1. Arachidonic acid is released from cell membranes and metabolized via either the cyclooxygenase pathway or lipoxygenase pathway to produce prostaglandins, thromboxanes, leukotrienes, and lipoxins. 2. These metabolites are involved in various physiological and pathological processes such as inflammation, hemostasis, smooth muscle contraction, and pain sensation. 3. Nonsteroidal anti-inflammatory drugs function by inhibiting cyclooxygenase, thereby blocking prostaglandin production and reducing inflammation.

1. ARACHIDONIC ACID METABOLISM
Dr Nainika Sharma
Dept. of Periodontics

2. HISTORY OF PG
 1930's Discovered by Kurzok & Lieb
 Characterized and named by Goldblatt &
von Euler, thought substances came from
prostate gland, hence the name
prostaglandin (abbreviated PG)
 1960 Bergstrom - elucidated chemical
structure of PGs
 1971 Vane - discovered that MOA of aspirin
is inhibition of PG formation
 mid 1970s - 80s Samuelsson - elucidated
structure of thromboxane and lipoxygenase
metabolites
 1982 Bergstrom, Vane & Samuelsson
shared Nobel Prize for work in elucidation of
the "Arachidonic Acid Cascade"
VANE
Samuelsson

3. INTRODUCTION
 ARACHIDONIC ACID is a 20 C polyunsaturated
fatty acid derived primarily from dietary linoleic acid.
 Present as a component of cell membrane
phospholipids.
 Products derived from the metabolism of
arachidonic acid affect a variety of metabolic
processes including inflammation and hemostasis.

4.  Metabolites of A.A are found in virtually all cells and
tissues.
 Each cell type appears to have a characteristic balance
of metabolites.
 Compounds are synthesized locally , on demand, and
are not stored for future release.
 They act locally in the area in which they are found and
in general do not have distant sites of action, as do
many other types of chemical modulators .

5. HOW IS ARACHIDONIC ACID
METABOLISM ACTIVATED ?
Arachidonic acid is released
from cell membranes
phospholipids via cellular
phospholipases that are
activated by mechanical,
chemical or physical stimuli
or by inflammatory mediators
such as C5a.
Metabolism proceeds along
one of the two major
enzymatic pathways.

6. CYCLOOXYGENASE PATHWAY
Thromboxane
synthase Prostacyclin
synthase
PGD2

7.  cyclooxygenase – 2 isoforms
cyclooxygenase 1 (COX-1) and cyclooxygenase 2
(COX-2).
COX-1 is normally present in most tissues.
COX-2 is normally present in brain and kidney and is
induced in most tissues during inflammation and
injury.

8. PRODUCTS OF CYCLOOXYGENASE
PATHWAY AND THEIR FUNCTIONS
 Thromboxane A2 : causes vasoconstriction,
promotes platlet aggregation
 Prostacyclin (PGI2) : causes vasodilation, inhibits
platlet aggregation
 PGD2 & PGE2 : cause vasodilation and increase
vascular permeability

9. EFFECT OF PROSTAGLANDINS ON
NERVOUS SYSTEM
 PGs are thought to be modulators of neuronal
activity They can increase or decrease release of
neurotransmitters and cause changes in behavior.
 PGs can also sensitize pain receptors.
Anandamide binds to marijuana receptors and
causes analgesia and decreased locomotion.
 PGs given intraventricularly into the brain can
induce fever.

10. EFFECT OF PROSTAGLANDINS ON SMOOTH
VASCULAR SMOOTH MUSCLE
 PGI 2 is the predominant PG produced by vascular
tissue, mainly by endothelium.
 PGI 2 and PGE 2 - relax muscle, cause
vasodilation .
 Thromboxane A2 (TxA2) – contracts muscle,
causes vasoconstriction

11. EFFECT OF PROSTAGLANDINS ON GI
SMOOTH MUSCLES
 Generally PGs increase contraction and motility.
This is often a side effect following the
administration of PGs in other body areas.

12. EFFECT OF PROSTAGLANDINS ON
UTERINE SMOOTH MUSCLES
 PGs cause contraction of uterine smooth muscle.
 PGs are approved for induction of abortion and also
for induction of full-term labor .
 Normal uterine production of PGs is thought to
contribute to menstrual cramping.
 The NSAID ibuprofen is effective in reducing
cramping.

13. EFFECT OF PROSTAGLANDINS ON GI
FUNCTION
 PGE2 and PGI2 inhibit gastric acid secretion
 induced by feeding, histamine or gastrin.
 PGs also increase GI mucous secretion.
 Inhibition of PGs by NSAIDs (except selective COX -2 inhibitors) will
therefore have pro-ulcerogenic effects (increased acid, decreased
mucous).
 For this reason, stable PG analogs (Misoprostol) are now used in anti-
ulcer therapy.
 Also, selective COX -2 inhibitors, which do not decrease GI synthesis of
protective PGs by COX-1, are available.

