NON-STEROIDAL ANTI-INFLAMMATORY DRUGS

INTRODUCTION
Non-steroidal anti-inflammatory drugs, usually abbreviated to NSAIDs or NAIDs, but also
referred to as non-steroidal anti-inflammatory agents/analgesics (NSAIAs) or non-steroidal anti-
inflammatory medicines (NSAIMs), are drugs with analgesic and antipyretic (fever-reducing)
effects and which have, in higher doses, anti-inflammatory effects.

The term "non-steroidal" is used to distinguish these drugs from steroids, which - among a broad
range of other effects - have a similar eicosanoid-depressing, anti-inflammatory action.
As analgesics, NSAIDs are unusual in that they are non-narcotic. The most prominent members
of this group of drugs are aspirin, ibuprofen, and naproxen, all of which are available over the
counter in many areas.

MECHANISM OF ACTION

Most NSAIDs act as nonselective inhibitors of the enzyme cyclooxygenase (COX), inhibiting

both the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isoenzymes. COX
catalyzes the formation of prostaglandins and thromboxane from arachidonic acid (itself derived
from the cellular phospholipid bilayer by phospholipase A2). Prostaglandins act (among other
things) as messenger molecules in the process of inflammation. This mechanism of action was
elucidated by John Vane (1927–2004), who later received a Nobel Prize for his work
(see Mechanism of action of aspirin). Many aspects of the mechanism of action of NSAIDs
remain unexplained, for this reason further COX pathways were hypothesized. The COX-
3pathway was believed to fill some of this gap but recent findings make it appear unlikely that it
plays any significant role in humans and alternative explanation models are proposed.

NSAIDS have antipyretic activity and can be used to treat fever. Fever is caused by elevated
levels of prostaglandin E2, which alters the firing rate of neurons within the hypothalamus, that
control thermoregulation. Antipyretics work by inhibiting the enzyme COX, which causes the
general inhibition of prostanoid biosynthesis (PGE2) within the hypothalamus. PGE2 signals to
the hypothalamus to increase the body's thermal set point. Ibuprofen has been shown to be more
effective as an antipyretic than acetaminophen. Arachidonic acid is the precursor substrate for
cyclooxygenase leading to the production of prostaglandins F, D & E.

Classification:

NSAIDs can be broadly classified based on their chemical structure.

Propionic acid derivatives

 Ibuprofen
 Naproxen
  Fenoprofen
 Ketoprofen
 Flurbiprofen
 Oxaprozin

Acetic acid derivatives

 Indomethacin
 Sulindac
 Etodolac
 Ketorolac
 Diclofenac (Safety alert by FDA)
 Nabumetone

Enolic acid (Oxicam) derivatives

 Piroxicam
 Meloxicam
 Tenoxicam
 Droxicam
 Lornoxicam
 Isoxicam

Fenamic acid derivatives

 Mefenamic acid
 Meclofenamic acid
 Flufenamic acid
 Tolfenamic acid

Selective COX-2 inhibitors (Coxibs)

 Celecoxib (FDA alert)

 Rofecoxib (withdrawn from market)
 Valdecoxib (withdrawn from market)
 Parecoxib FDA withdrawn
 Lumiracoxib TGA cancelled registration
 Etoricoxib FDA withdrawn
 Firocoxib used in dogs and horses
Examples:

NSAIDs within a group will tend to have similar characteristics and tolerability. There is little
difference in clinical efficacy among the NSAIDs when used at equivalent doses. Rather,
differences among compounds tend to be with regards to dosing regimens (related to the
compound's elimination half-life), route of administration, and tolerability profile. Some more
common examples are given below.

Sulphonanilides:
 Nimesulide (systemic preparations are banned by several countries for the potential risk of
hepatotoxicity)

Others:
 Licofelone

Licofelone acts by inhibiting LOX (lipooxygenase) & COX and hence known as 5-LOX/COX
inhibitor.

