Drugs used in Dyspepsia and Peptic Ulcer Disease

There are three major landmarks in the management of peptic ulcer disease. The first was the introduction of the H2 receptor antagonists (H2RA) of which the first was cimetidine. This gave effective acid suppression for the first time. The second was the introduction of the proton pump inhibitors (PPI) of which omeprazole was the first. This gave more profound and more prolonged suppression of gastric acid. The third was the discovery that Helicobacter pylori is associated with much peptic ulcer disease, and with this came the rationale for eradication of the organism. As a result of these innovations, the need for surgery for peptic ulcer has been dramatically reduced.

H pylori infection is associated with about 95% of duodenal ulcers and 80% of gastric ulcers. The remainder are mainly related to NSAIDs. Biphosphonates and corticosteroids may also be implicated.

• Symptomatic management of ulcer dyspepsia and non-ulcer dyspepsia
• Healing of gastric or duodenal ulcers
• Eradication of Helicobacter pylori
• Healing of ulcers related to drugs. This is usually the NSAIDs and in some cases it may be desirable to continue the drug and to give something to heal the ulcers.

• Many of the drugs used in the management of peptic ulcer disease carry a warning that they should not be used in pregnancy or whilst breast feeding. This is usually because of lack of information about safety in pregnancy rather than evidence of adverse effects in pregnancy.
• The exception is misoprostol, a prostaglandin analogue, that should be avoided in pregnancy as it may cause abortion. Indeed, gynaecologists sometimes use it for that end.
• If H pylori eradication is used, it may be necessary to avoid a certain antibiotic if the patient is allergic. For example, amoxicillin may be replaced by either metronidazole or tetracycline.

• Beware of the possibility of failing to diagnose gastric malignancy.
• PPIs are metabolised mostly in the liver. In liver disease, do not exceed the following doses:
  • 20mg daily for omeprazole, pantoprazole, and esomeprazole;
  • 30mg daily for lansoprazole
  • There are no data on the use of rabeprazole in people with severe hepatic impairment so the manufacturer advises caution.
• Omeprazole and esomeprazole may interfere with warfarin monitoring.
• If metronidazole is used, remember to warn the patient to avoid alcohol.

The article on peptic ulcer disease includes a list of warning signs that may suggest that the patient has a gastric malignancy rather than a peptic ulcer. Malignancy needs to be diagnosed and treated accordingly. Acid suppression will ease the pain of gastric carcinoma and in doing so may delay diagnosis. Acid suppression in malignancy is not contraindicated. It can give in relief in palliative care. Care is required so as not to miss the diagnosis.

Management is not just pharmacological but should include attention to lifestyle. This may include stopping smoking, more regular meals, ceasing excessive alcohol consumption and possibly stopping drugs that may be contributing to the problem. There may be times that it is necessary to continue these drugs but treatment may be given to heal ulcers and to prevent recurrence.

• Antacids are cheap, simple and may be all that is required for relief of occasional symptoms. Most antacids contain a mixture of aluminium hydroxide that tends to cause constipation and magnesium hydroxide that tends to cause diarrhoea. The balance between the two cannot be assured and there may be disturbance of bowel function. If a large amount of antacid is being consumed, consider acid suppression. The BNF advises that complexes such as hydrotalcite confer no special advantage.
• The H2RAs provide a swift and effective means of acid suppression and can be used intermittently to achieve control of symptoms. The PPIs are more prolonged in action, produce more profound acid suppression and are more expensive. Their greater efficacy may still provide value for money.
• Attempts should be made to eradicate Helicobacter pylori whenever it is found, whether the diagnosis is duodenal ulcer, gastric ulcer, NSAID induced ulcer or even non-ulcer dyspepsia.
• Only chelated bismuth should be used. It is rather unpleasant to take but it is effective at helping to eradicate H pylori and may have a place in second line treatment after previous failure of eradication.
• Misoprostol tends to be used to heal NSAID associated ulcers. Using a prostaglandin analogue to heal ulcers caused by prostaglandin antagonism is logical but it does tend to cause diarrhoea too and may be unacceptable. Proprietary combinations of NSAID with misoprostol are available.
• Prokinetic agents have fallen from favour. NICE says that cisapride is no longer licenced whilst the evidence for metoclopramide and domperidone is limited.¹

Symptomatic relief

Simple antacids will usually give symptomatic relief of fairly short duration. However, such relief is very non-specific and should not be taken as indicative of peptic ulcer disease. Heartburn may also occur in this condition although it is more typical of gastro-oesophageal reflux disease. An antacid alginate mixture is usually preferred for reflux.

