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

Absorption, Distribution, and Elimination. Diclofenac has rapid
absorption, extensive protein binding, and a t 1/2
of 1-2 hours
(Table 34–1). The short t 1/2
makes it necessary to dose diclofenac
considerably higher than would be required to inhibit COX-2 fully
at peak plasma concentrations to afford inhibition throughout the
dosing interval. There is a substantial first-pass effect, such that only
~50% of diclofenac is available systemically. The drug accumulates
in synovial fluid after oral administration, which may explain why
its duration of therapeutic effect is considerably longer than its
plasma t 1/2
. Diclofenac is metabolized in the liver by a member of the
CYP2C subfamily to 4-hydroxydiclofenac, the principal metabolite,
and other hydroxylated forms; after glucuronidation and sulfation,
the metabolites are excreted in the urine (65%) and bile (35%).
Therapeutic Uses. Diclofenac is approved in the U.S. for the longterm
symptomatic treatment of rheumatoid arthritis, osteoarthritis,
ankylosing spondylitis, pain, primary dysmenorrhea, and acute
migraine. Four oral formulations are available: immediate-release
tablets (CATAFLAM, others) and capsules (ZIPSOR), delayed-release
tablets [VOLTAREN, VOLTAROL (U.K.), others], extended-release
tablets (VOLTAREN-XR, others), and a powder for oral solution (CAM-
BIA). The usual daily oral dosage is 100-200 mg, given in several
divided doses. For migraine, one packet of powder (50 mg) dissolved
in 1-2 oz of water is administered. Diclofenac for topical
use is available as a gel (VOLTAREN) and as a transdermal patch
(FLECTOR); systemically active concentrations released from these
preparations are thought to contribute more to symptom relief than
direct transport through the skin into the inflamed tissue.
Diclofenac also is available in combination with misoprostol,
a PGE 1
analog (ARTHROTEC). This combination retains the efficacy
of diclofenac while reducing the frequency of GI ulcers and erosions.
In addition, an ophthalmic solution of diclofenac (VOLTAREN,
others) is available for treatment of postoperative inflammation following
cataract extraction and postoperative pain and photophobia
following corneal refractive surgery.
Adverse Effects. Diclofenac produces side effects (particularly
GI) in ~20% of patients, and ~2% of patients discontinue therapy
as a result. The incidence of serious GI adverse effects did not differ
between diclofenac and the COX-2–selective inhibitors, celecoxib
(Juni et al., 2002) and etoricoxib (Cannon et al., 2006),
likely because diclofenac exhibits a degree of COX-2 selectivity
that is similar to that of celecoxib. The drug carries the same black
box warning as all other tNSAIDs regarding cardiovascular
events. Hypersensitivity reactions have occurred following topical
application.
Modest elevation of hepatic transaminases in plasma occurs
in 5-15% of patients. Although usually moderate, transaminase values
may increase more than 3-fold in a small percentage of patients.
The elevations usually are reversible. Another member of this phenylacetic
acid family of NSAIDs, bromfenac, was withdrawn from the
market because of its association with severe, irreversible liver injury
in some patients. Bromfenac was re-licensed in the U.S. in 2005 as
an ophthalmic solution (XIBROM) for postoperative ocular inflammation
and pain following cataract extraction. The structurally similar
nepafenac (NEVANAC) was licensed as an ophthalmic in the same year
for the same indication. Lumiracoxib, another diclofenac analog (see
the following section), was withdrawn from the market in several
countries due to liver toxicity. Transaminases should be measured
during the first 8 weeks of therapy with diclofenac, and the drug
should be discontinued if abnormal values persist or if other signs or
symptoms develop. Other untoward responses to diclofenac include
CNS effects, rashes, allergic reactions, fluid retention, edema, and
renal function impairment. The drug is not recommended for children,
nursing mothers, or pregnant women. Consistent with its preference
for COX-2, and unlike ibuprofen, diclofenac does not interfere
with the antiplatelet effect of aspirin (Catella-Lawson et al., 2001).
Lumiracoxib
Lumiracoxib is an analog of diclofenac; it differs only by an additional
methyl group and one fluorine substitution for chlorine.
Lumiracoxib has greater COX-2 selectivity in vitro than any of the
currently available coxibs. Its structural similarity to diclofenac is
thought to account for their common hepatic adverse event profiles
that may occur via a mechanism independent from COX inhibition.
Lumiracoxib’s potency is similar to that of naproxen. It is used at
daily doses of 100 or 200 mg for osteoarthritis and 400 mg for acute
pain. Lumiracoxib is not approved in the U.S., and marketing authorization
was revoked in 2007 in many countries following reports of
serious liver toxicity. Refer to earlier editions of this text for further
details.
PROPIONIC ACID DERIVATIVES
Ibuprofen, the most commonly used tNSAID in the U.S.,
was the first member of the propionic acid class of
NSAIDs to come into general use and is available without
a prescription in the U.S. Naproxen, also available
without prescription, has a longer but variable t 1/2
, making
twice-daily administration feasible (and perhaps once
daily in some individuals). Oxaprozin also has a long t 1/2
and may be given once daily. Figure 34–4 shows the
chemical structures of propionic acid derivatives.
Mechanism of Action. Propionic acid derivatives are nonselective
COX inhibitors with the effects and side effects common to other
tNSAIDs. Although there is considerable variation in their potency
as COX inhibitors, this is not of obvious clinical consequence. Some
of the propionic acid derivatives, particularly naproxen, have prominent
inhibitory effects on leukocyte function, and some data suggest
that naproxen may have slightly better efficacy with regard to analgesia
and relief of morning stiffness. This suggestion of benefit
accords with the clinical pharmacology of naproxen that suggests
that some but not all individuals dosed with 500 mg twice daily sustain
platelet inhibition throughout the dosing interval.
Therapeutic Uses. Ibuprofen, naproxen, flurbiprofen, fenoprofen,
ketoprofen, and oxaprozin, are available in the U.S. Several additional
agents in this class, including fenbufen, carprofen, pirprofen,
indobufen, and tiaprofenic acid, are in use or under study in other
countries.
Propionic acid derivatives are approved for use in the symptomatic
treatment of rheumatoid arthritis and osteoarthritis. Some
also are approved for pain, ankylosing spondylitis, acute gouty
arthritis, tendinitis, bursitis, and migraine and for primary dysmenorrhea.
Small clinical studies suggest that the propionic acid
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CHAPTER 34
ANTI-INFLAMMATORY, ANTIPYRETIC, AND ANALGESIC AGENTS; PHARMACOTHERAPY OF GOUT