PROSTAGLANDINS & RELATED COMPOUNDS (EICOSANOIDS) - PowerPoint PPT Presentation

prostaglandins related compounds eicosanoids n.
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PROSTAGLANDINS & RELATED COMPOUNDS (EICOSANOIDS)

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  1. PROSTAGLANDINS & RELATED COMPOUNDS(EICOSANOIDS)

  2. Membrane lipids supply the substrate for the synthesis of eicosanoids and PAF • PAF is formed by a smaller number of cell types LEOKOCYTES, PLATELETS & ENDOTHELIAL CELLS

  3. EICOSANOIDS and PAF lipids contribute to • inflammation • Smooth muscle tone • Hemostasis • Thrombosis • Parturition • Gi secretion

  4. Other important targets include platelets and monocytes, kidneys, CNS, autonomic presynaptic nerve terminals, sensory nerve endings, endocrine organs, adipose tissue, and the eye. They are not preformed in cells but are generated from phospholipids on demand

  5. Eicosanoids arachidonate metabolites – PGs, PGI2, TXA2, LTs, hepoxilins-are molecules that comprise 20 carbon atoms and have 3, 4 or 5 double bonds are members of a family of related polyunsaturated fatty acids • They are local hormones and are generally synthesized and catabolized close to their site of action, and have many physiological and pathological actions.

  6. The immediate fatty acid precursor of most eicosanoids in individuals on a standard mixed diet is arachidonic acid; this is formed from dietary linoleic acid found in quantities in vegetable oils such as sunflower oil. Linoleic acid is converted in the liver in several steps to the eicosanoid precursor arachidonic acid, which is then incorporated into glycerophospholipids in cells • arachidonic acid is released under the influence of lipases like phospholipase A2 and can then be converted to eicosanoids

  7. PHYSICAL, CHEMICAL and HORMONAL STIMULI ACTIVATE PLA2 • The initial products of the action of COX on arachidonic acid are unstable intermediates known as cyclic endoperoxides. TXA2 is a powerful vasoconstrictor and aggregator of platelets.

  8. THE ARACHIDONIC ACID CASCADE hydroperoxyeicosatetranoicacid

  9. Generally, the initial rate-limiting step in eicosanoid synthesis is the liberation of arachidonate from phospholipids by phospholipase A2 (PLA2) This occurs in response to • General cell damage • Thrombin action on platelets • C5a on neutrophils • BK on fibroblasts • Antigen-antibody reactions on mast cells

  10. Cyclooxygenase COX occurs as at least three isoenzymes, • COX-1, COX-2 and COX-3, • COX-1 was thought to be mainly a constitutive 'housekeeping' enzyme localised to the endoplasmic reticulum. It can be produced in the resting state by many cells and contributes to the regulation of several homeostatic processes such as renal and gastric blood flow, gastric cytoprotection and platelet aggregation. • COX-2 was thought to be mainly an inducible enzyme, induced by inflammatory stimuli

  11. Metabolism • Rapidly inactivated. The prostaglandin-specific enzymes are present in high concentration in the lung, and 95% of infused PGE2, PGE1 or PGF2α is inactivated on first passage. The half-life of most prostaglandins in the circulation is less than 1 minute. Receptors • There are five main classes of prostanoid receptors all of which are typical G-protein-coupled receptors. They are termed DP, FP, IP, EP and TP receptors, respectively, depending on whether their ligands are PGD2, PGF2α, PGI2, PGE2 or TXA2.

  12. ACTIONS OF PROSTANOIDS • PGD2 causes vasodilatation, inhibition of platelet aggregation, relaxation of gastrointestinal and uterine muscle, and modification of release of hypothalamic/pituitary hormones. It has a bronchoconstrictor effect through an action on TP receptors. • PGF2α causes myometrial contraction in humans , and bronchoconstriction in other species (cats and dogs). • PGI2 causes vasodilatation, inhibition of platelet aggregation , renin release and natriuresis through effects on tubular reabsorption of Na+. • TXA2 causes vasoconstriction, platelet aggregation and bronchoconstriction (more marked in guinea pig than in humans).

