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Prostaglandins

Dr.C.V.NARASIMHA MURTHY
INTRODUCTION
 These are a class of eicosanoids and were discovered
through their effect on smooth muscle.
 Produced & released by nearly all mammalian cells;
(Except RBCs)
 Perform a variety of functions
 These are produced in minute amounts and are not
stored.
CLASSIFICATION

Cyclooxygenase Lipoxygenase
STRUCTURE
 The structure of PG is based on hypothetical 20C parent saturated acid
called “Prostanoic Acid”

 All naturally occuring PGs are 20C fatty acids containing a cyclopentane
ring.
 All PGs have:
 -OH group at 15th position
 trans double bond at 13th position
CLASSIFICATION OF PGS
 PG-E group: PGE-1, PGE-2 & PGE-3
 Functional group: βhydroxyketone
 PG-F group: PGF1α, PGF2α & PGF3α
 Functional group: 1,3-diols
 PG-A group: PGA-1, PGA-2 & 19-OH PGA-1

Functional group: β unsaturated ketone


 PG-B group: PGB-1, PGB-2 & 19-OH PGB-1


BIOSYNTHESIS
 Synthesized aerobically from polyunsaturated fatty acids.
 Multienzyme complex called Prostaglandin H Synthase (PGHS)
 PGHS has two components Cyclo-oxygenase system & Peroxidase system
 PGHS is present as two isozymes PGHS 1 & PGHS 2
 Acyl Hydrolase ( phospholipase A2), released from the cell membrane/
lysosome hydrolyses membrane phospholipids into lysophospholipids &
arachidonic acid.
 Arachidonic acid is converted to PG by oxidative cyclization with
Cyclooxygenase of PGHS ( ER, Microsomes & cell membrane)
 This system forms the first unstable cyclic endopreoxide PG-G2.
 PG-G2 is converted into PG-H2 by Peroxidase enzyme of peroxidase
component of PGHS System.
 PG-H2 is the precursor of Prostanoids
Diet

CELL

ARACHIDONIC ACID

CYCLIC-ENDO-
PEROXIDES
Peroxidase
PHYSIOLOGICAL EFFECT
CYTOTEC
 Also known as misoprostol, manufactured by Searle (pfizer)
 Cytotec was approved 12 years ago by the FDA for its intended
purpose: to prevent ulcers in people who take non-steroidal anti-
inflammatory drugs like aspirin or naproxen. misoprostol is a
synthetic PGE1 analogue
 When administered, misoprostol
 stimulates increased secretion of the protective mucus that lines
the gastrointestinal tract
 increases mucosal blood flow, thereby increasing mucosal
integrity.
 It is sometimes co-prescribed with non-steroidal anti-
inflammatory drugs (NSAIDs) to prevent the occurrence of
gastric ulceration, a common adverse effect of the NSAIDs.
 Used for inducing labor at or near term : 0.5mg/ml
 Used for terminating pregnancy: 5μg/ml
PHYSIOLOGICAL EFFECTS
PHYSIOLOGICAL EFFECT
 Platelet Aggregation &
Thrombosis
PGI2: ( Inhibit Aggregation)
 Released by endothelial cells

 Responsible for non-


adherence of platelets to
healthy blood vessels
PGE2 & TXA2: ( Promote
Clotting Process)
 Produced by platelets,
accounts for spontaneous
aggregation of platelets to
thrombin, collagen at the site
of injury
.
Major Site(s) of
Eicosanoid Major Biological Activities
Synthesis
inhibits platelet and leukocyte aggregation, decreases T-cell
proliferation and lymphocyte migration and secretion of
PGD2 mast cells
IL-1Α and IL-2; induces vasodilation and production of
cAMP

increases vasodilation and cAMP production, enhancement of


the effects of bradykinin and histamine, induction of uterine
kidney, spleen,
PGE2 contractions and of platelet aggregation; decreases T-cell
heart
proliferation and lymphocyte migration and secretion of
IL-1Α and IL-2
kidney, spleen, increases vasoconstriction, bronchoconstriction and smooth
PGF2α
heart muscle contraction
a short-lived precursor to thromboxanes A2 and B2, induction of
PGH2 many sites
platelet aggregation and vasoconstriction
inhibits platelet and leukocyte aggregation, decreases T-cell
heart, vascular
proliferation and lymphocyte migration and secretion of
PGI2 endothelial
IL-1Α and IL-2; induces vasodilation and production of
cells
cAMP
induces platelet aggregation, vasoconstriction, lymphocyte
TXA2 platelets
proliferation and bronchoconstriction
TXB2 platelets induces vasoconstriction
CATABOLISM OF PG
 Rapidly removed from circulation.
 Upto 90% PGs are destroyed in liver.
INHIBITORS
Inhibitor Example Mode of
Action
False substrates 5,8,11,14- -
eicosatetraynoic acid
(TYA)

