Specific Nonsteroidal Antiinflammatory Drugs
The acidic NSAIDs include the salicylates and an in-creasing number of other compounds. The latter agents, as a group, share many common properties: they may have toxicities, are highly protein bound and have the potential for interacting with other protein-bound drugs. The choice of a particular agent often depends on the reaction of the patient. Table 36.3 illustrates phar-macokinetic properties of selected NSAIDs.
Among the salicylates, aspirin and sodium salicylate are by far the most commonly used.
The salicylates are useful in the treatment of minor musculoskeletal disorders such as bursitis, synovitis, tendinitis, myositis, and myalgia. They may also be used to relieve fever and headache. They can be used in the treatment of inflammatory disease, such as acute rheu-matic fever, rheumatoid arthritis, osteoarthritis, and cer-tain rheumatoid variants, such as ankylosing spondylitis, Reiter’s syndrome, and psoriatic arthritis. However, other NSAIDs are usually favored for the treatment of these chronic conditions because of their lower inci-dence of GI side effects. Aspirin is used in the treatment and prophylaxis of myocardial infarction and ischemic stroke.
Aspirin is available as capsules, tablets, enteric-coated tablets (Ecotrin), timed-release tablets (ZORprin), buffered tablets (Ascriptin, Bufferin), and as rectal sup-positories. Sodium salicylate is available generically. Other salicylates include choline salicylate (Arthropan), choline magnesium trisalicylate (Trilisate), and magne-sium salicylate (Momentum).
Although aspirin itself is pharmacologically active, it is rapidly hydrolyzed to salicylic acid after its absorp-tion, and it is the salicylate anion that accounts for most of the anti-inflammatory activity of the drug. The supe-rior analgesic activity of aspirin compared with sodium salicylate implies that aspirin has an intrinsic activity that is not totally explainable by its conversion to sali-cylic acid. Aspirin inhibits COX-1 to a much greater ex-tent than COX-2; sodium salicylate is more selective for COX-1. This, combined with the ability of aspirin to acetylate proteins, might account for some of the thera-peutic and toxicological differences between aspirin and the other salicylates.
The binding of salicylic acid to plasma proteins varies with its plasma concentrations. At serum salicylic acid concentrations of less than 100 μg/mL, 90 to 95% is protein bound; at 100 to 400 μg/mL, 70 to 85% is pro-tein bound; and at concentrations greater than 400 μg/mL, 20 to 60% is protein bound. The plasma con-centration of salicylate that is associated with anti-inflammatory activity (200–300 μg/mL) is about six times that needed to produce analgesia. At these higher concentrations, salicylate metabolism is reduced, result-ing in a longer half-life for the drug. This reaction is a consequence of the saturable enzyme systems that me-tabolize salicylates. The plasma half-life for salicylate has been estimated to be 3 to 6 hours at the lower (anal-gesic) dosage and 15 to 30 hours at the higher (anti-inflammatory) dosages. The rate of hydrolysis of aspirin to salicylic acid is not dose limited, and no differences in the absorption of aspirin have been observed between arthritic patients and normal individuals.
The most common adverse effects produced by the salicylates are GI disturbances. Occult blood loss from the GI tract, peptic ulceration, and rarely, severe GI hemorrhage can occur. Because salicylic acid is highly bound to plasma proteins, it may be displaced by other highly protein-bound drugs such as oral anticoagulants, sulfonylureas, phenytoin, penicillins, and sulfonamides. The nonacetylated salicylates have greatly reduced effects on blood loss and produce fewer adverse GI effects. In addition, they may be somewhat kidney spar-ing. Salicylates may provoke hypersensitivity reactions and prolonged bleeding time in some individuals. Tinnitus, hearing impairment, blurred vision, and light-headedness are indicators of toxic dosages. The use of aspirin in conjunction with any other NSAID is not rec-ommended because of the lack of evidence that such combinations increase efficacy and because of the in-creased potential for an adverse reaction. Salicylates are contraindicated in children with febrile viral illnesses because of a possible increased risk of Reye’s syn-drome.
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.
Adverse reactions are common with the use of these drugs but usually do not result in serious morbidity. GI and CNS effects and prolonged bleeding may occur. Fluid retention, skin rashes, and ocular toxicity also oc-cur, but with much lower frequency than with the sali-cylates. The selectivity for COX-1 and COX-2 varies from drug to drug and accounts for some of the differ-ences in toxicity. None of the agents seems to be clearly more efficacious than the others; however, they generally cause less GI blood loss and fewer other adverse reac-tions than does aspirin, and the overall incidence of ad-verse reactions may be lower with these drugs.
