ETIOPATHOGENICAL ASPECTS OF NONSTEROIDAL ANTI- INFLAMMATORY DRUGS IN ELDERLY Mihaela Bursova¹, Gabriela Lilios², Maria Suta³, Gh.

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1 ETIOPATHOGENICAL ASPECTS OF NONSTEROIDAL ANTI- INFLAMMATORY DRUGS IN ELDERLY Mihaela Bursova¹, Gabriela Lilios², Maria Suta³, Gh. Taralunga² 1.CLINICAL EMERGENCY COUNTY HOSPITAL CONSTANŢA, GERIATRICS DEPARTAMENT 2. FACULTY OF PHARMACY, OVIDIUS UNIVERSITY, CONSTANŢA 3. FACULTY OF MEDECINE, OVIDIUS UNIVERSITY, CONSTANŢA Summary Nonsteroidal anti-inflammatory (NSAIDs) induced gastritis still represent one of the most frequent medical problems, especially in elderly patients, due to its increased prevalence and also due to its increased morbidity and mortality. Although gastritis are often associated with NSAIDs, evidences about predicting factors of their development in patients taking NSAIDs are poor. In addition, the ulcerogenic potentials of the newer NSAIDs are still compared with those of more established preparations (conventional NSAIDs). The aim of this study was to identify the relationship between the type of NSAIDs and their potential to produce gastric complications and also between NSAIDs and HP infection. Altogether 172 long term NSAIDs users, aged 65 years or over, were studied. The presence of abdominal complaints, previous history of ulcers, endoscopic and histological features and Helicobacter Pylori status were all assessed. NSAIDs were classified into conventional drugs(group 1) and newer agents(group 2). Group 1 included indomethacin, diclofenac,ketoprofen, piroxicam. Group 2 included meloxicam, celecoxib, etoricoxib. As in other recent clinical trials, at risk patients in our study ( 65 of age, concurrently taking low-dose aspirin ) taking conventional NSAIDs had a higher incidence of gastric complications (bleedings) than those taking selective COX-2 inhibitors. The HP infection status was very important to asses, but it was possible only for 120 patients. To these patients the result were 68 HP positive and 52 HP negative. HP infection and NSAIDs are independent risk factors for chronic gastritis and no difference in terms of gastric complications was observed between these two groups. (NSAIDs users HP positive and NSAIDs users HP negative) Key words: gastritis, NSAIDs, elderly, endoscopy, helicobacter pylori. Introduction NSAIDs are extensively used pharmaceuticals agents they are well known and widely used for their antiinflammatory, analgetic and antipyretic properties. Incidence of gastrointestinal side effects of NSAIDs is relatively high and common, being an important cause of death (over 2000 person in Great Britain and possibly in USA, especially in elderly) Over the years several attemps have been made to predict the complications of gastritis (ulcerations, bleedings, perforations). Despite the increase frequency of gastritis in patients taking 202 abursova@yahoo.com nonsteroidal anti-inflammatory drugs (NSAIDs) very little is known about the risk factors for their development. Some aspect are not clear because: 1. NSAIDs-induced gastritis can be completely asymptomatic. 2. Various NSAIDs may differ or not in their potential to produce gastritis. 3. The precise contribution of HP infection to NSAIDs-related gastritis is not fully defined. 4. The specificity of some serological tests for HP may be low in chronic NSAIDs users, especially in elderly (Taha, 1994).

