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1. Indian Journal of Dental Sciences. www.ijds.inSeptember 2012 Issue:3, Vol.:4All rights are reserved Review Article Indian Journal of Dental Sciences E ISSN NO. 2231-2293 P ISSN NO. 0976-4003 1 Kavita MittalNSAIDs - HOW SAFE ARE THEY 2 Sudhir Mittal 3 Anil Sharma 1 Prof & Head, Dept Of PedodonticsAbstract Desh Bhagat Dental College & Hospital, MuktsarThis article analyses the drugs used to treat the symptoms and signs of inflammation. Most currently 2 Prof & Head, Dept Of Pedodonticsavailable 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 Orthodonticssynthesis of prostaglandins and thromboxane. The inhibition of cox-2 is thought to mediate , at least College Of Dental Sciences, Bhavnagar, Gujratin 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 Mittalresult from decreased prostaglandin formation. The potential therapeutic advantage of selective Prof & Headcox-2 inhibitors is discussed. Dept Of Pedodontics Desh Bhagat Dental College & Hospital, Muktsar Email - email@example.comKey Words thNSAIDs- mechanism of action, selective cox-2 inhibitors, side effects of cox-1 inhibition, choice of Submission : 04 December 2011NSAIDs th Accepted : 15 June 2012 Quick Response CodePain, irrespective of the cause, is most Since NSAIDs find place in everycommon reason for which patient seeks prescription , it is must to understand , indental treatment. Dentist must be able to addition to therapeutic benefits , thediagnose 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 collectivelyAppropriate dental treatment removes unrelated which non theless share certain called eicosanoids. Eicosanoids are mostthe condition causing pain and usually therapeutic actions and side effects. They universally distributed autocoids in theprovides rapid resolution of the are frequently called NSAIDs. To body. Practically every cell and tissue issymptoms. In addition to the above , understand the unwanted side effects , in capable of synthesizing one or moresupportive drug therapy is given as an addition to therapeutic effect as anti- types of PGs and LTs. There are noadjunct to relieve patient from pain. Of inflammatory , it is important to preformed stores of PGs and LTs. Theymany dental conditions like pulpitis , understand the process of inflammation. are synthesized locally at the rategingivitis/periodontitis , pericoronitis , governed by the release of arachidonicperiapical 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 ,andIn addition to antibiotics to cover the thermal or physical injury ). Each type of Prostacyline ) , while Lipooxyganaseinfection , anti-inflammatory (steroidal stimuli provokes a characteristic pattern pathways generates open chainor 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 ofSteroids can also be used for pain erythema , edema , tenderness , and pain. TX- thromboxane , PGI - Prostacycline ,management but their use should be very HPETE - hydroperoxy eicosatetraenoicselective and limited. Inflammatory response occurs in three acid , HETE - Hydroxy eicosatetraenoic phases acid , SRS-A - Slow reacting substance ofNSAIDs are prescribed to every patient -acute transient phase anaphylaxis.coming for dental treatment with pain -delayed sub-acute phaseand 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
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 Functionscatalyse the same reactions. Side Effects Of NSAIDs - PGE2 and PGI2 increase water , Na+ andA splice variant of Cox -1 ( designated as The principal basis for therapeutic action K+ excretion and have a diuretic effectsCOX -3 ) has been found in dog brain. of NSAIDs is the inhibition of - PGE2 have been shown to have aThis 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 thiscells. 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 describedpresent in insignificant amounts , is PGI2 , PGE2 and PGD2 evoke release ofinducible 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 asprocess. gastric or intestinal ulceration. Highly intra-renal regulator of blood flow as wellIt 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 tohouse keeping ) functions such as gastric ulceration. Gastric damage is brought sympathetic stimulation and othermucosa , hemostasis and maintenance of about by two mechanisms- influences may be facilitated by Pgs.renal functions while those produced by Although local irritation by oralcox-2 leads to inflammation and other administered drug allows back diffusion Effcts of NSAIDs due to inhibition ofpathological changes. of acid into gastric mucosa and induce synthesis of PgsHowever , 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 renalbrain constitutively express cox-2 which administration can also cause damage function in normal condition butmay play physiological role. and bleeding. becomes significant in patients with CHF , hypovolemia , hepatic cirrhosis, renalCyclic eicosanoids produce a wide In gastric mucosa , gastric prostaglandins disease and in patients receiving diureticsvariety of actions depending upon the (PGs ) especially PGI2 and PGE2 serve as or anti- hyrertensives.particular PGs , species on which tested , cytoprotective agents. These eicosanoidstissue , hormonal status and other factors. inhibits acid secretion by the stomach by Acute renal failure may be precipitatedPGs differ in their potency to produce a - under these circumstances because ofgiven action and different PGs -enhancing mucosal blood flow - COX-1 dependent impairment of renalsometimes have opposite effects. Even - promotes secretion of cytoprotective blood flow and reduction of g.f.r. canthe 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 onimplicated 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
