NSAIDs non steroidal antiinflammatory drugs - PowerPoint PPT Presentation

1 / 37
About This Presentation
Title:

NSAIDs non steroidal antiinflammatory drugs

Description:

Allopurinol inhibits synthesis of uric acid by competing for the enzyme xanthine ... Allopurinol xanthine oxidase Alloxanthine. Glucocorticoids - inhibit phagocytosis ... – PowerPoint PPT presentation

Number of Views:635
Avg rating:3.0/5.0
Slides: 38
Provided by: drtheresa
Category:

less

Transcript and Presenter's Notes

Title: NSAIDs non steroidal antiinflammatory drugs


1
NSAIDs(non steroidal anti-inflammatory drugs)
  • Biol 4407/Bioc 4806.5/
  • Nesc 4376/PHC 5409B
  • Dr.T.C. Peterson

2
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.
  •  
  •  

3
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
4
INFLAMMATORY 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.

5
Mediators of inflammation
6
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

7
Major pathways
8
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.

9
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.

10
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

11
Prostaglandin inhibitory activity correlates to
anti-inflammatory effect
12
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
  •  

13
(No Transcript)
14
Salicylate structure
15
Pyrazolone structure
16
Indole structure
17
(No Transcript)
18
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
19
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
20
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
21
(No Transcript)
22
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)
23
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.
24
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
25
(No Transcript)
26
DIETARY MANIPULATION OF INFLAMMATION
Arachidonic Acid (AA) -eicosatetraenoic acid (4
double bonds) Eicosapentaenoic acid (EPA) -5
double bonds
27
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.
28
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!!
29
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!!
30
Inflammatory events in the gouty joint
31
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
  •  

32
ANTI-INFLAMMATORY DRUGS AND GOUTY ARTHRITIS
  • Colchicine
  • indomethacin
  • adrenal steroids
  • new NSAIDS e.g. sulindac (acute gout)
  • probenecid, sulfinpyrazone
  • allopurinol

33
(No Transcript)
34
Mechanism 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
  •  

35
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.

36
Glucocorticoids
  • examples prednisone
  • dexamethasone
  • Side effects
  • osteoporosis
  • impaired wound healing
  • edema, hypertension, congestive heart failure
  • CNS effects (euphoria - psychosis)
  • Cushingoid Syndrome

37
(No Transcript)
Write a Comment
User Comments (0)
About PowerShow.com