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Received: December 27^th 2013

Accepted: May 28^th 2014

Safety nonsteroidal antiinfl ammatory drugs

Teodoro Julio Oscanoa-Espinoza^a

^aSección de Farmacología, Facultad de Medicina, Universidad Nacional Mayor de San Marcos, Lima, Perú. Instituto de Investigaciones, Facultad de Medicina, Universidad San Martin de Porres, Lima, Perú

Comunicación con: Teodoro Julio Oscanoa-Espinoza

Telephone: (511) 324 2983 extension 44081Teléfono: (511) 324 2983 extensión 44081

Email: tjoscanoae@gmail.com; teodoro.oscanoa@essalud.gob.pe

The choice of a specific medication belonging to a drug class is under the criteria of efficacy, safety, cost and suitability. NSAIDs currently constitute one of the most consumed drug in the world, so it is very important review of the safety aspects of this drug class. This review has the objective of analyze the safety of NSAIDs on 3 main criteria: gastrolesivity, cardiotoxicity and nephrotoxicity.

Keywords: Nonsteroidal anti-inflammatory drugs; Cyclooxygenase inhibitors; Gastrointestinal damage; Renal insufficiency; Hypertension

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Nonsteroidal anti-inflammatory drugs (NSAIDs) are currently one of the most prescribed and consumed pharmacological groups in the world. The reasons for mass consumption range from the status of their sale without a prescription and their use in various pain syndromes, to the prevention of cardiovascular and cerebrovascular ischemic events. The trend of further increase in consumption is expected, as at the moment their indications are expanding to the prevention of colorectal cancer,¹ breast cancer,² and Alzheimer’s disease.³ Therefore, it is unavoidable to focus attention on the safety aspects of NSAIDs in order to make rational use of them and prevent any disease caused by this drug class.

History of NSAIDs

If the fascinating history of NSAIDs could be summarized and put on a timeline, undoubtedly some crucial moments would emerge: their birth based on herbal medicine, the discovery of acetylsalicylic acid, the discovery of ibuprofen, serious events of benaxoprofen, the climax (and fall) of coxibs, and the post-coxibs era.

3,500 years ago, Hippocrates prescribed the extract and leaves of willow bark to treat fever and inflammation. 1899 acetylsalicylic acid was commercially introduced, a more acceptable form and better flavor than the salicylic acid which in turn came from salicin, the active ingredient of the plant Salix alba.

In 1961, the English professor Stewart Adams discovered the anti-inflammatory properties of ibuprofen in guinea pigs. In 1976 the British scientist John Vane discovered that the mechanism of acetylsalicylic acid is inhibition of prostaglandin production by blocking the enzyme prostaglandin synthetase or cyclooxygenase (COX), the crucial discovery winning him the Nobel Prize for Medicine granted in 1982. The essential reason to group different drugs with different chemical structures under the name is because all NSAIDs inhibit the COX enzyme. The success of acetylsalicylic acid in the treatment of rheumatoid arthritis and osteoarthritis had two direct consequences on the development of NSAIDs: the appearance of new molecules, and the recognition of the COX enzyme as a therapeutic target in inflammatory diseases. 

The benaxoprofen is an NSAID with two curious records in the history of medicine safety, the first is that it had the shortest stay on the pharmaceutical market, only lasting about 3 months (May to August 1982) before being withdrawn for its association with liver toxicity and kidney failure, up to 72 deaths having been reported, the population most affected being the elderly. As a second record, it boasts the presentation of the most documents for a lawsuit, with about 1.2 million pages, only comparable to the claims during the trial of thalidomide with approximately 30,000 pages.⁴

