EICOSANOID METABOLISM

EICOSANOIDS C20 polyunsaturated fatty acids e.g. Arachidonic acid Eicosanoids physiologically, pathologically and pharmacologically active compounds PG Prostaglandins TX - Thromboxanes LT - Leukotrienes LX - Lipoxin

STRUCTURE

FUNCTIONS Physiologic:- act as local hormones through G protein linked receptors biochemical effects inflammatory response (calor, rubor, tumor, dolor) gastric integrity renal function smooth muscle contraction (intestine / uterus / bronchus) blood vessel diameter platelet homeostasis Pathologic:- hypersensitivity ( allergic reaction may be fatal)

DIFFERENCE FROM HORMONES Produced in small amounts Produced by all tissues( not in glands) Act locally Not stored Short half life

SYNTHESIS- SUBSTRATE 1. The dietary Essential fatty acids Linoleic (ш 6, 18 C, dienoic fatty acid) and Linolenic acids (ш 6 eicosa trienoic fatty acid) Arachidonic acid 2. Arachidonic acid is found in the plasma membrane phospholipids at C2/ diet 3. Phospholipase A2 causes the hydrolytic release of Arachidonic acid ARACHIDONIC ACID has 20 C and 4 double bonds 20:4 (5,8,11,14)

EICOSANOID SYNTHESIS Dietary precursor is the Essential Fatty acid, linoleic acid (ω6 fatty acid) desaturated elongated Arachidonic acid ( ω6 FA ) membrane bound phospholipids released by Phospholipase A2

SYNTHESIS OF ARACHIDONIC ACID

EICOSANOID SYNTHESIS

2 PATHWAYS FOR ARACHIDONIC ACID 2 pathways compete for Arachidonic substrate:- Cyclo oxygenase PG2, TX2 (Prostanoids) Lipooxygenase LT4, LX4

3 GROUPS OF EICOSANOIDS

CYCLOOXYGENASE PATHWAY Prostaglandin H synthase enzyme (PGH synthase) Enzyme is bound to Endoplasmic reticulum Enzyme has 2 catalytic activities:- (1) Fatty acid cyclooxygenase (COX) requires 2 molecules of Oxygen (2) Peroxidase dependent on reduced Glutathione oxidative cyclization of Arachidonic acid PGH2 variety of PG and TX(PGD, PGE2, PGF2, PGG2, TXA2, PGI2) Each cell type produces only 1 type of prostanoid Cyclooxygenase is a suicide enzyme (self catalyzed destruction PG activity)

OXIDATION AND CYCLIZATION OF ARACHIDONIC ACID

CYCLOOXYGENASE PATHWAY

PGH SYNTHASE ISOZYMES 2 isozymes :- COX 1 and COX 2 1. COX 1 present in most tissues required for healthy gastric tissue, renal homeostasis 2. COX 2 - limited no. of tissues platelet aggregation induced by products of activated immune cells and inflammatory cells Calor, Rubor, Tumor, Dolor of Inflammation

INHIBITION OF PG SYNTHESIS Steroidal anti inflammatory agent ( Cortisol):- Phospholipase A2 Arachidonic acid Non steroidal anti inflammatory agents(nsaids) (Aspirin, Indomethacin, Phenylbutazone, Ibuprofen):- Cyclooxygenase by competing with Arachidonate COX 1 and COX2 PGH2 { Aspirin toxicity systemic inhibition of COX 1 and COX2 damage to stomach and kidneys + blood clotting } { Celecoxib (COX 2 inhibitor) inflammatory process but COX 1 physiologic functions maintained risk of heart attacks ( due to PGI2) }

FUNCTIONS OF PROSTAGLANDINS PGE2 (most tissues) vasodilation relaxation of smooth muscle acid secretion from stomach release of Renin from JG cells uterine contractions labor

FUNCTIONS OF PROSTAGLANDINS PGF2α(most tissues) Vasoconstriction Bronchoconstriction Contraction of smooth muscle Progesterone secretion + regression of Corpus Luteum interrupts early pregnancy + onset of labor termination of pregnancy / Labor

CLINICAL USES OF EICOSANOIDS Induction of labor Prevention of conception Termination of pregnancy Relief of Asthma and nasal congestion Control BP in Hypertension HCl formation in peptic ulcer PGD2 is sleep promoting substance

THROMBOXANES TXA2 is produced by COX-1 in activated platelets adherence+ aggregation of circulating platelets contraction of vascular smooth muscle (vasoconstriction) formation of blood clots(thrombi) PGI2 (Prostacyclin) produced by COX2 in vascular endothelial cells platelet aggregation + vasodilation thrombogenesis Opposing effects of TXA2 and PGI2 thrombi (at site of injury only) Aspirin COX1 TXA2 in platelets( inhibition cant be overcome because of lack of nuclei) COX2 PGI2 in endothelial cells (inhibition can be overcome because of nuclei can generate more enzyme) thrombi risk of stroke / heart attack (by low dose Aspirin)

SYNTHESIS OF THROMBOXANES AND PROSTACYCLINS

LIPOOXYGENASE PATHWAY Lipooxygenases enzymes (LOXs) linear hydroperoxy acids (- OOH) 5 Lipooxygenase converts Arachidonic acid 5-hydroperoxy-6,8,11,14 eicosa tetra enoic acid (5-HPETE) Leucotrienes (4 double bonds) (in leucocytes, platelets and macrophages) mediators of allergic response and inflammation NSAIDS do not affect their synthesis Inhibitors of 5- lipooxygenase and leucotriene receptor antagonists treatment of Asthma

LIPOOXYGENASE PATHWAY

LIPOOXYGENASE PATHWAY Lipoxins:- conjugated tetraenes arising in leucocytes

PHYSIOLOGIC ACTIONS OF LEUKOTRIENES AND LIPOXINS Leukotrienes :- Slow reaction g substance of anaphylaxis (SRS-A) is mixture of Leukotrienes Bronchoconstriction, Inflammatory/ hypersensitivity reaction e.g. Asthma Lipoxins :- Anti inflammatory role i.e. counter regulatory compounds (Chalones) of immune response