1Anti-inflammatory analgesicdrugsPL331 Winter 2007Karen [email protected] reading:Pharmacology and Therapeutics forDentistry, 5th edition, Yagiela et alChapter 21: pages 331-364Inflammation• Complex reaction of innate immune system– Occurs in vascularized tissues– Accumulation and activation of leukocytes andplasma proteins• Triggered by infection, toxin exposure, or cellinjury• Vascular changes promote leukocyte recruitment• Local adaptive immune responses amplify theinflammatory responseThree 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 tissueinjury)1. Chemical mediators or autacoids (Bradykinin,serotonin, Histamine, NO, prostaglandins,leukotrienes, ILs)2. Vascular system (flow and permeability changes, EC)3. Migration of blood cells, chemotaxis (neutrophils,mast cells, NK)4. Innate immune response (“first line of defense”)5. Time course is minutes to hours2↑ 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 respose2. Can be beneficial and/or destructive hypersensitivity reactions autoimmune diseasesInnate immunity• Natural or native immunity• Rapid response to microbes• Physical and chemical barriers• Phagocytic cells (neutrophils andmacrophages) and NK cells• Blood proteins (complementsystem) and other mediators• Cytokines: secreted proteinsthat regulate and control cells ofthe immune systemAdaptive Immunity• Specific or acquiredimmunity• Exquisite specificityfor a large diversityof distinct foreignantigens• Memory and robustresponse to 2ndexposure• Lymphocytes andtheir products (Tand B cells)Immune 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 cells3Humoral and Cell-mediated ImmunityPhases of Adaptive Responses• Recognition Phase: Specific recognition of adistinct antigenic determinant (clonal selectinhypothesis) by lymphocyte clones• Activation Phase: Protein synthesis (secretedcytokines, cytokine receptors), cellularproliferation, differentiation into effector andmemory cells• Effector Phase: Elimination of antigen by bothlymphoid and nonlymphoid cellsInnate ImmunityAdaptive ImmunityIII. Chronic inflammation• Vascular system (flow and permeability changes, EC)• 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 destruction4• Protective: controls infection andpromotes tissue repair• Destructive: causes tissue damage,necrosis, and diseaseTwo sides of the Inflammatory ResponseClinical 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 & leukotrines)2. Bradykinin (vasoactive plasma peptides formed from kinnogens; vasodilator, Ò vascular permeability & pain)3. Cytokines (IL-1 and TNFa released from tissue macrophages and see Òvascular permeability and Òadhesion molecule expression )4. Chemokines (chemoattractants, IL-8, RANTES, MCP-1)5. Complement (activated by Ab-Ag complexes, LPS or endotoxin, lyse bacteria, Ò EC permeability, opsonization)6. Clotting mediators (activated by platelets or collagen, Hageman/Factor XII) 7. Thromboxanes (platelets aggregation & vasoconstriction)8. Histamine (IgE mediated or complement [C3a and C5a]mediated release from mast cells and basophils, vasodilator, Ò permeability of capillaries)9. Serotonin: vasoconstrictor released by mast cells10. Angiogenic factors (VEGF, FGF)11. 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 Ò vasodilation and PGs syn.13. Pathogen produced (bacterial LPS, OMP, fMLP) Inflammatory Mediators (con’t)Therapeutic strategies• Ú pain and arrest tissue damage• 3 main classes of drugs to Ú pain– NSAIDs: Úpain and Úinflammation– Glucocorticoids (but toxicity asso. with chroniccorticosteriod use, so used only for acute episodes)– SAARDs (slow acting antirheumatic drugs) or DMARDs(disease modifying antirheumatic drugs) but these arealso very toxic• NSAIDs are the drug of choice5Nonsteroidal 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– 2 types of cyclooxygenase enzymes: COX-1 and COX-2• COX-1: wide spread constitutive enzyme and important in tissuehomeostasis• COX-2: induced in inflammatory cells by IL-1 and TNF-a• COX-3: a splice variant of COX-1 (also referred to as COX-1b or-1v)–