COX-2 selectivity

Glucocorticoids increase the risk of gastrointestinal complications caused by NSAEDs. Considerable caution is necessary when using NSAIDs in patients with severe liver and kidney damage and they should not be combined with coumarines. Owing to the limited experience obtained, these precautions and contraindications also apply to COX-2-selective inhibitors. 

Due to the short period of clinical use, the interaction profile of COX-2-selective inhibitors cannot be entirely described at the present time. 

Oxicams, e.g. piroxicam, tenoxicam, meloxicam and lornoxicam are non-specific inhibitors of COX. Like diclofenac, meloxicam inhibits COX-2 ten times more potently than COX-1. This property can be exploited clinically with doses up to 7.5 mg per day, but at higher doses COX-1-inhibition becomes clinically relevant. Since the dose of meloxicam commonly used is 15 mg daily, this agent cannot be regarded as a COX-2-selective NS AID and considerable caution needs to be exercised when making comparisons between the actions of meloxicam and those of other conventional NSAIDs. The average daily dose in anti-rheumatic therapy is 20 mg for piroxicam and tenoxicam, 7.5-15 mg for meloxicam and 12-16 mg for lornoxicam. Oxicams have long elimination half-lives (lornoxicam 3-5 h, meloxicam - 20 h, piroxicam 40 h and tenoxicam 70 h). 

The indications for these agents are in principle identical to those of the non-selective NSAIDs although the substances have not yet received approval for the whole spectrum of indications of the conventional NSAIDs. Because they lack COX-1-inhibiting properties, COX-2-selective inhibitors show fewer side effects than conventional NSAIDs. However, they are not free of side effects because COX-2 has physiological functions that are blocked by the COX-2 inhibitors. The most frequently observed side effects are infections of the upper respiratory tract, diarrhoea, dyspepsia, abdominal discomfort and headache. Peripheral oedema is as frequent as with conventional NSAIDs. The frequency of gastrointestinal complications is approximately half that observed with conventional NSAIDs. 

With the availability of NSAIDs with COX-2 selectivity, clinicians postulated that these agents would avoid the need to add an additional prophylactic agent to therapy in patients with PUD risk factors. However, selective COX-2 inhibitors have not been shown to be any more effective than the combination of a PPI and a non-selective NSAID in reducing the incidence of ulcers, and questions remain regarding their long-term cardiovascular safety. 

Clinical trial evidence supports many NSAID medications in the acute treatment of migraines with and without aura.30 The currently marketed cyclooxygenase-2 (COX-2) selective... 

Most NSAIDs (e.g., ibuprofen, naproxen, and others) inhibit both COX-1 and COX-2 isoforms. That is, they are nonselective inhibitors of the COX enzyme system. Whereas inhibition of COX-2 is responsible for beneficial effects, inhibition of COX-1 is responsible for the most common and important adverse effects of NSAIDs. COX-2-selective inhibitors have been produced and marketed in attempts to preserve the beneficial effects of COX-2 inhibition while avoiding the deleterious effects associated with inhibition of the COX-1 enzyme. This approach has not been entirely successful, as discussed below. 

The advent of COX-2-selective inhibitors has led to unexpected results. By selectively inhibiting the COX-2 isoform, COX-2-selective NSAIDs increase the risk of cardiovascular events in certain patientsP COX-2 is responsible for the production of prostacyclin, a vasodilatory and antiplatelet substance. On the other hand, COX-1 controls the production of thromboxane A2, a vasoconstrictor and platelet aggregator. Selective inhibition of COX-2 results in decreased prostacyclin levels in the face of stable thromboxane A2 levels. An imbalance in the thromboxane A2 prostacyclin ratio ensues, which creates an environment that favors thrombosis. 

Cyclooxygenase-2 (COX-2)-selective inhibitors produce results comparable with those of traditional NSAIDs. However, cardiovascular safety concerns and the high cost of COX-2 inhibitors argue against their use for this disorder. 

Nonspecific NSAIDs bhd to Cox-1 and Cox-2 Cox-2 selective agents bind In Cqx-2 pocket... 

