The term ‘peptic ulcer’ describes a condition in which there is a discontinuity in the entire thickness of the gastric or duodenal mucosa that persists as a result of acid and pepsin in the gastric juice (Fig. 12.1). Oesophageal ulceration due to acid reflux is generally classified under GORD. This definition excludes carcinoma and lymphoma, which may also cause gastric ulceration, and also excludes other rare causes of gastric and duodenal ulceration such as Crohn’s disease, viral infections and amyloidosis. About 10% of the population in developed countries is likely to be affected at some time by peptic ulcer, with the prevalence for active ulcer disease being about 1% at any particular point in time.

Fig. 12.1 Duodenal ulcer seen at endoscopy. Note also a visible blood vessel that is a stigma of recent haemorrhage.

Peptic ulcer disease often presents to clinicians as dyspepsia. However, not all patients with dyspepsia have peptic ulcer disease. Dyspepsia is defined as persistent or recurrent pain or discomfort centred in the upper abdomen. The most common causes of dyspepsia are non-ulcer or functional dyspepsia, GORD and peptic ulcer. Other causes include gastric cancer, pancreatic or biliary disease. Peptic ulcer accounts for 10–15% of dyspepsia, and oesophagitis for about 20%. However, 60–70% of patients have no obvious abnormality and have functional dyspepsia or endoscopy-negative GORD. Dyspepsia is a common symptom and affects about 40% of people annually. It is the reason for 5–10% of consultations with primary care physicians, and up to 70% of referrals to gastro-intestinal units are patients with dyspepsia. However, the widely adopted test and treat recommendation for uninvestigated dyspepsia has reduced endoscopy referrals.

Epidemiology

The incidence of duodenal ulcer is now declining, which follows the decline in H. pylori infection. However, hospital admission rates for gastro-intestinal bleeding associated with gastric and duodenal ulcers are rising, especially in older patients. This is probably a consequence of increased prescriptions for low-dose aspirin, NSAIDs, antiplatelets, anticoagulants and selective serotonin reuptake inhibitors (SSRI). Over the previous decade there has been an increase in idiopathic peptic ulcer disease in patients who test negative for H. pylori and who do not take NSAIDs or aspirin. In some countries, up to one-quarter of peptic ulcers are idiopathic and there is a decrease in prevalence of H. pylori infection. Idiopathic ulcers should be investigated to attempt to identify the underlying cause following careful reassessment of H. pylori status and medication history.

Infection by H. pylori, a spiral bacterium of the stomach, remains an important epidemiological factor in causing peptic ulcer (Fig. 12.2). Most H. pylori infections are acquired by oral–oral and oral–faecal transmission. The most important risk factors for H. pylori infection are low social class, overcrowding and home environment during childhood, for example, bed sharing. Transmission may occur within a family, a fact demonstrated by the finding that family members, especially spouses, may have the same strain of H. pylori. H. pylori seropositivity increases with age as colonisation persists for the lifetime of the host. Subjects who become infected with H. pylori when young are more likely to develop chronic or atrophic gastritis with reduced acid secretion that may protect them from developing duodenal ulcer. However, it may promote development of gastric ulcer as well as gastric cancer. Duodenal ulcer seems to develop in those who are infected with H. pylori at the end of childhood or later. Historically, developing countries have a higher ratio of duodenal ulcer to gastric ulcer but as rates of H. pylori infection decline with improvements in hygiene and rates of gastric ulcer increase with the use of ulcerogenic drugs, this ratio of duodenal to gastric ulcer is declining. The prevalence of H. pylori still tends to be higher in the Asian adult population in whom a lower parietal cell mass has been found. These factors together with slower metabolism may explain the greater efficacy of PPIs in Asian populations. There may be other genetic, environmental or cultural factors influencing peptic ulcer disease.

Fig. 12.2 Helicobacter pylori. The Gram-negative spiral bacterium H. pylori, formerly known as Campylobacter pylori, was isolated serendipitously from patients with gastritis by Barry Marshall and Robin Warren in 1982. Seven years later, it was conceded that H. pylori is responsible for most cases of gastric and duodenal ulcer.

Pathogenesis

There are two common forms of peptic ulcer disease: those associated with the organism H. pylori and those associated with the use of aspirin and NSAIDs. Less common is ulcer disease associated with massive hypersecretion of acid which occurs in the rare gastrinoma (Zollinger–Ellison) syndrome.

Helicobacter pylori

This organism is a Gram-negative microaerophilic bacterium found primarily in the gastric antrum of the human stomach (see Fig. 12.2). Ninety-five percent or more of duodenal ulcers and 80–85% of gastric ulcers are associated with H. pylori. The bacterium is located in the antrum and the acid-secreting microenvironment of the corpus of the stomach is less hospitable to the bacterium. In the developed world, reinfection rates are low, about 0.3–1.0% per year, whereas in the developing world reinfection rates are higher, approximately 20–30%. Ulcerogenic strains of H. pylori, ulcer-prone hosts, age of infection and interaction with other ulcerogenic factors such as NSAIDs determine peptic ulcer development following H. pylori infection. The contribution of H. pylori infection to the risk of ulcers in NSAID users is not clear but there appears to be an additive effect. The risk of peptic ulcer in long-term NSAID users is greater in those who test positive for H. pylori and eradication of H. pylori in these patients prior to commencing NSAID treatment has been shown to reduce the risk of H. pylori NSAID-associated peptic ulcer.

Although the majority of species in the H. pylori genus have been associated with pathology, some are more virulent than others which probably explains why, in combination with host-related factors, only 5–10% of those infected go on to develop peptic ulcer disease.

The underlying pathophysiology associated with H. pylori infection involves the production of cytotoxin-associated gene A (CagA) proteins and vacuolating cytotoxins, such as vac A, which activate the inflammatory cascade. CagA status and one genotype of the vac A gene are also predictors of ulcerogenic capacity of a strain. In addition, a number of enzymes produced by H. pylori may be involved in causing tissue damage and include urease, haemolysins, neuraminidase and fucosidase.

Gastrin is the main hormone involved in stimulating gastric acid secretion, and gastrin homeostasis is also altered in H. pylori infection. The hyperacidity in duodenal ulcer may result from H. pylori-induced hypergastrinaemia. The elevation of gastrin may be a consequence of bacterially mediated decrease of antral D cells that secrete somatostatin, thus losing the inhibitory modulation of somatostatin on gastrin, or direct stimulation of gastrin cells by cytokines liberated during the inflammatory process. Long-standing hypergastrinaemia leads to an increased parietal cell mass. High acid content in the proximal duodenum leads to metaplastic gastric-type mucosa, which provides a niche for H. pylori infection followed by inflammation and ulcer formation.

Non-steroidal anti-inflammatory drugs

Three patterns of mucosal damage are caused by NSAIDs. These include superficial erosions and haemorrhages, silent ulcers detected at endoscopy and ulcers causing clinical symptoms and complications. Weak acid NSAIDs, such as acetylsalicylic acid, are concentrated from the acidic gastric juice into mucosal cells, and may produce acute superficial erosions via inhibition of COX and by mediating the adherence of leucocytes to mucosal endothelial cells. Enteric coating may prevent this superficial damage but does not demonstrate any clinical benefit in terms of reduction of gastro-intestinal bleeding or ulceration (Bhatt et al., 2008). The major systemic action of NSAIDs that contributes to the formation of ulcers is the reduction of mucosal prostaglandin production. All NSAIDs share the ability to inhibit COX (Fig. 12.3). The presence of NSAID-induced ulcers does not correlate with abdominal pain and NSAIDs themselves often mask ulcer pain. Approximately 20% of patients taking NSAIDs experience symptoms of dyspepsia but symptoms correlate poorly with the presence of mucosal damage. Ulcers and ulcer complications occur in approximately 4% of NSAID users every year. Patients taking NSAIDs have a four-fold increase in risk of ulcer complications compared with non-users. The risk of ulcer bleeding in low-dose aspirin users is two- to three-fold and there may be differences in risk factors. For example, the risk with aspirin is less influenced by age than the risk associated with NSAIDs (McQuaid and Laine, 2006) and H. pylori may have greater influence on the risk of bleeding with low-dose aspirin than with NSAIDs (Lanza et al., 2009).