ANTI-INFLAMMATORY EFFECTS OF NSAIDs

This effect of NSAIDs is due to the inhibition of the enzyme COX, which converts arachidonic
acid to prostaglandins, TXA2 and prostacyclin. Acetylsalicylic acid irreversibly inactivates
COX-1 and COX-2 by acetylation of a specific serine residue. Other NSAIDs reversibly inhibit
COX-1 and COX-2
Additional anti-inflammatory mechanism may include:
1. Interference with the potentiative action of other mediators of inflammation – bradykinin,
histamine, serotonin
2. Modulation of T-cell function
3. Stabilization of lysosomal membranes
4. Inhibition of chemotaxis

ANALGESIC EFFECT OF NSAIDs

This effect of NSAIDs is thought to be related to the peripheral inhibition of prostaglandin

production, but it may also be due to the inhibition of pain stimuli at a subcortical site. NDAIDs
prevent the potentiating action of prostaglandins on endogenous mediators of peripheral nerve
stimulation (e.g. bradykinin)

ANTIPYRETIC EFFECT OF NSAIDs

This effect is believed to be related to inhibition of the interleukin-1 and interleukin-6 induced
production of prostaglandins in the hypothalmus and the resetting of the termoregulatory system,
leading to vasodilation and increased heat loss
CLINICAL USES O NSAIDs

1) Analgesia
2) Inflammation
3) Antipyresis
4) Antiplateled effect
5) Cancer preventive agents

Precautions:
Nonsteroidal anti-inflammatory drugs can cause a number of side effects, some of which may be very
serious (See Side effects). These side effects are more likely when the drugs are taken in large doses or
for a long time or when two or more nonsteroidal anti-inflammatory drugs are taken together. Health care
professionals can help patients weigh the risks of benefits of taking these medicines for long periods.
Do not take acetaminophen, aspirin, or other salicylates along with other nonsteroidal anti-inflammatory
drugs for more than a few days unless directed to do so by a physician. Do not take ketorolac (Toradol)
while taking other nonsteroidal anti-inflammatory drugs unless directed to do so by a physician.
Because older people are more sensitive than younger adults to nonsteroidal anti-inflammatory drugs,
they may be more likely to have side effects. Some side effects, such as stomach problems, may also be
more serious in older people.
Serious side effects are especially likely with one nonsteroidal anti-inflammatory drug, phenylbutazone.
Patients age 40 and over are especially at risk of side effects from this drug, and the likelihood of serious
side effects increases with age. Because of these potential problems, it is especially important to check
with a physician before taking this medicine. Never take it for anything other than the condition for which it
was prescribed, and never share it—or any other prescription drug—with another person.
Some nonsteroidal anti-inflammatory drugs can increase the chance of bleeding after surgery (including
dental surgery), so anyone who is taking the drugs should alert the physician or dentist before surgery.
Avoiding the medicine or switching to another type in the days prior to surgery may be necessary.
Some people feel drowsy, dizzy, confused, light-headed, or less alert when using these drugs. Blurred
vision or other vision problems also are possible side effects. For these reasons, anyone who takes these
drugs should not drive, use machines or do anything else that might be dangerous until they have found
out how the drugs affect them.
Nonsteroidal anti-inflammatory drugs make some people more sensitive to sunlight. Even brief exposure
to sunlight can cause severe sunburn, rashes, redness, itching, blisters, or discoloration. Vision changes
also may occur. To reduce the chance of these problems, avoid direct sunlight, especially from mid-
morning to mid-afternoon; wear protective clothing, a hat, and sunglasses; and use a sunscreen with a
skin protection factor (SPF) rating of at least 15. Do not use sunlamps, tanning booths or tanning beds
while taking these drugs.

ADVERSE EFFECTS

The widespread use of NSAIDs has meant that the adverse effects of these 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.

NSAIDs, like all drugs, may interact with other medications. For example, concurrent use of
NSAIDs and quinolones may increase the risk of quinolones' adverse central nervous
systemeffects, including seizure.

Combinational risk:

If a COX-2 inhibitor is taken, one should not use a traditional NSAID (prescription or over-the-
counter) concomitantly. In addition, patients on daily aspirin therapy (e.g. for reducing
cardiovascular risk) need to be careful if they also use other NSAIDs, as the latter may block[the
cardioprotective effects of aspirin.

Cardiovascular:

A recent meta-analysis of all trials comparing NSAIDs found an 80% increase in the risk of
myocardial infarction with both newer COX-2 antagonists and high dose traditional anti-
inflammatories compared with placebo.

