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

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, AT 1
-
receptor antagonists, and ACE inhibitors.
Sulindac
Sulindac (CLINORIL, others) is a congener of
indomethacin, which was developed in an attempt
to find a less toxic but effective alternative (see
Haanen, 2001).
Mechanism of Action. Sulindac is a prodrug and
appears to be either inactive or relatively weak in vitro.
The active sulfide metabolite is >500 times more potent
than sulindac as an inhibitor of COX but less than half
as potent as indomethacin. The early notion that gastric
or intestinal mucosa is not directly exposed to high concentrations
of active drug after oral administration of
sulindac provided an initial rationale for the claim that
sulindac results in a lower incidence of GI toxicity than
indomethacin. However, this notion ignores the fact that
the mucosa of the GI tract is directly exposed to circulating
levels of active drug and no advantage of sulindac
over non-indomethacin NSAIDs has materialized
in clinical practice. Similarly, early clinical studies
suggesting that sulindac, in contrast to other NSAIDs,
did not alter renal PG levels and therefore might avoid
the association with hypertension in susceptible individuals,
have been discredited (Kulling et al., 1995). In
short, the same precautions that apply to other NSAIDs
regarding patients at risk for GI toxicity, cardiovascular
risk, and renal impairment also apply to sulindac.
Absorption, Distribution, and Elimination. The metabolism and
pharmacokinetics of sulindac are complex. About 90% of the drug
is absorbed in humans after oral administration (Table 34–1). Peak
concentrations of sulindac in plasma are attained within 1-2 hours,
while those of the sulfide metabolite occur ~8 hours after oral
administration. Sulindac undergoes two major biotransformations.
It is oxidized to the sulfone and then reversibly reduced to the sulfide,
the active metabolite. The sulfide is formed largely by the
action of bowel microflora on sulindac excreted in the bile. All three
compounds are found in comparable concentrations in human
plasma. The t 1/2
of sulindac itself is ~7 hours, but the active sulfide
has a t 1/2
as long as 18 hours. Sulindac and its metabolites undergo
extensive enterohepatic circulation, and all are bound highly to
plasma protein. Little of the sulfide (or of its conjugates) is found
in urine. The principal components excreted in the urine are the sulfone
and its conjugates, which account for nearly 30% of an administered
dose; sulindac and its conjugates account for ~20%. Up to
25% of an oral dose may appear as metabolites in the feces.
Therapeutic Uses. Sulindac has been used mainly for
the treatment of rheumatoid arthritis, osteoarthritis,
ankylosing spondylitis, tendonitis, bursitis, acute
painful shoulder, and the pain of acute gout. Its analgesic
and anti-inflammatory effects are comparable
to those achieved with aspirin. The most common
dosage for adults is 150-200 mg twice a day. A use
proposed for sulindac is to prevent colon cancer in
patients with familial adenomatous polyposis (see
“Cancer Chemoprevention”).
Adverse Effects. Although the incidence of toxicity is lower than
with indomethacin, untoward reactions to sulindac are common. The
typical NSAID GI side effects are seen in nearly 20% of patients.
CNS side effects as described earlier for indomethacin in “Adverse
Effects and Drug Interactions” are seen in ≤10% of patients. Rash
and pruritus occur in 5% of patients. Transient elevations of hepatic
transaminases in plasma are less common.
Etodolac
Therapeutic Uses. Etodolac is an acetic acid derivative with some
degree of COX-2 selectivity (Figure 34–1). Thus, at anti-inflammatory
doses, the frequency of gastric irritation may be less than with
other tNSAIDs (Warner et al., 1999). A single oral dose (200-400 mg)
of etodolac provides postoperative analgesia that typically lasts for
6-8 hours. Etodolac also is effective in the treatment of osteoarthritis,
rheumatoid arthritis, and mild to moderate pain, and the drug
appears to be uricosuric. Sustained-release preparations are available,
allowing once-a-day administration.
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CHAPTER 34
ANTI-INFLAMMATORY, ANTIPYRETIC, AND ANALGESIC AGENTS; PHARMACOTHERAPY OF GOUT