Lipid chemistry

1. EICOSANOIDS
(Part-I)
Prostanoids t.&-- -
EICOSANOIDS Leukotrienes (LTs)
Lipoxins
Lipid Chemistry- 11
Prostaglandins
Prostacyclins
Thromboxanes

2. Specific Learning Objectives
FDefine eicosanoids
2. Classify eicosanoids with examples.
3. Describe the synthesis of prostanoids in brief.
4. Describe the therapeutic ust•s of prostaglandins.
5. Describe the hibito ofeicosanoid synthesis & their therapeutic uses.

3. 10
Chemical Structure of Prostaglandins
OH
20
COOH
20
COOH
20
Prostanoic acid
PGE2
PGF2a

4. OH
20
COOH
20
PGI2

5. Prostaglandins
• Derivative of prostanoic acid (20 C Fatty acid)
Prosta noic acid
PGs are most potent biologically active substances.
Prostaglandins ITrue Hormones l
Site of Production
All tissues Specialized endocrine
(except erythrocytes) organs
Site ofAction
l..ocal action Far away from
(Paracrine effect) site of production
Metabolism Near site ofsynthesis Site distant from
sire of origin
PGs are produced in very small amounts and have low half-lives.

6. I
1 series
Classification of Prostaglandins
9 Classes of PGs are known
PGA, PGB, PGC, PGD, PGE, PGF, PGG, PGH, PGI
PGs are classified into three series.
-
I
2 series 3 series
(1 double bond) (2 double bonds) (3 double bonds)
from from from
Linoleic acid Arachidonic acid Linolenic acid
PGE1 PGE2 PGE3
Most common & naturally occurring
Primary prostaglandins -- Commonly found throughout the body
PGE1, PGFia. PGE2, PGF2a, PGG2, PGH2, PGI2
u

7. Biosynthesis of Prostaglandins & Thromboxanes
IMembrane bound Phospholipid(Lecithin) I
~ Phospho/ipase A2
Lysophospholipid ~ J
+ Epinephrine/Tbrombin/Bradykinin
Phospholipase C
Phosphatidylinositol - - - - - Arachidonic acid
Lipo-oxyg!!nase _[ ___~
I L k . I
: eu otnens :
L
Lipoxins __ :
I
ICyclo-oxygenase +Catecholamines
PGG2
Peroxidase
PGH2
2 GSH
GSSG

8. Biosynthesis of Prostaglandins & Thromboxanes
PGI Synthase
r
PGl2
Endothelium
Prostacyclins
~ merase
1
l
lsomerase
l
TXA Synthase I
PGD2 ___ PGE
2
TXA2
Mast cells / l Platelet
Reductase Thromboxane A,
Adenyl cyclase - - - PGF2a
Biological +-CAMP +---- ATP
effects

9. Biological actions
Prostacyclins Thromboxanes
• Vascular endothelium • Platelets
• Vasodilatation • Vasoconstriction
• Inhibit platelet aggregation • Cause platelet aggregation
• Prevents thrombus formation • Promote thrombus formation

10. Biological Actions and Clinical Applications
~ Effects on CVS • Prostacyclin or PGI2 (vascular endothelium.)
-inhibits platelet aggregation caused by TXA2
-protective effect on vessel wall against deposition
of platelets.
• Vascular Endothelial injury - decrease PGI2-Platelet
aggregation -Thrombosis
• PGE2-Vasodilation-Decreases BP
• PGF2a- Vasoconstriction- Increases BP

11. Biological Actions and Clinical Applications
['Effects on Ovary and Uterus I■ The PGFzastimulates the uterine muscles.
Effects on Respiratory Tract
■ used for medical termination ofpregnancy.
■ Inducing labour to hasten delivery ofa baby.
■ PGE-Arresting postpartum Haemorrhage.
■ The PGF2a is a constrictor ofbronchial smooth muscle
■ But PGE2 is a potent bronchodilator.
■ PGE series are used in aerosols for relieving
bronchospasm

12. Biological Actions and Clinical Applications
Effects on GIT
Effects on Kidney
■ PGs in general inhibit gastric secretion and increase
intestinal motility.
• Enhance mucin secretion
■ Used therapeutically in treatment ofacid peptic disease.
• PGs cause vasodilation in kidney- increased blood flow-
increased urinary output.
• Increase Na, K, Cl absorption from renal tubules.

13. Biological Actions and Clinical Applications
Effects on Immunity and Inflammation
• The PGE2 and D2 produce inflammation by increasing
capillary permeability.(Erythema and wheal)
• PGE2 reduces both T and B cell functions.
• PGE2 is a sleep promoting substance.
• PGE2 decreases lipolysis
IMetabolic effects I • Increases glycogenesis
• Mobilizes Calcium from bones

14. Inhibitors of Prostanoid synthesis
IMembrane bound Phospholipid I
~ Phospholipase A2
Corticosteroids u,
+ Epinephrine/Thrombin/Bradykinin
. - - - -.....;3:.,___ __,
Arachidonic acid
• Phenylbutazone ~ Cyclo-oxygenaseI"suicide" enzyme I
• Aspirin ~
• Indomethacin ~
• Ibuprofen + Catecholamines
INSAIDs l PGG2
PGH2
COX-1 constitutive form
COX-2 Inducive form

