1. Lipid-Derived Autocoids
Eicosanoids and Platelet-Activating Factor

2. Lipid-Derived Autocoids
Membrane lipids supply the substrate for the synthesis of eicosonoids and PAF.
Eicosonoids-arachidonate metabolits, including PGs, PGI2, TxA2, LTs, lipoxins and hepoxilins, are not stored but are produced, by most cells, when a variety of physical, chemical, and hormonal stimuli activate acycl hydrolases that make arachidonate available.

3. Lipid-Derived Autocoids
Membrane glycerophosphocoline derivatives can be modified enzymathically to produce PAF.
PAF is formed by a smaller number of cell types, principally Leucocytes, Platelets, and endothelial cells.

4. Lipid-Derived Autocoids
Eicosanoids and PAF lipids contribute to inflammation, smooth muscle tone, hemostasis, thrombosis, parturition, and GI secretion.

5. Lipid-Derived Autocoids
Several classes of drugs, most notably Aspirin, the tNSAIDs and spicific inhibitor of COX-2, such as the Coxibs, owe their principle therapeutic effects to blockade of eicosanoid formation.

6. EICOSANOIDS History 1930 Kurzrok and Lieb 1935 von Euler Prostaglandin
1962 Samuelsson, Bergström PGE1 PGF1α
1964 Bergstrom and Van Dorp biosynthesis of PGE2
1971 Vane, Smith and Willis, Aspirin and NSAIDs

7. PGs, LTs, and related compounds are called eicosanoids, Precursor essential fatty acids contain 20 carbons and 3,4,5 double bonds:
8,11,14-eicosatrienoic acid (dihomo--linolenic acid)
5,8,11,14-eicosatetraenoic acid (AA)
5,8,11,14,17-eicosapentaenoic acid (EPA)

8. Eicosanoids Biosynthesis
Phosphatidylcholine and phosphatidylethanolamine
cPLA2 (cytosolic, Ca2+_dependent)
sPLA2 (secratory)
iPLA2 (Ca2+ _independent)
COXs, Lipoxygenases (LOXs), and CYPs

16. Products of PG G/H synthases
Complex microsomal enzymes
COX and hydroperoxidase (HOX) activities
Prostanoids (PGs, Prostacyclin, PGI2, and TxA2)
COX-1 and COX-2

17. Products of Lipoxygenases (LOXs)
HPETE → HETE
These are five active human LOXs-
5(S)-LOX, 12(S)-LOX,12(R)-LOX;
15(S)-LOX-1, and 15(S)-LOX-2
5-LOX pathway leads to the synthesis of the LTs.
FLAP
LTC4, LTD4, and LTE4 (SRS-A)

18. Products of CYPs epoxyeicosatrienoic acids (EETs)
endothelial cells (EDHFs)

19. Other Pathways non-enzymatic free radical catalyzed oxidation of AA
Isoprostanes
their formation is suppressed by antioxidants.
endocannabinoids arachidonylethanolamide (anandamide) and 2-arachidonoylglycerol

20. Inhibitors of Eicosanoid Biosynthesis
PLA2 - Glucocorticoids (annexins )
COX-2 – induced expression – Glucocorticoides
COXs- Aspirin and tNSAIDs
COX and 5-LOX – Licofelone
COX-2 – Coxibs
TX synthase
LOXs - Zileuton

21. Eicosanoid Catabolism
pulmonary circulation - PGE2
TXA2 – (t1/2 – 30 seconds)
PGI2 – (t1/2 – 3 minutes)
LTs – long acting

22. Pharmacological Properties of Eicosanoids
Prostaglandin Receptors
Cell Signaling Pathways and Expression
Receptors for LTs
Endogenous PGs, Txs, and LTs:
- Functions in Physiological and Pathological Processes

24. Platelets Platelet aggregation leads to activation of membrane
PLs → AA → eicosanoids
In human platelets, TxA2 and 12-HETE
Low dose Aspirin
TxB2 – unstable angina, MI, and stroke
PGI2 – Inhibition platelet aggregation and disaggregation performed clumps
Vascular injury
COX-2 inhibitors

