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risk populations only.7 The prevalence of endoscopically confirmed gastrointestinal ulcers in NSAID users is quoted to be between 15% and 30%. Between 12% to 30% of NSAID-induced ulcers are gastric ulcers, whereas 2% to 19% are duodenal ulcers. NSAID-induced ulcers are symptomatic only in 1% of patients after three to six months and in 2 to 4% of patients after one year. Inappropriately they do not correlate well with pain because the action of NSAIDs may mask the ulcer pain.2 Drug-induced peptic Understanding the method by which NSAIDs cause gastric damage has helped in the development of prophylactic agents that ulcer disease 1 red uce their toxicity. The mechanism by which NSAIDs are thought to damage the Valerie Vella B Pharm(Hons), PgDip Clin Pharm (Aberdeen) gastrointestinal tract is four-fold. Clinical Pharmacist, St Luke’s Hospital, Guardamangia, Malta a) Topical injury Email: [email protected] Originally it was thought that NSAIDs damaged the gastric epithelium by Key words: Peptic ulcer, medicines, , gastrointestinal protection, intracellular accumulation of these drugs in gastrointestinal toxicity an ionised state.1 However the fact that enteric-coated formulations, pro-drugs, For more than a century, peptic ulcer disease has been a rectal and parenteral administration of 1 major cause of morbidity and mortality. Peptic ulcer disease NSAIDs still resulted in gastrointestinal is a heterogeneous group of disorders involving the damage despite the apparent absence of gastrointestinal tract and results from an imbalance between direct mucosal contact implies a minor role the aggressive forces of gastric acid and pepsin and the for topical injury1,2. defensive mechanisms of the gastric mucosa.1,2,3 b) Inhibition of synthesis In 1971 Vane discovered that NSAIDs act by the inhibition of the Introduction supplements, corticosteriods, anticoagulants enzyme that converts to Following the discovery of the and chemotherapy play a role. prostaglandins. As prostaglandins play a association of peptic ulcer disease with major role in the maintenance of Helicobacter pylori infection there has been Non-steroidal anti-inflammatory gastroduodenal defence mechanisms; their a decline in the prevalence of drugs (NSAIDs) depletion due to NSAIDs and impairs uncomplicated peptic ulcer disease. In Commonly prescribed for a variety of cytoprotection resulting in mucosal injury, contrast, a striking rise in admissions for musculoskeletal complaints such as erosions and ulceration.1, 8 ulcer haemorrhage and perforation among rheumatoid arthritis and short-term elderly people is now being observed. This management of pain in osteoarthritis, 4,5 c) Nitric Oxide rise has been attributed to the increased NSAIDs are associated with both upper and Recent attention has focused on the use of non-steroidal anti-inflammatory lower gastrointestinal tract complications. role of nitric oxide (NO) in maintenance of drugs (NSAIDs) and low-dose aspirin.1 Drug- Prevalence rates vary significantly6 as gastric-mucosal blood flow.1 Like induced peptic ulcers are not exclusive to estimates do not make a distinction prostaglandins nitric oxide has been shown anti-inflammatory drugs, other medicines between causal and non-causal associations to increase mucosal blood flow, stimulate such as bisphosphonates, potassium or because estimates are observed in high- mucus secretion and inhibit neutrophil

