Nonsteroidal Antiinflammatory Drugs (NSAIDs)

1. NonsteroidalAntiinflammatory Drugs (NSAIDs)

2. Inflammation is a defense reaction caused by tissue damage or injury • Can be elicited by numerous stimuli including: • infectious agents • antigen-antibody interaction • ischemia • thermal and physical injury

3. Characterized by: • Redness (rubor): vasodilation of capillaries to increase blood flow • Heat (calor): vasodilation • Pain (dolor): Hyperalgesia, sensitization of nociceptors • Swelling (tumor): Increased vascular permeability (microvascular structural changes and escape of plasma proteins from the bloodstream) • Loss of function (functiolaesa) • Inflammatory cell transmigrationthrough endothelium and accumulation at the site of injury

5. Mediators of Inflammation • Vasoactive amines (Histamine, Serotonin) • Platelet activating factor (PAF) • Complement system • Kinin system • Cytokines • Nitric oxide • Adhesion Molecules • Arachidonic acid metabolites: • Prostaglandins (PGs) • Thromboxane A2 (TXA2) • HETE (hydroxy-eicosatetraenoic acid) • Leukotrienes (LTs) • mediated by cyclooxygenases (COX)

7. Two main forms of Cyclooxygenases (COX) • Cyclooxygenase-1 (COX-1) • Produces prostaglandins that mediate homeostatic functions • Constitutively expressed • Plays an important role in • Gastric mucosa • Kidney • Platelets • Vascular endothelium • Cyclooxygenase-2 (COX-2) • Produces prostaglandins that mediate inflammation, pain, and fever. • Induced mainly in sites of inflammation by cytokines

8. Inflammatory responses occur in three distinct phases: • An acute transient phase, characterized by: • local vasodilation • increased capillary permeability • A delayed, subacute phase, most prominently characterized by: • infiltration of leukocytes and phagocytic cells • A chronic proliferative phase, in which: • tissue degeneration and fibrosis occur

10. Mechanism of action of NSAIDs • Antiinflammatory effect • due to the inhibition of the enzymes that produce prostaglandin H synthase (cyclooxygenase, or COX), which converts arachidonic acid to prostaglandins, and to TXA2 and prostacyclin.

11. Aspirin irreversibly inactivates COX-1 and COX-2 by acetylation of a specific serine residue. • This distinguishes it from other NSAIDs, which reversibly inhibit COX-1 and COX-2.

12. Analgesic effect • The analgesic effect of NSAIDs is thought to be related to: • the peripheral inhibition of prostaglandin production • may also be due to the inhibition of pain stimuli at a subcortical site. • NSAIDs prevent the potentiating action of prostaglandins on endogenous mediators of peripheral nerve stimulation (e.g., bradykinin).

13. Antipyretic effect • The antipyretic effect of NSAIDs is believed to be related to: • inhibition of production of prostaglandins induced by interleukin-1 (IL-1) and interleukin-6 (IL-6) in the hypothalamus • the “resetting” of the thermoregulatory system, leading to vasodilatation and increased heat loss.

14. Therapeutic uses • Inflammation • NSAIDs are first-line drugs used to arrest inflammation and the accompanying pain of rheumatic and nonrheumatic diseases, including rheumatoid arthritis, juvenile arthritis, osteoarthritis, psoriatic arthritis, ankylosing spondylitis, Reiter syndrome, and dysmenorrhea. • Pain and inflammation of bursitis and tendonitis also respond to NSAIDs.

15. NSAIDs: • do not significantly reverse the progress of rheumatic disease • they slow destruction of cartilage and bone • allow patients increased mobility and use of their joints.

16. Treatment of chronic inflammation requires use of these agents at doses well above those used for analgesia and antipyresis • the incidence of adverse drug effects is increased.

17. Drug selection is generally dictated by the patient's ability to tolerate the adverse effects, and the cost of the drugs. • Antiinflammatory effects may develop only after several weeks of treatment.

18. Analgesia • NSAIDs alleviate mild-to-moderate pain by: • decreasing PGE- and PGF-mediated increases in pain receptor sensitivity. • They are more effective against pain associated with integumental structures (pain of muscular and vascular origin, arthritis, and bursitis) than with pain associated with the viscera.

19. Antipyresis • NSAIDs reduce elevated body temperature with little effect on normal body temperature.

20. Aspirin (acetylsalicylic acid) • Nonacetylatedsalicylates: • sodium salicylate • magnesium salicylate • cholinesalicylate • sodium thiosalicylate • sulfasalazine • mesalamine • salsalate

21. Pharmacologic properties: • Salicylates are weak organic acids; • aspirin has a pKa of 3.5. • These agents are rapidly absorbed from the intestine as well as from the stomach, where the low pH favors absorption.

22. Salicylates are hydrolyzed rapidly by plasma and tissue esterases to acetic acid and the active metabolite salicylic acid. esterases

24. Metabolism

25. Salicylates have a t1/2 of 3—6 hours after short-term administration. • Long-term administration of • high doses (to treat arthritis) or • toxic overdose • increases the t1/2 to 15—30 hours because the enzymes for glycine and glucuronide conjugation become saturated.

27. Unmetabolized salicylates are excreted by the kidney. • If the urine pH is raised above 8, clearance is increased approximately fourfold as a result of decreased reabsorption of the ionized salicylate from the tubules.

28. Therapeutic uses of Salicylates : • Salicylatesare used to treat: • rheumatoid arthritis • juvenile arthritis • osteoarthritis • other inflammatory disorders • 5-Amino salicylates(mesalamine, sulfasalazine) • can be used to treat Crohn's disease.

