Pregnancy and Lactation.

In the hours before parturition,

there is induction of myometrial COX-2 expression,
and levels of PGE2 and PGF2α increase markedly
in the myometrium during labor (Slater et al., 2002).
Prolongation of gestation by NSAIDs has been demonstrated
in model systems and in humans. Some
NSAIDs, particularly indomethacin, have been used
off-label to terminate preterm labor. However, this use
is associated with closure of the ductus arteriosus and
impaired fetal circulation in utero, particularly in
fetuses older than 32 weeks’ gestation. COX-2–selective
inhibitors have been used off-label as tocolytic agents;
this use has been associated with stenosis of the ductus
arteriosus and oligohydramnios. Finally, the use of
NSAIDs and aspirin late in pregnancy may increase the
risk of postpartum hemorrhage. Therefore, pregnancy,
especially close to term, is a relative contraindication
to the use of all NSAIDs. In addition, their use must be
weighed against potential fetal risk, even in cases of
premature labor, and especially in cases of pregnancyinduced
hypertension (Duley et al., 2004).
Hypersensitivity. Certain individuals display hypersensitivity
to aspirin and NSAIDs, as manifested by symptoms
that range from vasomotor rhinitis, generalizedurticaria, and bronchial asthma to laryngeal
edema,
bronchoconstriction, flushing, hypotension, and shock.
Aspirin intolerance is a contraindication to therapy
with any other NSAID because cross-sensitivity can
provoke a life-threatening reaction reminiscent of anaphylactic
shock. Despite the resemblance to anaphylaxis,
this reaction does not appear to be immunological
in nature.
Although less common in children, this cross-sensitivity may
occur in 10-25% of patients with asthma, nasal polyps, or chronic
urticaria and in 1% of apparently healthy individuals. It is provoked
by even low doses (<80 mg) of aspirin and apparently involves COX
inhibition. Cross-sensitivity extends to other salicylates, structurally
dissimilar NSAIDs, and rarely acetaminophen (see “Adverse
Effects” in the “Acetaminophen” section). Treatment of aspirin
hypersensitivity is similar to that of other severe hypersensitivity
reactions, with support of vital organ function and administration of
epinephrine. Aspirin hypersensitivity is associated with an increase
in biosynthesis of LTs, perhaps reflecting diversion of AA to LOX
metabolism. Indeed, results in a small number of patients suggest
that blockade of 5-LOX with the drug zileuton or off-label use of
the LT-receptor antagonists may ameliorate the symptoms and signs
of aspirin intolerance, albeit incompletely.
Aspirin Resistance. All forms of treatment failure with
aspirin have been collectively called aspirin resistance.
Although this has attracted much attention, there
is little information concerning the prevalence of a stable,
aspirin-specific resistance or the precise mechanisms
that might convey this “resistance.” Genetic
variants of COX-1 that co-segregate with resistance
have been described, but the relation to clinical outcome
is not clear.
Reye’s Syndrome. Due to the possible association with
Reye’s syndrome, aspirin and other salicylates are contraindicated
in children and young adults <20 years of
age with viral illness–associated fever. Reye’s syndrome,
a severe and often fatal disease, is characterized
by the acute onset of encephalopathy, liver dysfunction,
and fatty infiltration of the liver and other viscera
(Glasgow and Middleton, 2001). The etiology and
pathophysiology are not clear, nor is it clear whether a
causal relationship between aspirin and Reye’s syndromeexists (Schror, 2007). However, the
epidemiologic
evidence for an association between aspirin use and
Reye’s syndrome seemed sufficiently compelling that
labeling of aspirin and aspirin-containing medications
to indicate Reye’s syndrome as a risk in children was
first mandated in 1986 and extended to bismuth subsalicylate
in 2004. Since then, the use of aspirin in children
has declined dramatically, and Reye’s syndrome has
almost disappeared. Acetaminophen has not been

Drug Interactions
Angiotensin-converting enzyme (ACE) inhibitors act,
at least partly, by preventing the breakdown of kinins
that stimulate PG production. Thus, it is logical that
NSAIDs might attenuate the effectiveness of ACE
inhibitors by blocking the production of vasodilator and
natriuretic PGs. Due to hyperkalemia, the combination
of NSAIDs and ACE inhibitors also can produce
marked bradycardia leading to syncope, especially in
the elderly and in patients with hypertension, diabetes
mellitus, or ischemic heart disease. Corticosteroids and
SSRIs may increase the frequency or severity of GI
complications when combined with NSAIDs. NSAIDs
may augment the risk of bleeding in patients receiving
warfarin both because almost all tNSAIDs suppress
normal platelet function temporarily during the dosing
interval and because some NSAIDs also increase warfarin
levels by interfering with its metabolism; thus,
concurrent administration should be avoided. Many
NSAIDs are highly bound to plasma proteins and thus
may displace other drugs from their binding sites. Such
interactions can occur in patients given salicylates or
other NSAIDs together with warfarin, sulfonylurea
hypoglycemic agents, or methotrexate; the dosage of
such agents may require adjustment to prevent toxicity.
Patients taking lithium should be monitored because
certain NSAIDs (e.g., piroxicam) can reduce the renalexcretion of this drug and lead to
toxicity, while others
can decrease lithium levels (e.g., sulindac).

