This article analyzes nonsteroidal anti-inflammatory drugs (NSAIDs) and their mechanisms of action, side effects, and safety. Most NSAIDs inhibit both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), which can lead to unwanted side effects from decreased prostaglandin formation, particularly those causing gastric ulcers. Selective COX-2 inhibitors were developed to reduce these side effects while maintaining analgesic effects. The article discusses the roles of COX-1 and COX-2 in prostaglandin synthesis and various physiological processes. It also summarizes the potential side effects of NSAIDs on the gastric mucosa, kidneys,

1. Indian Journal of Dental Sciences. www.ijds.in
September 2012 Issue:3, Vol.:4
All rights are reserved
Review Article
Indian Journal
of Dental Sciences
E ISSN NO. 2231-2293 P ISSN NO. 0976-4003
1
Kavita Mittal
NSAIDs - HOW SAFE ARE THEY 2
Sudhir Mittal
3
Anil Sharma
1
Prof & Head, Dept Of Pedodontics
Abstract Desh Bhagat Dental College & Hospital, Muktsar
This article analyses the drugs used to treat the symptoms and signs of inflammation. Most currently 2
Prof & Head, Dept Of Pedodontics
available nonsteroidal anti -inflammatory drugs inhibit both cyclooxygenase -1 ( cox -1 ; constitutive Bhojia Dental College, Baddi
3
) and cyclooxygenase -2 (cox-2 ; induced in settings of inflammation) activities , and thereby Prof & Head, Dept Of Orthodontics
synthesis of prostaglandins and thromboxane. The inhibition of cox-2 is thought to mediate , at least College Of Dental Sciences, Bhavnagar, Gujrat
in part , the antipyretic , analgesic and anti-inflammatory action of NSAIDs , but the simultaneous Address For Correspondence:
inhibition of cox-1 results in unwanted side effects, particularly those leading to gastric ulcers , that Dr. Kavita Mittal
result from decreased prostaglandin formation. The potential therapeutic advantage of selective Prof & Head
cox-2 inhibitors is discussed. Dept Of Pedodontics
Desh Bhagat Dental College & Hospital, Muktsar
Email - care@jalandhardentalcare.com
Key Words
th
NSAIDs- mechanism of action, selective cox-2 inhibitors, side effects of cox-1 inhibition, choice of Submission : 04 December 2011
NSAIDs th
Accepted : 15 June 2012
Quick Response Code
Pain, irrespective of the cause, is most Since NSAIDs find place in every
common reason for which patient seeks prescription , it is must to understand , in
dental treatment. Dentist must be able to addition to therapeutic benefits , the
diagnose the cause and have a strategy for safety of NSAIDs.
its management.
Successful management of pain includes NSAIDs
-accurate diagnose of the condition The anti-inflammatory, analgesic and
-and appropriate dental treatment. antipyretic drugs are a heterogenous In the body , PGs , TXs ( thromboxane)
group of compounds often chemically and LTs ( leukoterines ) are collectively
Appropriate dental treatment removes unrelated which non theless share certain called eicosanoids. Eicosanoids are most
the condition causing pain and usually therapeutic actions and side effects. They universally distributed autocoids in the
provides rapid resolution of the are frequently called NSAIDs. To body. Practically every cell and tissue is
symptoms. In addition to the above , understand the unwanted side effects , in capable of synthesizing one or more
supportive drug therapy is given as an addition to therapeutic effect as anti- types of PGs and LTs. There are no
adjunct to relieve patient from pain. Of inflammatory , it is important to preformed stores of PGs and LTs. They
many dental conditions like pulpitis , understand the process of inflammation. are synthesized locally at the rate
gingivitis/periodontitis , pericoronitis , governed by the release of arachidonic
periapical abscess , or post extraction etc. In brief, inflammation process involves a acid from membrane lipids in response to
, pain is usually caused by inflammation series of events that can be elicited by appropriate stimuli.
and infection. numerous stimuli ( e.g. infectious agents , Cyclooxygenase ( COX ) pathway
ischemia , antigen-antibody reaction , generates eicosanoids ( PGs , TXs ,and
In addition to antibiotics to cover the thermal or physical injury ). Each type of Prostacyline ) , while Lipooxyganase
infection , anti-inflammatory (steroidal stimuli provokes a characteristic pattern pathways generates open chain
or non-steroidal) are used widely to of response that represents a relatively compounds ( LTs ).
manage the pain. Non-steroidal provides minor variation. All tissues have cox , can form PGG2 ,
excellent relief due to their anti-
PGH2 which are unstable compounds.
