about adverse effect ,usage in different diseases.

1. Rational Use of NSAIDs
By: Somayyeh nasiripour
Clinical pharmacist
Assistant professor in IUMS

2. • (NSAIDs) are in use throughout the world .NSAIDs are popular because of
their versatile effectiveness as analgesics, antipyretics, and as
antiinflammatory agents. Aspirin is also used as an anti-thrombotic agent
• More than 17 million Americans use various nonsteroidal
antiinflammatory drugs (NSAIDs) on a daily basis, making this class of
drugs one of the most commonly used in the world
• The Center for Disease Control in the United States predicts that, with the
aging of the population, there will be a significant increase in the
prevalence of painful degenerative and inflammatory rheumatic
conditions. This will probably lead to a parallel increase in the use of
NSAIDs.
• Each year, approximately 60 million NSAID prescriptions are written, with
the number of prescriptions for older patients approximately 3.6-fold
higher than that for younger patients
• Increased use of NSAIDs in an aging population will increase the number
of adverse events related to NSAID use. It has been estimated that 5 to 7
percent of hospital admissions are related to adverse effects of drugs, and,
of these hospitalizations, those that result from gastrointestinal, nervous
system, renal, or allergic effects of non- aspirin NSAIDs are responsible for
approximately 11 to 12 percent

4. COX-1 is expressed in most tissues, but variably.
regulating normal cellular processes (such as gastric cytoprotection,
vascular homeostasis, platelet aggregation, and kidney function).
COX-1 activity is stimulated by hormones or growth factors.
COX-2 is constitutively expressed in the brain, kidney, bone, and probably
in the female reproductive system.
Its expression at other sites, including the cardiovascular system, is
increased during states of inflammation or, experimentally, in response to
mitogenic stimuli.
Both COX isoforms are regulated by physiologic stimuli.
Increased expression of COX-2 mRNA and protein has been noted in
patients with hypertension, heart failure, and diabetic nephropathy

5. • A presumed advantage of the coxibs was a
reduction in gastrointestinal toxicity compared
to nsNSAIDs. However, an increased risk of
ischemic cardiovascular disease has been
described with rofecoxib, celecoxib , and
valdecoxib.

6. Therapeutic use and variability of response in adults

7. • All NSAIDs appear to be absorbed completely, have
negligible first pass hepatic metabolism, are tightly
bound to albumin, and have small volumes of
distribution.
• Patients with hypoalbuminemia may, therefore, have
higher free serum concentrations of drug.
• At equipotent doses, the clinical efficacy of the various
NSAIDs in patient populations is similar
• in contrast, individual responses are highly variable

8. • Some of the observed individual differences with
specific NSAIDs are particularly evident with respect to
toxicity
• As an example, it is not unusual for indomethacin to
induce headaches after a single dose in some patients.
• More commonly, individual patients have more
symptoms or signs of gastrointestinal toxicity with one
NSAID than with another
• Some differences in toxicity may be explained by
variations in absorption, distribution, and metabolism.
Differences in the mode of action may be important as
well.

9. HYPOTHESES CONCERNING
VARIABILITY OF RESPONSE
•
Mechanism of action. Some NSAIDs are more potent inhibitors of
prostaglandin synthesis, while others are more effective in altering other
nonprostaglandin mediated biologic events.
Observed variations in patient response may result in part from the
pharmacodynamics of a particular drug. Thus, it is believed that, if a patient
fails an NSAID of one class, the substitution of an NSAID of a different class is
a reasonable therapeutic option.
Each attempt to achieve a response should probably last for about two
weeks.

10. Overview of adverse effects

11. Risk factor
• The risk of acute renal failure is increased in patients with existing glomerular
disease, renal insufficiency, hypercalcemia, in states of effective volume
depletion (such as heart failure and cirrhosis), and in the presence of true
volume depletion due to gastrointestinal or renal salt and water losses.
The risk of gastrointestinal toxicity is increased by the presence of one or more
of the following: a prior history of a gastrointestinal event (ulcer, hemorrhage),
age >60, a high dose of a NSAID, the concurrent use of glucocorticoids, and the
concurrent use of anticoagulants (eg, aspirin , warfarin , or clopidogrel ).
Chronic as opposed to short-term use, untreated Helicobacter pylori infection,
and use of (SSRI) may also increase the risk of bleeding or perforation

12. GASTROINTESTINAL EFFECTS

13. • Mucosal damage by aspirin and NSAIDs is
primarily a consequence of inhibition of COX-1
in the upper GI tract.
• COX-1 inhibition reduces mucosal generation
of protective prostaglandins such as PGE2

14. SYSTEMIC VERSUS TOPICAL EFFECTS
• Aspirin and many other NSAIDs are carboxylic acid
derivatives
As a result, they are not ionized at the acidic pH found
in the gastric lumen and thus can be absorbed across
the gastric mucosa.
Once the drug moves from the acidic environment of
the gastric lumen into the pH–neutral mucosa, the
drug ionizes and is trapped temporarily in epithelial
cells where it may damage these cells.

