A) INTRODUCTION

After the development of aspirin in the late 1800's, numerous other drugs were
discovered and used as antipyretics, analgesics and anti-inflammatory. These
drugs were regarded as a group and became known as "aspirin-like drugs".
The term nonsteroidal anti-inflammatory drug (NSAID) was first applied to
phenylbutazone after its introduction into clinical practice in 1949, three years
after the demonstration of the anti-inflammatory properties of glucocorticoids
It wasn't until the 1970’s when Vane.It hypothesized the mechanism of action of
these drugs are now known that they inhibit the activity of the enzyme cyclo-
oxygenase (COX), which mediates the synthesis of endogenous
prostaglandins.
Not all the mechanisms of action of NSAIDs are completely understood
especially in the treatment of inflammatory disorders.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most
widely prescribed and used drugs in the community for rheumatologic as well
as nonrheumatologic conditions which include acute and chronic pain, biliary
and ureteric colic, dysmenorrhea, fever, closure of patent ductus arteriosus in
infants, and other applications that derive from their suppression of
prostaglandin synthesis.
These drugs reduce the signs and symptoms of established inflammation
without eliminating the underlying causes of it; they have no effect on the
clinical course of the disease process and don't protect against tissue or joint
injury.
It has been estimated that one in seven Americans is likely to be treated with
an NSAID for a chronic rheumatologic disorder. More than 80 million
prescriptions are written each year, accounting for about 4.5% of all
prescriptions written in the United States (U. S.).
B) NSAIDs give three actions

►Antipyretic effect:

Normal body temperature is regulated by a center in the hypothalamus that

ensures a balance between heat loss and heat production. Fever occurs when
there is a disturbance of this hypothalamic’thermostat’, which lead to the set point
of body temperature being raised. NSAIDs reset the thermostat. Once there has
been return to the normal set point, the temperature-regulating mechanism then
operates to reduced temperature. Normal temperature is not affected byNSAIDs.
NSAIDs are thought to be antipyretic largely through inhibition of
prostaglandin production in the hypothalamus. During an inflammatory reaction.
bacterial endotoxin cause released from macrophage of a pyrogen-IL-1.which
stimulates the generation ,in the hypothalamus ,of E-type prostaglandins and
these, in turn, cause the elevation of the set-point for temperature.COX_2 may
have a role here since it is induced by IL-1 in blood vessel endothelium in the
hypothalamus.cox-3 may be implicated in fever.
There is some evidence that prostaglandin is not the only mediators of fever;
hence NSAIDs may have an additional antipyretic effect by mechanism as yet
unknown.

►Analgesic effect:
NSAIDs are mainly effective against pain associated with inflammation or tissue
damage because they decrees production of the PGs that sensitize
nocioreceptor to inflammatory mediator such as bradykinin.there for they are
effective in arthritis, bursitis, pain of muscular and vascular orrigine toothache,
dysmenorrhoea, the pain of post partum states and the pain of cancer
metastases in bone –all condition that are associated with increased
prostaglandin synthesis.

In combination with opoids, they decresed postoperative pain and in some

cases can reduced the requirement for pods by as much as one third. Their
ability to relive headache may be related to the abrogation of the vasodilator
effect of prostaglandin on the cerebral vasculature.
There is some evidence that they have a central effect by an action in the spinal
cord.

►Anti-inflammatory effects:
There are many chemical mediators of the inflammatory and allergic response.
Each facet of the response-Vasodilation, increased vascular permeability, cell
accumalation, etc-can be produced by several different mechanism, furthermore,
different mediators may be of particular importance in different inflammatory and
allergic condition and some mediators have complex interaction with other; for
example, small amount of nitric oxide stimulate cyclo-oxygenase activity, while
large amount inhibit it.
Drug such as the NSAIDs reduced mainly those components of the
inflammatory and immune response in which the product of COX-2 action play a
significant part, namely;