2 These study aimed therefore, to assess if the type of NSAIDs or the H. Pylori status are important in order to influence the clinical and endoscopical aspects of NSAIDs gastritis in elderly. Gastroduodenal mucosa possesses an array of defensive mechanisms and nonsteroidal anti-inflammatory drugs (NSAIDs) have a deleterious effect on most of them. NSAIDs appear to cause gastro-duodenal damage, by two main mechanisms: a physiochemical disruption of the gastric mucosal barrier and a systemic inhibition of gastric mucosal protection, through inhibition of cyclo-oxygenase activity of gastro-intestinal (GI) mucosa. A reduced synthesis and secretion of mucus and bicarbonate, an impairment of mucosal blood flow and an increase of acid secretion represent the main consequences of NSAID-induced prostaglandin (PG) deficiency. Additional mechanisms which may add to the damage have been demonstrated. These include uncoupling of oxidative phosphorylation, reduced mucosal cell proliferation and DNA synthesis as well as neutrophil activation. After administration of NSAIDs, neutrophil adherence to the vascular endothelium occurs, with consequent reduced mucosal perfusion and release of tissue-damaging mediators (Scarpignato, 1995). Material and methods This study was performed on 172 patients (136 F /36 M, aged 65 years) admitted in Gastroenterology Department of Constanta Emergency Clinical Hospital between Octomber 2006 Octomber In this period 306 elderly patients with gastritis were identified, but only those 172 with NSAIDs induced gastritis were further studied (56.2%). All the pacients were considered long- term users of NSAIDs (they had taken drugs at least 4 weeks in the last 3 months). Patients were excluded if they were <65 years old, if they had had gastric surgery or if they had taken anti-ulcer drugs or antibiotics within a week of endoscopy. All of them 203 underwent upper digestive endoscopy for various gastric complaints. Biopsies were taken from the antrum for H. Pylori testing (by histology -two specimens and also by a Rapide Urease Test- RUT) and from lesions if present. The RUT, in which presence of bacterial urease in the biopsy sample causes a color change on a special medium, is the diagnostic method of choice on tissue samples. Histologic staining of biopsy samples was done for those pacients with negative RUT results, but suspicious clinical findings. Biopsy specimens were stained with hematoxyline-eosine and with modified Giemsa for H. Pylori and RUT was performed with CLO test. RUT and histologic staining each have a sensitivity and specificity of 90%. The endoscopic examination was usefull also to describe the lesions NSAIDsinduced (size, number, site and type: edema, eritema, erosions, ulcerations, hemorrhaging lesions). Blood was taken to measure the haemoglobin concentration, erythrocyte sedimentation rate (ESR) and C reactive protein (CRP). Gastritis was classified according to the Sydney Sistem. The following characteristics were assessed : 1. Upper abdominal symptoms; 2. Presence of comorbidities (cardio vascular diseases, diabetes, CRF, cerebral strokes, COPD, osteoporosis, malignances) 3. Previous history of ulcers ; 4. Helicobacter Pylori status. NSAIDs were divided into two groups: group 1 (conventional or older agents) including indomethacin, dyclofenac, ketoprofen, piroxicam and group 2 (newer agents ) including lornoxicam, meloxicam, celecoxib, etoricoxib. The potential of most of the newer preparations to produce gastritis had been assessed previously in short term trials only.

