Postaglandins & their related compounds

prostacyclins (PGI), thromboxanes (TXA),

leukotrienes (LT) & lipoxins are collectively

known as eicosaniods, they all contain 20C.

Structure of prostaglandins:

Prostaglandins are derivatives of 20-carbon

fatty acid - prostanoic acid, hence known as

prostanoids.

This has a cyclopentane ring (formed by

carbon atoms 8 to 12) & two side chains, with

carboxyl group on one side.

Prostaglandins differ in their structure due to

substituent group & double bond on

cyclopentane ring.

Most important prostaglandins (PGF2 &

PGF2α), prostacyclins (PGI2), thromboxanes

(TXA2) & leukotrienes (LTA4).

Arachidonic acid (5,8,11,14 - eicosatetraenoic

acid) is the precursor for most of the

prostaglandins in humans.

It occurs in the endoplasmic reticulum.

Release of arachidonic acid from membrane

bound phospholipids by phospholipase A2.

It occurs due to a specific stimuli by

hormones – epinephrine or bradykinin.

Oxidation & cyclization of arachidonic acid

to PGG2 which is then converted to PGH2 by

peroxidase.

PGH2 serves as the immediate precursor for

the synthesis of a number of prostaglandins,

including prostacyclins & thromboxane.

This is known as cyclic pathway of

arachidonic acid.

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.

Corticosteroids (e.g. cortisol) prevent the

formation of arachidonic acid by inhibiting

the enzyme phospholipase A2.

Anti-inflammatory drugs inhibit the synthesis

of prostaglandins, prostacyclins &

thromboxane.

They block the action of cyclooxygenase.

Aspirin irreversibly inhibits cyclooxygenase.

All the eicosanoids are metabolized rapidly.

Degradation occur in lung & liver.

Two enzymes, namely 15-α-hydroxy PG

dehydrogenase & 13-PG reductase, convert

hydroxyl group at C15 to keto group & then

to C13 and C14 dihydroderivative.

Prostaglandins act as local hormones.

PGs are produced in almost all the tissues.

PGs are not stored & they are degraded to

inactive products at the site of their

production.

PGs are produced in very small amounts &

have low half-lives.

Regulation of blood pressure:

The prostaglandins (PGE, PGA & PGl2) are

vasodilator in function.

This results in increased blood flow and

decreased peripheral resistance to lower the

blood pressure.

PGs serve as agents in the treatment of

hypertension.

Inflammation:

PGEI & PGE2 induce the symptoms of

inflammation (redness, swelling, edema etc.)

due to arteriolar vasodilation.

PGs are natural mediators of inflammatory

reactions of rheumatoid arthritis, psoriasis,

conjunctivitis etc.

Corticosteroids are used to treat these

inflammatory reactions, since they inhibit

prostaglandin synthesis.

Reproduction:

PGE2 & PGF2 are used for the medical termination of

pregnancy & induction of Iabor.

Pain and fever:

Pyrogens (fever producing agents) promote

prostaglandin synthesis leading to the formation of

PGE2 in hypothalamus-regulation of body temperature.

PGE2 along with histamine & bradykinin cause pain.

Migraine is also due to PGE2.

Aspirin & other non-steroidal drugs inhibit PG synthesis

& thus control fever & relieve pain.

Regulation of gastric secretion:

Prostaglandins (PGE) inhibit gastric secretion.

PGs are used for the treatment of gastric ulcers.

PGs stimulate pancreatic secretion & increase

the motility of intestine which often causes

diarrhea.

Influence on immune system:

Macrophages secrete PGE which decreases the

immunological functions of B-& T-lymphocytes.

Effects on respiratory function:

PGE is a bronchodilator whereas PGF acts

as a constrictor of bronchial smooth

muscles.

PGE & PGF oppose the actions of each other

in the lungs.

PGEI & PGE2 are used in the treatment of

asthma.

Influence on renal functions:

PGE increases glomerular filtration rate &

promotes urine output.

Excretion of Na+ & K+ is also increased by PGE.

Effects on metabolism:

Prostaglandins influence certain metabolic

reactions, through the mediation of cAMP.

PGE decrease lipolysis, increases glycogen

formation & promotes calcium mobilization.

Platelet aggregation & thrombosis:

The prostaglandins – prostacyclins (PGI2),

inhibit platelet aggregation.

Thromboxanes (TXA2) & prostaglandin E2

promote platelet aggregation & blood

clotting that might lead to thrombosis.

Mechanism of action of PGs:

PGE increases cAMP & PGF increases cGMP.

They are used in the treatment of gastric

ulcers, hypertension, thrombosis, asthma etc.

Prostaglandins are also employed in the

medical termination of pregnancy,

prevention of conception, induction of labor

etc.

Leukotrienes are synthesized by leucocytes,

mast cells, lung, heart, spleen etc., by

lipoxygenase pathway of arachidonic acid.

Leukotrienes (A4, B4, C4, D4 & E4) are

synthesized through the intermediate, 5-

hydroperoxyeicosatetraenoic acid (5-HPETE).

Leukotrienes (C4, D4 & E4) are components of

slow-reacting substances of anaphylaxis (SRS-

A), released after immunological challenge.

SRS-A is 100 -1,000 times more potent than

histamine or prostaglandins in its action as a

stimulant of allergic reactions.

Leukotrienes are implicated in asthma,

inflammatory reactions, hypersensitivity

(allergy) and heart attacks.

Leukotrienes cause contraction of smooth

muscles, bronchoconstriction,

vasoconstriction, adhesion of white blood

cells & release of lysosomal enzymes.

Lipoxins are involved in vasoactive &

immunoregulatory functions.

Textbook of Biochemistry – U Satyanarayana