Antiinflammatory Agents and Nonsteroidal Antiinflammatory Drugs (NSAIDs)

1. Antiinflammatory Agents and Nonsteroidal Antiinflammatory Drugs (NSAIDs)

2. Groups of anti-inflammatory agents and mechanism of action: 1) nonsteroidal anti-inflammatory drugs - NSAI 2) glucocorticosteroids (GCS) + - Phospholipids Arachidonic acid Cyclic endoperoxydases glucocorticosteroids LK Phospholipase А2 - Cyclooxygenases (COG-1, COG-2, COG-3) NSAID ProstaglandinsThromboxan InflammationPainFeverVasoconstriction Increasing of platelets aggregation - depressing effect - stimulating effect - +

3. NSAIDs • Large and chemically diverse group of drugs with the following properties: • Analgesic • Antiinflammatory • Antipyretic

4. NSAIDs: Mechanism of Action • Activation of the arachidonic acid pathway causes: • pain • headache • fever • inflammation

5. Arachidonic Acid Pathway

6. NSAIDs: Mechanism of Action Analgesia—treatment of headaches and pain • Block the undesirable effects of prostaglandins, which cause headaches

7. NSAIDs: Mechanism of Action Antipyretic: reduce fever • Inhibit prostaglandin E2 within the area of the brain that controls temperature

8. NSAIDs: Mechanism of Action Relief of inflammation • Inhibit the leukotriene pathway, the prostaglandin pathway, or both

9. NSAIDs Six structurally related groups: • Acetic acids • Carboxylic acids • Propionic acids • Enolic acids • Fenamic acids • Nonacidic compounds

10. NSAIDs: Acetic Acid • diclofenac sodium (Voltaren) • diclofenac potassium (Cataflam) • etodolac (Lodine) • indomethacin (Indocin) • sulindac (Clinoril) • tolmetin (Tolectin)

11. NSAIDs: Carboxylic Acids Acetylated • aspirin (ASA) • choline magnesium salicylate (Trilisate) • diflunisal (Dolobid) Nonacetylated • salicylamide • salsalate (Disalcid) • sodium salicylate

12. NSAIDs: Propionic Acids • fenoprofen (Nalfon) • flurbiprofen (Ansaid) • ibuprofen (Motrin, others) • ketoprofen (Orudis) • ketorolac (Toradol) • naproxen (Naprosyn) • oxaprozin (Daypro)

13. NSAIDs: Other Agents Enolic acids • phenylbutazone (Butazolidin) • piroxicam (Feldene) Fenamic acids • meclofenamic acid (Meclomen) • mefenamic acid (Ponstel) Nonacidic compounds • nabumetone (Relafen)

14. NSAIDs: Other Agents COX-2 Inhibitors • celecoxib (Celebrex) • rofecoxib (Vioxx)

15. Acetylsalicylic acid

16. Aspirin С

17. Aspirin

18. Butadion

19. Indometacin (methyndol)

20. Ibuprofen (brufen)

21. Piroxicam

22. Sodium diclofenac

23. Voltaren

24. NSAIDs: Drug Effects • Analgesic (mild to moderate) • Antigout • Antiinflammatory • Antipyretic • Relief of vascular headaches • Platelet inhibition (ASA)

25. NSAIDs: Therapeutic Uses • Relief of mild to moderate pain • Acute gout • Various bone, joint, and muscle pain • Osteoarthritis • Rheumatoid arthritis • Juvenile rheumatoid arthritis • Dysmenorrhea • Fever

26. NSAIDs: Specific Agents salicylates (aspirin) • More potent effect on platelet aggregation and thermal regulatory center in the brain • analgesic • antipyretic • antiinflammatory • Antithrombotic effect: used in the treatment of MI and other thromboembolic disorders

27. NSAIDs: Specific Agents phenylbutazone (Butazolidin) • Greater effects on uric acid production and excretion, in addition to antiinflammatory effects • More commonly used for treatment of gout

28. NSAIDs: Side Effects Gastrointestinal • dyspepsia, heartburn, epigastric distress, nausea **GI bleeding **mucosal lesions (erosions or ulcerations) • Misoprostol (Cytotec) can be used to reduce these dangerous effects.

