More than 20 different nonsteroidal anti-inflammatory drugs (NSAIDs) are available commercially, and these agents are used worldwide for their analgesic antipyretic and anti-inflammatory effects in patients with multiple medical conditions. NSAIDs, including aspirin, do not generally change the course of the disease process in those conditions, where they are used for symptomatic relief.
Nonsteroidal anti-inflammatory drugs (NSAIDs) produce their therapeutic activities through inhibition of cyclooxygenase (COX), the enzyme that makes prostaglandins (PGs). They share, to a greater or lesser degree, the same side effects, including gastric and renal toxicity. Recent research has shown that there are at least two COX isoenzymes. COX-1 is constitutive and makes PGs that protect the stomach and kidney from damage. COX-2 is induced by inflammatory stimuli, such as cytokines, and produces PGs that contribute to the pain and swelling of inflammation. Thus, selective COX-2 inhibitors should be anti-inflammatory without side effects on the kidney and stomach. Of course, selective COX-2 inhibitors may have other side effects and perhaps other therapeutic potential. For instance, COX-2 (and not COX-1) is thought to be involved in ovulation and in labor. In addition, the well-known protective action of aspirin on colon cancer may be through an action on COX-2, which is expressed in this disease. Moreover, NSAIDs delay the progress of Alzheimer’s disease. Thus, selective COX-2 inhibitors may demonstrate new important therapeutic benefits as anticancer agents, as well as in preventing premature labor and perhaps even retarding the progression of Alzheimer’s disease. Cyclo-oxygenase products, mainly PGE2, modulate the classical signs of inflammation. The two best studied inflammatory roles of cyclo-oxygenase products are induction of swelling and pain. In the case of ‘swelling’ PGEs are thought to cause plasma exudation in a synergistic fashion with other mediators such as complement factor 5a. One of the most important inflammatory disease targets associated with cyclo-oxygenase-2 is arthritis. In animal models of arthritis cyclo-oxygenase-2 is induced and thought to be responsible for the associated increase in PG production. The primary site of action is the cyclooxygenase (COX) enzyme, which catalyzes the conversion of arachidonic acid to prostaglandin and endoperoxide. Prostaglandins modulate components of inflammation. They also are involved in control of body temperature, pain transmission, platelet aggregation, and other effects. They are not stored by cells, but are synthesized and released on demand. Their half-lives are only minutes long. Therefore, if you control the enzyme that makes prostaglandins, then you control the prostaglandins themselves.
NSAIDs undergo hepatic transformations variously by CYP2C8, 2C9, 2C19 and/or glucuronidation. Half-lives of the NSAIDs vary but in general can be divided into “short-acting” (less than six hours, including ibuprofen, diclofenac, ketoprofen and indomethacin) and “long-acting” (more than six hours, including naproxen, celecoxib, meloxicam, nabumetone, and piroxicam). Patients with hypoalbuminemia (due, for example, to cirrhosis or active rheumatoid arthritis) may have a higher free serum concentration of the drug. Assessment of toxicity and therapeutic response to a given NSAID must take into account the time needed to reach the steady state plasma concentration (roughly equal to three to five half-lives of the drug). The pathogenesis of symptomatic peptic ulcer disease caused by exposure to NSAIDs is mainly a consequence of systemic (post-absorptive) inhibition of gastrointestinal mucosal cyclooxygenase (COX) activity. A closer look at the nonprescription analgesics revealed their potential harm when used by solid-organ transplant recipients. Excretion into breast milk is thought to be minimal, however it should be used with caution by women who are breast feeding
NSAIDs are widely used, frequently taken inappropriately and potentially dangerously. Nevertheless, ibuprofen exhibits few adverse effects. The major adverse reactions include the affects on the gastrointestinal tract (GIT), the kidney and the coagulation system. Based on clinical trial data, serious GIT reactions prompting withdrawal of treatment because of hematemesis, peptic ulcer, and severe gastric pain or vomiting showed an incidence of 1.5% with ibuprofen compared to 1% with placebo and 12.5% with aspirin. Ibuprofen was a potential cause of GI bleeding, increasing the risk of gastric ulcers and damage, renal failure, epistaxis, apoptosis, heart failure, hyperkalaemia, confusion and bronchospasm. It has been estimated that 1 in 5 chronic users (lasting over a long period of time) of NSAIDs will develop gastric damage which can be silent.