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- 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 distur-bances occur with some regularity. GI symptoms also are more frequent and severe than with most other NSAIDs. Hematopoietic side effects (e.g., leukopenia, hemolytic anemia, aplastic anemia, purpura, thrombo-cytopenia, and agranulocytosis) also may occur. Ocular effects (blurred vision, corneal deposits) have been ob-served in patients receiving indomethacin, and regular ophthalmological examinations are necessary when the drug is used for long periods. Hepatitis, jaundice, pan-creatitis, and hypersensitivity reactions also have been noted.
Sulindac (Clinoril) is chemically related to in-domethacin and is generally used for the same indica-tions. It is a prodrug that is metabolized to an active sul-fide metabolite and an inactive metabolite. The most frequently reported side effects are GI pain, nausea, di-arrhea, and constipation. The incidence of these effects is lower than for indomethacin, presumably because sulindac is a prodrug and thus the active metabolite is not highly concentrated at the gastric mucosa. As with indomethacin, a rather high incidence of CNS side ef-fects (dizziness, headache) also occurs.
Tolmetin (Tolectin) is indicated for the relief of os-teoarthritis, rheumatoid arthritis, ankylosing spondylitis, and moderate pain. It is ineffective in gouty arthritis for unknown reasons. Tolmetin can inhibit both COX-1 and COX-2 but has a moderate selectivity for COX-1. The most frequently reported side effects are GI distur-bance and CNS reactions (e.g., headache, asthenia, and dizziness). These effects are less frequently observed than after aspirin or indomethacin use. Blood pressure elevation, edema, and weight gain or loss have been associated with tolmetin administration. Tolmetin me-tabolites in urine have been found to produce pseudo-proteinuria in some laboratory tests.
Ketorolac (Toradol), an NSAID chemically related to indomethacin and tolmetin, is mainly used as an anal-gesic, not for the treatment of inflammatory disease. It is available in oral, parenteral, and topical formulations.
Etodolac (Lodine) is indicated for the treatment of osteoarthritis, rheumatoid arthritis, and acute pain. It in-hibits 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.
Diclofenac (Voltaren, Cataflam) is approved for use in rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, dysmenorrhea, and topically for the treat- ment of ocular inflammation and actinic keratosis. Diclofenac exhibits approximately equal selectivity for COX-1 and COX-2. The most common adverse reac-tions are GI disturbances and headache. A reversible el-evation of serum transaminases occurs in 15% of pa-tients.
Ibuprofen (Advil, Motrin) is used as an analgesic and antipyretic as well as a treatment for rheumatoid arthritis and degenerative joint disease. The most fre-quently observed side effects are nausea, heartburn, epigastric pain, rash, and dizziness. Incidence of GI side effects is lower than with indomethacin. Visual changes and cross-sensitivity to aspirin have been reported. Ibuprofen inhibits COX-1 and COX-2 about equally. It decreases platelet aggregation, but the duration is shorter and the effect quantitatively lower than with as-pirin. Ibuprofen prolongs bleeding times toward high normal value and should be used with caution in pa-tients who have coagulation deficits or are receiving an-ticoagulant therapy.
Fenoprofen (Nalfon) is chemically and pharmaco-logically similar to ibuprofen and is used in the treat-ment of rheumatoid arthritis, osteoarthritis, and mild to moderate pain. GI effects such as dyspepsia and pain are most common, although dizziness, pruritus, and pal-pitations may occur. GI bleeding, sometimes severe, has been reported, and interstitial nephritis has been rarely associated with this drug. Concomitant administration of aspirin decreases the biological half-life of fenopro-fen by increasing the metabolic clearance of hydroxy-lated fenoprofen. Chronic administration of pheno-barbital also decreases the drug’s half-life.
Naproxen (Naprosyn) also has pharmacological properties and clinical uses similar to those of ibupro-fen. It exhibits approximately equal selectivity for COX-1 and COX-2 and is better tolerated than certain NSAIDs, such as indomethacin. Adverse reactions re-lated to the GI tract occur in about 14% of all patients, and severe GI bleeding has been reported. CNS com-plaints (headache, dizziness, drowsiness), dermatologi-cal effects (pruritus, skin eruptions, echinoses), tinnitus, edema, and dyspnea also occur.
Ketoprofen (Orudis) is indicated for use in rheuma-toid and osteoarthritis, for mild to moderate pain, and in dysmenorrhea. The most frequently reported side ef-fects are GI (dyspepsia, nausea, abdominal pain, diar-rhea, constipation, and flatulence) and CNS related (headache, excitation). Edema and increased blood urea nitrogen have also been noted in more than 3% of patients. Ketoprofen can cause fluid retention and in-creases in plasma creatinine, particularly in the elderly and in patients taking diuretics.
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.
Oxaprozin (Daypro) is approved for the treatment of osteoarthritis and rheumatoid arthritis. Its long half-life allows for once daily dosing. The most frequently re-ported adverse effects of this drug are nausea, vomiting, and dyspepsia.