29. NSAIDs: Side Effects Renal • reductions in creatinine clearance • acute tubular necrosis with renal failure

30. NSAIDs: Side Effects Cardiovascular • noncardiogenic pulmonary edema

31. NSAIDs: Salicylate Toxicity • Adults: tinnitus and hearing loss • Children: hyperventilation and CNS effects • Effects arise when serum levels exceed 300g/mL. • Metabolic acidosis and respiratory alkalosis may be present.

32. NSAIDs: Nursing Implications • Before beginning therapy, assess for conditions that may be contraindications to therapy, especially: • GI lesions or peptic ulcer disease • Bleeding disorders • Assess also for conditions that require cautious use. • Perform lab studies as indicated (cardiac, renal, liver studies, CDC, platelet count).

33. NSAIDs: Nursing Implications • Perform a medication history to assess for potential drug interactions. • Several serious drug interactions exist: • alcohol • heparin • phenytoin • oral anticoagulants • steroids • sulfonamides

34. NSAIDs: Nursing Implications • Salicylates are NOT to be given to children under age 12 because of the risk of Reye’s syndrome. • Because these agents generally cause GI distress, they are often better tolerated if taken with food, milk or an antacid to avoid GI irritation. • Explain to patients that therapeutic effects may not be seen for 3 to 4 weeks.

35. NSAIDs: Nursing Implications • Educate patients about the various side effects of NSAIDs, and to notify their physician if these effects become severe or if bleeding or GI pain occur. • Patients should watch closely for the occurrence of any unusual bleeding, such as in the stool. • Enteric-coated tablets should not be crushed or chewed.

36. NSAIDs: Nursing Implications • Monitor for therapeutic effects, which vary according to the condition being treated: decrease in swelling, pain, stiffness, and tenderness of a joint or muscle area

37. GLUCOCORTICOIDS • Reduce inflammation and immune responses • In clinical practice since 1948 • $10,000,000,000./year market size in US

38. Steroid Hormones: Derived from Cholesterol Lipid Soluble: Able to cross plasma membrane by passive diffusion

39. PHYSIOLOGICAL EFFECTS OF GLUCOCORTICOIDS •  Regulation of carbohydrate, protein and lipid metabolism •  Maintenance of fluid and electrolyte balance • Preservation of normal function of the cardiovascular system, the immune system, the kidney, skeletal muscle, the endocrine system and the nervous system • Preservation of organismal homeostasis

40. GR GR

41. Effects of Glucocorticoids on Components of Inflammatory/Immune Responses CELL TYPE FACTOR COMMENTS Macrophages Prostaglandins, Inhibition of COX-2, Monocytes Leukotrienes Phospholipase A2 IL-1, IL-6. TNF Inhib. Transcript., Release Endothelial Cells ICAM-1. ELAM-1 Inhib. Transcript., Release IL-1, Prostagl., Leuko. As above Basophils Histamine, Leukotriene Inhib. IgE Release Lymphocytes IL-1, IL-2, IL-3, etc As above

42. The anti-inflammatory and immunosuppressive actions of glucocorticoids play an important role in preventing potential damaging effects of an unopposed inflammatory response and can be exploited therapeutically

43. Glucocorticoids: Side Effects

44. The beneficial effects of systemic glucocorticoids to limit inflammation is counter-balanced by its many adverse side effects

45. The broad anti-inflammatory actions of glucocorticoids are due primarily to transcriptional repression of many pro-inflammatory genes in multiple cell types by the glucocorticoid receptor.

46. From Glass and Rosenfeld

48. Relative Potencies of Glucocorticoids Compound Anti-Inflammatory Na+ -Retaining Duration Potency Potency of Action Cortisol 1 1 S Cortisone 0.8 0.8 S Prednisolone 4 0.8 I Triamcinolone 5 0 I Betamethasone 25 0 L Dexamethasone 25 0 L • S, short (i.e., 8–12 hour biological half-life); I, intermediate (i.e., 12–36 hour biological half-life); L, long (i.e., 36–72 hour biological half-life)

49. IMPORTANT CONCEPT 7:Structural modifications of the natural glucocorticoid cortisol generate hormones with enhanced half-life and more potent and efficacious glucocorticoid activity

50. Antiseptics and Disinfectants