Pharmacodynamics

In 1991 the existence of two isoforms of COX was demonstrated, which were called COX-1 and COX-2, each encoded by different genes, having similar chemical structures and 60% concordance in the amino acid sequence and singular expression patterns. The COX-1 isoform is expressed or produced in a constant form (constitutive, i.e., without any stimulus) in many tissues, whereas COX-2 is induced by inflammatory processes. COX-1 has an important physiological role, protecting the gastric mucosa, controlling renal blood flow, plus several roles in homeostasis, immune and pulmonary response, central nervous system, cardiovascular, and reproductive functions. COX-2, produced by inflammatory stimulation, in turn caused by various endogenous products such as cytokines, endotoxins, and growth factors, creates prostaglandins. Prostaglandins contribute to the development of edema, flushing, fever, and hyperalgesia. COX-2 is also expressed in normal vascular endothelial cells, which secrete prostacyclin in response to endothelial damage (shearing stress).⁵ Actually, all that described above, related to the physiology of COX-1 and COX-2, describes the conceptualization held on this topic for most of the 1990s or the twentieth century. 

In critical retrospective analysis, the discovery in 1992 of COX-2 was the origin of the hypothesis that says that PGE2 and PGI2 prostaglandins (with protective function of the gastric mucosa) were produced by the constitutive expression of COX -1, while the anti-inflammatory prostaglandins were produced by way of induction of COX-2 isoform. A more elaborate and currently discredited extrapolation of this hypothesis was launched in 1993 by Meade et al., who related these findings with a common adverse reaction of NSAIDs which is gastric damage, and warned for the future by insisting that:

"these results suggest that will be possible to design an NSAID with isoenzyme specificity, an isozyme-specific NSAID that can maintain the synthesis of cytoprotective prostaglandins in the stomach, reducing the formation of ulcers, while reducing the synthesis of proinflammatory prostaglandins...".⁶ Prophecy fulfilled, when in 1999 celecoxib and rofecoxib are launched (known as "coxibs"), both selective COX-2 inhibitors, with an impressive advertising strategy based on their lower gastric damage compared to other "classic" NSAIDs, and achieve dramatic success in sales, surpassing one billion dollars in the 15 months following its launch.⁷

A theoretical model prevalent at the time was written by Dr. Vane in 1998, stating: "NSAIDs get their anti-inflammatory activity by inhibiting COX 2, while their side effects such as gastric irritation, are due to COX-1 inhibition"^.8 That is to say, COX-1 was the "defender" of the gastric mucosa, while the prostaglandins induced by COX-2 caused inflammation and pain. The questionable metaphor of good and evil about gastric damage induced by NSAIDs had been built. 

COX-1 and COX-2 enzymes play an important role in cardiovascular homeostasis; the two work in opposition to each other but in perfect harmony, maintaining a physiological balance. On one hand, COX-1 activity is related to the synthesis of thromboxane A2 (TXA2), mainly in platelets; the effects of TXA2 are: platelet aggregation, vasoconstriction, and smooth muscle cell proliferation. On the other hand, COX-2 mediates prostacyclin synthesis in macrovascular endothelial cells, having opposing effects to its counterpart COX-1. Prostacyclin causes relaxation of vascular smooth muscle cells and causes vasodilation, it also has antiplatelet activity acting on IP platelet receptors. Selective inhibition of COX-2 could break this delicate balance in the physiology of hemostasis, the mechanisms involved in this phenomenon would be a relative decrease in prostacyclin production, while TXA2 production is unchanged. This imbalance tips the balance and promotes platelet aggregation, increasing the risk of thrombosis and vascular events.⁵

Starting in 2001, the heyday of the coxibs seemed to come to an end with the demonstration that these drugs could alter the natural balance between the prothrombotic activity of thromboxane A2 (TXA2) and the antithrombotic activity of prostacyclin (PGI2), triggering cardiovascular thrombotic events.⁹ Although it should be noted that already in 1998, Mitchel of the Critical Care Unit at the Royal Brompton Hospital in London, had postulated the likely cardiotoxicity of these drugs.¹⁰ In September 2004 rofecoxib is removed from the global pharmaceutical market. Subsequently, in 2005 the Food and Drug Administration of the United States (FDA) withdrew valdecoxib; on the other hand, celecoxib is still on the market but under a black box warning of adverse cardiovascular effects. In 2007 lumiracoxib follows the same fate, which was never approved by the FDA, and was withdrawn from several countries for its high liver toxicity. Currently it is thought that the cardiotoxicity of coxibs is an effect of the class.¹¹

