1. Prostaglandins& Related Compounds

2. 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 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

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 arachidonic acid The eicosanoids derived compounds include the prostaglandins (PGs), thromboxanes (TXs), leukotrienes (LTs)and lipoxins(LXs). The PGs,TXs and prostacyclins are collectively identified as prostanoids. 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 arachidonic acid The eicosanoids derived compounds include the prostaglandins (PGs), thromboxanes (TXs), leukotrienes (LTs)and lipoxins(LXs). The PGs,TXs and prostacyclins are collectively identified as prostanoids.

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

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 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 synthase

13. 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 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

14. 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 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

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

19. Role of Prostaglandins in Platelet homeostasis

20. 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 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