NON-STEROIDAL ANTI-

INFLAMMATORY DRUGS
Philip Sasi
• NSAID are among the most widely used
all drugs
• There are now more than 50 different
NSAIDs on the global market
• Several are available over-the counter
and often taken without prescription for
minor aches and pains
• There are many different formulations
available (tablets, injections and gels)
• All NSAIDs particularly the “classic” can
have significant unwanted effects,
especially in the elderly
• Newer agents have fewer adverse actions
• All NSAIDs have pharmacological actions
(anti-inflammatory, analgesic and
antipyretic effects) similar to those of
aspirin, the archetypal NSAID
• Also NSAIDs share same type of
mechanism-based side effects (gastric
irritation, effect on renal blood flow and
inhibition of platelet function
 Pharmacological Actions
Analgesic effect
• NSAIDs are effective against mild or
moderate pain especially that arising
from inflammation or tissue damage
• They decrease production of the
prostaglandins that sensitise nociceptive
receptors to inflammatory mediators such
as bradykinin
• Therefore, effective against all conditions
associated with increased level
prostaglandin synthesis such as
– Arthritis
– Bursitis
– Pain of muscular and vascular origin
– Toothache
– Dysmenorrhoea
– Pain of postpartum states
– Pain of cancer metastases
• In combination with opiods, they decrease
postoperative pain (reduce requirement for
opiods)
• Their ability to relieve headache may be
related to the abrogation of the vasodialtor
effect of prostaglandins on the cerebral
vasculature
• Inflammatory lesions increase
prostaglandin within the spinal cord
causing facilitation of transmission from
nociceptive afferents, and thus NSAIDs
may have less well-characterized central
action
Antipyretic effect
• NSAIDs reset the raised hypothalamic set
point of body temeperature in febrile
patients
• Normal body temperature in humans is not
affected by NSAIDs
• NSAIDs exert their antipyretic action
largely through inhibition of prostagleandin
production in the thalamus
• The production of E-type prostaglandins
in the hypothalamus is increased during
inflammation
• This ia an effect of IL-1 (pyrogen released
from macrophages) inducing COX-2 in
vascular endothelium
Anti-inflammatory effects
• NSAIDs reduce mainly those
components of the inflammatory and
immune response in which
prostaglandins, mainly derived from
COX-2, play a significant part
• These include vasodilatation, oedema
and pain
• Therefore, NSAIDs supress pain,
swelling and increased blood flow but
have little or no action on the actual
progress of underlying chronic disease
itself
• As a class, NSAIDs are generally without
effect on the other aspects of inflammation
such as
– Leukocyte migration
– Lysosomal enzyme release
– Toxic oxygen radical production
• These contribute to tissue damage in
chronic inflammatory conditions (e.g.
rheumatoid arthritis, vasculitis and
nephritis)
 Mechanism of Cyclo-
oxygenase Inhibitory Action
• Most NSAIDs inhibit only the initial
dioxygenation reaction in the sysnthesis
of cyclo-oxygenase pathyway
• They are generally “competitive
reversible” inhibitors, but there are
differences in their time course
• Generally, NSAIDs inhibit COX-1 rapidly,
but inhibition of COX-2 is more time
dependent and often irreversible
• To block the enzyme, NSAIDs (the
hydrophobic channel) forms a hydrogen
bond with arginine residue at position 120,
preventing substrate fatty acids entering the
catalytic domain
• A single amino acid change (isoleucin to
valine at position 523 on the structure of the
entrance of this channel in COX-2 results in
a bulky side pocket not found in COX-1 –
basis for enzyme selectivity of NSAIDs
• Aspirin is an anomaly, it enters the active
site and acetylates a serine at position at
position 530, irreversibly inactivating
COX-1.
• This is he bases for aspirin’s long-lasting
effects on platelets
• Other actions besides inhibition of COX
may contribute to the anti-inflammatory
effects of some NSAIDs
• Some NSAIDs e.g. Sulindac have oxygen
radical-scavenging effects as well as COX
inhibition and may decrease tissue damage
• Aspirin also inhibits the expression of the
transcription factor, nuclear factor (NF) !B,
which has a key role in the transcription of
genes for inflammatory mediators
Common Unwanted Effects of
NSAIDs
• Overall, the burden of unwanted side
effects associated with the clinical use of
NSAIDs is high
• When classic NSAIDs are used in joint
diseases (fairly high dose and prolonged
use) there is high incidence of side effects
particularly in GIT, liver, kidney, spleen,
blood and bone marrow
• Gastrointestinal disturbances
– COX-2-selective drugs have less GIT
toxicity
• Skin reactions
• Adverse renal effects
• Other unwanted effect
– CNS effects
– Bone marrow disturbances
– Liver disorders
– Paracetamol overdose causes liver failure
– Approximately 5 % of patients exposed to
NSAIDs may experience aspirin-sensitive
asthma
• All NSAIDs (except COX-2 inhibitors)
prevent platelet aggregation and may
prolong bleeding (aspirin is the main
member associated with this problem)
The principal groups of NSAIDs with examples
Drug Dose Dosage
(mg) interval (h)
Salicylates
Aspirin 900 4
Diflunisal 500 12
Benorilate 4000 12
Pyrazolones
Phenylbutazone 100 8
Azapropazone 300 8
Drug Dose (mg) Dosage
interval (h)
Indoles
Indomethacin 50 8
Sulindac 200 12
Etodolac 400 8
Fenamates
Mefenamic acid 500 8
Flufenamic acid 200 8
Drug Dose (mg) Dosage
interval (h)
Propionates
Ibuprofen 400 8
Naproxen 250 8
Ketoprofen 50 6
Phenylacetates
Dicofenac 50 8
Drug Dose (mg) Dosage
interval (h)
Oxicams
Piroxicam 20 daily
Tenoxicam 20 daily
Meloxicam 7.5 - 15 daily
Other
Nabumetone 100 daily
Drug Dose (mg) Dosage
interval (h)
Cox-2 inihibitors
Celecoxib 200 daily
Etoricoxib 60 - 90 daily
Valdecoxib 10-20 daily
Nonselective Cyclooxygenase (COX)
Inhibitors
• Examples of nonselective COX inhibitors
are:
– aspirin
– ibuprofen
– indomethacin
– ketorolac
– ketoprofen
– naproxen
– piroxicam
– sulindac
• Somewhat selective COX-2 inhibitors
include meloxicam and etodolac
• Celecoxib is a selective COX-2 inhibitor,
the only selective COX-2 agent available
now
• For pain, the analgesic strength profile is
ketorolac > naproxen > ibuprofen >
aspirin.