Drug Interactions. The plasma concentration of salicylates generally

is little affected by other drugs, but concurrent administration of
aspirin lowers the concentrations of indomethacin, naproxen, ketoprofen,
and fenoprofen, at least in part by displacement from plasma
proteins. Important adverse interactions of aspirin with warfarin, sulfonylureas,
and methotrexate are mentioned earlier in “Drug
Interactions.” Other interactions of aspirin include the antagonism
of spironolactone-induced natriuresis and the blockade of the active
transport of penicillin from CSF to blood. Magnesium-aluminum
hydroxide antacids can alkalize the urine enough to increase salicylic
acid clearance significantly and reduce steady-state concentrations.
Conversely, discontinuation of antacid therapy can increase
plasma concentrations to toxic levels

Indomethacin
Indomethacin (INDOCIN, others), a methylated indole
derivative, was introduced in 1963 and is indicated for
the treatment of moderate to severe rheumatoid arthritis,
osteoarthritis, and acute gouty arthritis; ankylosing
spondylitis; and acute painful shoulder. Although
indomethacin is still used clinically, mainly as a steroidsparing
agent, toxicity and the availability of safer alternatives
have limited its use. Indomethacin is available
in an injectable form for the closure of patent ductus
arteriosus.
Mechanism of Action. Indomethacin is a more potent
nonselective inhibitor of the COXs than is aspirin; it
also inhibits the motility of polymorphonuclear leukocytes,
depresses the biosynthesis of mucopolysaccharides,
and may have a direct, COX-independent
vasoconstrictor effect. Indomethacin has prominent
anti-inflammatory and analgesic–antipyretic properties
similar to those of the salicylates.
Absorption, Distribution, and Elimination. Oral indomethacin has
excellent bioavailability. Peak concentrations occur 1-2 hours after
dosing (Table 34–1). The concentration of the drug in the CSF is
low, but its concentration in synovial fluid is equal to that in plasma
within 5 hours of administration. There is enterohepatic cycling of
the indomethacin metabolites and probably of indomethacin itself.
The t1/2 in plasma is variable, perhaps because of enterohepatic
cycling, but averages ~2.5 hours.
Therapeutic Uses. Indomethacin is estimated to be
~20 times more potent than aspirin. A high rate of intolerance
limits the long-term analgesic use of indomethacin.
Likewise, it is not commonly used as an analgesic or
antipyretic unless the fever has been refractory to other
agents (e.g., Hodgkin’s disease). When tolerated,
indomethacin often is more effective than aspirin.
Indomethacin is FDA approved for closure of persistent
patent ductus arteriosus in premature infants who weigh between
500 and 1750 g, who have a hemodynamically significant patent
ductus arteriosus, and in whom other supportive maneuvers have
been attempted. The regimen involves intravenous administration of
0.1-0.25 mg/kg every 12 hours for three doses, with the course
repeated one time if necessary. Successful closure can be expected
in >70% of neonates treated. The principal limitation of treating
neonates is renal toxicity, and therapy is interrupted if the output of
urine falls to <0.6 mL/kg/hr. Renal failure, enterocolitis, thrombocytopenia,
or hyperbilirubinemia are contraindications to the use of
indomethacin. Treatment with indomethacin also may decrease the
incidence and severity of intraventricular hemorrhage in low-birthweight
neonates (Ment et al., 1994).

Adverse Effects and Drug Interactions. A very high percentage

(35-50%) of patients receiving usual therapeutic doses of
indomethacin experience untoward symptoms, and ~20% must discontinue
its use because of the side effects. GI adverse events are
common and can be fatal; elderly patients are at significantly greater
risk. Diarrhea may occur and sometimes is associated with ulcerative
lesions of the bowel. Acute pancreatitis has been reported, as
have rare, but potentially fatal, cases of hepatitis. The most frequent
CNS effect (indeed, the most common side effect) is severe frontal
headache, occurring in 25-50% of patients who take the drug for
long periods. Dizziness, vertigo, light-headedness, and mental confusion
may occur. Seizures have been reported, as have severe
depression, psychosis, hallucinations, and suicide. Caution is
advised when administering indomethacin to elderly patients or to
those with underlying epilepsy, psychiatric disorders, or Parkinson’s
disease, because they are at greater risk for the development of serious
CNS adverse effects. Hematopoietic reactions include neutropenia,
thrombocytopenia, and rarely aplastic anemia.
The total plasma concentration of indomethacin plus its inactive
metabolites is increased by concurrent administration of
probenecid, but indomethacin does not interfere with the uricosuric
effect of probenecid. Indomethacin antagonizes the natriuretic and
antihypertensive effects of furosemide and thiazide diuretics and
blunts the antihypertensive effect of β-receptor antagonists, AT1-
receptor antagonists, and ACE inhibitors.