15. THE CENTRAL ROLE OF
(PROSTAGLANDINS)
• PGs such as PGE2 protect the mucosal lining from
injury by luminal acid-pepsin.
• COX-1 is a constitutive enzyme with a fairly
steady rate of expression in most cells of the
body.
• In contrast, COX-2 is expressed in many cells only
when bacterial polysaccharides, pro-
inflammatory cytokines such as TNFa or IL-1b, or
growth factors (mitogens) induce its expression.
• COX-3 in the brain may be one target of
acetaminophen

16. • The healthy gastric and duodenal mucosa constitutively use COX-1
to produce its mucosal-protective PGs
• Many NSAIDs block COX-1 and COX-2 more or less equally (ie, are
non-selective) and thus may impair gastric PG production at low
(<1µM) concentrations
• Examples include ibuprofen , indomethacin , and naproxen .
• Drugs that more selectively inhibit COX-2 than COX-1 have less
suppressive effects on gastric PG synthesis
• Examples include celecoxib and etodolac
• inhibitors of COX-2, and also COX–3 inhibitors such as
acetaminophen , preserve PG-mediated GI mucosal protection
• However, COX-2 selective inhibitors may still block COX-1 at
clinically recommended doses and thus have the potential to also
block COX-1 in the stomach and duodenum and cause damage

17. Gastric damage
• Aspirin doses as low as 10 mg/day inhibit gastric PG generation
considerably and can damage the stomach
• GI damage increases as the aspirin dose is raised
• After low-dose aspirin therapy is stopped, the human stomach requires 5-
8 days to recover its COX-1 activity and its ability to synthesize protective
PGs, suggesting a very slow turnover of gastric COX-1
• gastric mucosa somewhat resembles the platelet, which requires 10 to 14
days to recover from aspirin
• In contrast to aspirin , which acetylates COX irreversibly, most NSAIDs
inhibit COX-1 and COX–2 reversibly
• Nevertheless, even transient COX-1 inhibition in the gastric mucosa by an
NSAID is sufficient to predispose the stomach to injury.
• That this injury is due to loss of PG-mediated cytoprotection is supported
by the observation that NSAID-related gastric damage is prevented by PGE
analogs such as misoprostol
• (H2RAs), have little or no protective effect against NSAID-induced gastric
damage. On the other hand, the relative failure of H2RAs to protect the
stomach from damage by NSAIDs can be overcome by using higher H2RA
doses or by using more potent acid-inhibitory compounds such as the
proton pump inhibitors.

18. Duodenal damage
• Aspirin doses as low as 325 mg every other day
increase the risk of duodenal ulcers
• In contrast to the stomach, damage to the
duodenal mucosa by aspirin and NSAIDs seems to
depend highly upon gastric acid.
• Thus, not only misoprostol but also by histamine-
2 blockers with their modest acid inhibition can
largely prevent endoscopic evidence of duodenal
injury by NSAIDs.
• PPIs are also highly effective.

19. ROLE OF HELICOBACTER PYLORI
INFECTION
• At least two meta-analyses concluded that
NSAID use and H. pylori infection represent
independent and synergistic risk factors for
uncomplicated and bleeding peptic ulcer
disease
Patients with a history of uncomplicated or complicated peptic
ulcers (gastric, duodenal) should be tested for H. pylori prior to
beginning a course of NSAID or low dose aspirin therapy.
If present, H. pylori should be treated with appropriate therapy,
even if it is believed that the prior ulcer was due to NSAIDs.

20. RISK OF GASTROINTESTINAL COMPLICATIONS
duration of therapy:> 1 w
Age ≥60 years
history of ulcer disease or complication,
Dyspepsia or gastroesophageal reflux
disease (GERD) symptoms
higher NSAID dose(s),
a past history of peptic ulcer disease
dual antiplatelet therapy
concurrent use of glucocorticoids,
anticoagulants, and clopidogrel (and probably
of, bisphosphonates and [SSRIs])

