PROSTAGLANDINS

Dr. Mohammed Shakil Akhtar

 Chapter Outlines

 Introduction.
 Synthesis of Prostaglandins and Leukotrienes.
 Inhibitors of Synthesis.
 Biochemical Functions.
 Biomedical Applications.
 Introduction
 Prostaglandins (PG) and their related compounds-Prostacyclins
(PGI), thromboxanes (TXA), Leukotrienes (LT) are collectively
known as eicosaniods.

 Eicosanoids are considered as locally acting hormones with a

wide range of biochemical functions.

 Prostaglandins differ from a true hormone in :

They are formed in almost all tissues rather than in
specialized glands.
 They generally act locally rather than by circulating in the
blood to the far target tissues.
 Prostaglandins are metabolized to inactive products at their site
of synthesis and are not stored in any tissues

 Act through G-protein linked receptors to elicit their

biochemical effects
 Prostaglandins
Formed from C-20
polyunsaturated fatty
acids Arachidonic
acid to give rise to
the eicosanoids;
Prostaglandins (PG), Prostacyclin
Prostacyclin(PGI),
thromboxanes (TX),
and leukotrienes (LT). Thromboxanes

Leukotrienes
Synthesis of Prostaglandins
 The dietary precursor of the
prostaglandins is the essential
fatty acid, linoleic acid. It is
elongated and desaturated to
arachidonic acid, the immediate
precursor of prostaglandins.

 Arachidonic acid is released from

membrane-bound phospholipids by
phospholipase A2 in response to a
variety of signals like epinephrine
bradykinin and interleukins.
 Overview of Synthetic Pathway

Membrane Phospholipids
Epinephrine
Phospholipase A2
Bradykinin
Interleukins
Arachidonic Acid

Lipoxygenase Cyclooxygenase (COX)

Prostanoids
Leukotrienes (LT) Prostaglandins (PG)
Prostacyclins (PGI)
Thromboxanes (TXA2)
 Membrane Phospholipids

Phospholipase A2 - Glucocorticoids

Arachidonic Acid
Lipoxygenase
COX1 - NSAID (Aspirin) - COX2

5-HPETE PGG2
-
Celocoxib
2GSH
Peroxidase
LTA4
GSSG

PGH2
TXA2 Synthase
LTB4 LTC4 Thromboxane A2 (TXA2)
PGI2 Synthase
Prostacyclin (PGI2)
LTD4 PGF2 Synthase
Prostaglandin F2 (PGF2)
PGE2 Synthase
Prostaglandin E2 (PGE2)
LTE4
 Membrane Phospholipids

Phospholipase A2 - Glucocorticoids

Arachidonic Acid
Lipoxygenase
COX1 - NSAID (Aspirin) - COX2

5-HPETE PGG2
-
Celocoxib
2GSH
Peroxidase
LTA4
GSSG

PGH2
TXA2 Synthase
LTB4 LTC4 Thromboxane A2 (TXA2)
PGI2 Synthase
Prostacyclin (PGI2)
LTD4 PGF2 Synthase
Prostaglandin F2 (PGF2)
PGE2 Synthase
Prostaglandin E2 (PGE2)
LTE4
 Synthesis of PGH2: The first step in the synthesis of
prostaglandins is the oxidative cyclization of free arachidonic
acid to yield PGG2 by Cycloxygenase. PGG2 is then converted
to PGH2 by Peroxidase, which is dependent on reduced
glutathione

 PGH2 is converted to a variety of prostaglandins,

Prostacyclins and thromboxanes (collectively known as
prostanoids), by specific synthases.
Cycloxygenase has two isozymes, denoted as COX-1 and COX-2.

 COX-1 is present endogenously in most tissues, and

is required for maintenance of healthy gastric tissue,
renal homeostasis, and platelet aggregation.

 COX-2 is inducible in response to products of

activated immune and inflammatory cells. The increase
in prostaglandin synthesis subsequent to the induction
of COX-2 mediates the pain, heat, redness, and swelling
of inflammation, and the fever of infection.
The synthesis of prostaglandins is inhibited by a number of
compounds.

 Cortisol (a steroidal anti-inflammatory agent) inhibits

phospholipase A2 activity and, therefore, the precursor of the
prostaglandins, arachidonic acid, is not available.

 Aspirin, Indomethacin, and Phenylbutazone (Non-Steroidal Anti-

Inflammatory Agents [NSAIDS]) inhibit both COX-1 and COX-2 and,
therefore, prevent the synthesis of the parent prostaglandin, PGH2.

 Inhibition of COX-1, results in damage to the stomach and the

kidneys, and impaired clotting of blood as seen in aspirin
toxicity.