Fig. 12.3 Arachidonic acid pathway.

Each year, in the UK population over the age of 60 years, there are ∼︀3500 hospitalisations and over 400 deaths associated with NSAIDs. The risk of ulcer complications (Box 12.1) is progressive depending upon the number of risk factors present (Lanza et al., 2009). The most important risk factors are a history of ulcer complications and advancing age, particularly over 75 years. Ulcers have been found to be more common in patients who have taken NSAIDs for less than 3 months, with the highest risk observed during the first month of treatment. The risk increases with higher doses of NSAID but mucosal damage occurs with even very low doses of NSAIDs, particularly aspirin. Corticosteroids alone are an insignificant ulcer risk, but potentiate the ulcer risk when added to NSAIDs, particularly in daily doses of at least 10 mg prednisolone (Lanza et al., 2009).

Box 12.1 Risk factors for NSAID ulcers

Age greater than 65 years

Previous peptic ulceration/bleeding

High dose of NSAID or more than one NSAID (including aspirin)

Short-term history of NSAID use (<1 month)

Concomitant corticosteroid or anticoagulant use

Cardiovascular disease

Low-dose aspirin (75 mg/day) alone increases the risk of ulcer bleeding and this effect may be due to the antiplatelet action, independent of other risk factors. Concomitant use of aspirin with NSAIDs further increases the risk. There is no evidence that anticoagulants increase the risk of NSAID ulcers but they are associated with an increase in the risk of haemorrhage. The presence of cardiovascular disease is also considered as an independent risk factor.

Selective cyclo-oxygenase-2 inhibitors

The gastro-intestinal side effects of conventional NSAIDs are mediated through the inhibition of COX-1 (see Fig. 12.3). COX-1 stimulates synthesis of homeostatic prostaglandins while COX-2 is predominantly induced in response to inflammation. Selective COX-2 inhibitors tend not to reduce the mucosal production of protective prostaglandins to the same extent as NSAIDs. COX-2 inhibitors are, therefore, considered to be safer than non-selective NSAIDs in patients at high risk of developing gastro-intestinal mucosal damage. Although studies have confirmed the reduction of endoscopic and symptomatic ulcers (Hooper et al., 2004), an increase in cardiovascular risk, including heart attack and stroke, has resulted in the withdrawal of some COX-2 inhibitors from the market. Additional contraindications are now in place for those COX-2 inhibitors that remain on the market. Amongst the new contraindications is the recommendation that they should not be taken by patients with established heart or cerebrovascular disease, or taken in combination with low-dose aspirin as this negates any beneficial gastro-intestinal protective effects. The need for and choice of anti-inflammatory agent should therefore take into account gastro-intestinal, cardiovascular and other risks such as potential cardio-renal effects. For all agents, the lowest effective dose should be used for the shortest duration.

Candidates for COX-2 inhibitors are patients at high risk of NSAID-related gastro-intestinal events but who do not require low-dose aspirin therapy. The lowering of risk of gastro-intestinal events is similar for COX-2 inhibitors and non-selective NSAIDs combined with a gastroprotective agent.

Nitric oxide-releasing NSAIDs

Nitric oxide (NO)-releasing NSAIDs are being investigated to see if the gastric mucosa protection associated with nitric oxide prevents ulceration when prostaglandins are inhibited by NSAIDs (Fiorucci et al., 2007). Nitric oxide is coupled to the NSAID via an ester, resulting in prolonged release of nitric oxide. Nitric oxide itself has anti-inflammatory effects adding to the potency of the NSAID. Animal studies suggest NO-releasing agents, such as naproxcinod, have minimum cardiovascular and gastro-intestinal toxicity.

Clinical manifestations

Upper abdominal pain occurring 1–3 h after meals and relieved by food or antacids is the classic symptom of peptic ulcer disease. The relationship to meals is more marked in duodenal ulcer than in gastric ulcer. However, the symptoms of peptic ulcer disease lack specificity; they do not distinguish between duodenal ulcer, gastric ulcer or functional dyspepsia. Anorexia, weight loss, nausea and vomiting, heartburn and eructation can all occur with peptic ulcer disease. Patients with predominant symptoms of heartburn are likely to have GORD. Complications of peptic ulcer disease may occur with or without previous dyspeptic symptoms. These are haemorrhage, chronic iron-deficiency anaemia, pyloric stenosis and perforation. In the elderly, the presentation is more likely to be silent and gastro-intestinal bleeding may be the first clinical sign of disease. Peptic ulcer bleeding is the most frequent and severe complication of peptic ulcer disease. Physical examination may be negative or reveal epigastric tenderness. Peptic ulcers in the past tended to relapse and remit, and 70–80% of ulcers relapse within 1–2 years after being healed by antisecretory therapy. This tendency to relapse is dramatically reduced by eradication of H. pylori.

Patient assessment

Presenting symptoms of dyspepsia require careful assessment to judge the risk of serious disease or to provide appropriate symptomatic treatment. Symptom subgroups such as ulcer, reflux and dysmotility type may be useful in identifying the predominant symptom subgroup to which a patient belongs. Many patients have symptoms which fit more than one subgroup (Box 12.2). Many patients seek reassurance, lifestyle advice and symptomatic treatment with a single consultation, others have chronic symptoms. In some cases, medications may be the cause of dyspepsia and should be reviewed (Box 12.3).

Patients at any age who present with alarm features (Box 12.4) should be referred for endoscopic investigation. These groups of patients are at a higher risk of underlying serious disease such as cancer, ulcers or severe oesophagitis. Referral is also recommended for patients over the age of 55 if symptoms are unexplained or persistent despite initial management (NICE, 2004; SIGN, 2003). Malignant disease is rare in young people and in those without alarm features.

Box 12.4 Alarm features

Dysphagia

Pain on swallowing

Unintentional weight loss

Gastro-intestinal bleeding or anaemia

Persistent vomiting

On NSAIDs or warfarin

Patients with predominant reflux-like symptoms are likely to respond to acid-suppressing therapy and one month’s treatment of standard dose of PPI should be given in patients whose symptoms persist despite antacid and lifestyle adjustment. Eradication of H. pylori is not beneficial in GORD.

In those patients who do not have reflux-like dyspepsia, testing for the presence of H. pylori is recommended. Eradication treatment should be prescribed for those who test positive and empirical acid suppression for those who test negative. The small proportion of patients with symptoms due to ulcers should be cured. Overall, in functional dyspepsia, symptom control is poor but a small and significant benefit of eradication treatment has been shown. Acid suppression is only of benefit in a small proportion of patients with functional dyspepsia. There is no evidence to support other pharmacological therapies and non-pharmacological strategies may have a future role in functional dyspepsia. Patients should be reassured that the condition is common and not serious. National guidelines (NICE, 2004) provide algorithms to guide practitioners through the management of patients presenting with dyspepsia (Fig. 12.4A and B).

Fig. 12.4 (A) Decision algorithm for management of uninvestigated dyspepsia. (B) Decision algorithm for management of non-ulcer dyspepsia.

Investigations

Endoscopy

Endoscopy is generally the investigation of choice for diagnosing peptic ulcer, and the procedure is sensitive, specific and safe. However, it is also invasive and expensive. Routine endoscopy in patients presenting with dyspepsia without alarm features (see Box 12.4) is not necessary. Endoscopic investigation should be undertaken in patients with alarm features and in those patients over 55 years who present with unexplained or persistent symptoms of dyspepsia. Biopsies may be taken to exclude malignancy and uncommon lesions such as Crohn’s disease.

Patients with upper gastro-intestinal bleeding have traditionally undergone endoscopy whether as an emergency or on the next available list. Most patients do not require endoscopy and in those at low risk, endoscopy and admission to hospital can be avoided by application of a scoring system. The most widely used is the Rockall risk scoring system which includes endoscopic findings to predict poor outcome. Pre-endoscopic scoring systems are available (Stanley et al., 2009) such as the abbreviated Rockall score or the Glasgow–Blatchford score (GBS) which identify low-risk patients who can be managed safely without endoscopy or admission to hospital.

