Fig. 15.1 Biosynthetic path of eicosanoids (see text for description). Prostaglandins are found in virtually all tissues of the body.

most tissues, especially stomach, platelets and kidneys. COX-2 is inducible (10-20-fold) by inflammatory stimuli in many cells including macrophages, synoviocytes, chondrocytes, fibroblasts and endothelial cells, and only in low concentration in the gastrointestinal mucosa. Crucially, NSAIDs differ in their relative inhibition of the two isoforms of COX, recognition of which has lead to the development of selective COX-2 inhibitors. Such drugs have less adverse effects, especially on the gastrointestinal tract (see below).

• Arachidonic acid is also metabolised by lipoxygenase to straight-chain hydroperoxy acids and then to leukotrienes which cause increased vascular permeability, vasoconstriction, bronchoconstriction, as well as chemotactic activity for leucocytes (whence their name). Inhibitors of lipoxygenase, e.g. zileuton, and leukotriene receptor antagonists, e.g. montelukast, zafirlukast, have found a place in the therapy of asthma (see p. 559).

• Lipoxins are lipoxygenase-derived eicosanoids that probably down-regulate inflammation in the gastrointestinal tract and other organs by antagonising effects of TNF-a.

In health, PGs have a number of important physiological roles, namely:

• protection of the gastrointestinal tract (PGE2 and pgi2)

• renal homeostasis (PGE2 and PGI2)

• vascular homeostasis (PGI2 and TXA2)

• uterine function, embryo implantation and labour (PGF2)

• regulation of the sleep-wake cycle (PGD2)

Synthetic analogues of prostaglandins are being used in medicine, namely:

• PGI2: epoprostenol (inhibits platelet aggregation, used for extracorporeal circulation and primary pulmonary hypertension).

• PGE |: alprostadil (used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects, and for erectile dysfunction by injection into the corpus cavernosum of the penis); misoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs); gemeprost (used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for termination of pregnancy).

• PGE2: dinoprostone (used as cervical and vaginal gel to induce labour and for late therapeutic abortion).

• PGF2a: dinoprost (termination of pregnancy).

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