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Eicosanoids- Chemistry and function

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Eicosanoids- Chemistry and function

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Eicosanoids- Chemistry and function

  1. 1. Eicosanoids- Chemistry and Functions Professor (Dr.) Namrata Chhabra 29-Apr-18 Namrata Chhabra 1
  2. 2. Eicosanoids • Prostaglandins and related compounds are collectively known as Eicosanoids. • Most are produced from Arachidonic acid, a 20-carbon polyunsaturated fatty acid (5,8,11,14-eicosatetraenoic acid). 29-Apr-18 Namrata Chhabra 2
  3. 3. Eicosanoids- Classification Eicosanoids Prostanoids Prostaglandins Prostacyclins Thromboxanes Leukotrienes Lipoxins 29-Apr-18 Namrata Chhabra 3
  4. 4. Characteristic structural features of prostaglandins 1) A trans double bond is present between 13th and 14th carbon atom 2) An alpha oriented -OH group is present at 15th position 3) Differences in the main groups are due to difference in structure of cyclopentane ring. 29-Apr-18 Namrata Chhabra 5
  5. 5. Prostaglandins(PGs) Prostaglandins (PGs) PG- F PG- A PG- B PG-C and DPG-E PG- G and H 29-Apr-18 Namrata Chhabra 6
  6. 6. Series of prostaglandins • There are 3 series of prostaglandins: • Series-1 contain one double bond at 13-14 position (Trans) • Series-2 have two double bonds at 13-14 (trans) and 5-6 (Cis) • Series-3 – have three double bonds at 13-14 (trans) , 5-6 (Cis) and 17-18 (Cis) positions. 29-Apr-18 Namrata Chhabra 7
  7. 7. Series of prostaglandins 29-Apr-18 Namrata Chhabra 8
  8. 8. Types of Prostaglandins • PG-E: PGE1,PGE2 and PGE3 • PG-F: PGF1α,PGF2αand PGF3α • PG-A: PGA1,PGA2 and PGA3 • PG-B: PGB1,PGB2 ,19-OH-PGB1and 19-OH-PGEB2 29-Apr-18 Namrata Chhabra 9
  9. 9. Synthesis of Eicosanoids 29-Apr-18 Namrata Chhabra 10
  10. 10. Sources of Arachidonic acid 29-Apr-18 Namrata Chhabra 11
  11. 11. Release of Arachidonic acid Release of Arachidonic acid Activation of phospholipase A2 Binding of ligand to cell surface 29-Apr-18 Namrata Chhabra 12
  12. 12. Steps of synthesis of Prostanoids • Pathway is also called Cyclo- oxygenase pathway or cyclic pathway. • The type of prostanoid produced is determined by which downstream enzyme is present • Usually one downstream enzyme predominates in a given cell. 29-Apr-18 Namrata Chhabra 14
  13. 13. PGH synthase Isoforms • Each PGHS isoform catalyzes two separate reactions. 1) The first reaction (Arachidonate to PGG2) involves insertion of two molecules of oxygen and Cyclization of the fatty acid backbone. • This step is catalyzed by the cyclo-oxygenase activity of PGHS-1 or -2; it is these cyclo- oxygenase activities (also called COX-1 and COX-2) that are inhibited by nonsteroidal anti- inflammatory drugs (NSAIDs). 29-Apr-18 Namrata Chhabra 15
  14. 14. PGH synthase Isoforms 2) The second step (PGG2 to PGH2) involves the reduction of the hydro peroxide on C15 to an alcohol and is catalyzed by the peroxidase activity of PGHS-1 or -2. 29-Apr-18 Namrata Chhabra 16
  15. 15. Significance of PGH synthase isoforms There are two isoforms- PGH Synthase 1 and 2 PGH Synthase 1 – Basal form(constitutive) Many cells, including platelets and gastric mucosal cells, have moderate levels of the “basal” isoform, PGHS-1. Functions attributed to PGHS-1 include: • Regulating hemostasis and vascular tone, • Renal function, and Maintaining gastric mucosal integrity. 29-Apr-18 Namrata Chhabra 17
  16. 16. Significance of PGH synthase isoforms • PGH Synthase 2- Inducible form Present in a smaller number of cells, such as macrophages, vascular endothelial cells, and fibroblasts. • Participate in cell proliferation, inflammation, carcinogenesis, and parturition. PGHS-2 are induced in response to cytokines or mitogens. 29-Apr-18 Namrata Chhabra 18
  17. 17. Catabolism of Prostaglandins • All Arachidonic acid derivatives are quickly inactivated in the body by : • Self-catalyzed destruction of cyclooxygenase ("suicide enzyme”). • 15-hydroxyprostaglandin dehydrogenase. The OH group present at 15th position is changed to a keto group. 29-Apr-18 Namrata Chhabra 19
  18. 18. Characteristic features of prostaglandins 1) Act as local hormones. 2)Show the effects near the site of synthesis(autocrine and Paracrine effects) 3) Are not stored in the body 4) Have a very short life span and are destroyed within seconds or few minutes. 29-Apr-18 Namrata Chhabra 20
