The Eicosanoids: Prostaglandins (PG) Thromboxanes Leukotrienes Related Compounds

1. The Eicosanoids: Prostaglandins (PG) Thromboxanes Leukotrienes Related Compounds

2. Eicosanoids

• Oxygenated products of
polyunsaturated, long-chain, fatty acids
From Greek eikosi ("twenty")
• Found in animals & plants
• Highly potent
• Wide spectrum of biologic activity

3.

4. Linolenic acid an omega 3 fatty acid

• component of cell membranes
• essential for normal growth and development
• converted to longer chain omega-3 fatty acids:
eicosa pentaenoic acid (EPA)
( major constituent of oils from fatty fish like salmon)
&
docosa hexaenoic acid (DHA)
• These omega-3 fatty acids protect
CAD, sudden cardiac death, heart failure
through anti
- arrhythmic,-thrombotic,
-atherosclerotic, -inflammatory mechanism

5. ARACHIDONIC ACID (AA) 5,8,11,14-eicosa tetra enoic acid

• An omega-6 fatty acid 20:4(ω-6)
• arachis – peanut
• AA, derived from:
1-dietary linoleic acid (a omega 6 Fatty acid)
2- as dietary constituent ingested
• Released/ mobilized from membrane phospholipids by one
or more lipases : phospholipase A 2 (PLA 2 )
• AA transformed into metabolites called eicosanoids

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7.

8.

9. Types of Phospholipases

1- Cytosolic (c) PLA 2:
Chemical & physical stimuli, Ca dependent,
high affinity for AA, acute release of AA
2- Inducible secretory (s) PLA 2:
in sustained or intense stimulation produce AA
3- Ca -independent (i) PLA 2
Under non-stimulated conditions, liberated AA
reincorporated into cell membranes
negligible eicosanoid biosynthesis
4- Combination of PLC & di glyceride lipase

10.

11. Prostanoids: PGs, TXA, prostacyclin

• Generated from PGH 2 by terminal enzymes
isomerases & synthases
• Expressed in relatively cell-specific fashion
• Chemical Differences of PGs :
(1) substituents of pentane ring ( E in PGE )
(2) number of side chains double bonds
(subscript :PGE 1, 2 )

12.

13. Shift in product formation by changing precursor

• ThromboxaneA2 (TXA 2 ), powerful vasoconstrictor &
platelet agonist, synthesized from AA via COX
• metabolism of EPA by COX→ TXA3 relatively inactive
• Fatty acids of cold-water fish & plant substitute AA
dietary EPA supplement →
↓cardiovascular disease & cancer
• 3-Series PG eg:PGE3 , partial agonists or antagonists
of 2-series PG

14. Endoperoxide Synthases (Cyclooxygenases)

• PGH synthase-1 (COX-1) expressed constitutively in most cells
• produce prostanoid for housekeeping: gastric epithel. protection
• PGH synthase-2 (COX-2) inducible by stimulus
• immediate early-response gene product
• up-regulate by:
shear stress, growth factors, tumor promoter, cytokines
major source of prostanoids in inflam. & cancer
• Exceptions:
1- Endothel. COX-2: constitutive prostacyclin (PGI 2)
2- Renal COX2-derived prostanoids:
normal renal develop/function

15.

16. PGH 2 metabolism products

PGI 2
TXA 2
PGE2
PGF 2α
By:
prostacyclin, thromboxane, PGE & PGF synthases
(PGIS, TXAS, PGES & PGFS)

17.

18. Enzyme types

2 enzymes for PGF 2α synthesis:
9,11-endo peroxide reductase from PGH 2
9-keto reductase from PGE 2
3 enzymes for PGE 2 synthases:
microsomal (m) PGES-1
more inducible mPGES-2
cytosolic PGES
2 enzymes for PGDS isoforms:
lipocalin-type
hematopoietic PGDS

19. Products of Lipoxygenase

• AA metabolism by 5-, 12-, 15-lipoxygenases (LOX)
→ hydro peroxy eicosa tetraenoic acid (HPETEs)→
hydroxy derivatives (HETEs) & leukotrienes
• most investigated leukotrienes: products of 5-LOX

20.