• Vasodilatation
• Odema
• Pain
C) They can be classified into several groups

NSAIDs
Six structurally related groups:
• Acetic acids, Carboxylic acids, Propionic acids
• Enolic acids,Fenamic acids,Nonacidic compounds
NSAIDs: Acetic Acid
• Diclofenac sodium, diclofenac potassium, etodolac
• Indomethacin, sulindac, tolmetin
NSAIDs: Carboxylic Acids
Acetylated
• Aspirin (ASA)
• Choline magnesium
• Diflunisal
Nonacetylated
• Salicylamide
• Salsalate
• Sodium salicylate
NSAIDs: Propionic Acids
• Fenoprofen, flurbiprofen, ibuprofen
• Ketoprofen, ketorolac
• Naproxen, oxaprozin

NSAIDs: Other Agents

Enolic acids
• Phenylbutazone
• Piroxicam
Fenamic acids
• Meclofenamic acid
• Mefenamic acid
Nonacidic compounds
• Nabumetone
NSAIDs: Other Agents
COX-2 Inhibitors

• Celecoxib, rofecoxib
►Traditional NSAIDs can be grouped into three classes based on their modes of
inhibition of COX:

Class I: Simple, competitive, reversible inhibitors that compete with

arachidonic acid for binding to the COX active site.

Included in this class are: Ibuprofen; Piroxican; Sulindac sulfide;

Flufenamate; Mefenamic acid and Naproxen.
Class II: Competitive, time dependent, reversible inhibitors that bind to the
COX active site in a first phase, to form reversible enzyme inhibitor
complexes, that if retained for a sufficient time, cause a non covalent
conformational change in the protein, associated with tighter binding.

Included in this class are: Indomethacin; Flurbiprofen, Meclofenamic

acid and Diclofenac.
Class III: Competitive, time dependent, irreversible inhibitors that form an
enzyme inhibitor complex after a covalent conformational change in
the protein. Included in this class is: Aspirin.

The acetylation of COX-1 by aspirin is an irreversible process that

inhibits COX activity but not the peroxides activity. Aspirin's
antiplatelet effects (which only have COX-1) last for the lifetime of the
cell.
Mechanism of action of NSAIDs: -

Sir John Vane3 clarified the main mechanism of action of NSAIDs in 1971.
He noted the inhibition by aspirin, of prostaglandin synthesis.

It was noted that cells synthesized prostaglandins in response to tissue

injury. Inhibition of these prostaglandins inhibited inflammation. Whilst the
prostaglandin hypothesis is generally accepted as being the most important,
we now know that the mechanisms are more complex and involve additional
non-prostaglandin dependent pathways.

In the prostaglandin-mediated process, Cyclooxygenase metabolizes

arachidonic acid to form prostaglandin end peroxides, (Figure 2.). These
include the prostaglandins, prostacycline and thromboxane.

Blocking of the cyclo-oxygenase enzyme results in a reduction in the

formation of prostaglandins. The prostaglandins in fact are both
physiologically important and potentially pathologically harmful. PGE 2 is the
principal eicosanoid formed from arachidonic acid. It is a crucial mediator of
inflammatory changes.
1) Aspirin

Aspirin is a weak organic acid – acetyl salicylic acid. It has antipyretic, anti-
inflammatory and analgesic effects. It also has antiplatelet activity.

Mode of Action

The antipyretic and anti-inflammatory effects of the salicylates are primarily

due to the blockage of prostaglandin synthesis (by inhibiting cyclo-oxygenase
enzyme irreversibly) at the thermo regulating centers in the hypothalamus and
at peripheral target sites.

They also prevent the sensitization of pain receptors to both mechanical and
chemical stimuli. It has a uricosuric effect in large doses (5-6 gm/day). But in
doses generally used, it decreases urate excretion (1-2 gm/day). Salicylates
also causes hyperventilation by stimulation of respiratory center.

