COX isoenzymes

The development of the COXIBs has been based on the hypothesis COX-1 is the physiological COX and COX-2, the pathophysiological isoenzyme. Inhibition of the pathophysiological COX-2 only is assumed to result in fewer side effects as compared to non-selective inhibition of both COX isoenzymes (Fig. 2). Celecoxib, etoricoxib and lumiracoxib (in some countries also parecoxib) are the only COXIBs currently approved. 

A non-allergic mechanism imderlying precipitation of asthmatic attacks by aspirin in hypersensitive patients was proposed over 30 years ago [4]. It was founded on pharmacological inhibition of COX of arachidonic acid and explained a cross-reactivity between different NSAIDs varying in chemical structure. This COX theory was confirmed by several studies [11] and was further refined following discovery of the second COX isoenzyme - COX-2. At least two COX isoenzymes, COX-1 and COX-2, are coded by separate genes. Their role in inflammation, asthma and anaphylaxis has been reviewed previously [12]. 

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. 

Two COX isoenzymes have been identified COX-1 and COX-2. Inhibition of COX-1 activity is considered a major contributor to NSAID Gl toxicity. The function of the COX-2 isoenzyme is induced during pain and inflammatory stimuli. 

Clinical use Etodolac (Bellamy, 1997) is a drug, invented before the discovery of the COX isoenzymes. Thus, there was clinical experience with the drug, before it was shown, that etodolac has a 10-fold selectivity for COX-2 compared to COX-1 in human whole blood. Etodolac belongs to the first generation of COX-2 inhibitors (Vane et al., 1998). Clinical data indicate fewer gastrointestinal side-effects in comparison to naproxen (Taha et al., 1989 Bianchi Porro et al., 1991). Etodolac is a racemate with an active (S)-enantiomer and an inactive (R)-enantiomer. 

Ketorolac shows a balanced inhibition of both COX-isoenzymes in a variety of assay systems and is a racemate with an active (S)-enantiomer. 

Clinical use Lornoxicam (Pruss et al., 1990) is a nonsteroidal anti-inflammatory drug with a strong and balanced inhibition of both COX isoenzymes. 

Clinical use Metamizol is the water-soluble sodium sulfonate of amidopyrine. After oral administration it is rapidly hydrolyzed to the active 4-methyl-amino-antipyrine and metabolized to various metabolites (Levy et al., 1995 scheme 47). Metamizol has strong analgesic, spasmolytic and antipyretic action, but no anti-inflammatory properties. The exact mechanism of action is unknown but may include inhibition of prostaglandin synthesis. Inhibition of both COX isoenzymes has been demonstrated, although only in extremely high concentrations, thus questioning the relevance of this activity. 

Clinical use Naproxen (Todd and Clissold, 1990) is a nonsteroidal anti-inflammatory drug used for the treatment of mild to moderate pain and inflammatory pain conditions such as rheumatoid arthritis, osteoarthritis, soft tissue disorders, postoperative pain and dysmenorrhoea. It is also used to treat migraine. Naproxen shows balanced inhibition of both COX isoenzymes in a cellular assay and a preference for COX-1 in a whole blood assay and in an enzyme assay using recombinant human enzymes. 

Despite its long clinical history after its discovery in 1893 (von Mering, 1893), the mechanism of action of paracetamol is not fully understood. It shows some weak inhibition of the COX isoenzymes and there is speculation on a third COX isoenzyme, COX-3, induced during the resolution phase of an inflammatory response, that might be specifically targeted by paracetamol (Willoughby et al., 2000). Furthermore, there is evidence for a possible central analgesic effect mediated indirectly by 5-HT (Courade et al., 2001). 

FIGURE 33-4. Tissue distribution and actions of cyclooxygenase (COX) isoenzymes. Nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin (ASA) inhibit COX-1 and COX-2 to varying degrees COX-2 inhibitors inhibit only COX-2. Broken arrow indicates inhibitory effects. 

Results from ex vivo assays performed at ABG and at William Harvey Research Limited were compared with a 2-tailed Pearson correlation test analysis was performed twice, once for each Cox isoenzyme, using data pooled from both NSAIDs (ibuprofen and celecoxib) together. For Cox-1, R squared was 0.67 (p <0.01) and for Cox-2, R squared was 0.92 (p <0.001). 

Based on an increasing body of data, Frolich proposes a simple alternative to the usual chemical classification of NSAIDs, allowing one to predict a drug s major effects according to its relative inhibition of the constitutive and inducible COX isoenzymes. 

Diclofenac is an NSAID with anti-inflammatory, analgesic, and antipyretic activity. It is an amino-phenyl-acetic acid derivative that inhibits prostaglandin biosynthesis to produce analgesic, antipyretic, and anti-inflammatory activity secondary to its nonselec-tive inhibition of the cyclooxygenase (COX) isoenzymes, COX-1 and COX-2. It lies approximately in the middle of the COX-l/COX-2 inhibitory spectrum. Uniquely among NSAIDs, diclofenac opens KCNQ2/3 potassium channels and may inhibit sensory neuronal depolarization. Please refer to the oral diclofenac chapter for additional information. 

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