Wireless capsule endoscopy is also available to investigate NSAID-induced ulceration of the small intestine causing gastro-intestinal haemorrhage and is preferable to radiological imaging.

Radiology

Double-contrast barium radiography should detect 80% of peptic ulcers. However, endoscopy is more accurate and almost always preferred. A Gastrograffin® meal is used to diagnose peptic perforation in patients presenting with an acute abdomen, if a plain abdominal X-ray is not diagnostic.

H. pylori detection

There are several methods of detecting H. pylori infection. They include non-invasive tests such as serological tests to detect antibodies, [¹³C] urea breath tests and stool antigen tests. Urea breath tests have a sensitivity and specificity over 90% and are accurate for both initial diagnosis and confirmation of eradication. The breath test is based on the principle that urease activity in the stomach of infected individuals hydrolyses urea to form ammonia and carbon dioxide. The test contains carbon-labelled urea which, when hydrolysed, results in production of labelled carbon dioxide which appears in the patient’s breath. The stool antigen test uses an enzyme immunoassay to detect H. pylori antigen in stool. This test also has a sensitivity and specificity over 90% and can be used in the initial diagnosis and also to confirm eradication. However, the breath test is preferable and more convenient. Serological tests are based on the detection of anti-H. pylori IgG antibodies but are not able to distinguish between active or previous exposure to infection. Near patient serology tests are not recommended (Malfertheiner et al., 2007) as they are inaccurate.

Invasive tests requiring gastric antral biopsies include urease tests, histology and culture. Of these, the biopsy urease test is widely used. Agar-based biopsy urease tests are designed to be read at 24 h, whereas the strip-based biopsy urease tests can be read at 2 h following incubation with the biopsy material. Increasing the number of biopsy samples increases the sensitivity of the test as infection can be patchy. The accuracy of the urea breath test or biopsy urease test can be reduced by drug therapy; therefore, it is recommended to discontinue PPIs at least 2 weeks before testing and discontinue antibiotics at least 4 weeks before testing to reduce the risk of false-negative results.

The faecal occult blood test is not specific for or sensitive to detection of NSAID-induced gastric damage. A full blood count may provide evidence of blood loss from peptic ulcer.

Treatment

Complications of peptic ulcer disease

Bleeding peptic ulcer

Peptic ulcer is the most common cause of non-variceal upper gastro-intestinal bleeding. Most patients with bleeding peptic ulcer are clinically stable and stop bleeding without any intervention, whereas other outcomes include re-bleeding and mortality. Endoscopy allows identification of the severity of disease as well as endoscopic haemostatic therapy which is successful in reducing mortality. Endoscopic therapy is necessary only in patients who exhibit high-risk stigmata (active bleeding, non-bleeding visible vessel, adherent clot) on endoscopy.

A number of pharmacological agents have been used for endoscopic injection therapy such as 1:10,000 adrenaline (epinephrine), human thrombin and fibrin glue. Mechanical endoscopic treatment options include thermocoagulation using a heater probe or endoscopic clipping. Combination therapies are superior to monotherapy and a combination of adrenaline 1:10,000 with either thermal or mechanical treatment is recommended (SIGN, 2008; Barkun et al., 2010). Need for surgery, re-bleeding rates and mortality are reduced but bleeding recurs in about 10% of patients and can cause death. Patients with uncontrolled bleeding should receive repeat endoscopic treatment, arterial embolisation or surgery. The risk of recurrent bleeding following endoscopic therapy is reduced by increasing intragastric pH during the first 3 days after the initial bleed and eradication of H. pylori. Biopsies taken at the time of endoscopy are used to detect H. pylori, or the urea breath test can be used once oral intake is established and H. pylori eradication therapy is indicated in those who test positive. Successful eradication of H. pylori reduces the rate of re-bleeding to a greater extent than antisecretory non-eradicating therapy (Gisbert et al., 2004). Following successful H. pylori eradication and healing of the ulcer, there is no need to continue maintenance antisecretory therapy beyond 4 weeks unless required for prophylaxis of ulcer complications in those continuing to take aspirin or NSAIDs (SIGN, 2008).

Acid suppression reduces the re-bleeding rate and should be given to those patients at high risk of re-bleeding following endoscopic haemostatic therapy. The rationale for this is based on the fact that gastric acid inhibits clot formation and if intragastric pH is maintained above 6 during the first 3 days after the initial bleed, there is opportunity for clot stabilisation and haemostasis. Meta-analysis suggests PPIs significantly reduce re-bleeding rates compared with H₂-receptor antagonists and are the preferred choice of treatment (Leontiadis et al., 2006). In similar dosage regimens, there is no data to suggest any PPI is more efficacious than another. The optimal dose and route of PPI is unknown in this indication, although reduction in mortality is observed in high-risk patients when high dose PPI therapy is given (e.g. 80 mg bolus omeprazole, pantoprazole or esomeprazole followed by 8 mg/h for 72 h) following endoscopic haemostasis (Leontiadis et al., 2007; SIGN, 2008; Barkun et al., 2010).

The use of intravenous PPI therapy before endoscopy in patients with upper gastro-intestinal bleeding does not affect clinical outcome such as re-bleeding, need for surgery or mortality (Dorward et al., 2006). However, this may reduce the need for endoscopic therapy (Lau et al., 2007) as demonstrated in Asian patients in whom PPIs are more effective. Its benefits are not clear and it is not possible to identify patients with a greater likelihood of being at high risk. Therefore, the use of PPIs is not recommended prior to diagnosis by endoscopy (SIGN, 2008) but may be beneficial if early endoscopy is delayed (Barkun et al., 2010).

In those patients at low risk for re-bleeding and in whom endoscopic therapy is not indicated, usual therapeutic doses of oral PPI are given for 4 weeks to heal the ulcer. Aspirin or NSAIDs should be avoided but if strongly indicated, these patients are given concomitant PPI therapy following successful eradication of H. pylori. The effect of H. pylori eradication on the risk of recurrent ulcer bleeding is greater in patients taking low-dose aspirin than in those taking NSAIDs (Chan et al., 2001). A possible explanation (Lanza et al., 2009) for this might be that aspirin provokes bleeding in H. pylori ulcers and after healing, aspirin is less likely to cause ulceration.

In patients for whom there is a clear indication to continue aspirin therapy, addition of a PPI is of benefit in the prevention of recurrent bleeding in aspirin users (Lai et al., 2002). Clopidogrel alone is not a safer alternative than this combination in terms of prevention of recurrent ulcer bleeding. Cardiovascular and gastro-intestinal risks must be taken into consideration when deciding how long aspirin should be discontinued after a gastro-intestinal bleed. In some cases, low-dose aspirin can be restarted with concurrent PPI treatment within 7 days (Barkun et al., 2010). When the combination of aspirin and clopidogrel is indicated, concomitant PPI therapy is recommended in patients at high risk of gastro-intestinal complications despite the potential drug interaction between PPIs and clopidogrel. An increased risk of myocardial infarction has been observed with the combination of clopidogrel and PPIs (MHRA, 2009). Causality is unclear but it is suggested that through competitive enzyme inhibition, PPIs metabolised by CYP2C19 reduce the conversion of clopidogrel to its active metabolite. Concomitant use is discouraged but if necessary, separation of dosage timing is recommended (Laine and Hennekens, 2010).

Pyloric stenosis

Malignancy is the most common cause of gastric outlet obstruction. Peptic ulcer disease is the underlying cause in about 10% of cases. There is limited anecdotal evidence that incomplete gastric outlet obstruction may improve within several months of successful H. pylori eradication. Conventional treatment with acid-suppressive therapy may also help. If medical therapy fails to relieve the obstruction, endoscopic balloon dilation or surgery may be required.

