Dr.

Bambang Sri Nugroho,Sp PD

Departmenf Of Internal Medicine
General Hospital Of Dr.Soedarso,
Pontianak,West Kalimantan,Indonesia

Membrane Phospholipids
(-)

Glucocorticoids

Arachidonic acid

COX
(-)
NSAIDs

PGE2 / PGI2

PGE2 / PGI2

TXA2 / PGI2

PGE2

Gastric cytoprotection

Renal blood flow

Haemostasis

Inflammation

Membrane Phospholipids
(-)

Glucocorticoids
(-)

Arachidonic acid

Endotoxins
Cytokines
Mitogens

(+)
COX -1 ( - )

(-)

COX -2

Classical NSAIDs
Stomach : PGE2 / PGI2

Kidney : PGE2 / PGI2

Platelets : TXA2
Endothelium : PGI 2

Inflammation :
Macrophages
synoviocytes

(-)

Selective
COX-2
inhibitor

Physiological
Stimulus

Inhibition by
NSAIDs

COX -1
Constitutive

TXA2
Platelets

PGI 2
Endothelium
Stomach
mucosa
etc

PGE2
Kidney
etc

Physiological functions
SIDE EFFECTS OF NSAIDs

Inflammatory
Stimulus
Inhibition by
NSAIDs

Macrophages/Other Cells
COX -2
Induced

Proteases

PGs

Other
Inflammatory
mediators

Inflammation

ANTI-INFLAMMATORY EFFECTS OF
NSAIDs

Corticosteroid

Disturbance on Cell
Membrane

Tinoridine HCL :
Stabilize Bio
Membrane
Lyososomes

Membrane Phospholipids

Arachidonic acid

COX -2

COX -1

Non Selective NSAID

Prostaglandin
associated with :
GI muscosal integrity
Platelet Function

Prostaglandin
associated with :
Pain, Fever,
Inflammation

Selective
NSAID

NSAIDs provide some symptomatic relief in

rheumatoid arthritis but do not prevent
erosions or alter disease progression.
They are not appropriate for monotherapy
and should only be used in conjunction with
DMARDs.
A large number of NSAIDs are available; all
appear equivalent in terms of efficacy

NSAIDs work in arthritis by the same

mechanism that causes side effects: inhibition
of COX, the enzyme that converts arachidonic
acid to prostaglandins.
Although prostaglandins play important roles
in promoting inflammation and pain, they also
help maintain homeostasis in several organs
especially the stomach, where prostaglandin E
serves as a local hormone responsible for
gastric mucosal cytoprotection.

The discovery that COX exists in two isomers

COX-1 (which is expressed continuously in
many cells and is responsible for the salutary
effects of prostaglandins) and COX-2 (which is
induced by cytokines and expressed in
inflammatory tissues)was initially of little
practical consequence since all traditional
NSAIDs inhibit both isomers.

Celecoxib, a selective COX-2 inhibitor, is FDAapproved for the treatment of osteoarthritis

and rheumatoid arthritis. Compared with
traditional NSAIDs, COX-2 inhibitors are as
effective for treating rheumatoid arthritis but
less likely in some circumstances to cause
upper gastrointestinal tract adverse events
(eg, obstruction, perforation, hemorrhage, or
ulceration).

Long-term use of COX-2 inhibitors, particularly

in the absence of concomitant aspirin use, has
been associated with an increased risk of
cardiovascular events, leading to the removal
of some COX-2 inhibitors from the US market
and intense scrutiny of all drugs in that class.

For traditional NSAIDs that inhibit both COX-1 and

COX-2, gastrointestinal side effects, such as gastric
ulceration, perforation, and gastrointestinal
hemorrhage, are the most common serious side
effects. The overall rate of bleeding with NSAID
use in the general population is low (1:6000 users
or less) but is increased by long-term use, higher
NSAID dose, concomitant corticosteroids or
anticoagulants, the presence of rheumatoid
arthritis, history of peptic ulcer disease or
alcoholism, and age over 70.

Twenty-five percent of all hospitalizations and

deaths from peptic ulcer disease result from
traditional NSAID therapy.
Each year, 1:1000 patients with rheumatoid
arthritis will require hospitalization for NSAIDrelated gastrointestinal bleeding or
perforation.

Although all traditional NSAIDs can cause

massive gastrointestinal bleeding, the risk may
be higher with indomethacin and piroxicam,
probably because these drugs preferentially
inhibit COX-1 in the stomach.
One approach to reducing the gastrointestinal
toxicity of traditional NSAIDs is to add either a
proton pump inhibitor (eg, omeprazole 20 mg
orally daily) or misoprostol.

The efficacy of misoprostol is limited by its

poor tolerability; 20% of patients discontinue
the medication because of diarrhea and
bloating associated with full doses (200 mcg
orally four times daily). Giving smaller
amounts of misoprostol (eg, 100 mcg four
times daily) or using less frequent dosing (eg,
200 mcg twice daily) improves tolerance while
reducing efficacy only modestly.

Misoprostol is an abortifacient and is

contraindicated in patients who are or might
become pregnant. Sucralfate, antacids, and
ranitidine either do not work or do not work
as well as proton pump inhibitors. The
expense of proton pump inhibitors and
misoprostol dictates that their use should be
reserved for patients with risk factors for
NSAID-induced gastrointestinal toxicity (noted
above).

Patients who have recently recovered from an NSAIDinduced bleeding gastric ulcer appear to be at high risk
for rebleeding (about 5% in 6 months) when an NSAID
is reintroduced, even if prophylactic measures such as
proton pump inhibitors are used. NSAIDs can also
affect the lower intestinal tract, causing perforation or
aggravating inflammatory bowel disease.
Acute liver injury from NSAIDs is rare, occurring in
about 1 of every 25,000 patients using these agents.
Having rheumatoid arthritis or taking sulindac may
increase the risk.

All of the NSAIDs, including aspirin and the COX-2

inhibitors, can produce renal toxicity, including
interstitial nephritis, nephrotic syndrome,
prerenal azotemia, and aggravation of
hypertension. Hyperkalemia due to
hyporeninemic hypoaldosteronism may also be
seen rarely. The risk of renal toxicity is low but is
increased by age over 60, a history of renal
disease, congestive heart failure, ascites, and
diuretic use. COX-2 inhibitors appear to cause as
much nephrotoxicity as traditional NSAIDs.

Platelet function and prolong bleeding time. For

all older NSAIDs except aspirin, the effect on
bleeding time resolves as the drug is cleared.
Aspirin irreversibly inhibits platelet function, so
the bleeding time effect resolves only as new
platelets are made.
COX-2 inhibitors, which differ from other NSAIDs
in not inhibiting platelet function, do not increase
the risk of bleeding with surgical procedures as
most NSAIDs do.

Unfortunately, this failure to inhibit platelets is

now known to lead to increased risks of
myocardial infarction and stroke, particularly
when the medications are used in high doses
for prolonged periods of time.
Patients requiring low-dose aspirin who are
not compliant have a greater risk of
developing a thrombotic event while taking a
COX-2 inhibitor than while taking a traditional
NSAID.

Whether combination therapy with low-dose

aspirin and a COX-2 inhibitor maintains the
gastrointestinal advantage of selective COX-2
inhibitors is not yet known.
Although groups of patients with rheumatoid
arthritis respond similarly to NSAIDs, individuals
may respond differentlyan NSAID that works
for one patient may not work for another. Thus, if
the first NSAID chosen is not effective after 23
weeks of use, another should be tried.