Eicosanoids are physiologically active substances derived from 20-carbon polyunsaturated fatty acids. They include prostaglandins, thromboxanes, leukotrienes, and others. Arachidonic acid is the most prevalent eicosanoid precursor in humans. Eicosanoids are produced by almost all mammalian cells and act as local messengers. They have diverse roles including inflammation, smooth muscle contraction, platelet aggregation, and reproductive functions. Nonsteroidal anti-inflammatory drugs inhibit eicosanoid production.

1. EICOSANOIDS
PRESENTER : Dr DNYANESH AMLE
MODERATOR: Dr SARITA AGARWAL

2. INTRODUCTION
 Eicosanoids:
 Greek: eikosi twenty→
 Physiologically and pharmacologically active
substances derived from 20 C Poly-
unsaturated Fatty Acids
 Produced by Almost all mammalian cells
 Not synthesised in advance /stored : synthesised as
and when needed
 Act as short range messengers : Autocrine/paracrine

3. History
 1930 Ulf von Euler – Prostaglandins
 1960- aspirin like drugs acts by inhibiting PG
synthesis
 1982 John vane ,Sune bergstrom and Bengt
Samuelsson got nobel prize for work on
eicosanoids

4.  The eicosanoids include:
1. the prostaglandins
2. thromboxanes
3. leukotrienes
4. hydroperoxyeicosatetraenoic acids
(HPETEs)
5. hydroxyeicosatetraenoic acids (HETEs)
6. lipoxins

5. 5
Eicosanoid
LeukotrienesProstanoid
Thromboxane
Prostacyclin
Prostaglandins
Lipoxins

6.  Three major precursors of eicosanoids
 DiHomo ϒ LA
 Archidonic Acid
 Eicosa Pentanoic Acid

7. Sources
 Cell membrane:
 Phospatidyl choline
 Phospatidyl inositol/ethanolamine
phosphoglycerides
 Mostly ER
 Released by action of PLA2
 PLA2 is stimulated by verious stimuli eg.
Histamin, bradykinin, epinephrine,cytokines etc
 Inhibited by corticosteroids

8. Arachidonic acid is synthesised
 From linoleic acid
 Phospholipid Hydrolysis
 Phospholipase A 2
 Phospholipase C

11.  arachidonic acid: m o st pre vale nt e ico sano id
pre curso r in hum ans
 ω 6 fatty acid

12. ARACHIDONIC ACID METABOLISM

13. /Lipoxins
/LXA4

14. PROSTAGLANDINS
 Pro stag landins : de rivative s o f the hypo the tical
C20 fatty acid prostanoic acidinwhichcarbon
atoms 8to 12fo rm a cyclo pe ntane ring

15.  PG A – PG I :substituents on the cyclopentane
ring

16.  Thromboxanes

17.  Numerical subscript : number of double bonds
contained on the side chains of the
cyclopentane ring

18. PGH Synthase
 Also called prostaglandin H synthase
/prostaglandin endoperoxide synthase/COX
 Heme-containing enzyme
 Mambrane bound
 Contains two catalytic activities
 cyclooxygenase activity
 peroxidase activity
 Cyclooxygenase Is a “Suicide Enzyme”
 15 hydroxyprostaglandin dehydrogenase

20. Fate of PGH2
 Fate of PGH2 thus synthesised ,depends on the
relative activities of the enzymes catalyzing the
specific interconversions

21.  Platelets thromboxane synthase, which
mediates
 the formation of thromboxane A2 (TxA2), a
vasoconstrictor
 and stimulator of platelet aggregation (an
initial
 step in blood clotting; Section 35-1).Vascular
endothelial
 cells contain prostacyclin synthase, which
catalyzes the synthesis
 of prostacyclin I2 (PG I2)

23. MECHANISM OF ACTION
 G protein coupled receptors
 Second messengers
 cAMP: PGD,PGE,PGF
 Ca: TXA2,PGF2α
 Adenylate cyclase-cAMP-Protein kinase A
 Sometimes by direct activation on cAMP

24. CATABOLOISM
 Eicosanoids: Very short half life
 Catabolised by
1. Oxidation of hydroxyl group(c-15)
2. Reduction of double bonds(c-13)
3. Β oxidation
 TXA2 : initial modification involving clevage of
bond between C9-C11

25. LINEAR PATHWAY
 Lipoxigeneses
 Introduce hydro-peroxy (–OOH) groups
 Lipoxigenes 5-Neutrophils
 Lipoxigenes 12 – platelets
 Lipoxigenes 15 - eosinophils
 Arachidonic acid hydroperoxy-eicosatetraenoic→
acids(HPETEs) by the 5-, 12-,& 15-lipoxygenases
 Hepoxilins hydroxy epoxy derivatives of 12→
HPETE