Mepacrine - Inhibits
phospholipase A
Gluco-corticoids Cortisol, Inhibit the
Betamethasone transcription of
PGHS-2
NSAIDS Aspirin, Inhibit COO
indomethacin,
ibuprofen
Cu++ & Inhibit PGE
dihydrolipoamide formation but
increses PGF
STIMULANTS
 Trauma, hypoxia, angiotensin II, bradikinin, Vassopressin,
increase PG synthesis by activating Phospholipase A2
 Catecholamines enhance PG synthesis by activating
COO
 Addition of G-SH stimulates synthesis of PGE
NSAID: ASPIRIN
 Acetyl salicylic acid (Aspirin) is an effective anti-platelet aggregator.
 It irreversibly acetylates the platelets COO system and inhibits it thus hampering in
formation of Thromboxane A2
 At time same time it opposes the formation of PGI2 in the endothelial cells, which is
a vasodilator.

CLINICAL USES:
 Management of angina & MI

 Prevention of stroke & cerebral ischemic attacks


Source: 1971, Nature
 The aim of the study was to work out the mechanism
of action of aspirin like drugs.
 In studies carried out by Piper & Vane (1969), it was
discovered that on being challenged sensitized lungs of
guinea pigs release a substance called RCS (rabbit
aorta contracting substance) along with histamine,
prostaglandins (PGE2 & PGF2α)
 Experiment: Guinea pig lung synthesize PGs from
arachidonic acid.
 Lungs from a guinea pig were excised rapidly and
washed with ice cold buffer.
 The tissue was homogenized and centrifuged and the
supernatant was used.
 The homogenate was incubated with arachidonic acid
for 30’ at 37°C with gentle shaking.
 A zero time sample was taken.
 The reaction was stopped by heating the flask till the
proteins coagulated, then diluted in 0.9% saline.
 The samples were assayed on isolated stomach strips
& colon of rat.
 The activity was assayed by bracketing the
contractions induced by sample between smaller and
larger contractions induced by the standards.
 It was found that PGE2 contracted the stomach strips
and had no effect on colon
 PGF2α contracted the colon and had weaker effect on

stomach.
 In some experiments, the reaction was terminated by decreasing the
pH to 3 with HCl, and then extracting the sample.
 The extracts were dried under reduced pressure. The residue was
chromatographed on TLC plates with markers of authentic PGE2 &
PGF2α. The area on the strip corresponding with the marker was
scraped in a test shaken with a medium. It was then assayed on rat
colons & stomach strips.
 The zero time activity of PGE2 was 120-750ng and that of PGF2α was
60-150ng.
 This activity didn’t increase when cell extract was incubated without
arachidonic acid.
 On incubation with arachidonic acid, the activity of PGE2 increased by
100-500ng/ml and 220-520ng/ml for PGF2α.
 Experiment: Test for Inhibition
 To test the inhibition of prostaglandin synthesis, varying
amount of indomethacin, sodium acetylsalicylate, sodium
salicylate were added to the incubation flask. The inhibitor
of generation by a drug is expressed as the percentage
inhibition of the control generation.
 Indomethacin, sodium acetylsalicylate, sodium salicylate
all inhibited the generation of PG like activity.
 By calculating the ID50 it was inferred that indomethacin
was 23 times more potent than aspirin as an inhibitor of
synthesis of PGF2α and sodium salicylate was less potent
than aspirin for the same purpose.
 Similar results were obtained for PGE2 activity on stomach
strips.
 Two different lung homogenate enzyme samples were taken and
incubated with arachidonic acid.
 The zero time activity for PGF2α was 40ng/ml and that of PGE2 was
5ng/ml.
 After 30’ incubation activity increased to 160ng/ml for PGF2α and
50ng/ml for PGE2.
 After incubation with indomethacin or aspirin there was no increase in
the activity of PGs over zero time.
 The results show that the three anti-inflammatory acids inhibit the synthesis of
prostaglandins.
CONCLUSION
 The generation of prostaglandins by a cellfree enzyme
preparation in vitro was measured by bioassay.
Aspirin-like drugs inhibited the formation of
prostaglandins. This enzyme inhibition was proposed as
the mechanism of therapeutic action and side effects of
aspirin-like drugs, implicating prostaglandins in
inflammation.

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