Zollinger–Ellison syndrome

This rare syndrome consists of a triad of non-β islet cell tumours of the pancreas that contain and release gastrin, gastric acid hypersecretion and severe ulcer disease. Extrapancreatic gastrinomas are also common and may be found frequently in the duodenal wall. A proportion of these patients have tumours of the pituitary gland and parathyroid gland (multiple endocrine neoplasia type I). Surgical resection of the gastrinoma may be curative. Medical management consists of greater than standard doses of PPIs. The somatostatin analogue octreotide is also effective but has no clear advantage over PPIs. Patients with idiopathic peptic ulcer disease should be investigated for Zollinger–Ellison syndrome and gastrinoma.

Stress ulcers

Severe physiological stress such as head injury, spinal cord injury, burns, multiple trauma or sepsis may induce superficial mucosal erosions or gastroduodenal ulcerations. These may lead to haemorrhage or perforation. Mechanical ventilation and the presence of coagulopathies place patients at particular risk of stress-related mucosal bleeding and may warrant prophylactic treatment (Quenot et al., 2009). Diminished blood flow to the gastric mucosa, decreased cell renewal, diminished prostaglandin production and, occasionally, acid hypersecretion are involved in causing stress ulceration. Intravenous acid-suppression therapy, histamine H₂-receptor antagonists and PPIs, and nasogastric tube administration of sucralfate (4–6 g daily in divided doses) have been used to prevent stress ulceration in the intensive care unit until the patient tolerates enteral feeding. The most commonly used regimen is intravenous ranitidine 50 mg every 8 h reducing to 25 mg in severe renal impairment. Current evidence does not support routine use of prophylaxis and reports of complications associated with bacterial overgrowth in the gastro-intestinal tract in patients receiving acid suppressants should limit use only to those at high risk. Complications include association with hospital acquired Clostridium difficile diarrhoea (Dial et al., 2004) and pneumonia (Herzig et al., 2009).

Uncomplicated peptic ulcer disease

Treatment of endoscopically proven uncomplicated peptic ulcer disease has changed dramatically in recent years (Fig. 12.5A and B). Curing of H. pylori infection and discontinuation of NSAIDs are key elements for the successful management of peptic ulcer disease.

Fig. 12.5 (A) Management algorithm for gastric ulcer. (B) Management algorithm for duodenal ulcer.

H. pylori eradication

It is known that H. pylori infection is associated with over 90% of duodenal ulcers and 80% of gastric ulcers. Cure of this infection with antibiotic therapy and simultaneous treatment with conventional ulcer-healing drugs facilitates symptom relief and healing of the ulcer and reduces the ulcer relapse rate. Antibiotics alone, or acid-suppressing agents alone, do not eradicate H. pylori. Both therapies act synergistically as growth of the organism occurs at elevated pH and antibiotic efficacy is enhanced during growth. Additionally, increasing intragastric pH may enhance antibiotic absorption. Recent studies limited to one country (Italy) suggest that sequential antibiotic treatment may be advantageous in overcoming emerging antibiotic resistance but the complexity of sequential regimens has the potential to affect adherence (Jafri et al., 2008)

High eradication rates are achieved by a short course of triple therapy consisting of a PPI, clarithromycin and amoxicillin or metronidazole in a twice-daily simultaneous regimen. European guidelines recommend 1 week of therapy, whereas the US guidelines recommend 10–14 days of therapy and achieve 7–9% better eradication rates (Malfertheiner et al., 2007).

Triple therapy consists of:

• OCA: omeprazole 20 mg, clarithromycin 500 mg and amoxicillin 1 g or

• OCM: omeprazole 20 mg, clarithromycin 250 mg and metronidazole 400 mg.

A lower dose of clarithromycin (250 mg twice daily) is effective and recommended when combined with metronidazole (NICE, 2004). However, some prescribers prefer to recommend 500 mg twice daily to achieve consistency and avoid prescribing errors.

Omeprazole may be replaced with any of the other PPI drugs. Local resistance rates determine the most appropriate first-line regimen, with OCA preferred in areas of high metronidazole resistance. In the UK, resistance to metronidazole has been reported in about 50% of H. pylori isolates, and resistance to clarithromycin in about 10%, although this is rising. Resistance to amoxicillin is rare. Sensitivity testing is of little value as in vitro resistance to either drug does not preclude eradication when those drugs are used as part of a triple therapy regimen. In patients with hypersensitivity to penicillin, the OCM regimen or substitution of amoxicillin from the OCA regimen with tetracycline 500 mg twice daily is used. If patients have recently received antibiotic treatment for any indication, a regimen avoiding that antibiotic is preferred.

Failure of a first-line regimen to achieve eradication will necessitate treatment with another triple therapy regimen or with a bismuth-based quadruple regimen. Recommended second-line triple therapy regimens include a PPI, amoxicillin or tetracycline and metronidazole. Most four-drug regimens contain bismuth subsalicylate, metronidazole, tetracycline or amoxicillin and a PPI and are generally not as well tolerated by patients as triple therapy regimens. Quadruple therapy may be used first- line where there is high prevalence of clarithromycin resistance. The indication should be reviewed in patients who are refractory to conventional as well as quadruple eradication therapies, to determine the importance of eradication before proceeding to endoscopic biopsies and determination of antibiotic sensitivity after culture. This strategy is rarely justified in dyspepsia.

Successful eradication relies upon patients adhering to their medication regimen. It is, therefore, important to educate patients about the principles of eradication therapy and also about coping with common adverse effects associated with their regimen. Diarrhoea is the most common adverse effect and should subside after treatment is complete. In rare cases, this can be severe and continue after treatment. If this happens, patients should be advised to return to their doctor as rare cases of antibiotic-associated colitis have been reported. If drugs are not taken as intended, then non-adherence may result in antibiotic resistance, should the antibiotic concentration at the site of infection decrease to a level where resistance may emerge.

If eradication is successful, uncomplicated active peptic ulcers heal without the need to continue ulcer-healing drugs beyond the duration of eradication therapy (Gisbert et al., 2004). Patients with persistent symptoms after eradication therapy should have their H. pylori status rechecked. This should be carried out no sooner than 4 weeks after discontinuation of therapy to avoid false-negative results due to suppression rather than eradication of the organism. If the patient is H. pylori positive, an alternative eradication regimen should be given. If eradication was successful but symptoms persist, gastro-oesophageal reflux or other causes of dyspepsia should be considered.

Patients who have had a previous gastro-intestinal bleed from a gastric ulcer should continue ulcer-healing therapy for a further 3 weeks in addition to eradication therapy. H. pylori eradication should be confirmed. The need for routine endoscopy to confirm ulcer healing is unclear but should be undertaken where malignancy is suspected.

Other accepted indications for H. pylori eradication include mucosal-associated lymphoid tissue (MALT) lymphoma of the stomach, severe gastritis, and in patients with a high risk of gastric cancer such as those with family history of the disease.

Treatment of NSAID-associated ulcers

NSAID-associated ulcers may be H. pylori positive. Although the presence of H. pylori may enhance the efficacy of acid suppression, eradication is generally recommended in infected patients with NSAID-associated ulcers as it is difficult to differentiate between H. Pylori or NSAID as the cause of the ulcer (Malfertheiner et al., 2009). If NSAIDs are discontinued, most uncomplicated ulcers heal using standard doses of a PPI, H₂-receptor antagonist, misoprostol or sucralfate. Healing is impaired if NSAID use is continued. Studies have demonstrated conflicting results, in terms of the comparative healing rates between PPIs and H₂-receptor antagonists, in this situation (Yeomans et al., 2006; Goldstein et al., 2007). PPIs demonstrate higher healing rates at 4 weeks but similar healing rates to H₂-receptor antagonists at 8 weeks. There is no evidence that high-dose PPI is better than treatment with the standard dose. Although effective, misoprostol use is limited by treatment-related adverse events.

Prophylaxis of NSAID ulceration

NSAIDs should be avoided in patients who are at risk of gastro-intestinal toxicity (see Box 12.1). However, some patients with chronic rheumatological conditions may require long-term NSAID treatment, in which case the lowest effective dose should be used. Dyspepsia is not a risk factor for ulcer complications but in those patients at high risk of ulcer complication, the NSAID should be stopped and investigation undertaken if dyspepsia develops.