Pharmacokinetics

After oral adminstration, aspirin is well absorbed from the GIT and
hydrolyzed to salicylates and acetic acid in the tissues, where salicylates
exert its effects. Onset of action is 15-30 min after ingestion ad lasts for
4-8 hours. Salicylate crosses both the blood brain barrier and the
placenta. It undergoes hepatic metabolism and is excreted in the urine

2) Paracetamol

Paracetamol is a non-narcotic nonsalicylate analgesic. Unlike other NSAIDS,

it has little or no anti-inflammatory activity.

Mode of Action

It acts by inhibiting prostaglandin synthesis in the CNS (hence acting as

antipyretic and analgesic). It has weak anti-inflammatory activity in the
peripheral tissues and does not inhibit platelet aggregation.
Pharmacokinetics

It is readily absorbed from the upper GIT. Onset of action is 30 minutes after
ingestion. Duration of effects is 2-5 hours. It is metabolized predominantly in
the liver and excreted in the urine mainly as the glucuronide and sulphate
conjugates.

3) Ibuprofen

Ibuprofen is a non-steroidal anti-inflammatory agent of the prop ionic acid

group, possessing anti-inflammatory, analgesic and antipyretic activity.

Mode of Action

It is a reversible inhibitor of the cyclo-oxygenase enzyme. Thus, it inhibits the

synthesis of prostaglandins, and not that of leukotrienes.

Pharmacokinetics

It is readily absorbed from the GIT. It is extensively bound to plasma proteins

and is excreted in the urine mainly as metabolites and their conjugates. Onset
of analgesia is 30-60 min after ingestion. Duration of action is 6-8 hours.

4) Diclofenac

Diclofenac is a non-steroidal anti-inflammatory agent with anti-

inflammatory, antipyretic activities used for a variety of painful and
inflammatory conditions.

Mode of Action

It is a cyclo-oxygenase inhibitor. Its anti-inflammatory property is due to

decreased prostaglandin synthesis in the tissues.
Pharmacokinetics

On oral administration, completely absorbed in a fasting state. It is

subject to first-pass metabolism and only 50% is bioavailable. Onset of
action is 10 minutes. Duration is 8 hours. It penetrates the synovial fluid
and is detected in breast milk. Excreted in the form of glucoronide and
sulphate conjugates, mainly in the urine but also in the bile.

5) Indomethacin:

Indomethacin is an NSAID with anti-inflammatory, antipyretic, analgesic

properties.

Mode of Action

It is a highly potent inhibitor of prostaglandin synthesis in peripheral tissues.

Apart from its anti-inflammatory Indications, it may be used in medical closure
of P.D.A. (as an I.V. Preparation).

Pharmacokinetics

Well absorbed orally. Onset of action is 30 min after ingestion. Duration of

effects is for 4-6 hrs. Metabolized in the liver and excreted in the urine as
gluconoride conjugates
 6) Celecoxib

Celecoxib is a nonsteroidal anti-inflammatory drug (NSAID) that is used

to treat arthritis, pain, menstrual cramps, and colonic polyps.
Prostaglandins are chemicals that are important contributors to the
inflammation of arthritis that causes the pain, fever, swelling and
tenderness. Celecoxib blocks the enzyme that makes prostaglandins
(cyclo-oxygenase 2), resulting in lower concentrations of prostaglandins.
As a consequence, inflammation and its accompanying pain, fever,
swelling and tenderness are reduced.

Celecoxib differs from other NSAIDs in that it causes less inflammation

and ulceration of the stomach and intestine (at least with short-term
treatment) and does not interfere with the clotting of blood

Celecoxib is approved as an adjunctive (secondary) treatment among

patients with FAP. The cramping and pain during menstrual periods is
due to prostaglandins, and blocking the production of prostaglandins
with Celecoxib reduces the cramps and pain.

