NSAIDS1 (Nonsteroidal anti-inflammatory drugs) are drugs with the function of antipyretic, analgesic and anti-inflammation during a usage of higher dose. The name of Nonsteroidal is to distinguish from the steroidal agent which appears before NSAIDS. However, John Vane found out the basic mechanism of aspirin before the steroid was found. NSAIDS are a non-selective inhibitor. NSAIDS will inhibit the enzyme cyclooxygenase which include cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). The Arachidonic acid has two metabolic pathways which are Cyclooxygenase pathway and lipooxygenase pathway. Cyclooxygenase is an enzyme that will catalyse the production and formation of prostanoids Prostaglandin H2 by oxidation. The Prostaglandin H2 is then able to convert by specific enzyme to other Prostaglandins e.g. PGI2 and PGD2 etc. ,which can act as mediator .this mediator is allowed to bind to specific receptor on cell and promote different response.
According to the chemical structure, different types of NSAIDS are classified into different groups. They can be classified as Propionic acid derivatives (e.g. ibuprofen), Acetic acid derivatives (e.g. Indomethacin), Enolic acid (Oxicam) derivatives (e.g. Isoxicam), Fenamic acid derivatives (e.g. Fenamic acid derivatives) and Selective COX-2 inhibitors (e.g. Rofecoxib which was withdrawn from the market). A similar tolerability and characteristics (e.g. half life) will be shown with the same group of NSAIDS. While Aspirin is a irreversible inhibitor but ibuprofen and diclofenac are reversible.
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Is defined as,"an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage." by the international association for the study of pain (ISAP)9 . Pain can be simply classified as fast pain and slow pain. In addition, the fast pain impulses and slow pain impulse are transmitted through AÎ´ fiber and C fiber respectively.
The pain pathway is a two-way traffic pathway with descending pathway and ascending pathway. The descending pathway gives an inhibitory effect of pain sensation. The descending pathway is from the conscious brain to the subconscious brain and spinal cord, which is the place that allows the control and gating of the pain messages flowing to the cerebral cortex (Gate theory).
In general, pain is caused by potentially damaging stimuli which stimulates the nociceptor. The stimulated nociceptor will then send pain message (signal impulse) through the ascending pathway to cerebral cortex by network of relay neuron. This process is called nociception which cause the pain sensation.
Therefore Nociceptor is also called pain receptor. The activation of nociceptor caused by different type of inflammatory mediators e.g. Bradykinin, Prostaglandins etc. acting to it from the extracellular fluid.
The Prostaglandin is an inflammatory mediator. They are produced in every nucleated cell except lymphocytes cell of our body.
Prostaglandin, which consists of 20 carbon atoms, is lipid compound and is produced enzymatically from fatty acids of Membrane Phospholipids.
First membrane phospholipids react with cPLA2 (Ca2+-dependent) (Phospholipases A). cPLA2 is an enzyme that will release the fatty acid form the membrane phospholipids by hydrolysis. This causes the formation of Arachidonic acid. The Arachidonic acid is then brought to a cyclooxygenase pathway. In the cyclooxygenase pathway, Arachidonic acid is being oxidized by COX-1 and COX-2, which both are cyclooxygenase and located at blood vessels, stomach and the kidneys, into Prostaglandin H2 (PGH2). In addition COX-1 operate the production of prostaglandins at the baseline level, which COX-2 is responsible for the production of prostaglandins when there is a stimulation e.g. inflammation. Prostaglandin H2 (PGH2) which is biologically inactive prostaglandins. It needs to be activated by PGE synthase and PGD synthase to produce biologically active prostaglandins PGE2 and PGD2. As a result, during inflammation prostaglandin levels are increased as the COX-2 is being activated by the stimulus. The increased amount of prostaglandin released from the cell will act as mediator when binding to nociceptor instead of being pain mediator. More significantly is the increase in the sensitivity of nociceptors to other mediator. As a result the normally non-excitable 'silent nociceptor' is switched into a more easily excitable state. The excited receptor will then send a pain message (impulse) to the brain via an ascending pathway.
