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NSAIDS NOTES and Tables
Brief Summary 2016
NSAIDs
A.
B.
C.
D.
E.
F.
Aspirin and other salicylates (last lec.)
Propionic acid derivatives
Acetic acid derivatives
Oxicam derivatives
Fenamates
Other agents (diclofenac, ketorolac, Tolmetin
and nabumetone, diflunisal)
All material in this lecture is copyrighted© 2007
All material in this lecture is copyrighted©
2007
Pharmacokinetics
• NSAIDs: weak organic acids except nabumetone
(ketone prodrug metabolized to acidic active drug).
• Most are well absorbed & food does not
substantially change bioavaialbility.
• Renal excretion is the most important route for
elimination,
• However, nearly all NSAIDs undergo enterohepatic
circulation.
• The degree of lower GI irritation correlates with
amount of enterohepatic circulation.
All material in this lecture is copyrighted© 2007
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Newer NSAIDS
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• Diclofenac lowers body temperature in
animals with antigen-induced fever. Although
the mechanism of antipyretic effect of NSAIDs
is not known, it has been suggested that
suppression of prostaglandin synthesis in the
CNS (probably in the hypothalamus) may be
involved. In rats, the antipyretic activity of
diclofenac 0.5 mg/kg was similar to that of 1.2,
24, 35, 55, or 185 mg/kg of indomethacin,
ibuprofen, phenylbutazone, naproxen, or
aspirin, respectively.
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Gastrointestinal Risk
• Different NSAIDs confer different gastrointestinal
risk. Risk is high with some of the longer acting
NSAIDs (e.g., piroxicam [57 hours], ketorolac [up
to ten hours], and sustained-release
formulations), perhaps due to longer mucosal
exposure. Ibuprofen seems to have the lowest risk
of gastrointestinal events. This might be because
low doses are typically used, possibly owing to
nonprescription availability, or because it has a
short half-life (two hours)
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GI Risk- summary
• In summary, the bulk of evidence suggests
that ibuprofen and the agents with relatively
more COX-2 selectivity have the lowest
gastrointestinal risk, and piroxicam and
ketorolac have the highest risk
• [Evidence level B; case-control and cohort
studies].
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• A systematic review of observational studies revealed
that risk of upper gastrointestinal bleeding or
perforation was not increased by celecoxib.
• GI Risk was low with ibuprofen then diclofenac,
meloxicam, indomethacin, ketoprofen, naproxen,
piroxicam, and ketorolac.
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• A selective COX-2 inhibitor should provide pain relief
with lower gastrointestinal risk. Among "traditional"
NSAIDs, meloxicam, nabumetone, and etodolac have
some COX-2 selectivity and seem to be less likely
than less selective NSAIDs to cause gastrointestinal
events.
• The selective COX-2 inhibitor celecoxib (Celebrex) is
associated with about a 20% lower risk of bleeding
compared to traditional NSAIDs.
• But this benefit is negated in patients who take
aspirin concomitantly.
• Furthermore, celecoxib does not seem to be safer
than non-selective NSAIDs past six months of use.
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Cardiovascular risk
• In addition to the hypertension and heart failure concerns
with all NSAIDs, NSAIDs seem to increase the risk of
cardiovascular events (heart attack, stroke, death) to
varying degrees, even in healthy people.
 Adverse cardiovascular events associated with NSAIDs are
thought to be caused by NSAIDs upsetting the balance
between vasoconstricting, platelet aggregating
thromboxane A2 (produced by COX-1) and opposing
vasodilating prostacyclin (produced by COX-2). This may
lead to vasoconstriction, platelet aggregation, and
thrombosis.
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• - NSAIDs that tend to be more COX-2 selective
could therefore be assumed to have more
cardiovascular risk.
• - In fact, the COX-2 selective agents rofecoxib
(Vioxx), valdecoxib (Bextra), and lumiracoxib
(Prexige, Canada only) were withdrawn from
the market due to cardiovascular risk.
