Rheumatoid arthritis NSAIDs

The toxicity of aminoglycosides in the kidney and other organs is concentration-dependent. Antibiotics such as kanamycin and gentamycin have their half-lives doubled in elderly patients. The elderly commonly suffer from osteoarthritis and (less commonly) rheumatoid arthritis. NSAIDs must be carefully used in geriatric patients, as they cause GI toxicity. For example, aspirin causes GI irritation... 

FIGURE 89-4. Algorithm for treatment of rheumatoid arthritis. RA, rheumatoid arthritis NSAID, nonsteroidal anti-inflammatory drugs Rx, therapy DMARD, disease-modifying anti rheumatic drug. 

NSAIDs are used as the first-line treatment of rheumatoid arthritis, osteoarthritis, systemic lupus erythematosis and other inflammatory diseases, and are thus amongst the most widely used dtugs in the developed world. This widespread use inevitably entailed a considerable associated morbidity, in particular a high incidence of gastric toxicity. In the USA alone, perforations, ulcers and bleeds lead to the hospitalisation of 100,000 patients per year, and about 15% of these die while under intensive care. 

The first two selective COX-2 inhibitors to be marketed and subjected to in depth clinical trials were celecoxib and rofecoxib. Both compounds are as effective as standard NSAIDs in rheumatoid arthritis, osteoarthritis and for pain following orthopaedic or dental surgery. Gastrointestinal side effects were far fewer than with comparator diugs and in fact were no... 

The salicylates and nonsteroidal anti-inflammatory drug (NSAIDs) are important in the treatment of arthritic conditions. For example, the salicylates and NSAIDs are used in the treatment of rheumatoid arthritis (a chronic disease characterized by inflammatory changes within the body s connective tissue) and osteoarthritis (a noninflammatory joint disease resulting in degeneration of the articular cartilage and... 

The miscellaneous drugp are used to treat a variety of musculoskeletal disorders. Ffenicillamine, methotrexate (MTX), and hydroxychloroquine are used to treat rheumatoid arthritis in patients who have had an insufficient therapeutic response to or are intolerant of other antirheumatic drugp such as the sailcylates and NSAIDs. The Summary Drug Table Drug s Used to Tream Musculoskeletal Disorders provides additional information about these and other drug s. One compound, hylan G-F 20, listed in the Summary Drug Table is not used for rheumatoid arthritis, but rather, for osteoarthritis knee pain. It is a viscous, elastic... 

FIGURE 54-2. Outl ine of the management of rheumatoid arthritis. (From Guidelines for the management of rheumatoid arthritis 2002 update. Arthritis Rheum 2002 46(2) 328-346, with permission.) DMARD, disease-modifying antirheumatic drug NSAID, nonsteroidal antiinflammatory drug ... 

Gold salts have had a long history of use in rheumatoid arthritis.269,270 The development of orally active auranofin (also known as Ridaura (50), Figure 23) was a major improvement over the early injectable gold preparations which were polymeric (e.g., (51)—(53)). However, use has declined with the popularity of nonsteroidal antiinflammatory drugs (NSAIDS) such as indo-methacin a recent estimate of the commercial value for auranofin was 6 million. The mechanism... 

COX-2 Inhibitor Celecoxib (Celebrex, Pfizer) inhibits the enzyme COX-2, which is involved in pain and inflammation, but it has no effect on the COX-1 enzyme, which helps to maintain stomach lining. It is prescribed for the relief of pain and symptoms of osteoarthritis and rheumatoid arthritis. Previously, nonsteroidal anti-inflammatory drugs (NSAIDs) were used. NSAIDs inhibit both COX-1 and COX-2 enzymes and cause stomach bleeding (see Case Study 2). 

