Page 662 - Basic _ Clinical Pharmacology ( PDFDrive )

648 SECTION VI Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout

Oral ibuprofen is often prescribed in lower doses (<1600 mg/d), The effectiveness of ketoprofen at dosages of 100–300 mg/d
at which it is analgesic but not anti-inflammatory. It is available is equivalent to that of other NSAIDs. Its major adverse effects
over the counter in low-dose forms. are on the GI tract and the central nervous system (see common
Ibuprofen oral and IV is effective in closing patent ductus adverse effects above).
arteriosus in preterm infants, with much the same efficacy and
safety as indomethacin. A topical cream preparation appears to Nabumetone
be absorbed into fascia and muscle; ibuprofen cream was more Nabumetone is the only nonacid NSAID in current use; it is
effective than placebo cream in the treatment of primary knee OA. given as a ketone prodrug (Figure 36–1) and resembles naproxen
A liquid gel preparation of ibuprofen, 400 mg, provides prompt in structure. Its half-life of more than 24 hours (Table 36–1) per-
relief and good overall efficacy in postsurgical dental pain. mits once-daily dosing, and the drug does not appear to undergo
In comparison with indomethacin, ibuprofen decreases urine enterohepatic circulation. Renal impairment results in a doubling
output less and also causes less fluid retention. The drug is of its half-life and a 30% increase in the area under the curve.
relatively contraindicated in individuals with nasal polyps, angio- Its properties are very similar to those of other NSAIDs,
edema, and bronchospastic reactivity to aspirin. Aseptic menin- though it may be less damaging to the stomach. Unfortunately,
gitis (particularly in patients with SLE), and fluid retention have higher dosages (eg, 1500–2000 mg/d) are often needed, and this
been reported. The concomitant administration of ibuprofen and is a very expensive NSAID.
aspirin antagonizes the irreversible platelet inhibition induced by
aspirin. Thus, treatment with ibuprofen in patients with increased Naproxen
cardiovascular risk may limit the cardioprotective effects of aspi-
rin. Furthermore, the use of ibuprofen concomitantly with aspirin Naproxen is a naphthylpropionic acid derivative. It is the only
may decrease the total anti-inflammatory effect. Common adverse NSAID presently marketed as a single enantiomer. Naproxen’s free
effects are listed on page 645 rare hematologic effects include fraction is significantly higher in women than in men, but half-life
agranulocytosis and aplastic anemia. is similar in both sexes (Table 36–1). Naproxen is effective for the
usual rheumatologic indications and is available in a slow-release
Indomethacin formulation, as an oral suspension, and over the counter. A topical
preparation and an ophthalmic solution are also available.
Indomethacin, introduced in 1963, is an indole derivative The incidence of upper GI bleeding in over-the-counter use is
(Figure 36–1). It is a potent nonselective COX inhibitor and may low but still double that of over-the-counter ibuprofen (perhaps
also inhibit phospholipase A and C, reduce neutrophil migration, due to a dose effect). Rare cases of allergic pneumonitis, leukocy-
and decrease T-cell and B-cell proliferation. toclastic vasculitis, and pseudoporphyria as well as the common
Indomethacin differs somewhat from other NSAIDs in its NSAID-associated adverse effects have been noted.
indications and toxicities. It has been used to accelerate closure of
patent ductus arteriosus. Indomethacin has been tried in numer- Oxaprozin
ous small or uncontrolled trials for many other conditions, includ-
ing Sweet’s syndrome, juvenile RA, pleurisy, nephrotic syndrome, Oxaprozin is another propionic acid derivative NSAID. As noted
diabetes insipidus, urticarial vasculitis, postepisiotomy pain, and in Table 36–1, its major difference from the other members of
prophylaxis of heterotopic ossification in arthroplasty. this subgroup is a very long half-life (50–60 hours), although
An ophthalmic preparation is efficacious for conjunctival oxaprozin does not undergo enterohepatic circulation. It is mildly
inflammation and to reduce pain after traumatic corneal abra- uricosuric. Otherwise, the drug has the same benefits and risks
sion. Gingival inflammation is reduced after administration of that are associated with other NSAIDs.
indomethacin oral rinse. Epidural injections produce a degree of
pain relief similar to that achieved with methylprednisolone in Piroxicam
postlaminectomy syndrome. Piroxicam, an oxicam (Figure 36–1), is a nonselective COX
At usual doses, indomethacin has the common side effects inhibitor that at high concentrations also inhibits polymorpho-
listed above. The GI effects may include pancreatitis. Headache nuclear leukocyte migration, decreases oxygen radical production,
is experienced by 15–25% of patients and may be associated with and inhibits lymphocyte function. Its long half-life (Table 36–1)
dizziness, confusion, and depression. Renal papillary necrosis has permits once-daily dosing.
also been observed. A number of interactions with other drugs Piroxicam can be used for the usual rheumatic indications.
have been reported (see Chapter 66). When piroxicam is used in dosages higher than 20 mg/d, an
increased incidence of peptic ulcer and bleeding (relative risk up
Ketoprofen to 9.5) is encountered (see common adverse effects above).
Ketoprofen is a propionic acid derivative that inhibits both COX Sulindac
(nonselectively) and lipoxygenase. Its pharmacokinetic charac-
teristics are given in Table 36–1. Concurrent administration of Sulindac is a sulfoxide prodrug. It is reversibly metabolized to
probenecid elevates ketoprofen levels and prolongs its plasma the active sulfide metabolite and has enterohepatic cycling; this
half-life. prolongs the duration of action to 12–16 hours.