FDA CATEGORY FOR DRUG USE IN PREGENCYNSAIDs promotes salt and water CATEGORY Interpretationretention 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. ORchloride 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 thecause edema in some patients treatedwith 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 haveuse 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 mayImpairment 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 drugsCOX-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 PGI2produced by vascular endotheliumprobably constitutes a mutually ANALGESIC USE IN PREGNANCY OR LACTATIONantagonistic system preventing Drugs FDA category for drug use in pregnancy May be used during pregnancy May Be Used While Breast Feedingaggregation of platelets in circulation and Acetaminophen B Yes Yesinducing aggregation on injury , when ASA C/Db Do not use in third trimester Cautionplugging and thrombosis are needed. Diclofenac C/D Do not use in third trimester CautionNSAIDs inhibits the synthesis of both Flurbiprofen B/D Do not use in third trimester YesTXA2 and PGI2 , but effects on platelets Ibuprofen B/D Do not use in third trimester YesTXA2 (cox-1 generated aggregating Ketorolac B/D Do not use in third trimester Yesagent ) predominates.This accounts for the ability of these Ketoprofen B/D Do not use in third trimester Yesdrugs to increase the bleeding time. Naproxen B/D Do not use in third trimester YesAspirin particularly have irreversible Codeine C Low dose, short duration is acceptable Yeseffect on cox activity , effect lasting for Oxycodone B Low dose, short duration is acceptable Yesmore than three days and require new Hydromorphone B Low dose, short duration is acceptable Yesplatelet productions for the restoration of Mepridine B Low dose, short duration is acceptable cautionenzyme activity. Pentazocine B Low dose, short duration is acceptable cautionThis side effect has been exploited in theprophylactic treatment of thromboembolic disorders.Acute administration of 400-800mg ofselective cox-2 inhibitor (celecoxib) inhuman beings has been found to suppressPGI2 production by about 80% , withoutinhibiting cox-1 generated TXA2production and platelet aggregation.This suggests that cox-2 is a major sourceof PGI2 production in vivo. Since animportant action of PGI2 is thought to besuppression of platelet activation ,alteration of TXA2/PGI2 ratio thataccompanies selective inhibition of cox2is theoretically prothrombotic. Clinical muscles.relevance of this finding remains to be LTC4 and LTD4 are broncho constrictor in Other Side Effectsdetermined but can be considered when many species including humans. - Intolerancechoosing an NSAIDs for the treatment of Asthma may be induced due to imbalance Certain individuals display intolerance topatients particularly prone to thrombotic between dilators PGs and constrictors aspirin and most NSAIDs. This isevents. Lts. In few individuals , aspirin like drugs manifest by symptoms that range from including cox 1 inhibitors , consistently vasomotor rhinitis with profuse wateryOn 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 bronchialPGE2 relax bronchial and tracheal This sensitivity is not shared by selective asthma to laryngeal edema and bronchomuscles. cox-2 inhibitors indicating that constriction , flushing , hypotension , andPGE2 and PGI2 produce broncho-dilation. suppression of cox-1 at the pulmonary shock. These reactions are not limited toTXA2 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
intolerance to aspirin will also react when If acetaminophen is insufficient , opioids themselves in producing different sidegiven 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 isimmunological 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 inescapablydiversion 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 withdramatically in the hours before are considered safe in lactation. consideration of risk factors in the givenparturition. 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 experienceprogression of labour and delivery. So , Vast majority of NSAIDs are organic of the patient, acceptability andinhibition of synthesis of PGs can delay acids and act as reversible competitive individual preference. Patients differ inand retard labour. However, labour can inhibitors of cyclooxygenase activity. their analgesic response to differentoccur in the absence of Pgs. However , these drugs do not inhibit the NSAIDs. If one NSAIDs isAccordingly some NSAIDs have been metabolism of arachidonate by unsatisfactory in a patient , it does notused as tacolytic agents to inhibit pre lipooxygenase. In fact , inhibition of mean that other will also beterm 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 thatThe use of analgesics during pregnancy that is available to lipooxygenase. availability of such a wide range ofhas 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 Referencesduring pregnancy is removal of the has led to the recent development of 1. GOODMAN & GILLMANS - Thesource of pain using local anesthesia. If , clinically useful agents that selectively pharmacological basis ofhowever , post operative pain is present , inhibit Cox-2. These drugs show distinct Therapeutics-Tenth Editionan analgesic may be necessary and therapeutic advantages over non 2. ROBBINS - Pathological basis ofs 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 EditionAcetaminophen is clearly the analgesic is predominant cyclooxygenase at the site 3. K.D TRIPATHI - Essentials ofof choice in all stages of pregnancy. The of inflammation but not at sites such as Medical Pharmacology - Sixthuse of NSAIDs , including ASA , is less gastrointestinal tract. Thus, cox2 editionfavourable , 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 1ineffective contractions during labour , effects of non selective cyclooxygenaseincreased bleeding during delivery or inhibitors.premature closure of ductus arteriosus ofthe heart. NSAIDs are therefore NSAIDs have their spectrum of adversecontraindicated 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