Aspirin, NSAIDs, and COX-2 Inhibitors

The most common NSAID is aspirin, or acetylsalicylic acid, whose use goes back to the late 1800s. It had been known from before the time of Hippocrates in 400 bc that fevers could be lowered by chewing the bark of willow trees. The active agent in willow bark was found in 1827 to be an aromatic compound called salicin, which could be converted by reaction with water into salicyl alcohol and then oxidized to give salicylic acid. Salicylic acid turned out to be even more effective than salicin for reducing fever and to have analgesic and anti-inflammatory action as well. Unfortunately, it also turned out to be too corrosive to the walls of the stomach for everyday use. Conversion of the 

Although extraordinary in its powers, aspirin is also more dangerous than commonly believed. A dose of only about 15 g can be fatal to a small child, and aspirin can cause stomach bleeding and allergic reactions in longterm users. Even more serious is a condition called Reye s syndrome, a potentially fatal reaction to aspirin sometimes seen in children recovering from the flu. As a result of these problems, numerous other NSAIDs have been developed in the last several decades, most notably ibu-profen and naproxen. 

Like aspirin, both ibuprofen and naproxen are relatively simple aromatic compounds containing a side-chain carboxylic acid group. Ibuprofen, sold under the names Advil, Nuprin, Motrin, and others, has roughly the same potency as aspirin but is less prone to cause stomach upset. Naproxen, sold under the names Aleve and Naprosyn, also has about the same potency as aspirin but remains active in the body six times longer. 

Aspirin and other NSAIDs function by blocking the cyclooxygenase (COX) enzymes that carry out the body s synthesis of prostaglandins (Section 6.3). There are two forms of the enzyme, COX-1, which carries out the normal physiological production of prostaglandins, and COX-2, which mediates the body s response to arthritis and other inflammatory conditions. Unfortunately, both COX-1 and COX-2 enzymes are blocked by aspirin, ibuprofen, and other NSAIDs, thereby shutting down not only the response to inflammation but also various protective functions, including the control mechanism for production of acid in the stomach. 

Medicinal chemists have devised a number of drugs that act as selective inhibitors of the COX-2 enzyme. 

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Moyad MM An introduction to aspirin, NSAids, and COX-2 inhibitors for the primary prevention of cardiovascular events and cancer and their potential preventive role in bladder carcinogenesis part II. Semin Urol Oncol. 2001 19 306-316. 

Kune GA. Colorectal cancer chemoprevention aspirin, other NSAID and COX-2 inhibitors. Aust NZ JSurg 2000 70 452 155. 

Non-narcotic analgesics (see chart) are used to treat mild to moderate pain. Many of these medications are not addictive and available over-the-counter. Non-narcotic analgesics are used to treat headaches, menstmal pain (dysmenor-rheal), pain from inflammation, minor abrasions, muscular aches and pain, and mild-to-moderate arthritis. Non-narcotic analgesics also lower elevated body temperature (antipyretic). Non-narcotic analgesics include acetaminophen and NSAIDs (aspirin, ibuprofen, and COX-2 inhibitors), which were discussed in Chapter 12. 

It follows that drugs selectively inhibiting the COX-2 enzyme offer certain advantages over aspirin and nonselective NSAIDs. Selective COX-2 inhibitors should decrease the production of prostaglandins that... 

NSAIDs can be classified on the basis of their COX inhibitory and selective properties. Most NSAIDs inhibit both COX-1 and COX-2 to some extent. Most are mainly COX-1 inhibitory, e.g., aspirin, ibuprofen, diclofenac, naproxen, while some are COX-2 inhibitory, e.g., celecoxib, rofecoxib, and lumiracoxib. Vane et al. established the relative inhibitory potencies of NSAID COX-1 and COX-2 inhibitors. NSAIDs with the highest gastrointestinal toxicity have the highest COX-1 selectivity. 

