Indomethacin, introduced in 1963, is an indole derivative (Figure 36–1). It is a potent nonselective COX inhibitor and may also inhibit phospholipase A and C, reduce neutrophil migration, and decrease T-cell and B-cell proliferation.
Indomethacin differs somewhat from other NSAIDs in its indications and toxicities. It has been used to accelerate closure of patent ductus arteriosus. Indomethacin has been tried in numerous small or uncontrolled trials for many other conditions, including Sweet’s syndrome, juvenile RA, pleurisy, nephrotic syndrome, diabetes insipidus, urticarial vasculitis, postepisiotomy pain, and prophylaxis of heterotopic ossification in arthroplasty.
An ophthalmic preparation is efficacious for conjunctival inflammation and to reduce pain after traumatic corneal abrasion. Gingival inflammation is reduced after administration of indomethacin oral rinse. Epidural injections produce a degree of pain relief similar to that achieved with methylprednisolone in postlaminectomy syndrome.
At usual doses, indomethacin has the common side effects listed above. The GI effects may include pancreatitis. Headache is experienced by 15–25% of patients and may be associated with dizziness, confusion, and depression. Renal papillary necrosis has also been observed. A number of interactions with other drugs have been reported (see Chapter 66).
Ketoprofen is a propionic acid derivative that inhibits both COX (nonselectively) and lipoxygenase. Its pharmacokinetic characteristics are given in Table 36–1. Concurrent administration of probenecid elevates ketoprofen levels and prolongs its plasma half-life.
The effectiveness of ketoprofen at dosages of 100–300 mg/d is equivalent to that of other NSAIDs. Its major adverse effects are on the GI tract and the central nervous system (see common adverse effects above).
Nabumetone is the only nonacid NSAID in current use; it is given as a ketone prodrug (Figure 36–1) and resembles naproxen in structure. Its half-life of more than 24 hours (Table 36–1) permits once-daily dosing, and the drug does not appear to undergo enterohepatic circulation. Renal impairment results in a doubling of its half-life and a 30% increase in the area under the curve.
Its properties are very similar to those of other NSAIDs, though it may be less damaging to the stomach. Unfortunately, higher dosages (eg, 1500–2000 mg/d) are often needed, and this is a very expensive NSAID.
Naproxen is a naphthylpropionic acid derivative. It is the only NSAID presently marketed as a single enantiomer. Naproxen’s free fraction is significantly higher in women than in men, but half-life is similar in both sexes (Table 36–1). Naproxen is effective for the usual rheumatologic indications and is available in a slow-release formulation, as an oral suspension, and over the counter. A topical preparation and an ophthalmic solution are also available.
The incidence of upper GI bleeding in over-the-counter use is low but still double that of over-the-counter ibuprofen (perhaps due to a dose effect). Rare cases of allergic pneumonitis, leukocytoclastic vasculitis, and pseudoporphyria as well as the common NSAID-associated adverse effects have been noted.
Oxaprozin is another propionic acid derivative NSAID. As noted in Table 36–1, its major difference from the other members of this subgroup is a very long half-life (50–60 hours), although oxaprozin does not undergo enterohepatic circulation. It is mildly uricosuric. Otherwise, the drug has the same benefits and risks that are associated with other NSAIDs.