P R O S TA G L A N D I

NS
Bhumika Sharma
B M S III year
 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
 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 &Peroxidasesystem
 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
Cyclooxygenaseof PGHS( ER, Microsomes&cellmembrane)
 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-E NDO-
PEROXIDES
P eroxidase
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: ( InhibitAggregation)
 Released by endothelial cells

 Responsible non-
for 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
.
Eicosanoid Major Site(s) of Major Biological Activities
Synthesis
inhibits platelet and leukocyte aggregation, decreases T-cell
proliferation and lymphocyte migration and secretion of
P GD 2 mast cells
IL-1Α and IL-2; induces vasodilation and production of
cAMP

increases vasodilation and cAMP production, enhancement of

the effects of bradykinin an d histamine, induction of uterine
P GE 2 kidney, spleen,
contractions and of platelet aggregation; decreases T-cell
h eart
proliferation and lymphocyte migration and secretion of
IL-1Α and IL-2
kidney, spleen, increases vasoconstriction, bronchoconstriction and smooth
P GF 2α
h eart muscle contraction
a short-lived precursor to thromboxanes A2 an d B 2 , induction of
P GH 2 many sites
platelet aggregation and vasoconstriction

heart, vascular inhibits platelet and leukocyte aggregation, decreases T-cell

proliferation and lymphocyte migration and secretion of
P GI 2 en doth elial
IL-1Α and IL-2; induces vasodilation and production of
cells
cAMP
induces platelet aggregation, vasoconstriction, lymphocyte
TXA2 platelets
proliferation and bronchoconstriction
TXB 2 platelets induces vasoconstriction
CATABOLISM OF PG
 Rapidly removed from circulation.
 Upto 90% PGs are destroyed in liver.
INHIBITORS
Inhibitor Ex ampl e Mode of
Action
False substrates 5,8,11,14- -
eicosatetraynoic acid
(TYA)

Mepacrine - Inhibits
phospholipase A
Gluco-corticoids Cortisol, Inhibit the
Betam ethasone transcription of
PGHS-2
NSAIDS Aspirin, Inhibit COO
in domet h a cin ,
ibuprofen
Cu++ & Inhibit PGE
dih ydr olipoamide 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 C O O system and inhibits it thus hampering in
formation of ThromboxaneA2
 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, Nat ure
 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 t h a t 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
s upe r natant was used.
 The homogenate was incubated with arachidonic acid
for 30’ a t 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 t h a t 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 t h a t indomethacin
was 23 times more potent t h a n aspirin as a n inhibitor of
synthesis of PGF2α and sodium salicylate was less potent
t h a n 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 showthat 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.