Issue 10 Summer 2005 Journal of the Malta College of Pharmacy Practice 15 adherence.1 In animals NO-releasing potential of coxibs demonstrate conflicting acute coronary syndrome.22 The risk of NSAIDs produce less gastric damage than data. 9, 15, 16,17 gastric and duodenal ulcers with clopidogrel their parent drugs and they even promote is between 0.1 – 1.0%.22 Unfortunately ulcer-healing.1,9 Cyclo-oxygenase inhibiting clopidogrel is not a solution to patients who nitric oxide donators are unable to take aspirin because of d) Neutrophil-mediated injury COX-inhibiting nitric oxide donators, gastrointestinal complications. A number of Neutrophil adherence to the CINODs, are a new class of analgesic drugs small studies have in fact revealed that in endothelium of gastric microcirculation designed to provide analgesic efficacy patients with a history of bleeding and damages the mucosa by liberating oxygen- through COX-inhibition and peptic ulcer the combination of aspirin and free radicals, releasing proteases and gastrointestinal safety through the a proton pump inhibitor is safer than obstructing capillary blood flow. NSAIDs protective effects of controlled nitric oxide clopidogrel in terms of bleeding side are thought to stimulate neutrophil donation9,18. AZD3582 was the first CINOD effects.23 adherence by up-regulation of adhesion to enter clinical development.19 Although molecules.1 initial reports were promising, a recent Bisphosphonates The overall result is that NSAIDs cause study has indicated that the much Bisphosphonates such as alendronate, damage as they impair the ability of the expected superior gastrointestinal etidronate and risedronate, are now used gastrointestinal mucosa to respond to tolerability of AZD3582 is no better than extensively in the treatment of patients injury.9 Not all NSAIDs have the same that provided by .20 with osteoporosis and Paget’s disease and potential to cause peptic ulcer disease, in prophylaxis of osteoporosis.24,25 All fact in low doses (up to 1200mg Aspirin bisphosphonates cause gastrointestinal daily) is said to have the same Odds Ratio2 Aside from its use as an anti- side-effects14,26 however post-marketing as in causing upper inflammatory, aspirin in low dose is surveillance indicated that alendronate and gastrointestinal bleeding.7 also frequently indicated for the secondary risedronate are associated with severe has a low odds ratio although higher than prevention of thrombotic cerebrovascular oesophageal reactions and gastric and that for ibuprofen. Indomethacin, or cardiovascular disease.4,5,21 Incidence of duodenal ulceration.14,25,27,28,29 It is unclear naproxen and have an peptic ulcers has been reported to be as whether variation in ulcerogenic potential intermediate odds ratio† whereas high as 35%.7 Advising patients to take reflects differences in dosing, formulation azapropazone and , has a very enteric coated tablets or to take the or chemical structure.29 high odds ratio, and should thus be preparation after food may minimise Studies with alendronate indicate that avoided in high-risk patients7, 8,10,11,12,13 gastrointestinal symptoms as dyspepsia, the oesophageal damage is consistent with but as for NSAIDs ulceration is mainly a topical irritant effect.28 Failure of Cyclo-oxygenase (COX 2) attributable to its systemic effect on alendronate tablets to pass through the selective inhibitors prostaglandin synthesis.5 Co-prescription oesophagus may result in prolonged local There are at least two isoforms of of aspirin with standard NSAIDs augments mucosal exposure to the drug, leading to cyclo-oxygenase: COX 1 and COX 2. The the risk of such complications and risk erosive or ulcerative mucosal damage with former is found in high concentrations in reduction of upper gastrointestinal events inflammation and thickening of the platelets, vascular endothelial cells, the associated with COX 2 selective inhibitors oesophageal wall.30 For most part such stomach and in kidney collecting tubules may not be evident when they are reactions can be avoided by appropriate and is responsible for the prostaglandins combined with aspirin.4 administration of the alendronate tablets. which are essential for maintenance of These include swallowing the tablet whole normal endocrine function, renal function, Clopidogrel with plenty of water (not less than 200ml) gastric mucosal integrity and haemostasis.4 Clopidogrel is an antiplatelet drug on an empty stomach at least thirty COX 2 is significantly increased by indicated for the prevention of minutes before food while sitting or inflammatory and mitogenic stimuli. By atherothrombotic events in patients standing. Patients should also be reminded selectively blocking COX 2, COX 2 selective suffering from myocardial infarction, to stand or sit upright for at least one hour inhibitors have a theoretical advantage ischaemic stroke or established peripheral after taking the tablet.31 On the other hand over the traditional NSAIDS with respect to arterial disease.21,22 It is also given in gastroduodenal injury appears to be an red ucti on in GI side-effects.4,14 Published combination with aspirin in patients acute phenomenon not associated with clinical trials assessing the gastroerosive suffering from non-ST segment elevation significant complications, except in high-

†Odds ratio (OR) is defined as the odds of an event happening in the experimental group expressed as a proportion of the odds of an event happening in the control group. If OR is greater than one, then the effects of the treatment are more than those of the control treatment.