inflammatory and analgesic effect. At microscopic level , response is usually
accompanied by familiar clinical signs of
Steroids can also be used for pain erythema , edema , tenderness , and pain. TX- thromboxane , PGI - Prostacycline ,
management but their use should be very HPETE - hydroperoxy eicosatetraenoic
selective and limited. Inflammatory response occurs in three acid , HETE - Hydroxy eicosatetraenoic
phases acid , SRS-A - Slow reacting substance of
NSAIDs are prescribed to every patient -acute transient phase anaphylaxis.
coming for dental treatment with pain -delayed sub-acute phase
and sometimes they are prescribed even , -chronic proliferative phase Cyclooxygenase ( COX )
when not required.
©Indian Journal of Dental Sciences. (September 2012 Issue:3, Vol.:4) All rights are reserved. 124

2. diffusion of H+ ions in the gastric mucosa.
Deficiency of PGs reduces mucus and
HCO3- secretion , tends to enhance acid
secretion and may promote mucosal
ischemia. Thus NSAIDs enhance
aggressive factors in the gastric mucosa
and are ulcerogenic.
Side effects may range from mild
dyspepsia and heart burn to ulceration
sometimes with fatal results.
These side effects are produced by all
NSAIDs to varying extents : relative
gastric toxicity is a major consideration
in the choice of NSAIDs.
On Renal Functions
Adverse effects on renal functions are
Biosynthesis of protaglandins (PG) and leukotrienes (LT) well recognised with the use of non
selective NSAIDs.
Cox is known to exist in two forms - pathological status.
Cox-1 and Cox -2 while both forms Role of PGs in Renal Functions
catalyse the same reactions. Side Effects Of NSAIDs - PGE2 and PGI2 increase water , Na+ and
A splice variant of Cox -1 ( designated as The principal basis for therapeutic action K+ excretion and have a diuretic effects
COX -3 ) has been found in dog brain. of NSAIDs is the inhibition of - PGE2 have been shown to have a
This iso-enzyme is inhibited by prostaglandin synthesis. Since different frusemide like inhibitory effect on Cl-
paracetamol but its role in human is not PGs , as described earlier , are implicated reabsorption as well.
known. in different physiological functions in the - they cause renal vasodilation and inhibit
body , their inhibition by the NSAIDs tubular reabsorption.
COX-1 is a constitutive enzyme in most will have some adverse effects. So in - PGE2 antagonises ADH action and this
cells. Its activity is not changed once the addition to sharing many therapeutic adds to diuretic effect .
cell is fully grown. activities , NSAIDs share several - TXA2 cause renal vasodilation.
COX -2 on the other hand , normally unwanted side effects as described
present in insignificant amounts , is PGI2 , PGE2 and PGD2 evoke release of
inducible by cytokines , growth factors , On Gastric Mucosa rennin.
and other stimuli during inflammatory Most common is the propensity to induce As a result , PGs appear to function as
process. gastric or intestinal ulceration. Highly intra-renal regulator of blood flow as well
It is believed that eicosanoids produced selective cox2 inhibitors lack the as tubular reabsorption in kidneys.
by cox-1 participate in physiological ( propensity to induce gastric or intestinal Rennin release in response to
house keeping ) functions such as gastric ulceration. Gastric damage is brought sympathetic stimulation and other
mucosa , hemostasis and maintenance of about by two mechanisms- influences may be facilitated by Pgs.
renal functions while those produced by Although local irritation by oral
cox-2 leads to inflammation and other administered drug allows back diffusion Effcts of NSAIDs due to inhibition of
pathological changes. of acid into gastric mucosa and induce synthesis of Pgs
However , certain sites in the kidney and t i s s u e d a m a g e , p a r e n t e r a l NSAIDs have little effects on renal
brain constitutively express cox-2 which administration can also cause damage function in normal condition but
may play physiological role. and bleeding. becomes significant in patients with CHF
, hypovolemia , hepatic cirrhosis, renal
Cyclic eicosanoids produce a wide In gastric mucosa , gastric prostaglandins disease and in patients receiving diuretics
variety of actions depending upon the (PGs ) especially PGI2 and PGE2 serve as or anti- hyrertensives.
particular PGs , species on which tested , cytoprotective agents. These eicosanoids
tissue , hormonal status and other factors. inhibits acid secretion by the stomach by Acute renal failure may be precipitated
PGs differ in their potency to produce a - under these circumstances because of
given action and different PGs -enhancing mucosal blood flow - COX-1 dependent impairment of renal
sometimes have opposite effects. Even - promotes secretion of cytoprotective blood flow and reduction of g.f.r. can
the same PG may have opposite effect mucus in the intestine worsen renal insufficiency.
