Coxibs inhibitors

Highly selective COX-2 inhibitors - coxibs (rofecoxib, celecoxib, or less popular - valdecoxib, etoricoxib parecoxiband lumiracoxib) - were found to be well tolerated in a series of placebo-controlled clinical trials [8]. However, rofecoxib and valdecoxib have been withdrawn from the market because of an increased incidence... 

Recent data suggest that COX-2 inhibitors, including rofe-coxib, valdecoxib, and celecoxib, may increase the risk for MI and stroke.47 There is also some evidence that the non-selective NSAIDs may increase the risk for cardiovascular events.47,48 Rofecoxib was withdrawn from the market in late 2004 because of safety concerns. The FDA requested the withdrawal of valdecoxib from the market in 2005. The FDA also asked the manufacturers of celecoxib and non-selective NSAIDs (prescription and over-the-counter) to include information about the potential adverse cardiovascular effects of these drugs in their product labeling. The cardiovascular risk with COX-2 inhibitors and NSAIDs may be greatest in patients with a history of, or with risk factors for, cardiovascular disease. The American Heart Association recommends that the use of COX-2 inhibitors be limited to low-dose, short-term therapy in patients for whom there is no appropriate alternative.48 Patients with cardiovascular disease should consult a clinician before using over-the-counter NSAIDs. 

Fitzgerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 2001 345 433-442. 

COX-1 and COX-2 are the targets of the nonsteroidal anti-inflammatory drugs (NSAID, see Chapter 28). Indirectely the effect of these enzymes is also inhibited by corticosteroids (see also Chapter 26) through a decrease of the availibility of its substrate arachidonic acid by inhibition of phospholipase A2. Relatively new drugs, known as COX-2 selective inhibitors or coxibs (celecoxib, rofecoxib and others), are used as specific inhibitors of COX-2. 

Coxibs (COX-2 inhibitors NSAIDs with COX-1-sparing effect) ... 

NSAID Selective COX-2 inhibitors a. Coxibs (celecoxib, rofecoxib)... 

Highly selective COX-2 inhibitors (e.g. celecoxib, second and third generation of COX-2 inhibitors, sometimes called coxibs)... 

Chavez-Eng, C. M., Constanzer, M. L., and Matuszewski, B. K. (2000). Determination of rofe-coxib (MK-0966), a cyclooxygenase-2 inhibitor, in human plasma by high-performance liquid chromatography with tandem mass spectrometric detection. J. Chromatogr. B Biomed. Set Appl. 748 31-39. 

Cyclooxygenase type 2 [COX-2] inhibitors -coxib Celecoxib Pain, inflammation (15)... 

Similarly, the sodium salt of the poorly soluble COX-2 inhibitor pare-coxib, parecoxib sodium (Dynastat ), was designed as a parenteral analgesic for the management of acute pain to improve solubility of the parent compound. On administration, parecoxib sodium is converted rapidly and essentially completely to the pharmacologically active... 

Rofecoxib, a furanose derivative, is a potent, selective COX-2 inhibitor (Table 36-1). In the USA, rofecoxib is approved for osteoarthritis and rheumatoid arthritis, and it also appears to be analgesic and antipyretic—in common with other NSAIDs. This drug does not inhibit platelet aggregation and appears to have little effect on gastric mucosal prostaglandins or lower gastrointestinal tract permeability. At high doses it is associated with occasional edema and hypertension. Other toxicities are similar to those of other coxibs. 

Valdecoxib, a diaryl-substituted isoxazole, is a new highly selective COX-2 inhibitor. Pharmacokinetic characteristics and dosage in arthritis are set forth in Table 36-1. In primary dysmenorrhea, dosage is 20 mg twice daily, and the drug is as effective as nonselective NSAIDs for this indication. Gastrointestinal and other toxicities are similar to those of the other coxibs. Valdecoxib has no effect on platelet aggregation or bleeding time. Serious reactions have been reported in sulfonamide-sensitive individuals. 

COX-2 inhibitors shown in Fig. 3.11 decrease in the order M5 > SC-558 > rofe-coxib. 

Silva J, Styhler A, Trimble LA, Nicoll-Griffith DA. In vitro metabolism considerations, including activity testing of metabolites, in the discovery and selection of the COX-2 inhibitor etori-coxib (MK-0663). Bioorg. Med. Chem. Lett., 2001, 11, 1059-1062 (b) Friesen RW, Brideau C, Chan CC, Charleson S, Deschenes D, Dube D, Ethier D,... 

Phelan KM, Mosholder AD, Lu S. Lithium interaction with the cyclooxygenase 2 inhibitors rofecoxib and cele-coxib and other nonsteroidal anti-inflammatory drugs. J Clin Psychiatry 2003 64 1328-34. 

Davies NM, McLachlan AJ, Day RO, Williams KM. Clinical pharmacokinetics and pharmacodynamics of cele-coxib a selective cyclo-oxygenase-2 inhibitor. Clin Pharmacokinet 2000 38(3) 225 12. 

COX-1 and COX-2 are of similar molecular mass (approximately 70 and 72 kDa respectively), with 65% amino acid sequence homology and near-identical catalytic sites. The most significant difference between the isoenzymes, which allows for selective inhibition, is the substitution of isoleucine at position 523 in COX-1 with valine in COX-2. The relatively smaller Val523 residue in COX-2 allows access to a hydrophobic side-pocket in the enzyme (which Ile523 sterically hinders). Drugs, such as the coxibs, bind to this alternative site and are considered to be selective inhibitors of COX-2. 

The possible association of NSAlDs with inflammatory bowel disease is a matter of controversy (SEDA-25,131), and there is little clinical experience with the selective COX-2 inhibitors. Coxibs should not be prescribed for patients with chronic inflammatory bowel disease until more experience has accumulated. 

Although the scientific literature has been flooded by articles and reviews on the use of selective COX-2 inhibitors (coxibs), the safe prescribing and use of these compounds is controversial (28-31). 

Suggestions for improved gastrointestinal safety of COX-2-selective inhibitors have come from two studies, which addressed the problem of sample size by pooling published and unpublished randomized, double-blind trials of varying design and duration, comparing cele-coxib, rofecoxib, non-selective NSAIDs (diclofenac, ibu-profen, nabumetone), and placebo in patients with osteoarthritis and/or rheumatoid arthritis. 

We have no data on the possible interaction between H. pylori status and the ability of COX-2-selective inhibitors to cause gastrointestinal toxicity. However, one would expect that when patients use COX-2 inhibitors H. pylori infection would remain a source of continuing ulcer risk, requiring eradication. Although there are no trials, this approach is supported by data from the VIGOR study, in which the residual risk of ulcers in patients taking rofe-coxib was approximately doubled in H. py/on-infected compared with non-infected patients (112). 

In conclusion, hyperkalemia associated with the use of traditional NSAIDs or the coxibs becomes a clinical risk in individuals with significantly decreased renal function and/or in those with the combination of decreased renal function and use of an ACE inhibitor. 

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