25. Vascular Tone
Prostanoids modulate vascular tone locally COX-2 derived PGI2
PGI2 – Pulmonary hypertension
PGE2 – maintenance of renal blood flow
PGI2 and PGE2 – septic shock
PGs – maintanence of placental blood flow
COX-2 derived PGE2 (DA)
EETs - hypertension

26. Inflammatory Vascular Disease
TxA2 - atherogenesis
PGI2 - atheroprotective
COX-2 - abdominal aortic aneurism formation
LTs

27. Lung
A complex mixture of autacoids is released when sensitized lung tissue is challenged by the appropriate antigen.
COX-derived (PGE2, PGF2α, TxA2, PGD2 ,and PGI2).
CysLTs probably dominate during allergic constriction of the airway.
CysLT-receptor antagonists and 5-LOX inhibitors are effective in the treatment of human asthma.
slow LT metabolism in lung.

28. Kidney
Long-term use of all COX inhibitors is limited by the development of hypertension, edema, and congestive heart failure in a significant number of patients.
COX-2 derived PGE2 and PGI2 (RBF and salt excretion).
Biosynthesis of PGE2 and PGI2 is increased by factors that reduce renal blood flow.
Bartter's syndrome
inhibition of COX-2

29. Inflammatory and Immune Responses
PGs and LTs are synthesized in response to a host of stimuli that elicit inflammatory and immune responses, and contribute significantly to inflammation and immunity.
Prostanoids generally promote acute inflammation.
LTs are potent mediators of inflammation.
LTB4 in chemotaxis, adhesion, and recruitment of leukocytes.
Increased vascular permeability

30. Heart PGI2 and PGE2 protect against oxidative
injury in cardiac tissue.

31. Reproduction and Parturition
PGF2α appears important for luteolysis.
COX-2 generates prostanoids (PGF2α and TxA2) that are important in the final stages of parturition.

32. Cancer COX-2 - in models of colon, breast, lung, and other cancers.
NSAIDs and cancers.
PGE2 and TxA2 - pro-carcinogenic mediators.
CysLTs and LTB4

33. Pharmacological Effects
Cardiovascular System Eye
Platelets CNS
Inflammation and Immunity Endocrine system
Smooth Muscle Bone
Kidney

34. Cardiovascular effect
local vascular tone and renal actions.
PGE2, PGI2, and PGD2 elicit vasodilation and a drop in blood pressure .
PGD2 (flushing, nasal stuffiness, and hypotension)
TxA2 – potent vasoconstrictor
LTC4 and LTD4 – Hypotension, permeability
EET - EDHFs

35. Platelets LD of PGE2 - aggregation
HD of PGE2 – Inhibition of aggregation
PGI2 and PGD2 - Inhibition of aggregation
COX-1 is dominant
COX-2 - Megakaryocytes and immature platelet
TxA2
the major product of COX-1 in platelets
thrombin and ADP
endogenous inhibitors, NO and PGI2

36. Inflammation and Immunity
LTs - pro-inflammatory
lipoxins - anti-inflammatory
prostanoids (PGE2 and PGI2) both kinds of activity
LOX-2 is dominant
PGs – inhibit lymphocyte function and proliferation
DP2 (most cells) – is a potent leukocyte chemoattractant
LTB4 -is a potent activator and chemotactic agent for neutrophils, T lymphocytes, eosinophils, monocytes, dendritic cells, and mast cells
LTB4 - aggregation of eosinophils and promotes degranulation and the generation of superoxide.
LTB4 - promotes adhesion of neutrophils to vascular endothelial cells (transendothelial migration)
LTB4 - stimulates synthesis of pro-inflammatory cytokines from macrophages and lymphocytes.
Mast cell–generated LTB4 also may contribute significantly to T lymphocyte migration

37. Smooth Mucsle Bronchial and Tracheal muscle.
TxA2, PGF2α, and PGD2 contract
PGE2 and PGI relax
CysLTs Bronchoconstrictors
Bronchial mucus secretion
(muscle edema)

38. Smooth Mucsle Uterus PGF2α, and PGE2
Together with Oxytocin is essential for the onset of parturition.
Uterine responsiveness to PGs increases as pregnancy progresses but remains smaller than the response to Oxytocin.

