1. PROSTAGLANDINS & RELATED COMPOUNDS (EICOSANOIDS)

2. Membrane lipids supply the substrate for the synthesis of eicosanoids and PAF
PAF is formed by a smaller number of cell types LEOKOCYTES, PLATELETS & ENDOTHELIAL CELLS

3. EICOSANOIDS and PAF lipids contribute to
inflammation
Smooth muscle tone
Hemostasis
Thrombosis
Parturition
Gi secretion

4. Other important targets include platelets and monocytes, kidneys, CNS, autonomic presynaptic nerve terminals, sensory nerve endings, endocrine organs, adipose tissue, and the eye.
They are not preformed in cells but are generated from phospholipids on demand

5. Eicosanoids arachidonate metabolites – PGs, PGI2, TXA2, LTs, hepoxilins-are molecules that comprise 20 carbon atoms and have 3, 4 or 5 double bonds are members of a family of related polyunsaturated fatty acids
They are local hormones and are generally synthesized and catabolized close to their site of action, and have many physiological and pathological actions.

6. The immediate fatty acid precursor of most eicosanoids in individuals on a standard mixed diet is arachidonic acid; this is formed from dietary linoleic acid found in quantities in vegetable oils such as sunflower oil. Linoleic acid is converted in the liver in several steps to the eicosanoid precursor arachidonic acid, which is then incorporated into glycerophospholipids in cells
arachidonic acid is released under the influence of lipases like phospholipase A2 and can then be converted to eicosanoids

7. PHYSICAL, CHEMICAL and HORMONAL STIMULI ACTIVATE PLA2
The initial products of the action of COX on arachidonic acid are unstable intermediates known as cyclic endoperoxides.
TXA2 is a powerful vasoconstrictor and aggregator of platelets.

8. THE ARACHIDONIC ACID CASCADE
hydroperoxyeicosatetranoicacid

9. Generally, the initial rate-limiting step in eicosanoid synthesis is the liberation of arachidonate from phospholipids by phospholipase A2 (PLA2)
This occurs in response to
General cell damage
Thrombin action on platelets
C5a on neutrophils
BK on fibroblasts
Antigen-antibody reactions on mast cells

10. Cyclooxygenase COX occurs as at least three isoenzymes,
COX-1, COX-2 and COX-3,
COX-1 was thought to be mainly a constitutive 'housekeeping' enzyme localised to the endoplasmic reticulum. It can be produced in the resting state by many cells and contributes to the regulation of several homeostatic processes such as renal and gastric blood flow, gastric cytoprotection and platelet aggregation.
COX-2 was thought to be mainly an inducible enzyme, induced by inflammatory stimuli

11. Metabolism
Rapidly inactivated. The prostaglandin-specific enzymes are present in high concentration in the lung, and 95% of infused PGE2, PGE1 or PGF2α is inactivated on first passage. The half-life of most prostaglandins in the circulation is less than 1 minute.
Receptors
There are five main classes of prostanoid receptors all of which are typical G-protein-coupled receptors. They are termed DP, FP, IP, EP and TP receptors, respectively, depending on whether their ligands are PGD2, PGF2α, PGI2, PGE2 or TXA2.

12. ACTIONS OF PROSTANOIDS
PGD2 causes vasodilatation, inhibition of platelet aggregation, relaxation of gastrointestinal and uterine muscle, and modification of release of hypothalamic/pituitary hormones. It has a bronchoconstrictor effect through an action on TP receptors.
PGF2α causes myometrial contraction in humans , and bronchoconstriction in other species (cats and dogs).
PGI2 causes vasodilatation, inhibition of platelet aggregation , renin release and natriuresis through effects on tubular reabsorption of Na+.
TXA2 causes vasoconstriction, platelet aggregation and bronchoconstriction (more marked in guinea pig than in humans).