  19. 19. Characteristic features of prostaglandins (contd.) 5) Production increases or decreases in response to diverse stimuli or drugs. 6) Are very potent in action. Even in minute (nanogram concentration), biological effects are observed. PGs Local hormones Not stored Short lifespan Stimulus based production Potent Required in small amounts 29-Apr-18 Namrata Chhabra 21
  20. 20. Physiological roles of Prostaglandins 1) Inflammation i) Fever- PGs induce fever by stimulating the thermoregulatory center in the brain. ii) Pain- PGs sensitize pain receptors to stimulation, as a result increase pain perception. iii) Swelling-There is vasodilatation and increased capillary permeability induced by PGS which is responsible for swelling of the inflamed tissue. iv Erythema, wheal and Flare is also induced by PGs like PGE and PGD2. v) PGD2 is considered an important mediator of anaphylaxis 29-Apr-18 Namrata Chhabra 22
  21. 21. Effect on smooth muscle Intestinal Bronchial Vascular Uterine PGE and PGF produce contraction of the longitudinal smooth muscles producing diarrhea, cramps and reflux of bile. Clinical significance- Diarrhea and abdominal cramps are the commonly observed as side effects of PGs. PGFs contract and PGEs relax bronchial smooth muscles. Clinical significance- PGE1 and PGE2 are therapeutically used as bronchodilators. PGEs cause vasodilatation. PGF2 α , and PG A2 cause vasoconstriction. Clinical significance- Systemic blood pressure falls in response to PGEs and PGAs PGE1, PGE2 and PGF2α cause uterine contractions. Clinical significance- • PGE2 is used for the induction of labor at or near term. • In higher dosage PGEs are used as abortifacients in first and second trimester of pregnancy. • They are also responsible for causing dysmenorrhea. 29-Apr-18 Namrata Chhabra 23
  22. 22. Effect on platelets • PGE1 cause inhibition of platelet aggregation. • Clinical significance- PGE1 has been used for harvesting and storage of blood platelets for therapeutic transfusion. 29-Apr-18 Namrata Chhabra 24
  23. 23. Effect on Kidney • PGEs cause: • ↑ in renal plasma flow, • ↑GFR, • ↑diuresis, • Natriuresis, and • kaliuresis is also induced by the action of PGE2 29-Apr-18 Namrata Chhabra 25
  24. 24. Effect on Gastrointestinal secretions • PGE1and E2 inhibit gastric secretions and are required for maintaining the integrity of gastric mucosa. • The effect is opposite on the pancreatic and intestinal secretions. There is increase in the volume, enzyme and electrolyte content of the pancreatic and intestinal secretions in response to PGE1. • Watery diarrhea results in response to administration of PGE1. 29-Apr-18 Namrata Chhabra 26
  25. 25. Effect on Endocrine glands • PGEs have insulin like effects, They inhibit lipolysis and the effects on carbohydrate metabolism are same as insulin • PTH(Parathormone) like effects are also seen on bone metabolism by PGs. They mobilize calcium from bones producing hypercalcemia. • Thyrotropin like effects-are seen on thyroid gland. • Steroidogenic effects are seen on the adrenal tissue.es 29-Apr-18 Namrata Chhabra 27
  26. 26. Immunological Response • PGEs secreted by macrophages : • modulate or decrease the functions of • T and B lymphocytes . 29-Apr-18 Namrata Chhabra 28
  27. 27. Clinical role of PGs Tissue growth Inflammation And fever Regulation of sleep wake cycles Regulation of blood pressure Blood clotting Immune system modulation Reproductive processes 29-Apr-18 Namrata Chhabra 29
  28. 28. Prostacyclins and Thromboxanes 1)Prostacyclins(PGI) contain another ring between 6 th and 9th carbon atoms. 2) Thromboxanes (TX) have a six membered Oxane ring. There are three series for Thromboxanes as well as for Prostacyclins. 29-Apr-18 Namrata Chhabra 30
  29. 29. Functions of Prostacyclins • Synthesized in heart and vascular endothelial cells. • Inhibit platelet and leukocyte aggregation • Decrease T-cell proliferation ,lymphocyte migration and secretion of IL-1α and IL-2 • Induce vasodilatation and production of cAMP • Prevent clot formation. 29-Apr-18 Namrata Chhabra 31
  30. 30. Functions of Thromboxanes • Synthesized by platelets, • Induce platelet aggregation, • Promote vasoconstriction, • Lymphocyte proliferation • Bronchoconstriction and • Promote clot formation 29-Apr-18 Namrata Chhabra 32
