Non-steroidal anti-inflammatory drug

1
Non- steroidal anti-inflammatory drug
Coated 200 mg ibuprofen tablets, a common
NSAID
Nonsteroidal anti-inflammatory drugs, usually abbreviated to
NSAIDs or NAIDs, are drugs with analgesic, antipyretic
(fever-reducing) and, in higher doses, with anti-inflammatory effects
(reducing inflammation). The term "nonsteroidal" 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.
NSAIDs are sometimes also referred to as nonsteroidal anti-inflammatory agents/analgesics (NSAIAs) or
nonsteroidal anti-inflammatory medicines (NSAIMs). The most prominent members of this group of drugs are
aspirin, ibuprofen, and naproxen partly because they 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 A
2
). 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). A newly discovered COX-3 may also have some role.
NSAIDS have antipyretic activity and can be used to treat fever
[1]

[2]
. Fever is caused by elevated levels of
prostaglandin E2, which alters the firing rate of neurons within the hypothalamus that control thermoregulation
[1]

[3]
. Antipyretics work by inhibiting the enzyme COX, which causes the general inhibition of prostanoid biosynthesis
(PGE2) within the hypothalamus
[1]

[2]
. PGE2 signals to the hypothalamus to increase the body's thermal set point
[2]
[4]
. Ibuprofen has been shown to be more effective as an antipyretic than acetaminophen
[3]

[5]
.
Classification
NSAIDs can be broadly classified based on their chemical structure.
Propionic acid derivatives
Ibuprofen
[6]
Naproxen
Fenoprofen
Ketoprofen
Flurbiprofen
Oxaprozin
Fever is caused by elevated levels of
[1] [3]
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
2] [1] [2] [2
(PGE2) within the hypothalamus

. PGE2 signals to the hypothalamus to increase the body's thermal set point
[3] [5] [4] [4]
. Ibuprofen has been shown to be more effective as an antipyretic than acetaminophen
Non-steroidal anti-inflammatory drug
2
Acetic acid derivatives
Indomethacin
Sulindac
Etodolac
Diclofenac (Safety alert by FDA
[7]
)
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
[8]
)
Rofecoxib (withdrawn from market
[9]
)
Valdecoxib (withdrawn from market
[10]
)
Parecoxib FDA withdrawn
Lumiracoxib TGA cancelled registration
Etoricoxib FDA withdrawn
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)
FDA
[[7]
Diclofenac (Safety alert by F )
Non-steroidal anti-inflammatory drug
3
Others
Licofelone
Licofelone acts by inhibiting LOX (lipooxygenase) & COX and hence known as 5-LOX/COX inhibitor.
Uses
NSAIDs are usually indicated for the treatment of acute or chronic conditions where pain and inflammation are
present. Research continues into their potential for prevention of colorectal cancer, and treatment of other conditions,
such as cancer and cardiovascular disease.
NSAIDs are generally indicated for the symptomatic relief of the following conditions:
[11]
Rheumatoid arthritis
[12]
Osteoarthritis
Inflammatory arthropathies (e.g. ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome)
Acute gout
Dysmenorrhoea (menstrual pain)
Metastatic bone pain
Headache and migraine
Postoperative pain
Mild-to-moderate pain due to inflammation and tissue injury
Pyrexia (fever)
Ileus
Renal colic
They are also given to neonate infants whose ductus arteriosus is not closed within 24 hours of birth
Aspirin, the only NSAID able to irreversibly inhibit COX-1, is also indicated for inhibition of platelet aggregation.
This is useful in the management of arterial thrombosis and prevention of adverse cardiovascular events. Aspirin
inhibits platelet aggregation by inhibiting the action of thromboxane -A.
In 2001 NSAIDs accounted for 70,000,000 prescriptions and 30 billion over-the-counter doses sold annually in the
United States.
[13]
One study has suggested that taking NSAIDs while smoking marijuana may prevent the death of brain cells resulting
from THC intoxication.
[14]
However, neurotoxicity of marijuana is still a matter of dispute.
Pharmacokinetics
Most nonsteroidal anti-inflammatory drugs are weak acids, with a pKa of 3-5. They are absorbed well from the
stomach and intestinal mucosa. They are highly protein-bound in plasma (typically >95%), usually to albumin, so
that their volume of distribution typically approximates to plasma volume. Most NSAIDs are metabolised in the liver
by oxidation and conjugation to inactive metabolites which are typically excreted in the urine, although some drugs
are partially excreted in bile. Metabolism may be abnormal in certain disease states, and accumulation may occur
even with normal dosage.
Ibuprofen and diclofenac have short half-lives (2`3 hours). Some NSAIDs (typically oxicams) have very long
half-lives (e.g. 20`60 hours).
Ibuprofen and diclofenac have short half-lives (2`3 hours). Some NSAIDs (typically oxicams) have very long
20` half-lives (e.g. 2 `60 hours).
Non-steroidal anti-inflammatory drug
4
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.
[13]
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 system effects, including seizure.
[15]

