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 analgesic action of NSAIDs may mask
`the ulcer pain.2
`Understanding the method by which
`NSAIDs cause gastric damage has helped in
`the development of prophylactic agents that
`reduce their toxicity.1 The mechanism by
`which NSAIDs are thought to damage the
`gastrointestinal tract is four-fold.
`
`a) Topical injury
`Originally it was thought that NSAIDs
`damaged the gastric epithelium by
`intracellular accumulation of these drugs in
`an ionised state.1 However the fact that
`enteric-coated formulations, pro-drugs,
`rectal and parenteral administration of
`NSAIDs still resulted in gastrointestinal
`damage despite the apparent absence of
`direct mucosal contact implies a minor role
`for topical injury1,2.
`
`b) Inhibition of prostaglandin synthesis
`In 1971 Vane discovered that NSAIDs
`act by the inhibition of cyclooxygenase the
`enzyme that converts arachidonic acid to
`prostaglandins. As prostaglandins play a
`major role in the maintenance of
`gastroduodenal defence mechanisms; their
`depletion due to NSAIDs and aspirin impairs
`cytoprotection resulting in mucosal injury,
`erosions and ulceration.1, 8
`
`c) Nitric Oxide
`Recent attention has focused on the
`role of nitric oxide (NO) in maintenance of
`gastric-mucosal blood flow.1 Like
`prostaglandins nitric oxide has been shown
`to increase mucosal blood flow, stimulate
`mucus secretion and inhibit neutrophil
`
`Drug-induced peptic
`ulcer disease
`
`Valerie Vella B Pharm(Hons), PgDip Clin Pharm (Aberdeen)
`
`Clinical Pharmacist, St Luke’s Hospital, Guardamangia, Malta
`Email: valerie.vella@gov.mt
`
`Key words: Peptic ulcer, medicines, prostaglandins, gastrointestinal protection,
`gastrointestinal toxicity
`
`For more than a century, peptic ulcer disease has been a
`major cause of morbidity and mortality.1 Peptic ulcer disease
`is a heterogeneous group of disorders involving the
`gastrointestinal tract and results from an imbalance between
`the aggressive forces of gastric acid and pepsin and the
`defensive mechanisms of the gastric mucosa.1,2,3
`
`Introduction
`Following the discovery of the
`association of peptic ulcer disease with
`Helicobacter pylori infection there has been
`a decline in the prevalence of
`uncomplicated peptic ulcer disease. In
`contrast, a striking rise in admissions for
`ulcer haemorrhage and perforation among
`elderly people is now being observed. This
`rise has been attributed to the increased
`use of non-steroidal anti-inflammatory
`drugs (NSAIDs) and low-dose aspirin.1 Drug-
`induced peptic ulcers are not exclusive to
`anti-inflammatory drugs, other medicines
`such as bisphosphonates, potassium
`
`supplements, corticosteriods, anticoagulants
`and chemotherapy play a role.
`
`Non-steroidal anti-inflammatory
`drugs (NSAIDs)
`Commonly prescribed for a variety of
`musculoskeletal complaints such as
`rheumatoid arthritis and short-term
`management of pain in osteoarthritis, 4,5
`NSAIDs are associated with both upper and
`lower gastrointestinal tract complications.
`Prevalence rates vary significantly6 as
`estimates do not make a distinction
`between causal and non-causal associations
`or because estimates are observed in high-
`
`Issue 10 Summer 2005
`
` Journal of the Malta College of Pharmacy Practice 15
`
`

