SANTOSH MEDICAL

COLLEGE, GHAZIABAD
MBBS 2023-24
EICOSANOIDS

MODULATOR: PRESENTED BY:

DR. ERAM MAM PRACHI ARORA (91)
PRAKHYAT (92)
PRANSH (93)
PRASHA SHARMA
(94)
PRISHA SINGH (95)
CONTENTS
Introduction
Classification
Synthesis
Regulation and Inhibition
Functions
Biological Actions and Clinical Applications
EICOSANOIDS
They are 20 C compounds.
It is derived from arachidonic acid.
The term is now used to describe a family of
closely related derivatives of hypothetical
C20 molecule named Prostanoic acid.
They are extremely potent compounds that
elicit a wide range of responses, both
physiologic and pathologic.
Prostanoic acid
Though bearing action similarity with
hormones, eicosaniods differ from true
hormones:

Produced in small amounts in almost all

tissues rather than in specialized glands.

Acts locally rather than after transport in

blood to distant sites.

Very short lived; rapidly catabolized; and are

not stored.
PROSTAGLANDINS
1st discovered in human semen by Ulf Von
Euler in 1930; were found to stimulate
uterine contraction and reduce blood
pressure.
Presumed to be synthesized by prostate
gland hence the name.
Later realized were synthesized in all tissues
except erythrocytes.
This has a cyclopentane ring and two side
chains, with carbonyl group on one side.
Prostaglandins differ in their structure due to
substituent group and double bond on
cyclopentane ring.
NOMENCLATURE
Abbreviated as PG, with the class designated
by a capital letter A,B,C,D,E AND F, followed
by a number.
PGE AND PGF; 1st isolated from the biological
fluids.
The letters refer to different rings structure,
except in PGG and PGH: same ring structure.
In the same series, depending upon double
bonds on the side chains designated as
PGE1, PGE2, PGE3.. etc.
PGD2, PGE2, PGF2 and pgi2 and
thromboxane A2 are widely distributed.
THROMBOXANES
Named so because they are identified first in
thrombocytes.
Structure is similar to PGs, but have an
oxygen atom in the cyclic ring and contains a
six numbered heterocyclic oxane ring.
The most common thromboxane, TXA2,
contains an additional oxygen atom attached
both to carbon 9 and carbon 11 of the ring.
TXA2- Vasoconstriction and platelet
aggregation thus helping clot formation.
Inhibited by aspirin.
TXB2- A stable degradation product of TXA2,
plays a role in acute hepatoxicity induced by
acetaminophen.
CYCLOOXYGENASE PATHWAY-CYCLIC PATHWAY
(SYNTHESIS OF PROSTAGLANDINDS AND
THROMBXANES)

Occurs in endoplasmic reticulum.

In humans, the most important precursor for
prostaglandins is arachidonic acid, a
polysaturated fatty acid with four double
bonds.
Stored in cell membrane as the C2 ester of
phosphatidylinositol and other phospholipids.
The dietary precursor of the prostaglandins
is the essential fatty acid, linoleic acid.
Site: in all types of mammalian cells except
RBCs.
1.RELEASE OF ARACHIDONIC ACID:

Arachidonic acid is incorporated into

membrane- bound phospholipids.
Initially, arachidonic acid is released from
these phospholipids by phospholipase A2 in
response to a variety of signals. It is
activated by hormones like epinephrin,
bradykinin etc.
2.SYNTHESIS OF PGH2: synthesis is oxidative
1st step in prostglandin
cyclization of free arachidonic acid to yield
PGH2 by prostagladin endoperoxide synthase.
PGH synthase exhibits 2 catalytic activities:
Cyclooxygenase (COX) and peroxidase.
Initial step: Catalyzed by a cyclooxygenase
and forms the five- membered ring with the
addition of 4- atoms of oxygen. 2 between C-9
and 11, and 2 at C-15 to form an unstable
endoperoxide, PGG2.
The hydroperoxy group at C-15 of PGG2 is
quickly reduced to a hydroxyl group by a
peroxidase to form another endoperoxide,
PGH2.
3.CONVERSION OF PRIMARY PROSTAGLANDIN
TO OTHER EICOSANIODS:

Enzymes-> cell specific, like: PGE synthase

and PGD synthase and so on.

Thus, vascular endothelium produces PGE

and PGI and platelets produce
thromboxanes(TXs).

In kidney and spleen,

Isomerase catalyses production of PGE2

Reductase catalyses production of PGF2.