 Inhibitors specific for COX-2 (Celecoxib) reduce pathologic

inflammatory processes while maintaining the physiologic
functions of COX-1.
Cyclooxygenase-a suicide enzyme :
 Prostaglandin synthesis can be partly controlled by
suicidal activity of the enzyme Cyclooxygenase. This
enzyme is capable of undergoing self-catalysed
destruction to switch off PG synthesis.
 Biochemical Actions
Thromboxane A2 (TXA2)
 Produced by platelets.
 Promotes platelet aggregation and blood clotting
leading to thrombosis .
 Vasoconstriction.
 Contraction of smooth muscle.

Prostacyclin (PGI2)
 Produced by endothelium of blood vessels.
 Inhibits platelet aggregation.
 Vasodilatation

Thus thromboxane and Prostacyclin are antagonist in their

action. The balance between the two is important in the
regulation of hemostasis and thrombosis.
Regulation of blood pressure :

 The prostaglandins (PGE2), and Prostacyclin (PGI2) are

vasodilator in function. This results in increased blood flow
and decreased peripheral resistance to lower the blood
pressure.

Inflammation:

 The prostaglandins PGE1, and PGE2 induce the symptoms of

inflammation (redness, swelling, edema) due to arteriolar
vasodilation.
Corticosteroids are frequently used to treat these
inflammatory reactions, since they inhibit prostaglandin
synthesis
Reproduction:
 PGE1 and PGE2 cause uterine contractions and are used
for the medical termination of pregnancy and induction of
labor.

Pain and fever:

 Pyrogens (fever producing agents) promote prostaglandin
biosynthesis leading to the formation of PGE2 in the
hypothalamus, the site of regulation of body temperature.
PGE2 along with histamine and bradykinin cause pain.

 Aspirin and other non-steroidal drugs inhibit PG

synthesis and thus control fever and relieve pain.
Regulation of gastric secretion :

 Prostaglandins (PGE) inhibit gastric secretion. PGs

are used for the treatment of gastric ulcers.

Effects on respiratory function:

 PGE is a bronchodilator whereas PGF acts as a constrictor
of bronchial smooth muscles. Thus, PGE and PGF oppose
the actions of each other in the lungs.
PGE1 and PGE2 are used in the treatment of asthma.
Synthesis of Leukotrienes
 Membrane Phospholipids

Phospholipase A2 - Glucocorticoids

Arachidonic Acid
Lipoxygenase
COX1 - NSAID (Aspirin) - COX2

5-HPETE PGG2
-
Celocoxib
2GSH
Peroxidase
LTA4
+ glutathione GSSG

PGH2
TXA2 Synthase
LTB4 LTC4 Thromboxane A2 (TXA2)
- glutamate PGI2 Synthase
Prostacyclin (PGI2)
LTD4 PGF2 Synthase
Prostaglandin F2 (PGF2)
- glycine PGE2 Synthase
Prostaglandin E2 (PGE2)
LTE4
 Synthesis of Leukotrienes
 Leukotrienes are synthesized mainly in leucocytes and
mast cells, by lipoxygenase pathway of arachidonic acid.

 Arachidonic acid is converted by Lipoxygenase to

5-hydroxyeicosatetraenoic acid (5-HPETE)

 5-HPETE is converted to a series of leukotrienes, the

nature of the final products varying according to the
tissue.

 Lipoxygenases are not affected by NSAIDS.

 Leukotrienes are mediators of allergic response and

inflammation.
 Biochemical Functions
 Anaphylaxis is a violent and fatal allergic reaction.
Leukotrienes (LTC4, LTD4 and LTE4) are the components of slow-
reacting substances of anaphylaxis (SRS-A), released after
immunological challenge.

 They are more potent than histamine or prostaglandins in its

action as a stimulant of allergic reactions. Leukotrienes are
implicated in asthma, inflammatory reactions and
hypersensitivity (allergy) .

 Leukotrienes cause contraction of smooth muscles,

bronchoconstriction, vasoconstriction, adhesion of white blood
cells and release of lysosomal enzymes.
Biomedical Applications
 Prostaglandins perform diversified functions. For this reason,
PGs (or other derivatives) are the most exploited in therapeutic
applications.

Cardiovascular uses
 PGI2 (prostacyclin) and PGE2: Treatment of systemic and
pulmonary arterial hypertension.

 PGE1 is indicated for keeping the ductus arteriosus open until

surgery in neonates having certain cardiac malformations.

Digestive uses
 Misoprostol, an analog of PGE1, has antisecretory and
cytoprotective gastric effects. It decreases acid secretion and
increases pepsin, mucin and bicarbonate secretion. It is
indicated in the treatment of gastroduodenal ulcer and for the
prevention of NSAID-induced ulcers.
Gynecological and obstetrical uses

 Prostaglandins E1 and E2 induce cervical dilatation and

uterine contractions. Hence are employed in the medical
termination of pregnancy and induction of labor.

Ophthalmologic uses

 Analog of PGF2 prostaglandin, administered in ophthalmic

solution, lowers intraocular pressure by increasing aqueous
humor outflow. Hence used in treating Glaucoma.

Respiratory uses

PGE1 and PGE2 cause bronchodilation and are used in

bronchial asthma.