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Will Inhibitors Of Cyclooxygenase 2 Ever Play A Prominent Role As Therapeutic Agents?
Cyclooxygenase 2 belongs to a group of enzymes called Cyclooxygenases, which are responsible in the synthesis of prostaglandins. Emer M. Smyth, PhD & Garret A. FitzGerald, MD (2007) state that there are currently three known Cyclooxygenases; however COX-3 has only been recently witnessed, with high concentrations in the heart and brain. Health Technology Assessment 2008 [online]. COX-2 is responsible in the formation of prostanoids in inflammation and cancer. Bertram G. Katzung et al. (2007; 294). Therefore, this shows that COX-2 needs to be regulated in order to maintain degree of inflammation. COX-2 inhibitors are thus important and I attempt to illustrate the differences between selective COX-2 inhibitors and NSAID's.
Rheumatoid arthritis is a condition in which in which inflammation occurs and nonsteroidal anti-inflammatory drugs (NSAID's) are often administered in order to reduce inflammation and swelling. This effect is achieved as they prevent chemicals causing inflammation from being synthesised. Guardian 2009 [online]. The majority of NSAID's act in a way that prevent cyclooxygenases from synthesising prostaglandins. However, this inhibition of the enzymes is non-selective and therefore results in various side effects such as decrease in thromboxane leading to renal impairments. This is due to the fact that there is a desirable inhibition of COX-2 enables the “antipyretic, analgesic, and anti-inflammatory action of NSAID”; but also an undesirable inhibition of COX-1 resulting in a decrease of prostaglandin and thromboxane, leading to such problems as stomach ulcers and “renal toxicity”. This introduces the belief that it may be important to use selective COX-2 inhibitors and it has been found that Celecoxib, a selective COX-2 inhibitor, causes a reduction in unwanted side effects relating to the GI system in the treatment of rheumatoid arthritis. Chris J. van Boxtel et al. (2001; 389). One would say that this is a breakthrough in medicine, as the more traditional NSAID's such as Ibuprofen for instance, have been related to such GI toxicity issues. Therefore it is important to understand the fact that by achieving the wanted effects of inhibiting the COX-2 enzyme whilst simultaneously diminishing the inhibition of the COX-1 enzyme is the most desirable effect. “Anorexia, heartburn, nausea, dyspepsia, diarrhoea and abdominal pain” are a few of the commonest symptoms encountered by the use of NSAID's however some may be as serious as gastric ulcers, in which the lining of the stomach begins to shed. Health Technology Assessment 2008 [online]. Therefore I believe that such side-effects should be avoided at all costs and if the introduction of selective COX-2 inhibitors is the answer to this; then this is truly an advantage in aiding patient safety.
The majority of NSAID's work in such a way that they reversibly inhibit the action of the COX enzymes; however aspirin differs from this trend. Aspirin acts on the body and inhibits the enzyme irreversibly by undergoing a covalent interaction with the enzyme. This therefore leads to inhibition of thromboxane synthesis and in turn the inhibition of platelet aggregation. Chris J. van Boxtel et al. (2001; 390). This factor illustrates potential dangers for prolonged aspirin use; and therefore the GI risks encountered.
Various selective COX-2 have been manufactured throughout the previous years; the most popular being Celecoxib. Some may see the selective nature of these being advantageous due to the anti-inflammatory actions with reduction in prostaglandin and thromboxane synthesis; however two known selective COX-2 inhibitors, Rofecoxib and Valdecoxib were withdrawn from market. Bertram G. Katzung et al. (2007; 579). The selective COX-2 inhibitors are referred to as coxibs; they act in the same way as the more traditional NSAID's however by almost halving the unwanted GI toxicity issues. This appears to be advantageous; however the familiar renal toxicity issues arising when using NSAID's are still present. Bertram G. Katzung et al. (2007; 579). It is clear to see that by reducing the risk of possible GI side effects that coxibs are far more advanced; but it makes one wonder why such drugs would be withdrawn from the market. Rofecoxib and Valdecoxib were withdrawn due to increased cases of cardiovascular thrombotic events. Rofecoxib was sold under the brand name of Vioxx and it was removed voluntarily due to increased cases in heart attacks and stroke. As of 2005 it was also considered that Celecoxib may increase risk of any cardiovascular events, in some cases being fatal. However studies are still being undertook to see if any action will be required in the future. FDA U.S Food and Drug Administration (2009). Other coxibs include Etoricoxib; which is available in the UK; however still pending for use in the USA, Meloxicam and Valdecoxib. Celecoxib is the most widely used out of all the coxibs and has resulted in fewer endoscopic ulcers, “no more oedema or renal effects”; which other NSAID's encounter. Although this is the case, they still incur the same amount of adverse effects. Another noticeable factor is the fact that it interacts with Warfarin. Bertram G. Katzung et al. (2007; 579). It has also been found that Aspirin interacts with Warfarin which is an anticoagulant. Warfarin is a substance that is highly protein bound; however Aspiring displaces this from binding sites and consequently the Warfarin is free in the blood at high concentrations and because it has a narrow therapeutic range, there are possibilities of it becoming highly toxic. Such considerations need to be considered when prescribing NSAID's, be it selective or non-selective.
The situation at present is in the favour of the more traditional NSAID's such as Diclofenac, Fenoprofen, and Ketoprofen to name a few. “Current NICE guidance recommends the use of COX-2 selective drugs in high-risk individuals (i.e. age 65+ years; previous history of GI events; patients taking concomitant anticoagulants or corticosteroids) with OA and RA. Individuals not at high risk are recommended to remain on non-selective NSAIDs.” Health Technology Assessment 2008 [online]. This indicates that professionals still prefer prescribing the more traditional NSAID's with the knowledge of the side-effects they pose.
In conclusion one believes that the more selective coxibs are a major development in medicinal products as they have the potential to almost half the cases of GI disorders which may prove to be fatal; however there is still a reason as to why they are second choice to the non-selective NSAID's. I believe that until there is substantial evidence showing that the benefits of the coxibs outweigh the risk of possible cardiovascular thrombotic events; there will be no development in their case. It is clear to see why people still prefer the non-selective NSAID's even after posing such risks due to the fact that the coxibs pose equally fatal risks. There will only be consideration into using them as widespread products if great leaps are made in proving that they are beneficial to patients in the long run. This is due to the fact that the safety of patients in the number one priority and as it stands at the moment; both types of NSAID's are equal contributors to risks.
FDA U.S Food and Drug Administration, 2009, COX-2 Selective (includes Bextra, Celebrex, and Vioxx) and Non-Selective Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). Retrieved 18 November 2009 from http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm103420.htm
Guardian, 2009, Rheumatoid arthritis Nonsteroidal anti-inflammatory drugs (NSAIDs). Retrieved 18 November 2009 from http://www.guardian.co.uk/lifeandstyle/besttreatments/rheumatoid-arthritis-treatments-nonsteroidal-antiinflammatory-drugs-nsaids
Health Technology Assessment, 2008, Cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs (etodolac, meloxicam, celecoxib, rofecoxib, etoricoxib, valdecoxib and lumiracoxib) for osteoarthritis and rheumatoid arthritis: a systematicreview and economic evaluation. Retrieved 18 November 2009 from http://www.hta.ac.uk/fullmono/mon1211.pdf
Katzung, B.G. et al., 2007, Basic And Clinical Pharmacology, 10th Edition. Pg 294,579. New York: McGraw Hill.
Van Boxtel, C.J. et al., 2001, Drug Benefits and Risks International Textbook of Clinical Pharmacology.pg 390. Chichester: John Wiley & Sons, LTD