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

the chosen agent should be prescribed to determine initial
patient tolerance. Older patients may require lower
doses than younger patients to reduce the risk of toxicity.
Regulatory agencies stress use of the lowest effective
dose for the shortest possible duration of treatment.
Alterations in dosing may take several days (>3-4 t 1/2
)
to translate into clinically detectable changes. Delayed
distribution into the synovial compartment may extend
this interval. Indeed, some NSAIDs that are short lived
in plasma are sustained in synovial fluid and may
afford sufficient relief even when administered at intervals
longer than their plasma t 1/2
time. If the patient
does not achieve therapeutic benefit from one NSAID,
another may be tried. For mild arthropathies, the
scheme outlined earlier in this paragraph, together with
rest and physical therapy, probably will be sufficiently
effective. When the patient has sleeping problems
because of pain or morning stiffness, a larger proportion
of the daily dose may be given at night. However,
patients with more debilitating disease may not
respond adequately, prompting the initiation of more
aggressive therapy with disease-modifying anti-rheumatic
drugs (see below). The experience in children is limited
to a small number of drugs, which are dosed by
age and body weight.
Some adverse effects may manifest in the first
weeks of therapy; however, the risk of gastric ulceration
and bleeding accumulates with the duration of dosing.
Combination therapy with more than one NSAID
is to be avoided. A number of risk factors for GI complications
have been determined in epidemiological
studies. Patients at high risk for GI complications
should be prescribed a gastroprotective agent. These
patients also are potential candidates for a COX-
2–selective NSAID.
Placebo-controlled trials have established that
selective inhibition of COX-2 confers an increased risk
of heart attack and stroke. The likelihood of hazard
would be expected to be related to selectivity attained
in vivo, dose, potency and duration of action, and duration
of dosing, as well as the underlying cardiovascular
risk profile of an individual patient. It seems likely that
some of the older drugs with COX-2 selectivity (e.g.,
diclofenac) may closely resemble celecoxib. The cardiovascular
hazard from both celecoxib and rofecoxib,
the two inhibitors for which data are available from
placebo-controlled trials lasting >1 year, appeared to
increase with chronicity of dosing. This is consistent
with a mechanism-based acceleration of atherogenesis
directly via inhibition of PGI 2
and indirectly due to the
rise in blood pressure consequent to inhibition of COX-
2-derived PGE 2
and PGI 2
. Similarly, the increased risk
conferred by rofecoxib has been shown to dissipate
slowly, if at all, in the year after drug cessation. If a
COX-2–selective inhibitor is prescribed, it should be
used at the lowest possible dose for the shortest period
of time.
Patients at risk of cardiovascular disease or prone
to thrombosis should not be treated with COX-2-selective
NSAIDs. Small absolute risks of thrombosis attributable
to these drugs may interact geometrically with small
absolute risks from genetic variants like factor V Leiden
or concomitant therapies, such as anovulant oral contraceptives.
Some tNSAIDs (ibuprofen, naproxen) have
been shown to interfere with the antiplatelet activity of
low-dose aspirin, and aspirin’s cardioprotective effect
may be diminished in patients who take low-dose
aspirin and a tNSAID concomitantly. The administration
of immediate-release (not enteric-coated) aspirin
should be separated from the dose of tNSAID to avoid
the interaction. For example, ibuprofen should not be
taken within 30 minutes of the ingestion of low-dose
aspirin and low-dose aspirin should not be ingested
within 8 hours of a dose of ibuprofen. Patients at high
risk for cardiovascular events should preferentially use
analgesics that do not interfere with platelet action.
DISEASE-MODIFYING
ANTI-RHEUMATIC DRUGS
Rheumatoid arthritis is an autoimmune disease that
affects ~1% of the population. The pharmacological
management of rheumatoid arthritis includes symptomatic
relief through the use of NSAIDs. However,
although they have anti-inflammatory effects, NSAIDs
have minimal, if any effect on progression of joint
deformity. DMARDs (disease-modifying anti-rheumatic
drugs), on the other hand, reduce the disease activity of
rheumatoid arthritis and retard the progression of
arthritic tissue destruction. DMARDs include a diverse
group of small molecule non-biologicals and biological
agents (mainly antibodies or binding proteins), as summarized
in Table 34–3.
Treatment with single non-biological DMARDs can achieve
remission or at least a state of very low disease activity in a large
number of rheumatoid arthritis patients (Saag et al., 2008).
Combinations of non-biological DMARDs (e.g., methotrexate +
sulfasalazine, methotrexate + hydroxychloroquine, methotrexate +
leflunomide, methotrexate + sulfasalazine + hydroxychloroquine)
are indicated for patients with moderate or high disease activity or
prolonged disease duration or for those who fail to respond to a single
compound. Biological DMARDs remain reserved for patients
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CHAPTER 34
ANTI-INFLAMMATORY, ANTIPYRETIC, AND ANALGESIC AGENTS; PHARMACOTHERAPY OF GOUT