the presentation contain information on eicosanoids also cover the prostaglandin, thromboxanes, leukotrienes topic.

1. Eicosanoids
(prostaglandin, thromboxanes, leukotrienes)
Ravish Yadav

2. Eicosanoids
•Major classes of eicosanoids.
•Precursors of eicosanoids.
•Major pathways of eicosanoid synthesis
(cyclooxygenase and lipoxygenase).
•Important functions of eicosanoids.
•Important inhibitors of eicosanoid synthesis

3. Eicosaniods
• Derived from 20-crabon polyunsaturated fatty acids
• Paracrine or autocrine messengers molecules
• Short half-lives (10 secs – 5 mins) so that functions are usually limited to
actions on nearby cells.
• Bind to specific cell surface G-protein coupled receptors, and generally
increase cAMP levels. May also bind to nuclear receptors and alter gene
transcription.
• Wide variety of functions

4. Major Classes of Eicosanoids
•Prostaglandins
•Thromboxanes
•Prostacyclins
•Leukotrienes
•HETES

5. • Induction of inflammation
• Mediation of pain signals
• Induction of fever
• Smooth muscle contraction (including uterus)
• Smooth muscle relaxation
• Protection of stomach lining
• Simulation of platelet aggregation
• Inhibition of platelet aggregation
• Sodium and water retention
Effects of Eicosaniods

7. Precursors of Eicosanoids
•Arachidonic acid (ω6)
•Eicosatrienoic acid (g-linolenic acid, ω6)
•Eicosapentaenoic Acid (ω3)

8. Dietary Linoleic Acid (C18: ∆9,12) (from plant oils)
Elongase
Desaturase
Arachidonic Acid (C20: ∆5, 8, 11, 14)
Membrane Phospholipids

10. Phosphatidyl choline
Arachidonic acid
Phospholipase A2
Ca++
Phosphatidylinositol bisphosphate
Phospholipase C
1,2 Diacylglycerol
Arachidonic acid Monoacylglycerol
DAG
lipase
Arachidonic acid
MAG
lipase
Arachidonic acid release from membrane
lipids
Stimulus

12. Pathways for Arachidonic Acid Metabolism
Arachidonic acid
Cyclo-oxygenase
Pathway
PGG2
Prostaglandins
Thromboxanes
lipoxygenase
Pathway
HPETE
Leukotrienes
HETE
Lipoxins

14. Prostaglandins – Structural Features
PGA, PGD, PGE, PGF, PGG, PGH, PGI
Depending on the functional groups present at X and Y
PGF 1, 2 or 3
Depending on the number of double bonds present in the linear hydrocarbon
chain

15. PGF 1, 2 or 3

16. Thromboxane A2 (TXA2) - structure

17. CYCLO-OXYGENASE
PATHWAY
PG and TX synthesis
2GSH
2GSSG
PGD2
PGD synthase
PGF2a
PGE 9-keto
reductase
PGE2
PGE synthase
PGI2
PGI synthase
TXA2
TXA synthase

18. PGI2 (prostacyclin) is located
predominantly in vascular
endothelium. Main effects:
•vasodilatation
•inhibition of platelet aggregation
TxA2 is found in the platelets.
Main effects:
•platelet aggregation
•vasoconstriction
PROSTANOIDS (PGs & Txs)

19. Several thromboxane
A2-receptor antagonists
may be able to restrict further
infiltration of inflammatory cells
in atherosclerotic vessels,
thus stabilizing vulnerable plaques
in the related cardiovascular
diseases.

21. PGE1
•alprostadil (prodrug – used to maintain
the patency of the ductus arteriosus in neonates
with congenital heart defects, and for treatment
of erectile dysfunction by injection
into the corpus cavernosum of the penis);
•misoprostol (used for prophylaxis of
peptic ulcer associated with NSAIDs);
•gemeprost
used as pessaries to soften the uterine
cervix and dilate the cervical canal prior to
vacuum aspiration for termination
of pregnancy.

