Prostaglandins & Related compounds

EICOSANOIDS Compounds that originate from polyunstaurated fatty acids with 20 carbons Prostaglandins (PG) Prostaglandins (PG) Thromboxanes (TX) Thromboxanes (TX) Leukotrienes (LT) Leukotrienes (LT)

Eicosanoids Eicosanoids cont. Potent Potent compounds Their action mediated by plasma & nuclear receptors not not stored in tissues short half-life Have extremely short half-life (rapidly metabolized) Eicosanoids Differ from true hormones in that they: bothphysiologicpathologic Elicit both physiologic & pathologic responses very small amounts Produced in very small amounts all tissues In almost all tissues (not by a specialized glands) Act locally Act locally (not transported in blood to distant sites)

Synthesis of Prostaglandins (PG) & Thromboxanes (TX) Dietcell membrane PL (esp. PI) Diet cell membrane PL (esp. PI) linoleic acid linoleic acid (18 carbons, 2 double bonds) elongation & desaturation Arachidonic acid (20 carbons, 4 double bonds) PG & TX Sources of arachidonic acid: Sources of arachidonic acid: Dietary linoleic acid 1- Dietary linoleic acid Phospholipids of cell membrane : by phospholipase A2 2- Phospholipids of cell membrane : by phospholipase A2

Synthesis of PGH 2 Arachidonic acid is subject to oxidative cyclization by prostaglandin endoperoxidase synthase to yield PGH 2 Prostaglandin endoperoxidase synthase has 2 catalytic activities: COX 1- COX (cycoloxygenase) peroxidase 2- peroxidase PGH 2 variety of PGs & TXs PGH 2 is converted to a variety of PGs & TXs

COXPeroxidase PGH 2 Linoleic acid In diet Arachidonic acid COX-1Peroxidase PG & TX Synthesis of PG & TX

Isozymes of PG endoperoxidase synthase COX-1 constitutively synthesis in most tissues required to healthy Maintain healthy gastric tissue, renal homeostasis Physiological Role & platelet aggregation ( Physiological Role ) COX-2 inducible in a limited number of cells in response to inflammation (substances from inflam.cells) Resulting in increased PG synthesis causing pain, heat, redness & swelling of inflammation inflammation & fever in infection ( Pathological Role ) ( Pathological Role )

Inhibition of Prostaglandins Synthesis Steroidal anti-inflammatory agent 1- Steroidal anti-inflammatory agent (as CORTISOL ) Inhibits phospholipase A 2 activity 1- Cortisol Inhibits phospholipase A 2 activity So, the precursor arachidonic acid is not available inhibits COX-2 not 2- Cortisol inhibits COX-2 (but not COX-1)

2- All non-steroidal anti-inflammatory agents (as aspirin, indomethacin & phenylbutazone) (as aspirin, indomethacin & phenylbutazone) COX-2 Inhibits COX-2 So, prevent synthesis of PGH 2 (anti inflammatory) BUT BUT: COX-1 They also inhibit COX-1 with subsequent (aspirin's toxicity): Damage to stomach & kidneys Impaired clotting of blood 3- Inhibitors of COX-2 (as celecoxib) COX-1 Maintain the physiologic functions of COX-1 (no inhibition of COX-1) COX-2 While having anti-inflammatory power (inhibition of COX-2) BUT BUT: Their use has been associated with increased risk of heart attacks Inhibition of Prostaglandins Synthesis

Role of PG in Platelet Homeostasis Thromboxane A 2 (TXA 2 ) Thromboxane A 2 (TXA 2 ) produced by activated platelets promotes adherence & aggregation of platelets thrombotic So, promotes formation of blood clots (thrombotic) Prostacyclin (PGI 2 ) Prostacyclin (PGI 2 ) produced by vascular endothelial cells inhibits platelet aggregation anti thrombotic So, prevents formation blood clots (anti thrombotic)

In platelets As aspirin inhibits TXA2 production in platelets by irreversible inhibition of COX-1 as platelets can not synthesize more COX-1 (no nucleus) So, TXA2 synthesis is permanently inhibited in platelets In endothelium Although COX-1 is inhibited also in endothelium. However, this is not permanent as more COX-1 can be synthesized (endothelium is nucleated) So, prostacyclin synthesis is not inhibited in endothelium Basis of : Low-dose aspirin therapy To avoid risk of stroke & heart attacks (by decreasing formation of thrombi) Aspirin has Antithrombogenic Effect