1. Eicosanoids The eicosanoids include: the prostaglandins thromboxanes
leukotrienes
hydroperoxyeicosatetraenoic acids (HPETEs)
hydroxyeicosatetraenoic acids (HETEs).

2. Most catabolism occurs in the lung.
The eicosanoids all have short plasma half-lives (typically 0.5—5 min).
Most catabolism occurs in the lung.
Metabolites are excreted in the urine.
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

3. Various eicosanoids are synthesized throughout the body
synthesis can be very tissue specific:
PGI2 is synthesized in endothelial and vascular smooth muscle cells.
Thromboxane synthesis occurs primarily in platelets.
HPETEs, HETEs, and the leukotrienes are synthesized predominantly in mast cells, white blood cells, airway epithelium, and platelets.

4. Biosynthesis
Arachidonic acid, the most common precursor of the eicosanoids, is formed by two pathways:
Phospholipase A2-mediated production from membrane phospholipids; this pathway is inhibited by glucocorticoids.
Phospholipase C.

5. Prostaglandins Stimulus phospholipids Phospholipase A2 Phospholipase C
5-lipoxygenase enzyme (LOX)
Arachidonic acid
Cyclo-oxygenase
enzyme (COX)
(HPETEs and HETEs)
PGH2
LTB4 LTC2 LTD4 LTE2
PGD2 PGE2 PGF2α PGI2 TXA2

7. Membrane-bound phospholipid
Prostaglandins
Membrane-bound phospholipid
Arachidonic acid
COX
V.C.
↑Platelet
Aggreg.
Contract
smooth
muscle
2e¯
Reductase
TX A synthetase
PGH2
TXA2
PGF2
PGD
synthetase
PGI synthetase
synthetase
PGE
V.D.
↓platelet
Aggreg.
V.D.
↓platelet
Aggreg.
PGD2
PGI2
PGE2
Dehydration
(non enzymatic
Inflammation
Immunity
fertility
Anti-
inflammatory
PGJ2
Dehydration
(non enzymatic
Anti-inflammatory
15-d-PGJ2
PGA2
V.D., antiviral,
antituomr

8. 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

9. Eicosanoids Hydroperoxy and hydroxy fatty acids (HPETEs and HETEs)
leukotrienes
A.B,C.D.E LTC4andLTD4
→bronchospasm.

10. Effects of prostaglandins
Mediate inflammation:
cause vasodilation  redness, heat (PGE1, PGE2, PGD2, PGI2)
increase vascular permeability  swelling (PGE2, PGD2, PGI2)
Regulate pain and fever (PGE2)
PGE2, PGF2 stimulate uterine muscle contractions during labor
Prostaglandins of the PGE series inhibit gastric acid secretions (synthetic analogs are used to treat gastric ulcers)
Regulate platelet aggregation: PGI2 = potent inhibitor of platelet aggregation
PGE2 inhibits reabsorption of Na+ and water in the collecting duct. PGI2: vasodilatation and regulation of glomerular filtration rate.

11. Eicosanoids
Actions:
TXA2 contracts arteries and veins and bronchi, and causes platelet aggregation.
PGI2 de-aggregate platelets clumps & reduces myocardial infarct size & ischemic organ damage

12. Actions: LTB4 is chemotactic for polymorphs, esinophils and monocytes.
 PGF2α(contracts uterus), TXA2, LTC4, D4 contract bronchi while PGE1, PGE2 and I2 relax the bronchi.
 PGE1, PGE2 induce fever, stimulate renin release,while (PGE2, PGI2) protect stomach against ulcer.
LTB4 is chemotactic for polymorphs, esinophils and monocytes.

13. Inhibitors of eicosanoid biosynthesis:
Eicosanoids
Inhibitors of eicosanoid biosynthesis:
Glucocorticoids
Stimulate the synthesis of a protein called lipocortin which inhibit the activity of phospholipase A2 so inhibit synthesis of eicosanoids.
Non steroidal anti-inflammatory drugs (NSAIDs) as aspirin, indomethadn, ibuprofern
Inhibit cyclo-oxygenase enzyme (aspirin acetylates it).