21. RELATIONSHIP BETWEEN DYSPEPTIC SYMPTOMS AND
GASTRODUODENAL MUCOSAL INJURY
aspirin and many NSAIDs, and even acetaminophen , may
produce dyspeptic symptoms (epigastric discomfort, upper
abdominal pain, nausea, epigastric fullness or bloating), especially
as the dose of the drug is increased.
little correlation between the dyspeptic symptoms sometimes seen
with these drugs and the presence or absence of erosive/ulcerative
lesions in the stomach and duodenum.
evaluating gastric and duodenal toxicity of NSAIDs should not
include dyspepsia as a part of a combined GI endpoint

22. Comparison between NONSELECTIVE NSAIDS
complications was highest with
indomethacin (relative risk {RR} 2.25)
followed by naproxen (RR 1.83),
diclofenac (RR 1.73), piroxicam (RR 1.66),
tenoxicam (RR 1.43), ibuprofen (RR 1.43),
and meloxicam (RR 1.24).
associated with a high risk of GI toxicity, particularly
when used in higher doses, in older patients, and for
more than five days.
One study found that ketorolac was 5.5 times more
likely to cause GI toxicity than other NSAIDs
Because of the risks associated with ketorolac (both
gastrointestinal and renal), its use is generally
restricted to short-term pain treatment

23. ENTERIC-COATED AND BUFFERED ASPIRIN
It has been proposed that a way to prevent gastrointestinal (GI) toxicity from
aspirin is the use of enteric-coated or buffered aspirin.
Enteric-coated aspirin is designed to resist disintegration in the stomach,
dissolving in the more neutral-to-alkaline environment of the duodenum.
Although enteric-coated aspirin diminishes endoscopic signs of gastroduodenal
injury, it does not appear to protect against the clinically relevant end point of
gastrointestinal bleeding
These findings are not surprising, since injury severe enough to induce bleeding
is thought to reflect the systemic rather than the topical effects of aspirin
The systemic effect of aspirin on the stomach and duodenum probably explains
why buffered aspirin is no more effective than plain aspirin in preventing ulcer
bleeding

24. SELECTIVE COX-2 INHIBITORS
Two related isoforms of COX exist: COX-1 and COX-2
COX-1 is involved in gastric and duodenal cytoprotection
COX-2 is involved in inflammation and perhaps healing of
gastroduodenal lesions.
It has been proposed that the ideal NSAID would inhibit the inducible COX-2
isoform (thereby decreasing tissue inflammation) without having any effect
on the constitutive COX-l isoform (thereby minimizing gastrointestinal [GI]
toxicity)

25. data suggest that COX-2 inhibitors are associated a
reduced risk of gastrointestinal bleeding compared
with nonselective NSAIDs but the risk is increased
compared with placebo.
Thus, COX-2 inhibitors may be safer than
conventional NSAIDs for reduction in the risk of
gastrointestinal bleeding but are still associated with
an increased risk.
patients receiving both aspirin
and a selective COX-2 inhibitor
may require prophylactic
antiulcer therapy if they are at
increased risk for gastroduodenal
toxicity.
Patients taking warfarin concomitantly
with a selective COX-2 inhibitor have
an increased risk of hospitalization for
upper gastrointestinal bleeding
The magnitude of risk was similar to
the risk in anticoagulated patients
taking nonselective NSAIDs, suggesting
that the COX-2 inhibitors may not be
protective in this population.
concern with using a selective COX-2 inhibitor
compared to a nonselective NSAID is their
cardiovascular risk

26. PREVENTION STRATEGIES
using misoprostol or a proton pump inhibitor (PPI) together with a
nonselective nonsteroidal antiinflammatory drug (NSAID)
using a selective COX-2 inhibitor with or without a PPI
None of these approaches is universally effective and their cost-
effectiveness
Clinical studies of PPIs have suggested that they are better
tolerated but have slightly lower efficacy compared to full-dose
misoprostol (ie, 200 micrograms four times daily)

27. H2 receptor antagonists
• Standard doses of H2 receptor antagonists
were not effective for the prevention of
NSAID-induced gastric ulcers in most reports,
although they may prevent duodenal ulcers

28. CONSENSUS STATEMENTS AND
GUIDELINES

29. Patients who are at high GI/high CV risk should not receive NSAIDs, including COX-2 inhibitors.
Patients at high GI/low CV risk should receive a COX-2 inhibitor in combination with either a PPI
or misoprostol .
Patients at moderate GI/low CV risk should receive a COX-2 inhibitor alone or a conventional
NSAID + either a PPI or misoprostol .
Patients at moderate GI/high CV risk should receive naproxen (due to its putative
cardioprotective properties) and either a PPI or misoprostol . This same strategy is endorsed for
patients at low GI/high CV risk.
Patients at low GI/low CV risk can receive a conventional NSAID alone, although the "least
ulcerogenic NSAID at the lowest effective dose" is recommended (see 'Nonselective NSAIDs'
above).
All patients regardless of risk who are about to start long-term traditional NSAID therapy should
be considered for testing for H. pylori and treated if positive.

