PROSTAGLANDINS

PROSTAGLANDINS

1. P rostaglandins Gandham . Rajeev Email:[email protected]

2. Postaglandins & their related compounds prostacyclins ( PGI), thromboxanes (TXA), leukotrienes (LT) & lipoxins are collectively known as eicosaniods , they all contain 20C. Structure of prostaglandins: Prostaglandins are derivatives of 20-carbon fatty acid - prostanoic acid, hence known as prostanoids.

3. This has a cyclopentane ring (formed by carbon atoms 8 to 12) & two side chains, with carboxyl group on one side. Prostaglandins differ in their structure due to substituent group & double bond on cyclopentane ring. Most important prostaglandins (PGF2 & PGF2 α ), prostacyclins ( PGI2 ), thromboxanes (TXA2) & leukotrienes ( LTA4).

4. P rostaglandins

5. Arachidonic acid ( 5,8,11,14 - eicosatetraenoic acid) is the precursor for most of the prostaglandins in humans. It occurs in the endoplasmic reticulum. Release of arachidonic acid from membrane bound phospholipids by phospholipase A2. It occurs due to a specific stimuli by hormones – epinephrine or bradykinin . Synthesis of prostaglandins

6. Oxidation & cyclization of arachidonic acid to PGG2 which is then converted to PGH2 by peroxidase. PGH2 serves as the immediate precursor for the synthesis of a number of prostaglandins , including prostacyclins & thromboxane. This is known as cyclic pathway of arachidonic acid.

7. Synthesis of prostaglandins

8. Cyclooxygenase Cyclooxygenase – a suicide enzyme. Prostaglandin synthesis can be partly controlled by suicidal activity of the enzyme cyclooxygenase. This enzyme is capable of undergoing self- catalysed destruction to switch off PG synthesis.

9. Corticosteroids (e.g. cortisol) prevent the formation of arachidonic acid by inhibiting the enzyme phospholipase A2. Anti-inflammatory drugs inhibit the synthesis of prostaglandins, prostacyclins & thromboxane. They block the action of cyclooxygenase. Aspirin irreversibly inhibits cyclooxygenase. Inhibition of PG synthesis

10. All the eicosanoids are metabolized rapidly. Degradation occur in lung & liver. Two enzymes, namely 15- α - hydroxy PG dehydrogenase & 13-PG reductase , convert hydroxyl group at C15 to keto group & then to C13 and C14 dihydroderivative. Degradation of prostaglandins

11. Prostaglandins act as local hormones. PGs are produced in almost all the tissues. PGs are not stored & they are degraded to inactive products at the site of their production. PGs are produced in very small amounts & have low half-lives. Biochemical actions of prostaglandins

12. Regulation of blood pressure: The prostaglandins ( PGE , PGA & PGl2 ) are vasodilator in function. This results in increased blood flow and decreased peripheral resistance to lower the blood pressure. PGs serve as agents in the treatment of hypertension.

13. Inflammation: PGEI & PGE2 induce the symptoms of inflammation (redness, swelling, edema etc.) due to arteriolar vasodilation. PGs are natural mediators of inflammatory reactions of rheumatoid arthritis, psoriasis, conjunctivitis etc . Corticosteroids are used to treat these inflammatory reactions , since they inhibit prostaglandin synthesis.

14. Reproduction: PGE2 & PGF2 are used for the medical termination of pregnancy & induction of Iabor . Pain and fever: P yrogens (fever producing agents) promote prostaglandin synthesis leading to the formation of PGE2 in hypothalamus-regulation of body temperature. PGE2 along with histamine & bradykinin cause pain. Migraine is also due to PGE2. Aspirin & other non-steroidal drugs inhibit PG synthesis & thus control fever & relieve pain.

15. Regulation of gastric secretion: Prostaglandins ( PGE ) inhibit gastric secretion. PGs are used for the treatment of gastric ulcers. PGs stimulate pancreatic secretion & increase the motility of intestine which often causes diarrhea. Influence on immune system: Macrophages secrete PGE which decreases the immunological functions of B-& T-lymphocytes.

16. Effects on respiratory function: PGE is a bronchodilator whereas PGF acts as a constrictor of bronchial smooth muscles. PGE & PGF oppose the actions of each other in the lungs . PGEI & PGE2 are used in the treatment of asthma.

17. Influence on renal functions: PGE increases glomerular filtration rate & promotes urine output. Excretion of Na + & K + is also increased by PGE . Effects on metabolism: Prostaglandins influence certain metabolic reactions, through the mediation of cAMP . PGE decrease lipolysis, increases glycogen formation & promotes calcium mobilization.

18. Platelet aggregation & thrombosis: The prostaglandins – prostacyclins ( PGI2), inhibit platelet aggregation. Thromboxanes (TXA2) & prostaglandin E2 promote platelet aggregation & blood clotting that might lead to thrombosis. Mechanism of action of PGs: PGE increases cAMP & PGF increases cGMP .

19. Biomedical applications of PGs They are used in the treatment of gastric ulcers, hypertension , thrombosis , asthma etc. Prostaglandins are also employed in the medical termination of pregnancy , prevention of conception, induction of labor etc.

20. Leukotrienes are synthesized by leucocytes, mast cells, lung, heart, spleen etc., by lipoxygenase pathway of arachidonic acid. Leukotrienes (A4, B4 , C4, D4 & E4) are synthesized through the intermediate, 5-hydroperoxyeicosatetraenoic acid ( 5-HPETE). Leukotrienes

21. Synthesis of leukotrienes

22. Leukotrienes (C4, D4 & E4) are components of slow-reacting substances of anaphylaxis (SRS-A), released after immunological challenge. SRS-A is 100 -1,000 times more potent than histamine or prostaglandins in its action as a stimulant of allergic reactions. Leukotrienes are implicated in asthma, inflammatory reactions, hypersensitivity (allergy) and heart attacks.

23. Leukotrienes cause contraction of smooth muscles, bronchoconstriction, vasoconstriction, adhesion of white blood cells & release of lysosomal enzymes. Lipoxins are involved in vasoactive & immunoregulatory functions.

24. Textbook of Biochemistry – U Satyanarayana References

25. Thank You