Gastrointestinal safety of NSAIDs

 

Mechanism of NSAID gastropathy

The gastric mucosa has one of the most effective defensive systems of the body, able not only to resist damage, but also to repair it once it has occurred. Prostaglandins PGI2 and PGE2 play a very important role in this defense system, stimulating the secretion of mucus and bicarbonate, and maintaining blood flow to the mucosa. The pathophysiological basis for NSAID gastropathy is precisely inhibiting the synthesis of these prostaglandins, leading to less mucus and bicarbonate secretion, and reducing blood flow to the gastric mucosa. Additionally, NSAIDs induce an increase in the adhesion of leukocytes (mainly neutrophils) to the vascular endothelium of the gastrointestinal microcirculation, which has proven to be an early and critical event in the pathogenesis of gastric injury induced by these drugs.¹²

The foundation of coxibs was always that COX-2 did not have an essential role in the modulation of the defense mechanisms of the gastric mucosa, however, a surprising paradigm change, there is currently evidence that COX-2 not only forms a part of this system, but contributes significantly to the resolution of gastrointestinal injury.¹² The evidence for this statement is:

 

• Gastric lesion by NSAIDs is associated with inhibition of both COX-1 and COX-2, not of one of them separately: it has been demonstrated experimentally that mice with functional cancellation (Knockout) of the COX-1 gene do not spontaneously develop gastric lesions, despite the fact that prostaglandin synthesis is negligible, although they are susceptible to damage induced by an NSAID.¹³ Furthermore, the selective inhibition of COX-1 or COX-2 does not result in intestinal injury, but the suppression of both isoforms of COX does lead to damage of this organ.¹⁴ The current concept of gastric damage associated with NSAIDs is that prostaglandins derived from COX-1 and COX-2 contribute to the defense system of the gastric mucosa. NSAIDs would induce suppression of COX-1 causing reduced blood flow of the gastric mucosa, while suppression of COX-2 would increase leukocyte adherence to vascular endothelium, an early phenomenon of gastric injury induced by NSAID.¹⁵
• Impairment of "adaptive gastric cytoprotection effect" associated with selective COX-2 inhibition: in experimental animals, exposure to 20% ethanol before 70% significantly decreases gastric lesions, compared with the initial exposure of ethanol 70%; this phenomenon is called adaptive gastric cytoprotection.¹⁶ Pretreatment with selective COX-2 inhibitors inhibits this adaptive gastric response.¹⁷
• Role of COX-2 in gastric injury after ischemia-reperfusion: in experimental models of resistance to gastric injury by ischemia-reperfusion, pretreatment with selective COX-2 inhibitors worsens gastric injury.¹⁸ It has been postulated that the ability of COX-2 inhibitors to increase adhesion to vascular endothelium plays a pathophysiological role in this context.
• COX-2 modulates resistance to luminal irritants when other mediators of gastric mucosal defense are gone: when the synthesis of nitric oxide – an important component of gastric mucosa defense - is experimentally inhibited, administration of COX-2 results in gastric injury.¹⁹ Something similar occurs with the ablation of sensory afferent nerves of the gastric lumen,²⁰ but through altered regulation of blood flow in the gastric mucosa.
• COX-2 is involved in the healing process of the gastric ulcer: the expression of COX-2 is very low in the normal stomach, however, in the margins of an ulcer its expression is very strong, precisely where epithelial proliferation occurs to repair the damage. Therefore, it is not surprising that not only the "classic" NSAIDs but also the coxibs delay the healing of an ulcer by disrupting the angiogenic process.²¹ It has been observed in experiments that both celecoxib (coxib) and any conventional NSAID (flurbiprofen) alter the balance of pro- and anti-angiogenic factors in serum, promoting angiogenesis inhibition, therefore, both delay the healing process of an established ulcer.²² Furthermore, it has been found that the expression of COX-2 is elevated in ulcerated gastric mucosa in various stimuli, such as: Helicobacter pylori infection,²³ acetylsalicylic acid, and stress induced by cold.²⁴
• Beneficial role of COX-2 enzyme: currently there is sufficient evidence to make a list of beneficial effects of the COX-2 enzyme in the body, including: homeostasis in neuronal development and brain development, protection from myocardial infarction, endothelial protection (production of prostaglandin PGI2), protection against allergens, renal homeostasis (regulation of renal flow, renin synthesis), homeostasis of intestinal mucosa, bone formation, and others.²⁵