15. COX (Cyclo-oxygenase)
COXI
• Constitutive enzyme
• Not regulated, Level is constant
• Selectively inhibits gastric secretion
including HCI without decreasing
mucin secretion
(Protective to gastric mucosa)
• Required for maintenance ofhealthy
gastric tissue, renal homeostasis,
platelet aggregation
COX II
• Inducible by inflammatory stimuli
like cytokines, growth factors etc.
• Major mediator ofinflammatory response
(production of pro-inflammatory PGs like
PGD2 & PGE2 to produce pain, fever, swelling
~

16. Therapeutic Uses ofinhibitors
• Aspirin ~ IArachidonic acid I
• Phenylbutazone !(:'I
• Indomethacin ::,I Cyclo-oxygenase (COX)
• Ibuprofen
I PGG2 1
INSAIDs l
Inhibit both COX I & II
I
Leads to gastritis
Nephrotoxicity
Impaired blood clotting
ICelecoxib I
Specific COX II inhibitors
Decrease inflammation, pain, fever but
maintain protective effect of COX on
gastric mucosa.

17. I ❖ Low dose Aspirin(75mg/day) in CAD (prevention ofheart attacks).
Platelet
J
NoTXA2
Decreased
Platelet Aggregation
&
thrombus formation
J
Arachidonic acid
PGG2
Platelets cannot regenerate COX
Endothelial cells
Lowdose-
No significant action
J
Completely blocks TXA2
Partially inhibits PGI2
J
Resynthesize cyclooxygenase.
e

18. Leukotrienes & Lipoxins
Eicosanoids
• Prostaglandins
r Arachidonic acid ~
Prostanoids I ~iuoxin,i
I
Leukotrienes
• LXA4
• LTA4 • LXB4
• LTB4
• Prostacyclins • LTC4
• Thromboxanes • LTD4
• LTE4
OH OH
OH OH
' I
COOH
HO OH
COOH
LTB4
COOH
a

19. Biosynthesis of Eicosanoids
IMembrane bound Phospholipid(Lecithin) I
~ Phospholipase A2
Lysophospholipid .-/ J
+ Epinephrine/Thrombin/Bradykinin
Phospholipase C
Phosphatidylinositol - - - - ~ Arachidonic acid
Lipo-oxygenase
I L k . i
1 eu otnens 1
I I
: Lipoxins __ :
Cyclo-oxygenase +Catecholamines
• Prostaglandins
PGH2 - --..i • Prostacyclins
• Thromboxanes

20. Lipooxygenase
5-LOX 12-LOX 15-LOX
Arachidonate Arachidonate Arachidonate
5-lipoxygenase 12-lipoxygenase 15-lipoxygenase
1--_..t--'
Leukotrienes ---~ Lipoxins
White blood cells (leukocytes),
mast cells, lung, spleen,
brain and heart
a

21. Biosynthesis of Leukotrienes
Arachidonic acid
5-lipo-oxygenase4ij~j=- 5-LOX activating protein
-__,;i~----,
5-HPETE
5-hydroperoxyeicosatetraenoic acid
LTA4 hydrolase '
LTA4
Neutrophils LTB
Monocytes 4
Glutathione """"--I ,TC sy th
One ofthe most potent l L 4 n ase Mast cells
inflammation-mediating lipids Eosinophils
,,,,' LTC4
,,,, .rt
,,
,,,,'Glutamate
Slow-reacting substance "'
ofanaphylaxis (SRSA) +--------------- LTD4
.... ~
............ Glycine
............
........ LTE
4

22. Functions of Leukotrienes
Inflammation and immediate hypersensitivity reactions
LTB4
• Increased chemotaxis of
polymorphonuclear leukocytes
• Release of lysosomal enzymes
• Adhesion of white blood cells
• Contraction of smooth muscle
• Bronchoconstriction
• Vasoconstriction
• Slow reacting substance of anaphylaxis
• Involved in pathophysiology ofAsthma

23. Biosynthesis of Lipoxins
[Arachidonic acid
l5-/ipo-oxygenase
Leukocytes
15-HPETE I
l
LTA4 -""?"''-----
12-/ipo-oxygenase
Most common variety LXA4 LXB4
L..-...:.J- - - -1---...:..J
Arachidonic acid
15-/ipo-oxygenase
15-HPETE
Epithelial cells
(Airway)
Leukocytes

24. Lipoxins: Biochemical functions
~
• They are anti-inflammatory and decrease immune response.
• Counteract the actions ofthe pro-inflammatory eicosanoids (primarily LTB4 but also
PGE2 and TXA2).
• They inhibit neutrophil chemotaxis and adhesion to endothelium.
• Block IL-8 (chemokine) expression, block TNF-a release and actions, stimulate TGF-~ action
• Stimulate phagocytosis & superoxide ion generation to kill microorganisms
• Immunoregulatory function.

25. Inhibitors of Leukotrienes & Lipoxins
Leukotriene receptor antagonists Lipoxygenase inhibitors
M
onte!ulcasj
Useful in the treatment ofasthma
(5-lipoxygenase inhibitor)
Used to preventwhet ing, shortness ofbreath,
coughing, and chest tightness due to asthma
IX,
-=--..... Normal airway
C ft~
.-----•Asthmatic airway
a