1Anti-inflammatory analgesicdrugsPL331 Spring 2009Pharmacology for DentistryKaren [email protected] reading:Pharmacology and Therapeutics forDentistry, 5th edition, Yagiela et alChapter 21: pages 331-3642Inflammation• Complex reaction of innate immune system– Occurs in vascularized tissues– Accumulation and activation of leukocytes and plasmaproteins• Triggered by infection, toxin exposure, or cell injury• Vascular changes promote leukocyte recruitment• Local adaptive immune responses amplify theinflammatory response3Three phases to inflammation1. Acute inflammationautocoids, innate immune responses2. Immune response (subacute inflammation)adaptive immune responseinduction and effector phases3. Chronic inflammationInflammatory responseI. Acute inflammation (initial response to tissue injury inducedby a pathogen or noxious substance)1. Chemical mediators or autacoids (Bradykinin, serotonin,Histamine, NO, prostaglandins, leukotrienes, ILs)2. Vascular system (flow and permeability changes)3. Migration of blood cells, chemotaxis (neutrophils, mast cells,NK)4. Innate immune response (“first line of defense”)5. Adaptive immune response6. Time course is minutes to hours4! vasodilation, vascular permeability and pain Serotonin: ! vascular permeability, some effect on vasodilation Histamine: ! vasodilation and vascular permeabilityBradykinin: Prostaglandins: ! vasodilation; ! bloodflow; !redness, edema and heat; !vascular permeability;!chemotaxis and ! migration of WBC; ! pain Leukotrienes: ! vascular permeabilityand chemotaxis!Autocoids mediate initial response to tissue injuryII. Immune response or subacuteinflammation (immune competent cell activation)1. Innate and adaptive responses to antigeninnate: recognition by tissue M" of specificpathogen-associated molecular patterns (PAMPs)adaptive: induction and effector phase of both cellmediated and humoral mediated response2. Can be beneficial and/or destructive hypersensitivity reactions autoimmune diseases5Innate immunity• Natural or native immunity• Rapid response to microbes• Physical and chemical barriers• Phagocytic cells (neutrophils andmacrophages) and NK cells• Blood proteins (complement system)and other mediators• Cytokines: secreted proteins thatregulate and control cells of theimmune system• Increase in vascular permeabilityAdaptive Immunity• Specific or acquiredimmunity• Exquisite specificityfor a large diversityof distinct foreignantigens• Memory and robustresponse to 2ndexposure• Lymphocytes andtheir products (Tand B cells)6Immune SystemInnate ImmunityRapid kineticsNonspecific responseBaseline responseMediated by phagocytes,physical and chemicalbarriers, blood proteinsAdaptive ImmunitySlower kineticsSpecific responseIncrease response withrepeat exposureMediated by lymphocytesand their products (Band T cells)Humoral and Cell-mediated AdaptiveImmune Responses1) Humoral: mediated by B-cell secreted Abs! Extracellular microbes and their toxins! Specific effector functions (promotephagocytosis or granule release)2) Cell-mediated: mediated by T-cells! Intracellular microbes (inaccessible to Abs)including viruses! Destruction of intracellular microbe or lysis ofinfected cells7Humoral and Cell-mediated ImmunityInnate ImmunityAdaptive Immunity8III. Chronic inflammation• Vascular system (flow and permeability changes)• Migration of blood cells (infiltrate of lymphocytes &monocytes)• Chemical mediators (chemokines, cytokines, Igs,coagulation• Adaptive immune response• Time course is weeks to years• Tissue proliferation and destruction• Protective: controls infection andpromotes tissue repair• Destructive: causes tissue damage,necrosis, and diseaseTwo sides of the Inflammatory Response9Clinical features of inflammation• Tumor (edema/swelling)• Rubor (redness)• Calor (heat/fever)• Dolor (pain)• Loss of functionThese features are due to an inflammatory responseand the products of a number of cell types includingactivated mast cells, leukocytes, macrophages,eosinophils, endothelial cells, platelets, et al.Inflammatory Mediators/Signaling Molecules(see Table 21-1 and Box 21-1)1. Arachidonic acid derivatives: prostaglandins, thromboxanes & leukotrines2. Bradykinin: vasoactive plasma peptides formed from kinnogens; vasodilator, " vascular permeability & pain3. Cytokines: IL-1 and TNF# released from tissue macrophages and see "vascular permeability and "adhesion molecule expression 4. Chemokines: chemoattractants, IL-8, RANTES, MCP-15. Complement: activated by Ab-Ag complexes, LPS or endotoxin, lyse bacteria, " EC permeability, opsonization6. Clotting mediators: activated by platelets or collagen, Hageman/Factor XII107. Thromboxanes: (platelets aggregation & vasoconstriction8. Histamine: IgE mediated or complement [C3a and C5a]mediated release from mast cells and basophils, vasodilator, " permeability of capillaries9. Serotonin: vasoconstrictor released by mast cells10. Angiogenic factors: VEGF, FGF11. Platelet activating factor: (from platelets, EC, macrophages & mast cells; vasodilator, stimulates prostaglandin syn.)12. Nitric oxide: (NO) released from EC and causes smooth muscles to relax and " vasodilation and PGs syn.13. Pathogen produced: (bacterial LPS, OMP, fMLP) Inflammatory Mediators (con’t)Therapeutic strategies• # pain and arrest tissue damage• 3 main classes of drugs to # pain– NSAIDs: #pain and #inflammation– Glucocorticoids: inhibition of induction of the cyclooxygenases(but toxicity asso. with chronic corticosteriod use, so used onlyfor acute episodes)– SAARDs (slow acting antirheumatic drugs) or DMARDs (diseasemodifying antirheumatic drugs) but these are also very toxic• NSAIDs are the drug of choice11Nonsteroidal anti-inflammatorydrugs (NSAIDS)• One of the most widely used therapeutic agents (Rx andnon-Rx forms)• Inhibit arachidonate cyclooxygenase and thus inhibitproduction of prostaglandins (PG) and thromboxanes (TX)– 3 types of cyclooxygenase enzymes: COX-1, COX-2 & COX-3• COX-1: wide spread constitutive enzyme and important in tissuehomeostasis• COX-2: induced in inflammatory cells by IL-1 and TNF-#• COX-3: a splice variant of COX-1 (also referred to as COX-1b or-1v)– NSAIDS generally inhibit both isoenzymes, thus :• COX-1 inhibition: GI distress• COX-2 inhibition: anti-inflammatory effect– Goal is to develop NSAIDS with a selective action on COX-2Arachidonic acid (AA)• AA