30. Nonselective NSAIDs: Adverse cardiovascular
effects
may have several adverse effects on the cardiovascular system:
• interference with the beneficial antiplatelet activity of aspirin ,
• an increase in cardiovascular events,
• exacerbation of heart failure.

31. INTERFERENCE WITH BENEFICIAL
EFFECTS OF ASPIRIN
• effects of aspirin for secondary or primary prevention
of cardiovascular disease result from irreversible
acetylation of the active site of cyclooxygenase (COX)
in platelets; these effects may be attenuated by prior
or ongoing administration of some nonselective
NSAIDs, including ibuprofen and naproxen
• regular NSAID use should be avoided, if possible
• In patients who require NSAIDs on an occasional short-
term basis, we suggest that aspirin be taken at least
two hours before the NSAID

32. presumed mechanism
• nonselective NSAIDs compete with aspirin for a
common binding site on COX-1 and prevents aspirin
from binding
• As a result, aspirin is unable to acetylate a serine
residue on COX-1, an irreversible reaction that inhibits
COX-1 for the remaining life of the platelet
pharmacodynamic interaction is not seen with:
celecoxib or diclofenac
The inhibitory effect of naproxen on platelet function is greater than that of
ibuprofen and its half-life is significantly longer
Acetaminophen may be an effective alternative to NSAIDs in some
patients

33. Nonselective nonaspirin NSAIDs
• The use of most nonselective NSAIDs is associated with
an increased risk of adverse cardiovascular events
• absolute risk is low, but risk increases with higher
doses or frequency of use
• Naproxen appears to be the safest with respect to
such risk, although an increased risk of myocardial
infarction or stroke with naproxen use has also been
reporte
• The author prefers to use naproxen or ibuprofen at the
lowest effective dose in such patients, based upon the
available data and clinical experience.

34. COX-2 selective inhibitors
• Several COX-2 selective inhibitors (eg,
rofecoxib) have been withdrawn from the
market because of an increased risk of
ischemic cardiovascular events

35. EXACERBATION OF HEART DISEASE
• Use of NSAIDs may cause worsening of heart failure and an
increased risk of new events, including myocardial
infarction, in patients with established heart disease.
• suggest that nonselective NSAIDs be avoided in patients
with an acute myocardial infarction (MI), unstable angina,
or heart failure; during the perioperative period in patients
undergoing coronary artery bypass graft surgery; and in
patients with a history of a prior MI
If NSAIDs are required, they should be used at the lowest effective dose
and for the shortest duration necessary for the given indication. We
suggest naproxen for patients with known cardiovascular disease or
increased cardiovascular risk who require treatment with a nonselective
NSAID

36. Heart failure
• first occurrence of HF was not significantly different
from that in individuals who did not use NSAIDs
• Data are also available for the effect of nonselective
NSAIDs on the risk of exacerbation of preexisting HF
The adjusted risk of rehospitalization for HF was significantly increased in patients on
diclofenac or ibuprofen , and to a numerical but non-significant level for users of
naproxen
There was a dose-dependent increase in risk of death, which was highest with
diclofenac .
Higher doses of ibuprofen (>1200 mg/day) and naproxen (>500 mg/day), but not lower
doses, were also associated with an increased risk of death

37. mechanism for HF exacerbation
• increase in afterload resulting from NSAID-
induced systemic vasoconstriction, which can
lead to a further reduction in cardiac contractility
and cardiac output in advanced HF
• Patients at greatest risk for this complication
usually are hyponatremic at presentation
In addition, the vasoconstriction associated with NSAID therapy
(including aspirin at a dose ≥325 mg/day) may partially or totally reverse
the unloading effect of ACE inhibitors or angiotensin II receptor blockers

38. ELEVATION IN BLOOD PRESSURE
• Nonselective NSAIDs can raise the blood pressure
and worsen control of hypertension in patients
already being treated.
• nonselective NSAIDs should be used with caution
in such patients, and if required, they should be
used at the lowest effective dose and for the
shortest duration necessary for the given
indication

39. ACC/AHA guidelines on acute MI or
unstable angina
• 2007 American College of Cardiology/American Heart
Association guidelines on the management of acute
myocardial infarction (ST elevation or non-ST elevation)
or unstable angina strongly recommended immediate
cessation all nonaspirin NSAIDs at presentation and
made a weak recommendation for avoiding their use
during hospitalization
• At hospital discharge, the guidelines concluded that it
is reasonable to use a nonselective NSAID, such as
naproxen , for patients with chronic musculoskeletal
disorders if initial treatment with acetaminophen or
small doses narcotics is insufficient