under different circumstances. Since , - juxtaglomerular COX-2 dependant Na+
virtually all cells and tissues are capable Inhibition of synthesis of cox 1 and water retention.
of forming PGs , they have been mediated gastro protective PGs (PGE2 - ability to cause papillary necrosis on
implicated as mediators or modulators of and PGI2) renders the stomach more habitual intake.
a number of physiological processes and susceptible to damage by inducing back
©Indian Journal of Dental Sciences. (September 2012 Issue:3, Vol.:4) All rights are reserved. 125

3. FDA CATEGORY FOR DRUG USE IN PREGENCY
NSAIDs promotes salt and water CATEGORY Interpretation
retention by reducing the PGs induced A Adequate, well-controlled studies in pregnant women have not shown an increased risk of fetal abnormalities to the fetus in any trimester of pregnancy.
inhibition of both reabsorption of B Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate and well-controlled studies in pregnant women. OR
chloride and action of ADH. This may
Animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the
cause edema in some patients treated
with NSAIDs. Neuropathy is fetus in any trimester.
uncommonly associated with long term C Animal studies have shown an adverse effect and there are no adequate and well-controlled studies in pregnant women. OR No animal studies have
use of individual NSAIDs. been conducted and there are no adequate and well-controlled studies in pregnant women.
D Adequate well-controlled or observational studies in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy may
Impairment Of Platelet Functions outweigh the potential risk. For example, the drug may be acceptable if needed in a life-threatening situation or serious disease for which safer drugs
COX-1 generated TXA2 - is a potent cannot be used or are ineffective.
aggregating agent , and PGI2 - produced X Adequate well-controlled or observational studies in animals or pregnant women have demonstrated positive evidence of fetal abnormalities or risks.
by vascular endotheliumis is an anti-
The use of the product is contraindicated in women who are or may become pregnant.
aggregating prostanoids.
TXA2 produced by platelets and PGI2
produced by vascular endothelium
probably constitutes a mutually ANALGESIC USE IN PREGNANCY OR LACTATION
antagonistic system preventing Drugs FDA category for drug use in pregnancy May be used during pregnancy May Be Used While Breast Feeding
aggregation of platelets in circulation and Acetaminophen B Yes Yes
inducing aggregation on injury , when ASA C/Db Do not use in third trimester Caution
plugging and thrombosis are needed. Diclofenac C/D Do not use in third trimester Caution
NSAIDs inhibits the synthesis of both
Flurbiprofen B/D Do not use in third trimester Yes
TXA2 and PGI2 , but effects on platelets
Ibuprofen B/D Do not use in third trimester Yes
TXA2 (cox-1 generated aggregating
Ketorolac B/D Do not use in third trimester Yes
agent ) predominates.
This accounts for the ability of these Ketoprofen B/D Do not use in third trimester Yes
drugs to increase the bleeding time. Naproxen B/D Do not use in third trimester Yes
Aspirin particularly have irreversible Codeine C Low dose, short duration is acceptable Yes
effect on cox activity , effect lasting for Oxycodone B Low dose, short duration is acceptable Yes
more than three days and require new Hydromorphone B Low dose, short duration is acceptable Yes
platelet productions for the restoration of Mepridine B Low dose, short duration is acceptable caution
enzyme activity.
Pentazocine B Low dose, short duration is acceptable caution
This side effect has been exploited in the
prophylactic treatment of thromb
oembolic disorders.
Acute administration of 400-800mg of
selective cox-2 inhibitor (celecoxib) in
human beings has been found to suppress
PGI2 production by about 80% , without
inhibiting cox-1 generated TXA2
production and platelet aggregation.
This suggests that cox-2 is a major source
of PGI2 production in vivo. Since an
important action of PGI2 is thought to be
suppression of platelet activation ,
alteration of TXA2/PGI2 ratio that
accompanies selective inhibition of cox2
is theoretically prothrombotic. Clinical muscles.
