Non-steroidal anti-inflammatory drug
Non-steroidal anti-inflammatory drugs, usually abbreviated to NSAIDs, are drugs with analgesic, antipyretic and anti-inflammatory effects: they reduce pain, fever and inflammation. NSAIDs are sometimes referred to as non-steroidal anti-inflammatory agents (NSAIAs). They act by inhibiting the enzyme cyclooxygenase, which catalyses the formation of prostaglandins from arachidonic acid (itself derived from the cellular phospholipid bilayer by phospholipase A2).
| Table of contents |
|
2 History 3 Landmark: COX-2 |
Method of action
Most known NSAIDs act as non-selective inhibitors of cyclooxygenase - they inhibit both the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isoenzymes. Examples of non-selective NSAIDs include the salicylates (including aspirin), diclofenac, indomethacin, ibuprofen, ketoprofen, naproxen and piroxicam. COX-1 is also found in the stomach lining, but the prostaglandins here serve a protective role, preventing the stomach mucosa from being eroded by its own acid. When COX-1 inhibitors lower stomach prostaglandin levels, their protective effects are lost, and stomach ulcerss and internal bleeding can result.
Paracetamol (acetaminophen), owing to its cyclooxygenase inhibition, is sometimes grouped together with the NSAIDs. Paracetamol, however, does not have any significant anti-inflammatory properties and is not a true NSAID. Though it has not been clearly elucidated, it is suspected that this lack of anti-inflammatory properties may be due to the cyclooxygenase inhibition of paracetamol occurring predominately in the central nervous system. There is also some speculation that paracetamol acts through inhibition of the recently discovered COX-3 isoform (see below).
History
Beginning in 1829, with the isolation of salicylic acid from the folk remedy, willow bark, NSAIDs have become an important part of the pharmaceutical treatment of pain (at low doses) and inflammation (at higher doses), due largely to their lack of undesirable side effects such as sedation, respiratory depression, or addiction. As they became accepted as generally safe, NSAIDs previously available by prescription only, e.g. ibuprofen, have now become over the counter drugs.
Prescription NSAIDs are usually dispensed for more severe acute or chronic pain and inflammation, e.g. osteo and rheumatoid arthritis, sports and other traumatic injury, chronic overuse injuries, post-surgical pain, and dysmenorrhoea, while research continues into their potential for treatment of other conditions, such as cancer and cardiovascular disease. Osteoarthritis accounts for 25% of visits to primary care physicians and half of all NSAID prescriptions; it is estimated that 80% of the population will have radiographic evidence of osteoarthritis by age 65, although only 60% of those will be symptomatic. In 2001, NSAIDs accounted for 70,000,000 prescriptions and 30 billion over the counter sales annually in the United States. With the aging of the Baby Boomer generation and the concomitant rise in the incidence of osteoarthritis and other such conditions for which NSAIDs have proved particularly useful, even more use will be made of these compounds. With such widespread use, the negative side effects of even generally safe drugs will be seen with increasing frequency. In the case of NSAIDs, the main such effect is gastrointestinal irritation, ranging from mild dyspepsia to bleeding, and ulcers, particularly during long-term therapy, complicating some therapies. Other side effects are inhibition of bone healing, cardiovascular side effects including inhibition of blood clotting via deactivation of platelets, and renal effects, including increases in blood pressure due to the effect of NSAIDs on prostaglandins in the kidneys that mediate blood pressure regulation. For these reasons, NSAID treatment of patients with congestive heart disease, nephritis, hyper or hypotension, or chronic renal disease is also more complex.
NSAIDs act by inhibiting synthesis of prostaglandins, a class of molecules by which the body responds to injuries. Unfortunately, along with such negative effects as inflammation and pain, prostaglandins also have a positive role, mediating the maintenance and repair of the gastrointestinal tract; this leads to the observed gastrointestinal side effects seen with prostaglandin inhibition by NSAIDs, e.g. gastric erosion, gastroduodenal ulceration, and ulceration of the small and large bowel. These effects are dose-dependent, and in many cases severe enough to pose the risk of ulcer perforation, upper gastrointestinal bleeding, and death, limiting the use of NSAID therapy. An estimated 10-20% of NSAID patients experience dyspepsia, and NSAID-associated upper gastrointestinal adverse events are estimated to result in 103,000 hospitalizations and 16,500 deaths per year in the United States, and represent 43% of drug-related emergency visits. Many of these events are avoidable; a review of physician visits and prescriptions estimated that unnecessary prescriptions for NSAIDs were written in 42% of visits.1
Attempts to differentiate between various NSAIDs in terms of clinical efficacy have not discovered great differences. Rather, differences between compounds tended to fall into the realm of convenience in dosing or route of application and of patient tolerance. Successful gastrointestinal-sparing NSAID preparations concentrated either on gross chemical properties such as acetylation and pH, or on combining the NSAID with a protective agent; suppressing acid production, most successfully by coprescription of a proton pump inhibitor, e.g. Esomeprazole (Nexium), suppression of acid production by histamine receptor H2 antagonists, e.g. cimetidine (Tagamet) and ranitidine (Zantac), or supplementation with the synthetic prostaglandin misoprostol (Cytotec); for instance, Arthotec, which combines Diclofenac with misoprostol in a single pill. This technique may be effective, but expensive.
While it was hoped that this COX-2 selectivity would reduce gastrointestinal adverse drug reactions (ADRs) there is little conclusive evidence that this is true. The original study touted by Searle (now part of Pfizer), showing a reduced rate of ADRs for celecoxib, was later revealed to be based on preliminary data - the final data showed no significant difference in ADRs when compared with diclofenac. Rofecoxib, however, has been shown to produce significantly fewer gastrointestinal ADRs compared to naproxen. The same study raised an as yet unresolved question regarding the cardiovascular/cardioprotective safety of the coxibs - a statistically insignificant increase in the incidence of myocardial infarctions was observed in patients on rofecoxib. Further studies are currently underway to resolve these questions.
In fact, Simmons also recently co-discovered COX-3 in 2002 and analyzed this new isozyme's relation to acetaminophen (paracetamol, Tylenol), arguably the most used drug in the world for pain. "Thus, inhibition of COX-3 could represent a primary central mechanism by which these drugs decrease pain and possibly fever," according to the study "COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: Cloning, structure, and expression," Chandrasekharan et al (Simmons is last author). The clinical ramifications and knowledge of COX isozymes are therefore rapidly expanding and could perhaps offer significant hope for future treatments of pain, inflammation and fever.
References
1. “Understanding NSAIDs: from aspirin to COX-2”;Gary A. Green; Clin Cornerstone 3(5):50-59, 2001.Landmark: COX-2
The discovery of the existence of COX-2 in 1991 by Daniel L. Simmons at Brigham Young University in Provo, Utah raised the hope of developing an effective NSAID without the gastric problems characteristic of these agents so far. The relatively selective COX-2 oxicam, meloxicam, was the first step towards developing a true COX-2 selective inhibitor. The newest class of NSAIDs, the coxibs, including celecoxib, rofecoxib, valdecoxib, parecoxib and etoricoxib; can be considered as true selective inhibitors of COX-2.