Newer NSAIDs: selective COX inhibitors

COX-2 inhibitors
The discovery of COX-2 in 1991 by Daniel L. Simmons at Brigham Young
University raised the hope of developing an effective NSAID without the gastric
problems characteristic of these agents. It was thought that selective inhibition of
COX-2 would result in anti-inflammatory action without disrupting gastro
protective prostaglandins.
COX-1 is a constitutively expressed enzyme with a "house-keeping" role in
regulating many normal physiological processes. One of these is in the stomach
lining, where prostaglandins serve a protective role, preventing the stomach
mucosa from being eroded by its own acid. When non-selective COX-1/COX-2
inhibitors (such as aspirin, ibuprofen, and naproxen)) lower stomach
prostaglandin levels, these protective effects are lost and ulcers of the stomach
or duodenum and potentially internal bleeding can result. COX-2 is an enzyme
facultative expressed in inflammation, and it is inhibition of COX-2 that produces
the desirable effects of NSAIDs.
The relatively selective COX-2 inhibiting oxicam, meloxicam, was the first step
towards developing a true COX-2 selective inhibitor. Coxibs, the newest class of
NSAIDs, can be considered as true COX-2 selective inhibitors, and include
celecoxib, rofecoxib, valdecoxib, parecoxib and etoricoxib.

►Controversies with COX-2 inhibitors

While it was hoped that this COX-2 selectivity would reduce gastrointestinal
adverse drug reactions (ADRs), there is little conclusive evidence that this is true.
The original study touted by Searle showing a reduced rate of ADRs for
celecoxib, was later revealed to be based on preliminary data - the final data
showed no significant difference in ADRs when compared with diclofenac.
Rofecoxib however, which has since been withdrawn, had been shown to
produce significantly fewer gastrointestinal ADRs compared to naproxen.
(Bombardier et al 2000). This study, the VIGOR trial, raised the issue of the
cardiovascular safety of the Coxibs - a statistically insignificant increase in the
incidence of myocardial infarctions was observed in patients on rofecoxib.
Further data, from the Approve trial, showed a relative risk of cardiovascular
events of 1.97 versus placebo - a result which resulted in the worldwide
withdrawal of rofecoxib in October 2004.
►COX-3 inhibitors
Simmons also co-discovered COX-3 in 2002 and analyzed this new isozyme's
relation to acetaminophen, arguably the most widely used analgesic drug in the
world. The authors postulated that inhibition of COX-3 could represent a primary
central mechanism by which these drugs decrease pain and possibly fever.
Therapeutic Uses
• Relief of mild to moderate pain
• Acute gout
• Various bone, joint, and muscle pain
• Osteoarthritis
• Rheumatoid arthritis
• Juvenile rheumatoid arthritis
• Dysmenorrhea
• Fever

A Adverse effects
The widespread use of NSAIDs has meant that the adverse effects of these
relatively safe drugs have become increasingly prevalent. The two main adverse
drug reactions (ADRs), associated with NSAIDs relate to gastrointestinal (GI)
effects and renal effects of the agents.
These effects are dose-dependent, and in many cases severe enough to pose
the risk of ulcer perforation, upper gastrointestinal bleeding, and death, limiting
the use of NSAID therapy. An estimated 10-20% of NSAID patients experience
dyspepsia, and NSAID-associated upper gastrointestinal adverse events are
estimated to result in 103,000 hospitalizations and 16,500 deaths per year in the
United States, and represent 43% of drug-related emergency visits. Many of
these events are avoidable; a review of physician visits and prescriptions
estimated that unnecessary prescriptions for NSAIDs were written in 42% of
visits. (Green, 2001)
►Gastrointestinal ADRs
The main ADRs associated with use of NSAIDs relate to direct and indirect
irritation of the gastrointestinal tract (GIT). NSAIDs cause a dual insult on the GIT
- the acidic molecules directly irritate the gastric mucosa; and inhibition of COX-1
reduces the levels of protective prostaglandins.
Common gastrointestinal ADRs include: (Rossi, 2004)

