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.
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
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.
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
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
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: bronchospam;bronchoconstriction
-may be desirable for asthmatics or inflammation plus
allergic response
-ex.Orudis
21.
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
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!!
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.
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.
