Eicosanoid chemistry and metabolism explained in details, Beast of use for medical students.

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