[16]
Combinational risk
If a COX-2 inhibitor is taken, one should not use a traditional NSAID (prescription or over-the-counter)
concomitantly.
[17]
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.
[18]
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.
[19]
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.
[19]
Gastrointestinal
The main ADRs (adverse drug reactions) 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. Inhibition of prostaglandin
synthesis in the GI tract causes increased gastric acid secretion, diminished bicarbonate secretion, diminished
mucous secretion and diminished trophic effects on epithelial mucosa.
Common gastrointestinal ADRs include:
[11]
Nausea/Vomiting
Dyspepsia
Gastric ulceration/bleeding
[20]
.
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.
[21]
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.
[11]
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.
A recent meta-analysis of all trials comparing NSAIDs found an 80% increase in the risk of myocardial infarction
18]
placebo.
[1
with both newer COX-2 antagonists and high dose traditional anti-inflammatories compared with p
failure.
[1
was associated with more than 10-fold increase in heart f
NSAIDs aside from (low-dose) aspirin are associated with a doubled risk of symptomatic heart failure in patients
without a history of cardiac disease.
failure.
[1
o 20 percent of hospital admissions for congestive heart f
. 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. Inhibition of prostaglandin
synthesis in the GI tract causes increased gastric acid secretion, diminished bicarbonate secretion, diminished
mucous secretion and diminished trophic effects on epithelial mucosa.
include:
[[11]
Common gastrointestinal ADRs i
Nausea/Vomiting
Dyspepsia
bleeding
[[20]
Gastric ulceration/b

