الملف الشخصي
مشاهدة مشاركات المنتدى
رسالة خاصة
مضادات الإلتهاب اللاستيروئيدية Anti-inflammatory Drugs
(مقدمة عن آلية الإلتهاب)
Inflammation
•It is a normal, protective response to tissue injury caused by
- tissue trauma,
- noxious chemicals or
- microbiological agents
Inflammation is the body’s effort to inactivate or destroy invading microorganisms, remove irritants and set the stage for tissue repair
When healing is complete, the inflammatory process usually subsides
•Inflammation is sometimes inappropriately triggered by an innocuous agent or an autoimmune disease (e.g. pollen, asthma, rheumatoid arthritis)
•Defense reactions themselves may cause progressive tissue injury
Inflammatory mediators
•Inflammation is triggered by the release of chemical mediators
•The specific mediators vary with the type of inflammatory process,
•Include: amines (histamines, 5-HT), lipids (prostaglandins), small peptides (bradykinin), larger peptides (IL-1)
Prostaglandins
•= unsaturated fatty acid derivatives containing 20 carbons that include a cyclic ring structure ‘eicosanoids’
•All NSAIDS act by inhibition of the synthesis of prostaglandins
A. Role of prostaglandins as local mediators
•Produced in minute amounts by virtually all tissues
•Act locally on the tissues in which they are synthesized
•Rapidly metabolized to inactive compounds at their sites of action
•Do not circulate in blood in significant concentrations
•Thromboxanes
•Leukotrienes
•Hydroperoxyeicosatetraenoic acid (HPETEs)
•Hydroxyeicosatetraenoic acids (HETEs)
Related lipids, synthesized from the same precursors as PG are and using interrelated pathways
B. Synthesis of prostaglandins
1.Cyclooxygenase pathway
2.Lipoxygenase pathway
1. Cyclooxygenase pathway
•All eicosanoids with ring structures(i.e. prostaglandins, thromboxanes and prostacyclins)
•Two related isoforms of COX enzyme have been described
•COX-1:physiologic production of prostanoids“house-keeping enzyme”- regulates normal cellular processes (gastric epithelial cytoprotection, platelet aggregation, vascular homeostasis and kidney function)
•COX-2:causes elevated production of prostanoids in that occurs in sites of disease and inflammation(e.g. oxidative stress, injury, ischemia, seizures, neuro-degenerative diseases)
•COX-2 is constitutively expressed in some tissues such as the brain, kidney and bone
•Its expression at other sites is increased during states of inflammation
2. Lipoxygenase pathway
•Several lipoxygenases can act on arachidonic acid to form leukotrienes or lipoxins depending on the tissue
•Antileukotriene drugs (e.g. zileuton, zafirlukast and montelukast) à treatment of moderate to severe allergic asthma
C. Actions of prostaglandins
•Many actions mediated by binding to a variety of cell receptors that operate via G proteinsà subsequently activate or inhibit adenylyl cyclase or stimulate phospholipase C
•PGF2a, leukotrienes and TXA2 mediate certain actions by activating phosphatidylinositol metabolism and increase intracellular Ca2+
D. Functions in the body
•PG and their metabolites produced endogenously act as local signals that fine-tune the response of a specific cell type
•Functions vary widely depending on the tissue
- release of TXA-2 from plateletsà aggregation
- release of TXA-2 in some smooth musclesà contraction
- release of PG in some allergic and inflammatory reactions
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