Pfizer s tenidap (CP-66,248) (157), another enolic compound, was also more potent (500-fold) toward CO over 5-LO inhibition in human ISN (0.032 /iM and 18 /iM, respectively) [379-381]. Efficacy in rheumatoid arthritis clinical trials has been reported [380,382] in patients, serum levels of acute phase proteins and synovial fluid levels of IL-1 were reduced by tenidap, in contrast to the lack of this effect with NSAIDs. Besides CO/5-LO inhibition, a variety of in vitro activities have been reported, including a number of effects on monocyte functions and differentiation [379], inhibition of neutrophil degranulation [382], inhibition of the activation of neutrophil collagenase [383], inhibition of leukocyte-endothelial cell adhesion [384], and inhibition of LTB4-induced neutrophil chemotaxis [385]. Al-... 

One of the first compounds reported to inhibit 5-LO was the NSAID benox-aprofen (167) (reviewed in [405]). This drug (marketed by Lilly as Oraflex ) was effective in rheumatoid arthritis, but was withdrawn because of phototoxicity, liver toxicity and reports of drug-related deaths [406]. The typical NSAID anti-inflammatory profile of this compound was remarkable for its very weak seminal vesicle CO activity [407]. Additional in vivo activities were found for benoxaprofen which were not shared by other NSAIDs, particularly inhibition of leukocyte influx in the carrageenan sponge, carrageenan pleurisy, and rat Arthus pleurisy models monocytes were affected more than neutrophils [408-411]. More recently, benoxaprofen was reported to inhibit the adhesion of monocytes to endothelium [412]. 

The first-line agents in the treatment of rheumatoid arthritis are non-steroidal anti-inflammatory drugs such as diclofenac. Diclofenac and indometacin, another NSAID, tend to have similar activity hov/ever, indometacin has a higher incidence of side-effects and therefore diclofenac is more appropriate for initial treatment. Sodium aurothiomalate is classified as a disease-modifying antirheumatic drug and is used as a second-line treatment in rheumatoid arthritis, but has been superseded by methotrexate, administered v/eekly. Paracetamol is often indicated in the management of osteoarthritis. Local intra-articular injections of dexamethasone may be administered for the relief of soft-tissue inflammatory conditions. 

Arthritis patients at high risk of w/cers Treatment of the signs and symptoms of osteoarthritis or rheumatoid arthritis in patients at high risk of developing NSAID-induced gastric and duodenal ulcers and their complications. 

Nonsteroidal anti-inflammatory drug (NSAID)-associated gastric ulcers For reducing the risk of NSAID-associated gastric ulcers in patients with a history of documented gastric ulcer who require the use of an NSAID for treatment of the signs and symptoms of rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. 

Chiidren Mefenamic acid and meclofenamate are not recommended in children younger than 14 years of age. Indomethacin is not recommended in children 14 years of age and younger, except in circumstances that warrant the risk. Safety and efficacy of meloxicam has not been established in children younger than 18 years of age. Tolmetin and naproxen are the only agents labeled for juvenile rheumatoid arthritis. Safety and efficacy of tolmetin in infants younger than 2 years of age are not established. Safety and efficacy of other NSAIDs in children are not established. 

Rheumatoid arthritis (RA enteric-coated tablets) Treatment of patients with RA who have responded inadequately to salicylates or other nonsteroidal anti-inflammatory drugs (NSAIDs). 

Juvenile rheumatoid arthritis (JRA delayed-release tablets) In the treatment of pediatric patients 6 years of age and older with polyarticular-course JRA who have responded inadequately to salicylates or other NSAIDs. 

Polyarticular-course juvenile rheumatoid arthritis (JRA) Management of children with active polyarticular-course JRA who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy including full-dose NSAIDs. 

Selective COX-2 inhibitors are ideal agents to combine with chemoradiotherapy for several reasons. First, they have been shown to enhance the effect of various chemotherapeutic agents and radiation on cancer cells. Second, selective COX-2 inhibitors are relatively safe. They do not have severe gastrointestinal toxicity, which is common in many nonselective NSAIDs. For example, celecoxib, a selective COX-2 inhibitor which is currently being used for patients with arthritis, is 375-fold more selective for COX-2 compared to COX-1 (94), and in large randomized, multicenter, placebo-controlled, double-blind trials conducted in patients with rheumatoid arthritis, celecoxib proved to be less toxic than nonselective inhibitors of COX-1 and COX-2, and no more toxic than a placebo (95). Third, high-dose celecoxib (600 mg bid) has no effect on serum thromboxane or platelet function (96). This is obviously important in patients receiving... 

