NSAIDs (non steroidal anti- inflammatory drugs)

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.

Complement system histamine serotonin bradykinin - major contributors to symptoms of inflammation leukotrienes - increase vascular permeability - increase mobilization of endogenous mediators of inflammation prostaglandins PGE 2 ‑ promote edema and leukocyte infiltration PGI 2 ‑ increase vascular permeability, enhance pain producing properties of bradykinin Mediators of the inflammatory response

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 BUTremember that the inflammatory cells have the potential to destroy surrounding tissue.

Mediators of inflammation

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

Major pathways

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.

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.

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

Prostaglandin inhibitory activity correlates to anti- inflammatory effect

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

Salicylate structure

Pyrazolone structure

Indole structure

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, hemostasis 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 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!!

Inflammatory events in the gouty joint

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

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

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

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 A 2.

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