22. PGE2 causes:
•contraction of pregnant uterus
•inhibition of gastric acid secretion
•contraction of GI smooth muscles
PGF2α – main effects:
•contraction of bronchi
•contraction of myometrium

23. PGF2α (dinoprost)
PGE2 (dinoprostone)
aregiven for:
•induction of labour
•termination of pregnancy
PGE1 (gemeprost)
Dorland’s Illustrated
Medical Dictionary
(2003, 2004)

24. Main
actions
of the
eicosanoids
Lüllmann, Color Atlas
of Pharmacology –
2nd Ed. (2000)

25. Cyclooxygenase (COX) is found
bound to the endoplasmatic
reticulum. COX exists in
3 isoforms:
•COX-1 (constitutive) acts
in physiological conditions.
•COX-2 (inducible) is
induced in inflammatory cells
by pathological stimulus.
•COX-3 (in brain)

26. Some Functions of Prostaglandins
PGI2, PGE2, PGD2
•↑ Vasodilation, cAMP
•↓ Platelet and leukocyte aggregation, IL1 and
IL2, T-cell proliferation, lymphocyte migration
PGF2a
•↑ Vasoconstriction, Bronchoconstriction,
smooth muscle contraction
TXA2
•↑ Vasoconstriction, Platelet aggregation,
lymphocyte proliferation, bronchoconstriction

27. Natriuresis: The excretion of an excessively large amount of sodium in the urine.

28. Lipoxygenase pathway

30. Leukotrienes
• The straight chain lipoxygenase products of
arachidonic acid are produced by a more limited number of tissues
(LTB4, mainly by neutrophils; LTC4, and LTD4-the cysteinyl LTs-mainly
by macrophages), but probably they are pathophysiologically as
important as PGs

31. Some Functions of Leukotrienes
LTB4
• ↑ Vascular permeability, T-cell proliferation,
leukocyte aggregation, IL -1, IL-2, IFN-g
LTC4 and LTD4
• ↑ Bronchoconstriction, Vascular permeability,
IFN-g

33. Leukotrienes and allergies
• Leukotrienes are a hundred
times more potent than
histamine
• Histamine provided a rapid
response to an allergen
• In the later stages leukotrienes
are principally responsible for
inflammation, smooth muscle
constriction, constriction of the
airways and mucous secretion
form mucosal epithelium

34. Anti inflammatory Drugs inhibit Eicosanoid Synthesis
LeukotrienesProstaglandins,
thromboxanes
NSAIDs
Membrane lipids
Arachidonic Acid
Steroids
Phospholipase A2

38. Synthesis and degradation

42. PLASMA KININS
(Bradykinin and Kallidin)
Plasma kinins are polypeptides split off from a
plasma globulin Kiininogen by the action of specific
enzymes Kallikreins .
the two important plasma kinins, Kallidin (decapeptide) and
Bradykinin (nonapeptide) were discovered around 1950 by
two independent lines of investigation into the hypotensive
activitv of urine and certain snake venoms. These and other
biological fluids were found to act indirectly: they contained
enzymes which generated active substances in the plasma.

45. Mechanism of Aspirin Action

47. • Low dose aspirin has an anti -
thromobogenic effect and lowers the risk
of heart attacks and strokes.
• It inhibits the formation of TXA2 in
platelets, by inhibition of COX-1 which
cannot be overcome because platelets
have no nucleus.
• Endothelial cells have a nucleus and
synthesis more COX-1 enzyme needed for
the normal prostaglandin functions
Aspirin and cardiovascular disease

48. Omega-6/omega-3 fatty acid balance
• w6 and w3 are not interconvertible in humans
(mammals).
• Diets rich in w3 fatty acids result in high
content of these fatty acids in membrane
phospholipids
Recommended ratio: 1-4: 1 (w6 : w3)
Typical western diet: 14-25: 1 (w6 : w3)

49. A diet rich in omega-6 FAs shifts the
physiological state to one that is
proinflammatory, prothrombotic and
proaggregatory… leading to heart disease in
susceptible individuals
Omega-6/omega-3 fatty acid balance