3 In a recent clinical trial, at-risk patients (>65 years of age and/or a history of ulcers) taking conventional NSAIDs or selective COX-2 inhibitors were studied over a 6-mo period; 17.1 and 16.5%, respectively, developed clinically significant ulcers. As well as documenting the high susceptibility of this group of patients to the ulcerogenic effects of NSAIDs, this study confirmed previous reports that selective COX-2 inhibitors offered little, if any, benefit in high- risk patients (Laine, 2006). NSAIDs induce injury/bleeding via three key pathways: inhibition of cyclooxygenase (COX)-1 activity, inhibition of COX-2 activity, and direct cytotoxic effects on the epithelium. Effects produced via only one of these pathways (e.g., selective inhibition of COX-1 or of COX-2) are unlikely to produce significant damage (Wallace, 2008). Gastroduodenal bicarbonate secretion is mediated by prostaglandin E receptors and stimulated by the prostone lubiprostone. Toll-like receptor (TLR)4 signaling is protective against gastric injury. Intestinal alkaline phosphatase (IAP) is a chemosensor that regulates the duodenal mucosal surface ph. ischemia/reperfusion-related gastric mucosal damage. Heat shock protein 70 (HSP70) protects the gastric mucosa through inhibition of apoptosis, proinflammatory cytokines, and cell adhesion molecules (CAMs). HSP90 may be a contributing factor in impaired adaptive cytoprotection. Proteinaseactivated receptor-1 (PAR-1) is protective against Helicobacter-induced gastritis, mediated by the suppression of proinflammatory pathways. IKK β/nf-κb signaling decreases chronic Helicobacterinduced inflammation by inhibiting cellular apoptosis and necrosis. Activation of A2A adenosine receptors decreases inflammation and gastritis but leads to persistent Helicobacter pylori infection (defoneska, 2010). Results and discussions Statistical analyses included the χ² test, logistic regression, and the 95% confidence intervals for the estimated relative risk (odds ratio ) where appropriate. A total of 172 patients were studied. Their demographic characteristics are show in table 1. Lot Demographic characteristic Gender F= 136 (79,1%); M= 36 (20,9%) y= 76 (44,2%) Age y = 76 (44,2%) >85 y = 20 (11,6%) Urban = 122 (70,9%) Mediu Rural = 50 (29,1%) Lipopolysaccharide (LPS) increases gastric permeability; IAP secreted during fat digestion may detoxify colonic LPS. NADPH oxidase activity mediates 204 Table 1. Demographic characteristics The clinical symptoms were uncomplicated (epigastric pain, pirosis, nausea and vomiting, bloating )-93 % or complicated (bleeding)- 7%. (table 2) Lot Clinical symptoms Epigastric pain 100 (58,1%) Pirosis 27 (15,7%) Nausea and vomiting 25 (14,5%) Bloating 8 (4,7%) Upper digestive 12 (7%) hemorrhage Table 2. Clinical symptoms

4 All the patients were considered chronic NSAIDs. 124 patients took group 1 NSAIDs and 38 patients group 2 NSAIDs. In group 1 there were 16 patients taking association of two conventional NSAIDs (table 3). All the patients in group two took only one newer NSAIDs. Group 1 NSAIDs n=124 (72%) Indomethacin: 8 Diclofenac: 42 Ketroprofen: 46 Piroxicam: 12 Diclofenac+Ketoprofen: 6 Indomethacin+Ketoprofen:5 Diclofenac+Piroxicam:5 Table 3.Classification of NSAIDs. Group 2 NSAIDs n=38 (28%) Movalis:10 Etoricoxib: 18 Celecoxib: 20 Because of the practical possibilities the tests for H. Pylori infection were performed only to 120 patients. In this group 68 patients were HP positive (49 of 68 women, 72% and 19 of 68 men, 28%) and 52 patients were HP negative (48 of 52 women,92% and 4 of 52 men, 8%). According with the age, the distribution of patients with H. Pylori infection is presented in table 4. Due to their comorbidities (coronary disease, CHF) many of the patients (128 of 172, 74%) obligatory took aspirin in low prophylactic doses. Low dose-aspirin increases the risk of upper GI bleeding by approximately 2- fold. When NSAIDs are added to low-dose aspirin, the risk of bleeding increases approximately 2- to 4-fold as compared with low-dose aspirin alone (Laine, 2006). 99 patients associated aspirin with group 1 NSAIDs (99 of 124, 80%) and presented the following clinical symptoms: o Epigastric pain: (63 of 99, 63%) o Pirosis ( 13 of 99, 13%) o Nausea and vomiting (10 of 99, 10%) o Bloating (2 of 99, 2%) o Upper digestive hemorrhage (11 of 99, 11%). 