Non-steroidal anti-inflammatory drugs are a category of drugs that possess analgetic belongingss and are the most normally used drugs in the direction of ague and chronic hurting. NSAIDs besides have anti-inflammatory effects and antipyretic effects ( decrease of temperature during febrility ) ( Rang, Dale et Al. 2007 ) . Although there are some fluctuations, drugs of this household achieve their effects chiefly via suppression of the enzyme cyclo-oxygenase ( COX ) . COX exists as three isoforms ; COX-1, COX-2 ( inducible ) and COX-3. COX-1, the first isoform to be identified, is constitutively expressed in the organic structure under basal conditions where it functions to keep stomachic mucous membrane, cause thrombocyte collection and bring forth vascular prostacyclin ( a potent vasodilative ) . Therefore, suppression of COX-1 is unwanted ( Gotlieb, 1999 ) , and is what causes side effects such as drawn-out hemorrhage, GI ulcers and compromised nephritic blood flow ( Rang, Dale et Al. 2007 ) . COX-2, on the other manus, is expressed merely in inflammatory cells, and is responsible for the production of prostanoids ( prostaglandin E2, prostacyclin and thromboxane A2 ) which are involved in interceding the inflammatory-response. Presently, the function of COX-3 in worlds is non understood. The physiological effects of COX-1 and COX-2 are summarised in figure 1 ( below ) :
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FIGURE 1 An overview of the effects of COX-1 and COX-2, and the drugs
that inhibit their actions ( self-generated ) .
Drugs belonging to the NSAID category are by and large non-selective, i.e. they inhibit both COX-1 and COX-2 isoforms, e.g. acetylsalicylic acid and isobutylphenyl propionic acid. However, a newer category of NSAIDs that became available in the late ninetiess are COX-2 selective ( coxibs ) . The selectivity of NSAIDs for COX-1 and COX-2 is determined by the size of their side groups. COX-1 and COX-2 have really similar constructions. In fact, they merely differ by a few amino acids – the most of import amino acid alteration being from Ile-523 in COX-1 to Val-523 in COX-2. This individual amino acid alteration allows entree to a deeper hydrophobic pocket in COX-2 non accessible in COX-1 ( due to bulkiness of isoleucine compared to valine ) , which causes a 25 % addition in size of the active site ( Knights et al. , 2010 ) . The deep pit of COX-2 therefore licenses entry of NSAIDs with larger side groups in comparing to COX-1 which can non suit larger side groups – this is the footing of COX-2 specificity among assorted NSAIDs ( Rang, Dale et al. , 2007 ) . Despite this, one time both non-selective and COX-2 selective inhibitors are inside COX-1 or COX-2, they cause suppression in the same manner by organizing H bonds with Arg-120 and barricading entry of the arachidonic acid substrate into the catalytic sphere. In general, suppression of COX-1 is reversible and occurs more quickly than suppression of COX-2, which is mostly irreversible. Figure 2 ( below ) shows the critical residues in the constructions of the COX isozymes:
hypertext transfer protocol: //img.medscape.com/article/733/075/733075-fig2.jpg
FIGURE 2 Comparison of the critical residues in the COX isozymes.
Ile-523 and Val-523 of COX-1 and COX-2 severally are important in finding whether or non an Nonsteroidal anti-inflammatory can come in. COX-2 exposes a deeper pit in which the substrate can come in ; hence COX-2 selective inhibitors ( with big side groups ) may come in merely COX-2.
Isoleucine to valine permutation opens up the hydrophobic ‘side ‘ pocket in COX-2 comparative to COX-1, 2010. [ Online image ] Available at: hypertext transfer protocol: //www.medscape.com/viewarticle/733075_2 [ Accessed February 2nd 2011 ]
COX-1 and COX-2 green goods prostanoids from arachidonic acid or other fatty acid substrates through really similar mechanisms. COX-1 and COX-2 are associated with heme and exist as homodimers in intracellular membranes. They are bifunctional enzymes, and therefore catalyze two distinguishable reactions ( Rang, Dale et al. , 2007 ) . In the first measure, besides known as the dioxygenase measure, 2 molecules of O2 are added to Cs 15 and 11, to organize the cyclised and oxygenated intermediate PGG2 ( prostaglandin G2 ) . PGG2 so undergoes a peroxidase reaction in which it is converted to PGH2 ( prostaglandin H2 ) , with a hydroxyl group at C 15. From here, isomerases, reductases or synthases can change over PGH2 into other prostanoids such as thromboxane A2 ( TxA2 ) , PGE2 and PGI2 ( Griffin, 2008 ) . Figure 3 ( below ) summarises the function of COX enzymes in prostanoid synthesis:
FIGURE 3 Mechanisms catalysed by COX in the synthesis of prostanoids. COX enzymes are bifunctional enzymes that catalyse two stairss, ensuing in production of PGH2. This is so converted to other prostanoids utilizing isomerases, reductases and synthases.
