Pge2j

Figure 24.14 • Conversion of arachidonic acid to prostaglandins.

including PGE2, PGD2, PGF2a, PGI2 (prostacyclin), and thromboxane A2 (TXA2) (Fig. 24.14).138139

Among the PGs synthesized by the action of either COX-1 or COX-2 isozymes, PGI2 and PGE2 made at the site of injury (via COX-2 isozyme in the inflammatory cells such as monocytes and macrophages) and also in the brain, are known to play a dominant role in mediating inflammation and inducing hyperanalgesia.132 However, their synthesis in the GI tract (via COX-1 isozyme) and in the renal tubules (via COX-1 and COX-2 isozymes), is essential to provide cytoprotective action for restoring the integrity of the stomach lining and maintaining renal functions in an otherwise compromised kidney as a result of constant insult.132,138 Thus, inhibition of PGE2 synthesis by the conventional NSAIDs in the parietal cells removes its ability to modulate histamine-mediated release of gastric acid from the parietal cells, whereas blockade of PGI2 and PGE2 synthesis in the epithelial cells in the stomach linings also prevents their action on the biosynthesis and release of bicarbonate and mucous gel desperately needed to repair damage resulting from erosion caused by gastric acid and other aggressive fac-tors.127,129,132 Thus, it should not be surprising to note that NSAID-induced gastric ulcers can only be prevented clinically with coadministration of misoprostol, a stable PGE analog, but not with either the histamine H2-antagonists, sucralfate, or any proton pump inhibitors such as omepra-zole.127 Furthermore, maintenance of kidney function, especially in patients with congestive heart failure, liver cirrhosis, or renal insufficiency, is reliant on the action of PGI2 and PGE2 to restore normal renal blood flow. Thus, NSAID use (both COX-1 and COX-2 inhibitors) will increase the risk of renal ischemia and therefore is contraindicated in these patients.129

The readers should consult Chapter 26 of this text on "Prostanglandins, Leukotrienes, and Other Eicosanoids" for a detailed discussion of PGs, their physiological and pathophysiological functions, and their corresponding PG receptors.

Structure-Activity Relationships of NSAIDs

It is well established that the therapeutic potency of the conventional NSAIDs are highly correlated with their ability to induce upper GI toxicity.127 But, are all NSAIDs other than coxibs really equally effective in the treatment of pain and inflammation? Some insight might be found by exploring how these chemically diverse classes of drugs bind to their molecular targets (i.e., their selectivity for COX-2 relative to COX-1).140 Thus, the benefit/risk profile of individual NSAIDs, as reflected by their COX selectivity, may be more clinically relevant for predicting the risk of GI complications. Table 24.1 summarizes a few representative drugs from different NSAID classes with their recommended daily

TABLE 24.1 Comparison of Relative Risk of NSAID-Induced Gastrointestinal Complication

Dosing Range Relative Risk for COX-2/COX-1

Drug Trade Name (Total Daily Dose) GI complication Selectivity Ratio

TABLE 24.1 Comparison of Relative Risk of NSAID-Induced Gastrointestinal Complication

Dosing Range Relative Risk for COX-2/COX-1

Drug Trade Name (Total Daily Dose) GI complication Selectivity Ratio

Not on NSAIDs

Was this article helpful?

0 0
Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

Get My Free Ebook


Post a comment