Dr. RAGHU PRASADA M SMBBS,MDASSISTANT PROFESSOR, DEPT. OF PHARMACOLOGYSSIMS & RC. 1

Prostaglandins and related compounds are collectively knownas eicosanoids. Eicosanoids are important regulatorymolecules

Most are produced from arachidonic acid, a 20-carbonpolyunsaturated fatty acid (5,8,11,14-eicosatetraenoic acid).

The eicosanoids are considered "local hormones."

They have specific effects on target cells close to their siteof formation. They are rapidly degraded, so they are nottransported to distal sites within the body.

There is evidence for involvement of eicosanoids inintracellular signal cascades.

Two classes: Prostaglandins/thromboxanes, andLeukotrienes

Prostaglandins – mediate pain sensitivity,inflammation and swelling

Thromboxanes – involved in blood clotting,constriction of arteries

Leukotrienes – attract white cells, involvedinflammatory diseases (asthma, arthritis, etc..)

Examples of eicosanoids:prostaglandins, prostacyclinsthromboxanes, leukotrienesepoxyeicosatrienoic acids.

They have roles in:inflammation, feverregulation of blood pressure, blood clottingimmune system modulationcontrol of reproductive processes & tissue growthregulation of sleep/wake cycle.

Prostaglandins & related compounds are transportedout of the cells that synthesize them.Most affect other cells by interacting with plasmamembrane G-protein coupled receptors.

Depending on the cell type, the activated G-protein may stimulate or inhibit formation of cAMP, ormay activate a phosphatidylinositol signal pathwayleading to intracellular Ca++ release.Another prostaglandin receptor, designated PPARg, isrelated to a family of nuclear receptors withtranscription factor activity.

Prostaglandin H2 Synthase productionof PGs, PGI2 & TXA2

PG endoperoxides (PGG2 & PGH2) aremore potent & long-acting than thePGs to which they decompose

TXA2 formed mainly in platelets by TXsynthase mediating vasoconstriction &platelet aggregation

PGI2, formed mainly in endotheliumby PGI synthase opposes TXA2

COOH

COOHO

O

OH

COOHO

O

OOH

2 O2

2 e

arachidonic acid

PGG2

PGH2

Cyclooxygenase

Peroxidase

PGI2/D2/E2 →dila on of arterioles, pre-capillary sphincters & post-capillary veins → increased blood flow & cardiac outputTXA2 is a potent vasoconstrictorTXA2 & PGI2 are potent platelet aggregation inducer & inhibitorrespectively Vasoconstriction, Platelet aggregation, lymphocyteproliferation, bronchoconstrictionPGI2 de-aggregate platelets clumps & reduces myocardial infarct size &ischemic organ damagePGI2, PGE2, & NO are simultaneously released from endotheliumPGE2 inhibits B- & T-lymphocyte activation & proliferation, inhibitingantibodies & lymphokines production

Smooth muscle:Bronchial muscle relaxation by PGE2 & PGI2, butconstriction by TXA2, LTC4 & LTD4Human pregnant uterus is contracted by PGE1/2, and PGF2αGIT: PGEs & PGI2 inhibit gastric acid secretion & reducepepsin contentThey increase bicarbonate, mucus & blood flowIncreased electrolyte/water movement into intestinallumen (diarrhea)TXA2 is pro-ulcerogenic

Platelet Aggregation &Thrombosis

PGI2: ( Inhibit Aggregation) Released by endothelial cells Responsible for non-adherenceof platelets to healthy bloodvessels

PGE2 & TXA2: ( Promote ClottingProcess)Produced by platelets, accountsfor spontaneous aggregation ofplatelets to thrombin, collagen atthe site of injury

Renal System PGs enhance urine

formation, natriuresis,& kaliuresis via actionon renal blood flow &tubules

PGD2, PGE2, PGI2stimulate renin release

PGs inhibit water re-absorption under ADHeffect

Nervous systemHyperthermia by PGE2, related pyrogen-induced feverAntipyretic action of ASA & NSAIDs is via inhibition ofCOX-1, -2 & -3Algesia induction & pain sensitization to histamine, BKor mechanical stimuliAnalgesic action of ASA & NSAIDs is via inhibition ofCOXs

Eicosanoid

Major Site(s) ofSynthesis Major Biological Activities

PGD2 mast cells

inhibits platelet and leukocyte aggregation,decreases T-cell proliferation and lymphocytemigration and secretion of IL-1Α andIL-2; induces vasodilation and production ofcAMP

PGE2kidney, spleen,heart

increases vasodilation and cAMP production,enhancement of the effects of bradykininand histamine, induction of uterinecontractions and of platelet aggregation;decreases T-cell proliferation and lymphocytemigration and secretion of IL-1Α andIL-2

PGF2α kidney, spleen,heart

increases vasoconstriction,bronchoconstriction and smooth musclecontraction

.

PGI2, PGE2, PGD2↑ Vasodila on, cAMP↓ Platelet and leukocyte aggrega on, IL1 and IL2, T-cell proliferation, lymphocyte migrationPGF2a↑ Vasoconstric on, Bronchoconstric on, smoothmuscle contractionTXA2↑ Vasoconstric on, Platelet aggrega on, lymphocyteproliferation, bronchoconstriction

Eicosanoid

Major Site(s) ofSynthesis

Major Biological Activities

PGH2 many sitesa short-lived precursor to thromboxanes A2and B2, induction of platelet aggregationand vasoconstriction

PGI2heart, vascularendothelial cells

inhibits platelet and leukocyte aggregation,decreases T-cell proliferation andlymphocyte migration and secretion of IL-1Α and IL-2; induces vasodilationand production of cAMP

.

Uterine Stimulation Carboprost (15-methyl PGF2α) Used by IM route for induction of abortion between

12th -20th gestational weeks Used at a dose of 250 μg every 1-3 hrs Dinoprost (PGF2α) Injection form for intra-amniotic administration Used to induce labour or abortion

Misoprostol is a synthetic methyl ester analogue of PGE1Used to prevent drug-induced gastric ulceration duringNSAIDs, corticosteroid or anticoagulant therapyIt can be used alone or in combination with antacids forduodenal ulcer treatmentNot used for pregnant women or whom are planningpregnancy

Epoprostenol (PGI2): It is used as a heparin replacement in some

hemodialysis patients Used to prevent platelet aggregation in extracorporal

circulation systemsImpotence

Alprostadil (PGE1) was used by in jection into corporacavernosa to maintain erection

Replaced by PDE-V inhibitors

Eicosanoid Major Site(s) ofSynthesis Major Biological Activities

TXA2 plateletsinduces platelet aggregation,vasoconstriction, lymphocyte proliferationand bronchoconstriction

TXB2 platelets induces vasoconstriction

LTB4 ↑ Vascular permeability, T-cell proliferation,

leukocyte aggregation, IL -1, IL-2, IFN-g

LTC4 and LTD4 ↑ Bronchoconstric on, Vascular permeability, IFN-g

LTs have no therapeutic uses, but LTs antagonists haveAnti-asthma medications:5-Lipoxygenase Inhibitors, e.g., zileutin

Leukotriene-receptor antagonists;montelukast, & zafirlukast