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

and physical therapy, generally is effective. When the
symptoms are limited either to trouble sleeping because
of pain or significant morning stiffness, a single NSAID
dose given at night may suffice. Patients with more
debilitating disease may not respond adequately to full
therapeutic doses of NSAIDs and may require aggressive
therapy with second-line agents. Substantial interand
intraindividual differences in clinical response have
been noted.
Pain. When employed as analgesics, these drugs usually
are effective only against pain of low to moderate
intensity, such as dental pain. Although their maximal
efficacy is generally much less than the opioids,
NSAIDs lack the unwanted adverse effects of opiates in
the CNS, including respiratory depression and the
potential for development of physical dependence. Coadministration
of NSAIDs can reduce the opioid dose
needed for sufficient pain control and reduce the likelihood
of adverse opioid effects. NSAIDs do not change
the perception of sensory modalities other than pain.
They are particularly effective when inflammation has
caused peripheral and/or central sensitization of pain
perception. Thus, postoperative pain or pain arising
from inflammation, such as arthritic pain, is controlled
well by NSAIDs, whereas pain arising from the hollow
viscera usually is not relieved. An exception to this is
menstrual pain. The release of PGs by the endometrium
during menstruation may cause severe cramps and other
symptoms of primary dysmenorrhea; treatment of this
condition with NSAIDs has met with considerable success
(Marjoribanks et al., 2003). Not surprisingly, the
selective COX-2 inhibitors such as rofecoxib and etoricoxib
also are efficacious in this condition. NSAIDs are
commonly used as first-line therapy to treat migraine
attacks and can be combined with second-line drugs,
such as the triptans (e.g., TREXIMET, which is a fixeddose
combination of naproxen and sumatriptan), or
with antiemetics to aid relief of the associated nausea.
NSAIDs lack efficacy in neuropathic pain.
Fever. Antipyretic therapy is reserved for patients in
whom fever in itself may be deleterious and for those
who experience considerable relief when fever is lowered.
Little is known about the relationship between
fever and the acceleration of inflammatory or immune
processes; it may at times be a protective physiological
mechanism. The course of the patient’s illness may be
obscured by the relief of symptoms and the reduction of
fever by the use of antipyretic drugs. NSAIDs reduce
fever in most situations, but not the circadian variation
in temperature or the rise in response to exercise or
increased ambient temperature. Comparative analysis
of the impact of tNSAIDs and selective COX-2
inhibitors suggests that COX-2 is the dominant source
of PGs that mediate the rise in temperature evoked by
bacterial lipopolysaccharide (LPS) administration
(McAdam et al., 1999). This is consistent with the
antipyretic clinical efficacy of both subclasses of
NSAIDs. It seems logical to select an NSAID with
rapid onset for the management of fever associated with
minor illness in adults.
Fetal Circulatory System. PGs have long been implicated
in the maintenance of patency of the ductus arteriosus,
and indomethacin, ibuprofen, and other
tNSAIDs have been used in neonates to close the inappropriately
patent ductus. Conversely, infusion of PGE 2
maintains ductal patency after birth. Both COX-1 and
COX-2 appear to participate in maintaining patency of
the ductus arteriosus in fetal lambs (Clyman et al.,
1999), while in mice COX-2 appears to play the dominant
role (Loftin et al., 2002). It is not known which
isoform or isoforms are involved in maintaining
patency of the fetal ductus in utero in humans.
In mice, PGE 2
maintains a low ductal smooth muscle cell tone
via the G s
-coupled receptor EP 4
that increases intracellular cyclic
AMP. In the late gestational period, pulmonary expression of an
enzyme that eliminates PGE 2
from the bloodstream, PG 15-OH
dehydrogenase (PGDH), is rapidly upregulated (Coggins et al.,
2002). At birth, PGE 2
blood concentrations are dramatically reduced
by pulmonary PGDH and by additional exposure of circulating PGE 2
to this enzyme with the increase of pulmonary blood flow. Due to
reduced EP 4
signaling, intracellular cyclic AMP concentrations in the
ductus arteriosus drop, and vasodilating effects are outweighed by
vasoconstrictor signals, which initiate remodeling. However, surprisingly
little information about the human ductal physiology exists, and
a role for PGDH remains to be established in humans.
Cardioprotection. Ingestion of aspirin prolongs bleeding
time. For example, a single 325-mg dose of aspirin
approximately doubles the mean bleeding time of normal
persons for 4-7 days. This effect is due to irreversible
acetylation of platelet COX and the consequent
inhibition of platelet function until sufficient numbers
of new, unmodified platelets are released from
megakaryocytes. It is the permanent and complete
suppression of platelet TxA 2
formation that is thought
to underlie the cardioprotective effect of aspirin. Aspirin
reduces the risk of serious vascular events in high-risk
patients (e.g., those with previous myocardial infarction)
by 20-25%. Low-dose (<100 mg/day) aspirin,
which is relatively (but not exclusively) selective for
COX-1, is as effective as higher doses (e.g., 325 mg/day)
but is associated with a lower risk for GI adverse events.
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CHAPTER 34
ANTI-INFLAMMATORY, ANTIPYRETIC, AND ANALGESIC AGENTS; PHARMACOTHERAPY OF GOUT