16 Journal of the Malta College of Pharmacy Practice Issue 10 Summer 2005 risk situations such as the presence of Practice Points motility disorders or concurrent use of NSAIDs or anticoagulants.25 In a small study •Patients should always receive correct •Patients with active peptic ulcers administration instructions. This is should be advised to avoid smoking, carried out on 26 healthy volunteers the especially important when dispensing excessive intake and over-the- risk of gastric ulcers in patients taking medicines known to cause topical counter preparations containing aspirin alendronate and naproxen increased to 38% gastrointestinal damage. and NSAIDs. compared to 8% in those receiving • Gastroprotective agents as proton pump •Bleeding peptic ulcers have a mortality alendronate alone.32 inhibitors and should be rate of about 6%, therefore patients co-prescribed with NSAIDs to protect should thus be made familiar with the Potassium supplements against gastrointestinal side-effects. symptoms of peptic ulcers such as lack •Patients complaining of dyspepsia or of appetite an early sense of fullness Potassium chloride in some of its solid frequently consuming antacids should with eating, nausea, vomiting, forms may be retained in a fixed location be questioned about gastrointestinal bloating, blood in the stools or black, within the oesophagus resulting in symptoms and referred if deemed tarry stools. oesophageal haemorrhage. It is thought necessary. that oesophageal injury is caused by the wax-matrix of slow release tablets. These Anticoagulants Illicit drugs Acute gastrointestinal haemorrhage is a Crack was introduced as an illicit street tablets should be avoided in patients with severe complication of peptic ulcers in drug in 1986 and since then in America the significant cardiomegaly particularly those patients receiving long-term oral number of patients treated for who have undergone cardiac surgery as anticoagulant therapy.36 Correspondingly gastroduodenal perforations due to crack has these conditions seem to favour tablet the risk of peptic ulcer in patients receiving increased significantly.43 In a retrospective retention in the oesophagus. They should also be prescribed with caution in patients intravenous or subcutaneous unfractionated study of all patients undergoing surgical 37,38 with a history of peptic ulcers.30 heparin can be as high as 10%. management for peptic ulcer disease in a Patients should always be advised to Although the risk of peptic ulcer with low teaching hospital in California it was swallow potassium chloride tablets whole molecular weight heparins has not yet been revealed that patients with recent use of with fluid during meals while sitting or quantified, their use in patients with either crack and/or alcohol are more likely 44 standing.21 a history or an active peptic ulcer is to present with duodenal perforations. contraindicated,39,40 the same holds for the Occurrence rate is believed to be of 16%.43 Corticosteroids use of unfractionated heparin. Although controversial over the years, Concomitant administration of Conclusion current evidence suggests that anticoagulation with NSAIDs magnifies the In theory any drug, which is 33,36 corticosteriods alone do not impart risk and is preferably avoided. administered via the oral route, can cause detectable risk for peptic ulceration.33 gastrointestinal injury. Highly caustic Nevertheless the product characteristics of Chemotherapy coatings and direct injury can commonly used corticosteriods still indicate A number of cytotoxics used in the lead to acute inflammation, which can for that they should be used with caution in management of cancer may induce acute the most part be avoided by appropriate patients with a history of peptic mucosal injury to the stomach and administration instructions.30 Drugs causing 40 ulceration.34,35 Additionally they state that duodenum. In two separate studies carried gastrointestinal toxicity as a consequence of corticosteriods may be responsible for out on a total of 410 patients receiving a systemic effect should be co-prescribed peptic ulcers with possible perforation and either a combination of cyclophosphamide, with suitable prophylactic agents such as haemorrhage.34,35 methotrexate and 5-fluorouracil, or 5- proton pump inhibitors and misoprostol. The Corticosteroids may exacerbate NSAID- fluorouracil alone revealed that if importance of gastroprotection is vital in induced ulceration.33,34,35 Combination use gastroprotection with omeprazole was not preventing patient morbidity and mortality in a case control study of 1415 patients provided the risk of chemotherapy-induced especially in patients with a number of risk increased the risk for peptic ulcer disease gastroduodenal mucosal injury was factors which include patients over the age compared to corticosteroid alone by four significantly higher.41,42 of sixty, smokers, patients with a history of times.33 Some studies have in fact theorised Another study indicates that duodenal, peptic ulcer disease, and patients on high that corticosteriods act only as an NSAID gastric or pyloric ulcerations and erosions doses of NSAIDs, or concomitant use of specific risk magnifier.7 associated with hepatic artery infusion of anticoagulants, aspirin, bisphosphonates or 5-fluorouracil have responded to corticosteriods.3,6,8 discontinuation of chemotherapy.33

18 Journal of the Malta College of Pharmacy Practice Issue 10 Summer 2005 References

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