39. Gastrointestinal Muscle
PGEs and PGFs stimulate contraction of the main longitudinal muscle from stomach to colon
PGs reduce transit time in the small intestine and colon.
Diarrhea, cramps, and reflux of bile have been noted in response to oral PGE.
PGEs and PGFs stimulate the movement of water and electrolytes into the intestinal lumen (watery diarrhea).
PGE2 appears to contribute to the water and electrolyte loss in cholera (therapy with tNSAIDs).
The LTs have potent contractil effect.

40. Gastric and Intestinal Secretions
PGE2 and PGI2 increased mucus secretion (cytoprotection), reduced acid secretion, and reduced pepsin content.
PGE2 and PGI2 - vasodilatory properties and direct effects on secretory cells
PGE2 and its analogs also inhibit gastric damage caused by a variety of ulcerogenic agents and promote healing of duodenal and gastric ulcers.
COX-1 -dominant source (physiological conditions)
COX-2 - predominates during ulcer healing.
CysLTs – constrict blood vessels (gastric damage)

41. Kidney Both the renal medulla and cortex synthesize prostanoids.
PGE2 and PGI2 – (COX-2 derived) increase medullary blood flow and inhibit tubular sodium reabsorption.
Expression of medullary COX-2 is increased during high salt intake.
COX-1-derived products promote salt excretion in the collecting ducts
PGE2 and PGI2 increase renal BF and GF through their local vasodilating effects (marginally functioning kidneys and volume-contracted states).
PGE2 and PGI2 - increase renin release

42. Eye
PGF2α - decreases intraocular pressure (IOP) effective in the treatment of open-angle glaucoma

43. CNS
The induction of fever by a range of endogenous and exogenous pyrogens appears to be mediated by PGE2
The body tempreture set points, is elevated by endogenous pyrogens (IL-1β, IL-6, TNF-α, and Interferone)
The initial phase of thermoregulatory response to pyrogens is mediated by ceramide release in neurons of the preoptic area in the anterior hypothalamus.
the late response in the endothelium of blood vessels in the preoptic hypothalamic area to form PGE2.
PGE2 can cross the blood-brain barrier and acts on thermosensitive neurons.
PD2 – increase extracellular adenosin. Facilitates induction of sleep.
COX-2-derived prostanoids are implicated in several degenerative disorders (e.g. AD, PD).

44. Pain
Inflammatory mediators, (LTs and PGs) increase the sensitivity of nociceptors and potentiate pain perception.
Both PGE2 and PGI2 reduce the threshold to stimulation of nociceptors (peripheral sensitization).
Both COX-1 and COX-2 are expressed in the spinal cord under basal conditions and release PGs in response to peripheral pain stimuli.
PGE2, PGD2, PGI2, and PGF2α, can increase excitability in pain transmission neuronal pathways in the spinal cord, (hyperalgesia and allodynia).
LTB4- hyperalgesia
Amplification system for the pain mechanism (in inflammatory process)

45. Endocrine System
PGE2 increases ACTH, growth hormone, prolactin, and gonadotropins.
Other effects (steroid production, insulin release, and thyroid-like effects).
Critical role of PGF2α (induce an oxytocin-dependent decline in progesterone levels).
PGE2 - positive-feedback loop to induce oocyte maturation required for fertilization during and after ovulation.

46. Bone PGs are strong modulators of bone metabolism.
COX-1 is expressed in normal bone
COX-2 is upregulated in certain settings (inflammation and mechanical stress).
PGE2 - bone formation and Bone resorption

47. Therapeutic Uses
Stable agonists, inhibiting eicosanoid formation, and antagonizing eicosanoid formation
Therapeutic abortion (Dinoprostone, misoprostol, and carboprost)
Gastric cytoprotection (misoprostol)
Impotence (PGE1)- second line treatment of erectile dysfunction.
Maintenance of PDA – congenital heart disease (PGE1)
Pulmonary Hypertension – long term therapy with PGI2 (epoprostenol)
Glaucoma – long term PGF2α derivative (latanoprost)