14.  Non-steroidal anti -inflammatory drugs (NSAIDs) inhibit
cyclooxygenase metabolism.
Aspirin - irreversibly acetylates cyclooxygenase 1 and 2
 Most other NSAIDs - reversibly, competitively inhibit cyclooxygenase 1
and 2
 Selective cyclooxygenase 2 (COX - 2) inhibitors – Celecoxib–
reversibly, competitively, inhibit COX -2, which is normally present in
brain and kidney and is induced in other tissues during inflammation.
Relatively little effect on COX-1, which is present in most tissues and
important to protect GI mucosa and induce platelet aggregation.

15. EFFECT ON ENDOCRINE SYSTEM
 Exogenous PGs can stimulate the release of
several hormones. However the exact role of PGs
in endocrine function has not been adequately
explored. PGs are known, however, to stimulate
calcium metabolism and bone resorption.

16. ROLE IN INFLAMMATION
 Arachidonic acid metabolites are important in
inflammation. Evidence supporting this conclusion
includes that:
 1. exogenous PGs and LTs can promote
inflammation.
 2. PGs and L T s are found in inflammatory
exudates.
 3. drugs which inhibit cyclooxygenase, reduce
inflammation.

17. ARACHIDONIC ACID METABOLITES
CONTRIBUTE TO INFLAMMATION BY
 Arachidonic acid metabolites contribute to inflammation by:
 1. increasing capillary permeability
 2. inducing local vasodilation and thus redness
 3. promoting infiltration of inflammatory cells
 4. production of tissue injuring oxygen
free radicals during the synthesis of PGs and LTs
 5. producing inflammation-associated hyperalgesia (increased
pain)

18. PG RECEPTORS
 There are currently nine known receptors of
prostaglandins on various cell types.
 • Prostaglandins ligate a subfamily of cell surface
seven-transmembrane receptors, G-protein-
coupled receptors.

19. ODONTOGENIC CYSTS & PG
PRODUCTION
 Odontogenic cysts produced significant quantities of
bone-resorbing prostaglandins (PGs) in tissue culture.
The follicular and periapical cysts released a mixture of
PGEs and PGFs, while the keratocysts released only
PGE2. There were also quantitative differences
between the cyst types. Follicular cysts produced small
quantities, as did keratocysts when allowance was
made for their thin walls, whereas periodontal cysts are
capable of relatively high activity

20. LIPOXYGENASE PATHWAY
5-LIPOXYGENASE
5-LIPOXYGENASE

21. LEUKOTRIENE B4
 Leukotriene B4 is one of the most potent chemotactic agents
known
 Triggers several functional responses important for host
defence.
 It causes neutrophils to adhere to vascular endothelial cells
and enhances the rate of migration of neutrophils into extra-
vascular tissues,
 secretion of lysosomal enzymes,
 activation of NADPH oxidase activity,
 nitric oxide formation
 phagocytosis.

22.  Leukotriene C4, together with LTD4 and LTE4, which
jointly comprise the slow-acting substance of anaphylaxis
are known to exert a range of pro-inflammatory effects
 constriction of the airways and vascular smooth muscle
 increasing plasma exudation and oedema,
 enhanced mucus secretion.
 They are important mediators in asthma especially, but also
in other inflammatory conditions, including cardiovascular
disease, cancer, and gastrointestinal, skin, and immune
disorders, again exerting their effects through three distinct
G-protein coupled receptors.

23.  They are important mediators in asthma especially,
but also in other inflammatory conditions, including
cardiovascular disease, cancer, and
gastrointestinal, skin, and immune disorders, again
exerting their effects through distinct G-protein
coupled receptors.

24. LIPOXIN PRODUCTION

25.  Lipoxins (LX) are a relatively new class of eicosanoids only
discovered in 1984 .
 Both in vitro and in vivo studies indicate that lipoxins help
mediate leukocyte function, inhibit chemotaxis of
polymorphonuclear leukocytes, and may have roles in
inflammation and wound healing . Lipoxin A4 is strongly
attracted to receptors on polymorphonuclear leukocytes,
especially neutrophils. It appears that LXA4 acts to oppose
some leukocyte responses to leukotrienes

26. . For example, the binding of LXA4 to polymorphonuclear
leukocytes inhibits chemotactic responses and degranulation
induced by LTB4. By competing for receptor sites, LXA4
inhibits vasoconstriction induced by LTD4 By inhibiting
neutrophil and eosinophil migration and adhesion, lipoxins act
as regulators of inflammation

27. LIPOXIN A4 AND PERIODONTITIS
 Lipoxin A4 has been found to inhibit P. gingivalis-
induced neutrophil influx, cyclooxygenase-2 expression
and prostaglandin E2 secretion, which is done without
promoting any further spreading of the infection.
 Also inhibits P.gingivalis induced reactive oxygen
species production.

28. REFERENCES
 Robbin’s Basic Pathology 9th Edition
 Harsh Mohan Textbook of Pathology 6th edition
 M.harris.Odontogenic cyst growth and
prostaglandin induced bone resorption.Ann R Coll
Surg Eng.1978 March; 60(2): 85–91.
 www.cs.stedwards.edu/chem/Chemistry/CHEM43/..
./FUNCTION.HTM