relevance of this finding remains to be LTC4 and LTD4 are broncho constrictor in Other Side Effects
determined but can be considered when many species including humans. - Intolerance
choosing an NSAIDs for the treatment of Asthma may be induced due to imbalance Certain individuals display intolerance to
patients particularly prone to thrombotic between dilators PGs and constrictors aspirin and most NSAIDs. This is
events. Lts. In few individuals , aspirin like drugs manifest by symptoms that range from
including cox 1 inhibitors , consistently vasomotor rhinitis with profuse watery
On Broncheal Muscles induce asthma possibly by diverting secretion , angioneurotic edema ,
In general , PGFs and PGD2 contracts and arachidonic acid to produce excess LTs. generalized urticaria , and bronchial
PGE2 relax bronchial and tracheal This sensitivity is not shared by selective asthma to laryngeal edema and broncho
muscles. cox-2 inhibitors indicating that constriction , flushing , hypotension , and
PGE2 and PGI2 produce broncho-dilation. suppression of cox-1 at the pulmonary shock. These reactions are not limited to
TXA2 constricts human bronchial smooth site is responsible for the reaction. aspirin. An individual who exhibits
©Indian Journal of Dental Sciences. (September 2012 Issue:3, Vol.:4) All rights are reserved. 126

4. intolerance to aspirin will also react when If acetaminophen is insufficient , opioids themselves in producing different side
given any of other NSAIDs , despite their are considered acceptable during effects and there are large inter-
chemical diversity , thereby ruling out pregnancy provided they are given for a individual variation. No single drug is
immunological basis for this reaction. short duration . Chronic opioid use can superior to others for every patient.
Inhibition of COX with consequent result in fetal dependence, premature Choice of the drug is inescapably
diversion of arachidonic acid to LTs may delivery & growth retardation. As with empirical.
be involved , but there is no proof. pregnancy, acetaminophen is the
analgesic of choice in lactation. ASA and The cause and nature of pain (mild ,
-Prolongation of gestation by NSAIDs diclofenac may increase bleeding and moderate or severe ; acute or chronic ;
Synthesis of prostaglandins increases should be avoided if possible. Opioids ratio of pain ; inflammation) along with
dramatically in the hours before are considered safe in lactation. consideration of risk factors in the given
parturition. PGs are thus postulated to patient govern the selection of analgesic.
have a major role in the initiation and Choice Of NSAIDs Also to be considered are past experience
progression of labour and delivery. So , Vast majority of NSAIDs are organic of the patient, acceptability and
inhibition of synthesis of PGs can delay acids and act as reversible competitive individual preference. Patients differ in
and retard labour. However, labour can inhibitors of cyclooxygenase activity. their analgesic response to different
occur in the absence of Pgs. However , these drugs do not inhibit the NSAIDs. If one NSAIDs is
Accordingly some NSAIDs have been metabolism of arachidonate by unsatisfactory in a patient , it does not
used as tacolytic agents to inhibit pre lipooxygenase. In fact , inhibition of mean that other will also be
term labour. COX theoretically could lead to unsatisfactory. Some subjects feel better
increased formation of leukotrienes by on a particular drug , but not on a closely
-NSAIDs in pregnancy and lactation increasing the amount of arachidonate related ones. It is in this context that
The use of analgesics during pregnancy that is available to lipooxygenase. availability of such a wide range of
has been recently reviewed , and the NSAIDs may be welcomed.
findings are summarized in the Table 1. Cox 1 and Cox 2 differ in their sensitivity
to inhibition by certain anti-
Optimal management of dental pain inflammatory drugs. This observation References
during pregnancy is removal of the has led to the recent development of 1. GOODMAN & GILLMAN'S - The
source of pain using local anesthesia. If , clinically useful agents that selectively pharmacological basis of
however , post operative pain is present , inhibit Cox-2. These drugs show distinct Therapeutics-Tenth Edition
an analgesic may be necessary and therapeutic advantages over non 2. ROBBINS - Pathological basis of
s h o u l d b e m a d e a v a i l a b l e . selective NSAIDs agents , since COX- 2 Diseases -Sixth Edition
Acetaminophen is clearly the analgesic is predominant cyclooxygenase at the site 3. K.D TRIPATHI - Essentials of
of choice in all stages of pregnancy. The of inflammation but not at sites such as Medical Pharmacology - Sixth
use of NSAIDs , including ASA , is less gastrointestinal tract. Thus, cox2 edition
favourable , particularly late in inhibitors are anti-inflammatory but do 4. UPDENT April - June 2009 ; Vol : 8 ,
pregnancy. NSAIDs may predispose to not possess many of the adverse side Number 1
ineffective contractions during labour , effects of non selective cyclooxygenase
increased bleeding during delivery or inhibitors.
premature closure of ductus arteriosus of
the heart. NSAIDs are therefore NSAIDs have their spectrum of adverse
contraindicated in the third trimester . effects. They differ quantitatively among
Source of Support : Nill, Conflict of Interest : None declared
©Indian Journal of Dental Sciences. (September 2012 Issue:3, Vol.:4) All rights are reserved. 127