NSAIDs aside from (low-dose) aspirin are associated with a doubled risk of symptomatic heart
failure in patients without a history of cardiac disease. In patients with such a history, however,
use of NSAIDs (aside from low-dose aspirin) was associated with more than 10-fold increase in
heart failure. If this link is found to be causal, NSAIDs are estimated to be responsible for up to
20 percent of hospital admissions for congestive heart failure.

Gastrointestinal:

The main adverse drug reactions (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 and COX-2
reduces the levels of protective prostaglandins. Inhibition of prostaglandin synthesis in the GI
tract causes increased gastric acid secretion, diminished bicarbonate secretion, diminished mucus
secretion and diminished trophiceffects on epithelial mucosa.

Common gastrointestinal ADRs include:

 Nausea/Vomiting
 Dyspepsia
 Gastric ulceration/bleeding.
  Diarrhea

Risk of ulceration increases with duration of therapy, and with higher doses. In attempting to
minimise 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. Recent studies show that over 50% of patients
taking NSAIDs have sustained damage to their small intestine. Studies show that risk of
ulceration is less with Nabumetone than with Ibuprofen alone.

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.

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, gastric (but not necessarily intestinal) adverse effects can be reduced through
suppressing acid production, by concomitant use of a proton pump inhibitor, e.g. omeprazole,
esomeprazole; or the prostaglandin analogue misoprostol. Misoprostol is itself associated with a
high incidence of gastrointestinal ADRs (diarrhea). While these techniques may be effective,
they prove to be expensive for maintenance therapy.

Inflammatory bowel disease:

NSAIDs are never to be used in individuals with Inflammatory Bowel Disease (e.g., Crohn's
Disease or Ulcerative Colitis) due to their tendency to cause gastric bleeding and form ulceration
in the gastric lining. Pain relievers such as paracetamol (also known as acetaminophen) or drugs
containing codeine (which slows down bowel activity) are safer medications for pain relief in
IBD

Renal:

NSAIDs are also associated with a relatively high incidence of renal adverse drug reactions
(ADRs). The mechanism of these renal ADRs is due to changes in renal haemodynamics (blood
flow), ordinarily mediated by prostaglandins, which are affected by NSAIDs. Prostaglandins
normally cause vasodilation of the afferent arterioles of the glomeruli. This helps maintain
normal glomerular perfusion and glomerular filtration rate (GFR), an indicator of renal function.
This is particularly important in renal failure where the kidney is trying to maintain renal
perfusion pressure by elevated angiotensin II levels. At these elevated levels, angiotensin II also
constricts the afferent arteriole into the glomerulus in addition to the efferent arteriole one it
normally constricts. Prostaglandins serve to dilate the afferent arteriole; by blocking this
prostaglandin-mediated effect, particularly in renal failure, NSAIDs cause unopposed
constriction of the afferent arteriole and decreased renal perfusion pressure. Horses are
particularly prone to these adverse affects compared with other domestic animal species.
Common ADRs associated with altered renal function include:

 Salt and fluid retention

 Hypertension (high blood pressure)

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.

In rarer instances NSAIDs may also cause more severe renal conditions:

 Interstitial nephritis
 Nephrotic syndrome
 Acute renal failure
 Acute tubular necrosis

NSAIDs in combination with excessive use of phenacetin and/or paracetamol may lead to
analgesic nephropathy.

Photosensitivity:

Photosensitivity is a commonly overlooked adverse effect of many of the NSAIDs. It is

somewhat ironic that these anti-inflammatory 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 substituents, affects the
decarboxylation mechanism. While ibuprofen is somewhat of an exception, having weak
absorption, it has been reported to be a weak photosensitising agent.

Antirheumatic Drugs 

Definition:
Antirheumatic drugs are drugs used to treat rheumatoid arthritis

Rheumatoid Arthritis:

Definition:
Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes inflammation and deformity of the
joints. Other problems throughout the body (systemic problems) may also develop, including inflammation
of blood vessels (vasculitis), the development of bumps (called rheumatoid nodules) in various parts of
the body, lung disease, blood disorders, and weakening of the bones (osteoporosis).