Nabumetone (Relafen) is approved for rheumatoid arthritis, osteoarthritis, and pain management. Its long half-life allows for once-daily dosing. Although this drug is a weak inhibitor of COX, it is metabolized in the liver to 6-methoxy-2-naphthylacetic acid (6-MNA), a strong COX inhibitor that is chemically similar to naproxen. As with most NSAIDs, GI side effects are most commonly reported. The incidence of gastric ul-ceration is lower with nabumetone than with many other NSAIDs. This is due to its nature as a prodrug, not to COX-2 selectivity. Lower-bowel complaints, rashes, and CNS disturbances are common adverse effects.
Celecoxib (Celebrex) and rofecoxib (Vioxx) are highly selective COX-2 inhibitors. Because of this, they produce less erosion of the GI mucosa and cause less inhibition of platelet aggregation than do the nonselective COX in-hibitors. Short-term (6 months-to a year) clinical trials have shown that celecoxib and rofecoxib produce less GI toxicity than nonselective NSAIDs. However, seri-ous GI bleeding and ulceration have occurred in pa-tients taking these drugs, and long-term prospective studies of their safety have yet to be completed. Like the nonselective NSAIDs, the selective COX-2 inhibitors can produce renal side effects such as hypertension and edema.
Celecoxib is indicated for the treatment of os-teoarthritis and rheumatoid arthritis. Its use is con-traindicated in individuals with hypersensitivity to sul-fonamides or other NSAIDs. It should be used with caution in persons with hepatic disease. Interactions oc-cur with other drugs that induce CYP2C9 (e.g. ri fampin) or compete for metabolism by this enzyme (e.g. fluconazole, leflunomide). The most common adverse reactions to celecoxib are mild to moderate GI effects such as dyspepsia, diarrhea, and abdominal pain. Serious GI and renal effects have occurred rarely.
Rofecoxib is approved for the treatment of os-teoarthritis, dysmenorrhea, and acute pain. The most common adverse reactions to rofecoxib are mild to moderate GI irritation (diarrhea, nausea, vomiting, dys-pepsia, abdominal pain). Lower extremity edema and hypertension occur relatively frequently (about 3.5%). It is not metabolized by CYP2C9, so rofecoxib should not be subject to some of the interactions seen with celecoxib. However, its metabolism is increased by the coadministration of rifampin, which acts as a nonspe-cific inducer of hepatic metabolism.
The oxicams are as effective as indomethacin, and their long half-life allows for once-daily dosing. Piroxicam (Feldene) is indicated for the treatment of rheumatoid arthritis and osteoarthritis. Piroxicam is a nonspecific COX inhibitor that has a much higher affinity for COX-1 than COX-2. This may account for the large proportion (over 30%) of patients receiving long-term therapy who have reported side effects. Adverse GI re-actions have been the most frequently reported side ef-fect, but edema, dizziness, headache, rash, and changes in hematological parameters have also occurred in 1 to 6% of patients. Piroxicam can cause serious GI bleeding, ulceration, and perforation, particularly in the elderly, if the recommended dosage is exceeded or if aspirin is be-ing taken concurrently.
Meloxicam (Mobic), recently introduced for the treatment of osteoarthritis, is also used for rheumatoid arthritis and certain acute conditions. Although meloxi-cam is sometimes reported to be a selective COX-2 in-hibitor, 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 pirox-icam and several other NSAIDs.
Two compounds of the fenamate class of antiinflamma-tory drugs are marketed in the United States. Mefenamic acid (Ponstel) is indicated only for analgesia and primary dysmenorrhea when therapy will not ex-ceed 1 week. Meclofenamate sodium (Meclomen) is prescribed for rheumatoid arthritis and osteoarthritis.
The fenamates show no clear superiority in anti-inflammatory activity and may produce more adverse effects than other NSAIDs. Diarrhea may be severe enough to necessitate discontinuation of drug use. Other adverse GI reactions include nausea, vomiting, abdominal pain, bleeding, and peptic ulceration. Decreases in the hematocrit or hemoglobin values oc-cur in approximately one-sixth of patients taking meclofenamic acid, but these do not usually require dis-continuation of therapy. Because of the rare possibility of drug-induced hemolytic anemia, hematological analyses should be performed on patients receiving long-term therapy if anemia is suspected.
The phenylbutazone-type drugs include phenylbuta-zone, oxyphenbutazone, antipyrine, dipyrone, and aminopyrine. The use of these drugs has decreased be-cause of their propensity to cause blood dyscrasias. Only antipyrine, used in as otic drops with benzocaine (Otocalm), is available in the United States today; phenylbutazone is used in Canada, and dipyrone is used in some European countries.
Acetaminophen (Tylenol) is an effective antipyretic and analgesic that is well tolerated at therapeutic doses. It has only weak antiinflammatory activity; thus, it is not useful in the treatment of rheumatoid arthritis and other inflammatory conditions.