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Antiinflammatory Agents and Nonsteroidal Antiinflammatory Drugs (NSAIDs) Groups of anti-inflammatory agents and mechanism of action: 1) nonsteroidal anti-inflammatory drugs - NSAI 2) glucocorticosteroids (GCS) + Phospholipids glucocorticosteroids Phospholipase LK А2 Arachidonic acid NSAID Cyclooxygenases (COG-1, COG-2, COG-3) Cyclic endoperoxydases Prostaglandins Inflammation Pain Fever Thromboxan Vasoconstriction Increasing of platelets aggregation - - depressing effect + - stimulating effect NSAIDs Large and chemically diverse group of drugs with the following properties: Analgesic Antiinflammatory Antipyretic NSAIDs: Mechanism of Action Activation of the arachidonic acid pathway causes: pain headache fever inflammation Arachidonic Acid Pathway NSAIDs: Mechanism of Action Analgesia—treatment of headaches and pain Block the undesirable effects of prostaglandins, which cause headaches NSAIDs: Mechanism of Action Antipyretic: reduce fever Inhibit prostaglandin E2 within the area of the brain that controls temperature NSAIDs: Mechanism of Action Relief of inflammation Inhibit the leukotriene pathway, the prostaglandin pathway, or both NSAIDs Six structurally related groups: Acetic acids Carboxylic acids Propionic acids Enolic acids Fenamic acids Nonacidic compounds NSAIDs: Acetic Acid diclofenac sodium (Voltaren) diclofenac potassium (Cataflam) etodolac (Lodine) indomethacin (Indocin) sulindac (Clinoril) tolmetin (Tolectin) NSAIDs: Carboxylic Acids Acetylated aspirin (ASA) choline magnesium salicylate (Trilisate) diflunisal (Dolobid) Nonacetylated salicylamide salsalate (Disalcid) sodium salicylate NSAIDs: Propionic Acids fenoprofen (Nalfon) flurbiprofen (Ansaid) ibuprofen (Motrin, others) ketoprofen (Orudis) ketorolac (Toradol) naproxen (Naprosyn) oxaprozin (Daypro) NSAIDs: Other Agents Enolic acids phenylbutazone (Butazolidin) piroxicam (Feldene) Fenamic acids meclofenamic acid (Meclomen) mefenamic acid (Ponstel) Nonacidic compounds nabumetone (Relafen) NSAIDs: Other Agents COX-2 Inhibitors celecoxib (Celebrex) rofecoxib (Vioxx) Acetylsalicylic acid Aspirin С Aspirin Butadion Indometacin (methyndol) Ibuprofen (brufen) Piroxicam Sodium diclofenac Voltaren NSAIDs: Drug Effects Analgesic (mild to moderate) Antigout Antiinflammatory Antipyretic Relief of vascular headaches Platelet inhibition (ASA) 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 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 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 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. NSAIDs: Side Effects Renal reductions in creatinine clearance acute tubular necrosis with renal failure NSAIDs: Side Effects Cardiovascular noncardiogenic pulmonary edema NSAIDs: Salicylate Toxicity Adults: tinnitus and hearing loss Children: hyperventilation and CNS effects Effects arise when serum levels exceed 300g/mL. Metabolic acidosis and respiratory alkalosis may be present. 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). 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 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. 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. 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 GLUCOCORTICOIDS • Reduce inflammation and immune responses • In clinical practice since 1948 • $10,000,000,000./year market size in US Steroid Hormones: Derived from Cholesterol Lipid Soluble: Able to cross plasma membrane by passive diffusion 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 GR GR Effects of Glucocorticoids on Components of Inflammatory/Immune Responses CELL TYPE FACTOR COMMENTS Macrophages Monocytes Prostaglandins, Leukotrienes Inhibition of COX-2, Phospholipase A2 IL-1, IL-6. TNF Inhib. Transcript., Release Endothelial Cells ICAM-1. ELAM-1 IL-1, Prostagl., Leuko. Inhib. Transcript., Release As above Basophils Histamine, Leukotriene Inhib. IgE Release Lymphocytes IL-1, IL-2, IL-3, etc As above 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 Glucocorticoids: Side Effects 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 proinflammatory genes in multiple cell types by the glucocorticoid receptor. From Glass and Rosenfeld 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) IMPORTANT CONCEPT 7: Structural modifications of the natural glucocorticoid cortisol generate hormones with enhanced half-life and more potent and efficacious glucocorticoid activity Antiseptics and Disinfectants Antiseptics and Disinfectants Most desirable quality is the ability to destroy microorganisms They have 2 uses: disinfect instruments and treat infections in oral cavity and on body surfaces 2 different agents may have to be used to achieve adequate cleaning Actions of Antiseptics and Disinfectants Agent Action antiseptic inhibits growth of microorganisms disinfectant chemical applied to objects fungicide destroys fungi germicide destroys bacteria preservative prevents decomposition sanitizer reduces the number of bacteria sporicide destroys spores Drug List Antiseptics and Disinfectants alcohol, isopropyl hexachlorophene (pHisoHex) povidone-iodine (Betadine) sodium hypochlorite (Clorox) hexachlorophene (pHisoHex) Surgical scrub and bacteriostatic skin cleanser Especially effective against gram-positive bacteria Do not leave on skin for an extended period of time Drug List Antiseptics and Disinfectants Heavy Metal Compounds silver nitrate zinc oxide (Desitin Creamy) Drug List Antiseptics and Disinfectants Orals benzocaine (Hurricaine, Orabase-B) carbamide peroxide (Gly-Oxide Oral) cevimeline (Evoxac) chlorhexidine gluconate (Hibiclens) clove oil (Eugenol) Drug List Antiseptics and Disinfectants Others benzalkonium chloride (Zephiran) hydrogen peroxide phenytoin (Dilantin) What characteristics make an ideal antiseptic? Answer: can inhibit all forms of microorganisms, nontoxic, does not induce sensitization, can penetrate tissues and body fluids, water soluble, noncorrosive, inexpensive