COX-2 inhibitors such as celecoxib are associated with adverse effects such as nephrotoxicity and a potential increased risk of myocardial infarction (see Chaps. 55 and 15 for additional information). Combination of COX-2 inhibitors with alcohol may increase GI adverse effects. All NSAIDs should be used with caution in patients with aspirin-induced asthma.31... 

Aspirin is one of the most important NSAIDs because it decreases pain at predominantly peripheral sites with little cortical interaction and thus has few CNS effects. The prototypical COX-2 inhibitors are celecoxib (Celebrex) and its chemical cousin, rofecoxib (Vioxx). In addition to a role in inflammatory processes,... 

The NSAIDs (eg, indomethacin, ibuprofen see Chapter 36) block both prostaglandin and thromboxane formation by reversibly inhibiting COX activity. The traditional NSAIDs are not selective for COX-1 or COX-2. Selective COX-2 inhibitors, which were developed more recently, vary—as do the older drugs—in their degree of selectivity. Indeed, there is considerable variability between (and within) individuals in the selectivity attained by the same dose of the same NSAID. Aspirin is an irreversible COX inhibitor. In platelets, which are anuclear, COX-1 (the only isoform expressed in mature platelets) cannot be restored via protein biosynthesis, resulting in extended inhibition ofTXA2 biosynthesis. 

Selectivity for COX-1 versus COX-2 is variable and incomplete for the older NSAIDs, but many selective COX-2 inhibitors have been synthesized. The selective COX-2 inhibitors do not affect platelet function at their usual doses. In testing using human whole blood, aspirin, ibuprofen, indomethacin, piroxicam, and sulindac are somewhat more effective in inhibiting COX-1. The efficacy of -2-selective drugs equals that of the older NSAIDs, while gastrointestinal safety may be improved. On the other hand, selective COX-2 inhibitors may increase the incidence of edema and hypertension. As of December 2008, celecoxib and the less selective meloxicam are the only COX-2 inhibitors marketed in the USA. Rofecoxib and valdecoxib, two previously marketed, selective COX-2 inhibitors, have been withdrawn from the market due to their association with increased cardiovascular thrombotic events. Celecoxib has an FDA-initiated "black box" warning concerning cardiovascular risks. It has been recommended that all NSAID product labels be revised to include cardiovascular risks. 

Thus, NSAIDs tend to be differentiated on the basis of toxicity and cost-effectiveness. For example, the gastrointestinal and renal side effects of ketorolac limit its use. Some surveys suggest that indomethacin or tolmetin are the NSAIDs associated with the greatest toxicity, while salsalate, aspirin, and ibuprofen are least toxic. The selective COX-2 inhibitors were not included in these analyses. 

Aspirin is the only known NSAID that covalently bonds to serine and inhibits COX-1 more significantly than COX-2. Many systematic structural modifications have been carried out resulting in the development of APHS characterized by a 60-fold increase in activity and a 100-fold increase in selectivity for COX-2 than aspirin. Inhibition of COX-2 also occurs by acetylation of the same serine residue that is acetylated by aspirin, indicating that the mechanism of APHS inhibition is not identical to that of other selective COX-2 inhibitors (Kalgutkar et al., 1998a 1998b). 

Ongoing research led to the development of COX-2 selective inhibitors (e.g., rofecoxib and celecoxib). Celecoxib (Celebrex ) was approved by the FDA in 1998 to treat osteoarthritis and rheumatoid arthritis. Rofecoxib (Vioxx ) was approved in May 1999 to treat osteoarthritis, acute pain, and dysmenorrhea. Sales for the two drugs in 1999 were 1.5 billion and 373 million, respectively. Clinical studies have indicated a significant reduction in GI perforation, ulceration, or bleeding with the COX-2 inhibitors. The recognition of multiple COX isoforms has had one of the greatest impacts on the development of NSAIDs since the original synthesis of aspirin more than a century ago. 

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