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

dose-dependent relief from inflammation in osteoarthritis and
rheumatoid arthritis. The European Medicines Agency advises that
these medicines should not be used in patients with ischemic heart
disease or stroke and that prescribers should exercise caution when
using selective COX-2 inhibitors in patients with risk factors for
heart disease such as hypertension, hyperlipidemia, diabetes, smoking,
or peripheral arterial disease. As for all NSAIDs, the agency
advises the lowest effective dose for the shortest possible duration of
treatment.
Celecoxib
Celecoxib (CELEBREX) was approved for marketing in
the U.S. in 1998. Details of its pharmacology have been
reviewed (Davies et al., 2000).
Absorption, Distribution, and Elimination. The bioavailability of
oral celecoxib is not known, but peak plasma levels occur at 2-4 hours
after the dose is taken. The elderly (≥65 years of age) may have up to
2-fold higher peak concentrations and AUC values than younger
patients (≤55 years of age). Celecoxib is bound extensively to plasma
proteins. Little drug is excreted unchanged; most is excreted as carboxylic
acid and glucuronide metabolites in the urine and feces. The
elimination t 1/2
is ~11 hours. The drug commonly is given once or
twice per day during chronic treatment. Renal insufficiency is associated
with a modest, clinically insignificant decrease in plasma concentration.
Celecoxib has not been studied in patients with severe renal
insufficiency. Plasma concentrations are increased by ~40% and 180%
in patients with mild and moderate hepatic impairment, respectively,
and dosages should be reduced by at least 50% in patients with moderate
hepatic impairment. Celecoxib is metabolized predominantly by
CYP2C9. Although not a substrate, celecoxib is an inhibitor of
CYP2D6. Clinical vigilance is necessary during co-administration of
drugs that are known to inhibit CYP2C9 and drugs that are metabolized
by CYP2D6. For example, celecoxib inhibits the metabolism of
metoprolol and can result in its accumulation.
Therapeutic Uses. Celecoxib is approved in the U.S. for the management
of acute pain in adults, for the treatment of osteoarthritis,
rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing
spondylitis, and primary dysmenorrhea. The recommended dose for
treating osteoarthritis is 200 mg/day as a single dose or divided as
two 100-mg doses. In the treatment of rheumatoid arthritis, the recommended
dose is 100-200 mg twice per day. In the light of its cardiovascular
hazard, physicians are advised to use the lowest possible
dose for the shortest possible time. Current evidence does not support
use of celecoxib as a first choice among the tNSAIDs.
Celecoxib also is approved for the chemoprevention of polyposis
coli; however, placebo-controlled trials revealed a dose-dependent
increase in myocardial infarction and stroke (Solomon et al., 2006).
Adverse Effects. Placebo-controlled trials have established that
celecoxib confers a risk of myocardial infarction and stroke and this
appears to relate to dose and the underlying risk of cardiovascular
disease that anteceded drug administration. Effects attributed to
inhibition of PG production in the kidney—hypertension and
edema—occur with nonselective COX inhibitors and also with celecoxib.
Studies in mice and some epidemiological evidence suggest
that the likelihood of patients’ developing hypertension while on
NSAIDs reflects the degree of inhibition of COX-2 and the selectivity
with which it is attained. Indeed, the prevalence of hypertension
is higher in patients taking etoricoxib than diclofenac,
consistent with the greater selectivity for inhibition of COX-2 of
the former drug (Cannon et al., 2006; Laime et al., 2007). Thus, the
risk of thrombosis, hypertension, and accelerated atherogenesis are
mechanistically integrated. The coxibs should be avoided in patients
prone to cardiovascular or cerebrovascular disease. None of the coxibs
has established superior efficacy over tNSAIDs. Celecoxib carries
the same cardiovascular and GI black box warning as tNSAIDs.
Although selective COX-2 inhibitors do not interact to prevent the
antiplatelet effect of aspirin, it now is thought that they lose their GI
advantage over a tNSAID alone when used in conjunction with
aspirin. Experience with selective COX-2 inhibitors in patients who
exhibit aspirin hypersensitivity is limited, and caution should be
observed.
Parecoxib
Parecoxib is the only COX-2–selective NSAID administered
by injection and has been shown to be an effective
analgesic for the peri-operative period when
patients are unable to take oral medication. It is not
widely available, and clinical experience is limited.
Absorption, Distribution, and Elimination. Parecoxib is absorbed
rapidly (~15 minutes after intramuscular injection) and converted
(15-50 minutes) by deoxymethylation to valdecoxib, the active drug
(Table 34–1). Valdecoxib undergoes extensive hepatic metabolism
by CYPs 3A4 and 2C9 and non–CYP-dependent glucuronidation.
It is a weak inhibitor of CYP2C9 and a weak to moderate inhibitor
of CYP2C19. The metabolites of valdecoxib are excreted in the
urine. The t 1/2
is ~7-8 hours but can be significantly prolonged in the
elderly or those with hepatic impairment, with subsequent drug accumulation.
Therapeutic Uses. Parecoxib (DYNASTAT) is available in Germany
and Australia, but not in the U.K. or U.S., for management of acute
pain, including moderate to severe postsurgical pain. It is supplied as
a lyophilized powder equivalent to 20 or 40 mg parecoxib to be
reconstituted with sterile saline for injection.
Adverse Effects. The cardiovascular risk of parecoxib and valdecoxib
was detected in two postoperative pain management trials of
high-risk patients (Grosser et al., 2006). Patients undergoing coronary
bypass graft (CABG) surgery were initially treated intravenously
with parecoxib or placebo and then switched to oral
valdecoxib or placebo. The majority of cardiovascular events
occurred within days of treatment initiation in these populations,
who were subject to acute hemostatic activation after bypass surgery.
Clinical studies suggest that cardiovascular complications
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CHAPTER 34
ANTI-INFLAMMATORY, ANTIPYRETIC, AND ANALGESIC AGENTS; PHARMACOTHERAPY OF GOUT