Data suggests that H. pylori increases, has no effect on or decreases ulcer risk in NSAID users (Malfertheiner et al., 2007, 2009). The value of eradication of H. pylori in chronic NSAID users is, therefore, unclear but there may be some benefit in screening and eradicating H. pylori in patients about to start NSAIDs. The benefit is less apparent in those patients at low risk of peptic ulcer. In patients with a history of bleeding or non-bleeding ulcer, guidelines recommend screening for and eradicating H. pylori before starting low-dose aspirin (Bhatt et al., 2008). When using NSAIDs in patients with a previous bleeding ulcer, PPI maintenance therapy is more effective secondary prophylaxis than H. pylori eradication alone, but a combination of both treatments is additive.

Treatment options for ulcer prophylaxis in patients at risk of peptic ulcer but who require NSAIDs, include co-therapy with acid-suppressing agents or a synthetic prostaglandin analogue, or substitution of a selective COX-2 inhibitor for a non-selective NSAID (Hooper et al., 2004). Comparison of study outcomes requires interpretation of whether ulcers are detected symptomatically or by endoscopy. The prostaglandin analogue, misoprostol at a dose of 800 µcg daily is effective at reducing NSAID-associated ulcer complications and symptomatic ulcers. Adverse effects, primarily diarrhoea, abdominal pain and nausea, limit its use as lower doses are less effective. PPIs are effective at reducing endoscopically diagnosed ulcers and dyspepsia symptoms but the effect on symptomatic ulcers is unclear. Studies have not demonstrated any advantage in using higher than standard doses of PPIs to reduce risk of ulcers. Standard doses of H₂-receptor antagonists are effective at reducing the risk of endoscopic duodenal ulcers. However, reduction in the risk of gastric ulcers requires double this dose. Gastroprotective agents licensed for prophylaxis of NSAID ulceration are listed in Table 12.1.

Table 12.1 Drugs for prophylaxis for NSAID-induced ulceration

Drug	Licensed indication	Prophylaxis dose
Omeprazole	Prophylaxis of further DU or GU	20 mg every day
Esomeprazole	Prophylaxis of DU or GU	20 mg every day
Lansoprazole	Prophylaxis of DU or GU	15–30 mg every day
Pantoprazole	Prophylaxis of DU or GU	20 mg daily
Misoprostol	Prophylaxis of DU or GU	200 µcg 2–4 times a day
Ranitidine	Prophylaxis of DU	150 mg twice a day
Ranitidine	Prophylaxis of DU (unlicensed)	300 mg twice day

DU, duodenal ulcer; GU, gastric ulcer.

In low-dose aspirin users, standard-dose PPIs are more effective than high dose H₂-receptor antagonists in preventing recurrent ulcer bleeding following ulcer healing and eradication of H. pylori (Ng et al., 2010). However, in those patients who do not have a history of peptic ulcer bleeding, high-dose H₂-receptor antagonists might be an alternative to PPIs (Taha et al., 2009).

Given the contraindications to selective COX-2 inhibitors, their use is limited and further studies are required to clarify their place in minimising risk of ulcers in both primary and secondary prophylaxis. In patients with no history of peptic ulcer bleeding but with risk factors, a combination of COX-2 inhibitor with a PPI was similar in efficacy to a combination of non-selective NSAID with a PPI (Scheiman et al., 2006). In patients with a history of ulcer bleeding, a combination of selective COX-2 inhibitor with a PPI reduced recurrent ulcer bleeding compared to COX-2 inhibitor alone (Chan et al., 2007). This was not compared to a combination of a non-selective NSAID and a PPI. Although an earlier study suggested COX-2 inhibitors alone offered similar protection to that offered by a combination of non-selective NSAID with PPI (Lai et al., 2005), results suggest that in high-risk patients with a history of gastro-intestinal bleeding in whom an NSAID is indicated where alternative analgesic therapies have failed and in whom there are no contraindications to selective COX-2 inhibitors, a combination of PPI with a selective COX-2 inhibitor may be the safest strategy.

H. pylori-negative, NSAID-negative ulcers

Ulceration in the absence of H. pylori infection or NSAID or aspirin use is rare and validation of negative medication history and H. pylori status should be confirmed using biopsy samples and a careful medication history including over the counter preparations. Many analgesics contain aspirin or NSAIDs and some patients purchase low-dose aspirin.

Gastro-oesophageal reflux disease

GORD is the term used to describe any symptomatic clinical condition or histopathological alteration resulting from episodes of reflux of acid, pepsin and, occasionally, bile into the oesophagus from the stomach (Moayyedi and Talley, 2006). Heartburn is the characteristic symptom, and the patient may also complain of acid regurgitation and dysphagia. Complications include oesophageal stricture, oesophageal ulceration and formation of specialised columnar-lined oesophagus at the gastro-oesophageal junction known as Barrett’s oesophagus (Shaheen and Richter, 2009). The mechanism of acid reflux is multifactorial and involves transient lower oesophageal sphincter relaxations, reduced tone of the lower oesophageal sphincter, hiatus hernia and abnormal oesophageal acid clearance. The severity of inflammation of the oesophageal mucosa is described as categories of oesophagitis (Los Angeles A–D). However, approximately two-thirds of patients with GORD have normal mucosa on endoscopy. Hypersensitivity to normal acid exposure may be the cause of symptoms in this group of patients. Progression from non-erosive reflux disease to erosive oesophagitis and Barrett’s oesophagus is rare.

Management of GORD focuses on symptom control rather than endoscopic findings, and therefore careful symptom evaluation is required (Box 12.5). Patients with alarm features or those who fail to respond to medical treatment should be referred for endoscopic investigation. H. pylori eradication is not recommended in the management of GORD (Malfertheiner et al., 2007).

Box 12.5 Symptoms associated with gastro-oesophageal reflux disease

Heartburn and regurgitation

Belching

Upper abdominal discomfort

Bloating and postprandial fullness

Chest pain

Hoarseness

Cough

Strategies for initial treatment include lifestyle measures such as weight loss and smoking cessation in combination with antacids. These measures may be effective in patients with no significant impairment of quality of life. When quality of life is impaired, acid-suppression therapy is the basis of effective treatment. A course of standard-dose PPI therapy is most effective for symptom relief, healing of oesophagitis and maintenance of remission in patients with GORD (Fig. 12.6). Compared with erosive oesophagitis, there is a diminished response to acid suppression in non-erosive reflux disease but PPIs remain the most effective agents. Most patients respond after 4 weeks’ treatment and after initial control of symptoms, therapy can be withdrawn. If symptoms return, intermittent courses can be given or, alternatively, on-demand single doses can be taken immediately as symptoms occur. Patients who relapse frequently may require continuous maintenance therapy using the lowest dose of acid suppression which provides effective symptom relief.

Fig. 12.6 Management algorithm for gastro-oesophageal reflux disease.

Escalating doses can be used in the small number of patients who do not respond to initial treatment. These patients should be investigated to confirm diagnosis. Those with a normal upper endoscopy may require pH monitoring or motility tests. Twice-daily dosing may be required in patients with persistent symptoms. A selected group of patients may benefit from antireflux surgery rather than the escalation of acid-suppressing treatment. Patients with endoscopically severe oesophagitis (Los Angeles class C or D) should be kept on standard-dose PPIs long-term to maintain symptom relief and prevent the development of complications such as Barrett’s oesophagus or oesophageal adenocarcinoma.

Ulcer-healing drugs

Proton pump inhibitors

The PPIs are all benzimidazole derivatives that control gastric acid secretion by inhibition of gastric H⁺, K⁺-ATPase, the enzyme responsible for the final step in gastric acid secretion from the parietal cell (Fig. 12.7).

Fig. 12.7 Receptor stimulation of acid secretion.

The PPIs are inactive prodrugs that are carried in the bloodstream to the parietal cells in the gastric mucosa. The prodrugs readily cross the parietal cell membrane into the cytosol. These drugs are weak bases and therefore have a high affinity for acidic environments. They diffuse across the secretory membrane of the parietal cell into the extracellular secretory canaliculus, the site of the active proton pump (see Fig. 12.7). Under these acidic conditions the prodrugs are converted to their active form, which irreversibly binds the proton pump, inhibiting acid secretion. Since the ‘active principle’ forms at a low pH it concentrates selectively in the acidic environment of the proton pump and results in extremely effective inhibition of acid secretion. The different PPIs (omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole) bind to different sites on the proton pump, which may explain their differences in potency on a milligram per milligram basis.

