Celecoxib (Celebrex) was the first selective COX-2 inhibitor drug introduced into the market in 1998 for use in the treatment of RA, OA, acute pain, and menstrual pain. The real benefit is that it has caused fewer GI complications when compared with other conventional NSAIDs. It has also been approved for reducing the number of adenomatous colorectal polyps in familial adenomatous polyposis (FAP).

Celecoxib is well absorbed and undergoes rapid oxida-tive metabolism via CYP2C9 to give its inactive metabolites (Fig. 24.21).203 Thus, a potential drug interaction exists between celecoxib and warfarin because the active isomer of warfarin is primarily degraded by CYP2C9.

The Analgesic Antipyretics: Acetaminophen (Paracetamol) and Related Analogs

From a historical perspective, acetaminophen (paracetamol) and the related analgesic antipyretic drugs such as acetanilide, antipyrine, and dipyrone were introduced into the market about the same time as aspirin and the other salicylates (i.e., acetanilide, 1886; phenacetin, 1887; and acetaminophen, 1893).204 They were once the most widely used analgesic

Figure 24.21 • Metabolic biotransformation of celecoxib.

antipyretics for relieving pain and reducing fever because, unlike aspirin and salicylates, they do not cause ulceration or increase bleeding time.204 Among these agents, phenacetin was once a very popular analgesic antipyretic drug, more so than acetaminophen, because it was perceived to be safer than acetaminophen toward the stomach (i.e., less acidic in nature). Its use was continued until the late 1970s, even though Brodie and Axelrod had already reported in 1949 that acetaminophen was the active metabolite of acetanilide and phenacetin.205 In their elegant studies, acetanilide was found to undergo hepatic metabolism (i.e., via an aromatic hydroxylation) to acetaminophen, whereas only a small amount of the drug was hy-drolyzed to give aniline, which can be further N-hydroxylated to phenylhydroxylamine, the compound believed to be responsible for acetanilide toxicity because of methemoglobin formation. Phenacetin, on the other hand, was found to undergo mostly O-dealkylation to acetaminophen, whereas a small amount was converted by deacetylation to p-pheneti-dine, also responsible for methemoglobin formation.

Phenacetin only fell out of favor around 1980 when it was found to cause renal and urinary tract tumors in experimental animal models.206 Because of the toxicity described above, both acetanilide and phenacetin are now no longer available, thus acetaminophen is the only drug in this class that is still widely used worldwide because it is a safer and better tolerated pain medication.


Acetaminophen and other analgesic antipyretics have similar analgesic and antipyretic efficacies to the conventional NSAIDs such as aspirin, ibuprofen, or diclofenac. However, unlike the conventional NSAlDs, they lack the antiplatelet effects of aspirin or the GI side effects associated with NSAIDs. Acetaminophen also has little or no anti-inflam matory properties.

Although it has been in use for nearly a century, the mechanism of action of acetaminophen and related analgesic antipyretics remains unknown, but it is generally assumed that they work centrally by blocking a brain-specific enzyme, perhaps a COX-3 isozyme, responsible for the biosynthesis of prostaglandin.210

In 2002, Simmons et al.,211 through cloning studies, identified a distinct variant of the canine COX-1 isozyme found only in the canine brain, which was designated as the COX-3 isozyme and hypothesized this isozyme as the target for acetaminophen and related analgesic-antipyretic drugs because this isozyme was selectively inhibited by acetaminophen, phenacetin, antipyrine, and dipyrone. This hypothesis was further supported by the findings that acetaminophen produces analgesia and induces hypothermia centrally and that both of these actions are accompanied by a dose-dependent reduction of brain PGE2 levels that is not observed with diclofenac, a conventional NSAID.209 In addition, the peripheral levels of PGE2/PGI2 levels were reduced only by diclofenac but not by acetaminophen.210 Moreover, aceta-minophen-induced hypothermia was reduced in COX-1 but not COX-2 gene-deleted animal studies.209,212 These observations appear to provide additional support for hypothesis that the analgesia and hypothermia of acetaminophen are indeed mediated by inhibition of a distinct COX isozyme present only in the brain. However, most of the recent studies focusing on finding this elusive human COX-3 isozyme have not been successful.207,213,214 Moreover, a similar COX-1 variant identified and expressed in humans (this isozyme was designated as COX-1b) was not inhibited by acetaminophen even though it is active in catalyzing PGH2 synthesis in the brain. Thus, although the COX-3 isozyme may indeed be the molecular target responsible for acetaminophen action in canines, its role in humans is still unproven.213,214

In a recent commentary, Aronoff et al.208 suggested an alternative target (mechanism) by which acetaminophen (APAP) blocks the cyclooxygenase action. Their hypothesis is based on the fact that acetaminophen acts as a reducing co-substrate, thus actively competing with PGG2 for its conversion to PGH2, catalyzed by the peroxidase (POX) action of COX enzymes. Figure 24.22 summarizes some of the key mechanism of COX's action suggested by Aronoff et al.208 and includes the additional hypothesis suggested by Gram and Scott215 that acetaminophen acts by depleting the stores

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