 

On the evidence listed above, the current hypothesis about NSAID-induced gastric damage, is that COX-2 does not play an important role in the defense of the gastric mucosa at rest, but with an injury it helps COX-1 safeguard the integrity of the gastric mucosa.²⁵ Therefore gastric damage induced by coxibs is not apparent in healthy gastric mucosa, it only becomes apparent when the defense of the mucosa is damaged. Proof of this is that the coxibs lose their apparent advantage over the "classic" NSAIDs in patients taking low-dose acetylsalicylic acid,²⁶ requiring further protection with proton pump inhibitor in patients at risk.

Comparison of gastric damage induced by different NSAIDs  

In 2010, Elvira Masso et al. of the Centro Español de Investigación Farmacoepidemiológica published a systematic study of the variability between different NSAIDs and the likely risk of upper gastrointestinal bleeding.²⁷ The study included 9 studies published on this topic between 2000 and 2008, 2 being cohort, 3 nested case-control studies, and 4 case-control studies. In addition, it was tested whether the degree of inhibition of COX-1 and COX-2 in whole blood in vitro, using circulation media concentrations, predicted value of risk of upper gastrointestinal bleeding for each NSAID. The main findings were: a) the "traditional" NSAIDs and coxibs increase the risk of gastric bleeding or perforation, although the magnitude is different (approximately 4 versus 2 times, respectively); b) the profound and coincident inhibition (> 80%) of both COX isoenzymes (COX-1 and COX-2) was associated with greater risk, and c) NSAIDs with long elimination half-life and sustained release formulations were associated with a higher risk than NSAIDs with short elimination half-life.

The first message of the Masso et al. study is that NSAIDs have a very uneven gastric safety profile, ketorolac and piroxicam being the most gastrically harmful (Figure 1); with respect to ketorolac, it is recommended in acute pain conditions and for a very short time, and as for the second, since 2007 the EMEA (European Medicines Agency) has issued an alert emphasizing its gastric damage²⁸ and restricting its use. Ibuprofen still has the better safety profile (regarding patients with gastrointestinal risk), because celecoxib is the only one that surpasses it, its choice is subject to the cardiovascular risk of the patient. The second message of this research is that there are no traditional or new NSAIDs (read: coxibs), the group is still simply called NSAIDs, in which the gastrointestinal safety profile is not determined to be selective or non-selective for COX-2, unless it is that it significantly inhibits both isozymes (COX-1 and COX-2) simultaneously. It is important to note that the conclusions of the study in discussion, are practically an exact clinical translation of what was already known experimentally since 1999.¹⁸

