DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

990 After absorption, piroxicam is extensively (99%) bound to
plasma proteins. Concentrations in plasma and synovial fluid are
similar at steady state (e.g., after 7-12 days). Less than 5% of the
drug is excreted into the urine unchanged. The major metabolic
transformation in humans is hydroxylation of the pyridyl ring (predominantly
by an isozyme of the CYP2C subfamily), and this inactive
metabolite and its glucuronide conjugate account for ~60% of
the drug excreted in the urine and feces.
SECTION IV
INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
Therapeutic Uses. Piroxicam is approved in the U.S. for the treatment
of rheumatoid arthritis and osteoarthritis. Due to its slow onset
of action and delayed attainment of steady state, it is less suited for
acute analgesia but has been used to treat acute gout. The usual daily
dose is 20 mg, and because of the long t 1/2
, steady-state blood levels
are not reached for 7-12 days.
Adverse Events. Approximately 20% of patients experience side
effects with piroxicam, and ~5% of patients discontinue use because
of these effects. In 2007, the European Medicines Agency reviewed
the safety of orally administered piroxicam and concluded that its
benefits outweigh its risks, but advised it should no longer be used
first-line, nor should it be used for the treatment of acute (short-term)
pain and inflammation. Piroxicam was singled out for special review
because of signals that it is associated with more GI and serious skin
reactions than other nonselective NSAIDs.
Meloxicam
Therapeutic Uses. Meloxicam (MOBIC, others) is FDA-approved for
use in osteoarthritis. It has been reviewed (Davies and Skjodt, 1999;
Fleischmann et al., 2002). The recommended dose for meloxicam is
7.5-15 mg once daily.
Adverse Events. On average, meloxicam demonstrates ~10-fold
COX-2 selectivity in ex vivo assays. However, this is quite variable,
and a clinical advantage or hazard has yet to be established for the
drug. Indeed, even with surrogate markers, the relationship to dose
is nonlinear. There is significantly less gastric injury compared to
piroxicam (20 mg/day) in subjects treated with 7.5 mg/day of
meloxicam, but the advantage is lost with a dosage of 15 mg/day.
Other Oxicams
A number of other oxicam derivatives are under study or in use outside
the U.S. These include several prodrugs of piroxicam (ampiroxicam,
droxicam, and pivoxicam), which have been designed to reduce
GI irritation. However, as with sulindac, any theoretical diminution in
gastric toxicity associated with administration of a prodrug is offset
by gastric COX-1 inhibition from active drug circulating systemically.
Other oxicams under study or in use outside the U.S. include
lornoxicam, cinnoxicam, sudoxicam, and tenoxicam. The efficacy
and toxicity of these drugs are similar to those of piroxicam.
Lornoxicam is unique among the enolic acid derivatives in that it has
a rapid onset of action and a relatively short t 1/2
(3-5 hours).
PYRAZOLON DERIVATIVES
This group of drugs includes phenylbutazone, oxyphenbutazone,
antipyrine, aminopyrine, and dipyrone; currently, only antipyrine
eardrops are available for human use in the U.S. These drugs were
used clinically for many years but have essentially been abandoned
because of their propensity to cause irreversible agranulocytosis.
Dipyrone was reintroduced in the E.U. a decade ago because epidemiological
studies suggested that the risk of adverse effects was
similar to that of acetaminophen and lower than that of aspirin.
However, the use of dipyrone remains limited. The pyrazolone derivatives
are discussed in previous editions of this book and may be
accessed on the G&G website.
DIARYL HETEROCYCLIC
COX-2–SELECTIVE NSAIDS
The first COX-2–selective NSAIDs were diaryl heterocyclic
coxibs. Celecoxib is the only such compound
still approved in the U.S. Etoricoxib is approved in several
countries; rofecoxib and valdecoxib were withdrawn
worldwide and have been discussed in previous
editions. Parecoxib is a water soluble, injectable prodrug
of valdecoxib marketed for treatment of acute pain
in several countries. Lumiracoxib, a structural analog
of the phenylacetic acid derivative diclofenac, also is
not available in the U.S. and has been discussed earlier
(see “Lumiracoxib”).
Chemistry. Most members of the diaryl heterocyclic family of selective
COX-2 inhibitors consist of a central 1,2-diaryl heterocyclic
moiety. Celecoxib is a diaryl substituted pyrazole compound; valdecoxib
is a diaryl substituted isoxazol derivative. Valdecoxib was
made water soluble for parenteral use (parecoxib) by coupling propionic
acid via an amide group to its sulfonamide moiety. Etoricoxib
is slightly different; it is a monoaryl substituted bipyridine, which
results in a three-ring configuration that is superimposable onto the
diaryl heterocyclic pharmacophore. Celecoxib, valdecoxib, and its
prodrug parecoxib contain a sulfonamide moiety that bares the risk
for cross-reactivity in patients with sulfonamide hypersensitivity and,
thus, must be avoided in such patients. Etoricoxib has a methylsulfonyl
group that is thought to be free of such risk.
Mechanism of Action. Compounds with higher affinity for COX-2
than COX-1 were identified in screens of combinatorial libraries.
Subsequent crystallography revealed a hydrophobic pocket in the
substrate binding channel of COX-2, which is absent in COX-1
(Figure 34–2). Thus, selective inhibitors of COX-2 are molecules
with side chains—the third ring—that fit within this hydrophobic
pocket but are too large to block COX-1 with equally high affinity.
There is considerable difference in response to the coxibs among
individuals (Fries et al., 2006), and it is not known how the degree
of selectivity may relate to either efficacy or adverse effect profile,
although it seems likely to be related to both. No controlled clinical
trials comparing outcomes among the coxibs have been performed.
Several tNSAIDs (e.g., nimesulide, diclofenac, meloxicam) exhibit
relative selectivity for COX-2 inhibition in whole blood assays that
resembles that of celecoxib (FitzGerald and Patrono, 2001; Brune
and Hinz, 2004).
Therapeutic Uses. All COX-2–selective NSAIDs have been shown
to afford relief from postextraction dental pain and to afford