  13. Smoothmuscle Vascular TXA2 is a potentvasoconstrictorand a cellmitogen PGF2α is also a vasoconstrictor PGI2 and PGE2 causevasodilationby ↑ cAMPand ↓smoothmuscleicCa

  14. GI Most of thePGsandTXsactivategismoothmuscle • Airways Respiratorysmoothmuscle is relaxedby PGI2 and PGE2 andcontractedby PGD2, TXA2 and PGF2α DP1 and DP2 receptorknockoutmicesuggest an important role of thisprostanoid in….. Leukotienesalsocausebronchoconstriction

  15. Platelets PGD2 and PGI2 inhibitaggregation (↑ cAMP) TXA2 plateletaggregatorandamplifiestheeffects of othermorepotentplateletagonistssuch as thrombin

  16. Kidney PGE2 PGI2 major, TXA2 and PGF2αsecond Theyplayimportantroles in maintainingbpandregulatingrenalfunctionespecially in marginallyfunctioningkidneys, PGE2 PGI2 maintainbloodflowandgfrthroughtheirlocalvasodilatingeffect TheymodulatebpbyregulatingwaterandNaexcretion

  17. ReproductiveOrgans • Studies of knock-outmice →PG in reproductionandandparturition EP2 deficientmice →preimplantationdefect • PGswerediscovered in seminalfluid but theconc of them is reallylow PGE1 enhancepenileerectionbyrelaxingthesmoothmuscle of corporacavernosa

  18. Fever PGE2 ↑ body temperature Endogenouspyrogensrelease IL-1 which in turnpromotesthesynthesisandrelease of PGE2

  19. THE ROLE OF PROSTANOIDS IN INFLAMMATION • PGE2 PGI2 are associated with inflammation • Enhance edema formation and leukocyte infiltration by promoting blood flow to the inflamed area • PGE2 PGI2 ↑ vascular permeability and leukocyte infiltration • PGE2 ↓ the immunologic response by ↓ differentiation of B lymphocytes into antibody-secreting plasma cells →depressing the humoral response

  20. Bone Metabolism PGE2 ↑ bone turnoverstimulation of bone resorptionandandformation • EYE PGE and PGF derivativesloweintraocularpressure

  21. NT PGE ↓ therelase of NE frompostganglionicsympatheticnerveendings PGE2, PGI2 sensitizetheperipheralnerveendingtopainfulstimuli

  22. CANCER Largehumanepidemiologicstudies →NSAIDsuse is associatedwithsignificantreductioninrelative risk fordevelopingcolon, breast, lungandothercancers. PGE2 principaloncogenicprostanoidfacilitatesinitiation, progressionandmetastasis→proliferation, angiogenesis, inhibapoptosis, augmentingcellularinvasiveness, modulateimmunosuppression

  23. Leukotrienes • 5-Lipoxygenase oxidizes arachidonate to give 5-hydroperoxyeicosatetraenoic acid (5-HPETE), which is converted to leukotriene (LT) A4. This, in turn, can be converted to either LTB4 or to a series of glutathione adducts, the cysteinyl-leukotrienes LTC4, LTD4 and LTE4. • LTB4, acting on specific receptors, causes adherence, chemotaxis and activation of polymorphs and monocytes, and stimulates proliferation and cytokine production from macrophages and lymphocytes. • LTB4 is an important mediator in all types of inflammation; the cysteinyl-leukotrienes are of particular importance in asthma.

  24. LKs • LTB4 is a potent chemoattractant for T lymphocytes, eosinophils, monocytes and mast cells • LKs have been implicated in pathogenesis of inflammation→asthma, inflammatory bowel disease

  25. CV12S-HETE promotes vascular smooth muscle cell proliferation (injury after angioplasty • 12RHETE potent ↓ Na/K ATPase in the cornea • LTC4 and LTD4 reduce myocardial contractility and coronary blood flow→cardiac depression

  26. GI Human colonicepithelialcellssynthesize LTB4 (chemoattractantforneutrophils) Colonicmucosa of peoplewithinflammatorybdcontain ……………..

  27. AIRWAYS LTC4 and LTD4 potentvasoconstrictors • RENAL 20-HETE →vasoconstriction of renalarteries …….

  28. SUMMARY DIAGRAM

  29. Clinical uses of prostanoids • Gynecological and obstetric • PGE2 and PGF2α have potent oxytocic actions. (termination of pregnancy): dinaprostone (20 mg vaginal suppository3-5 h intervals) gemeprost or misoprostol (metabolically stable prostaglandin PGE analogue) • induction of labor: dinoprostone (0.5 mg) or misoprostol • postpartum hemorrhage: carboprost (250µg im inj). • Gastrointestinal • to prevent ulcers associated with non-steroidal anti-inflammatory drug use: misoprostol • Cardiovascular • primary pulmonary hypertension: epoprostenolt1/2 3-5 min; PGI2 analogue Iloprost t1/2 30min • Ophthalmic • open-angle glaucoma: latanoprost eye drops. Bimatoprost, travoprost and unoprostone are also available.

  30. CLINICALLY USED PGs & ANALOGS