21. Sites of leukotrienes synthesis

• 5-LOX present in:
leukocyte
(neutro-,baso-, eosin & monocyte-macrophages),
dendritic
mast cell

22. Transcellular biosynthesis

• Non-leukocyte cells (eg, endothel. cells)
have enzymes downstream of 5-LOX/FLAP
take up & convert leukocyte-derived LTA 4
or
endothelial cell use platelet PGH2 to synthesis PGI2

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24.

25. LTC 4 & LTD 4

LTC 4 & LTD 4
• Slow-reacting substance of anaphylaxis (SRS-A)
• secrete in asthma & anaphylaxis
• Potent bronchoconstrictor
Antileukotriene drug development:
1- 5-LOX enzyme inhibitors
2- leukotriene-receptor antagonists
3- inhibitors of: FLAP & phospholipase A 2

26. Isoprostanes

• COX independent production
Not formed by COX so not inhibited by
aspirin/NSAIDs
• Large amount
x10 greater in blood/urine than COX derived PG
• Storable

27. Isoprostanes Functions

• Biomrker of oxidative stress
• Potent vasoconstrictor
in infu. to renal & other vessels
• may activate prostanoid receptors
• Leukocyte & platelet adhesive interactions
angiogenesis, inflam.
• Multiple isoprostanes formed coincidentally in oxidant
stress→ difficult to assess their biologic functions

28. Receptor Mechanisms

• Eicosanoids, not circulating hormone, Short t1/2
• Ligands bind to G Pr -coupled receptors on cell
surface in autocrine/ paracrine fashion
• A single gene product identified for:
PGI 2 (IP), PGF 2α (FP), & TXA 2 (TP) receptors
• 4 distinct PGE 2 receptors (EPs 1–4) &
2 PGD 2 receptors

29. 1- Vascular Smooth Muscle Vasoconstrictors eicosanoids

1-TXA 2 potent
Only SMC mitogen eicosanoid
SMC exposure to testosterone up-regulates SMC TP
expression
2- PGF 2α
3- Isoprostane 8-iso-PGF 2α ( iPF 2 αIII)
via TP receptor

30. Vasodilatation

1- Vascular PGI 2
synthesis by COX-2 in SM & endothel. cells (major)
inhibits SMC prolif., use in pulmonary HT
2- PGE 2 produced by endothel.cells
vasodilator in microcirculation
↑ cAMP & ↓ Ca of SM, via IP & EP 4 receptors
3- PGD 2 vasodilator esp in niacin- induced flushing

31. 2. Gastrointestinal tract smooth muscle

• Contraction:
Longitudinal muscle by & PGF 2α & PGE2 (via EP3)
(via FP)
Circular muscle by PGF 2α & weakly by PGI 2
use of PGE 2 or PGF 2α → colicky cramps
• Powerful contract. by Leukotrienes
o Relaxtion by PGE 2 (via EP 4 )

32. 3. Airways Respiratory SM

• Relaxed by PGE 2 & PGI 2
• Constrict by PGD 2, TXA 2, PGF 2α, cysteinyl LT
> histamine
also stimulate mucus secretion→ mucosal edema
• Bronchospasm in 10% of NSAID users, Shift AA
from COX metabolism to leukotriene formation

33. B. Platelets

• Low concent. PGE 2 ↑aggregation (via EP 3 )
• higher concent. inhibit (via IP)
PGD 2 (via DP 1), PGI 2 (via IP) inhibit aggregat.
↑cAMP

34. TXA 2 & Aspirin

TXA 2 & Aspirin
• ↑ TXA 2 synthesis in platelet activation /aggregation
↑ urinary metabolites of TXA2 in MI & stroke
• Irreversible inhibit of TXA 2 biosynthesis by
chronic low dose aspirin
10% TXA2 synthesis by macrophage COX-2 in smoker
insensitive to low-dose aspirin
o Inverse dose-response relation of Aspirin:
inhibit of PGI 2 synthesis at higher doses

35. BP & renal function regulation

BP & renal function regulation
• Cortical COX2-derived PGE2& PGI2
1- maintain RBF & GFR via local vasodilating
esp in marginally functioning kidney &
volume-contract state
2- modulate systemic BP regulation water&Na excr
• ↑medullary COX -2 express & mPGES-1
in high salt intake
• COX- 2-derived prostanoids ↑medullary blood
flow & inhibit tubular Na reabsorption

36. Hypertension (HT)

• HT associated ↑TXA 2, ↓PGE 2 & PGI 2 synthesis
in some animal models
• ↑TXA 2 formation in cyclosporine nephrotoxicity
PGF 2α may ↑ BP by renin release
FP antagonists potential antihypertensives