  31. 31. Inhibitors of Prostanoids synthesis 1) Corticosteroids act as anti-inflammatory agents because they inhibit Phospholipase A2 expression, reducing arachidonate release. 29-Apr-18 Namrata Chhabra 33
  32. 32. Inhibitors of Prostanoids synthesis 2)Non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin and derivatives of ibuprofen inhibit : • Cyclooxygenase activity of PGH Synthase. • Formation of prostaglandins involved in fever, pain, & inflammation. • Blood clotting by blocking thromboxane formation in platelets. • Most NSAIDs inhibit both COX I & COX II. 29-Apr-18 Namrata Chhabra 34
  33. 33. Inhibitors of Prostanoids synthesis 3)Selective COX-2 inhibitors - Celecoxib and Rofecoxib. • coxibs very useful for anti- inflammatory and antiproliferative therapy with reduced gastrointestinal side effects, • it also makes them ineffective as antiplatelet agents and consequently can increase cardiovascular risks. 29-Apr-18 Namrata Chhabra 35
  34. 34. Leukotrienes • Identified as LTs. • A family of conjugated trienes formed in leukocytes, platelets, and macrophages by the lipoxygenase pathway in response to both immunologic and nonimmunologic stimuli. 29-Apr-18 Namrata Chhabra 36
  35. 35. Lipoxins • Lipoxins are a family of conjugated tetraenes also arising in leukocytes. • They are formed by the combined action of more than one lipoxygenase. 29-Apr-18 Namrata Chhabra 37
  36. 36. Steps of synthesis of Leukotrienes 29-Apr-18 Namrata Chhabra 38
  37. 37. Steps of Synthesis of Lipoxins 29-Apr-18 Namrata Chhabra 39
  38. 38. Functions of Leukotrienes • Leukotrienes have roles in inflammation. • They are also implicated in asthmatic constriction of the bronchioles. • The peptidoleukotrienes, LTC4, LTD4 and LTE4 are components of slow-reacting substance of anaphylaxis (SRSA). (The subscript 4 in each molecule refers to the number of carbon- carbon double bonds presen. 29-Apr-18 Namrata Chhabra 40
  39. 39. Slow-reacting substance of anaphylaxis (SRS-A) • Slow-reacting substance of anaphylaxis (SRS-A) is a mixture of leukotrienes C4, D4, and E4. • This mixture is a potent constrictor of the bronchial airway musculature. • These leukotrienes together with leukotriene B4 also cause vascular permeability, • Chemotaxis and activation of leukocytes and • are important regulators in many diseases involving inflammatory or immediate hypersensitivity reactions, such as asthma. 29-Apr-18 Namrata Chhabra 41
  40. 40. Reason for Aspirin induced Asthma • Aspirin inhibits the COX pathway and diverts arachidonic acid metabolites to the LO pathway. • This also leads to a decrease in the levels of PGE2, the anti- inflammatory PG. • LTC4 synthase overexpression further increases the number of cysteinyl LTs, tilting the balance toward inflammation and broncho constriction 29-Apr-18 Namrata Chhabra 42
  41. 41. Reason for Aspirin induced Asthma 29-Apr-18 Namrata Chhabra 43
  42. 42. Pharmacological applications of Eicosanoids 1)Cardiovascular uses: • Pulmonary arterial hypertension, • Peripheral vascular disease • Patency of ductus arteriosus until surgery in neonates with cardiac malformations and • Platelet anti-aggregating agents. 29-Apr-18 Namrata Chhabra 44
  43. 43. Pharmacological applications of Eicosanoids 2) Digestive Uses- indicated in the treatment of : • Gastro duodenal ulcer and • Prevention of NSAID-induced ulcers. 29-Apr-18 Namrata Chhabra 45
  44. 44. Pharmacological applications of Eicosanoids 3) Gynecological and obstetrical uses – • Induce cervical dilatation • Induce uterine contractions, particularly in late pregnancy. • Used for medical termination of pregnancy and induction of labor. 29-Apr-18 Namrata Chhabra 46
  45. 45. Pharmacological applications of Eicosanoids 6) Ulcerative Colitis Mesalamine also called mesalazine or 5 aminosalicyclic acid has anti inflammatory properties in the colon and is used in the treatment of ulcerative colitis (Crohn's disease). In addition to cyclo-oxygenases, it also inhibits lipoxygenases. 7)Bronchial Asthma- PGE2 agonists and leukotrienes receptor antagonists are used for the treatment of bronchial asthma. 29-Apr-18 Namrata Chhabra 47
  46. 46. Summary 29-Apr-18 Namrata Chhabra 48
  47. 47. Thank you 29-Apr-18 Namrata Chhabra 49

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