14. Anti leukotriene drugs include :
Eicosanoids
Anti leukotriene drugs include :
a)Zileuton : inhibits 5-lipoxygenase enzyme.
b)Monteleukast and Zafirleukast: block cysteinyl leukotriene receptors.
Dazoxiben is a selective inhibitor of thromboxane A2 synthesis and so inhibits platelet aggregation.

15. Montelukast, Zafirlukast
Arachidonic acid
5-Lipoxygenase
Zileuton
Leukotrienes (LTs)
LTC4-
receptor
LTD4-
receptor
LTE4-
receptor
(-)
(-)
Montelukast, Zafirlukast

16. Eicosanoids
Steroidal and non-steroidal anti-inflammatory drugs may induce peptic ulcer due to inhibition of PGs generation by gastric mucosa.
Drugs inhibiting cyclo-oxygenase enzyme may induce bronchospasm?.

17. 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)

18. COX INHIBITORS NSAIDs Nonselective COX-1/COX-2 Inhibitors ibuprufen
Antipyretic
analgesics
COX-2
inhibitors
Selective (coxibs)
celecoxib, valdecoxib

19. Therapeutic uses of prostaglandins and other eicosanoids:
1.PGF2α(Dinoprost) and PGE2 (Dinoprostone) are used to induce abortion and labour.
They are better given intravaginal or intra-amniotic
Therapeutic uses of PGs :
Induce abortion & labour.
Treatment of Impotance
Treatment of glacuma
To decrease platelet aggregation
Treatment of petic ulcer
Treatment of pulmonary hypertension
PGE1 analog misoprostol combined with mifepristone or methotoexate( intravaginal or systemic) terminates early pregnancy.

20. Therapeutic uses of prostaglandins and other eicosanoids:
2. PGE2 induces bronchodilatation but produces irritation.
3.They are tried in peptic ulcer (PGE1 analogs, misoprostol).but their adverse effects , and the presence of more superior drugs in this line limited their use
4. PGE1(Alprostadil)& PGI2 to maintain the patency of ductus arteriosus so used as a presurgical therapy for neonates suffering from transdisposition of great arteries or pulmonary atresia.

21. Therapeutic uses of prostaglandins and other eicosanoids:
5. PGE1 (alprostadil) is injected into corpora cavernosa to maintain erection in treatment of impotence. Replaced by PDE-V inhibitors
6. Latanoprost, travaprost and bimatoprost are PGF2α derivatives which used topically in treatment of glaucoma.
7 -Epoprostenol (PGI2) to decrease platelet aggregation. Used to prevent platelet aggregation in extracorporal circulation systems

22. Therapeutic uses of PGs :
Induce abortion & labour.e.g PGF2 alpha,PGE2, PGE1 +
Treatment of Impotance e.g PGE1
Treatment of glaucoma e.g PGF2 alpha
To decrease platelet aggregation e.g PGI2
Treatment of petic ulcer e.g PGE1
Treatment of pulmonary hypertension e.g PGE1, PGI2

23. Aspirin Cyclooxygenase (Cox) (-) >1 g/24 h Endoperoxides (-)
Arachidonic acid
Cyclooxygenase (Cox)
(-)
>1 g/24 h
Aspirin
Endoperoxides
(-)
100 mg/24 h
Thromboxane A2 synthase
PGs
TxA2

24. Clinical Uses of Eicosanoids Inhibitors:
B – uses of eicosanoids blockers:
-Corticosteroids
Asthma: Leukotrien antagonists (Zafirleukast; Montelukast); or Lipoxegenase inhibitor e.g. Zileuton
Anti-inflammatory and RA (NSAIDs)
Antiplatelet action (Aspirin), Dazoxiben used as prophylaxis against blood coagulation
Dysmenorrhea (NSAIDs)