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