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

`
`necessary.
`
`0 Patiert with active peptic ulcers
`should be advised to avoid smoking,
`excessive alcohol intake and over-the-
`
`counter preparations containing aspirin
`ani NSAIDs.
`
`Bleeding peptic ulcers have a mortality
`rate of about 6%, therefore patient
`should thus be made familiar with the
`
`symptoms of peptic ulcers such as lack
`of appetite an early sense of fullness
`with eating, nausea, vomiting,
`bloating, blood in the stools or black,
`tany stools.
`
`risk situations such as the presence of
`
`Practice Points
`
`0 Patient should always receive conect
`administration instnrtions. This is
`
`especially important when dispensing
`medicires known to cause topical
`gastmintestinal rhmage.
`0 Gastxoprotective agerls as proton pump
`inhibitors and misoprostol should be
`co-prescribed with NSAIDS to protect
`against gastrointestinal side-effect.
`0 Patient complaining of dyspepsia or
`frequertly consuming antacids should
`be questioned about gastrointestinal
`symptoms ard referred if deemed
`
`motility disorders or concurrent use of
`
`NSAIDs or anticoagulants." In a small study
`
`carried out on 26 healthy volunteers the
`
`risk of gastric ulcers in patients taking
`
`alendronate and naproxen increased to 38%
`
`compared to 8% in those receiving
`alendronate alone”
`
`Potassium supplements
`Potassium chloride in some of it solid
`
`forms may be retained in a fixed location
`
`within the oesophagus resulting in
`
`oesophageal haemorrhage. It is thought
`
`that oesophageal injury is caused by the
`wax-matrix of slow release tablets These
`
`tablet should be avoided in patierts with
`
`significant cardiomegaly particularly those
`
`who have undergone cardiac surgery as
`these conditions seem to favour tablet
`
`retention in the oesophagus. They should
`also be prescribed with caution in patent
`
`with a history 0‘ peptic ulcers.”
`
`Patients should always be advised to
`
`swallow potassium chloride tablets whole
`
`with fluid drring meals while sitting or
`
`standing."
`
`Corticosteroids
`
`Although controversial over the years,
`
`Anticoagulants
`Acute gastrointestinal haemorrhage is a
`
`Illicit drugs
`Crack was introdrced as an illicit street
`
`severe complication of peptic ulcers in
`
`drug in 1986 and since then in America the
`
`patierts receiving long-tenn oral
`
`number of patient treated for
`
`anticoagulant therapy.“ Correspondingly
`
`gastroduodenal perforations tire to crack has
`
`the risk of peptic ulcer in patiert receiving
`intravenous or subcutaneous unfractionated
`
`increased significantly.“ In a retrospective
`
`study of all patierts undergoing surgical
`
`heparin can be as high as 10%.”-”
`
`mamgement for peptic ulcer disease in a
`
`Although the risk of peptic ulcer with low
`
`teaching hospital in California it was
`
`molecular weight heparirrs has not yet been
`
`revealed that patient with recent use of
`
`quantified, their use in patient with either
`
`crack cocaine and/or alcohol are more likely
`
`a history or an active peptic ulcer is
`contraindicated,”-“’ the same holds for the
`
`to present with duodenal perforations.“
`Occurrence rate is believed to be of 16%.“
`
`use of unfractionated heparin.
`Concomitant administration of
`
`Conclusion
`
`current evidence suggests that
`
`corticosteriods alone do not impart
`
`detectable risk for peptic ulceration.”
`
`Nevertheless the prodrct characteristics of
`
`commonly used corticosteriods still indicate
`
`that they should be used with caution in
`
`patients with a history of peptic
`
`ulceration.”'3‘ Additionally they state that
`
`corticosteriods may be responsible for
`
`peptic ulcers with possible perforation and
`
`haemorrhage.3‘«35
`
`Corticosteroids may eracerbate NSAID-
`induced ulceration.”3‘v3‘ Combination use
`
`in a case control study of 1415 patierts
`
`increased the risk for peptic ulcer disease
`
`compared to corticosteroid alone by four
`times.” Some studies have in fact theorised
`
`that corticosteriods act only as an NSAID
`
`specific risk magnifier.’
`
`anticoagulation with NSAIDs nngnifies the
`
`risk and is preferably avoided.”-3‘
`
`Chemotherapy
`A number of cytotoxics used in the
`
`In theory ary drug, which is
`administered via the oral route, can cause
`
`gastrointestinal injury. Highly caustic
`
`coatings and direct medication injury can
`lead to acute inflammation, which can for
`
`management of cancer may induce acute
`
`the most part be avoided by appropriate
`
`mucosal injury to the stomach and
`
`administration instrrxtions.” Dmgs causing
`
`duodenum.“’ In two separate studies carried
`
`gastrointestinal toxicity as a consequence of
`
`out on a total of 410 patients receiving
`
`a systemic effect should be co-prescribed
`
`either a combination of cyclophosphamide,
`methotrexate and 5-fluorouracil, or 5-
`fluorouracil alone revealed that if
`
`with suitable prophylactic agerts such as
`
`proton pump inhibitors and misoprostoL The
`
`importance of gastroprotection is vital in
`
`gastroprotection with omeprazole was not
`
`preventing patient morbidity and mortality
`
`proviied the risk a‘ chemotherapy-irduced
`
`especially in patient with a number of risk
`
`gastroduodenal mucosal injury was
`
`factors which include patient over the age
`
`significantly higher.‘W
`
`of sixty, smokers, patient with a history of
`
`Another study indicates that drorbnal,
`
`gastric or pyloric ulcerations and erosions
`
`associated with hepatic artery infusion of
`
`5-fluorouracil have responded to
`
`discontinuation of chemotherapy.”
`
`peptic ulcer disease, and patient on high
`doses d‘ NSAIDs, or concomitant use of
`
`anticoagulant, aspirin, bisphosphonates or
`corticosteriods.’-‘-'
`
`18
`
`Journal of the Malta College of Pharmacy Practice
`
`Issue 10 Summer 2005
`
`

`
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`
`Issue 10 Summer 2005
`
` Journal of the Malta College of Pharmacy Practice 19