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

992 attributable to COX-2–selective NSAIDs is proportional to baseline
cardiovascular risk and to the duration of drug exposure (Grosser
et al., 2006). All NSAIDs and celecoxib carry a black box warning
contraindicating their use for pain following CABG surgery.
Life-threatening skin reactions (including toxic epidermal
necrolysis, Stevens-Johnson syndrome, and erythema multiforme)
have been reported in association with valdecoxib, which contains a
sulfonamide group. The risk of hypersensitivity or skin reactions
applies also to parecoxib. The drug must be discontinued at the first
sign of rash, mucosal lesion, or any other sign of hypersensitivity.
This additional hazard renders valdecoxib an unlikely therapeutic
choice.
SECTION IV
INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
Etoricoxib
Etoricoxib is a COX-2–selective inhibitor with selectivity
second only to that of lumiracoxib.
Absorption, Distribution, and Elimination. Etoricoxib is incompletely
(~80%) absorbed and has a long t 1/2
of ~20-26 hours
(Table 34–1). It is extensively metabolized before excretion. Small
studies suggest that those with moderate hepatic impairment are
prone to drug accumulation, and the dosing interval should be
adjusted. Renal insufficiency does not affect drug clearance.
Therapeutic Uses. Etoricoxib (ARCOXIA) is approved in some countries
(not in U.S.) as a once-daily medicine for symptomatic relief in the
treatment of osteoarthritis, rheumatoid arthritis, and acute gouty arthritis,
as well as for the short-term treatment of musculoskeletal pain, postoperative
pain, and primary dysmenorrhea (Patrignani et al., 2003).
Common Adverse Effects. In keeping with other coxibs, etoricoxib
shows decreased GI injury as assessed endoscopically. The
European regulatory agency concluded that etoricoxib, along with
other coxibs, increased the risk of heart attack and stroke; the
agency specifically restricted its use in patients with uncontrolled
hypertension.
Rofecoxib
Rofecoxib (VIOXX) was introduced in 1999. Details of its pharmacodynamics,
pharmacokinetics, therapeutic efficacy, and toxicity
have been reviewed (Davies et al., 2003). Based on interim analysis
of data from the Adenomatous Polyp Prevention on Vioxx
(APPROVe) study, which showed a significant (2-fold) increase in
the incidence of serious thromboembolic events in subjects receiving
25 mg of rofecoxib relative to placebo (Bresalier et al., 2005),
rofecoxib was withdrawn from the market worldwide in 2004.
OTHER NONSTEROIDAL
ANTI-INFLAMMATORY DRUGS
Apazone (Azapropazone)
Apazone is a tNSAID that has anti-inflammatory, analgesic, and
antipyretic activity and is a potent uricosuric agent. It is available in
E.U. but not in U.S. Some of its efficacy may arise from its capacity to
inhibit neutrophil migration, degranulation, and superoxide production.
Apazone has been used for the treatment of rheumatoid
arthritis, osteoarthritis, ankylosing spondylitis, and gout but usually
is restricted to cases where other tNSAIDs have failed. Typical
doses are 600 mg three times per day for acute gout. Once symptoms
have abated, or for non-gout indications, typical dosage is
300 mg three to four times per day. Clinical experience to date suggests
that apazone is well tolerated. Mild GI side effects (nausea,
epigastric pain, dyspepsia) and rashes occur in ~3% of patients,
while CNS effects (headache, vertigo) are reported less frequently.
Precautions appropriate to other nonselective COX inhibitors also
apply to apazone.
Nimesulide
Nimesulide is a sulfonanilide compound available in Europe that
demonstrates COX-2 selectivity similar to celecoxib in whole-blood
assays. Additional effects include inhibition of neutrophil activation,
decrease in cytokine production, decrease in degradative enzyme
production, and possibly activation of glucocorticoid receptors
(Bennett, 1999).
Nimesulide is administered orally in doses ≤100 mg twice
daily as an anti-inflammatory, analgesic, and antipyretic. Its use in
the E.U. is limited to ≤15 days due to the risk of hepatotoxicity.
CLINICAL SUMMARY: NSAIDs
Both tNSAIDs and COX-2–selective NSAIDs have
anti-inflammatory, analgesic, and antipyretic activity
by virtue of inhibition of PG biosynthesis. Selective
inhibitors of COX-2 were developed to reduce GI
adverse effects but have never been shown to exhibit an
efficacy advantage over tNSAIDs, and most have been
eliminated from the market due to cardiovascular and
hepatic toxicities. Choice and dosing of an NSAID are
usually guided by multiple considerations, including
the therapeutic indication, patient age, coincident diseases
or allergies, the drug’s safety and interaction profile,
and cost considerations. Drugs with more rapid
onset of action and shorter duration of action (sometimes
marketed as rapid release or liquid formulations
that facilitate absorption) probably are preferable for
fever accompanying minor viral illnesses, pain after
minor musculoskeletal injuries, or headache, whereas
a longer duration of action may be preferable for management
of postoperative or arthritic pain.
The choice among tNSAIDs for the treatment of
chronic arthritic conditions such as rheumatoid arthritis
largely is empirical. Substantial differences in
response have been noted among individuals treated
with the same tNSAID and within an individual treated
with different tNSAIDs, even when the drugs are structurally
related. It is reasonable to give a drug for a week
or two as a therapeutic trial and to continue it if the
response is satisfactory. Initially, all patients should be
asked about previous hypersensitivity to aspirin or any
member of the NSAID class. Thereafter, low doses of