prostaglandins & related compounds. eicosanoids compounds that originate from polyunstaurated...
DESCRIPTION
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)TRANSCRIPT
Prostaglandins &Related compounds
EICOSANOIDS
Compounds that originate from polyunstaurated fatty acids with 20 carbons
• Prostaglandins (PG)• Thromboxanes (TX)• Leukotrienes (LT)
Eicosanoids cont.
• Potent compounds• Their action mediated by plasma & nuclear receptors• not stored in tissues• Have extremely short half-life (rapidly metabolized)
Eicosanoids Differ from true hormones in that they:
• Elicit both physiologic & pathologic responses
• Produced in very small amounts • In almost all tissues (not by a specialized glands)
• Act locally (not transported in blood to distant sites)
Synthesis of Prostaglandins (PG) & Thromboxanes (TX)
Diet cell membrane PL (esp. PI) linoleic acid (18 carbons, 2 double bonds) elongation & desaturation
Arachidonic acid (20 carbons, 4 double bonds)
PG & TX Sources of arachidonic acid: 1- Dietary linoleic acid 2- Phospholipids of cell membrane : by phospholipase A2
Synthesis of PGH2
• Arachidonic acid is subject to oxidative cyclization by prostaglandin endoperoxidase synthase
to yield PGH2
• Prostaglandin endoperoxidase synthase has 2 catalytic activities:
1- COX (cycoloxygenase) 2- peroxidase
• PGH2 is converted to a variety of PGs & TXs
COX
Peroxidase
PGH2
Linoleic acidIn diet
Arachidonic acid
COX-1
Peroxidase
PG & TX
Synthesis of PG & TX
Isozymes of PG endoperoxidase synthase
COX-1
• constitutively synthesis
• in most tissues• required to
Maintain healthy gastric tissue, renal homeostasis & 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 & fever in infection
(Pathological Role)
Inhibition of Prostaglandins Synthesis
1- Steroidal anti-inflammatory agent (as CORTISOL)
1- Cortisol Inhibits phospholipase A2 activity So, the precursor arachidonic acid is not available
2- Cortisol inhibits COX-2 (but not COX-1)
2- All non-steroidal anti-inflammatory agents (as aspirin, indomethacin & phenylbutazone)
• Inhibits COX-2 So, prevent synthesis of PGH2 (anti inflammatory)
• BUT: 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) • Maintain the physiologic functions of COX-1 (no inhibition of COX-1)• While having anti-inflammatory power (inhibition of COX-2)• BUT: Their use has been associated with increased risk of heart attacks
Inhibition of Prostaglandins Synthesis
Role of PG in Platelet Homeostasis
• Thromboxane A2 (TXA2)
produced by activated platelets promotes adherence & aggregation of platelets So, promotes formation of blood clots (thrombotic)
• Prostacyclin (PGI2)
produced by vascular endothelial cells inhibits platelet aggregation So, prevents formation blood clots (anti thrombotic)
In plateletsAs aspirin inhibits TXA2 production in platelets by irreversible inhibition of COX-1as platelets can not synthesize more COX-1 (no nucleus)So, TXA2 synthesis is permanently inhibited in platelets
In endotheliumAlthough 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