Again, detailed structural information at a molecular level was the key. Once these pictures were available slight chemical differences between the COX-1 and COX-2 isoenzymes could be seen COX-2 had a side pocket while COX-1 didn t. This meant that a molecule that could dock into the COX-2 side pocket (binding site) but not into COX-1 would specifically block COX-2 without touching COX-1. In 1999 this hope was realized with the availability of COX-2 selective anti-inflammatories such as Rofecoxib and Celecoxib that can be as much as 50-fold selective for the target. 

COX-2 selectivity of marketed compounds. Adapted with permission from T.D. Warner et al. Proceedings of the National Academy of Sciences, 96, 13, 7563 (1999). Copyright 1999 National Academy of Sciences, U.S.A. 

The efficacy and safety of cyclooxygenase-2 (COX-2) selective inhibitors (e.g., celecoxib) have not been fully assessed in gouty arthritis, but they are more costly than conventional NSAIDs and are unlikely to result in fewer GI complications because of the short duration of therapy. 

For OA patients who need an NSAID but are at high risk for GI complications, the ACR recommendations include either a COX-2 selective inhibitor or a nonselective NSAID in combination with either a proton pump inhibitor or misoprostol. 

Tramadol with or without acetaminophen has modest analgesic effects in patients with OA. It may also be effective as add-on therapy in patients taking concomitant NSAIDs or COX-2 selective inhibitors. As with opioids, tramadol may be helpful for patients who cannot take NSAIDs or COX-2 selective inhibitors. 

Patients with PUD should eliminate or reduce psychological stress, cigarette smoking, andtheuseofnonselectiveNSAIDs (including aspirin). Ifpossible, alternative agents such as acetaminophen, a nonacetylated salicylate (e.g., salsalate), or a COX-2 selective inhibitor should be used for pain relief. 

COX-2 selectivity was evaluated in vitro by using the human whole blood assays of COX isoenzyme activity. Three compounds, not bearing the sulfonamide group present in valdecoxib, have been found to be selective COX-1 inhibitors. 

Outlook Cyclooxygenase (COX) has two isozymes COX-1, a constitutive form present in stomach and kidney and COX-2, which is induced in inflammatory cells in response to appropriate stimuli. Presently available NSAIDs inhibit both isozymes. The search for COX-2-selective agents (Celecoxib, Ro-fecoxib) is intensifying because, in theory, these ought to be tolerated better. 

Crew TE, Elder DJE, Paraskeva C A. Cyclooxygenase-2 (COX-2) selective non-steroidal anti-inflammatory drug enhances the growth inhibitory effect of butyrate in colorectal carcinoma cells expressing COX-2 protein regulation of COX-2 by butyrate. Carcinogenesis 2000 21 69-77. 

Elder DJE, HaltonDE, Hague A, etal. Induction of apoptotic cell death in human colorectal carcinoma cell lines by a cyclooxygenase-2 (COX-2)-selective nonsteroidal anti-inflammatory drug independence from COX-2 protein expression. Clin Cancer Res 1997 3 1679-1683. 

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. 

Unfortunately, the cyclo-oxygenase-2-(COX-2-) selective inhibitors have been shown to carry an increased risk of thromboembolic events in long-term use, which limits their usefulness. For other NSAIDs... 

Treatment with COX-2 selective drugs has shown a lower likelihood of symptomatic ulcer or ulcer complications than treatment with non-selective NSAIDs, with non-selective NSAID risks varying dose-dependently and between drugs, with ibupro-fen lowest, and piroxicam and azapropazone amongst the highest. Whether COX-2 selective drugs pose no risk is unclear. 

Cardiovascular safety. Both drug types promote salt retention, can exacerbate heart failure and tend to raise blood pressure. COX-2 selective drugs also appear to raise the risks of thrombotic events, notably stroke and myocardial infarction, and recent evidence suggests that non-selective NSAIDs also raise these risks, though it is unclear whether to the same degree. For both drug types, dose and duration of treatment appear to affect risk. 

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