NSAIDs non steroidal antiinflammatory drugs

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NSAIDs(non steroidal anti-inflammatory drugs)

• Biol 4407/Bioc 4806.5/
• Nesc 4376/PHC 5409B
• Dr.T.C. Peterson

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THE 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.
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Mediators 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
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INFLAMMATORY SITE

•  Sensitized lymphocytes release soluble factors (
  which recruit mobilize macrophages to the
  inflammed tissue.)
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• Additional activated macrophages produce enhanced
  levels of enzymes and mediators
• Thereby involving macrophages in the defense
  against microorganisms and foreign antigens
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• BUT remember that the inflammatory cells have the
  potential to destroy surrounding tissue.

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Mediators of inflammation
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4 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

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Major pathways
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Eicosanoids

• 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.

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COX 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.

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ANTI-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

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Prostaglandin inhibitory activity correlates to
anti-inflammatory effect
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MECHANISM 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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Salicylate structure
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Pyrazolone structure
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Indole structure
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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
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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
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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 bronchospambronchocon
striction -may be desirable for asthmatics or
inflammation plus allergic response -ex.Orudis
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COX-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)
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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.
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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
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DIETARY MANIPULATION OF INFLAMMATION
Arachidonic Acid (AA) -eicosatetraenoic acid (4
double bonds) Eicosapentaenoic acid (EPA) -5
double bonds
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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.
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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!!
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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!!
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Inflammatory events in the gouty joint
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GOUTY 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
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ANTI-INFLAMMATORY DRUGS AND GOUTY ARTHRITIS

• Colchicine
• indomethacin
• adrenal steroids
• new NSAIDS e.g. sulindac (acute gout)
• probenecid, sulfinpyrazone
• allopurinol

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Mechanism of action of Allopurinol

• Allopurinol inhibits synthesis of uric acid by
  competing for the enzyme xanthine oxidase.
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• Hypoxanthine xanthine oxidase xanthine
  xanthine oxidase Uric
  acid
• Allopurinol xanthine oxidase Alloxanthine
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Glucocorticoids

• - 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.

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Glucocorticoids

• examples prednisone
• dexamethasone
• Side effects
• osteoporosis
• impaired wound healing
• edema, hypertension, congestive heart failure
  
• CNS effects (euphoria - psychosis)
• Cushingoid Syndrome

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