PPIs require an enteric coating to protect them from degradation in the acidic environment of the stomach. This delays absorption and a maximum plasma concentration is reached after 2–3 h. Different formulations have been developed for patients with swallowing difficulties but these still rely upon some form of enteric coating (Table 12.2). New immediate-release formulations are under development which may overcome problems with enteric-coated granules blocking enteral feeding tubes.

Table 12.2 Available formulations of proton pump inhibitors

Since these drugs irreversibly bind to the proton pump they have a sustained duration of acid inhibition which does not correlate with the plasma elimination half-life of 1–2 h. The apparent half-life is approximately 48 h. This prolonged duration of action allows once-daily dosing of PPIs, although twice-daily dosing is recommended in some cases of erosive oesophagitis or Barrett’s oesophagus when a sustained gastric pH of greater than 4.0 is required. All PPIs are most effective if taken about 30 min before a meal as they inhibit only actively secreting proton pumps. Meals are the main stimulus to proton pump activity. The optimal dosing time is 30–60 min before the first meal of the day.

Intravenous PPIs are most frequently used to prevent recurrent ulcer bleeding in high-risk patients. Intravenous preparations are therapeutically equivalent to oral preparations. In the UK, omeprazole, pantoprazole and esomeprazole can be given intravenously.

PPIs are metabolised in the liver to various sulphate conjugates that are extensively eliminated by the kidneys (80%). With the exception of severe hepatic dysfunction, no dose adjustments are necessary in liver disease or in renal disease. Apart from minor differences in bioavailability in the first few days of oral dosing, pharmacokinetics are similar among all PPIs. The antisecretory effect is also similar among all agents when administered chronically in equivalent standard doses.

Adverse drug reactions

Experience suggests that PPIs are a remarkably safe group of drugs. The most commonly reported side effects are diarrhoea, headaches, abdominal pain, nausea, fatigue and dizziness which resolve on drug discontinuation (Table 12.3). Possible mechanisms for diarrhoea include bacterial overgrowth, changes in intestinal pH and bile salt abnormalities. Diarrhoea is most commonly associated with lansoprazole, particularly in the elderly. Some cases of persistent chronic watery diarrhoea associated with lansoprazole have been diagnosed as microscopic colitis. This may be explained by the unique ability of lansoprazole to inhibit colonic proton pumps which may have an effect on colonic secretion and pH. Apart from the association between lansoprazole and diarrhoea, the incidence of adverse reactions is similar among the drugs in this group.

Table 12.3 Common adverse reactions to ulcer-healing drugs

Proton pump inhibitors	H₂-receptor antagonists	Sucralfate
Diarrhoea	Diarrhoea	Constipation
Headache	Headache
Abdominal pain	Abdominal pain
Nausea	Confusion
Fatigue
Dizziness

Loss of gastric acidity has been associated with colonisation of the normally sterile upper gastro-intestinal tract. Associations with increased risk of respiratory tract infections and C. difficile-associated disease have prompted more judicious use of PPIs. Long-term use may also decrease bone density and increase risk of hip fractures.

Drug interactions

The cytochrome P450 enzyme system is classified into a number of subgroups, several of which are involved in drug metabolism. All PPIs are metabolised to varying degrees by the same cytochrome P450 isoenzymes, CYP2C19 and CYP3A. All except rabeprazole are metabolised primarily via the CYP2C19 isoenzyme. This suggests rabeprazole may be less influenced by other drugs metabolised through this system or by genetic changes in hepatic metabolism. The affinity of individual PPIs for these enzymes influences the incidence of clinically relevant drug interactions.

• Pantoprazole has lower affinity for the enzyme system than the other PPIs and is also metabolised by a sulphotransferase which is non-saturable and not part of the cytochrome P450 system. Rabeprazole is also metabolised through a non-enzymatic pathway.

• Omeprazole inhibits CYP2C9 and 2C19, the isoenzymes involved in the metabolism of, for example, phenytoin (2C9), S-warfarin (2C9), diazepam (2C19) and R-warfarin (2C19). Omeprazole 40 mg daily can decrease the clearance of phenytoin, but phenytoin levels were unchanged after a dose of 20 mg of omeprazole daily. Therefore, phenytoin plasma concentrations should be monitored when omeprazole is taken concomitantly. Omeprazole may increase the coagulation time in patients receiving warfarin therapy, especially if doses higher than 20 mg daily are given. Changes in the plasma concentration of the less potent (R) enantiomer of warfarin have been observed; therefore, monitoring of the international normalised ratio (INR) is recommended during concomitant therapy. The metabolism of benzodiazepines, particularly diazepam, may be decreased by omeprazole. Similar interactions are likely with esomeprazole.

• Lansoprazole is a weak inducer of CYP1A2 and concurrent administration results in increased theophylline clearance.

Other isolated interactions have been reported:

• Omeprazole can increase the concentration of ciclosporin.

• Clarithromycin increases esomeprazole concentrations; however, omeprazole has also increased clarithromycin concentration.

• Lansoprazole has reduced the efficacy of the oral contraceptive pill.

• Clarithromycin has increased plasma lansoprazole concentration.

• Lansoprazole has increased plasma concentration of tacrolimus.

• Omeprazole has increased the concentration of escitalopram.

• Omeprazole has decreased renal elimination of methotrexate.

Approximately 3% of the Caucasian and 20% of the Asian population are poor metabolisers of PPIs due to genetic polymorphism associated with CYP2C19. High plasma concentrations are achieved and the relative capacity for metabolism by other isoenzymes may alter and result in drug interactions. In practice, the genotype of a patient is unknown. The relative contribution of CYP2C19 to PPI metabolism is greatest with omeprazole and least with rabeprazole. The observation of decreased clopidogrel activity and increased cardiovascular events has been linked to competitive inhibition of CYP2C19 possibly caused by concomitant treatment with PPIs.

The use of symptom-driven, on-demand PPI therapy may prove problematic if used concomitantly with warfarin or phenytoin. Careful monitoring should be undertaken. All acid-suppressing drugs potentially decrease the absorption of some drugs by increasing gastric pH. Reduction in absorption of ketoconazole and increased absorption of digoxin have been reported with PPIs. The absorption of drugs formulated as pH-dependent, controlled-release products may also be altered. Very few clinically important drug interactions have been reported despite the widespread use of these agents.

Clinical use

PPIs relieve symptoms and heal peptic ulcers faster than H₂-receptor antagonists. They also heal ulcers that are refractory to H₂-receptor antagonists. All PPIs provide similar H. pylori eradication rates and ulcer healing when used at their recommended doses. Standard doses of PPIs are used concomitantly with non-selective NSAIDs and with low-dose aspirin in patients at risk of peptic ulcers or ulcer bleeding. High dose intravenous PPIs are used to prevent recurrent bleeding in high-risk patients (active bleeding or non-bleeding visible vessel) during the initial 72 h after a bleed. In GORD, PPIs heal oesophagitis and control symptoms more rapidly than H₂-receptor antagonists. Differences between PPIs in terms of speed of symptom relief are observed only in the first few days of treatment. Patients with severe oesophagitis should continue long-term PPI therapy, whereas those with milder GORD should be stepped down in terms of acid suppression and therapy withdrawn if symptoms are controlled. On-demand therapy is used to maintain symptom control. Patients with functional dyspepsia should not routinely receive long-term treatment with PPIs. PPIs can be purchased over the counter for short-term relief of heartburn.

H₂-receptor antagonists

The H₂-antagonists are all structural analogues of histamine. They competitively block the histamine receptors in gastric parietal cells, thereby preventing acid secretion. Pepsinogen requires acid for conversion to pepsin and so when acid output is reduced, pepsin generation is, in turn, also reduced.

