Current Pharmaceutical Design - Volume 6, Issue 17, 2000

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used and effective treatments for pain and inflammation. They have a substantial toxicity profile with side effects mainly affecting the gastrointestinal tract, heart and kidneys. Although they comprise a chemically diverse group of drugs, NSAIDs are unified by a common mode of action - the ability to inhibit the enzyme cyclo-oxygenase (COX). This also accounts for much of their toxicity. The enzyme exists in at least 2 isoforms. COX-1 generates prostaglandins with physiological functions, COX-2 is induced by inflammation and its physiologic functions are unclear at present. Conventional NSAIDs, like diclofenac, ibuprofen, and naproxen, are non-selective COX inhibitors, blocking the production of both physiologic and inflammatory prostaglandins. In this chapter, we describe the main 'predictable' gastrointestinal, cardiac and renal toxicities that can be explained by such blockade and review the supporting clinical and epidemiological evidence.In this chapter, we describe the main 'predictable' gastrointestinal, cardiac and renal toxicities that can be explained by such blockade and review the supporting clinical and epidemiological evidence.In the gastrointestinal tract, the side effects associated with conventional NSAIDs are both local and systemic, and include ulceration, bleeding, perforation, and obstruction. The upper gastrointestinal tract is more commonly affected than the lower. The cardiac and renal side effects are most likely to occur in patients with existing heart or kidney disease, where prostaglandins play an essential role in maintaining the vasoconstrictor/dilator balance necessary for homeostasis. The patients at highest risk of toxicity are the elderly, those with a prior history of ulceration or bleeding, and those with a history of cardiac disease. Among such patients, the decision to prescribe NSAIDs requires careful consideration of the potential benefits and harms.

The common mechanism of action of aspirin and the chemically unrelated non-steroidal anti-inflammatory drugs (NSAIDs) is the inhibition of prostaglandin (PG) production due to interference with the enzymatic activity of cyclooxygenase (COX). These agents have long been used as effective treatments for arthritis. The recognition that the inducible isoform COX-2 was associated with inflammation and arthritis led to the hypothesis that PGs produced by a COX-2-dependent pathway were responsible for the inflammation, pain, and tissue destruction. Since the constitutive COX-1 enzyme was identified as responsible for gastroprotection and inhibition of platelet function, the potential for compounds that were both effective and safer than NSAIDs led to rapid development of agents that specifically inhibit COX-2. These agents have now been tested and approved for use by the US Food and Drug Administration for patients with osteoarthritis and rheumatoid arthritis. They have been shown equally effective to comparitor NSAIDs. More importantly, there is a 3.5-fold reduction in the incidence of endoscopic gastroduodenal ulcerations and early data suggesting a similar reduction in clinically significant perforations, symptomatic ulcers, and bleeds. In patients with arthritis at risk for gastrointestinal complications of NSAIDs, specific inhibitors of COX-2 provide an effective and apparently safer form of anti-inflammatory agent.

The kidney is the second most frequent target of serious adverse effects of non-steroidal antiinflammatory drugs (NSAIDs). The renal side effects of NSAIDs related to inhibition of cyclooxygenase (COX) comprise reduction in renal blood flow (RBF) and glomerular filtration rate (GFR), sodium/water retention, water intoxication and hyperkalemia.The discovery of two COX-isoenzymes, a constitutive COX-1, serving homeostatic prostanoid synthesis, and an inducible COX-2, responsible for proinflammatory prostanoid production, led to the development of new NSAIDs: Preferential and specific COX-2 inhibitors, promising minimal NSAID-typical toxicity with equivalent efficacy.However, we learned that there is no clear distinction in "physiologic" constitutive COX-1 and "inflammatory" inducible COX-2. This is particular true for the kidney of humans and other mammalians, where COX-2 was found constitutively in meaningful amounts. Animal experiments and clinical trials with preferential and specific COX-2 inhibitors revealed that COX-2 is the critical enzyme for sodium excretion, renin release and likely antagonism of antidiuretic hormone. Additionally, a significant role of COX-2 for nephrogenesis is suggested. For renal hemodynamics the given evidence point to COX-1 as the predominant enzyme, but further investigations are required.In summary, the gain of renal safety by use of preferential or specific COX-2 inhibitors is small or negligible with respect to sodium retention, hyperkalemia and probably water intoxication. These drugs may be advantageous regarding renal perfusion, but presently the same precautions as for conventional NSAIDs must be used

Recognition of two isoforms of cyclooxygenase and reports that nonsteroidal anti-inflammatory drugs may be beneficial in devastating neurological conditions such as Alzheimer's disease have led to increased interest in cyclooxygenase function in the nervous system. In the present paper we review current data on the multiplicity of cyclooxygenase and prostaglandin mediated effects in the central nervous system (CNS). We discuss CNS cells types, including neurons, glia, and cerebrovascular elements, where cyclooxygenases-1 and -2 are expressed under normal conditions or can be induced by physiological or pathological stimuli. We also address physiological processes such as pain sensitization, CNS inflammation and fever induction that are regulated or modified by cyclooxygenase activity. Finally, we describe potential roles of cyclooxygenase in neurological diseases and rationales for nonsteroidal anti-inflammatory drug use in the treatment of neurodegenerative disorders, stroke and CNS injury.