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Nonsteroidal anti-inflammatory drugs usually act as inhibitors which non-selectively inhibit both COX-1 and COX-2. As we know the Cox catalyses the formation of prostaglandins. Therefore, NSAIDS inhibit and reduce the formation of prostaglandin from Arachidonic acid. NASIDS result in reduced pain mediator and sensitivity of nociceptor. This could account for the pain relief by NSAIDS.
Aspirin is a good example of NSAIDs. The aspirin has an acetyl group which is hydrolysed and bound to the serine of at the alcohol group of the COX enzyme as an ester. This process will block the specific site (channel) of the enzyme. As a result the Arachidonic acid is not allowed to get into the active site, thus no prostaglandin is produced.
Caused by the increasing the level of prostaglandin E2, which will increase the firing rate of neuron of hypothalamus which disrupts the normal function of it. As the hypothalamus is the center of thermoregulation as a result of body temperature increase. NSAIDS will inhibit the formation of E2 and lower the body temperature
Side Effects of NSAIDS5
As we know NSAIDS is a non-selective inhibitor. The functions of COX-1 is important which involve homeostatic process, platelet aggregation, renal function, influences Kidney function and maintain normal gastric mucosa .The mucosa protection by COX-1 is reduce by the NSAIDS side effects which will cause Gastric ulcer and GI bleeding. People who suffer from RA and OA need to continuously intake NSAIDS to relief pain and anti- inflammation will have GI side effect.
Scientists want to invent a new medicine that could eliminate the side effects caused by the inhibition of COX-1.
In 1991 the scientists of Merck & Co. invented a medicine called Rofecoxib. This drug is a selective COX-2 inhibitor. Therefore it can greatly reduce the risk of Gastric ulcer and GI bleeding.
In VIGOR (Vioxx GI Outcome research) study, they compare the efficacy and adverse side effect of Rofecoxib and the NSAID naproxen. For the efficacy, the result shows a significantly fewer side effect of gastrointestinal Gastric ulcers and other upper gastrointestinal events reduce from 54%, to 1.4%, while the gastrointestinal tract bleeding reduces by 62% when compared to naproxen group. In addition, there are a smaller percentage of people received a gastro-protective medicine which having Vioxx than naproxen group. On the other hand, the result of over 12 months span shows that the patients with Rofecoxib treatment have a 4 times increased risk of suffering from acute myocardial infarction that patients with naproxen. They claim that there is no significant data show with the patients without high risk of cardiovascular, but only with high risk of cardiovascular patients.
Merck's scientists claim that as the naproxen has a protective effect, but at that time there is no evidence shows that there are such large protective effects (anti-platelet effect) to heart attack from naproxen .Therefore when Vioxx wide appear, it is being widely accepted by the world market and patient due to its own benefits.
After the submission of VIGOR study to the US Food and Drug Administration, it leads to introduction of Vioxx into the market in 2001, and then requested to show the warning of increasing adverse cardiovascular event in 2002.
In fact, before the VIGOR was published, the adverse cardiovascular events were taken out from the article. There were 3 additional heart attacks which occur within the low risk cardiovascular group and increase the risk of cardiovascular event by 4 to 5 times.
In 2001 Merck made another 3 year trial study 'the APPROVe study '. One of the aims of this study is in order to show if the rofecoxib is cardiovascular safe. It was shown that in this study there will be around two times more chance in Vioox group when compared to NSAIDs group of getting a cardiovascular event.
As proven by the APPROVe study which is the study of its own. On 30 of September 2004 Merck voluntarily withdrew the medicine from the international market.
When a research study is made to the public, it is important that both the efficacy and adverse said effect need to be fully disclosed but not only the favorable results. We cannot fabricate results
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If any of the results is hidden, it will be disapproved and the products will be withdrawn from the market.
Actually by the study of omerprazole and NSAIDS, using omerprazole, which is a proton pump inhibitor, together with NSAIDS is able to reduce the gastrointestinal side effect to 20%. As a result NSAIDS are able to use safer and give a less adverse side effect to the patient.