Prostaglandins

 

Prostaglandins

PKGhatak,MD

Prostaglandins are fatty acid derivatives. A 20-carbon fatty acid, with multiple unsaturated bonds and a 5- carbon ring is an essential fatty acid, known as Arachidonic acid, is a part of the cell membrane structure.

The enzyme Phospholipase A2 releases arachidonic acid from the plasma membrane. Depending on the type of stimulus and the enzymes present, the released arachidonic acid may follow one pathway or the other. 

One enzyme, lipoxygenase, catalyzes the conversion of arachidonic acid to one of several possible leukotrienes. Leukotrienes are important mediators of the inflammatory process.

Another enzyme, cyclooxygenase (COX), catalyzes the conversion of arachidonic acid to one of several possible endoperoxides. The endoperoxides undergo further modifications to form prostaglandins and thromboxane. Thromboxane and prostacyclin (PGI-2) have important functions in the process of blood coagulation.

Prostaglandins, Thromboxane and leukotrienes belong to a chemical group known as Proteinoids, also called Eicosanoids.

In 1935 Ulf von Euler discovered Prostaglandins, mistakenly believed it originated in the prostate gland, and he so named it. It is now known that all nucleated cells can produce prostaglandins. A new name is proposed but not approved yet.

Thromboxane A2 is produced by platelets from endoperoxide by the enzyme thromboxane synthase. Thromboxane A2 has a 6 -member carbon ring, unlike other prostaglandins. Thromboxane. Thromboxane is released from the platelets when blood vessels are disrupted. That initiates platelet adhesion, blood coagulation and vasoconstriction.

From endoperoxide, the Prostaglandins (PGs) are produced by the enzyme PG synthase. There are 4 prostaglandins (PG) – PGE2, PGI2, PGD2, and PGF2. The position of double bonds, hydroxyl group and ketone differentiate one from the other prostaglandins. PGs break down quickly once released by PG dehydrogenase (COX). Aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) can block PG dehydrogenase (COX). Paracetamol also acts on COX enzyme but its action is limited.

Like interleukins and cytokines, prostaglandins are very potent. PGs act on the same cell that produces PG (autocrine) or local nearby cells (paracrine). A tiny amount of PG produces a profound effect resembling the actions of hormones but action is confined to localized areas.

One characteristic of Prostaglandins is that the same prostaglandin will produce completely different responses based on the receptor they bind. The same prostaglandin will bind with different receptors producing completely different reactions. There are 8 subgroups of receptors – EP2, EP3, EP4, DP1, FP, IP, and TX. Two additional isoforms of the human TP, (TPα, TPβ) and FP (FPA FPB) and eight EP3 variants are generated through alternative splicing, which differs only in their C-terminal tails.

PGI2 is one of the most important prostaglandins for the vascular system. It maintains the health of endothelial cells, vascular smooth muscle cells functions and maintains the health of endothelial progenitor cells.

PGI2 is a potent vasodilator, and an inhibitor of platelet aggregation, leukocyte adhesion, and prevents smooth vascular muscle proliferation. PGI2 receptors are expressed in the kidney, liver, lung, platelets, heart, and aorta.

PGD2 is synthesized in both the central nervous system (CNS) and peripheral tissues. In the brain, PGD2 regulates sleep and pain perception.

PGD2 is produced by mast cells and it increases Eosinophils and Basophils in blood. PGD2 is an important factor in allergy and asthma.

PGF2α plays an important role in ovulation, contraction of the uterus and initiation of labor. It increases urinary bladder contractions and bronchoconstriction. PGF2α is used in the treatment of glaucoma.

PGE2 decreases acid secretion in the stomach protects and promotes mucus secretion in the stomach. PGE2 increases peristalsis of the GI tract and produces uterine contractions. It stops lipolysis, increases platelet aggregation, increases body temperature and pain in inflammation.

Inhibition of Prostaglandin synthesis.

Corticosteroids inhibit phospholipase A2 and supply of arachidonic acid is diminished and PG synthesis stops. Corticosteroid is antagonistic to PGE2 vasodilation and stabilizes lysosomal membrane and thereby diminishing release.

Aspirin inhibits both COX1 and COX2 resulting in the inhibition of PG synthesis. The action of Aspirin is irreversible on platelets and inhibition remains in place for the life of that group of platelets affected by aspirin.

NSAIDs. Non-steroidal anti-inflammatory drugs as a group produce reversible inhibition of COX 1 and COX2. There are more selective COX2 inhibitors with no or very few effects on COX1. Selective COX 2 inhibitors produce anti-inflammatory effects without decreasing GI protection and platelet functions.

These are important considerations in medical practice in prescribing anti-inflammatory drugs.

********************************************