this file is all about eicosanoids including prostaglandins,prostacyclins and leukutriens with its mechanism of formation and inhibitors of LOX and COX pathways

2. Islamic Republic of Afghanistan
Ministry of Higher Education
Ghalib university of Higher Education
Medical faculty
Supervised by: Dr.Zahra froq
Presenter: Mohammad Azizi

3.  Introduction of arachidonic acid
 Activation of PLA2
 cyclic and linear pathway
 COX and LOX inhibitors
 NSAIDs
 Therapeutic Uses of Eicosanoids
 Eicosanoid vs hormones
 Conclusion
 References
Contents:

4. Arachidonic acid metabolites (Eicosanoids)
• The eicosanoids are considered "local hormones.“
• Eicosanoids have strong hormone-like actions in the
tissues where they are produced
 They have specific effects on target cells close to their site of
formation.
 They are rapidly degraded, so they are not transported to distal
sites within the body.
• Eicosanoids are not stored and are very unstable
• In humans, arachidonic acid is formed from linoleic
acid:

5. How And Where Is Arachidonic Acid Generated?How And Where Is Arachidonic Acid Generated?

6. Ca
Injured cell
membrane
plasma
membrane
Phospholipase A2 activation :
The ligand can be
i.a. ATP released
from dying cells

8. Continuous….

10. Main sites of eicosanoid biosynthesis:
• Endothelial cells
• Leukocytes
• Platelets
• Kidney
• Unlike histamine, eicosanoids are NOT synthesized in advance and stored in
granules – when needed, they can be produced very quickly from arachidonate
released from membranes

12. Cyclo-oxygenase Isoforms (COX-1 vs COX-2&cox-3):
 three isoforms of COX
 All produce prostaglandins (PGE2, PGF2a, PGI2)
 COX-1 is constitutive, expressed in most tissues
 physiological and homeostatic role, cell signalling
 not influenced by steroid administration
 not increased by cytokines nor bacteria
 Continuously produce gastric mucosa, kidney ,platelets and vascular endothelial
cells
 COX-2 is inducible following inflammation, trauma, etc
 found in immunocompetent cells (e.g. leukocytes)
 pathophysiological role, maintains inflammation
 induced by cytokines (interleukin-1)
 inhibited by steroids
 COX-3 only in pathological conditions

14. Biological role of leukotrienes :
LTs are produced mainly in leukocytes
Leukotrienes are very potent constrictors of the bronchial airway muscles: (LTC4,
LTD4, and LTE4)
They increase vascular permeability
They cause attraction (LTB4) and activation of leukocytes (primarily eosinophils and
monocytes), promote diapedesis , enhance phagocytosis
They regulate vasoconstriction

15. LTs in host defense :
(induction of gene
expression)
(activation of NADPH oxidase)
(synthesis of iNOS)
(release from neutrophils)
(receptors for LTs)
(LTs promote diapedesis,
delay apoptosis of
leukocytes)

16. BUT:
Overproduction of LTB4 was demonstrated in:
Crohn's disease
rheumatoid arthritis
psoriasis
cystic fibrosis
Leukotrienes are also suspected of participating in
atherosclerosis development
Excessive bronchoconstriction can be found in some forms of
asthma

17. In general, eicosanoids mediate:
inflammatory response, notably as it involves the joints (rheumatoid arthritis),
skin (psoriasis)
production of pain and fever
regulation of blood pressure
regulation of blood clotting
regulation of renal function
control of several reproductive functions, such as the induction of labor

19. Inhibitors…..

24. They differ from hormones in the following aspects:
1.They are produced in small amounts in almost all tissues rather than
specialized glands.
2.They act locally rather than after transport to target tissues
3.They are not stored, have extremely short half life, and are metabolized rapidly
to inactive products at their site of synthesis.
4.Their biological effects are mediated by plasma and nuclear membrane
receptors, which are different in different organ systems.

25. • Induction of labour
• Therapeutic abortion
• On cardiovascular system
• Treatment of asthma
• Nose bleeding
Therapeutic Uses of Eicosanoids:

26. Conclusion:
 Prostaglandins, thromboxane and leukotrienes are known as eicosanoids
 They are produced in small amounts in almost all tissues,
 act locally, and have many important physiological and pathological functions
 The dietary precursor of eicosanoids is the essential fatty acid, linoleic acid
 Synthesis of prostaglandins begins with oxidative cyclization
of free arachidonic acid to yield PGH2 by prostaglandin
 endoperoxide synthase (cyclooxygenase)
 There are two isozymes of the synthase: COX-1 and COX-2,
which are important drug targets

27. References:
• Robbin’s basic pathology 9th edition
• Basic & clinical pharmacology 13th edition
• Lininger biochemistry
• Internet