29 patients associated aspirin with group 2 NSAIDs (29 of 48, 60%) and presented the following clinical symptoms: o Epigastric pain (18 of 29, 62%) o Pirosis (7 of 29, 24%) o Nausea and vomiting 3 of 29, 10%) o Upper digestive hemorrhage (1 of 29, 3%) Besides personal risk factors, the type and the dose of NSAIDs, duration of exposure to the drug and concomitant use of other drugs play an important role on NSAIDrelated GI side effects. AGE HP PATIENTS Table 4. Correlation of HP infection with age. Epidemiologic studies in elderly people have shown that the prevalence of HP infection increases with age, but tends to decrease after 85 years (Salles,2007 ) The same trend of prevalence curve was also meet in our study. 205 Conclusions Any patient taking NSAIDs has a significantly increased risk of developing GI complications. However, several risk factors lead to a significantly greater increased risk and, when present, should lead to a strong consideration of preventive strategies designed to decrease NSAID GI effects. The 5 risk factors that are most well documented and consistent across studies are: age >65; therapy with oral anticoagulants; corticosteroids and/or aspirin;

5 high-dose/multiple NSAIDs; history of peptic ulcer. Other factors have also been reported to be associated with increases in risk in some studies but not others. These include severity of osteoarthritis, comorbidities such as cardiovascular disease, and psychologic stress. The gastric effects of NSAIDs vary according to their acute or chronic use. Although some epidemiologic studies have suggested that the risk of NSAIDassociated GI events is highest in the first month and decreases markedly with longer use, 30 prospective randomized trials suggest that the rate of GI events remains relatively constant over time, indicating a continued risk and higher cumulative incidence with increasing duration of use (Soylu, 2008). NSAIDs induce clinically significant ulceration, bleeding, and/or obstruction in 1 4% of patients chronically taking these drugs. Even higher rates of ulceration are seen in patients with a history of peptic ulceration; in patients concurrently taking anticoagulants, low-dose aspirin, or glucocorticoids and in the elderly. Concluding all the above all the patients in our study were at high risk, because all of them were aged 65 and over (11.6% over 85 years old) and also were long-term users of NSAIDs. Almost all of the patients had comedication, because of their comorbidities (cardiovascular diseases, osteoporosis, COPD ). In our study the incidence of bleedings was greater, 6.97% (12 of 72) than in other studies (1-4%) and all of them were present in patients taking low-dose aspirin. Due to the many psychotraumatic events elderly patients at high risk to develop psychologic stress and thus, gastritis. Important advances have been made over the past two decades in order to understand the etiopathogenical mechanisms of NSAIDs-induced gastritis. While still not fully understood, the identification of key events in the development of gastritis after NSAID administration has provided many clues as to how to design new anti-inflammatory drugs with greater margins of safety. (phosphatidylcholine-conjugated NSAIDs, terminal prostaglandin synthase inhibitors, gaseous mediatorreleasing NSAIDs) References defoneska A, Kaunitz JD, Gastroduodenal defense. I. Curr Opin Gastroenterol., 26(6):604-10,2010 Laine L, GI risk and risk factors of NSAIDs. J cardiovasc Pharmacol., 47(1):60-66,2006 Salles N.,Mégraud F., Current management of Helicobacter pylori infections in the elderly. Expert Rev, Anti Infect. Ther., 5(5):845-56,2007 Scarpignato C., Nonsteroidal antiinflammatory drugs:how do they damage gastroduodenal mucosa? Dig Dis.13(1):9-39,1995 Soylu A., Dolapcioglu C.,Dolay K.,Ciltas A., Yasar N., Kalayci M., Alis H., Sever N., Endoscopic and histopathological evaluation of acute gastric injury in high-dose acetaminophen and nonsteroidal antiinflammatory drug ingestion with suicidal intent. World J Gastroenterol. 14(43): ,2008 Taha A S, Dahill S., Sturrock R. D., Lee F. D., Russel R. I., Predicting NSAID related ulcers-assessment of clinical an pathological risk factors and importance of differences in NSAID. Gut,35: ,1994 Wallace J.L.,Prostaglandins, NSAIDs, and gastric mucosal protection:why doesn t the stomach digest itself? Physiol.Rev. 88: ,