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Prostaglandins& Related Compounds

Prostaglandins& Related Compounds. Objectives. Origin of ecosanoids Ecosanoids role Overview of the structure Role of phospholipase A2 Cyclooxgenase isoenzymes Inhibitors of prostaglandin synthesis Aspirin induced asthma Low –dose aspirin therapy.

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Prostaglandins& Related Compounds

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  1. Prostaglandins& RelatedCompounds

  2. Objectives • Origin of ecosanoids • Ecosanoids role • Overview of the structure • Role of phospholipase A2 • Cyclooxgenaseisoenzymes • Inhibitors of prostaglandin synthesis • Aspirin induced asthma • Low –dose aspirin therapy

  3. The eicosanoids are a group of molecules derived from the C20 polyunsaturated fatty acids • The dietary precursor of PG is linoleic acid which is elongated & desaturated to arachidonicacid • The eicosanoids derived compounds include the prostaglandins (PGs), thromboxanes (TXs), leukotrienes (LTs)and lipoxins(LXs). • The PGs ,TXs and prostacyclinsare collectively identified as prostanoids.

  4. They are extremely potent compoundswith wide range of physiological, pathological & pharmacological effects Gastric integrity& renal function Regulate smooth muscle contraction ( SI & uterus ) Blood Vessel Diameter Hypersensitivity reactions Inflammatory responses Platelet homeostasis

  5. Properties of Ecosanoids • They simulate hormones but: • Produced in very small amounts • Produced in almost all tissues • Locally rather than transported • Not stored • Extremely short half-life • Act through nuclear & plasma membrane receptors

  6. Prostanoids

  7. Naming of Prostaglandins

  8. Prostacyclin Thromboxan

  9. Leukotrienes & Lipoxins

  10. Leukotriene Lipoxin

  11. PG endoperoxide synthase

  12. Cyclooxygenase Isoenzymes • There are 2 forms of the COX activity. • COX-1 is expressed constitutively in gastric mucosa, kidney, platelets, and vascular endothelial cells (imp for healthy tissue). • COX-2 is inducible and is expressed in macrophages and monocytes ( limited number of cells) in response to inflammation. It mediates pain, hotness, redness by PG synthesis

  13. Inhibitors of Prostaglandin synthesis • Cortisol inhibits the phospholipase A2 • Aspirin, indomethacin , and phenylbutazone (NASIDs) inhibit both COX1 & COX2 • Aspirin toxicity is due to COX1 inhibition reflected on damage of stomach, kidneys and impaired clotting of blood. • Selective inhibitors of COX2 as celebrix but the use of some of them may lead to increased risk of heart attack

  14. Leukotrienes are mediators of allergic response and inflammation • Aspirin-induced asthma is a response to overproduction of leukotrienes with NASIDs use. • NASIDs also favor synthesis of lipoxins lipid mediator with anti-inflammatory effects

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  16. TXA2 • Produced in platelets • induces platelet aggregation, • Vasoconstriction • Mobilizes intracellular calcium • Contraction of smooth muscles • PGI2 • Produced in vascular endothelial cells • inhibits platelet aggregation • induces vasodilation and production of cAMP

  17. Role of Prostaglandins in Platelet homeostasis

  18. Role of Aspirin • Aspirin has antithrombogenic effect. • It inhibits TXA2 synthesis from arachidonic acid in platelets by irreversible acetylation & inhibition of COX-1 • This irreversible cannot be overcome in anucleated platelets but can be overcomed by endothelial cells b/c they have nucleus • This is the basis of low-base aspirin therapy

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