 THROMBOXANE
They are highly active metabolites of the PGG2
and PGG2 type prostaglandin endoperoxides that
have the cyclopentane ring replaced by a six
membered oxygen containing ring.
The word thromboxane is derived from the fact
that these compounds have a thrombus forming
potential.
Thromboxane A synthase, present in the
endoplasmic reticulum, is abundant in lung and
platelets and catalyzes conversion of
endoperoxide PGH2 to TXA2.
The half life of TXA2 is very short in water as the
compound is transformed rapidly into inactive
thromboxane B2(TXB2).
REGULATION OF PROSTAGLANDIN
SYNTHESIS
INHIBITION:
Cortisol- inhibits phosphholipase A2 activity.
NSAIDs like aspirin, indomethacic, ibuprofen,
phenylbutazone inhibit both COX-1 and COX-
2 and thus prevent the synthesis of parent
prostaglandin, PGH2.
These NSAIDs have side effects like
gastrointestinal ulcers and renal
disturbances.
NSAID like Celecoxib is selective COX-2
inhibitors, thus are free from those side
effects.
Aspirin acetylates serine at the active site
and irreversibly inhibits cyclooxygenase.
Other NSAIDs: act as reversible inhibitors of
cyclooxygenase.
In platelets: TXA2 is not formed in aspirin
medication. So the is decreased platelet
aggregation.
Therefore, aspirin is useful in preventing
heart attacks(MI).
In endothelial cells: aspirin is useful PGI2
synthesis; but after few hours the endothelial
cells resynthesize cyclooxygenase.
Platelets cannot resynthesize
cyclooxygenase because -> they lack nuclei
and therefore cannot synthesize new mRNA.
Thus, aspirin completely blocks TXA2, but
only partially inhibits PGI2.
This difference is the basis of low- dose
aspirin therapy used to lower the risk of
stroke and heart attacks by decreasing
formation of thrombi.
Cyclooxygenase is a “suicide” enzyme.
PGs have very short half life about 30
seconds.
They are inactivated by 15-hydroxyl-
prostaglandin- dehydroenase which converts
15-OH group to keto group.
ACTIVATORS:
Bradykinin, epinephrine, thrombin,
angiotensin II, and vasopressin. Activates
phospholipase A2.

Catecholamines activates cyclooxygenase.

 BIOLOGICAL ACTIONS AND CLINICAL
APPLICATIONS OF PROSTAGLANDINS AND
THROMBOXANE
1. EFFECT ON CVS:
Prostacyclin or PGI2- is synthesized by the
vascular endothelium.
Vasodilatation
Inhibits platelet aggregation and has a
protective effect on vessel wall against
deposition of platelets.
Platelets attempting to stick to blood vessel
wall release endoperoxidase which enhance
production of prostacyclin by vascular
endothelial cells.
But any injury to the vessel wall inhibits PGI2
synthesis and promotes TXA2 synthesis
which causes
Vasoconstriction
Platelet aggregation
Thus, prostacyclin and thromboxane are
opposing in activity.
2. EFFECT OF OVARY AND UTERUS:
PGE2 and PGF2 stimulate uterine muscles to
contract and may be used in medical
termination pregnancy, inducing labor and to
control postpartum hemorrhage.
PGs are involved in LH induced ovulation.
In cattle, if PG is given, luteolysis takes place
and animal goes into estrus.
Better fertilization rate is achieved with
timely artificial insemination.
3. EFFECT ON RESPIRATORY TRACT:
PGF is a constrictor of bronchial smooth
muscle.
PGE is a potent bronchodilator. PGE series
are used in aerosols for relieving
bronchospasm.
4. EFFECT ON IMMUNITY AND
INFLAMMATION:
PGE2 and D2 produce inflammation by
increasing capillary permeability.
Thus, intradermal injection of PGs in man
causes wheal and flare similar to histamine
at the site of injury.
PG-E1 -> potent platelet aggregation
inhibitor.
So, it is useful for storage of blood platelets
for transfusion.
Moreover, PGEs secreted by macrophages ->
may decrease B and T lymphocyte functions.
5. EFFECT ON GI TRACT:
PGs in general inhibit gastric secretion and
increase intestinal motility.
The inhibitory effect on gastric secretion is
used therapeutically in treatment of acid
peptic disease.
Diarrhea may be unwanted side effect.
LEUKOTRIENS
They are produced from arachiodonic acid.
LT B4 is produced in neutrophils; it is the most
potent chemotactic agent. The number 4
denotes that there are 4 double bonds in the
structure.
The 12-lipo-oxygenase in platelets produces 12-
hydroxyeicosatetraeonic acid ( 12-HETE) and 15-
lipo-oxygenase in eosinophils produce 15-HETE.
The slow reacting substance of anaphylaxis (SRS-
A) contains LTC4, LTD4,LTD4 and LTE4.
They cause smooth muscle contraction, constrict
the bronchiolitis, increase capillary permeability,
activate leukocytes and produce
vasoconstriction.
LIPOXINS
They are group of compounds produced by
leukocytes.

They are conjugated tetraenes.

They are formed by sequential action of 5

and 15-lipo-oxygenase.

LXA4 is the most common immune response.

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