• For patients with cardiovascular disease or risk
factors for ischemic heart disease: acetaminophen,
aspirin, tramadol, opioids, or nonacetylated salicylates
(e.g., diflunisal; choline magnesium trisalicylate [U.S. only])
are recommended before moving to an NSAID.
• Keep in mind that aspirin and diflunisal seem to
have moderate gastrointestinal risk, although
diflunisal has been included in only a few studies.
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ACG Recommendations
CV Risk
GI Risk
Low
Low
choose an NSAID with the least GI risk at the
lowest effective dose when appropriate (e.g.,
ibuprofen).
Low
Moderate
use celecoxib or add a PPI or misoprostol to a
less COX-2 selective NSAID
Low
High
•
Recommendation
avoid NSAIDs if possible. Alternatively, use
celecoxib with a proton pump inhibitor or
misoprostol
[Evidence level B; lower quality RCT].
• For patients with low or moderate gastrointestinal
risk but high cardiovascular risk (e.g., history of
cardiovascular event, diabetes, hypertension,
hyperlipidemia, obesity) taking aspirin, choose
naproxen. These patients will also require a proton
pump inhibitor or misoprostol.
• Patients with high risk of both gastrointestinal and
cardiovascular risk should not receive an NSAID
(including celecoxib).
[Evidence level A; high-quality meta-analyses].
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• Etoricoxib (Arcoxia®). Selective COX-2 inhibitor.
Available as 60, 90 and 120 mg tablets. Given once to
twice daily. Similar cardiovascular risk to cox-2
selective agents. Not FDA approved.
• etoricoxib: significantly fewer upper GI
uncomplicated clinical events with etoricoxib than
with diclofenac, but no decrease in more serious
complicated events
• etoricoxib is currently sold in 63 countries but
received an FDA non-approval (further data
necessary to demonstrate a favorable risk-to-benefit
ratio)
Renal Risk
 NSAIDs induce abrupt decreases in GFR in at-risk patient
populations, specifically those with CHF, liver disease, the elderly,
or dehydrated patients. Indomethacin is associated with the
highest risk of NSAIDs-induced renal ischemia, where as aspirin
appears to have the lowest risk. Naproxen, ibuprofen, piroxicam
and diclofenac are considered intermediate in their relative
capacities to acutely compromise renal perfusion. Sulindac may
offer a “renal sparing” effect. Sulindac is a prodrug that is
converted to its active sulfide metabolite by the liver and then
becomes reversibly oxidized back to its parent compound in the
kidney; renal prostaglandin synthesis is essentially unaltered by
sulindac. Cases of sulindac-induced renal dysfunction have been
reported when the drug was administered to patients with
cirrhosis and ascites.
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Many patients taking bisphosphonates, such
as alendronate, ibandronate, and risedronate,
for osteoporosis may also be taking various
nonsteroidal antiinflammatory drugs (NSAIDs)
for arthritis or other disorders. Whereas both
of these drug classes can separately cause
gastrointestinal (GI) toxicity, it is important to
determine if the combination can have
additive negative effects on the GI tract.
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• In a recent report of rheumatoid arthritis patients
receiving NSAIDs for at least 3 months with or
without concurrent therapy with
bisphosphonates, GI ulcers occurred in 17% of
patients on NSAIDs without concurrent
bisphosphonates, and in 31% of patients
receiving bisphosphonates with NSAIDs.
• Conversely, some other studies looking at upper
GI bleeding or other GI adverse effects did not
find an increase in GI toxicity when
bisphosphonates were combined with NSAIDs,
compared with NSAIDs alone. Explain !!!
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Recommendations
Patients taking bisphosphonates should be advised not to
take OTC NSAIDs for minor problems such as colds and
minor aches and pains. Acetaminophen might be preferable
in such cases.
It is not known if using less than daily administration of
bisphosphonates reduces the risk of additive GI toxicity
when combined with NSAIDs, but theoretically it might.
In patients taking bisphosphonates who require long-term
therapy with NSAIDs, preliminary evidence suggests that
PPIs may reduce the risk of ulcers. Nonetheless, there is not
enough evidence to recommend that these patients be
routinely given prophylactic PPIs.
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