PROSTAGLANDINS & RELATED COMPOUNDS

(EICOSANOIDS)

• 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

• EICOSANOIDS and PAF lipids contribute to

• inflammation

• Smooth muscle tone

• Hemostasis

• Thrombosis

• Parturition

• Gi secretion

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

• 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.

• 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

TXA2 is a powerful vasoconstrictor and

aggregator of platelets.

•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.

THE ARACHIDONIC ACID CASCADE

hydroperoxyeicosatetranoicacid

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

• 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

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.

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).

• 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

• 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

• Platelets

PGD2 and PGI2 inhibit aggregation (↑ cAMP)

TXA2 platelet aggregator and amplifies the effects of other more potent platelet agonists such as thrombin

• 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

• 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

• Fever

PGE2 ↑ body temperature

Endogenous pyrogens release IL-1 which in turn promotes the synthesis and release of PGE2

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

• Bone Metabolism

PGE2 ↑ bone turnover stimulation of bone resorption and and formation

• EYE

PGE and PGF derivatives lowe intraocular pressure

• NT

PGE ↓ the relase of NE from postganglionic sympathetic nerve endings

PGE2, PGI2 sensitize the peripheral nerve ending to painful stimuli

• 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

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.

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

• 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

• GI

Human colonic epithelial cells synthesize LTB4 (chemoattractant for neutrophils)

Colonic mucosa of people with inflammatory bd contain ……………..

• AIRWAYS

LTC4 and LTD4 potent vasoconstrictors

• RENAL

20-HETE →vasoconstriction of renal arteries …….

SUMMARY DIAGRAM

• 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.

CLINICALLY USED PGs & ANALOGS