• Ketorolac, available as both oral tablets
and an intramuscular injection, was
developed specifically for postoperative
analgesia.
• Even though high doses of NSAIDs may
alleviate symptoms of rheumatoid
arthritis, these drugs do not reduce
progression of joint disease.
• Paracetamol (e.g., Tylenol), through
unknown mechanisms, has antipyretic
and analgesic actions similar to aspirin.
• However, since it is a very weak COX
inhibitor, its anti-inflammatory actions are
negligible.
• Paracetamol is particularly useful in
patients with aspirin allergies, peptic ulcer
disease, and bleeding disorders and in
those taking anticoagulant therapies
• Indomethacin is used in neonatal settings
to encourage closure of a patent ductus
arteriosus.
• The ductus arteriosus remains patent
(open) as a result of enhanced
prostanoid production.
• In fact, one reason NSAIDs should be
avoided during pregnancy is that they
may cause premature closure of the
ductus arteriosus, leading to pulmonary
hypertension in the fetus.
• Taking NSAIDs with food lessens the
risk of adverse GI effects.
• Ketorolac is especially problematic for
the GI tract, and this drug should never
be used for more than 5 days in a row
to avoid GI bleeding.
• Hypersensitivity to NSAIDs is possible,
particularly among patients with a
history of nasal polyps or asthma.
• Cross-reactivity between agents is
possible.
• Caution should be exercised when these
drugs are used in patients with asthma,
since the drugs can lead to unopposed
accumulation of leukotrienes, thereby
predisposing patients to
bronchoconstriction (shunting of
arachidonic acid to lipoxygenases; refer to
 Figure 10-2 Arachidonic acid metabolites.
Drugs that inhibit prostaglandin production
(burgundy) or mimic prostaglandin action
(green). In rare circumstances, inhibition of
cyclooxygenase with aspirin and NSAIDs
may shunt arachidonic acid to leukotrienes
and lead to bronchoconstriction. This is why
aspirin/NSAIDs are contraindicated in
asthmatics.
• NSAIDs are highly protein bound and can
displace other drugs from plasma protein
binding sites (with the exception of
acetaminophen, ibuprofen, and
indomethacin).
• This may increase the toxicity of
sulfonylureas, sulfonamides, and phenytoin.
• Plasma levels of methotrexate and lithium
may also be elevated with NSAIDs.
• Furthermore, chronic use of NSAIDs
may lead to nephritis, nephritic
syndrome, or acute renal failure, (i.e.,
via reduction of PGE2 and PGI2, which
normally maintain glomerular filtration
rate [GFR] and renal blood flow [RBF]).
• Because of the sodium retention
induced by NSAIDs, antihypertensive
therapies (e.g., ACE inhibitors, β-
blockers, and loop diuretics) are often
rendered less effective, and sodium
retention may also aggravate symptoms
of congestive heart failure.
• Renal complications are not seen with
chronic use of sulindac; however, this
drug can lead to pancreatitis.
• Indomethacin has been associated with
thrombocytopenia, agranulocytosis, and
CNS effects.
• Chronic diclofenac use is associated with
hepatotoxicity.
• Celecoxib causes hypersensitivity
reactions in patients with allergies to
sulfonamides.
• Acetaminophen overdoses can cause
hepatotoxicity, a situation that is
managed by administering intravenous
acetylcysteine
• Aspirin's unique mechanism (irreversible
inhibition of COX) allows it to be a potent
inhibitor of platelet aggregation (through
reduction of TxA2),
• This has led to its successful use in
primary and secondary prevention of
cardiovascular and cerebrovascular
events
• Recall that the actions of other NSAIDs
are not irreversible but are competitive in
nature.
• These disparate properties can be
problematic for patients who take aspirin
for cardiovascular protection, while
simultaneously using chronic NSAID
therapy for anti-inflammatory effects.
• If the NSAID reaches the COX active site
first, it blocks aspirin's ability to bind, thus
preventing the antiplatelet actions of
aspirin.
• In fact, patients taking both ibuprofen and
aspirin have a 73% increased risk of death
due to cardiovascular events compared with
patients taking aspirin alone.
• The bottom line is, if patients need both
types of therapy, it is best to administer the
"antiplatelet" aspirin first and delay other
NSAID therapy for several hours.