Description:
The skeletal system of the body is made up of different types of strong, fibrous tissue called connective
tissue. Bone, cartilage, ligaments, and tendons are all forms of connective tissue that have different
compositions and different characteristics.
The joints are structures that hold two or more bones together. Some joints (synovial joints) allow for
movement between the bones being joined (articulating bones). The simplest synovial joint involves two
bones, separated by a slight gap called the joint cavity. The ends of each articular bone are covered by a
layer of cartilage. Both articular bones and the joint cavity are surrounded by a tough tissue called the
articular capsule. The articular capsule has two components, the fibrous membrane on the outside and
the synovial membrane (or synovium) on the inside. The fibrous membrane may include tough bands of
tissue called ligaments, which are responsible for providing support to the joints. The synovial membrane
has special cells and many tiny blood vessels (capillaries). This membrane produces a supply of synovial
fluid that fills the joint cavity, lubricates it, and helps the articular bones move smoothly about the joint.
In rheumatoid arthritis (RA), the synovial membrane becomes severely inflamed. Usually thin and
delicate, the synovium becomes thick and stiff, with numerous infoldings on its surface. The membrane is
invaded by white blood cells, which produce a variety of destructive chemicals. The cartilage along the
articular surfaces of the bones may be attacked and destroyed, and the bone, articular capsule, and
ligaments may begin to wear away (erode). These processes severely interfere with movement in the
joint.

RA exists all over the world and affects men and women of all races. In the United States alone,
about two million people suffer from the disease. Women are three times more likely than men to
have RA. About 80% of people with RA are diagnosed between the ages of 35-50. RA appears to
run in families, although certain factors in the environment may also influence the development of
the disease.
PRECAUTIONS

Many antirheumatic drugs such as, for example, azathioprine (Imuran) and methotrexate
(Rheumatrex), are very powerful drugs. They are usually prescribed in severe cases, when all
other treatments have failed. Thus, they may have serious side effects, so it is important to be
monitored closely by a physician while taking any of these drugs.

SIDE EFFECTS

Hydroxychloroquine (Plaquenil) may cause vision problems. Anyone taking it should see an
ophthalmologist (a physician who specializes in treating eyes) for a thorough eye
examination every six months.

Methotrexate and penicillamine may cause birth defects. Women taking these drugs must stop
taking them during pregnancy and for several months before a planned pregnancy. Methotrexate
may also cause lung damage or fertility problems and should not be taken by anyone with serious
kidney or liver disease or by anyone who drinks alcohol.
Azathioprine may cause birth defects if either the man or woman is using it at the time of
conception. Anyone who uses this drug and is sexually active should consult with a physician
about an effective birth control method.

Other common side effects of antirheumatic drugs include abdominal cramps, diarrhea,

dizziness, loss of appetite, headache, nausea, vomiting, fever and chills, and mouth sores. A
variety of other side effects may occur. Anyone who has unusual symptoms while taking
antirheumatic drugs should notify the treating physician.

The gold compounds may cause serious blood problems by reducing the ability of the blood
forming organs to produce blood cells. These drugs may decrease the number of white blood
cells, red blood cells, or both. Patients taking these drugs should have regular blood counts.

Entanercept (Enbrel) may also cause blood problems, and some patients who received this drug
have developed eye problems and multiple sclerosis. It is not certain whether these reactions
were caused by entanercept, but multiple sclerosis has been seen in patients taking other drugs
which act against tumor necrosis factor.

INTERACTIONS

Antirheumatic drugs may interact with a variety of other medicines or other antirheumatic
drugs. When this happens, the effects of one or both of the drugs may change, or the risk of
side effects may be greater. Anyone who takes this type of drug should inform the
prescribing physician about any other medication he or she is taking. Among the drugs
that may interact with antirheumatic drugs are phenytoin (Dilantin), aspirin, sulfa drugs
such as Bactrim and Gantrisin, tetracycline and some other antibiotics and cimetidine
(Tagamet). NSAIDs such as ibuprofen (Motrin, Advil) are also known to interact with
other classes of antirheumatic drugs

REFERENCE

http://en.wikipedia.org/wiki/Non-steroidal_anti-inflammatory_drug

http://orthoinfo.aaos.org/topic.cfm?topic=a00284

http://www.medinfo.co.uk/drugs/nsaids.html