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NONSTEROIDAL ANTIINFLAMMATORY DRUGS
The nonsteroidal anti-inflammatory drugs (NSAIDs) have a variety of clinical uses as antipyretics, analgesics, and anti-inflammatory agents. They reduce body tem-perature in febrile states and thus are effective an-tipyretics. They are also useful as analgesics, relieving mild to moderate pain such as myalgia, dental pain, dysmenorrhea, and headache. Unlike the opioid analgesics, they do not cause neurological de-pression or dependence. As anti-inflammatory agents, NSAIDs are used to treat conditions such as muscle strain, tendinitis, and bursitis. They are also used to treat the chronic pain and inflammation of rheumatoid arthritis (adult onset and juvenile), osteoarthritis, and arthritic variants such as gouty arthritis and ankylosing spondylitis. While NSAIDs used to be the sole agent of choice for mild to moderate rheumatoid disease, they are now frequently used in conjunction with the disease-modifying antirheumatic drugs (DMARDs) early in the treatment of these disorders. This is because the NSAIDs reduce pain and inflammation associated with rheumatoid diseases but do not delay or reverse the dis-ease’s progress.
The anti-inflammatory actions of the NSAIDs are most likely explained by their inhibition of prostaglandin syn-thesis by COX-2. The COX-2 isoform is the predomi-nant COX involved in the production of prostaglandins during inflammatory processes. Prostaglandins of the E and F series evoke some of the local and systemic man-ifestations of inflammation, such as vasodilation, hyper-emia, increased vascular permeability, swelling, pain, and increased leukocyte migration. In addition, they in-tensify the effects of inflammatory mediators, such as histamine, bradykinin, and 5-hydroxytryptamine. All NSAIDs except the COX-2-selective agents inhibit both COX isoforms; the degree of inhibition of COX-1 varies from drug to drug. No one NSAID is empirically superior for the treatment of inflammatory diseases; in-stead, each individual’s response to and tolerance of a drug determines its therapeutic utility.
A number of the toxicities commonly caused by the NSAIDs result from the inhibition of prostaglandin synthesis (Table 36.2). The ability of NSAIDs to increase gastric acid secretion and inhibit blood clotting can lead to GI toxicity. Mild reactions, such as heartburn and in-digestion, may be decreased by adjusting the dosage, us-ing antacids, or administering the drugs after meals. Occult loss of blood from the GI tract and iron defi-ciency anemia are also possible. More serious toxicity can result from prolonged NSAID therapy, including peptic ulceration and rarely, GI hemorrhage.
NSAIDs can impair renal function, cause fluid reten-tion, and provoke hypersensitivity reactions, including bronchospasm, aggravation of asthma, urticaria, nasal polyps, and rarely, anaphylactoid reactions. These reac-tions may occur even in those who have previously used NSAIDs without any ill effects. NSAIDs inhibit uterine contraction and can cause premature closure of the fe-tal ductus arteriosus.
The spectrum of toxicity produced by each NSAID is related to its inhibition of specific COX isoforms. The earliest NSAIDs inhibit both isoforms of COX. Certain of these drugs are more specific for COX-1, whereas oth-ers inhibit COX-1 and COX-2 with roughly equal po-tency. More recently developed drugs selectively inhibit COX-2 and therefore do not elicit the GI and antiplatelet side effects common to drugs that inhibit COX-1.
Adverse effects that are not unequivocally related to inhibition of prostaglandin synthesis include hepatic effects (hepatitis, hepatic necrosis, cholestatic jaundice, increased serum aminotransferases), dermal effects (photosensitivities, Stevens-Johnson syndrome, toxic epidermal necrolysis, onycholysis), central nervous sys-tem (CNS) effects (headaches, dizziness, tinnitus, deaf-ness, drowsiness, confusion, nervousness, increased sweating, aseptic meningitis), ocular effects (toxic am-blyopia, retinal disturbances), and certain renal effects (acute interstitial nephritis, acute papillary necrosis).
Co-morbid factors that increase the risk of NSAID-induced GI bleeding include history of ulcer disease, advanced age, poor health status, treatment with certain drugs (discussed later), long duration of NSAID ther-apy, smoking, and heavy alcohol use. Because of their renal effects, NSAIDs must be used with caution in patients with renal impairment, heart failure, hyperten-sion, and edema.
The use of NSAIDs is contraindicated in persons who have had a hypersensitivity reaction to salicylates or any other NSAID. Asthmatics are at par-ticular risk for these reactions. NSAIDs should be used during pregnancy only if the potential benefit justifies the risk to the fetus.
A significant number of drug interactions are com-mon to most of the NSAIDs. The likelihood of NSAID-induced GI toxicity is increased by concomitant treat-ment with corticosteroids (long term), other NSAIDs, bisphosphonates, or anticoagulants. Certain NSAIDs can also compete for protein binding sites with war-farin, compounding the risk of GI bleeding if these drugs are coprescribed. Agents that cause thrombocy-topenia (e.g., myelosuppressive antineoplastic drugs) can also increase the likelihood that NSAIDs will cause bleeding. NSAIDs can decrease the clearance of methotrexate, resulting in severe hematological and GI toxicity. This does not appear to be a significant problem with low-dose methotrexate used in the treatment of rheumatoid arthritis; however, higher methotrexate doses used in the treatment of psoriasis or cancer may produce this toxicity. NSAIDs, when used in conjunc-tion with immunosuppressive agents, can mask fever and other signs of infection.
Because NSAIDs decrease prostaglandin synthesis in the kidney, these drugs can increase the nephrotox- icity of agents such as aminoglycosides, amphotericin B, cidofovir, cisplatin, cyclosporine, foscarnet, ganci-clovir, pentamidine, and vancomycin. NSAIDs can de-crease the renal excretion of drugs such as lithium. NSAIDs can decrease the effectiveness of antihyper-tensive drugs such as β-blockers and diuretics. The eld-erly and those with decreased renal function are at particular risk for this interaction. Elevated hepatic enzymes and hepatic toxicity can occur with some drugs.
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