Adapted from: Cyclooxygenase transition of arachidonic acid into prostaglandin H2 ( PGH2 ) , 2008. [ Online image ] Available at: hypertext transfer protocol: //www.medscape.com/viewarticle/733075_2 [ Accessed February 2nd 2011 ]
( C15 )
( C11 )
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The principle for the development of COX-2 selective inhibitors was to avoid GI perturbations such as bleedings and ulceration associated with COX-1 suppression ( NMIC, 2000 ) , which are enfeebling, and in the worst instances can be fatal. It is estimated that 34-46 % of patients on long-run NSAID therapy experience some sort of GI perturbation ( Vinod et al. , 2008 ) . COX-1 is responsible for the protection of the stomachic mucous membrane and suppression of acerb secernment, achieved by the production of prostaglandins.
Rofecoxib ( trade name = Vioxx ) was a COX-2 selective inhibitor, or aa‚¬E?coxibaa‚¬a„? , that was developed for the intervention of arthritis in 1999 but was withdrawn from the market in 2004 due to increased hazard of myocardial infarction and shot ( Topol et al. , 2004 ) . This was the biggest drug callback in history, since as Merck & A ; Co. , the drug company that produced Vioxx, generated $ 2.5billion the predating twelvemonth from Vioxx gross revenues entirely ( Reuters, 2006 ) . The first line of grounds against Rofecoxib that came to visible radiation was from the Vioxx Gastrointestinal Outcomes Research ( VIGOR ) survey, conducted in 2000. This survey revealed that amongst arthritic arthritis patients that were administered either Vioxx or Naprosyn ; the incidence of myocardial infarction in the Vioxx patients was five times greater than the naproxen patients ( Topol et al. , 2004 ) . This is now known to be an underestimation, since as other terrible cardiovascular effects such as shot and thromboses had non been wholly reported. In 2001, Dr Eric Topol, the first doctor to talk out against Vioxx, published a reappraisal article in the Journal of the American Medical Association ( JAMA ) aboard two other research workers, entitled Hazard of cardiovascular events associated with selective COX-2 inhibitors. In this article, they reviewed old clinical tests of Vioxx and concluded that it caused a treble addition in likeliness of blood coagulums, myocardial infarctions and shot ( Topol et al. , 2001 ) . Presented with this new grounds, Merck & A ; Co defended itself by proposing that old clinical tests were flawed and that the ground why incidence of myocardial infarction in Vioxx patients was significantly higher than in naproxen patients was because Naprosyn exhibited cardioprotective belongingss. This, nevertheless, was ne’er proven ( Topol et al. , 2001 ) . Succeeding the research conducted by Topol et Al, a series of extra surveies were conducted, all bring forthing farther grounds that Vioxx caused increased hazard of myocardial infarction in comparing with other NSAIDs or COX-2 specific inhibitors. Despite all this grounds against Vioxx, Merck & A ; Co. still concluded that the surveies were flawed. Not merely did Merck & A ; Co. fail to react to the grounds, but the nutrient and drug authorization ( FDA ) besides ignored the grounds, and did non demand that Merck & A ; Co. carry on its ain probes in defense mechanism. In a 2001 survey conducted by Robert S. Bresalier of the Anderson Cancer Centre, University of Texas, Vioxx was tested for its ability to forestall recurrent colon polyps in patients that had pre-cancerous colon polyps removed. This test, called the Adenomatous Polyp Prevention on Vioxx ( APPROVe ) test, was sponsored by Merck & A ; Co. , and an independent reappraisal was carried out alongside this test to look into the incidence of myocardial infarction or shot among the topics. After 18 months of Vioxx therapy, it was found that incidence of such thrombotic cardiac events increased by 1.6 % ( about doubled ) . Upon this consequence ( September 30th 2004 ) , Merck & A ; Co. recalled Vioxx from the market voluntarily ( NCI, 2005 ) . This callback drew attending to other coxibs being prescribed at the clip and led to the drug company Pfizer remembering Bextra ( trade name = Bextra ) from the market in April 2005. This was due to an increased hazard of myocardial infarction, shot and assorted serious tegument conditions, which were acknowledged the old twelvemonth ( FDA, 2005 ) .
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Sam M.T. , Gayathri D.S. , Prasanth V.V. , Vinod B. 2008. NSAIDs As Microspheres. The Internet Journal of Pharmacology. 6 ( 2 ) www.ispub.com/journal/the_internet_journal_of_pharmacology/volume_6_number_1_32/article/nsaids_as_microspheres.html [ Accessed February 2nd 2011 ]
