Prostaglandins PDF

Lippincott’s illustrated reviews Chapter 18 – Page 219 Lectures 32 Prostaglandins 1  Specific Objectives By the end of this lecture students can be able to: Discuss functions of eicosanoids. Discuss synthetic pathway of all prostaglandins and i...

Lippincott’s illustrated reviews Chapter 18 – Page 219 Lectures 32 Prostaglandins 1  Specific Objectives By the end of this lecture students can be able to: Discuss functions of eicosanoids. Discuss synthetic pathway of all prostaglandins and its regulation. 2  Prostaglandins, and the related compounds thromboxanes and leukotrienes, are collectively known as eicosanoids. Eicosanoids are 20 carbon compounds (Greek, eikosi = twenty), derived from arachidonic acid. Their names are: 1. Prostanoids, containing 1-a. Prostaglandins (PGs); 1-b. Prostacyclins (PGIs); 1-c. Thromboxanes (TXs) 2. Leukotrienes (LTs) 3  They are extremely potent compounds elicit a wide range of responses, both physiologic (inflammatory response) and pathologic (hypersensitivity). They ensure gastric integrity and renal function, regulate smooth muscle contraction (intestine and uterus are key sites) and blood vessel diameter, and maintain platelet homeostasis. Eicosanoids are not stored, and they have an extremely short half-life, being rapidly metabolized to inactive products. 4  Prostaglandins (PGs) They are the most potent biologically active substances; as low as one nanogram/ml of PG will cause smooth muscle contraction. All naturally occurring PGs belong to the 2 series. Prostaglandins are not stored and have very short half life, of about 30 seconds. The effects of prostaglandins on different tissues are different and some of these may oppose each other. Prostaglandins act as local hormones In most tissues, and 5 increases cAMP (cyclic AMP) level.  Synthesis of prostaglandin Prostaglandins are derived from the poly unsaturated fatty acids arachidonic acid which stored in membrane as phospholipids.. The arachidonic acid is released firstly by the action of phospholipase A2 on phospholipids. The next step is the formation of the PGH2, parent of all prostaglandins by oxidative cyclization of free arachidonic acid by PGH synthase 6  PGH synthase is an endoplasmic reticulum membrane- bound protein that has two catalytic activities: 1. Fatty acid cyclooxygenase (COX), which requires two molecules of O2. 2. Peroxidase, which is dependent on reduced glutathione. PGH2 is converted to a variety of prostaglandins and thromboxanes, by cell-specific synthases. 7 8  Regulation of Synthesis: The phospholipase (PL) is activated by epinephrine. Steroids inhibit PL and prevent release of arachidonic acid from membranes. Cyclooxygenase is activated by catecholamines and inhibited by nonsteroid anti-inflammatory drugs (NSAIDs). Aspirin acetylates serine in the active site and irreversibly inhibits the cyclo-oxygenase. 9 10  Biological Action and clinical application Effects on immunity: PGE2 and D2 produce inflammation by increasing capillary permeability. Cortisol and aspirin are strong anti-inflammatory drugs, because they inhibit prostaglandin synthesis. Moreover, PGE2 reduces both T and B cell functions. PGE2 is a sleep promoting substance. 11  Effects of PGs on CVS: (cardiovascular system) Prostacyclin or PGI2 is synthesized by the vascular endothelium. Major effect is vasodilatation. It also inhibits platelet aggregation and has a protective effect on vessel wall against deposition of platelets. Thromboxane (TXA2) is the main PG produced by platelets. The major effects are vasoconstriction and platelet aggregation. Prostacyclin and thromboxane are opposing in activity. 12 Effects on ovary and uterus: PGF2 stimulates the uterine muscles. Hence, PGF2 may be used for medical termination of pregnancy. Induce labor and arresting postpartum hemorrhage. Effects on respiratory tract PGF2 is a constrictor of bronchial smooth muscle; but PGE2 is a potent bronchodilator. PGE2 is used in aerosols for treating bronchospasm. 13 Effects on Gastrointestinal Tract PGs in general inhibit gastric secretion and increase intestinal motility. The inhibitory effect on gastric secretion is used therapeutically in treatment of acid peptic disease. But diarrhea may be an unwanted side effect. Metabolic Effects Prostaglandin PGE2 decreases lipolysis, increases calcium mobilization from bone and glycogen synthesis. 14 Leukotrienes (LTs) They are produced from arachidonic acid. LT B4 is produced in neutrophils; it is the most potent chemotactic agent (factor attracting cells to the inflammatory site). The number 4 denotes that there are 4 double bonds in the structure. They cause smooth muscle contraction, constrict the bronchioles, increase capillary permeability, activate leukocytes and produce vasoconstriction. 15 Lipoxins They are a group of compounds produced by leukocytes. LXA4 is the most common variety. It is anti-inflammatory and decreases immune response. 16 Reference Book: Vasudevan, D. M., Sreekumari, S., and Kannan, V.., 2011. Textbook of biochemistry for medical students, 6th Edition. 17