Cardiovascular safety of NSAIDs

In 2011, Dr. Sven Trelle et al. of the Institute of Social and Preventive Medicine of the University of Bern in Switzerland, published a meta-analytic study online on the cardiovascular safety of NSAIDs.²⁹ 31 clinical trials published up until 2009 were included, with 116,429 patients and with more than 115,000 patient-years of follow-up. Participants were randomized to naproxen, ibuprofen, diclofenac, celecoxib, etoricoxib, rofecoxib, lumiracoxib, or placebo.²⁹ The most important findings were: a) there is significant variation in the cardiovascular safety among different NSAIDs tested; b) the NSAID with the lowest cardiovascular risk is naproxen; c) NSAIDs exceeding 30% risk in several cardiovascular outcomes are: ibuprofen, diclofenac, etoricoxib and lumiracoxib; d) it cannot be proven that vascular risk is restricted only to coxibs, and e) it is possible to accept a risk of 1.3 to use an NSAID29,³⁰ (Figures 2, 3 and 4).

McGettigan et al.³¹ of the Hull York Medical School in the UK, published a systematic review on the cardiovascular risk of NSAIDs at usual doses in the community; 30 case-control studies were included, 184,946 cardiovascular events, 21 cohort studies, and descriptions of results of more than 2.7 million individuals exposed. The greatest cardiovascular risk was with etoricoxib 2.05 (odds ratio) (confidence interval: 1.45-2.88), etodolac 1.55 (1.28-1.87), rofecoxib 1.45 (95% confidence interval 1.33, 1.59), followed by diclofenac 1.40 (1.27, 1.55); the NSAIDs with the lowest risk were: ibuprofen 1.18 (1.11- 1.25) and naproxen 1.09 (1.02, 1.16). 

It is interesting to note that even with these results on the cardiovascular safety of NSAIDs, until 2013 the essential drug lists of 74 high-, middle- and low-income countries still listed diclofenac, while naproxen (the safest NSAID from the cardiovascular standpoint) is only on 27 of these lists in the countries investigated.³²

Mechanism of NSAID-induced cardiotoxicity

Research on the cardiotoxicity of NSAIDs warns that cardiovascular risk is associated with all NSAIDs studied, although with significant differences. These findings should encourage further research on the pathophysiological basis of the relationship between cardiovascular events and NSAIDs. The hypothesis that an imbalance between prostacyclin and thromboxane A2 increases the risk of thrombotic events should be added others. A differential effect of each NSAID has been postulated for the synthesis of thromboxane A2 and prostacyclin, nitric oxide production and endothelial function, blood pressure, water retention, and other kidney effects.²⁹ It is possible that the pharmacokinetics of NSAID is involved as well, as with drugs with a long half-life (such as rofecoxib) that interfere most with the COX-2 system, which could explain their adverse cardiovascular events.

Renal safety of NSAIDs

Dr. Jingjing Zhang et al. of Harvard Medical School in the United States conducted a meta-analytic study on renal and cardiovascular safety of coxibs, which included 114 clinical trials involving 116,094 participants with a total of 127 populations tested. The coxibs evaluated were rofecoxib, celecoxib, valdecoxib/parecoxib, etoricoxib, and lumiracoxib. A total of 6394 adverse events were observed (2760 cases of peripheral edema, 3489 of hypertension, 235 of renal dysfunction) and 286 episodes of arrhythmia.³³ The main findings of this study were: a) the heterogeneity of renal effects of coxibs evaluated suggests that these effects are not of the class, and b) rofecoxib was associated with an increased risk of peripheral edema, hypertension, and renal failure (Figure 5). 

In a study on the risk of acute renal failure associated with the use of NSAIDs in the general population, a database in the United Kingdom was used with 386,916 patients with ages between 50 and 84 years, and a relative risk was found of 3.2 (95% confidence interval 1.8-5.8). The relative risk of various NSAIDs was: meloxicam (8.05, 95% CI 1.98-32.81); diclofenac (3.2, 95% CI 1.38-7.05); naproxen (2.98, 95% CI 0.62-14.21), and ibuprofen (2.64, 95% CI 1.01-6.88). The incidence of acute renal failure found in this study was 1.1 cases per 100,000 person years.³⁴

