predominant form) and COX2.
 salicylates e.g., ASA
 phenylpropionic acids e.g., ibuprofen, ketoprofen
 pyrazalone derivatives e.g., phenylbutazone
 indole derivatives e.g., indomethacin
 Remission inducing / disease modifying drugs:
e.g. chloroquine, aurothioglucose, penicillamine,
prednisolone
Non-steroidal anti-inflammatory drugs (NSAIDs)
 All NSAIDs inhibit the cyclooxygenase required for conversion of
arachidonic acid to endoperoxide intermediate (PGG2 and PGH2).
 NSAIDs inhibit prostaglandin and thromboxane synthesis, they
are potent inhibitors of cyclooxygenase and eliminate all
prostaglandins and thromboxanes in every cell they reach
 Recall that prostaglandins and thromboxanes play crucial roles in:
Pain, Inflammation, Fever , Excessive blood clotting
Due to the adverse effects of Aspirin (esp. GI and
antiplatelet), many newer NSAIDS have been developed.
Ibuprofen: PROPIONIC ACID DERIVATIVE

-same potency as ASA .
-better tolerated (fewer side effects)
-ex. Advil; Motrin
Available over the counter (OTC)
Indomethacin: INDOLE DERIVATIVE

-more potent than ASA but inferior at doses tolerated by
rheumatoid arthritis patients.
-quite toxic
-PDA
Phenylbutazone:
PYRAZOLONE DERIVATIVE
-powerful anti-inflammatory drug
-usefulness is limited by its toxicity
-chiefly short-term therapy
Piroxicam:
-half-life = 45 hours
-administer once a day ( increased convenience)
-some GI disturbance
Sulindac:
-inactive pro-drug closely related to indomethacin
-must be metabolized by hepatic microsomal enzymes to
active form
-long duration of action (half-life = 8h)
-adverse effects less severe than other NSAIDS (ex. GI
and renal)
-ex. Clinoril
Ketoprofen:
-inhibits both cyclooxygenase and lipoxygenase
(decreases PGs, TXs, and LTs)
*recall LTs: bronchospam;bronchoconstriction
-may be desirable for asthmatics or inflammation plus
allergic response
-ex.Orudis
COX-2 INHIBITORS
Cyclooxygenase-1 (COX-1):
-constitutively expressed in wide variety of cells
all over the body.
-"housekeeping enzyme"
-ex. gastric cytoprotection,
Cyclooxygenase-2 (COX-2):
-inducible enzyme
-immediate-early gene product in inflammatory
and immune cells
-dramatically up-regulated during inflammation
(10-18X)
Adverse effects of NSAIDS are theorized to be due to
inhibition of COX-1 (ex. GI complications via decreased
PGE2 and potentially altered blood flow)
In some instances cytoprotectives e.g., misoprostol (PGE2

analogue) may be taken with NSAIDS to reduce GI effects.
Selective COX-2 inhibitors were developed

e.g., Celecoxib (Celebrex); Roficoxib (Vioxx) which was
withdrawn in 2004 due to serious CV effects and in Sept.
2007 Merck agreed to pay 4.8 billion dollars settlement.
Nitric Oxide-Releasing NSAIDS NO-NSAIDS
Less GI effects than parent NSAID from which

they are derived.
Comparable anti-inflammatory effect and superior

analgesic effect
Example: NO-naproxen
Parent NSAID: naproxen
Possible mechanism: nitric oxide would improve

gastric blood flow
DIETARY MANIPULATION OF
INFLAMMATION
Arachidonic Acid (AA) -eicosatetraenoic acid (4 double bonds)
Eicosapentaenoic acid (EPA) -5 double bonds

EPA
EPA is found in fish oil
It acts as a substrate for cyclooxygenases and

lipoxygenases (thus it competes with arachidonic acid
for the enzymes)
The prostaglandins, thromboxanes, and leukotrienes

produced from EPA are less active than AA
metabolites.
EPA continued
These products can then compete with products of AA

metabolism for shared target receptors.
Macrophages with a high content of EPA produce less

TNF and IL-l (key pro-inflammatory cytokines)
Thus,
• Dietary EPA supplementation can reduce tissue
injury due to PGs, TXs, LTs, and cytokines!!
EPA continued
Clinical studies have shown decreased morning stiffness

and joint pain in rheumatoid arthritis patients with EPA
supplementation
Potency approximates NSAIDS, with negligible side

effects!!
Body fluids supersaturate with urate and urate crystals
precipitate in tissues.
 Resulting in pain and inflammation
Phagocytosis of crystals by polymorphs and the

migration of leukocytes to the inflamed area
 Release inflammatory mediators into joint
 Colchicine
 indomethacin
 adrenal steroids
 new NSAIDS e.g. sulindac (acute gout)
 probenecid, sulfinpyrazone
 allopurinol
 Allopurinol inhibits synthesis of uric acid by competing
for the enzyme xanthine oxidase.
Hypoxanthine xanthine oxidase xanthine xanthine oxidase Uric

acid
Allopurinol xanthine oxidase Alloxanthine

 - inhibit phagocytosis
 - inhibit synthesis of IL‑1, TNF, PGs LTs.
 - inhibit antigen processing by
macrophages
 - stabilizes lysosomal membranes
 - inhibits accumulation of neutrophils and
monocytes at inflammation site.
 - inhibit phospholipase A2.
 examples: prednisone
dexamethasone
Side effects:
osteoporosis
impaired wound healing
edema, hypertension, congestive heart failure
CNS effects (euphoria ‑ psychosis)
Cushingoid Syndrome

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VIT

 1. The inflammatory response is a normal (desirable)

Additional activated macrophages produce enhanced levels of

Thereby involving macrophages in the defense against

BUT remember that the inflammatory cells have the potential to

 There are two forms of cyclooxygenase, COX1

Ibuprofen: PROPIONIC ACID DERIVATIVE

Indomethacin: INDOLE DERIVATIVE

In some instances cytoprotectives e.g., misoprostol (PGE2

Selective COX-2 inhibitors were developed

Less GI effects than parent NSAID from which

Comparable anti-inflammatory effect and superior

Possible mechanism: nitric oxide would improve

Eicosapentaenoic acid (EPA) -5 double bonds

It acts as a substrate for cyclooxygenases and

The prostaglandins, thromboxanes, and leukotrienes

These products can then compete with products of AA

Macrophages with a high content of EPA produce less

Clinical studies have shown decreased morning stiffness

Potency approximates NSAIDS, with negligible side

Phagocytosis of crystals by polymorphs and the

Hypoxanthine xanthine oxidase xanthine xanthine oxidase Uric

Allopurinol xanthine oxidase Alloxanthine

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