Nonsteroidalanti Inflammatory Drugs

NONSTEROIDALANTI INFLAMMATORY DRUGS

Salicylates and other similar agents used to treat rheumatic disease share the capacity to suppress the signs and symptoms of inflammation. These drugs also exert antipyretic and analgesic effects, but it is their anti-inflammatory properties that make them most useful in the management of disorders in which pain is related to the intensity of the inflammatory process.Since aspirin, the original NSAID, has a number of adverse effects, many other NSAIDs have been developed in attempts to improve upon aspirin’s efficacy and decrease its toxicity.

Chemistry & Pharmacokinetics

The NSAIDs are grouped in several chemical classes, as shown in Figure 36–1. This chemical diversity yields a broad range of phar-macokinetic characteristics (Table 36–1). Although there are many differences in the kinetics of NSAIDs, they have some gen-eral properties in common. All but one of the NSAIDs are weak organic acids as given; the exception, nabumetone, is a ketone prodrug that is metabolized to the acidic active drug.Most of these drugs are well absorbed, and food does not sub-stantially change their bioavailability. Most of the NSAIDs are highly metabolized, some by phase I followed by phase II mecha-nisms and others by direct glucuronidation (phase II) alone. NSAID metabolism proceeds, in large part, by way of the CYP3A or CYP2C families of P450 enzymes in the liver. While renal excretion is the most important route for final elimination, nearly all undergo varying degrees of biliary excretion and reabsorption (enterohepatic circulation). In fact, the degree of lower gastroin-testinal (GI) tract irritation correlates with the amount of entero-hepatic circulation. Most of the NSAIDs are highly protein-bound (∼ 98%), usually to albumin. Most of the NSAIDs (eg, ibuprofen, ketoprofen) are racemic mixtures, while one, naproxen, is pro-vided as a single enantiomer and a few have no chiral center (eg, diclofenac).All NSAIDs can be found in synovial fluid after repeated dos-ing. Drugs with short half-lives remain in the joints longer than would be predicted from their half-lives, while drugs with longer half-lives disappear from the synovial fluid at a rate proportionate to their half-lives.

Pharmacodynamics

NSAID anti-inflammatory activity is mediated chiefly through inhibition of prostaglandin biosynthesis (Figure 36–2). Various NSAIDs have additional possible mechanisms of action, including inhibition of chemotaxis, down-regulation of interleukin-1 pro-duction, decreased production of free radicals and superoxide, and interference with calcium-mediated intracellular events. Aspirin irreversibly acetylates and blocks platelet cyclooxygenase, while the non-COX-selective NSAIDs are reversible inhibitors.

Selectivity for COX-1 versus COX-2 is variable and incom-plete for the older NSAIDs, but selective COX-2 inhibitors have been synthesized. The selective COX-2 inhibitors do not affect platelet function at their usual doses. In testing using human whole blood, aspirin, ibuprofen, indomethacin, piroxicam, and sulindac are somewhat more effective in inhibiting COX-1. The efficacy of COX-2-selective drugs equals that of the older NSAIDs, while GI safety may be improved. On the other hand, selective COX-2 inhibitors may increase the incidence of edema and hypertension. As of August 2011, celecoxib and the less selec-tive meloxicam were the only COX-2 inhibitors marketed in the USA. Rofecoxib and valdecoxib, two previously marketed, selec-tive COX-2 inhibitors, were withdrawn from the market because of their association with increased cardiovascular thrombotic events. Celecoxib has a Food and Drug Administration initiated “black box” warning concerning cardiovascular risks. It has been recommended that all NSAID product labels be revised to men-tion cardiovascular risks.

The NSAIDs decrease the sensitivity of vessels to bradykinin and histamine, affect lymphokine production from T lympho-cytes, and reverse the vasodilation of inflammation. To varying degrees, all newer NSAIDs are analgesic, anti-inflammatory, and antipyretic, and all (except the COX-2-selective agents and the nonacetylated salicylates) inhibit platelet aggregation. NSAIDs are all gastric irritants and can be associated with GI ulcers and bleeds as well, although as a group the newer agents tend to cause less GI irritation than aspirin. Nephrotoxicity has been observed for all of the drugs for which extensive experience has been reported. 

Nephrotoxicity is due, in part, to interference with the autoregula-tion of renal blood flow, which is modulated by prostaglandins. Hepatotoxicity can also occur with any NSAID.

Although these drugs effectively inhibit inflammation, there is no evidence that—in contrast to drugs such as methotrexate and other DMARDs—they alter the course of any arthritic disorder.

Several NSAIDs (including aspirin) reduce the incidence of colon cancer when taken chronically. Several large epidemiologic studies have shown a 50% reduction in relative risk when the drugs are taken for 5 years or longer. The mechanism for this protective effect is unclear.

The NSAIDs have a number of commonalities. Although not all NSAIDs are approved by the FDA for the whole range of rheumatic diseases, most are probably effective in rheumatoid arthritis, sero-negative spondyloarthropathies (eg, psoriatic arthritis and arthritis associated with inflammatory bowel disease), osteoarthritis, local-ized musculoskeletal syndromes (eg, sprains and strains, low back pain), and gout (except tolmetin, which appears to be ineffec-tive in gout).

Adverse effects are generally quite similar for all of the NSAIDs:

1. Central nervous system: Headaches, tinnitus, and dizziness.

2. Cardiovascular: Fluid retention, hypertension, edema, andrarely, myocardial infarction, and congestive heart failure.

3. Gastrointestinal: Abdominal pain, dysplasia, nausea, vomit-ing, and rarely, ulcers or bleeding.

4. Hematologic: Rare thrombocytopenia, neutropenia, or evenaplastic anemia.

5. Hepatic: Abnormal liver function tests and rare liver failure.

6. Pulmonary: Asthma.

7. Skin: Rashes, all types, pruritus.

8. Renal: Renal insufficiency, renal failure, hyperkalemia, andproteinuria.