Eicosanoids PDF

The Eicosanoids and other fatty acids (Inflammatory and Pain Mediators) Deepak Gupta, PhD, RPh Learning Objectives Introduction to inflammation Acute vs chronic Chemical mediators of inflammation Eicosanoids and others Eicosanoids Enzymatic pathway to...

The Eicosanoids and other fatty acids (Inflammatory and Pain Mediators) Deepak Gupta, PhD, RPh Learning Objectives Introduction to inflammation Acute vs chronic Chemical mediators of inflammation Eicosanoids and others Eicosanoids Enzymatic pathway to synthesize eicosanoids Cyclooxygenase (COX-1, COX-2) Pathophysiological Implications Prostaglandins, Thromboxanes and Leukotrienes Sources and Functions Pharmacological Effects Clinical Uses Drug Targets Clinical Applications Role in Gout 2  What causes inflammation? Pathogens Cystitis Rheumatoid arthritis External injuries like scrapes Inflammatory bowel Bronchitis diseases Chemicals or radiation Dermatitis Ulcerative colitis Asthma Gout Is there any immune component involved? 3 Inflammation and the immune system Closely intertwined Inflammation is composed of a complex web of responses to tissue injury and infection The immune system includes the cells and soluble factors (antibodies and complement proteins) mediate the inflammatory response; eliminate the inciting inflammatory stimulus and initiate immunologic memory. 4 Inflammation: Overview 5 Inflammation: Body’s response to injury, pathogen invasion, or necrosis Meant to destroy the invader and repair damage (what if self-antigen?) Autoimmune conditions: auto-antibodies Immunological components--specific and non- specific Persisting inflammation = tissue damage 6 Inflammation: Hallmarks Inflammation Calor Dolor Rubor Tumor (warmth) (pain) (redness) (swelling) Elevated cellular metabolism (various factors) and mediators of inflammation------ Fever Stimulation of nociceptors------ Pain Vasodilation ----↑ blood flow-----Redness Extravasation of fluid &  permeability-----Swelling 7  Types of Inflammation Acute Chronic Initial response to tissue Sustained and inappropriate injury or infection response to inflammatory Involvement of innate stimulus (pathogens, self- immunity antigens) Accumulation of neutrophils Predominant accumulation of (mostly) macrophages Release of autacoids Involvement of adaptive (histamine, bradykinin, immunity (lymphocytes) prostaglandins, leukotrienes), cytokines and chemokines Implicated in autoimmune Self-limited process disease and organ plant rejections 8 Chemical Mediators of Inflammation Molecular mediators of inflammatory process and their signal transduction components are potential pharmacological targets. Endogenous mediators of inflammation and immunity, in some instances, overlap (e.g., cytokines) Wide range of molecules-histamine, complement components, eicosanoids, cytokines, and other agents. 9 Chemical Mediators of Inflammation I. Cytokines/Chemokines: IL-1, TNF-α, others II. Membrane-Derived Lipid Mediators Prostaglandins (PG) Leukotrienes (LT) Eicosanoids Thromboxanes and Others III. Produced through degranulation Histamine Heparin Serotonin Proteases 10  Eicosanoids “Eicosa” Greek word for twenty Derived from arachidonic acid 20 carbon polyunsaturated fatty acid) Eicosanoids: Prostaglandins (PG) Thromboxanes (TX) Leukotrienes (LT) Eicosanoids- pro-inflammatory and anti-inflammatory Short half-lives, local effects only Diverse physiological functions 11  Eicosanoids: Chemical Mediators of Inflammation and pain Vasodilation Prostaglandins (PGI2, PGE1, PGE2, PGD2) Increased vascular Leukotrienes (LTC4, LTD4,LTE4) permeability Chemotaxis and Leukotrienes (LTB4) leukocyte activation Pain Prostaglandins (PGE2, PGI2) 12 Eicosanoids-Overview 13 Eicosanoids-Overview Arachidonic acid-derived autocoids Involved in: ▪ Inflammatory conditions Major Diseases: ▪ Autoimmune diseases Gout ▪ Glomerulonephritis Rheumatoid arthritis Osteoarthritis ▪ Cancer Asthma ▪ Sleep disorders Other Autoimmune ▪ Alzheimer’s disease conditions Inflammatory bowel disease (IBD) 14  Eicosanoids: Overview Phospholipase A2 (PLA2) PLA2 is associated with receptors for various ligands (eg. IL-1, TNF-α) Ligand binding causes PLA2 activation 15  Eicosanoids Inflammation Other PGs like D2, E2, F2α, I2 and also TXA2 COX-1 COX-2 Lipooxygenase PGs: 20 carbon atoms, LTB4, LTC4, LTD4, LTE4 including a 5-carbon16 ring  Eicosanoids PGs TXs LTs Synthesis Synthesis Enzymes-COX-1 and COX-2 Enzyme- Properties and functions lipoxygenase Properties and functions 17  Eicosanoids PGs and Txs Inflammation Other PGs like D2, E2, F2α, I2 and also TXA2 COX-1 COX-2 PGs: 20 carbon atoms, including a 5-carbon18 ring  Cyclooxygenase Glycosylated, homodimeric, membrane bound, heme-containing enzymes. Leads to the formation of prostaglandins, prostacyclin, and thromboxanes Two major isoforms: cyclooxygenase-1 (COX-1) and cyclooxygenase- 2 (COX-2). Differ in cellular localization, tissue expression, and substrate requirement as well as in physiologic, pathologic, and pharmacological profiles. 