13. Smooth muscle
Vascular TXA2 is a potent vasoconstrictor and a cell mitogen
PGF2α is also a vasoconstrictor
PGI2 and PGE2 cause vasodilation by ↑ cAMP and ↓smooth muscle ic Ca

14. GI
Most of the PGs and TXs activate gi smooth muscle
Airways
Respiratory smooth muscle is relaxed by PGI2 and PGE2 and contracted by PGD2, TXA2 and PGF2α
DP1 and DP2 receptor knockout mice suggest an important role of this prostanoid in…..
Leukotienes also cause bronchoconstriction

15. Platelets
PGD2 and PGI2 inhibit aggregation (↑ cAMP)
TXA2 platelet aggregator and amplifies the effects of other more potent platelet agonists such as thrombin

16. Kidney
PGE2 PGI2 major, TXA2 and PGF2α second
They play important roles in maintaining bp and regulating renal function especially in marginally functioning kidneys, PGE2 PGI2 maintain blood flow and gfr through their local vasodilating effect
They modulate bp by regulating water and Na excretion

17. Reproductive Organs
Studies of knock-out mice →PG in reproduction and and parturition EP2 deficient mice →preimplantation defect
PGs were discovered in seminal fluid but the conc of them is really low
PGE1 enhance penile erection by relaxing the smooth muscle of corpora cavernosa

18. Fever
PGE2 ↑ body temperature
Endogenous pyrogens release IL-1 which in turn promotes the synthesis and release of PGE2

19. THE ROLE OF PROSTANOIDS IN INFLAMMATION
PGE2 PGI2 are associated with inflammation
Enhance edema formation and leukocyte infiltration by promoting blood flow to the inflamed area
PGE2 PGI2 ↑ vascular permeability and leukocyte infiltration
PGE2 ↓ the immunologic response by ↓ differentiation of B lymphocytes into antibody-secreting plasma cells →depressing the humoral response

20. Bone Metabolism
PGE2 ↑ bone turnover stimulation of bone resorption and and formation
EYE
PGE and PGF derivatives lowe intraocular pressure

21. NT
PGE ↓ the relase of NE from postganglionic sympathetic nerve endings
PGE2, PGI2 sensitize the peripheral nerve ending to painful stimuli

22. CANCER
Large human epidemiologic studies →NSAIDs use is associated withsignificant reductionin relative risk for developing colon, breast, lung and other cancers.
PGE2 principal oncogenic prostanoidfacilitates initiation, progression and metastasis→proliferation, angiogenesis, inhib apoptosis, augmenting cellular invasiveness, modulate immunosuppression

23. Leukotrienes
5-Lipoxygenase oxidizes arachidonate to give 5-hydroperoxyeicosatetraenoic acid (5-HPETE), which is converted to leukotriene (LT) A4. This, in turn, can be converted to either LTB4 or to a series of glutathione adducts, the cysteinyl-leukotrienes LTC4, LTD4 and LTE4.
LTB4, acting on specific receptors, causes adherence, chemotaxis and activation of polymorphs and monocytes, and stimulates proliferation and cytokine production from macrophages and lymphocytes.
LTB4 is an important mediator in all types of inflammation; the cysteinyl-leukotrienes are of particular importance in asthma.

24. LKs
LTB4 is a potent chemoattractant for T lymphocytes, eosinophils, monocytes and mast cells
LKs have been implicated in pathogenesis of inflammation→asthma, inflammatory bowel disease

25. CV12S-HETE promotes vascular smooth muscle cell proliferation (injury after angioplasty
12RHETE potent ↓ Na/K ATPase in the cornea
LTC4 and LTD4 reduce myocardial contractility and coronary blood flow→cardiac depression

26. GI
Human colonic epithelial cells synthesize LTB4 (chemoattractant for neutrophils)
Colonic mucosa of people with inflammatory bd contain ……………..

27. AIRWAYS
LTC4 and LTD4 potent vasoconstrictors
RENAL
20-HETE →vasoconstriction of renal arteries …….

28. SUMMARY DIAGRAM

29. Clinical uses of prostanoids Gynecological and obstetric
PGE2 and PGF2α have potent oxytocic actions. (termination of pregnancy): dinaprostone (20 mg vaginal suppository3-5 h intervals) gemeprost or misoprostol (metabolically stable prostaglandin PGE analogue)
induction of labor: dinoprostone (0.5 mg) or misoprostol
postpartum hemorrhage: carboprost (250µg im inj).
Gastrointestinal
to prevent ulcers associated with non-steroidal anti-inflammatory drug use: misoprostol
Cardiovascular
primary pulmonary hypertension: epoprostenol t1/2 3-5 min; PGI2 analogue Iloprost t1/2 30min
Ophthalmic
open-angle glaucoma: latanoprost eye drops. Bimatoprost, travoprost and unoprostone are also available.

30. CLINICALLY USED PGs & ANALOGS