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

(CELEBREX) currently is the only COX-2 inhibitor
licensed for use in the U.S.
The relative degree of selectivity for COX-2 inhibition is
lumiracoxib = etoricoxib > valdecoxib = rofecoxib >> celecoxib
(Figure 34–1). Although there were differences in relative hierarchies,
depending on whether screens were performed using recombinantly
expressed enzymes, cells, or whole-blood assays, most tNSAIDs
expressed similar selectivity for inhibition of the two enzymes. Some
compounds, conventionally thought of as tNSAIDs—diclofenac,
meloxicam, and nimesulide (not available in the U.S.)—exhibit selectivity
for COX-2 that is close to that of celecoxib in vitro (Figure 34–1)
(Warner et al., 1999; FitzGerald and Patrono, 2001). Indeed, meloxicam
achieved approval in some countries as a selective inhibitor of
COX-2. Thus, selectivity for COX-2 should not be viewed as an
absolute category; the isoform selectivity for COX-2 (just like selectivity
for β 1
adrenergic receptors) is a continuous rather than a discreet
variable, as illustrated in Figure 34–1.
Absorption, Distribution, and
Elimination
Absorption. Most NSAIDs are rapidly absorbed following oral
ingestion, and peak plasma concentrations usually are reached within
2-3 hours. All COX-2–selective NSAIDs are well absorbed, but peak
concentrations are achieved with lumiracoxib and etoricoxib in
~1 hour compared to 2-4 hours with the other agents. The poor aqueous
solubility of most NSAIDs often is reflected by a less than proportional
increase in area under the curve (AUC) of plasma
concentration–time curves, due to incomplete dissolution, when the
dose is increased. Food intake may delay absorption and sometimes
decreases systemic availability (i.e., fenoprofen, sulindac). Antacids,
commonly prescribed to patients on NSAID therapy, variably delay,
but rarely reduce, absorption. Most interaction studies performed
with proton pump inhibitors suggest that relevant changes in NSAID
kinetics are unlikely. Little information exists regarding the absolute
oral bioavailability of many NSAIDs, as solutions suitable for intravenous
administration often are not available. Some compounds
(e.g., diclofenac, nabumetone) undergo first-pass or presystemic
elimination. Acetaminophen is metabolized to a small extent during
absorption. Aspirin begins to acetylate platelets within minutes of
reaching the presystemic circulation.
Distribution. Most NSAIDs are extensively bound to plasma proteins
(95-99%), usually albumin. Plasma protein binding often is
concentration dependent (i.e., naproxen, ibuprofen) and saturable at
high concentrations. Conditions that alter plasma protein concentration
may result in an increased free drug fraction with potential toxic
effects. Highly protein bound NSAIDs have the potential to displace
other drugs, if they compete for the same binding sites. Most
NSAIDs are distributed widely throughout the body and readily penetrate
arthritic joints, yielding synovial fluid concentrations in the
range of half the plasma concentration (i.e., ibuprofen, naproxen,
piroxicam). Some substances yield synovial drug concentrations
similar to (i.e., indomethacin), or even exceeding (i.e., tolmetin),
plasma concentrations. Most NSAIDs achieve sufficient concentrations
in the CNS to have a central analgesic effect. Celecoxib is
particularly lipophilic, so it accumulates in fat and is readily transported
into the CNS. Lumiracoxib is more acidic than other
COX-2–selective NSAIDs, which may favor its accumulation at
sites of inflammation. Multiple NSAIDs are marketed in formulations
for topical application on inflamed or injured joints. However,
direct transport of topically applied NSAIDs into inflamed tissues
and joints appears to be minimal, and detectable concentrations in
synovial fluid of some agents (i.e., diclofenac) following topical
use are primarily attained via dermal absorption and systemic
circulation.
Elimination. Plasma t 1/2
varies considerably among NSAIDs. For
example, ibuprofen, diclofenac, and acetaminophen have relatively
rapid elimination (t 1/2
of 1-4 hours), while piroxicam has a t 1/2
of
~50 hours at steady state that can increase to up to 75 hours in the
elderly. Published estimates of the t 1/2
of COX-2–selective NSAIDs
vary (2-6 hours for lumiracoxib, 6-12 hours for celecoxib, and
20-26 hours for etoricoxib). However, peak plasma concentrations of
lumiracoxib at marketed doses considerably exceed those necessary
to inhibit COX-2, suggesting an extended pharmacodynamic t 1/2
.
Hepatic biotransformation and renal excretion is the principal route
of elimination of the majority of NSAIDs. Some have active metabolites
(e.g., fenbufen, nabumetone, meclofenamic acid, sulindac).
Elimination pathways frequently involve oxidation or hydroxylation
(Table 34–1). Acetaminophen, at therapeutic doses, is oxidized only
to a small fraction to form traces of the highly reactive metabolite,
N-acetyl-p-benzoquinone imine (NAPQI). When overdosed (usually
>10 g of acetaminophen), however, the principal metabolic pathways
are saturated, and hepatotoxic NAPQI concentrations can be
formed (see Chapters 4 and 6). Rarely, other NSAIDs also may be
complicated by hepatotoxicity (e.g., diclofenac, lumiracoxib).
Several NSAIDs or their metabolites are glucuronidated or otherwise
conjugated. In some cases, such as the propionic acid derivatives
naproxen and ketoprofen, the glucuronide metabolites can
hydrolyze back to form the active parent drug when the metabolite
is not removed efficiently due to renal insufficiency or competition
for renal excretion with other drugs. This may prolong elimination
of the NSAID significantly. NSAIDs usually are not removed by
hemodialysis due to their extensive plasma protein binding; salicylic
acid is an exemption to this rule. In general, NSAIDs are not recommended
in the setting of advanced hepatic or renal disease due to
their adverse pharmacodynamic effects.
Therapeutic Uses
All NSAIDs, including selective COX-2 inhibitors, are
antipyretic, analgesic, and anti-inflammatory, with the
exception of acetaminophen, which is antipyretic and
analgesic but is largely devoid of anti-inflammatory
activity.
Inflammation. NSAIDs find their chief clinical application
as anti-inflammatory agents in the treatment of
musculoskeletal disorders, such as rheumatoid arthritis
and osteoarthritis. In general, NSAIDs provide mostly
symptomatic relief from pain and inflammation associated
with the disease and are not considered to be
DMARDs. A number of NSAIDs are approved for the
treatment of ankylosing spondylitis and gout. The use
of NSAIDs for mild arthropathies, together with rest
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CHAPTER 34
ANTI-INFLAMMATORY, ANTIPYRETIC, AND ANALGESIC AGENTS; PHARMACOTHERAPY OF GOUT