40. celecoxib
• Celecoxib use conveys a small, dose-dependent risk of
cardiovascular events similar to most nonselective NSAIDs
• 2011 network meta-analysis : the risk of myocardial
infarction (MI) with celecoxib compared with placebo (RR,
1.35, 95% CI, 0.71-2.72) was lower than that for rofecoxib
(RR 2.12, 95% CI 1.26-3.56) or ibuprofen (RR 1.61, 95% CI
0.50-5.77), but greater than naproxen (RR 0.82, 95% CI
0.37-1.67), which had the most favorable cardiovascular
risk profile
• Cardiovascular risk may increase with celecoxib use soon
after it is initiated in patients with known coronary artery
disease.

41. NSAIDs: Acute kidney injury (acute renal failure)
and nephrotic syndrome

42. • Although renal prostaglandins are primarily vasodilators, they do
not play a major role in the regulation of renal hemodynamics in
normal subjects, since the basal rate of prostaglandin synthesis is
relatively low.
• By contrast, the release of these hormones (particularly
prostacyclin and prostaglandin E2) is increased by underlying
glomerular disease, renal insufficiency, hypercalcemia, and the
vasoconstrictors angiotensin II and norepinephrine.
• secretion of the latter hormones is increased in heart failure,
cirrhosis, and true volume depletion due to gastrointestinal or renal
salt and water losses
In these settings, vasodilator prostaglandins act to preserve renal blood flow and
glomerular filtration rate by relaxing preglomerular resistance. This is particularly
important with effective volume depletion in which the prostaglandins
antagonize the vasoconstrictor effects of angiotensin II and norepinephrine.

43. • Inhibition of prostaglandin synthesis with an NSAID in such
patients can lead to reversible renal ischemia, a decline in
glomerular hydraulic pressure and acute kidney injury
• The rise in the plasma creatinine concentration is seen
within the first 3-7 days of therapy, the time required for
attainment of steady state drug levels and therefore
maximum inhibition of prostaglandin synthesis
Compared with unexposed individuals, an increased risk of acute kidney
injury within 30 days of NSAID initiation was noted with the nonselective
NSAIDs other than naproxen (RR of 2.3), rofecoxib (RR 2.3), and
celecoxib (RR of 1.5).
There has been concern that ketorolac might have greater nephrotoxic potential
than other NSAIDs

44. • Low-dose aspirin (studied at approximately 40 mg per day), low-
dose over-the-counter ibuprofen , and perhaps sulindac appear to
be safer
• With aspirin , the inhibition of glomerular cyclooxygenase may only
be partial and transient, in contrast to the irreversible acetylation in
platelets
• However, even low-dose aspirin in elderly patients or aspirin used in
conjunction with indomethacin (and possibly other NSAIDS), may
lead to a decline in kidney function
• Over-the-counter ibuprofen in low doses is safe in most patients
.However, even low dose ibuprofen can reduce the glomerular
filtration rate in patients with reduced renal perfusion

45. Drug interactions
• A potentially clinically relevant interaction between
ibuprofen and aspirin referred to as “aspirin resistance”
has been observed in ex vivo platelet assays when
ibuprofen is administered to healthy controls before
aspirin. Similar effects, which also depend upon timing
of drug administration, have been demonstrated with
naproxen and may occur with other NSAIDs.
• anticoagulants, antiplatelet agents, antihypertensives,
calcineurin inhibitors ( cyclosporine and tacrolimus ),
digoxin , diuretics, glucocorticoids, lithium , selective
serotonin reuptake inhibitors (SSRIs), methotrexate
(MTX), and other medications

46. Drug Usual analgesic dose and
interval
Maximum dose per day
(mg
Ibuprofen* 400 mg every 4 to 6 hours 3200 acute, 2400 chronic
Naproxen 250 mg every 8 hours or
500 mg every 12 hours
1250 acute, 1000 chronic
Diclofenac 50 mg every 8 hours 150 mg
Indomethacin 25 to 50 mg every 8 to 12
hours
Controlled release: 75 mg
every 12 hours
150
Ketorolac (intravenous and
intramuscular)`
<65 yrs : 60 mg IV or IM
once 15 to 30 mg
every 6 hours
120
Meloxicam 7.5 to 15 mg every 24
hours
15
Piroxicam 10 to 20 mg every 24 hours 20

47. Mefenamic acid 250 mg every 6 hours 1000
Celecoxib 200 mg daily or 100 mg
every 12 hours
400