More profound and prolonged acid suppression may be achieved with a H2RA or, better still, a PPI. The problem is that if the patient is due for endoscopy, the ulcer may heal before the investigation is performed. It may also interfere with the diagnosis of H pylori infection.²

Ulcer healing

Both H2RAs and PPIs are usually produced at a standard dose and a lower (half) dose. Some may also be produced at a higher dose that is usually reserved for gastro-oesophageal reflux disease. To a considerable extent, the PPIs have superseded the H2RAs as they are more potent and have a longer effect, although the H2RAs are cheaper.

Clinical Knowledge Summaries recommend that if an ulcer is proven but H pylori testing is negative, then acid suppression at full dose should be offered for 1 or 2 months.³ A lower maintainance dose may be continued after. The full course should be taken as there is little correlation between the relief of symptoms and the healing of ulcers and if medication is stopped too soon the ulcer will relapse.

Helicobacter pylori eradication

The article on Helicobacter pylori gives much more detail about the diagnosis and treatment of the infection, including follow up. If the infection is suspected or demonstrated, then eradication is the logical course of action. NICE suggests that eradication should be offered if a test is positive¹ and they give grade A level of evidence. Clinical Evidence suggests that even in the absence of a history of ulceration, that the finding of the infection should lead to eradication. It is effective in non-ulcer dyspepsia.⁴

There are several regimes that are available. They usually consist of high dose acid suppression with a PPI and two antibiotics, also at quite high dose. The usual recommended duration of treatment is 7 days and it is said to give eradication in about 90% of cases. A 14 days course may produce a higher rate of eradication but the incidence of adverse effects may make compliance poor. Diarrhoea is common with two antibiotics at high dose. The BNF states that 2 week regimens using a proton pump inhibitor and a single antibacterial are licensed, but produce low rates of eradication and are not recommended.

The following is based on the recommendations of NICE¹:

• a PPI twice a day
• bismuth 120 mg four times a day
• metronidazole 400 mg three times a day
• oxytetracycline 500 mg four times a day, all for 7 days.

Reinforce the importance of compliance as it is not easy to take so many tablets so many times a day, even for just a week.

Ulcers associated with NSAIDs

If a drug is thought to be the cause of peptic ulceration, it is sensible to stop the drug or change it to another with a lower risk. There may be times when it is desirable to continue that drug. An old person may need treatment for arthritis to maintain mobility or aspirin may be required in cardiovascular disease. It is often possible to heal the ulcer without stopping the offending drug and a maintenance dose is continued to prevent relapse.⁶

• Clinical Knowledge Summaries recommend that omeprazole 20mg daily is preferable to ranitidine 150mg twice daily as the respective rates of healing are 80% and 63%.
• H2RAs are slow to heal the ulcers if the offending drug is not stopped and so, under these conditions, a PPI is preferred.
• H pylori eradication is no more effective than omeprazole alone to heal ulcers, but if the infection is present, then eradication will reduce the rate of relapse.
• H pylori is not associated with an increased risk of ulcer with NSAIDs in the elderly but there is an increased risk of bleeding.⁷

Misoprostol is a prostaglandin analogue that is both an antisecretory and a protective agent for the healing of both gastric and duodenal ulcers. Its use is limited as diarrhoea is a common adverse effect and acid suppression tends to be better tolerated. Only the higher doses of misoprostol match acid suppression for efficacy.

Patients should be reviewed at the end of a course of treatment, especially H pylori eradication, to confirm a satisfactory outcome.

It may be necessary to stop treatment if adverse effects become intolerable or are of a serious nature.

• During H pylori eradication, abdominal discomfort and diarrhoea are very common but the patient should be encouraged to persist to achieve eradication and to heal the ulcer permanently. Lactobacilli, usually ingested in the form of natural unpasteurised yoghurt, may be of value in replacing the natural flora of the gut and they may also have a suppressive effect on H pylori.⁸
• Adverse reactions to PPIs and H2RAs are usually rare and mild but severe problems can arise. Rare but not serious problems may include taste disturbance, peripheral oedema, photosensitivity, fever, arthralgia, myalgia and sweating. Serious problems include liver dysfunction, hypersensitivity reactions (including urticaria, angioedema, bronchospasm, anaphylaxis), depression, interstitial nephritis, blood disorders (including leucopenia, leucocytosis, pancytopenia, thrombocytopenia), and skin reactions (including Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous eruption).
• Misoprostol often causes diarrhoea and abdominal pain, especially at higher doses.