Another Canadian study with a database of 121,722 NSAID users and people over 65 years of age, found association with acute renal failure within the first 30 days of use, with relative risk of 2.05 (95% CI 1.61, 2.60); disaggregating rofecoxib had 2.31 (95% CI: 1.73, 3.08); naproxen 2.42 (95% CI: 1.52-3.85), and other NSAIDs (diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, mefenamic acid, nabumetone, phenylbutazone, piroxicam, salsalate, sulindac, tenoxicam, tiaprofenic acid, and tolmetin) 2.30 (95% CI: 1.60, 3.32) and celecoxib 1.54 (95% CI: 1.14, 2.09).³⁵

For reference, before the era of mass consumption of coxibs, in a study published in 2000, the NSAIDs most frequently associated (relative risk) with acute renal failure requiring hospitalization were: indomethacin (2.40 95% CI 1.44-4.00 ), piroxicam (1.95 95% CI 1.23-2.93), fenoprofen (1.75 95% CI 1.05-2.92), ibuprofen (1.63, 95% CI 1.23-2.08), ketoprofen (1.55, 95% CI 0.54-4.4), diclofenac (1.47 IC 95% 0.49-4.39), sulindac (1.40 95% CI 0.74-2.66), and naproxen (1.03, 95% CI 0.68-1.56)³⁶ ( Figure 6).

Mechanism of NSAID-induced nephrotoxicity

COX-1 plays a key role in renal physiology through several prostaglandins (prostacicllina, PGE2, and PGD2) which dilate the renal vasculature, decrease renal vascular resistance, and increase renal perfusion. This results in renal blood flow redistribution from the renal cortex to the nephrons in the intramedullary region. It can be deduced that inhibition of COX-1 could decrease total renal perfusion and redistribute renal flow to the cortex, a process leading to acute renal vasoconstriction, spinal ischemia, and in some cases acute renal failure.⁵

NSAIDS inhibit COX-1 and COX-2 enzymes, and renal disorders vary with the selectivity of these two enzymes, as well as the dose and time of administration. NSAID nephrotoxicity is rare in healthy people, but elderly patients and those with comorbidities (e.g., heart failure, liver cirrhosis, and chronic kidney disease) and drug interaction (such as convertase enzyme inhibitors, diuretics) may develop acute renal failure.

The principal adverse reactions of NSAIDs in the renal system are: acute renal failure due to renal hemodynamic changes, acute tubular necrosis, interstitial nephritis or papillary necrosis, and electrolyte disorders (hyponatremia and hyperkalemia), hypertension, and edema.

The coxibs are not exempt from adverse renal reactions. The conceptualization of COX-2 as an "inducible" enzyme, as is now known, is not real when it comes to kidney tissue; at this level it is a constitutive enzyme (continuous production) that is expressed at the level of the cortex, macula densa, thick ascending limb of the loop of Henle, medullary interstitial cells, renal papilla, and podocytes. The expression of COX-2 increases in renal ischemia, a NaCl depleted state; therefore prostanoids derived from COX-2 play an important role in maintaining the blood supply to the bone, salt excretion, and blood pressure. Yet another mechanism is that COX-2 mediates release of renin in the kidney. Inhibition of COX-2 may lead to renal ischemia, electrolyte disturbance, and elevated blood pressure, leading to fluid retention and decreased glomerular filtration rate. However, it should be clarified that NSAID nephrotoxicity apparently is not a class effect of coxibs.³⁴

In conclusion, the safety of the currently available NSAIDs, analyzed under criteria of gastric damage, cardiotoxicity, and nephrotoxicity, ostensibly differ. However, it can be said generally that the safest NSAID are still ibuprofen and naproxen, associated or not with proton-pump inhibitor or H2 antagonists if there is increased risk of gastric damage; considering the alternative of using coxibs in patients with a history of peptic ulcer disease and without cardiac comorbidity.

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