All the available drugs (cimetidine, ranitidine, famotidine, nizatidine) have similar properties. Maximum plasma concentration is reached within 1–3 h after administration. First-pass hepatic metabolism varies, ranitidine being most extensively metabolised which explains the difference between the intravenous and oral dose. All H₂-antagonists are eliminated to a variable and significant extent via the kidneys, and all require dosage reduction in moderate-to-severe renal impairment. They are equally effective at suppressing daytime and nocturnal acid secretion while they do not cause total achlorhydria. The evening dose of a H₂-antagonist is particularly important because during the daytime, gastric acid is buffered for long periods by food; however, during the night this does not occur and the intragastric pH may fall below 2.0 for several hours. For healing oesophagitis, intragastric pH must remain above 4.0 for 18 h or more per day. H₂-receptor antagonists are, therefore, not effective in healing oesophagitis. Adding a bedtime dose of H₂-receptor antagonist to PPI therapy may enhance nocturnal gastric pH control in patients in whom nocturnal gastric acid breakthrough is problematic.

The role of H₂-receptor antagonists in the management of peptic ulcer disease has diminished. H₂-receptor antagonists are less effective than PPIs in eradication regimens, in treating ulcers when NSAIDs are continued, and in prophylaxis of NSAID-induced ulcers. H₂-receptor antagonists do effectively heal ulcers in patients who discontinue their NSAID and they also have a role in continuing acid suppression for symptomatic treatment following eradication therapy. Their main role is in the empirical management of dyspepsia symptoms. If patients with mild symptoms gain adequate relief, it is not necessary to use a PPI. H₂-receptor antagonists are preferred over PPIs in the second-line treatment of heartburn in pregnancy, although there is growing evidence to support safe use of PPIs in those not controlled by H₂-receptor antagonists. H₂-receptor antagonists can be purchased in doses lower than those prescribed for the management of heartburn and indigestion.

Adverse drug reactions

H₂-receptor antagonists are a remarkably safe group of drugs with a lower risk of side effects than PPIs. The risk of any adverse reaction is below 3% and serious adverse reactions account for less than 1%. Diarrhoea and headache are the most common and occasionally mental confusion and rashes have been reported (see Table 12.3). Hepatotoxicity is a rare adverse effect. Cimetidine, due to its antiandrogenic effects, has been associated with gynaecomastia and impotence when used in high doses.

Drug interactions

Although many drug interactions have been suggested with cimetidine, many have only been demonstrated in vitro and are of doubtful clinical significance. Cimetidine inhibits the activity of cytochrome P450 and consequently retards oxidative metabolism of some drugs. This interaction is potentially important for drugs with a narrow therapeutic index. The clearance of theophylline is reduced to about 40% of normal, and raised plasma levels occur as a result. Phenytoin metabolism is reduced, and toxicity is theoretically possible. The metabolism of a number of benzodiazepines, including diazepam, flurazepam and triazolam, is impaired and levels are raised.

The interaction with warfarin has frequently been cited as justification to change to an alternative H₂-antagonist which binds less intensively to the CYP 450 system; however, careful investigation has shown that this interaction is complex. The metabolism of (R)-warfarin is affected to a greater degree than that of (S)-warfarin. As the (S) enantiomer is the more potent, the pharmacodynamic effects of the interaction may be modest, although the plasma warfarin concentrations may be increased. Current opinion suggests that warfarin may safely be added with appropriate monitoring when patients are already taking cimetidine in regular daily doses. Other H₂-antagonists should be used in patients who are difficult to stabilise on warfarin or for whom frequent monitoring is not feasible.

All acid-suppressing drugs potentially decrease the absorption of drugs such as ketoconazole and other pH-dependent controlled-release products by increasing gastric pH.

Bismuth chelate

Bismuth has been included in antacid mixtures for many decades but fell from favour because of its neurotoxicity. Bismuth chelate is a relatively safe form of bismuth that has ulcer-healing properties comparable to those of H₂-antagonists. Its mode of action is not clearly understood but it is thought to have cytoprotective properties. Bismuth is toxic to H. pylori and was one of the first agents to be used to eradicate the organism and reduce ulcer recurrence. Tripotassium dicitratobismuthate in combination with tetracycline, metronidazole and a PPI is used in quadruple therapy regimens in patients resistant to triple therapy.

Adverse drug reactions

Small amounts of bismuth are absorbed from bismuth chelate, and urinary bismuth excretion may be raised for several weeks after a course of treatment. The risks of bismuth intoxication are small if these products are used at the recommended dose and for short courses of treatment. Bismuth may accumulate in patients with impaired renal function. The most commonly reported events are nausea, vomiting, blackened tongue and dark faeces.

Sucralfate

Sucralfate is the aluminium salt of sucrose octasulphate. Although it is a weak antacid, this is not its principal mode of action in peptic ulcer disease. It has mucosal protective effects including stimulation of bicarbonate and mucus secretion and stimulation of mucosal prostanoids. At pH less than 4.0 it forms a sticky viscid gel that adheres to the ulcer surface and may afford some physical protection. It is capable of adsorbing bile salts. These activities appear to reside in the entire molecular complex and are not due to the aluminium ions alone. Sucralfate has no acid-suppressing activity. At a dose of 2 g twice daily, sucralfate is effective in the treatment of NSAID-induced duodenal ulcers, if the NSAID is stopped. However, it is not effective in the treatment and prevention of NSAID-related gastric ulcers. It has also been used in the prophylaxis of stress ulceration. The liquid formulation is often used as the tablets are large and difficult to swallow.

Adverse drug reactions

Constipation appears to be the most common problem with sucralfate, and this is thought to be related to the aluminium content (see Table 12.3). About 3–5% of a dose is absorbed, and therefore there is a risk of aluminium toxicity with long-term treatment. This risk is correspondingly greater in patients with renal impairment. Caution is required to avoid oesophageal bezoar formation around a nasogastric tube in patients managed in the intensive care unit.

Drug interactions

Sucralfate may bind to other agents in the gastro-intestinal tract and reduce the absorption of other drugs. Therefore, it should be taken at least 2 h following other medicines.

Antacids

Antacids have a place in symptomatic relief of dyspepsia, in particular symptoms associated with GORD. They have a role in the management of symptoms which sometimes remain for a short time after H. pylori eradication of uncomplicated duodenal ulcer.

The choice of antacid lies between aluminium-based and magnesium-based products, although many proprietary products combine both. Calcium-based products are unsuitable as calcium stimulates acid secretion. Antacids containing sodium bicarbonate are unsuitable for regular use because they deliver a high sodium load and generate large quantities of carbon dioxide. It should be noted that magnesium trisilicate mixtures contain a large amount of sodium bicarbonate. Some products contain other agents such as dimeticone or alginates. Products containing sodium alginate with a mixture of antacids are effective in relief of symptoms in GORD but are not particularly effectual antacids.

Aluminium-based antacids cause constipation, and magnesium-based products cause diarrhoea. When combination products are used, diarrhoea tends to predominate as a side effect. Although these are termed ‘non-absorbable’, a proportion of aluminium and magnesium is absorbed and the potential for toxicity exists, particularly with coexistent renal failure.

Antacids provide immediate symptom relief and a more rapid response is achieved with liquid preparations. They have a limited duration of action and need to be taken several times a day, usually after meals and at bedtime. Administration should be separate from drugs with potential for chelation, such as tetracycline and ciprofloxacin, and also pH-dependent controlled-release products.

Patient care

Patient education

Patients who present with symptoms of dyspepsia should be assessed in terms of risk of serious disease. Referral for investigation is indicated if they exhibit alarm features. Patients with predominant reflux-like symptoms are likely to respond to antacid/alginate medicines. In those with reflux-like symptoms, lifestyle should be assessed as weight loss is known to improve reflux symptoms in obese patients and raising the head of the bed may improve nocturnal symptoms of heartburn. A medication history, including purchased medicines, should be undertaken to identify likely or possible drug-induced causes of symptoms. Symptoms of dyspepsia are associated with many medicines including aspirin, NSAIDs and corticosteroids. Other agents are associated with gastro-oesophageal reflux and include those with antimuscarinic effects, for example, tricyclic antidepressants, or those which relax muscle tone, for example, calcium channel blockers and nitrates, or those which cause oesophageal mucosal damage, for example, biphosphonates. Clinical medication review allows assessment of the benefits and risks associated with medicines and referral to the prescriber may be necessary. Patients who do not respond to 2 weeks of symptomatic relief medication should be referred to the primary care doctor.