.
Diarrhea
d. Recent studies show that over 50% of patients taking NSAIDs have sustained damage to their small
intestine.
[[[21] [21]
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
rates.
[[11]
Diclofenac appear to have lower r
Non-steroidal anti-inflammatory drug
5
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.
[11]
Commonly, gastrointestinal 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 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 ateriole
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 to other domestic animal species.
Common ADRs associated with altered renal function include:
[11]
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.
[22]
In rarer instances NSAIDs may also cause more severe renal conditions:
[11]
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.
[23]
Non-steroidal anti-inflammatory drug
6
Photosensitivity
Photosensitivity is a commonly overlooked adverse effect of many of the NSAIDs.
[24]
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.
During pregnancy
NSAIDs are not recommended during pregnancy, particularly during the third trimester. 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.
[25]
Aspirin, however, is used together with heparin in pregnant
women with antiphospholipid antibodies.
[26]
In contrast, paracetamol (acetaminophen) is regarded as being safe and well-tolerated during pregnancy.
[27]
Doses
should be taken as prescribed, due to risk of hepatotoxicity with overdoses.
[28]
In France, the country's health agency contraindicates the use of NSAIDs, including aspirin, after the sixth month of
pregnancy.
[29]
Other
Common ADRs, other than listed above, include: raised liver enzymes, headache, dizziness.
[11]
Uncommon ADRs
include: hyperkalaemia, confusion, bronchospasm, rash.
[11]
Rapid and severe swelling of the face and/or body.
Ibuprofen may also rarely cause irritable bowel syndrome symptoms.
Most NSAIDs penetrate poorly into the central nervous system (CNS). However, the COX enzymes are expressed
constitutively in some areas of the CNS, meaning that even limited penetration may cause adverse effects such as
somnolence and dizziness.
In very rare cases, ibuprofen can cause aseptic meningitis.
As with other drugs, allergies to NSAIDs might exist. While many allergies are specific to one NSAID, up to 1 in 5
people may have unpredictable cross-reactive allergic responses to other NSAIDs as well.
[30]
Drug Interactions
Drug Severity Adverse Effect Recommendations
ACE Inhibitors (eg. Benazepril
Hydrochloride)
Moderate May decrease antihypertensive and natriuretic
effects
Monitor blood pressure and cardiovascular
function
Probenecid Moderate May result in reversal of the uricosuric effects
of the other drug
Avoid concurrent use of high-dose aspirin with
probenecid
Lithium Moderate May increase lithium plasma levels and
decrease its clearance renally
Monitor for lithium toxicity
Warfarin Moderate May result in an increased risk of bleeding Monitor PT (prothrombin time) and INR
(international normalized ratio)
Methotrexate Severe May result in increased risk of methotrexate
toxicity
DO NOT administer NSAIDs within 10 days of
high dose methotrexate
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.
25]
birth.
[2 [2
Additionally, they are linked with premature
[26]
pregnancy.
[2
In contrast, paracetamol (acetaminophen) is regarded as being safe and well-tolerated during
[28]
Non-steroidal anti-inflammatory drug
7
[31]

[32]

[33]

[34]

[35]

[36]

[37]

[38]

[39]

[40]
Chirality
Most NSAIDs are chiral molecules (diclofenac is a notable exception). However, the majority are prepared in a
racemic mixture. Typically, only a single enantiomer is pharmacologically active. For some drugs (typically
profens), an isomerase enzyme exists in vivo which converts the inactive enantiomer into the active form, although
its activity varies widely in individuals. This phenomenon is likely to be responsible for the poor correlation between
NSAID efficacy and plasma concentration observed in older studies, when specific analysis of the active enantiomer
was not performed.
Ibuprofen and ketoprofen are now available in single, active enantiomer preparations (dexibuprofen and
dexketoprofen), which purport to offer quicker onset and an improved side-effect profile. Naproxen has always
been marketed as the single active enantiomer.
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 gastroprotective 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 nonselective 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 facultatively 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 (now part of Pfizer), 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.
[41]
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.
Non-steroidal anti-inflammatory drug
8
COX-3 inhibitors
Simmons also co-discovered COX-3 in 2002 and analyzed this new isozyme's relation to paracetamol
(acetaminophen), arguably the most widely used analgesic drug in the world.
[42]
The authors postulated that
inhibition of COX-3 could represent a primary central mechanism by which these drugs decrease pain and possibly
fever.
The relevance of this research has been called into question as the putative COX-3 gene encodes proteins with
completely different amino acid sequences than COX-1 or COX-2. The expressed proteins do not show COX
activity and it is unlikely that they play a role in prostaglandin mediated physiological responses.
[43]
Veterinary use
Research supports the use of NSAIDs for the control of pain associated with veterinary procedures such as dehorning
and castration of calves. The best effect is obtained by combining a short-term local anesthetic such as lidocaine with
an NSAID acting as a longer term analgesic. However, most of the existing research data relates to ketoprofen while
the only NSAID currently available for labelled use in the United States is flunixin meglumine, indicated for
conditions other than post-operative pain.
External links
US National Library of Medicine: MedlinePlus Drug Information: Anti-inflammatory Drugs, Nonsteroidal
(Systemic)
[44]
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