Prostaglandins

Prostaglandins are end products of a chain reaction commencing with release of unsaturated fatty acids from cells. More modern terminology is use of the word "eicosanoid" instead of prostaglandin. Conversion of the fatty acids to various prostaglandins is effected via an enzyme complex termed "prostaglandin synthetase" or "cyclooxygenase", which is released from the cell membrane.

There are many steps involved in conversion of the fatty acids to prostaglandins. Prostaglandins are not only synthesized when tissues are injured, but are ubiquitous throughout the body. They are not stored but are synthesized upon need. They play a significant role as a local messenger in many normal functions, especially when cells are stimulated. Once produced, prostaglandins do not persist long at their site of formation. They rapidly diffuse to other sites or are rapidly metabolized. Most prostaglandins are so rapidly metabolized, they do not reach the systemic circulation for redistribution.

Migrating cells, especially phagocytes (cells which ingest; engulf), are directly involved with pain response. During phagocytosis (the act of engulfing; ingesting), enzymes designed for the digestion of foreign material, invading agents, and damaged cells may be discharged and act against the host tissues. Release of these enzymes results in production of prostaglandins, with consequent induction of pain.

High concentrations of prostaglandins cause pain by direct action upon nerve endings. More typically, however, at low concentrations, they markedly increase sensitivity to pain. The pain threshold may be so altered that even normally painless stimuli may be painful. This effect of prostaglandins is long-lasting and cumulative, so that continued production of even small amounts can sensitize nerves to other irritants.

Prostaglandins are also incriminated in pain perception within the nervous system. They are produced within the central nervous system and sensitize it to painful substances. Pain is thus induced in two ways (local and central) via direct sensitization of nerve receptors by prostaglandins.

Prostaglandins and Inflammation

There are many contributors to the inflammatory process, and prostaglandins are one of the more significant ones. Prostaglandins are one of the more potent mediators that cause increased blood flow, chemotaxis (chemical signals that summon white blood cells), and subsequent dysfunction of tissues and organs. They are a body's response to noxious agents, and as long as the noxious agents persist, prostaglandins will continue to be produced and add to the inflammatory process.

Prostaglandins and Fever (Pyrexia)

During an inflammatory process, infectious agents, toxins, and tissue fluids enter the circulation and cause fever. The evidence indicates this results from the production of prostaglandins in the central nervous system, specifically the anterior hypothalamus. With fever, depression (malaise) and inappetence may occur. Prostaglandins are also associated with these signs.

The production of fever by prostaglandins is supported by the fact that anti-inflammatory agents which inhibit prostaglandin production may also be antipyretic. It is not, therefore, surprising that both pain and fever are the first signs of inflammation to be relieved by antiprostaglandin therapy. Swelling and redness are alleviated more slowly.

Other Roles of Prostaglandins

Prostaglandins play a very significant role as a local messenger in many normal functions, especially when cells are stimulated. This is important because anti-inflammatory drugs alter prostaglandin function whether they be from normal activities or inflammatory in nature.

• Prostaglandins are involved in maintaining normal function of the cardiovascular, pulmonary, renal and gastrointestinal systems.
• Prostaglandins may decrease or increase blood pressure. Vascular effects vary in different organs and tissues.
• In the lungs, prostaglandins not only modify pulmonary circulation, they also modify ventilation by constricting or contracting airways. (Sidelight: In the newborn, as soon as the lung is functional, prostaglandins are instrumental in termination of umbilical blood flow and in the diversion of venous blood to the lung for proper aeration.)
• In the gastrointestinal tract, they decrease secretion of gastric juice and increase secretion of intestinal mucus. Prostaglandins increase the fluid content of the gut and may increase gut motility.

These effects of prostaglandins in normal body functions are important because they can be ameliorated by antiprostaglandin drugs. Antiprostaglandins not only affect the "bad" (inflammatory, pain, fever) effects, but also the "good" (blood pressure, air flow to lungs, gastric pH and intestinal mucus, renal function) effects of prostaglandins. It is the loss of activity of the "good" prostaglandins that leads to the side effects observed following use of antiprostaglandins. The most common side effects are gastrointestinal ulcers and renal insufficiency caused by disruption of renal blood flow.