• Nausea
• Dyspepsia
• Ulceration / bleeding
• Diarrhoea

Risk of ulceration increases with duration of therapy, and with higher doses. In
attempting to minimize GI ADRs, it is prudent to use the lowest effective dose for
the shortest period of time, a practice which studies show is not often followed.
There are also some differences in the propensity of individual agents to cause
gastrointestinal ADRs. Indomethacin, ketoprofen and piroxicam appear to have
the highest prevalence of gastric ADRs, while ibuprofen (lower doses) and
diclofenac appear to have lower rates. (Rossi, 2004)
Certain NSAIDs, such as aspirin, have been marketed in enteric-coated
formulations which are claimed to reduce the incidence of gastrointestinal ADRs.
Similarly, there is a belief that rectal formulations may reduce gastrointestinal
ADRs. However, in consideration of the mechanism of such ADRs and indeed in
clinical practice, these formulations have not been shown to have a reduced risk
of GI ulceration.
Commonly, gastrointestinal adverse effects can be reduced through suppressing
acid production, by concomitant use of a proton pump inhibitor, e.g. omeprazole;
or the prostaglandin analogue misoprostol. Misoprostol is itself associated with a
high incidence of gastrointestinal ADRs (diarrhoea). While these techniques may
be effective, they prove to be expensive for maintenance therapy.

►Renal ADRs
NSAIDs are also associated with a relatively high incidence of renal ADRs. The
mechanism of these renal ADRs is probably due to changes in renal
haemodynamics (blood flow), ordinarily mediated by prostaglandins, which are
affected by NSAIDs. Horses are particularly prone to these adverse affects
compared to other domestic animal species.
Common ADRs associated with altered renal function include: (Rossi, 2004)

• Salt and fluid retention

• Hypertension

These agents may also cause renal impairment, especially in combination with
other nephrotoxic agents. Renal failure is especially a risk if the patient is also
concomitantly taking an ACE inhibitor and a diuretic - the so-called "triple
whammy" effect. (Thomas, 2000)
In rarer instances NSAIDs may also cause more severe renal conditions: (Rossi,
2004)

• Interstitial nephritis
• Nephrotic syndrome
• Acute renal failure

►Photosensitivity
Photosensitivity is a commonly overlooked adverse effect of many of the
NSAIDs. (Moore, 2002) It is somewhat ironic that these antiinflammatory agents
may themselves produce inflammation in combination with exposure to sunlight.
The 2-arylpropionic acids have proven to be the most likely to produce
photosensitivity reactions, but other NSAIDs have also been implicated including
piroxicam, diclofenac and benzydamine.
Benoxaprofen, since withdrawn due to its hepatotoxicity, was the most
photoactive NSAID observed. The mechanism of photosensitivity, responsible for
the high photoactivity of the 2-arylpropionic acids, is the ready decarboxylation of
the carboxylic acid moiety. The specific absorbance characteristics of the
different chromophoric 2-aryl affects the decarboxylation mechanism. Whilst
ibuprofen is somewhat of an exception, having weak absorption, it has been
reported to be a weak photosensitizing agent.
►Pregnancy
NSAIDs are generally not recommended during pregnancy. While NSAIDs as a
class are not direct teratogens, they may cause premature closure of the fetal
ductus arteriosus and renal ADRs in the fetus. Additionally, they are linked with
premature birth (PMID 15013926).
However, aspirin, when used with heparin, may be beneficial in pregnancy for
women with antiphospholipid antibodies (PMID 15485103).
In contrast, paracetamol (acetaminophen) is regarded as being well-tolerated
during pregnancy (PMID 15733027). Doses should be taken as prescribed, due
to risk of hepatotoxicity with overdoses (PMID 16351032).

Other ADRs
Common ADRs, other than listed above, include: raised liver enzymes,
headache, and dizziness

Uncommon ADRs include: heart failure, hyperkalaemia, confusion,

bronchospasm, and rash

Reference:
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2. F.S.K.barar, “essentials of pharmacotherapeutics”,
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Dr. Mahesh d. burnade, “elements of pharmacology”,
fourteenth edition,2004-2005,page no: 387-389
4. H.P.Rang,M.M.Dale,J.M.Ritter,P.K.Moore,
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fifth edition,2003, page no: 630-633