29. Salicylic acid is used topically to treat: • plantar warts • fungal infections • corns

30. Aspirin • has significantly greater antithrombotic activity than other NSAIDs

31. Adverse effects: • Gastrointestinal effects • most common adverse effects of high-dose aspirin use (70% of patients): • nausea • vomiting • diarrhea or constipation • dyspepsia (impaired digestion) • epigastric pain • bleeding, and ulceration (primarily gastric).

32. These gastrointestinal effects are thought to be due to: • a direct chemical effect on gastric cells or • a decrease in the production and cytoprotective activity of prostaglandins, which leads to gastric tissue susceptibility to damage by hydrochloric acid.

33. The gastrointestinal effects may contraindicate aspirin use in patients with an active ulcer. • Aspirin may be taken with prostaglandins to reduce gastric damage. • Decrease gastric irritation by: • Substitution of enteric-coated or timed-release preparations, or • the use of nonacetylated salicylates, may decrease gastric irritation.

34. Hypersensitivity (intolerance) • Hypersensitivity is relatively uncommon with the use of aspirin (0.3% of patients); hypersensitivity results in: • rash • bronchospasm • rhinitis • Edema, or • an anaphylactic reaction with shock, which may be life threatening. • The incidence of intolerance is highest in patients with asthma, nasal polyps, recurrent rhinitis, or urticaria. • Aspirin should be avoided in such patients.

35. Cross-hypersensitivity may exist: • to other NSAIDs • to the yellow dye tartrazine, which is used in many pharmaceutical preparations. • Hypersensitivity is not associated with: • sodium salicylate or • magnesium salicylate.

36. The use of aspirin and other salicylatesto control fever during viral infections (influenza and chickenpox) in children and adolescents is associated with an increased incidence of Reye's syndrome, an illness characterized by vomiting, hepatic disturbances, and encephalopathy that has a 35% mortality rate. • Acetaminophen is recommended as a substitute for children with fever of unknown etiology.

37. Miscellaneous adverse effects and contraindications • May decrease the glomerular filtration rate, particularly in patients with renal insufficiency. • Occasionally produce mild hepatitis • Prolong bleeding time.

38. Aspirin irreversibly inhibits platelet COX-1 and COX-2 and, thereby, TXA2 production, suppressing platelet adhesion and aggregation. • The use of salicylates is contraindicated in patients with bleeding disorders • Salicylates are not recommended during pregnancy; they may induce: • postpartum hemorrhage • premature closure of the fetal ductus arteriosus.

39. Drug interactions

40. Aspirin Toxicity • In adults, salicylism(tinnitus, hearing loss, vertigo) occurs as initial sign of toxicity after aspirin or salicylate overdose or poisoning. • In children, the common signs of toxicity include hyperventilation and acidosis, with accompanying lethargy and hyperventilation.

41. Treatment of Aspirin Toxicityincludes: • correction of acid—base disturbances • replacement of electrolytes and fluids • cooling • alkalinization of urine with bicarbonate to reduce salicylate reabsorption • forced diuresis, hemodialysis • gastric lavage or emesis

42. Other nonsteroidalantiinflammatory drugs • NSAIDs are absorbed rapidly after oral administration. • These agents are extensively bound to plasma proteins, especially albumin. • They cause drug interactions due to the displacement of other agents, particularly anticoagulants, from serum albumin; these interactions are similar to those seen with aspirin.

43. NSAIDs are • metabolized in the liver • excreted by the kidney • The half-lives: #1 -45 h # most: 10 -20 h

44. These agents commonly produce: • gastrointestinal disturbances • cross-sensitivity with aspirin • Non-dose-relatedacute renal failure and nephrotic syndrome: • in combination with ACE inhibitors • More nephrotoxic: • Indomethacin • Meclofenamate • Tolmetin • phenylbutazone

46. Propionic acid derivatives (Ibuprofen, Fenoprofen, ketoprofen , naproxen) • There is no reported interaction of ibuprofen or ketoprofen with anticoagulants. • Fenoprofen has been reported to induce nephrotoxic syndrome. • Long-term use of ibuprofen is associated with an increased incidence of hypertension in women.

47. Sulindac, tolmetin, Ketorolac • Sulindac: • is a prodrug that is oxidized to a sulfone and then to the active sulfide • has a relatively long t1/2 (16 h) because of enterohepatic cycling. • Tolmetin: • has minimal effect on platelet aggregation; • it is associated with a higher incidence of anaphylaxis than other NSAIDs. • Tolmetin has a relatively short t1/2 (1 h). • Ketorolac: • is a potent analgesic with moderate antiinflammatory activity • can be administered: • intravenously or • topically in an ophthalmic solution.

48. Indomethacin • Use: As anti-inflammatory • Treatment of • Ankylosing spondylitis • Reiter syndrome • Acute gouty arthritis. • to speed the closure of patent ductus arteriosus in premature infants (otherwise, it is not used in children); • it inhibits the production of prostaglandins that prevent closure of the ductus.

49. Indomethacin is not recommended as a simple analgesic or antipyretic because of the potential for severe adverse effects. • Bleeding, ulceration • Headache • Occasional:Tinnitus, dizziness, or confusion

50. Piroxicam • Piroxicam is an oxicam derivative of enolic acid. • Piroxicam has t1/2 of 45 hours. • Like aspirin and indomethacin, bleeding and ulcerationare more likely with piroxicam than with other NSAIDs.