19  Two forms of Cyclooxygenases Cox-1 Cox-2 Housekeeping functions (no Induced during inflammation induction) (by proinflammatory – vascular homeostasis, cytokines: TNF-a, IL-1, IL-2, regulation of renal and EGF, IFN-g) GI blood flow, intestinal proliferation, renal Constitutive expression in function, brain, kidneys, endothelial Expressed constitutively cells (Expressed in stomach?) -gastric mucosa -kidneys Pro-inflammatory role -platelets Pharmacologically inhibited -endothelial cells by NSAIDs and COX-2 Can be pharmacologically selective inhibitors inhibited (low dose aspirin) 20  Pathophysiological Implications Cox-1 Cox-2 GI functions, Intestinal Pro-inflammatory role mucosal proliferation, Fever renal flow Pain Altered functions Transduction of pain signal in the spinal cord Platelet function GI mitogenesis Bleeding risk Renal adaptation to Anti-thrombogenesis stresses with aspirin Ovulation, placentation, and uterine contraction of labor 21  Eicosanoids Inflammation Other PGs like D2, E2, F2α, I2 and also TXA2 COX-1 COX-2 Lipooxygenase PGs: 20 carbon atoms, LTB4, LTC4, LTD4, LTE4 including a 5-carbon22 ring PGs: Overview Share a chemical structure, called prostanoid. Three major groups: PG1, PG2, and PG3 (based on number of double bonds). PG2 most prevalent (PGH2, PGD2, PGE2, PGF2α). PGH2 serves as the precursor of PGD2, PGE2, PGF2α, PGI2, and thromboxane A2). Production of a specific PG is dependent on cell-specific enzymes PGs have short half-lives-Act locally 23  PGs: Roles Play an important role in the development of pain, inflammation, and fever. Released from cells in response to chemical stimuli or physical trauma to perform local action. Able to sensitize sensory nerves to nociceptive stimuli and thereby amplify pain signals. Promote tissue inflammation by stimulating inflammatory cell chemotaxis, causing vasodilation and increasing capillary permeability, and edema. 24 PGs and TXs: Sources and Functions Prostaglandin/ Major source Major actions(s) thromboxane type PGE2 Many tissues Protection of gastric mucosa, Macrophages vasodilation, hyperalgesia, and mast cells Cytoprotective (GI), acid secretion (GI), mucus formation PGD2 Mast cells Vasodilation, inhibition of platelet Neurons activation, sleep, Alzheimer’s disease PGF2α Vascular smooth Vascular tone muscles Reproductive physiology Uterine smooth Bronchoconstriction muscles PGI2 Endothelial cells Vasodilation, inhibition of platelet (prostacyclin) activation TxA2 Platelets Vasoconstriction, bronchoconstriction, (thromboxane) platelet aggregation 25  Eicosanoids PGs TXs LTs Synthesis Synthesis Enzymes-COX-1 and COX-2 Enzyme- Properties and functions lipoxygenase Properties and functions 26  Eicosanoids Inflammation Other PGs like D2, E2, F2α, I2 and also TXA2 COX-1 COX-2 Lipooxygenase PGs: 20 carbon atoms, LTB4, LTC4, LTD4, LTE4 including a 5-carbon 27 ring LTs: Overview Leukotrienes are synthesized from arachidonic acid by lipoxygenases. Leukotrienes include: LTA, LTB4, LTC4, LTD4, LTE4 LTC4, LTD4, and LTE4 are potent bronchoconstrictors. 28 LTs: Roles and Functions 5-Lipoxygenase LTC4 LTD4 LTE4 Bronchoconstriction 29 Eicosanoids: Clinical Uses 30 Eicosanoids: Clinical Uses Tromethamine Oprostenol Dinoprostone Lubiprostone Bimatoprost Treprostinil Misoprostol Carboprost Alprostadil Latonprost Travoprost Iloprost, PGE1 based PGE2 PGF2α based PGI2 based based Erectile NSAID- Irritable Abortion Glaucoma Abortion primary dysfunc related bowl induction induction (2nd pulmonary tion gastric syndrom (2nd trimester) hypertensi ulcers e with trimester) on constipati on Patent 1st Labor Ocular Postpartum Pulmonary ductus trimester induction hypertens hemorrhage hypertensi arterios abortion at term ion on in us patients with heart failure 31 Drug Targets for inflammation 32  PLA2 Drug Targets COX-1 COX-2 Lipooxygenase LTB4, LTC4, LTD4, LTE4 Other PGs like D2, Inflammation E2, F2α, I2 and also TXA2 PLA2 inhibition: Corticosteroids Lipooxygenase inhibitors: Zileuton LT antagonists: Montelukast and Zafirlukast COX-1 vs COX-2 inhibition: NSAIDs TXA2 synthesis inhibitor: Aspirin 33 Drug Targets for inflammation Clinical Uses 34  Drug Targets for inflammation: Clinical Uses Corticosteroids NSAIDs Zileuton Zafirlukast and Montelukast Asthma Inflammation Mild to Mild to Arthritis Pain moderate moderate Allergies fever Asthma Asthma Gout Lupus Other immune conditions 35  SUMMARY Eicosanoids Inflammation Other PGs like D2, E2, F2α, I2 and also TXA2 COX-1 COX-2 Lipooxygenase PGs: 20 carbon atoms, LTB4, LTC4, LTD4, LTE4 including a 5-carbon36 ring Food for thought! Gout is characterized by pain and inflammation (due to deposition of uric acid crystals). Which of the following group of drugs can be useful for Gout? A. NSAIDs B. Steroids C. Montelukast D. PGE1 based drugs 37