28. Leukotrienes:
 synthesized by: WBC, mast cells,lung, spleen,
brain and heart
 Peptidoleukotrienes (LTC4,D 4,E 4): SRS-A
 LTB4: Chemotactic factor
 Implicated in
 Asthma
 Hypersensitivity reactions
 Myocardial infarction

29. LIPOXINS
 Lipoxins: antiinflammatory eicosanoids
 FLAP
 5-LO activity requires the presence of 5-lipoxyge-
nase-activating protein
 facilitates enzyme–substrate binding
 5-LO’s interaction with the membrane
 Inhibited by MK-591 rsulting in inhibition of
synthesis of leukotriens

30.  NSAIDs Inhibit PGH Synthase
 Aspirin
 Acetylation of serine 530
 Tyrosine 385
 Low doses of aspirin
 Triggers asthma

31. aspirin-acetylated
COX-2 retains
a residual 15-LO
activity (Steps 3 and
4 in Fig. 25-71)
through which it
initiates a pathway
that converts arachi-
donic acid to the
anti-inflammatory
agents called
aspirin-triggered epi-
lipoxins
Aspirin-triggered Epi-lipoxins

32. Theraputic aspects
 COX1 and COX 2
 COX inhibitors
 COX2 Specific inhibitor
 COX3
 TXA2 and PGI2

33. Actions:
 Vascular smooth muscle
 PGE2 and PGI2 are potent vasodilators in
most vascular beds.
 Thromboxane is a potent
vasoconstrictor.

34. Inflammation
PGE2 and PGI2 cause an increase in
blood flow and promote, but do not
cause, edema.
HETEs (5-HETE, 12-HETE, 15-HETE)
and leukotrienes B4 - chemotaxis
 LT C4,D4,E4 – SRS OF anaphylaxis

35. Bronchial smooth muscle
 PGFs - smooth muscle contraction.
 PGEs- smooth muscle relaxation
 Leukotrienes and thromboxane are potent
bronchoconstrictors and are the most likely
candidates for mediating allergic bronchospasm
 Zielueton :
 lipoxigenes 5 inhibitor
 Montelukast,zafirlukast
 leukotrien eceptor antagonist

36. Uterine smooth muscle
 PGE2 and PGF2α
 contraction of uterine smooth muscle in
pregnant women
 Nonpregnant uterusonpregnant uterus –
 variable response to PGs
 PGF2a causes contraction
 PGE2 causes relaxation.
 Induction of labor at term.
 Induction of labor is produced by:
 infusion of PGF2a (carboprost tromethamine)
[Hemabate] or

37. Therapeutic abortion:
A.Inducing abortion in the second trimester:
 Infusion of carboprost tromethamine
(PGF2α) or
 Administration of vaginal suppositories
containing dinoprostone(PGE2)
B.inducing first-trimester abortion:
 these prostaglandins are combined with
mifepristone (RU486)

38.  PGE2 and PGI2
 inhibit acid and pepsinogen
Secretion in the stomach
 Prostaglandins
 increase mucus, water, and electrolyte
secretion in the stomach and the intestine.
 Misoprostol [Cytotec]
 a methylated derivative of PGE1
 is approved for use in patients taking high
doses of NSAIDs to reduce gastric
ulceration.
Gastrointestinal tract

39. PGE2 and PGF2a
 increase the rate of longitudinal
contraction in the gut and decrease
transit time.
The leukotrienes
 potent stimulators of gastrointestinal
smooth muscle.

40.  TXA2
 is a potent inducer of platelet aggregation.
 PGI2 and PGE2
 inhibit platelet aggregation.
 PGEs
 induce erythropoiesis by stimulating the renal
release of erythropoietin.
 5-HPETE
 stimulates release of histamine
 PGI2 and PGD
 inhibit histamine release.
Blood

41. Management of ductus arteriosus
 Maintenance:
 is produced by PGE1 [Prostin VR] infusion
 PGE1 will maintain patency of the ductus
arteriosus, which may be desirable before
surgery
 Closure
 Indomethacin is given at birth to close the
PDA

42. Erectile dysfunction:
 Alprostadil (PGE1)
 injected directly into the corpus cavernosum or
administered as a transurethral suppository to
cause vasodilation and enhance tumescence.

43. Mimic endocrine hormones:
 Bind to G-protein-coupled receptors
 Secondary messenger- cAMP
 Profound physiological effects at extremely low
concentrations
 Mediate
 Inflammatory response
 Production of pain and fever
 Regulation of blood pressure
 The induction of blood clotting
 Control of several reproductive functions such
As the induction of labor
 Regulation of the sleep/wake cycle

44. But….
Unlike endocrine hormones
 Not transported in the bloodstream
 Chemically and biologically unstable
substances
 Local mediators(paracrine/auto crine)
 Act in the same environment in which
they are synthesized