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prostaglandin synthetic inhibitor
Indications
Diclofenac (Voltaren, Cataflam) is approved for use
in rheumatoid arthritis, osteoarthritis, ankylosing
spondylitis, dysmenorrhea, and topically for the treatment treatment
of ocular inflammation and actinic keratosis.
Diclofenac exhibits approximately equal selectivity for
COX-1 and COX-2. The most common adverse reactions
are GI disturbances and headache.A reversible elevation
of serum transaminases occurs in 15% of patients.
Biological Functions
Diclofenac (Voltaren) is a phenylacetic acid derivative
that is a potent inhibitor of COX and that has analgesic,
antiinflammatory, and antipyretic effects. Its use is accompanied
by side effects similar to those of other
NSAIDs. Indications for the drug include rheumatoid
arthritis, osteoarthritis, and ophthalmic inflammation
(use of an ophthalmic preparation).
Mechanism of action
Diclofenac is unique among the NSAIDs in that it possesses three possible mechanisms
of action: 1) inhibition of the arachidonic acid cyclooxygenase system (3 to 1,000 times more potent than other
NSAIDs on a molar basis), resulting in a decreased production of prostaglandins and thromboxanes; 2)
inhibition of the lipoxygenase pathway, resulting in decreased production of leukotrienes, particularly the
pro-inflammatory LKB4; and 3) inhibition of arachidonic acid release and stimulation of its reuptake, resulting in a
reduction of arachidonic acid availability.
Pharmacokinetics
Diclofenac is rapidly and completely (～100%) absorbed on oral administration, with peak plasma levels being
reached within 1.5 to 2.5 hours. The free acid (pKa = 4.0) is highly bound to serum proteins (99.5%), primarily
albumin. Only 50 to 60% of an oral dose is bioavailable because of extensive hepatic metabolism.
Clinical Use
Diclofenac is synthesized from N-phenyl-2,6-dichloroaniline. It is available in 120 different countries and,
perhaps, is the most widely used NSAID in the world. It was introduced in the United States in 1989 but was first
marketed in Japan in 1974. It ranks among the top prescription drugs in the United States. Diclofenac possesses
structural characteristics of both arylalkanoic acid and the anthranilic acid classes of anti-inflammatory drugs, and it
displays anti-inflammatory, analgetic, and antipyretic properties.
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Four major
metabolites resulting from aromatic hydroxylation have been identified. The major metabolite via CYP3A4 is the
4′-hydroxy derivative and accounts for 20 to 30% of the dose excreted, whereas the 5-hydroxy, 3′-hydroxy, and
4′,5-dihydroxy metabolites via CYP2C9 account for 10 to 20% of the excreted dose. The remaining drug is excreted
in the form of sulfate conjugates. Although the major metabolite is much less active than the parent compound, it may
exhibit significant biological activity, because it accounts for 30 to 40% of all of the metabolic products.
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