2. Groups of anti-inflammatory agents and mechanism of action: 1) nonsteroidal anti-inflammatory drugs - NSAI 2) glucocorticosteroids (GCS) glucocorticosteroids LK +- Phospholipase А 2 Phospholipids Arachidonic acid Cyclic endoperoxydases Prostaglandins Thromboxan Inflammation Pain Fever Vasoconstriction Increasing of platelets aggregation - + - depressing effect - stimulating effect NSAID - Cyclooxygenases ( COG-1, COG-2, COG-3 )

6.  Large and chemically diverse group of drugs with the following properties:  Analgesic  Antiinflammatory  Antipyretic

7.  Activation of the arachidonic acid pathway causes:  pain  headache  fever  inflammation

8. Gastro- intestinal tract Peptic ulcers and multiple micro-erosions Esophagitis and strictures Erosive damaging of large and small intestines Kidney Reversible acute kidney insufficiency Water-electrolyte disorders Chronic kidney insufficiency and interstitial fibrosis Interstitial nephritis Nephritic syndrome Cardio- vascular system Increasing of arterial hypertension Increasing of static cardiac insufficiency Increasing of stenocardia Liver Increasing of transaminases level Life-threatening liver insufficiency CNS Headache, somnolence confusion, disorders of behavior aseptic meningitis Blood system Thrombocytopenia Hemolytic anemia Granulocytopenia and aplastic anemia Bones, joints Disorders of cartilages and subchondral tissue OtherIncreasing of asthma and polypus of nose, skin rash

10. 1) Administer simultaneously with gastric protectors sucralfat, misoprostol, ranitidin, famotidin, omeprasol 2) Create and introduce NSAIDs which selectively inhibit COG-2 meloxycam, nimesulid, rofecoxib, celecoxib Prevention of development of GI complications while administering NSAIDs:

11. Directions of medical treatment of rheumatoid diseases: 1)NSAIDs 1)NSAIDs with the aim of depression of inflammatory process, pain, rigidness of muscles and joints, but don’t effect the currency of disease 2) Basis drugs (disease modifying) Methotrexat, hydroxychloroquin, sulfasalazin, gold containing drugs, penicillamin, purin derivatives (asathioprin and mercaptopurin) Alkilying drugs (chlorbutin and cyclophosphamid), cyclosporin 3) GCS 3) GCS are administered if there’s a lack of effect of NSAIDs and basis drugs in case of very severe currency of inflammatory process

12.  Analgesic (mild to moderate)  Antigout  Antiinflammatory  Antipyretic  Relief of vascular headaches  Platelet inhibition (ASA)

13.  Relief of mild to moderate pain  Acute gout  Various bone, joint, and muscle pain  Osteoarthritis  Rheumatoid arthritis  Juvenile rheumatoid arthritis  Dysmenorrhea  Fever

14. 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

17. phenylbutazone (Butazolidin)  Greater effects on uric acid production and excretion, in addition to antiinflammatory effects  More commonly used for treatment of gout

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

29. Renal  reductions in creatinine clearance  acute tubular necrosis with renal failure Cardiovascular  noncardiogenic pulmonary edema

30.  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.

31.  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).

32.  Perform a medication history to assess for potential drug interactions.  Several serious drug interactions exist:  alcohol  heparin  phenytoin  oral anticoagulants  steroids  sulfonamides

33.  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.

34.  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.

35.  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

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

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

38. 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

39. GR GR

40. CELL TYPEFACTORCOMMENTS MacrophagesProstaglandins,Inhibition of COX-2, MonocytesLeukotrienesPhospholipase A2 IL-1, IL-6. TNF  Inhib. Transcript., Release Endothelial CellsICAM-1. ELAM-1Inhib. Transcript., Release IL-1, Prostagl., Leuko.As above BasophilsHistamine, LeukotrieneInhib. IgE Release Lymphocytes IL-1, IL-2, IL-3, etcAs aboveIL-2 Effects of Glucocorticoids on Components of Inflammatory/Immune Responses

41. 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

42. Glucocorticoids: Side Effects

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

44. From Glass and Rosenfeld