Title: NSAIDs non steroidal antiinflammatory drugs
1NSAIDs(non steroidal anti-inflammatory drugs)
- Biol 4407/Bioc 4806.5/
- Nesc 4376/PHC 5409B
- Dr.T.C. Peterson
2THE INFLAMMATORY RESPONSE
-
- 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. -
-
3Mediators of the inflammatory response
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
4INFLAMMATORY SITE
- 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.
5Mediators of inflammation
64 signs of inflammation
- 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
7Major pathways
8Eicosanoids
- Eicosanoids a family of compounds that are the
products of three main pathways which use oxygen
as a major cosubstrate. - The three pathways are
- the cyclooxygenase pathway
- the lipoxygenase pathway
- the epoxygenase pathway.
9COX 1 and COX 2
- The key enzyme in the cyclooxygenase pathway is
the enzyme cyclooxygenase (COX). -
- There are two forms of cyclooxygenase, COX1 (the
predominant form) and COX2.
10ANTI-INFLAMMATORY DRUGS
- 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
11Prostaglandin inhibitory activity correlates to
anti-inflammatory effect
12MECHANISM OF ACTION
- 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 -
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14Salicylate structure
15Pyrazolone structure
16Indole structure
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18Due 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
19Phenylbutazone 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
20Sulindac -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 bronchospambronchocon
striction -may be desirable for asthmatics or
inflammation plus allergic response -ex.Orudis
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22COX-2 INHIBITORS Cyclooxygenase-1 (COX-1)
-constitutively expressed in wide variety of
cells all over the body. -"housekeeping enzyme"
-ex. gastric cytoprotection, hemostasis
Cyclooxygenase-2 (COX-2) -inducible enzyme
-immediate-early gene product in inflammatory
and immune cells -dramatically up-regulated
during inflammation (10-18X)
23Adverse 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.
24Nitric 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
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26DIETARY MANIPULATION OF INFLAMMATION
Arachidonic Acid (AA) -eicosatetraenoic acid (4
double bonds) Eicosapentaenoic acid (EPA) -5
double bonds
27EPA 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.
28EPA 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!!
29EPA 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!!
30Inflammatory events in the gouty joint
31GOUTY ARTHRITIS inflammatory mechanism
- 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
-
-
32ANTI-INFLAMMATORY DRUGS AND GOUTY ARTHRITIS
- Colchicine
- indomethacin
- adrenal steroids
- new NSAIDS e.g. sulindac (acute gout)
- probenecid, sulfinpyrazone
- allopurinol
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34Mechanism of action of 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
-
35Glucocorticoids
- - 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.
36Glucocorticoids
- examples prednisone
- dexamethasone
- Side effects
- osteoporosis
- impaired wound healing
- edema, hypertension, congestive heart failure
- CNS effects (euphoria - psychosis)
- Cushingoid Syndrome
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