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prostaglandins, prostacyclins, thromboxanes, leukotrienes

Eicosanoids. prostaglandins, prostacyclins, thromboxanes, leukotrienes . lipid-derived AUTOCOIDS. arachidonic acid C 20:4  5,8,11,14. The common precursor to these autocoids is arachidonic acid. hormones bind to receptors Ca 2+ released and activates phospholipases. acylhydrolases. 5.

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prostaglandins, prostacyclins, thromboxanes, leukotrienes

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  1. Eicosanoids prostaglandins, prostacyclins, thromboxanes, leukotrienes lipid-derived AUTOCOIDS

  2. arachidonic acid C20:45,8,11,14 The common precursor to these autocoids is arachidonic acid. hormones bind to receptors Ca2+released and activates phospholipases acylhydrolases 5 1 There are other eicosotrieneoic and - tetraenoic acids converted but arachidonic is the primary starting material in mammals.

  3. There are two pathways followed to the potent products. PGDs and PGEs are hydroxyketones, while PGFas are diols; PGIs are bicyclics; and Txs have 6-membered rings.

  4. This overview indicates the variety of products and complex reactions.

  5. The cyclic pathway starts with the COX enzymes. cyclic endoperoxides COX-1 is constitutive in most cells and tissues; exclusively in the stomach. COX-2 is induced by various stimuli such as cytokines, growth factors, endotoxins. It is constitutively expressed in some kidney cells and brain. The induction is blocked by glucocorticoids.

  6. The mechanism of the cyclooxygenase enzyme complex is amazing. Cyclooxygenase Mechanism

  7. The first products along the cyclic pathway have similar yet distinguishable features. reductase isomerase • PGF2a has different effects in different tissues • It is a potent constrictor in pulmonary veins and arteries but doesn’t alter blood pressure • Uterine muscle • contraction • In general, PGs shorten intestinal transit time In general, PGs contract or relax smooth muscle. • PGDs cause vasodilation in low concentrations and vasoconstriction in high concentrations • May be involved in sleep.

  8. PGE2 is the most studied of the prostaglandins. • PGEs are vasodilators for arterioles, pre-capillary sphincters, postcapillary venules • Blood pressure decreases • Blood flow to organs increases • Cause hypotension • Suppress immune response (PGE2 prevents B cells from maturing to B plasma cells. • Uterine muscle • nonpregnant - relaxation • pregnant – low conc – contraction – high – relaxation • Inhibit gastric acid secretion (volume, acidity, pepsin activity) • Stimulate water and electrolyte exit to small intestine • PGE2 is probably involved in affecting pyrogen-induced fever

  9. These “biotransformations” should look somewhat familiar. prostaglandin dehydrogenase PDH 13 reduction -oxidation -oxidation

  10. Thromboxanes share precursors with other eicosanoids. • Thromboxanes (Tx) are extremely potent stimulators of platelet aggregation. • Txs are produced by platelets • The pathway of Tx-stimulated platelet aggregation is extremely sensitive to inhibition by acetylsalicylic acid. • Uterine muscle • nonpregnant – contraction • Vasoconstrictor t1/2 = 30s inactive

  11. Prostacyclins have actions opposing those of thromboxanes. • Blood vessel endothelial cells especially produce prostacyclins • inhibits platelet aggregration at 1-10nM concentrations • Potent vasodilator (5X PGE) • Uterine muscle relaxation • Inhibit gastric acid secretion like PGEs endothelial cells produce PGI2 inhibit platelet aggregation platelets produce TxA2 t1/2 = 3 min induce platelet aggregation

  12. Leukotrienes are the products of the linear conversion pathway. • LTC and LTD – cause hypotension • reduction in coronary blood flow • low concentrations lead to exudation of plasma and vice versa • LTB – chemotactic agent • LTC and LTD – bronchial vasoconstriction (1000x more potent than histamine; also stimulate mucus secretion and edema FLAP Ca2+/ATP ACTIVE 5-lipooxygenase (cytosolic) moves to nuclear membrane INACTIVE PGEs and LTB4 cause pain by sensitizing nerve pain receptors (nociceptors) In general, leukotrienes contract smooth muscle.

  13. The interconversion of leukotrienes involves proteolytic cleavage. LTC4, LTD4, LTE4– mixture has been identified as slow-releasing substance of anaphylaxis LTC4 and LTD4 are bronchoconstrictors and reduce coronary blood flow leading to hypotension (in nanomolar amounts for the latter.

  14. Leukotriene receptor antagonists can be used to control asthma. zifurlukast Accolate® montelukast Singulair® 5-Lipoxygenase inhibitor zileuton (Zyflo®) These are used to treat bronchial constriction in asthma. Obviously there must be specific receptors for all of the eicosanoid subtypes.

  15. Various types of prostaglandin receptors activate or inhibit second messenger systems.

  16. Non Steroidal Anti Inflammatory Drugs (NSAIDs) affect the COX complexes either specifically or nonspecifically. Non-selective COX inhibitors acetylsalicylic acid irreversibly inhibits COX salicylates, propionic acid derivatives, enolic acids(oxicams), others Selective COX-2 inhibitors Celebrex®, Vioxx®, Bextra®

  17. Abortifacients may contain prostaglandins. given with PGE2 and mifepristone (RU-486) PGE1 is used to treat impotence in men and patent ductus arteriosus in neonates. misoprostol (Cytotec®) Other Uses

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