37. Central sensitization

• Peripheral pain stimulus →
↑spinal COX-1 &2 & PG release
• PG (mainly PG E2)→ ↑excitability spinal dorsal
horn neurons
1- ↑ pain intensity
2- extent area of pain perception
3- pain from normally innocuous stimuli

38. Bone Metabolism

• PG abundant in skeletal tissue
• produced by osteoblasts & hematopoietic cells
• major effect (esp PGE 2, acting on EP 4 )
↑bone turnover, stimulate resorption/ formation
• PG may mediate effects of mechanical forces on
bones & bone changes in inflam.

39. COX inhibitors musculoskeletal effects

• Slow skeletal muscle healing
interfere with PG effects on myocyte prolif.,
differentiation, fibrosis in response to injury
• NSAIDs, esp COX-2 inhibitors
delay bone healing in experimental fractures
• NSAID benefit? in Menopausal bone loss by PG

40. H. Eye

• PGE & PGF derivatives lower intraocular pressure
• mechanism? ↑ outflow of aqueous humor from
anterior chamber via uveoscleral pathway

41. PGE2 & cancer

PGE2 & cancer
• Principal oncogen: initiation, progress, metastasis via
↑prolif. Angiogenesis, invasiveness,
immunosuppress, inhibit apoptosis
• ↑express mPGES-1 in tumor, potential use of inhibit.
• ↓carcinogenesis in mice lack EP 1, 2, 4 receptor
Transactivation of epidermal growth factor receptor
linked with oncogenic activity of PGE 2
• TXA 2 procarcinogen
macrophage COX-2 /platelet COX-1 derived

42. Cancer & NSAIDS

Cancer & NSAIDS
• Pharmacol. inhibit or genetic delet. of COX-2→
inhibit tumor formation in models of colon, breast,
lung,….
• Incidental NSAIDs use ↓ risk of these cancers
• Chronic low-dose aspirin not lower incidence but
↓cancer death
• , COX ihibit. ↓ polyp formation in familial polyposis
• NSAID →↓Breast cancer risk esp in hormone recpt +

43. Syntheyic PG analogues

• Alprostadil (PGE 1 ) SM relaxant
1- infu. for maintain ductus arteriosus patent in
neonates with vessels transposition awaiting
cardiac surgery
2- treatment of impotence by inj, into cavernosa

44. Misoprostol (PGE1 analog)

1-approved for peptic ulcers prevention
• cytoprotective in high doses NSAIDs use for arthritis &
history of associated ulcer
2- combination with progesterone antag.: mifepristone
(RU 486)
extremely effective/safe abortifacient in early pregnancy
Or Plus MTX
• Side effect: diarrhea

45. Prostacyclin (PGI2) analogues

• epoprostenol in severe pulmonary
/portopulmonary HT &
prevent platelet aggregation in dialysis Machines
Thromboxane (TXA 2) undesirable
(aggregation of platelets, vasoconstriction)
TXA 2 –receptor antagonists & synthesis inhibitors

46. Ophthalmology—Latanoprost

• PGF2α derivative
• extensive use topically in open-angle glaucoma
• Bimatoprost, travoprost, unoprostone
newer, related drugs
↑outflow of aqueous humor→↓intraocular press.
Iranian & Pfizer

47. COXs inhibition by Nonsteroidal anti-inflammatory drugs (NSAIDs)

• Traditional NSAIDs not selective for COX-1 or -2
• Individual variability in selectivity
• Indomethacin & sulindac slightly selective for
COX-1
• Meclofenamate & ibuprofen: COX-1 = COX-2
inhib.

48. Celecoxib

• Selectively inhibit. of COX-2
• Advantage in patients seeking for pain relive
while suffering from peptic ulcer disease
• An expensive drug

49. Aspirin

• Acetylates & irreversibly inhibits both COX1 &
COX2 enzymes covalently
• Low doses (< 100 mg/d) inhibit platelet COX-1
(only isoform in mature nonuclei Platelet)→
inhibit of TXA 2 biosynthesis

50. Leukotrienes antagonists

1- 5-LOX inhibitor: zileuton
2- Selective CysLT 1 receptor antagonists:
montelukast, zafirlukast,, pranlukast
• in mild to moderate asthma
(less effective than inhaled CS)

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