The arylpropionic acid derivatives are useful for the treatment of rheumatoid arthritis and osteoarthritis, for reduction of mild to moderate pain and fever, and for pain associated with dysmenorrhea. Side effects of the drugs are similar to but less severe than those described for the salicylates. Those who are sensitive to salicylates also may be sensitive to and have adverse reactions when taking ibuprofen and related drugs. Acute hypersensitivity to ibuprofen has been reported in patients with lupus. The hypersensitivity reaction to sulindac can be fatal. The use of sulindac has also been linked to cases of acute pancreatitis. The use of dimethylsulfoxide (DMSO) topically in combination with sulindac has been reported to induce severe neuropathies. The concurrent use of ibuprofen with aspirin reduces the antiinflammatory effects of both drugs. Ibuprofen is contraindicated in patients with aspirin sensitivity leading to bronchiolar constriction and in patients with an-gioedema. As with all NSAIDs, renal and liver function should be normal for adequate clearance of the drugs. 

Diclofenac Voltaren) is a phenylacetic acid derivative that is a potent inhibitor of COX and that has analgesic, antiinflammatory, and antipyretic effects. Its use is accompanied by side effects similar to those of other NSAIDs. Indications for the drug include rheumatoid arthritis, osteoarthritis, and ophthalmic inflammation (use of an ophthalmic preparation). 

Celecoxib has been approved for the treatment of osteoarthritis and rheumatoid arthritis, and rofecoxib has been approved for the treatment of osteoarthritis, acute pain and primary dysmenorrhea. Celecoxib and rofecoxib do not appear to differ in efficacy for the treatment of osteoarthritis. However, neither drug has efficacy greater than that of the non-selective NSAIDs. Since the COX-2 enzyme appears to play an important role in colon cancer the COX-2 inhibitors may find future uses in the treatment or prevention of colorectal cancer. 

The prototypes of this large class of NSAIDs are in-domethacin and ibuprofen. These drugs are indicated for the relief of acute and chronic rheumatoid arthritis and osteoarthritis. In addition, a number of drugs of this class are also useful in ankylosing spondylitis, acute gouty arthritis, bursitis, and tendinitis. 

Indomethacin (Indocin) is used in the treatment of acute gouty arthritis, rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis. It is not recommended for use as a simple analgesic or antipyretic because of its potential for toxicity. While indomethacin inhibits both COX-1 and COX-2, it is moderately selective for COX-1. It produces more CNS side effects than most of the other NSAIDs. Severe headache occurs in 25 to 50% of patients vertigo, confusion, and psychological disturbances occur with some regularity. GI symptoms also are more frequent and severe than with most other... 

Etodolac (Lodine) is indicated for the treatment of osteoarthritis, rheumatoid arthritis, and acute pain. It inhibits COX-2 with slightly more selectivity than COX-1 and therefore produces less GI toxicity than many other NSAIDs. Common adverse effects include skin rashes and CNS effects. 

Flurbiprofen (Ansaid) is indicated for the treatment of rheumatoid arthritis and osteoarthritis. Its half-life, longer than that of many of the NSAIDs, allows for twice daily dosing. The most common adverse effects of flurbiprofen are similar to those of the other acidic NSAIDs. Flurbiprofen inhibits both COX isoforms about equally. 

Celecoxib is indicated for the treatment of osteoarthritis and rheumatoid arthritis. Its use is contraindicated in individuals with hypersensitivity to sulfonamides or other NSAIDs. It should be used with caution in persons with hepatic disease. Interactions occur with other drugs that induce CYP2C9 (e.g. ri-... 

Meloxicam (Mobic), recently introduced for the treatment of osteoarthritis, is also used for rheumatoid arthritis and certain acute conditions. Although meloxicam is sometimes reported to be a selective COX-2 inhibitor, it is considerably less selective than celecoxib or rofecoxib. Its adverse effects are similar to those of piroxicam and other NSAIDs however, the frequency of GI side effects is lower for meloxicam than for piroxicam and several other NSAIDs. 

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