Patients should be advised to seek the pharmacist’s advice when purchasing over-the-counter analgesic preparations. Patients with risk factors for peptic ulcer disease should be advised to avoid over-the-counter aspirin and NSAIDs and to use paracetamol-based products. Taking aspirin or NSAIDs with or after food may decrease the risk of dyspepsia symptoms but does not decrease the risk of ulcer complications. Before prescribing NSAID or aspirin therapy, patients should be assessed in terms of both cardiovascular and gastro-intestinal risk. Benefits must outweigh risks in NSAID users and if NSAIDs are necessary in those at risk of ulcer complications, prophylaxis should be prescribed. Consideration should be given to screening for H. pylori. Patients should be aware of the optimum time of administration of PPIs, the dose and duration of therapy. Misoprostol should not be used in pregnant women, and women of child-bearing age should be warned appropriately.

Patients with diagnosed peptic ulcer disease need to be educated about the current principles of therapeutic management determined by the diagnosis and, if appropriate, the balanced risks associated with continued aspirin or NSAID therapy. Uncomplicated disease requires a short course of treatment which may or may not include eradication of H. pylori. Patients need to know the importance of adherence to eradication therapy for successful treatment and to avoid development of resistance to antibiotics. Previous adverse reactions should be established; for example, patients who are sensitive to penicillin need an eradication regimen which does not include amoxicillin. Patients should be warned of the specific side effects to be expected from the regimen chosen for them and advised what to do should they experience any of these effects. Patients taking metronidazole must avoid alcohol as they might have a disulfiram-like reaction with sickness and headache. Patients also need to know how their therapy will be followed up. In most patients, a single treatment course is required and there is no need for maintenance therapy unless they require prophylaxis treatment to reduce risks associated with continued NSAID or low-dose aspirin therapy.

Patient monitoring

Treatment success in uncomplicated peptic ulcer disease is measured by review of the patient in terms of symptom control. Patients with complicated ulcers or those who continue to have symptoms will receive a urea breath test and/or an endoscopy to confirm successful eradication of H. pylori. Very few patients require follow-up endoscopy. Patients should be aware of what their review will entail and when their review will take place. If patients comply with their medication the review process may be kept to a minimum.

Following eradication therapy, some patients continue to experience symptoms of abdominal pain. Patients should be reassured that these symptoms will resolve spontaneously, but if necessary an antacid preparation can be recommended to relieve symptoms until review. Patients receiving treatment for NSAID-induced ulceration should continue their ulcer-healing therapy for 4 weeks. If the NSAID or aspirin has been discontinued there is no need to continue ulcer treatment therapy once the ulcer has healed unless the NSAID or aspirin must also be continued.

Patients with iron-deficiency anaemia following a bleeding ulcer may be prescribed oral iron therapy. If patients suffer side effects such as constipation or diarrhoea, the dose of iron should be reduced. Treatment with iron should be for at least 3 months. Iron preparations are best absorbed from an empty stomach but if gastric discomfort is felt, the preparation should be taken with food.

Some common therapeutic problems in the treatment of peptic ulcer disease are summarised in Table 12.4.

Table 12.4 Common therapeutic problems in peptic ulcer disease

	Comments
Ulcer-like symptoms of dyspepsia are not specific for peptic ulcer disease and are often present in functional (non-ulcer) dyspepsia	Predominant heartburn differentiates GORD from dyspepsia. Patients with GORD are likely to respond to antisecretory therapy
In uncomplicated patients with ulcer-like symptoms of dyspepsia, there is controversy about whether a 1-month course of acid suppression or test and for H. pylori should be carried out initially	Identification and eradication of H. pylori will benefit those with ulcers and a small proportion of H. pylori-positive patients with functional dyspepsia. A course of acid suppression will have similar outcomes but ulcers may relapse. Eradication of H. pylori plays no role in management of GORD
A test and treat policy is cost-effective compared with initial endoscopy in patients with uncomplicated dyspepsia	There is no evidence to support widespread eradication of H. pylori in primary care
Patients on proton pump inhibitors (PPIs) can have false-negative results for H. pylori	PPIs should be withdrawn at least 2 weeks before urea breath test or biopsy urease testing (endoscopy)
Following a 7-day eradication therapy regimen, antisecretory therapy can normally be stopped	Longer courses of acid-suppressive therapy should be reserved for patients with active ulcers complicated by bleeding and/or NSAID use
First-line eradication therapy comprises twice-daily PPI, amoxicillin 1 g and clarithromycin 500 mg	Metronidazole can be substituted in those patients allergic to amoxicillin and for second-line therapy. When combined with metronidazole, the dose of clarithromycin can be reduced to 250 mg
Use of high dose intravenous PPIs	Intravenous PPI use is not recommended before endoscopic diagnosis in gastro-intestinal bleeding. High dose intravenous PPI is recommended for 72 h after endoscopic haemostatic therapy in patients at high risk of re-bleeding from peptic ulcer
In patients with NSAID-associated active peptic ulcer disease who test positive for H. pylori, the cause of the ulcer may not be confirmed	The ulcer should be healed with a PPI for 4 weeks and H. pylori eradicated. Eradication of H. pylori reduces the risk of recurrent bleeding
The treatment of NSAID-associated ulcers may differ depending upon whether or not the NSAID must be continued	If NSAIDs are withdrawn, healing rates at 4 weeks are best with PPIs and are similar between H₂-receptor antagonists and PPIs after 8 weeks. PPIs are continued only if NSAIDs are continued
Patients in whom low-dose aspirin is indicated but have risk factors for peptic ulcer disease	Use of aspirin should be considered carefully, especially for primary prophylaxis of cardiovascular disease. Enteric coating does not reduce this risk. Clopidogrel is not a safer alternative than aspirin in combination with a PPI
There is an increased risk of bleeding with dual antiplatelet therapy	PPIs are thought to decrease conversion of clopidogrel to active metabolite, thus decreasing efficacy of clopidogrel. If dual antiplatelet therapy is indicated after PCI, use H₂ receptor antagonist unless high risk (previous gastro-intestinal bleed), when PPI indicated
NSAID use in elderly patients	Patients over 65 years of age are at increased risk of peptic ulcer disease associated with NSAIDs and often present with ‘silent ulcers’. NSAIDs (prescription and non-prescription) should be avoided in the elderly
Patients who are candidates for COX-2 inhibitors	COX-2 inhibitors are associated with less gastro-intestinal toxicity than non-selective NSAIDs. COX-2 inhibitors are contraindicated in cardiovascular disease. The reduction in gastro-intestinal risk associated with COX-2 inhibitors is similar to reduction in risk associated with non-selective NSAIDs in combination with gastroprotective agents
Criteria and regimens to administer for stress ulcer prophylaxis are unclear	Intravenous H₂-receptor antagonist therapy is given to patients at risk until enteral feeding is tolerated. Definite risk factors include mechanical ventilation, presence of coagulopathy and spinal cord injury. Controversial risks include head injury, sepsis, burns, multiple trauma, steroid therapy
Patients who require long-term PPI therapy	Those in whom long-term NSAIDs or low-dose aspirin are indicated and who have risk factors for associated upper gastro-intestinal complications. Patients with endoscopically diagnosed GORD who either have severe erosive oesophagitis or severe symptoms which can only be controlled with maintenance therapy

PCI, percutaneous coronary intervention.

Case studies

		Reference range
Sodium	138 mmol/L	135–145 mmol/L
Potassium	3.9 mmol/L	3.4–5.0 mmol/L
Creatinine	110 µmol/L	75–155 µmol/L
Blood glucose	6.8 mmol/L	<11.1 mmol/L
Total cholesterol	4.5 mmol/L	<4.0 mmol/L
Haemoglobin	12.0 g/dL	11.5–16.5 g/dL